Conditions: Diabetic Macular Edema Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 660
Healthy volunteers: no

Brief summary:
The primary objective of the study is to determine if treatment with high-dose aflibercept (HD) at intervals of 12 or 16 weeks provides non-inferior best corrected visual acuity (BCVA) compared to aflibercept dosed every 8 weeks.

The secondary objectives of the study are as follows:

* To determine the effect of HD vs. aflibercept on anatomic and other visual measures of response
* To evaluate the safety, immunogenicity, and pharmacokinetics (PK) of aflibercept

Detailed description:

Arms:
arm 1: Administered every 8 weeks after a loading phase arm 2: Administered every 12 weeks after a loading phase arm 3: Administered every 16 weeks after a loading phase

Interventions: intervention 1: aflibercept intervention 2: High-dose aflibercept
Intervention descriptions: intervention 1: Intravitreally (IVT) administered as a liquid formulation in a vial intervention 2: Intravitreally (IVT) administered as a liquid formulation in a vial

Protocol document:
Prot_000.pdf: 
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 
 
 
 
 
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Clinical Study Protocol 
 
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Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
 
 
 
 
 
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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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Page 5 
 
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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CONFIDENTIAL 
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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CONFIDENTIAL 
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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CONFIDENTIAL 
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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CONFIDENTIAL 
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 
Bandello F, Cunha-Vaz J, Chong NV, Lang GE, Massin P, Mitchell P, et al. New approaches for 
the treatment of diabetic macular oedema: recommendations by an expert panel. Eye 
2012;26(4):485-93. 
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: 
pathophysiology, screening, and novel therapies. Diabetes Care 2003;26(9):2653-64. 
Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ. et al. National, regional, and 
global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of 
health examination surveys and epidemiological studies with 370 country-years and 2.7 million 
participants. Lancet 2011;378:31-40. 
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-
related macular degeneration. Ophthalmology. 2014 Nov;121(11):2181 92. 
Huque M, Mushti S, Alosh M. Recycling of Significance Levels in Testing Multiple Hypotheses 
of Confirmatory Clinical Trials. In Biopharmaceutical Applied Statistics Symposium. Singapore: 
Springer; 2018:91-118. 
ICH E9 (R1) addendum on estimands and Sensitivity Analysis in Clinical Trials to the guideline 
on 
statistical 
principles 
for 
clinical 
trials. 
European 
Medicines 
Agency. 
https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-e9-r1-addendum-
estimands-sensitivity-analysis-clinical-trials-guideline-statistical_en.pdf. 
August 
30, 
2017. 
Accessed 26 August 2019. 
Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of 
diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 
or more years. Arch Ophthalmol 1984;102:527-32.  
Korobelnik J-F, Do DV, Schmidt-Erfurth U, Boyer DS, Holz FG, Heier JS, et al. Intravitreal 
aflibercept for diabetic macular edema. Ophthalmology 2014;121:2247-54. 
Ling R, Ramsewak V, Taylor D, Jacob J.et al. Longitudinal study of a cohort of people with 
diabetes screened by the Exeter Diabetic Retinopathy Screening Programme. Eye 2002;16(2):140-
5. 
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, 
controlled, double-masked, multicenter phase II study. Diabetes Care 2010;33(11):2399-405.  
McKay R, McCarty CA, Taylor HR. Diabetic retinopathy in Victoria, Australia: the visual 
impairment project. Br J Ophthalmol 2000;84(8):865-70. 
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. 
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: a pooled 
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 
2012;119(4):789-801.  
Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J. Vascular endothelial growth 
factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 2006;142;961-9. 
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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. 
1985;103(12):1796–1806. doi:https://doi.org/10.1001/archopht.1985.01050120030015 
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 
ethnic groups: a worldwide perspective. Surv Ophthalmol 2012; 57(4):347-70.  
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 
http://dx.doi.org/10.1016/ S0140-6736(17)31193-5. 
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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Signature Page for VV-RIM-00179129 v4.0
Signature Page for VV-RIM-00179129 v4.0 Approved
Approval/eSignature
00
Approval/eSignature
-2023 21:12:42 GMT+0000
Approval/eSignature
23 21:22:47 GMT+0000
Approval/eSignature
-2023 00:48:19 GMT+0000
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SAP_001.pdf: 
CONFIDENTIAL 
Page 1 of 95 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: 2.0 
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 
Protocol Number: 
VGFTe-HD-DME-1934 
Clinical Phase:  
2/3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatisticians: 
Project Biostatisticians: 
Clinical Trial Manager: 
Study Medical Director: 
Version/Date: 
Original (Version 1.0)     / 05 JUL 2022 
Amendment Version 2.0 / 19 AUG 2022 
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Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
NCT04429503


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Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 2 of 95 
 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
See appended electronic signature page 
Study Biostatistician   
  
 
 
See appended electronic signature page 
Study Pharmacokinetics 
 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
 
See appended electronic signature page 
Project Biostatistician  
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
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Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 3 of 95 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW ...............................................................................................................10 
1.1. 
Background/Rationale ................................................................................................10 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................11 
1.2.3. 
Exploratory Objectives ...............................................................................................11 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................11 
1.2.5. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................16 
3. 
ANALYSIS POPULATIONS ....................................................................................17 
3.1. 
The Full Analysis Set (FAS) .......................................................................................17 
3.2. 
The Per Protocol Set (PPS) .........................................................................................17 
3.3. 
The Safety Analysis Set (SAF) ...................................................................................17 
3.4. 
Pharmacokinetic Analysis Sets ...................................................................................17 
3.5. 
Immunogenicity Analysis Sets ...................................................................................18 
4. 
ANALYSIS VARIABLES .........................................................................................19 
4.1. 
Demographic and Baseline Characteristics ................................................................19 
4.2. 
Medical History ..........................................................................................................20 
4.3. 
Pre-Treatment / Concomitant Medication ..................................................................20 
4.4. 
Exposure, Compliance, Additional Treatment to Study Treatment ...........................20 
4.5. 
Efficacy Variable ........................................................................................................21 
4.5.1. 
Primary Efficacy Variable (s) .....................................................................................21 
4.5.2. 
Key Secondary Efficacy Variable(s) ..........................................................................21 
4.5.3. 
Additional Secondary Efficacy Variable(s) ................................................................21 
4.5.4. 
Exploratory Efficacy Variable(s) ................................................................................21 
4.6. 
Safety Variables ..........................................................................................................23 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................23 
4.6.2. 
Laboratory Safety Variables .......................................................................................23 
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4.6.3. 
Vital Signs ..................................................................................................................23 
4.6.4. 
12-Lead Electrocardiography (ECG) ..........................................................................23 
4.6.5. 
Other Ocular Safety Variables ....................................................................................24 
4.6.6. 
Surgeries .....................................................................................................................24 
4.7. 
Pharmacokinetic Variables .........................................................................................24 
4.8. 
Immunogenicity Variables (ADA) .............................................................................24 
5. 
STATISTICAL METHODS .......................................................................................25 
5.1. 
Demographics and Baseline Characteristics ...............................................................25 
5.2. 
Medical History ..........................................................................................................25 
5.3. 
Prior/concomitant Medications ...................................................................................25 
5.4. 
Patient Disposition ......................................................................................................25 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................26 
5.6. 
Analyses of Efficacy Variables ..................................................................................26 
5.6.1. 
Analysis of Primary Efficacy Variable .......................................................................26 
5.6.1.1. 
Primary Analysis for Primary Efficacy Variable ........................................................28 
5.6.1.2. 
Sensitivity Analyses for Primary Efficacy Variable ...................................................30 
5.6.1.2.1. 
ANCOVA using LOCF ..............................................................................................30 
5.6.1.2.2. 
ANCOVA with Multiple Imputation ..........................................................................31 
5.6.1.3. 
Supplementary Analyses for Primary Efficacy Variable ............................................32 
5.6.1.4. 
Subgroup Analyses for Primary Efficacy Variable ....................................................32 
5.6.2. 
Analysis of Key Secondary Efficacy Variables ..........................................................33 
5.6.2.1. 
Change from Baseline in BCVA Measured by the ETDRS Letter Score at 
Week 60 ......................................................................................................................33 
5.6.2.2. 
Proportion of patients with a ≥2 step improvement in DRSS at week 48 ..................33 
5.6.2.2.1. 
Sensitivity Analyses ....................................................................................................34 
5.6.3. 
Analysis of Additional Secondary and Exploratory Efficacy Variables ....................34 
5.6.4. 
Adjustment for Multiple Comparisons .......................................................................35 
5.7. 
Analysis of Safety Data ..............................................................................................36 
5.7.1. 
Adverse Events ...........................................................................................................36 
5.7.1.1. 
Subgroup Analyses .....................................................................................................37 
5.7.2. 
Clinical Laboratory Measurements.............................................................................38 
5.7.3. 
Analysis of Vital Signs ...............................................................................................38 
5.7.4. 
Analysis of 12-Lead ECG ...........................................................................................38 
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5.7.5. 
Analysis of Other Ocular Safety Variables ................................................................39 
5.7.6. 
Surgeries .....................................................................................................................39 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................39 
5.8.1. 
Analysis of Drug Concentration Data .........................................................................39 
5.8.2. 
Pharmacokinetics/Pharmacodynamics Analyses ........................................................40 
5.9. 
Analysis of Immunogenicity Data ..............................................................................40 
6. 
DATA CONVENTIONS ............................................................................................42 
6.1. 
Definition of Baseline .................................................................................................42 
6.2. 
Visit Windows ............................................................................................................42 
6.3. 
Unscheduled Assessments ..........................................................................................42 
6.4. 
Handling of Patients who Discontinue .......................................................................42 
6.5. 
Data Handling Convention for Missing Data .............................................................42 
7. 
INTERIM ANALYSIS ...............................................................................................44 
8. 
SOFTWARE ...............................................................................................................45 
9. 
REFERENCES ...........................................................................................................46 
10. 
APPENDIX.................................................................................................................47 
10.1. 
Summary of Statistical Analyses ................................................................................47 
10.2. 
Schedule of Time and Events .....................................................................................53 
10.2.1. 
Schedule of Time and Events (Main study) ...............................................................53 
10.2.2. 
Schedule of Time and Events (Dense PK substudy) ..................................................58 
10.3. 
NEI-VFQ-25 Sub-scale Scores and Total Score ........................................................59 
10.4. 
Detailed Definitions of Special AE Categories and Medical History 
Subgroups ...................................................................................................................60 
10.4.1. 
Medical history and AE grouping of hypertension .....................................................60 
10.4.2. 
AE grouping of intraocular inflammation ..................................................................62 
10.4.3. 
AE grouping of nasal mucosal events ........................................................................63 
10.4.4. 
Medical history of renal impairment ..........................................................................63 
10.4.5. 
Medical history of hepatic impairment .......................................................................64 
10.4.6. 
Medical history of cerebrovascular disease ................................................................75 
10.4.7. 
Medical history of ischemic heart disease ..................................................................82 
10.5. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................84 
10.6. 
Process to Derive Week 48 Data Cut-off ...................................................................86 
10.6.1. 
Visit Independent Data ...............................................................................................86 
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10.6.2. 
Study Medication Data ...............................................................................................87 
10.6.3. 
Visit Dependent Data ..................................................................................................87 
10.7. 
Process to Derive Week 60 Data Cut-off ...................................................................88 
10.8. 
SAS Procedures ..........................................................................................................88 
10.8.1. 
MMRM .......................................................................................................................88 
10.8.2. 
ANCOVA ...................................................................................................................88 
10.8.3. 
Multiple Imputation ....................................................................................................88 
10.8.4. 
Tipping Point Analysis ...............................................................................................89 
10.9. 
Additional Secondary Efficacy Variables and Analyses ............................................91 
10.9.1. 
Analysis Populations ..................................................................................................91 
10.9.1.1. 
Full Analysis Set (FAS) ..............................................................................................91 
10.9.1.2. 
Modified Full Analysis Set (mFAS) ...........................................................................91 
10.9.2. 
Additional Secondary Efficacy Variable(s) ................................................................91 
10.9.3. 
Additional Secondary Efficacy Analyses ...................................................................92 
 
LIST OF TABLES 
Table 1: Strategies for occurrence of intercurrent events (ICE) ....................................................27 
Table 2: The Testing Order of Hierarchical Testing Procedure in G-SAP and EP-SAP ...............35 
Table 3: Recoding of NEI-VFQ 25 items ......................................................................................59 
Table 4: Sub-scales of the NEI-VFQ 25 score ...............................................................................60 
Table 5: Criteria for Potentially Clinically Significant Values ......................................................84 
Table 6: Additional Secondary Efficacy Analyses – Alternative Tipping Point Analyses ...........93 
 
LIST OF FIGURES 
Figure 1: Study Flow Diagram ......................................................................................................14 
Figure 2: Dosing Schedule .............................................................................................................14 
 
 
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Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
2q8 
2 mg aflibercept every 8 weeks 
AAS 
ADA analysis set 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
APTC 
Anti-Platelet Trialists' Collaboration 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best corrected visual acuity 
BMI 
Body mass index 
BP 
Blood pressure 
BRVO 
Branch retinal vein occlusion 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CMH 
Cochran Mantel Haenszel 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRT 
Central retinal thickness 
CRVO 
Central retinal vein occlusion 
CSME 
Clinically Significant Macular Edema 
DME 
Diabetic macular edema 
DPKS 
Dense PK analysis set 
DR 
Diabetic retinopathy 
DRM 
Dose Regimen Modification 
DRSS 
Diabetic Retinopathy Severity Scale  
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
EP-SAP 
Statistical analysis plan for EMA and PMDA 
EOS 
End of study 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
FAS 
Full analysis set 
G-SAP 
Global statistical analysis plan 
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HbA1c 
Hemoglobin A1c 
HD 
High-dose 
HDq12 
High-dose aflibercept every 12 weeks 
HDq16 
High-dose aflibercept every 16 weeks 
HDL 
High-density lipoprotein 
ICF 
Informed consent form 
ICE 
Intercurrent event 
ICH 
International Council for Harmonisation 
IOP 
Intraocular pressure 
IRF 
Intraretinal fluid 
IVT 
Intravitreal 
IWRS 
Interactive web response system 
LOCF 
Last observation carry forward 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LS 
Least square 
MAR 
Missing at random  
MI 
Multiple imputation 
MCMC 
Markov Chain Monte Carlo 
mCNV 
Myopic choroidal neovascularization  
MedDRA 
Medical Dictionary for Regulatory Activities 
(MedDRA) HLT 
High Level Term 
MMRM 
Mixed-model repeated measures 
NAb 
Neutralizing antibody 
NAbAS 
NAb analysis set 
nAMD 
Neovascular “wet” age-related macular degeneration 
NEI-VFQ-25 
National Eye Institute Visual Functioning Questionnaire-25  
OC 
Observed case 
OCT 
Optical coherence tomography 
PCSV 
Potentially clinically significant value 
PK 
Pharmacokinetic 
PKAS 
PK analysis set 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
Per protocol set 
PT 
Preferred term 
RBC 
Red blood cell 
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SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
Standard deviation 
SD-OCT 
Spectral domain optical coherence tomography 
SI 
Standard international 
SOC 
System organ class 
SRF 
Subretinal fluid 
TEAE 
Treatment-emergent adverse event 
UPCR 
Urine protein:creatinine ratio 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
WHODD 
World Health Organization Drug Dictionary 
 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data for the phase 2/3 PHOTON, VGFTe-HD-DME-1934, 
study of high-dose (HD) aflibercept in patients with Diabetic Macular Edema (DME). This SAP 
is based on Protocol Amendment 4 dated April 28, 2022. 
1.1. 
Background/Rationale 
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. DME, a 
manifestation of diabetic retinopathy, is the primary cause of vision loss and blindness in patients 
with diabetes and the most frequent cause of blindness in young and middle-aged adults. If left 
untreated, approximately half of patients with DME will lose 2 or more lines of visual acuity 
(VA) within 2 years.  
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. 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 40 mg/mL 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. 
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 
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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 Phase 2/3 study (hereafter referred to as PHOTON) is designed as a randomized, double-
masked, active-controlled non-inferiority study to evaluate the safety and efficacy of a HD 
aflibercept with the intent of extending the dosing interval, with at least similar functional and 
potentially improved anatomic outcomes compared to the active control arm of 2 mg aflibercept 
(EYLEA).  The PHOTON study will investigate HD aflibercept dosed every 12 weeks (HDq12) 
or 16 weeks (HDq16) after 3 initial monthly injections vs. 2 mg aflibercept dosed every 8 weeks 
(2q8) after 5 initial monthly injections in patients diagnosed with DME. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of the study is to determine if treatment with HD aflibercept at intervals of 
12 or 16 weeks provides noninferior best corrected visual acuity (BCVA) compared to 2 mg 
aflibercept dosed every 8 weeks. 
1.2.2. 
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. 
1.2.3. 
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 
aflibercept, and the VEGF pathway 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
 Additional secondary efficacy endpoints and their analyses are added to this SAP for submission 
to the US FDA (based on the G-SAP that constitutes the primary analysis for the study). See 
Appendix 10.9 for details. 
 
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1.2.5. 
Revision History for SAP Amendments 
Version  
Date 
Version history 
1.0 
05 July 2022 
Initial version 
2.0 
19 August 2022 
Additional secondary efficacy 
variables and their analyses 
are added to the Appendix 
10.9 of the SAP 
 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
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. 
The study consists of a screening/baseline period, a treatment period, and an end of study (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 (Figure 1):  
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).  
Randomization of patients will be stratified based on  
• baseline central retinal thickness (CRT) (<400 μm, ≥400 μm),  
• prior DME treatment (yes, no), and  
• geographical region (Japan, Rest of world).  
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. 
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 Appendix 10.2.2. 
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 (see Schedule of Events in Appendix 10.2). 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  
 
 
Dose Regimen Modifications/Rescue Regimen 
For masking purposes, assessments for dose regimen modifications (DRMs) will be performed in 
all patients at all visits (through the interactive web response system [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) 
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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 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 Spectral domain optical coherence tomography (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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2.2. 
Sample Size and Power Considerations 
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 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 the 
comparison of HDq12 vs. 2q8, and subsequently 92% power for the comparison of HDq16 vs. 
2q8, for the primary endpoint assessing non-inferiority, with a 1-sided t-test at significance level 
of 0.025. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis: 
3.1. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients who received at least 1 dose of study 
medication; it is based on the treatment assigned to the patient at baseline (as randomized). FAS 
is the primary analysis set for efficacy endpoints. 
3.2. 
The Per Protocol Set (PPS) 
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 did not have any relevant important protocol violations 
that affect the primary efficacy variable. The final determination on the exclusion of patients 
from the PPS will be made on the masked data prior to the first database lock and described in a 
separate document. The PPS will be used for supplementary analysis of change from baseline in 
BCVA (non-inferiority only) at week 48 (primary endpoint) and week 60 (key secondary 
endpoint). 
Treatment assignment is based on the treatment received (as treated). In general, the randomized 
treatment group will be considered as the actual treatment group, unless the patient has not been 
treated at all after randomization. Isolated incorrect treatments will not constitute a change in the 
“as treated” assignment but will be considered as intercurrent events (refer to Section 5.6.1). 
3.3. 
The Safety Analysis Set (SAF) 
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. 
3.4. 
Pharmacokinetic Analysis Sets 
Two PK analysis sets will be defined. The PK analysis set (PKAS) includes all patients who 
received any study treatment and who had at least 1 non-missing PK result following the first 
dose of study drug.  Patients will be analyzed based on actual treatment received. 
The dense PK analysis set (DPKS) includes all patients who did not meet any of the additional 
exclusion criteria for Dense PK substudy who consented to Dense PK sampling (enrolled in PK 
sub study), received any study treatment, and with at least 1 non-missing dense PK result post 
first dose. Patients will be analyzed based on actual treatment received. 
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3.5. 
Immunogenicity Analysis Sets 
The ADA analysis set (AAS) includes all treated patients 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 Neutralizing antibody (NAb) assay. 
The NAb analysis set (NAbAS) includes all treated patients that are included in the ADA 
analysis set and that tested negative at all ADA sampling times or tested positive at one or more 
post-dose ADA sampling times and had at least one non-missing post-dose NAb result (either 
imputed or analysis result). Samples that tested negative for ADA are not assayed in the NAb 
assay and the corresponding NAb result are imputed as negative and included as such in the NAb 
analysis set. Patients in the NAbAS with multiple post-dose ADA results which consist of both 
imputed NAb-negative result(s) for ADA negative samples and only missing NAb results for all 
ADA-positive result(s), are set to NAb negative. Patients in the NAbAS that have at least one 
post-dose positive NAb analysis result are set to NAb positive even if other NAb results are 
missing. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic variables and baseline assessments will be summarized:  
• Age 
• Age category (<55 years, ≥55 years to <65 years, ≥65 years to <75 years, ≥75 years)  
• Sex (Female, Male) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other, Not Reported) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported) 
• Geographical region (Japan, Rest of World). 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m²) 
• BMI category (≤30 kg/m², >30 to ≤35 kg/m², >35 kg/m²) 
• Smoking history (Yes, No) 
• Hemoglobin A1c (HbA1c) 
• HbA1c category (≤8%, >8%) 
• Vital Signs (heart rate, blood pressure [BP] [systolic and diastolic], and temperature) 
• Intraocular pressure (IOP) in the study eye 
• Medical history: renal impairment (Normal, Mild, Moderate, Severe), hepatic 
impairment (Yes, No), hypertension (Yes, No), cerebrovascular disease (Yes, No), 
ischaemic heart disease (Yes, No). Detailed definitions are presented in Appendix 
10.4. 
• Duration of diabetes (years): defined as time from diagnosis (based on medical 
history data (MedDRA High Level Term (HLT) “diabetes mellitus”) to 
randomization 
• Diabetes type (Type 1, Type 2) 
• Diabetic Retinopathy Severity Scale (DRSS) in the study eye 
• BCVA (measured by Early Treatment Diabetic Retinopathy Study [ETDRS] letters) 
in the study eye 
• BCVA category (≤73 letters, >73 letters) 
• CRT in the study eye 
• Categorized CRT (<400 μm, ≥400 μm) 
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• National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) total 
score 
• Prior DME treatment in the study eye (Yes, No)  
• Presence of Clinically Significant Macular Edema (CSME) 
4.2. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA®). 
4.3. 
Pre-Treatment / Concomitant Medication 
Medications taken during the study will be recorded and will be coded using the World Health 
Organization Drug Dictionary (WHODD). 
Medications will be summarized as follows: 
• Prior medication is defined as medication that was started before a patient received 
first study treatment regardless of when it was stopped. 
• Concomitant medication is defined as medication that was ongoing at, or began 
after, the start of study treatment 
4.4. 
Exposure, Compliance, Additional Treatment to Study Treatment 
Exposure 
For each patient, the following variables will be used to examine exposure to study treatment for 
the study eye: 
• Total number of active injections through weeks 48, 60, and 96  
• Total number of sham injections through weeks 48, 60, and 96 
• Duration of treatment calculated (Weeks) as: [(last study treatment [active or sham] 
date) - (first study treatment [active or sham] date) + 28]/7 (28 days are added 
because of the minimum 4-week dosing interval in the study) 
• Proportion of patients in HDq16 group maintaining q16 dosing interval or longer 
through weeks 48, 60, and 96 
• Proportion of patients in HDq12 and HDq16 groups maintaining q12 dosing interval 
or longer through weeks 48, 60, and 96 
• Proportion of patients in HDq12 and HDq16 groups with q12 or q16 or longer dosing 
interval as the last intended dosing interval at week 48, week 60, and week 96  
• Proportion of patients in HDq12 and HDq16 groups shortening dosing interval to q8 
at week 16 or week 20 
• Proportion of HDq12 and HDq16 patients with a shortened dosing interval anytime 
through weeks 48, 60 and 96 
The following variables will be used to evaluate the fellow eye treatment 
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• Total number of aflibercept injections  
• Duration of fellow eye treatment calculated (Weeks) as: [(last fellow eye treatment 
date) - (first fellow eye treatment date) + 28]/7 (28 days are added because of the 
minimum 4-week dosing interval in the fellow eye in the study) 
Compliance 
Compliance with protocol-defined study treatments (active and sham) from baseline through the 
following time points will be assessed per patient:  48 weeks, 60 weeks and 96 weeks will be 
calculated as follows: 
Treatment Compliance = (Number of received injections [sham or active] through a given 
time period)/(Number of planned injections [sham or active] during period of participation in 
the study through the given time period) x 100% 
For the calculation of compliance all injections (regardless if they were sham or active) will be 
used. 
4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable (s) 
The primary efficacy variable is the change from baseline in BCVA (as measured by ETDRS 
letter score) at week 48. 
4.5.2. 
Key Secondary Efficacy Variable(s) 
The key secondary efficacy endpoints are: 
• Proportion of patients with a ≥2 step improvement in 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 5.6) 
4.5.3. 
Additional Secondary Efficacy Variable(s) 
The additional secondary efficacy endpoints are: 
 
Proportion of patients gaining ≥ 15 letters in BCVA from baseline 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 CRT at week 48 
• Proportion of patients without leakage on fluorescein angiography (FA) at week 48 
• Change from baseline in NEI-VFQ-25 total score at week 48 (scoring details can be 
found in Appendix 10.3) 
4.5.4. 
Exploratory Efficacy Variable(s) 
The exploratory efficacy endpoints will include the following: 
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• Change from baseline in BCVA at week 96 
• Proportion of patients gaining ≥ 15 letters in BCVA from baseline at week 60 and 96 
• Proportion of patients with BCVA ≥ 69 letters at week 60 and 96 
• Change from baseline in CRT at week 60 and 96 
• Proportion of patients without leakage on FA at week 60 and 96 
• Change from baseline in NEI-VFQ-25 total score at week 60 and 96 
• Proportion of patients without retinal fluid (total fluid, intraretinal fluid [IRF], 
subretinal fluid [SRF]) at the foveal center and in center subfield at week 48, week 
60, and week 96 
• Time to fluid-free retina over 48 weeks, 60 weeks, and 96 weeks (total fluid, IRF, 
SRF at foveal center and in the center subfield) 
• Proportion of patients with sustained fluid-free retina (defined as the absence of fluid 
for at least 2 consecutive visits and for all subsequent study visits) over 48 weeks, 60 
weeks, and 96 weeks (total fluid, IRF, SRF at foveal center and in the center subfield) 
Sustained fluid-free retina is defined as the absence of fluid for at least 2 consecutive 
visits and for all subsequent study visits. The first 2 consecutive visits cannot have 
missing assessment between these two consecutive visits. After the 2 consecutive 
visits, the missing assessments at subsequent visits can be ignored or treated them as 
dry when determined sustained fluid free retina.   
• Time to sustained fluid-free retina over 48 weeks, 60 weeks, and 96 weeks (total 
fluid, IRF, SRF at foveal center and in the center subfield) 
• Proportion of patients without CSME at week 48, week 60, and week 96 
• Proportion of patients with a ≥ 3 step improvement in DRSS at week 48, week 60, 
and week 96 
• Change from baseline in BCVA averaged over the period from Week 36 to Week 48 
• Change from baseline in BCVA average over the period from Week 48 to Week 60 
• Proportions of patients gaining and losing ≥ 5 or ≥ 10 letters at week 48, week 60, 
and week 96 
• Proportion of patients losing ≥ 15 letters at week 48, week 60, 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 (Week 96) 
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4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
An adverse event (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.  
All AEs are to be coded according to MedDRA. 
A Serious Adverse Event (SAE) is an AE that is classified as serious according to the criteria.  
Other variables for AE description and analysis will include AE Verbatim Term, AE start date 
and end date/ongoing and corresponding study day, AE duration, relationship of AE to study 
drug, relationship of AE to 2 mg aflibercept in the fellow eye, relationship of AE to injection 
procedure, relationship of AE to study conduct, seriousness, severity, action due to AE, treatment 
of AE and outcome. 
4.6.2. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, urinalysis and HbA1c. 
Clinical laboratory values will be converted to standard international (SI) units and grouped by 
function in summary tables. Functions are defined as follows: 
• Blood chemistry panel: Sodium, Potassium, Chloride, Carbon dioxide, Calcium, Glucose, 
Albumin, Total Protein (serum), Creatine, Blood urea nitrogen (BUN), Alanine 
aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase, 
Lactate dehydrogenase (LDH), Total bilirubin, Total cholesterol (Low-density lipoprotein 
[LDL] + high-density lipoprotein [HDL]), Triglycerides, Uric acid, Creatine 
phosphokinase (CPK) 
• Hematology panel: Hemoglobin, Hematocrit, Red blood cells (RBCs), White blood cells 
(WBCs), Red Cell Indices, Platelet count and Differential count (Neutrophils, 
Lymphocytes, Monocytes, Basophils, Eosinophils) 
• Urinalysis: Color, Clarity, pH, Specific gravity, Ketones, Protein, Urine 
protein:creatinine ratio (UPCR), Glucose, Blood, Bilirubin, Leukocyte esterase, Nitrite, 
WBC, RBC, Hyaline and other casts, Bacteria, Epithelial cells, Crystals, Yeast 
• HbA1c 
4.6.3. 
Vital Signs 
Variables of analysis for vital signs include temperature, BP (systolic and diastolic) and heart 
rate.  
4.6.4. 
12-Lead Electrocardiography (ECG) 
Variables of 12-Lead Electrocardiogram (ECG) include PR interval, QRS interval, RR interval, 
QT interval, QTc with Fridericia corrections, and heart rate. 
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4.6.5. 
Other Ocular Safety Variables 
Other ocular safety variables include intraocular pressure pre-dose in the study eye and fellow 
eye and post-dose in the study eye. 
4.6.6. 
Surgeries 
All the surgeries after informed consent are collected on the case report form (CRF) and are 
coded by MedDRA. Treatment emergent surgery is defined as surgery performed during the on-
treatment period (see Section 5.7.1). 
4.7. 
Pharmacokinetic Variables 
The PK variables are the concentrations of free, bound, adjusted bound, and total aflibercept in 
plasma at each time point. Plasma samples for drug concentration will be collected at the clinic 
visits specified in the protocol schedule of events. 
4.8. 
Immunogenicity Variables (ADA) 
The immunogenicity variables include ADA status, NAb status and titer at nominal sampling 
time/visit. Serum samples for ADA will be collected at the clinic visits specified in 
Appendix 10.2. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics variables will be summarized, by treatment group 
and overall, using descriptive statistics for FAS, SAF, and PPS. Disease characteristics of the 
study eye will be presented in a separate table.  
5.2. 
Medical History 
Medical history will be descriptively summarized, by treatment group and overall, for SAF. 
Summaries will show number and percentage of patients by primary system organ class (SOC) 
and preferred term (PT). The tables will be sorted by decreasing frequency of primary SOC. 
Within each primary SOC, PTs will be sorted by decreasing frequency in the total group. It will 
be summarized separately by ocular medical history in the study eye, ocular medical history in 
the fellow eye, and non-ocular medical history.   
5.3. 
Prior/concomitant Medications  
All prior/concomitant medications, dictionary coded by WHODD, will be descriptively 
summarized by treatment group for SAF. Summaries will present number and percentage of 
patients for the medication groups described in Section 4.3 for all medications, by decreasing 
frequency of Anatomical Therapeutic Chemical (ATC) level 1 followed by ATC level 2 in the 
total group. In case of equal frequency across anatomic or therapeutic categories, alphabetical 
order will be used. Patients will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. 
Concomitant medications will be summarized by the following periods: 
• Day 1 up to week 48 
• Day 1 up to week 60  
• Day 1 up to End of study (week 96) 
When medication start/end date is missing, the rules for determining whether a medication is 
prior, concomitant, or post-treatment, are specified in Section 6.5. 
5.4. 
Patient Disposition 
The disposition of patients in the study will be summarized by treatment group and overall. 
Percentages will be calculated using the number of randomized patients as the denominator. The 
following summaries will be provided: 
• The total number of screened patients who have signed the ICF, the number of screen 
failure and the reasons for screen failure. 
•  The total number of randomized patients who received a randomization number 
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• The total number of patients in each analysis set 
• The total number of patients who prematurely discontinued the study, and the reasons for 
discontinuation, and who completed the Week 48, Week 60, and Week 96 visits 
5.5. 
Extent of Study Treatment Exposure and Compliance 
The variables for dose exposure and compliance described in Section 4.4 will be summarized for 
the SAF, FAS, and PPS populations, using descriptive statistics by the following time periods: 
• Day 1 to week 48 (excluding treatment at week 48) 
• Day 1 to week 60 (excluding treatment at week 60) 
• Day 1 to End of study (week 96) 
5.6. 
Analyses of Efficacy Variables 
Due to differing requirements for the submission to regulatory authorities, 2 different analysis 
strategies will be applied, which will be detailed in this SAP document: a global statistical 
analysis plan (G-SAP), and a plan that specifically addresses requirements from EMA and 
PMDA (EP-SAP). 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. 
All efficacy analyses will be conducted using the FAS population. In addition, the change from 
baseline in BCVA at week 48 and week 60 will be analyzed using the PPS population as 
supplementary analyses. 
5.6.1. 
Analysis of Primary Efficacy Variable 
The primary analysis is based on the estimand concept. The estimand of primary interest will be 
based mainly 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. 
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. All efficacy analyses will be 
conducted using the FAS. 
• Variable: Change from baseline to week 48 in BCVA 
• Treatment condition: Intention to treat with HD aflibercept administered every 12 weeks 
(HDq12) after 3 initial monthly injections or every 16 weeks (HDq16) after 3 initial 
monthly injections each versus aflibercept 2 mg administered every 8 weeks (2q8) after 5 
initial monthly injections; dose regimen modifications as detailed in Section 2.1 do not 
affect patient's assigned ITT regimen. 
• Intercurrent events: Premature discontinuation from treatment; missed injections; use of 
prohibited medication; wrong study intervention administered, as displayed in Table 1. 
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• Population-level summary: Difference in least-square (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). 
Table 1: Strategies for occurrence of intercurrent events (ICE) 
Potential post-
randomization event 
Intercurrent 
event 
(yes/no) 
Estimand strategy 
Analysis strategy  
Premature 
discontinuation of study 
intervention before 
Week 48 
 
 
 
- 
Discontinuation of 
study at the same 
time 
Yes 
Hypothetical 
Non-observed data 
beyond discontinuation 
will be covered implicitly 
in the MMRM  
- 
Continuation of 
study beyond 
discontinuation of 
study intervention^   
Yes 
Hypothetical 
Observed data beyond last 
active injection prior to 
discontinuation + current 
treatment interval + 5 
days will be excluded 
from analysis. Missing 
and excluded data will be 
covered by the MMRM. 
Missed injection for any 
reason before Week 48 
 
 
 
- 
Planned to be sham 
Yes, but no 
impact 
N/A 
All observed data will be 
included in the analysis 
- 
Planned to be active, 
make-up given at 
next visit 
Yes 
Treatment policy 
All observed data will be 
included in the analysis 
- 
Planned to be active, 
make-up or 
scheduled active 
injection not given 
at next visit 
Yes 
Hypothetical 
Observed data beyond last 
active injection prior to 
the missed dose + current 
treatment interval + 5 
days will be excluded 
from analysis. Missing 
and excluded data will be 
covered by the MMRM. 
Shortening of dosing 
interval according to 
DRM criteria before 
Week 48 
No, DRM is 
considered 
part of the 
treatment 
regimen 
N/A 
 
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Use of a prohibited 
medication after the 
first dose of study 
medication ( 
Yes 
Hypothetical 
Observed data beyond 
first administration of 
prohibited medicine will 
be excluded from 
analysis. Missing and 
excluded data will be 
covered by the MMRM. 
Wrong study 
intervention before 
Week 48 
 
 
 
- 
Active injection 
given instead of 
sham 
Yes 
Treatment policy 
All observed data will be 
included in the analysis 
- 
Sham injection 
instead of active 
Yes 
Hypothetical 
Observed data beyond last 
active injection prior to 
the wrong dose + current 
treatment interval + 5 
days will be excluded 
from analysis. Missing 
and excluded data will be 
covered by the MMRM. 
- 
Wrong dose level 
given (eg, 2mg 
given instead of 
8mg)  
Yes 
Treatment policy 
All observed data will be 
included in the analysis 
^ This ICE will be handled in the same way as "Missed injection: Planned to be active, make-up or scheduled 
active injection not given at next visit, since the info of discontinuation from study intervention was not collected 
in the database.  
The following 2 hypotheses will be tested in the primary analysis:  
• HDq12 is non-inferior to 2q8 regarding the mean change in BCVA from baseline to 
week 48 using a non-inferiority margin of 4 letters:  
H10:  μ1 ≤ μ0 – 4 vs. H11:  μ1 > μ0 – 4,  
where μ0, μ1, are the mean change from baseline in BCVA at week 48 for 2q8 and 
HDq12, respectively. 
• HDq16 is non-inferior to 2q8 regarding the mean change in BCVA from baseline to 
week 48 using a non-inferiority margin of 4 letters: 
H30:  μ2 ≤ μ0 – 4 vs. H31:  μ2 > μ0 – 4,  
where μ0, μ2 are the mean change from baseline in BCVA at week 48 for 2q8, and 
HDq16, respectively. 
5.6.1.1. 
Primary Analysis for Primary Efficacy Variable 
For the analysis of the primary efficacy variable, a mixed model for repeated measurements 
(MMRM) will be used with baseline BCVA measurement as a covariate and treatment group 
(HDq16 vs. 2q8 and HDq12 vs. 2q8) and baseline CRT category (<400 μm, ≥400 μm), prior 
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DME treatment (yes, no), geographical region (Rest of world, Japan), and visit as fixed effects as 
well as terms for the interaction between baseline BCVA and visit and for the interaction 
between treatment and visit. A Kenward-Roger approximation will be used for the denominator 
degrees of freedom. Further, an unstructured covariance structure will be used. If the model does 
not converge, an appropriate covariance structure will be used instead. Only data up to Week 48 
will be used in this analysis. 
𝑌𝑖𝑗k = 𝛽0 + 𝛽𝑏𝑎𝑠𝑒𝐵𝐶𝑉𝐴 𝑥𝑖 + 𝛽𝑡𝑟𝑒𝑎𝑡
(𝑘)  + 𝛽𝑏𝑎𝑠𝑒−𝐶𝑅𝑇
(𝑛)
+ 𝛽𝑝𝐷𝑀𝐸
(𝑙)
+ 𝛽𝑟𝑒𝑔
(𝑚) + 𝛽𝑣𝑖𝑠𝑖𝑡
(𝑗)   + 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝑘,𝑗)
 + 
𝛽𝑏𝑎𝑠𝑒∗𝑣𝑖𝑠𝑖𝑡
(𝑗)
 𝑥𝑖+ 𝜖𝑖𝑗𝑘, 
where: 
 𝑌𝑖𝑗k is the change from baseline BCVA for 𝑖thpatient at 𝑗thvisit 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, 
𝛽𝑡𝑟𝑒𝑎𝑡
(𝑘)  is the fixed effect of treatment group 𝑘 
 𝛽𝑏𝑎𝑠𝑒−𝐶𝑅𝑇
(𝑛)
 is the fixed effect of categorized baseline CRT 𝑛, 
𝛽𝑝𝐷𝑀𝐸
(𝑙)
 is the fixed effect of prior DME treatment 𝑙, 
𝛽𝑟𝑒𝑔
(𝑚) is the fixed effect of region 𝑚, 
𝛽𝑣𝑖𝑠𝑖𝑡
(𝑗)  is the fixed effect of visit 𝑗, 
𝛽𝑏𝑎𝑠𝑒∗𝑣𝑖𝑠𝑖𝑡
(𝑗)
 the interaction between baseline BCVA and visit 𝑗, 
𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝑘,𝑗)
 the interaction between treatment 𝑘 and visit 𝑗, 
𝜖𝑖𝑗𝑘 is the residual error with 𝜖𝑖𝑗𝑘~𝑁(0, 𝜎2) and 𝑐𝑜𝑟𝑟(𝜖𝑖𝑗𝑘, 𝜖𝑖𝑗′𝑘,) = 𝜌(𝑘)_{𝑖, 𝑗′}, or 0 
otherwise. 
 
In terms of the estimators the population-level summary of the estimands (ie, the treatment effect 
at week 48) can then be expressed as 
𝐷𝐻𝐷𝑄12 = [𝛽𝑡𝑟𝑒𝑎𝑡
(𝐻𝐷𝑄12) + 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝐻𝐷𝑄12,𝑤48)] − [𝛽𝑡𝑟𝑒𝑎𝑡
(2𝑄8) + 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(2𝑄8,𝑤48) ] 
and 
𝐷𝐻𝐷𝑄16 = [𝛽𝑡𝑟𝑒𝑎𝑡
(𝐻𝐷𝑄16) + 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝐻𝐷𝑄16,𝑤48)] − [𝛽𝑡𝑟𝑒𝑎𝑡
(2𝑄8) + 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(2𝑄8,𝑤48) ]. 
Summary tables will include number of patients, LS mean change, (unadjusted) mean change 
and standard deviation (SD) and baseline means of each treatment group. For non-inferiority 
testing, the population level estimates comparing HDq16 vs. 2q8 (DHDQ16) and HDq12 vs. 2q8 
(DHDQ12), expressed as LS mean change, the test statistics, the degrees of freedom, and 
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corresponding p-values will be presented. Two-sided 95% confidence intervals will also be 
provided. 
In line with the definition of estimands (see above), the primary analysis will be performed on 
the FAS and patients will be analyzed within their original randomized group (regardless of any 
changes to dose interval). The MMRM assumes missing at random (MAR) for patients who 
discontinue the study prematurely, ie, missingness only depends on observed data. 
The following superiority testings will be performed as described in Section 5.6.4 for G-SAP 
strategy and EP-SAP strategy. 
• HDq12 is superior to 2q8 regarding the mean change in BCVA from baseline to 
week 48:  
H70:  μ1 ≤ μ0 vs. H71:  μ1 > μ0,  
where μ0, μ1, are the mean change from baseline in BCVA at week 48 for 2q8 and 
HDq12, respectively. 
• HDq16 is superior to 2q8 regarding the mean change in BCVA from baseline to 
week 48: 
H90:  μ2 ≤ μ0 vs. H91:  μ2 > μ0,  
where μ0, μ2 are the mean change from baseline in BCVA at week 48 for 2q8, and 
HDq16, respectively. 
An example of Statistical Analysis System (SAS) code for MMRM is presented in Appendix 
10.8   
5.6.1.2. 
Sensitivity Analyses for Primary Efficacy Variable 
Last observation carried forward (LOCF) will be conducted for patients who had at least one 
post-baseline value but discontinued prematurely or had an ICE as defined in Table 1 before 
week 48 and ANCOVA will be applied for the change from baseline in BCVA at week 48. 
Another approach assuming MAR will be implemented by using multiple imputation (MI). In 
addition, the tipping point analysis will be performed as a sensitivity analysis if the MI analysis 
results under MAR assumption show non-inferiority of the high dose groups compared to the 
low dose group. 
5.6.1.2.1. ANCOVA using LOCF 
For this sensitivity analysis of the primary efficacy variable, an analysis of covariance 
(ANCOVA) will be used with baseline BCVA measurement as a covariate and treatment group 
(HDq16 vs. 2q8 and HDq12 vs. 2q8) and the stratification variables (baseline CRT category 
[<400 μm, ≥400 μm], prior DME treatment [yes, no], geographical region [Rest of world, 
Japan]) as fixed factors. A separate variance term will be estimated for the three treatment 
groups. 
The observation at week 48 of patient 𝑖 receiving treatment 𝑡 can be written as follows: 
𝑌𝑖𝑡𝑟𝑏= 𝜇𝑡+ 𝛾𝑟+ 𝜂𝑐+ 𝜋𝑝+ 𝑥𝑖𝛽+ 𝜖𝑖𝑡𝑟𝑏 
where 
𝑌𝑖𝑡𝑟𝑏 is the change from baseline to week 48 for the 𝑖th patient, 
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𝜇𝑡 is the treatment effect, 
𝛾𝑟 is the geographic region effect (Rest of world, Japan), 
𝜂𝑐 is the categorized baseline CRT (<400 μm, ≥400 μm), 
𝜋𝑝 is the prior DME treatment (yes, no) 
𝑥𝑖 is the baseline BCVA of patient 𝑖, 
𝜖𝑖𝑡𝑟𝑏 is the residual error with 𝜖𝑖𝑡𝑟𝑏~𝑁(0, 𝜎𝑡
2 ) for treatment arm 𝑡. 
For this analysis missing week 48 BCVA data will be imputed by using LOCF. That means that 
the last non-missing post-baseline BCVA measurement prior to an ICE will be carried forward to 
week 48. 
Summary tables will include number of patients, LS mean change, (unadjusted) mean change 
and SD and baseline means of each treatment group. For non-inferiority testing the one-sided 𝛼 
of 0.025 for the population level estimates comparing HDq16 vs. 2q8 and HDq12 vs. 2q8, the 
estimates expressed as LS mean change including the one-sided confidence intervals (CIs) for 𝛼 
of 0.025, the test statistics, the degrees of freedom and corresponding p-values will be presented.  
This sensitivity analysis will be analyzed for the FAS. 
An example of SAS code for ANCOVA is presented in Appendix 10.8.  
5.6.1.2.2. ANCOVA with Multiple Imputation 
The primary efficacy variable at week 48 will be analyzed using MI with ANCOVA model 
based on the FAS. Data after occurrence of an ICE as defined in Table 1 will be excluded. MI 
methods involve three steps.  
I. 
Imputation 
Missing data up to week 48 will be imputed 50 times to generate 50 complete data sets by using 
the SAS procedure MI following the 2 steps below: 
Step 1: The monotone missing pattern is induced by Markov Chain Monte Carlo (MCMC) 
method in MI procedure using seed number 01934. 
Step 2: The missing data at subsequent visits will be imputed using the regression method for the 
monotone pattern with seed number 01934 and adjustment for covariates including treatment 
groups, baseline CRT category (<400 μm, ≥400 μm), prior DME treatment (yes, no), 
geographical region (Rest of world, Japan), baseline BCVA and all BCVA values at preceding 
visits.  
 
If the imputed data is outside the range of 0 to 100 in either step of imputation, truncation will be 
applied to the imputed data.   
II. 
Analysis 
The week 48 data of each of the 50 complete datasets will be analyzed using an ANCOVA 
model as specified in Section 5.6.2.2.1. 
III. 
Pooling 
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The SAS MIANALYZE procedure will be used to generate valid statistical inferences by 
combining results from the 50 analyses using Rubin’s formula (Rubin, 1987). 
An example of SAS code for MI is presented in Appendix 10.8.  
5.6.1.2.2.1. Tipping Point Analysis 
In order to check the assumption that the missing data are not MAR, a tipping point analysis will 
be conducted based on the multiple imputation analysis in Section 5.6.1.2.2. The objective of the 
tipping point analyses is to identify assumptions about the missing data under which the 
conclusions from the main analysis change, ie, under which non-inferiority cannot be shown 
anymore. These tipping point analyses will only be performed if the multiple imputation analysis 
results show non-inferiority of the high dose groups compared to the low dose group. In case the 
non-inferiority is shown, additional tipping point analyses will be repeated after reducing the 
imputed BCVA values in the high dose arms by ascending natural number of letters (1, 2, 3… 
etc.), with the goal to find for each high dose treatment group the “tipping point” that will 
significantly reverse the analysis result. The smallest delta, for which non-inferiority cannot be 
shown anymore, will be the “tipping point”. 
For each value of delta, summary tables will include number of patients, LS mean change, 
(unadjusted) mean change and SD and baseline means of each treatment group as well as the 
estimates expressed as LS mean change including the two-sided CIs, the test statistics, the 
degrees of freedom and corresponding p-values. 
An example of SAS code for tipping point analysis is presented in Appendix 10.8.  
5.6.1.3. 
Supplementary Analyses for Primary Efficacy Variable 
The primary analysis described in Section 5.6.1.1 will be repeated using the PPS. 
5.6.1.4. 
Subgroup Analyses for Primary Efficacy Variable 
Analyses will be performed in the following subgroups: 
• Sex: male, female 
• Age at enrollment: <55 years, ≥55 years to <65 years, ≥65 years to < 75 years, ≥75 
years  
• Race (only subgroups with sufficient sample size): White, Black or African 
American, Asian 
• Ethnicity: Not Hispanic or Latino, Hispanic or Latino 
• Baseline BCVA (≤73 letters, >73 letters) 
• Geographic region: Japan, Rest of the world 
• Baseline CRT category (<400 μm, ≥400 μm) 
• Prior DME treatment (yes, no) 
Subgroup analyses will be performed using the same model as in Section 5.6.1.1, except for 
those subgroups that are also stratification factors (geographic region, baseline CRT category, 
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and prior DME treatment), where these terms will be individually removed from the model 
(leaving the other 2 factors in). 
5.6.2. 
Analysis of Key Secondary Efficacy Variables 
5.6.2.1. 
Change from Baseline in BCVA Measured by the ETDRS Letter Score at 
Week 60 
The following 2 non-inferiority hypotheses will be tested for this key secondary endpoint under 
the EP-SAP only:  
• HDq12 is non-inferior to 2q8 regarding the mean change in BCVA from baseline to 
week 60 using a non-inferiority margin of 4 letters:  
H20:  μ1 ≤ μ0 – 4 vs. H21:  μ1 > μ0 – 4,  
where μ0, μ1, are the mean change from baseline in BCVA at week 60 for 2q8 and 
HDq12, respectively. 
• HDq16 is non-inferior to 2q8 regarding the mean change in BCVA from baseline to 
week 60 using a non-inferiority margin of 4 letters: 
H40:  μ2 ≤ μ0 – 4 vs. H41:  μ2 > μ0 – 4,  
where μ0, μ2 are the mean change from baseline in BCVA at week 60 for 2q8, and 
HDq16, respectively. 
The analysis of key secondary endpoints will be required for the submission to the EMA/PMDA 
regulatory authorities.  The change from baseline in BCVA at week 60 will be analyzed with the 
same methods and main and sensitivity summaries as for the primary endpoint described in 
Section 5.6.1. Only data up to Week 60 will be used in this analysis. 
The following superiority testings will also be performed as described in Section 5.6.4 (under the 
EP-SAP only) for this endpoint. 
• HDq12 is superior to 2q8 regarding the mean change in BCVA from baseline to week 60:  
H80:  μ1 ≤ μ0 vs. H81:  μ1 > μ0,  
where μ0, μ1, are the mean change from baseline in BCVA at week 48 for 2q8 and 
HDq12, respectively. 
• HDq16 is superior to 2q8 regarding the mean change in BCVA from baseline to week 60: 
H100:  μ2 ≤ μ0 vs. H101:  μ2 > μ0,  
where μ0, μ2 are the mean change from baseline in BCVA at week 48 for 2q8, and 
HDq16, respectively. 
Subgroup analyses will be performed on those subgroups listed in Section 5.6.1.4 using the same 
model described above, except for those subgroups that are also stratification factors (geographic 
region, baseline CRT category, and prior DME treatment), where these terms will be individually 
removed from the model (leaving the other 2 factors in). 
5.6.2.2. 
Proportion of patients with a ≥2 step improvement in DRSS at week 48 
The following 2 non-inferiority hypotheses will be tested for this key secondary variable on the 
FAS:  
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• HDq12 is non-inferior to 2q8 regarding the proportion of patients with a ≥2 step 
improvement in DRSS at week 48:  
H50:  pHDq12 ≤ p2Q8 – 0.15 vs. H51:  pHDq12 > p2Q8 – 0.15, 
where p2Q8, pHDq12, are the proportion of patients with a ≥2 step improvement in DRSS at 
week 48 for 2q8, and HDq12, respectively. 
• HDq16 is non-inferior to 2q8 regarding the proportion of patients with a ≥2 step 
improvement in DRSS at week 48:  
H60:  pHDq16 ≤ p2Q8 – 0.15 vs. H61:  pHDq16 > p2Q8 – 0.15, 
where p2Q8, pHDq16, are the proportion of patients with a ≥2 step improvement in DRSS at 
week 48 for 2q8, and HDq16, respectively. 
The non-inferiority margin is set at 15%. This endpoint will be analyzed by a Cochran-Mantel-
Haenszel (CMH) test stratified by baseline CRT category (<400 μm, ≥400 μm), prior DME 
treatment (yes, no), geographical region (Rest of world, Japan). Missing or non-gradable post-
baseline values will be imputed using LOCF procedure. Patients will be considered as non-
responders if all post-baseline measurements are missing or non-gradable. Strategies for 
occurrence of intercurrent events will be similar to Table 1, except the excluded data will be 
implemented by LOCF procedure.   
Additionally, a two-sided 95% Mantel-Haenszel confidence interval (Koch et al, 1990) for the 
difference of proportion adjusted for stratification factors (baseline CRT category [<400 μm, 
≥400 μm], prior DME treatment [yes, no], geographical region [Rest of world, Japan]) will be 
calculated using normal approximation. 
Subgroup analyses will be performed on those subgroups listed in Section 5.6.1.4 using the same 
model described above, except for those subgroups that are also stratification factors (geographic 
region, baseline CRT category, and prior DME treatment), where these terms will be individually 
removed from the model (leaving the other 2 factors in). 
5.6.2.2.1. Sensitivity Analyses 
The following sensitivity analysis will be performed for the proportion of patients with a ≥2 step 
improvement in DRSS at week 48 for the FAS:  
The above analysis will be repeated but for observed cases (OC) only, ie, observed data prior to 
the occurrence of an ICE. 
5.6.3. 
Analysis of Additional Secondary and Exploratory Efficacy Variables 
All additional secondary and exploratory efficacy variables (see Section 4.5.3 and Section 4.5.4) 
will be analyzed descriptively at each scheduled visit from baseline to week 48, week 60, and 
week 96, as applicable. These descriptive analyses will include statistical tests (with nominal p-
values) for the efficacy variables and two-sided 95% confidence intervals.  
For these statistical tests, continuous variables will be analyzed by the same repeated 
measurement models as for the primary endpoint.  
Binary endpoints will be analyzed by CMH methods adjusted by the stratification factors based 
on LOCF (ie, missing/non-gradable data will be imputed by the last valid data prior to ICE). The 
endpoint of proportion of patients with a ≥ 3 step improvement in DRSS will analyzed by the 
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same method as the proportion of patients with a ≥ 2 step improvement in DRSS as specified in 
Section 5.6.2.2.  For the other binary endpoints, only valid data (excluding missing/non-
gradable) will be included in the denominator when calculated the proportion. Sensitivity 
analysis will be performed by OC method (ie, observed data prior to an ICE).  
Time-to-event variables will be analyzed using the Kaplan-Meier method. Time to event will be 
calculated as duration from date of randomization to the event for the first time whereas 
intercurrent events are handled according to Table 1. Patients without the event will be censored 
at their last assessment date. The analysis will be using the study visits (ie, multiples of 4 weeks) 
and not the calendar time as unit. Each of the HD groups will be compared with the 2q8 group 
using a stratified log-rank test. Hazard ratios will be calculated using a stratified Cox 
proportional hazards model, including treatment group as factor and baseline CRT category 
(<400 μm, ≥400 μm), prior DME treatment (yes, no), geographical region (Rest of world, Japan) 
as strata. 
No multiplicity adjustments will be made for these efficacy analyses. 
5.6.4. 
Adjustment for Multiple Comparisons 
For the G-SAP strategy, statistical hypotheses of the primary endpoint (BCVA at week 48) and 
the key secondary endpoint (≥2 step improvement in DRSS at week 48) will be assessed 
together, after all patients completed week 48 (or discontinued prematurely) using the below 
described methods. 
For the EP-SAP strategy, statistical hypotheses of the primary endpoint (BCVA at week 48) and 
the key secondary endpoints (BCVA at week 60, ≥2 step improvement in DRSS at week 48) will 
be assessed together, after all patients completed week 60 (or prematurely discontinued) using 
the below described methods. 
The overall family-wise type 1 error will be controlled at 0.025 (one-sided tests) 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. 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 hypotheses will be 
tested in the order as specified in Table 2 for G-SAP and EP-SAP, respectively. 
Table 2: 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 
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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 
5.7. 
Analysis of Safety Data 
The safety variables as defined in Section 4.6  will be analyzed on the SAF for the periods from 
baseline/day 1 through week 48, week 60 and the end of study (week 96). The summary of safety 
results will be presented for each treatment group. Data will not be imputed for the safety 
analysis. 
5.7.1. 
Adverse Events  
Period of observation: The observation period will be divided into three segments:  
• 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 the first dose of study drug to the last dose of study drug 
(active or sham) plus 30 days. In the week 48 (week 60) analysis, for patients who are 
still participating in the study (ie, have not been withdrawn), all AEs up through the 
date of that visit will be considered on-treatment. 
• The post-treatment period is defined as after the end of the on-treatment period 
TEAEs are defined as events that are not present at baseline or represent the exacerbation of a 
pre-existing condition during the on-treatment period. 
TEAEs will further be summarized by the following categories: 
• Ocular TEAEs in the study eye  
• Ocular TEAEs in the fellow eye 
• Non-ocular TEAEs 
The following TEAE categories will also be summarized as described for TEAEs: 
• Study drug related TEAEs 
• Injection related TEAEs 
• Study conduct related TEAEs 
• 2mg aflibercept in the fellow eye related TEAEs 
• TEAEs leading to discontinuation 
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• TEAEs by maximum severity 
• TE SAEs 
• Study drug related TE SAEs 
• Injection related TE SAEs 
• TE SAEs by maximum severity 
Counts will be provided according to treatment group for each PT within each SOC. Percentages 
will be calculated using the number of patients from the SAF in each treatment group. 
Primary SOCs will be sorted according to alphabetical order. Within each primary SOC, PTs will 
be sorted by alphabetical order as well. For tables presenting severity of events, the worst 
severity will be chosen for patients with multiple instances of the same event. 
Treatment emergent APTC events (adjudicated), hypertension, intraocular inflammation, and 
nasal mucosal events will be tabulated. Detailed definitions for the latter 3 of these types of AEs 
are presented in Appendix 10.4. Please refer to APTC charter for more information for 
adjudication of APTC events. 
The following study periods will be used for TEAE summaries: 
• Day 1 to week 48 
• Day 1 to week 60 
• Day 1 to week 96 
5.7.1.1. 
Subgroup Analyses  
Subgroup analyses in TEAE reporting will be performed for the following subgroups: 
• Sex: male, female 
• Age at enrollment:  <55 years, ≥55 years to <65 years, ≥65 years to < 75 years, ≥75 
years 
• Race (only subgroups with sufficient sample size): White, Black or African 
American, Asian  
• Ethnicity: Not Hispanic or Latino, Hispanic or Latino 
• Geographic region: Japan, Rest of the world 
• Medical history of renal impairment 
• Medical history of hepatic impairment 
• Medical history of hypertension  
• Medical history of cerebrovascular disease 
• Medical history of ischaemic heart disease 
The medical history subgroups are defined in more detail in Appendix 10.4. 
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Summaries (by SOC and PT) of patients with each of the following types of TEAE will be 
provided for the above subgroups: 
• Ocular TEAEs in the study eye 
• Non-ocular TEAEs 
• Serious ocular TEAEs in the study eye 
• Serious non-ocular TEAEs 
5.7.2. 
Clinical Laboratory Measurements 
Baseline clinical laboratory analytes and change from Baseline in clinical laboratory analytes to 
each scheduled assessment time will be summarized with descriptive statistics.  
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 normal range values.  
Treatment-emergent high abnormalities are laboratory values that were normal or low at 
Baseline but high after treatment with study drug. Treatment-emergent high abnormalities will 
be summarized using SAF for patients who were normal or low at Baseline.  
Treatment-emergent low abnormalities are laboratory values that were normal or high at 
Baseline but low after treatment with study drug. Treatment-emergent low abnormalities will be 
summarized using SAF for patients who were normal or high at Baseline.  
A treatment-emergent potentially clinically significant value (PCSV) is a laboratory value that 
was normal at Baseline but met PCSV criteria after treatment with study drug. Definitions of 
PCSVs are listed in Appendix 10.5. Treatment Emergent PCSVs will be summarized using SAF 
for patients who did not meet the PCSV criterion at baseline. 
5.7.3. 
Analysis of Vital Signs 
The assessments of vital signs (heart rate, systolic/diastolic BP, and temperature) and their 
changes from Baseline will be summarized by visit. The Baseline for BP is defined as the 
average of all valid measurements taken prior to administration of study drug. The Baseline for 
other vital signs endpoints will be the latest available valid measurement taken prior to the 
administration of study drug, as specified in 6.1. 
Treatment Emergent PCSV for systolic/diastolic blood pressure will be summarized based on the 
using SAF and in the SAF for patients who do did not meet the PCSV criterion at baseline. 
Definition of PCSVs for blood pressure are listed in Appendix 10.5. 
5.7.4. 
Analysis of 12-Lead ECG 
The assessments of ECG parameters (P-R interval, QT interval, QTc interval, QRS interval, 
Ventricular rate and Heart rate) and their changes from Baseline will be summarized by visit.      
ECG status (ie, normal, abnormal) will be reported. Shift tables may be provided to present the 
post-baseline status according to the baseline status (normal or missing / abnormal) by treatment 
group. 
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5.7.5. 
Analysis of Other Ocular Safety Variables 
Pre-dose IOP measurements and their changes from baseline will be summarized by visit using 
descriptive statistics for the study eye and the fellow eye, respectively. Post-dose IOP 
measurements and their changes from pre-dose will be summarized for study eye.  The 
proportion of patients who meet the following criteria will be summarized descriptively: 
• ≥ 10 mmHg increase in IOP measurement from baseline to pre-dose measurement in the 
study eye (by visit and at any time) 
• ≥ 10 mmHg increase in IOP measurement from baseline to pre-dose measurement in the 
fellow eye (by visit and at any time) 
• > 21 mmHg for any pre-dose measurement in the study eye (by visit and at any time) 
• > 21 mmHg for any pre-dose measurement in the fellow eye (by visit and at any time) 
• ≥ 25 mmHg for any pre-dose measurement in the study eye (by visit and at any time) 
• ≥ 25 mmHg for any pre-dose measurement in the fellow eye (by visit and at any time) 
• ≥ 35 mmHg at any time (pre- or post-dose) in the study eye (by visit and at any time) 
• ≥ 35 mmHg at any time (pre- or post-dose) in the fellow eye (by visit and at any time) 
5.7.6. 
Surgeries 
Treatment emergent surgeries will be summarized by the following categories: 
• Ocular treatment emergent surgeries in the study eye  
• Ocular treatment emergent surgeries in the fellow eye 
• Non-ocular treatment emergent surgeries 
5.8. 
Analysis of Pharmacokinetic Data 
5.8.1. 
Analysis of Drug Concentration Data 
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   
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• 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. 
5.8.2. 
Pharmacokinetics/Pharmacodynamics Analyses 
Dose- and/or exposure-response analyses for efficacy and safety endpoints may be performed, as 
appropriate. 
5.9. 
Analysis of Immunogenicity Data 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics. Immunogenicity will be characterized per drug molecule by ADA status, ADA 
category and maximum titer observed in patients in the ADA analysis sets. 
The ADA status of each patient may be classified as one of the following: 
• Positive 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 4-fold the baseline titer value 
• Negative - If all samples are found to be negative in the ADA assay. 
The ADA category of each positive patient is classified as: 
Treatment-boosted - A positive result at baseline in the ADA assay with at least one post 
baseline titer result ≥4-fold the baseline titer value 
Treatment-emergent - A negative result or missing result at baseline with at least one positive 
post baseline result in the ADA assay. Patients that are treatment-emergent will be further 
categorized as follows: 
Persistent - A positive result in the ADA assay detected in at least 2 consecutive post baseline 
samples separated by at least a 16-week post baseline period [based on nominal sampling time], 
with no ADA-negative results in-between, regardless of any missing samples 
Transient - Not persistent or indeterminate, regardless of any missing samples 
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Indeterminate - A positive result in the ADA assay at the last collection time point only, 
regardless of any missing samples 
The maximum titer category of each patient is classified as: 
Low (titer <1,000) 
Moderate (1,000 ≤ titer ≤ 10,000) 
High (titer >10,000) 
The following will be summarized by treatment group and ADA titer level: 
Number (n) and percent (%) of ADA-negative patients 
Number (n) and percent (%) of pre-existing patients 
Number (n) and percent (%) of treatment-emergent ADA positive patients 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of study drug.  
6.2. 
Visit Windows 
The visits used for the analysis will be based on the nominal visits, ie, according to the case 
report form (CRF) assessment recorded by the investigator. No visit windows will be further 
defined. 
6.3. 
Unscheduled Assessments 
Unscheduled assessments will not be included in the summaries unless specified. 
If more than one value is available for a given visit, the visit value actually used for statistical 
summaries and analyses will be as follows: 
• The last non-missing repeated measurement, if respective visit is before start of treatment 
• The first non-missing repeated measurement, if respective visit is after start of treatment 
If an early termination visit is performed within the protocol-defined window of the next 
scheduled visit after the last previous visit, the visit-dependent assessments will be re-slotted to 
the next scheduled visit. 
6.4. 
Handling of Patients who Discontinue 
Patients who discontinue this study will not be replaced. The details for the handling of missing 
data due to patients who discontinue the study and study medication are described in Section 6.5.   
6.5. 
Data Handling Convention for Missing Data 
For the primary and secondary efficacy variables, missing observations will be dealt with as 
described in the efficacy analysis (Section 5.6) based on the analysis being performed. 
Pretreatment/concomitant medication 
For the tabulation of prior and concomitant medication, partially missing start dates of the 
medication will be imputed by the earliest possible time point, partially missing stop dates will 
be imputed by the latest possible time point. 
Adverse event 
It is important to determine whether AEs started during the on-treatment period. AEs with partial 
start dates will be imputed based on the following rules: 
1. If AE partial start date indicates it is before the first dose of study drug, then it will be 
imputed as the latest possible date 
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2. If AE partial start date has the same partial date as the first dose of study drug, then it will 
be imputed as the date of the first dose of study drug  
3. If AE partial start date indicates it is after the first dose of study drug, then it will be 
imputed as the earliest possible date.  
4. If imputed AE start date is later than AE end date, then impute the AE start date to AE 
end date. 
 
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7. 
INTERIM ANALYSIS 
No formal interim analyses will be performed. 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.  
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 (or higher) or R version 3.5.1 (or higher). 
 
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9. 
REFERENCES 
1. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. 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. 
3. Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine. 2009;28:586–604 
4. 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. 
5. Huque M, Mushti S, Alosh M. Recycling of Significance Levels in Testing Multiple 
Hypotheses of Confirmatory Clinical Trials. In Biopharmaceutical Applied Statistics 
Symposium. Singapore: Springer; 2018:91-118. 
6. 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. 
7. ICH E9 (R1) (2017) Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials 
8. Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ, 'Categorical Data Analysis' in 
Statistical methodology in the pharmaceutical sciences / edited by DA Berry, Marcel 
Dekker, 1990 
9. Rubin D E. Multiple Imputation for Nonresponse in Surveys. Wiley. 1987 
 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Change from 
baseline in BCVA 
at Week 48 
FAS, PPS 
Non-
inferiority of 
HDq12 vs 
2q8 and non-
inferiority of 
HDq16 vs 
2q8 in FAS 
MMRM 
LOCF 
ANCOVA: 
MI with 
ANCOVA, 
tipping 
point 
analysis 
Yes, for 
subgroups sex, 
age, race, 
ethnicity, 
geographic 
region, baseline 
BCVA 
category, 
baseline CRT 
category, prior 
DME treatment 
 
 
 
Superiority 
of HDq12 
vs 2q8 and 
superiority 
of HDq16 
vs 2q8 
Secondary Endpoints 
Change from 
baseline in BCVA 
at Week 60 
FAS, PPS 
Non-
inferiority of 
HDq12 vs 
2q8 and non-
inferiority of 
HDq16 vs 
2q8 in FAS 
MMRM 
Non-
inferiority in 
PPS; LOCF 
ANCOVA: 
MI with 
ANCOVA 
Yes, for 
subgroups sex, 
age, race, 
ethnicity, 
geographic 
region, baseline 
BCVA 
category, 
baseline CRT 
category, prior 
DME treatment 
Superiority 
of HDq12 
vs 2q8 and 
superiority 
of HDq16 
vs 2q8 
Proportion of 
patients with a ≥2 
step improvement 
in DRSS at week 
48 
FAS 
Non-
inferiority of 
HDq12 vs 
2q8 and non-
inferiority of 
HDq16 vs 
2q8 in FAS 
CMH test 
with LOCF 
OC  
Yes, for 
subgroups sex, 
age, race, 
ethnicity, 
geographic 
region, baseline 
BCVA 
category, 
baseline CRT 
category, prior 
DME treatment 
No 
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Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
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Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Proportion of 
patients gaining ≥ 
15 letters in 
BCVA from 
baseline at week 
48 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
CMH test 
with LOCF 
OC 
No 
No 
Proportion of 
patients with 
BCVA ≥ 69 
letters at week 48 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
CMH test 
with LOCF 
OC 
No 
No 
Change from 
baseline in CRT at 
week 48 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
MMRM 
No 
No 
No 
Proportion of 
patients without 
leakage on FA at 
week 48 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
CMH test 
with LOCF 
No 
No 
No 
Change from 
baseline in NEI- 
VFQ total score at 
week 48 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
MMRM 
No 
No 
No 
Proportion of 
patients without 
retinal fluid (total 
fluid, IRF, and/or 
SRF) at the foveal 
center and in 
center subfield at 
week 48, 60, and 
96 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
CMH test 
with LOCF 
No 
No 
No 
Time to fluid-free 
retina over 48, 60, 
and 96 weeks 
(total fluid, IRF 
and/or SRF at 
foveal center and 
in the center 
subfield) 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
Kaplan-
Meier 
No 
No 
No 
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Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 49 of 95 
Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Proportion of 
patients with 
sustained fluid-
free retina over 
48, 60, and 96 
weeks (total fluid, 
IRF and/or SRF at 
foveal center and 
in the center 
subfield) 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
CMH test 
with LOCF 
No 
No 
No 
Time to sustained 
fluid-free retina 
over 48, 60, and 
96 weeks (total 
fluid, IRF and/or 
SRF at foveal 
center and in the 
center subfield) 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
Kaplan-
Meier 
No 
No 
No 
Proportion of 
patients without 
CSME at week 
48, 60, and 96 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
CMH test 
with LOCF 
No 
No 
No 
Proportion of 
patients with a ≥ 3 
step improvement 
in DRSS at week 
48, 60, and 96 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
CMH test 
with LOCF 
OC 
No 
No 
Proportions of 
patients gaining 
and losing ≥ 5 or 
≥ 10 letters at 
week 48, 60, and 
96 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
CMH test 
with LOCF 
OC 
No 
No 
Proportion of 
patients losing ≥ 
15 letters at week 
48, 60, and 96 
FAS 
HDq12 vs 
2q8 and 
HDq16 vs 
2q8 
CMH test 
with LOCF 
OC 
No 
No 
Proportion of 
patients 
randomized to 
HDq16 
maintaining q16 
dosing interval or 
longer through 
weeks 48, 60, and 
96 
FAS 
Descriptive 
Descriptive 
statistics 
No 
No 
No 
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Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 50 of 95 
Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Proportion of 
patients 
randomized to 
HDq12 
maintaining q12 
dosing interval or 
longer through 
weeks 48, 60 and 
96 
FAS 
Descriptive 
Descriptive 
statistics 
No 
No 
No 
Proportion of 
patients with an 
assigned injection 
interval of ≥16 or 
≥20 weeks based 
on assessment at 
the last injection 
visit 
FAS 
Descriptive 
Descriptive 
statistics 
No 
No 
No 
 
 
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Statistical Analysis Plan 
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CONFIDENTIAL 
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Safety Analyses: 
Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse 
events 
SAF 
Percent of 
patients by 
SOC and PT: 
Up to 
Week 48 
Up to 
Week 60 
Up to 
Week 96 
Descriptive 
statistics 
No 
Yes, for 
subgroups 
sex, age, 
race, 
ethnicity, 
geographic 
region 
(Note: only 
for Ocular 
TEAEs in 
study eye, 
non-ocular 
TEAEs, 
Serious 
ocular 
TEAEs in 
study eye, 
Serious non-
ocular 
TEAEs) 
Subset 
analysis in 
those 
patients who 
receive 
bilateral 
aflibercept 
treatment 
Overall 
summary, 
ocular TEAE 
in study eye, 
ocular TEAE 
in fellow eye, 
non-ocular 
TEAE, drug-
related AE, 
injection-
procedure-
related TEAE, 
study-
conduct-
related TEAE, 
2mg-
aflibercept-in-
the-fellow-
eye-related 
TEAE, TEAE 
leading to 
discontinuatio
n, SAEs, drug-
related SAEs, 
injection-
procedure-
related SAE, 
study-
conduct-
related SAE, 
2mg-
aflibercept-in-
the-fellow-
eye-related 
SAE, Deaths, 
APTC events, 
intraocular 
inflammation 
events, 
hypertension 
events, and 
nasal mucosa 
events 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


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Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 52 of 95 
Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Clinical 
laboratory 
measurement
s (chemistry, 
hematology, 
urinalysis, 
HbA1c) 
SAF 
Summary by 
visit including 
changes from 
baseline 
Descriptive 
statistics 
No 
No 
Shift tables, 
PCSV summary 
Vital signs 
(temperature, 
pulse, and 
blood 
pressure) 
SAF 
Summary by 
visit including 
changes from 
baseline 
Descriptive 
statistics 
No 
No 
No 
12-Lead ECG 
SAF 
Summary by 
visit including 
changes from 
baseline 
Descriptive 
statistics 
No 
No 
ECG status 
(normal/abnorm
al) by visit, shift 
tables of ECG 
status 
Intraocular 
pressure 
SAF 
Summary by 
visit including 
changes from 
baseline 
Descriptive 
statistics 
No 
No 
Proportions of 
patients with ≥ 
10 mmHg 
increase in IOP 
measurement 
from baseline to 
any pre-dose 
measurement, > 
21 mmHg for 
any pre-dose 
measurement, ≥ 
25 mmHg for 
any pre-dose 
measurement, ≥ 
35 mmHg at 
any time 
Surgical 
procedures 
SAF 
Ocular 
surgeries in the 
study eye, 
percent of 
patients by PT 
Descriptive 
statistics 
No 
No 
Ocular 
surgeries in the 
fellow eye, non-
ocular surgeries 
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Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 53 of 95 
10.2. 
Schedule of Time and Events 
10.2.1. 
Schedule of Time and Events (Main study) 
 
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Regeneron Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 54 of 95 
 
 
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Regeneron Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 55 of 95 
 
 
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Regeneron Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 56 of 95 
 
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Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
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Footnotes for the Schedule of Events 
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 timepoints 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 in protocol shows additional measurements for 
patients enrolled in the dense PK substudy. 
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Statistical Analysis Plan 
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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 in protocol.  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. 
10.2.2. 
Schedule of Time and Events (Dense PK substudy) 
 
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10.3. 
NEI-VFQ-25 Sub-scale Scores and Total Score 
The calculation for NEI-VFQ-25 sub-scale scores and total score will be performed according to 
The National Eye Institute (2000). The algorithm is then: As a preparation of the VFQ-25 
calculation, the items of the questionnaire will be recoded according to Table 3 . In the further 
calculations, only the recoded item values will be used. For the recoded values, they generally 
represent the best possible result as “100” and the worst possible result as “0”. 
Table 3: Recoding of NEI-VFQ 25 items 
Item no. 
Original response to 
Recoded item 
1, 3, 4, 15c(a) 
1 
100 
2 
75 
3 
50 
4 
25 
5 
0 
2 
1 
100  
2 
80 
3 
60 
4 
40 
5 
20 
6 
0 
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 
16, 16a 
1 
100 
2 
75 
3 
50 
4 
25 
5 
0 
6 
* 
17, 18, 19, 20, 21, 22, 23, 24, 25 1 
0 
2 
25 
3 
50 
4 
75 
5 
100 
(a) Item 15c has four-response levels but is expanded to a five-levels using item 15b: if 15b=”1”, then 
15c=”0” / if 15b=(”2” or “3”), then 15c=”missing” 
* Here, Response choice “6” indicates that the person does not perform the activity because of non-
vision-related problems. If this choice is selected, the item is coded as “missing”. 
For the VFQ questionnaire, 12 sub-scal. es will be evaluated (see Table 4), and 11 of these 
sub‑scales will be included in the total VFQ score. 
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CONFIDENTIAL 
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Table 4: Sub-scales of the NEI-VFQ 25 score 
Sub-scale no. 
Sub-scale 
Number of 
items 
(Recoded) 
items to be 
averaged 
Sub-scale included 
in total scale 
1 
General Health 
1 
1 
No 
2 
General Vision 
1 
2 
Yes 
3 
Ocular Pain 
2 
4, 19 
Yes 
4 
Near Activities 
3 
5, 6, 7 
Yes 
5 
Distance Activities 
3 
8, 9, 14 
Yes 
Vision specific: 
6 
Social Functioning 2 
11, 13 
Yes 
7 
Mental Health 
4 
3, 21, 22, 25 
Yes 
8 
Role Difficulties 
2 
17, 18 
Yes 
9 
Dependency 
3 
20, 23, 24 
Yes 
10 
Driving 
3 
15c, 16, 16a 
Yes 
11 
Color vision 
1 
12 
Yes 
12 
Peripheral Vision 
1 
10 
Yes 
For a single sub-scale, the value will be determined as the average of the non-missing recoded 
item values assigned to this sub-scale. A sub-scale value will only be assessed as missing if all 
items for this sub-scale have “missing” as a result.  
The total score is calculated as the arithmetic mean of all non-missing sub-scales (except General 
Health): 
𝑡𝑜𝑡𝑎𝑙 𝑟𝑒𝑠𝑢𝑙𝑡=
(𝑠𝑢𝑚 𝑜𝑓 𝑛𝑜𝑛 −𝑚𝑖𝑠𝑠𝑖𝑛𝑔 𝑠𝑢𝑏− 𝑠𝑐𝑎𝑙𝑒 𝑣𝑎𝑙𝑢𝑒𝑠)
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏− 𝑠𝑐𝑎𝑙𝑒𝑠 𝑤𝑖𝑡ℎ 𝑛𝑜𝑛 −𝑚𝑖𝑠𝑠𝑖𝑛𝑔 𝑟𝑒𝑠𝑢𝑙𝑡 
Due to this calculation approach, the total result will be non-missing if at least one sub-scale 
result is non-missing. 
10.4. 
Detailed Definitions of Special AE Categories and Medical History 
Subgroups 
Prior to database lock these preferred terms will be updated as necessary based on the current 
MedDRA version. 
10.4.1. 
Medical history and AE grouping of hypertension 
Preferred term 
Accelerated hypertension 
Blood pressure ambulatory increased 
Blood pressure diastolic increased 
Blood pressure inadequately controlled 
Blood pressure increased 
Blood pressure systolic increased 
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Statistical Analysis Plan 
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CONFIDENTIAL 
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Preferred term 
Diastolic hypertension 
Endocrine hypertension 
Essential hypertension 
Hypertension 
Hypertension neonatal 
Hypertensive angiopathy 
Hypertensive cardiomegaly 
Hypertensive cardiomyopathy 
Hypertensive cerebrovascular disease 
Hypertensive crisis 
Hypertensive emergency 
Hypertensive encephalopathy 
Hypertensive end-organ damage 
Hypertensive heart disease 
Hypertensive nephropathy 
Hypertensive urgency 
Labile hypertension 
Malignant hypertension 
Malignant hypertensive heart disease 
Malignant renal hypertension 
Maternal hypertension affecting foetus 
Mean arterial pressure increased 
Neurogenic hypertension 
Orthostatic hypertension 
Page kidney 
Prehypertension 
Renal hypertension 
Renovascular hypertension 
Retinopathy hypertensive 
Supine hypertension 
Systolic hypertension 
White coat hypertension 
 
 
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10.4.2. 
AE grouping of intraocular inflammation  
Preferred term 
Anterior chamber cell 
Anterior chamber fibrin 
Anterior chamber flare 
Anterior chamber inflammation 
Aqueous fibrin 
Autoimmune uveitis 
Candida endophthalmitis 
Chorioretinitis 
Choroiditis 
Cyclitis 
Endophthalmitis 
Eye infection 
Eye infection bacterial 
Eye infection chlamydial 
Eye infection fungal 
Eye infection intraocular 
Eye infection staphylococcal 
Eye inflammation 
Hypopyon 
Infectious iridocyclitis 
Infective iritis 
Infective uveitis 
Iridocyclitis 
Iritis 
Mycotic endophthalmitis 
Necrotising retinitis 
Non-infectious endophthalmitis 
Noninfective chorioretinitis 
Pseudoendophthalmitis 
Uveitis 
Vitreal cells 
Vitreous fibrin 
Vitritis 
 
 
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Statistical Analysis Plan 
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CONFIDENTIAL 
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10.4.3. 
AE grouping of nasal mucosal events 
Preferred term 
Epistaxis 
Nasal inflammation 
Nasal mucosal erosion 
Nasal mucosal ulcer 
Nasal ulcer 
10.4.4. 
Medical history of renal impairment 
Renal impairment is defined by CRCL values. 
Categories for renal impairment: 
• CLCR >80ml/min (normal), 
• CLCR >50-80ml/min (mild), 
• CLCR >30-50 ml/min (moderate), 
• CLCR <=30ml/min or ‘requiring dialysis’ (severe) 
CLCR will be calculated using baseline values (creatinine, age, weight, sex) using the 
Cockcroft-Gault equation: 
Males:  
CLCR = (140-age)*body weight / (72*creatinine in mg/dL)  
Females: 
CLCR = (140-age)*body weight*0.85 / (72*creatinine in mg/dL) 
‘Requiring dialysis’ is defined by PT in medical history 
Preferred Term 
Continuous haemodiafiltration 
Dialysis 
Dialysis device insertion 
Haemodialysis 
Haemofiltration 
Peritoneal dialysis 
Removal of renal transplant 
Renal replacement therapy 
Renal transplant 
 
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10.4.5. 
Medical history of hepatic impairment 
Preferred term 
5'nucleotidase increased 
AST to platelet ratio index increased 
AST/ALT ratio abnormal 
Accessory liver lobe 
Acquired antithrombin III deficiency 
Acquired factor IX deficiency 
Acquired factor V deficiency 
Acquired factor VIII deficiency 
Acquired factor XI deficiency 
Acquired hepatocerebral degeneration 
Acquired protein S deficiency 
Acute graft versus host disease in liver 
Acute hepatic failure 
Acute hepatitis B 
Acute hepatitis C 
Acute on chronic liver failure 
Acute yellow liver atrophy 
Adenoviral hepatitis 
Alagille syndrome 
Alanine aminotransferase abnormal 
Alanine aminotransferase increased 
Alcoholic encephalopathy 
Alcoholic liver disease 
Allergic hepatitis 
Alloimmune hepatitis 
Ammonia abnormal 
Ammonia increased 
Anorectal varices 
Anorectal varices haemorrhage 
Anti factor X activity abnormal 
Anti factor X activity decreased 
Anti factor X activity increased 
Anti-liver cytosol antibody type 1 positive 
Antithrombin III decreased 
Ascites 
Aspartate aminotransferase abnormal 
Aspartate aminotransferase increased 
Asterixis 
Asymptomatic viral hepatitis 
Autoimmune hepatitis 
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Preferred term 
Bacterascites 
Benign hepatic neoplasm 
Benign hepatobiliary neoplasm 
Benign recurrent intrahepatic cholestasis 
Bile output abnormal 
Bile output decreased 
Biliary ascites 
Biliary cirrhosis 
Biliary fibrosis 
Bilirubin conjugated abnormal 
Bilirubin conjugated increased 
Bilirubin excretion disorder 
Bilirubin urine present 
Biopsy liver abnormal 
Blood alkaline phosphatase abnormal 
Blood alkaline phosphatase increased 
Blood bilirubin abnormal 
Blood bilirubin increased 
Blood bilirubin unconjugated increased 
Blood cholinesterase abnormal 
Blood cholinesterase decreased 
Blood fibrinogen abnormal 
Blood fibrinogen decreased 
Blood thrombin abnormal 
Blood thrombin decreased 
Blood thromboplastin abnormal 
Blood thromboplastin decreased 
Bromosulphthalein test abnormal 
Cardiohepatic syndrome 
Cerebrohepatorenal syndrome 
Child-Pugh-Turcotte score abnormal 
Child-Pugh-Turcotte score increased 
Cholaemia 
Cholangiosarcoma 
Cholestasis 
Cholestatic liver injury 
Cholestatic pruritus 
Chronic graft versus host disease in liver 
Chronic hepatic failure 
Chronic hepatitis 
Chronic hepatitis B 
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Preferred term 
Chronic hepatitis C 
Cirrhosis alcoholic 
Coagulation factor IX level abnormal 
Coagulation factor IX level decreased 
Coagulation factor V level abnormal 
Coagulation factor V level decreased 
Coagulation factor VII level abnormal 
Coagulation factor VII level decreased 
Coagulation factor X level abnormal 
Coagulation factor X level decreased 
Coagulation factor decreased 
Coma hepatic 
Complications of transplanted liver 
Computerised tomogram liver abnormal 
Congenital absence of bile ducts 
Congenital hepatic fibrosis 
Congenital hepatitis B infection 
Congenital hepatitis C infection 
Congenital hepatobiliary anomaly 
Congenital hepatomegaly 
Congenital viral hepatitis 
Congestive hepatopathy 
Cryptogenic cirrhosis 
Cystic fibrosis hepatic disease 
Cytokeratin 18 increased 
Cytomegalovirus hepatitis 
Deficiency of bile secretion 
Diabetic hepatopathy 
Dilatation intrahepatic duct congenital 
Drug-induced liver injury 
Duodenal varices 
Fatty liver alcoholic 
Flood syndrome 
Focal nodular hyperplasia 
Foetor hepaticus 
Galactose elimination capacity test abnormal 
Galactose elimination capacity test decreased 
Gallbladder varices 
Gamma-glutamyltransferase abnormal 
Gamma-glutamyltransferase increased 
Gastric variceal injection 
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Preferred term 
Gastric variceal ligation 
Gastric varices 
Gastric varices haemorrhage 
Gastrooesophageal variceal haemorrhage prophylaxis 
Gianotti-Crosti syndrome 
Glutamate dehydrogenase increased 
Glycocholic acid increased 
Glycogen storage disease type I 
Glycogen storage disease type III 
Glycogen storage disease type IV 
Glycogen storage disease type VI 
Graft versus host disease in liver 
Granulomatous liver disease 
Guanase increased 
HBV-DNA polymerase increased 
Haemangioma of liver 
Haemorrhagic ascites 
Haemorrhagic hepatic cyst 
Hepaplastin abnormal 
Hepaplastin decreased 
Hepatectomy 
Hepatic adenoma 
Hepatic amoebiasis 
Hepatic angiosarcoma 
Hepatic artery flow decreased 
Hepatic atrophy 
Hepatic calcification 
Hepatic cancer 
Hepatic cancer metastatic 
Hepatic cancer recurrent 
Hepatic cancer stage I 
Hepatic cancer stage II 
Hepatic cancer stage III 
Hepatic cancer stage IV 
Hepatic candidiasis 
Hepatic cirrhosis 
Hepatic cyst 
Hepatic cyst infection 
Hepatic cyst ruptured 
Hepatic cytolysis 
Hepatic echinococciasis 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 68 of 95 
Preferred term 
Hepatic encephalopathy 
Hepatic encephalopathy prophylaxis 
Hepatic enzyme abnormal 
Hepatic enzyme decreased 
Hepatic enzyme increased 
Hepatic failure 
Hepatic fibrosis 
Hepatic fibrosis marker abnormal 
Hepatic fibrosis marker increased 
Hepatic function abnormal 
Hepatic gas gangrene 
Hepatic haemangioma rupture 
Hepatic hamartoma 
Hepatic hydrothorax 
Hepatic hypertrophy 
Hepatic hypoperfusion 
Hepatic infection 
Hepatic infection bacterial 
Hepatic infection fungal 
Hepatic infection helminthic 
Hepatic infiltration eosinophilic 
Hepatic lesion 
Hepatic lipoma 
Hepatic lymphocytic infiltration 
Hepatic mass 
Hepatic necrosis 
Hepatic neoplasm 
Hepatic neuroendocrine tumour 
Hepatic pain 
Hepatic perfusion disorder 
Hepatic sarcoma 
Hepatic sequestration 
Hepatic steato-fibrosis 
Hepatic steatosis 
Hepatic vascular resistance increased 
Hepatic venous pressure gradient abnormal 
Hepatic venous pressure gradient increased 
Hepatitis 
Hepatitis A 
Hepatitis A antibody abnormal 
Hepatitis A antibody positive 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 69 of 95 
Preferred term 
Hepatitis A antigen positive 
Hepatitis A immunity confirmed 
Hepatitis A virus test positive 
Hepatitis B 
Hepatitis B DNA assay positive 
Hepatitis B DNA increased 
Hepatitis B antibody abnormal 
Hepatitis B antibody positive 
Hepatitis B antigen positive 
Hepatitis B core antibody positive 
Hepatitis B core antigen positive 
Hepatitis B e antibody positive 
Hepatitis B e antigen positive 
Hepatitis B immunity confirmed 
Hepatitis B reactivation 
Hepatitis B surface antibody positive 
Hepatitis B surface antigen positive 
Hepatitis B virus test positive 
Hepatitis C 
Hepatitis C RNA increased 
Hepatitis C RNA positive 
Hepatitis C antibody positive 
Hepatitis C core antibody positive 
Hepatitis C virus test positive 
Hepatitis D 
Hepatitis D RNA positive 
Hepatitis D antibody positive 
Hepatitis D antigen positive 
Hepatitis D virus test positive 
Hepatitis E 
Hepatitis E RNA positive 
Hepatitis E antibody abnormal 
Hepatitis E antibody positive 
Hepatitis E antigen positive 
Hepatitis E immunity confirmed 
Hepatitis E virus test positive 
Hepatitis F 
Hepatitis G 
Hepatitis H 
Hepatitis acute 
Hepatitis alcoholic 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 70 of 95 
Preferred term 
Hepatitis cholestatic 
Hepatitis chronic active 
Hepatitis chronic persistent 
Hepatitis fulminant 
Hepatitis infectious mononucleosis 
Hepatitis mumps 
Hepatitis neonatal 
Hepatitis non-A non-B 
Hepatitis non-A non-B non-C 
Hepatitis post transfusion 
Hepatitis syphilitic 
Hepatitis toxic 
Hepatitis toxoplasmal 
Hepatitis viral 
Hepatitis viral test positive 
Hepato-lenticular degeneration 
Hepatobiliary cancer 
Hepatobiliary cancer in situ 
Hepatobiliary cyst 
Hepatobiliary disease 
Hepatobiliary infection 
Hepatobiliary neoplasm 
Hepatobiliary scan abnormal 
Hepatoblastoma 
Hepatoblastoma recurrent 
Hepatocellular carcinoma 
Hepatocellular damage neonatal 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 
Hepatomegaly 
Hepatopulmonary syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Hepatosplenic abscess 
Hepatosplenic candidiasis 
Hepatosplenomegaly 
Hepatosplenomegaly neonatal 
Hepatotoxicity 
Hereditary haemochromatosis 
Herpes simplex hepatitis 
Hyperammonaemia 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 71 of 95 
Preferred term 
Hyperbilirubinaemia 
Hyperbilirubinaemia neonatal 
Hypercholia 
Hyperfibrinolysis 
Hypertransaminasaemia 
Hypoalbuminaemia 
Hypocoagulable state 
Hypofibrinogenaemia 
Hypoprothrombinaemia 
Hypothrombinaemia 
Hypothromboplastinaemia 
Icterus index increased 
Immune-mediated cholangitis 
Immune-mediated hepatic disorder 
Immune-mediated hepatitis 
Increased liver stiffness 
International normalised ratio abnormal 
International normalised ratio increased 
Intestinal varices 
Intestinal varices haemorrhage 
Intrahepatic portal hepatic venous fistula 
Ischaemic hepatitis 
Jaundice 
Jaundice cholestatic 
Jaundice hepatocellular 
Jaundice neonatal 
Kayser-Fleischer ring 
Kernicterus 
Leucine aminopeptidase increased 
Liver abscess 
Liver and pancreas transplant rejection 
Liver carcinoma ruptured 
Liver dialysis 
Liver disorder 
Liver function test abnormal 
Liver function test decreased 
Liver function test increased 
Liver induration 
Liver injury 
Liver iron concentration abnormal 
Liver iron concentration increased 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 72 of 95 
Preferred term 
Liver opacity 
Liver operation 
Liver palpable 
Liver sarcoidosis 
Liver scan abnormal 
Liver tenderness 
Liver transplant 
Liver transplant failure 
Liver transplant rejection 
Liver-kidney microsomal antibody positive 
Lupoid hepatic cirrhosis 
Lupus hepatitis 
Magnetic resonance imaging hepatobiliary abnormal 
Magnetic resonance proton density fat fraction measurement 
Mitochondrial aspartate aminotransferase increased 
Mixed hepatocellular cholangiocarcinoma 
Mixed liver injury 
Model for end stage liver disease score abnormal 
Model for end stage liver disease score increased 
Molar ratio of total branched-chain amino acid to tyrosine 
Multivisceral transplantation 
Necrolytic acral erythema 
Neonatal cholestasis 
Neonatal hepatomegaly 
Nodular regenerative hyperplasia 
Non-alcoholic fatty liver 
Non-alcoholic steatohepatitis 
Non-cirrhotic portal hypertension 
Ocular icterus 
Oedema due to hepatic disease 
Oesophageal varices haemorrhage 
Omental oedema 
Osteopontin increased 
Parenteral nutrition associated liver disease 
Perihepatic discomfort 
Perinatal HBV infection 
Peripancreatic varices 
Periportal oedema 
Peritoneal fluid protein abnormal 
Peritoneal fluid protein decreased 
Peritoneal fluid protein increased 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 73 of 95 
Preferred term 
Peritoneovenous shunt 
Pneumobilia 
Polycystic liver disease 
Porphyria acute 
Porphyria non-acute 
Portal fibrosis 
Portal hypertension 
Portal hypertensive colopathy 
Portal hypertensive enteropathy 
Portal hypertensive gastropathy 
Portal pyaemia 
Portal shunt 
Portal shunt procedure 
Portal tract inflammation 
Portal vein cavernous transformation 
Portal vein dilatation 
Portal vein flow decreased 
Portal vein pressure increased 
Portal venous system anomaly 
Portopulmonary hypertension 
Primary biliary cholangitis 
Progressive familial intrahepatic cholestasis 
Protein C decreased 
Protein S abnormal 
Protein S decreased 
Prothrombin level abnormal 
Prothrombin level decreased 
Prothrombin time abnormal 
Prothrombin time prolonged 
Prothrombin time ratio abnormal 
Prothrombin time ratio increased 
Radiation hepatitis 
Regenerative siderotic hepatic nodule 
Renal and liver transplant 
Retinol binding protein decreased 
Retrograde portal vein flow 
Reye's syndrome 
Reynold's syndrome 
Schistosomiasis liver 
Small-for-size liver syndrome 
Spider naevus 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 74 of 95 
Preferred term 
Splenic artery embolisation 
Splenic varices 
Splenic varices haemorrhage 
Splenorenal shunt 
Splenorenal shunt procedure 
Spontaneous bacterial peritonitis 
Spontaneous intrahepatic portosystemic venous shunt 
Steatohepatitis 
Stomal varices 
Subacute hepatic failure 
Sugiura procedure 
Sustained viral response 
Thrombin time abnormal 
Thrombin time prolonged 
Total bile acids increased 
Transaminases abnormal 
Transaminases increased 
Ultrasound liver abnormal 
Urine bilirubin increased 
Urobilinogen urine decreased 
Urobilinogen urine increased 
Varices oesophageal 
Varicose veins of abdominal wall 
Viral hepatitis carrier 
Weil's disease 
White nipple sign 
Withdrawal hepatitis 
X-ray hepatobiliary abnormal 
Yellow skin 
Zieve syndrome 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 75 of 95 
10.4.6. 
Medical history of cerebrovascular disease 
Preferred term 
Agnosia 
Amaurosis fugax 
Amyloid related imaging abnormalities 
Amyloid related imaging abnormality-microhaemorrhages 
and haemosiderin deposits 
Amyloid related imaging abnormality-oedema/effusion 
Angiogram cerebral abnormal 
Aphasia 
Balint's syndrome 
Basal ganglia haematoma 
Basal ganglia haemorrhage 
Basal ganglia infarction 
Basal ganglia stroke 
Basilar artery aneurysm 
Basilar artery occlusion 
Basilar artery perforation 
Basilar artery stenosis 
Basilar artery thrombosis 
Benedikt's syndrome 
Blood brain barrier defect 
Brachiocephalic arteriosclerosis 
Brachiocephalic artery occlusion 
Brachiocephalic artery stenosis 
Brain hypoxia 
Brain injury 
Brain stem embolism 
Brain stem haematoma 
Brain stem haemorrhage 
Brain stem infarction 
Brain stem ischaemia 
Brain stem microhaemorrhage 
Brain stem stroke 
Brain stem thrombosis 
Brain stent insertion 
CADASIL 
CARASIL syndrome 
CSF bilirubin positive 
CSF red blood cell count positive 
Capsular warning syndrome 
Carotid aneurysm rupture 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 76 of 95 
Preferred term 
Carotid angioplasty 
Carotid arterial embolus 
Carotid arteriosclerosis 
Carotid artery aneurysm 
Carotid artery bypass 
Carotid artery disease 
Carotid artery dissection 
Carotid artery dolichoectasia 
Carotid artery insufficiency 
Carotid artery occlusion 
Carotid artery perforation 
Carotid artery restenosis 
Carotid artery stenosis 
Carotid artery stent insertion 
Carotid artery stent removal 
Carotid artery thrombosis 
Carotid endarterectomy 
Carotid revascularisation 
Central nervous system haemorrhage 
Central nervous system vasculitis 
Central pain syndrome 
Cerebellar artery occlusion 
Cerebellar artery thrombosis 
Cerebellar atherosclerosis 
Cerebellar embolism 
Cerebellar haematoma 
Cerebellar haemorrhage 
Cerebellar infarction 
Cerebellar ischaemia 
Cerebellar microhaemorrhage 
Cerebellar stroke 
Cerebral amyloid angiopathy 
Cerebral aneurysm perforation 
Cerebral aneurysm ruptured syphilitic 
Cerebral arteriosclerosis 
Cerebral arteriovenous malformation haemorrhagic 
Cerebral arteritis 
Cerebral artery embolism 
Cerebral artery occlusion 
Cerebral artery perforation 
Cerebral artery restenosis 
Cerebral artery stenosis 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 77 of 95 
Preferred term 
Cerebral artery stent insertion 
Cerebral artery thrombosis 
Cerebral capillary telangiectasia 
Cerebral cavernous malformation 
Cerebral circulatory failure 
Cerebral congestion 
Cerebral cyst haemorrhage 
Cerebral endovascular aneurysm repair 
Cerebral gas embolism 
Cerebral haematoma 
Cerebral haemorrhage 
Cerebral haemorrhage foetal 
Cerebral haemorrhage neonatal 
Cerebral haemosiderin deposition 
Cerebral hypoperfusion 
Cerebral infarction 
Cerebral infarction foetal 
Cerebral ischaemia 
Cerebral microangiopathy 
Cerebral microembolism 
Cerebral microhaemorrhage 
Cerebral microinfarction 
Cerebral reperfusion injury 
Cerebral revascularisation 
Cerebral septic infarct 
Cerebral small vessel ischaemic disease 
Cerebral thrombosis 
Cerebral vascular occlusion 
Cerebral vasoconstriction 
Cerebral venous sinus thrombosis 
Cerebral venous thrombosis 
Cerebral ventricular rupture 
Cerebrovascular accident 
Cerebrovascular accident prophylaxis 
Cerebrovascular arteriovenous malformation 
Cerebrovascular disorder 
Cerebrovascular insufficiency 
Cerebrovascular pseudoaneurysm 
Cerebrovascular stenosis 
Charcot-Bouchard microaneurysms 
Chronic cerebrospinal venous insufficiency 
Claude's syndrome 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 78 of 95 
Preferred term 
Congenital cerebrovascular anomaly 
Congenital hemiparesis 
Delayed ischaemic neurological deficit 
Diplegia 
Dural arteriovenous fistula 
Dysarthria 
Embolic cerebellar infarction 
Embolic cerebral infarction 
Embolic stroke 
Epidural haemorrhage 
Extra-axial haemorrhage 
Extradural haematoma 
Extradural haematoma evacuation 
Extraischaemic cerebral haematoma 
Foetal cerebrovascular disorder 
Foville syndrome 
Haemorrhage intracranial 
Haemorrhagic cerebellar infarction 
Haemorrhagic cerebral infarction 
Haemorrhagic stroke 
Haemorrhagic transformation stroke 
Heidelberg classification 
Hemianaesthesia 
Hemiasomatognosia 
Hemiataxia 
Hemidysaesthesia 
Hemihyperaesthesia 
Hemihypoaesthesia 
Hemiparaesthesia 
Hemiparesis 
Hemiplegia 
Hunt and Hess scale 
Hypertensive cerebrovascular disease 
Hypoxic-ischaemic encephalopathy 
Inner ear infarction 
Internal capsule infarction 
Internal carotid artery deformity 
Intra-cerebral aneurysm operation 
Intracerebral haematoma evacuation 
Intracranial aneurysm 
Intracranial artery dissection 
Intracranial haematoma 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 79 of 95 
Preferred term 
Intracranial haemorrhage neonatal 
Intracranial tumour haemorrhage 
Intraventricular haemorrhage 
Intraventricular haemorrhage neonatal 
Ischaemic cerebral infarction 
Ischaemic stroke 
Lacunar infarction 
Lacunar stroke 
Lateral medullary syndrome 
Lateropulsion 
Malignant middle cerebral artery syndrome 
Medullary compression syndrome 
Meningorrhagia 
Metabolic stroke 
Migrainous infarction 
Millard-Gubler syndrome 
Modified Rankin score decreased 
Modified Rankin score increased 
Monoparesis 
Monoplegia 
Moyamoya disease 
NIH stroke scale abnormal 
NIH stroke scale score decreased 
NIH stroke scale score increased 
Paralysis 
Paraparesis 
Paraplegia 
Paresis 
Perinatal stroke 
Periventricular haemorrhage neonatal 
Pituitary apoplexy 
Pituitary haemorrhage 
Post cardiac arrest syndrome 
Post procedural stroke 
Post stroke depression 
Posthaemorrhagic hydrocephalus 
Precerebral arteriosclerosis 
Precerebral artery aneurysm 
Precerebral artery dissection 
Precerebral artery embolism 
Precerebral artery occlusion 
Precerebral artery thrombosis 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 80 of 95 
Preferred term 
Primary familial brain calcification 
Pseudo-occlusion of internal carotid artery 
Putamen haemorrhage 
Quadriparesis 
Quadriplegia 
Reversible cerebral vasoconstriction syndrome 
Reversible ischaemic neurological deficit 
Right hemisphere deficit syndrome 
Ruptured cerebral aneurysm 
Septic cerebral embolism 
Sigmoid sinus thrombosis 
Sneddon's syndrome 
Spinal artery embolism 
Spinal artery thrombosis 
Spinal cord haematoma 
Spinal cord haemorrhage 
Spinal cord infarction 
Spinal cord ischaemia 
Spinal epidural haematoma 
Spinal epidural haemorrhage 
Spinal stroke 
Spinal subarachnoid haemorrhage 
Spinal subdural haematoma 
Spinal subdural haemorrhage 
Spinal vascular disorder 
Spinal vessel congenital anomaly 
Stroke in evolution 
Subarachnoid haematoma 
Subarachnoid haemorrhage 
Subarachnoid haemorrhage neonatal 
Subclavian steal syndrome 
Subdural haematoma 
Subdural haematoma evacuation 
Subdural haemorrhage 
Subdural haemorrhage neonatal 
Superficial siderosis of central nervous system 
Superior sagittal sinus thrombosis 
Susac's syndrome 
Thalamic infarction 
Thalamus haemorrhage 
Thrombotic cerebral infarction 
Thrombotic stroke 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 81 of 95 
Preferred term 
Transient ischaemic attack 
Transverse sinus thrombosis 
Vascular encephalopathy 
Vascular stent occlusion 
Vascular stent stenosis 
Vein of Galen aneurysmal malformation 
Vertebral artery aneurysm 
Vertebral artery arteriosclerosis 
Vertebral artery dissection 
Vertebral artery occlusion 
Vertebral artery perforation 
Vertebral artery stenosis 
Vertebral artery thrombosis 
Vertebrobasilar dolichoectasia 
Vertebrobasilar insufficiency 
Vertebrobasilar stroke 
Visual agnosia 
Visual midline shift syndrome 
Weber's syndrome 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 82 of 95 
10.4.7. 
Medical history of ischemic heart disease 
Preferred term 
Acute coronary syndrome 
Acute myocardial infarction 
Angina pectoris 
Angina unstable 
Anginal equivalent 
Arterial revascularisation 
Arteriogram coronary abnormal 
Arteriosclerosis coronary artery 
Arteriospasm coronary 
Cardiac perfusion defect 
Cardiac ventricular scarring 
Chronic coronary syndrome 
Computerised tomogram coronary artery abnormal 
Coronary angioplasty 
Coronary arterial stent insertion 
Coronary artery bypass 
Coronary artery compression 
Coronary artery disease 
Coronary artery dissection 
Coronary artery embolism 
Coronary artery insufficiency 
Coronary artery occlusion 
Coronary artery reocclusion 
Coronary artery restenosis 
Coronary artery stenosis 
Coronary artery surgery 
Coronary artery thrombosis 
Coronary brachytherapy 
Coronary bypass stenosis 
Coronary bypass thrombosis 
Coronary endarterectomy 
Coronary no-reflow phenomenon 
Coronary ostial stenosis 
Coronary revascularisation 
Coronary steal syndrome 
Coronary vascular graft occlusion 
Coronary vascular graft stenosis 
ECG electrically inactive area 
ECG signs of myocardial infarction 
ECG signs of myocardial ischaemia 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 83 of 95 
Preferred term 
Electrocardiogram PR segment depression 
Electrocardiogram PR segment elevation 
Electrocardiogram ST segment abnormal 
Electrocardiogram ST segment depression 
Electrocardiogram ST segment elevation 
Electrocardiogram ST-T segment abnormal 
Electrocardiogram ST-T segment depression 
Electrocardiogram ST-T segment elevation 
External counterpulsation 
Haemorrhage coronary artery 
Infarction 
Ischaemic cardiomyopathy 
Ischaemic contracture of the left ventricle 
Kounis syndrome 
Myocardial hypoperfusion 
Myocardial hypoxia 
Myocardial infarction 
Myocardial ischaemia 
Myocardial necrosis 
Myocardial reperfusion injury 
Myocardial stunning 
Papillary muscle infarction 
Percutaneous coronary intervention 
Periprocedural myocardial infarction 
Positive vessel remodelling 
Post angioplasty restenosis 
Post procedural myocardial infarction 
Postinfarction angina 
Prinzmetal angina 
Scan myocardial perfusion abnormal 
Silent myocardial infarction 
Stent patency maintenance 
Stress cardiomyopathy 
Subclavian coronary steal syndrome 
Subendocardial ischaemia 
Vascular device occlusion 
Vascular graft occlusion 
Vascular graft restenosis 
Vascular graft stenosis 
Vascular graft thrombosis 
Vascular stent occlusion 
Vascular stent stenosis 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 84 of 95 
Preferred term 
Ventricular compliance decreased 
Wellens' syndrome 
 
10.5. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Table 5: Criteria for Potentially Clinically Significant Values 
Parameter 
Potentially clinically significant value (PCSV)  
Clinical Chemistry 
 
ALT 
> 3 ULN 
AST 
> 3 ULN 
Alkaline Phosphatase 
> 1.5 ULN 
Total Bilirubin 
> 1.5 ULN 
Conjugated Bilirubin 
> 35% Total Bilirubin (when Total Bilirubin >1.5 ULN) 
ALT and Total Bilirubin 
ALT > 3 ULN and Total Bilirubin > 2 ULN 
CPK 
> 3 ULN 
Creatinine 
 150 µmol/L (Adults) 
 30% from baseline 
Uric Acid 
Hyperuricemia: >408 µmol/L 
Hypouricemia: <120 µmol/L 
Blood Urea Nitrogen 
 17 mmol/L 
Chloride 
< 80 mmol/L 
> 115 mmol/L 
Sodium 
 129 mmol/L 
 160 mmol/L 
Potassium 
< 3 mmol/L 
 5.5 mmol/L 
Total Cholesterol 
 7.74 mmol/L (3 g/L) 
Triglycerides 
 4.6 mmol/L (4 g/L) 
Glucose 
- Hypoglycaemia 
- Hyperglycaemia 
 
 3.9 mmol/L and < LLN 
 11.1 mmol/L (unfasted),  7 mmol/L (fasted) 
HbA1c 
> 8 % 
Albumin 
 25 g/L 
Hematology 
 
WBC 
< 3.0 GIGA/L (non-Black), < 2.0 GIGA/L (Black),  16.0 
GIGA/L 
Lymphocytes 
> 4.0 GIGA/L 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 85 of 95 
Parameter 
Potentially clinically significant value (PCSV)  
Neutrophils 
< 1.5 GIGA/L (non-Black) 
< 1.0 GIGA/L (Black) 
Monocytes 
> 0.7 GIGA/L 
Basophils 
> 0.1 GIGA/L 
Eosinophils 
> 0.5 GIGA/L or 
> ULN if ULN  0.5 GIGA /L 
Hemoglobin 
Males : 115 g/L ( 7.14 mmol/L),  185 g/L (11.48 
mmol/L) 
Females :  95 g/L (5.9 mmol/L),  165 g/L (10.24 mmol/L) 
Decrease from Baseline  20 g/L (1.24 mmol/L) 
Hematocrit 
Males :  0.37 v/v,  0.55 v/v 
Females :  0.32 v/v,  0.5 v/v 
RBC 
 6 TERA/L 
Platelets 
< 100 GIGA/L 
Blood pressure 
 
Systolic BP  
≤ 95 mmHg and decrease from baseline ≥ 20 mmHg 
≥160 mmHg and increase from baseline ≥ 20 mmHg 
Diastolic BP 
≤ 45 mmHg and decrease from baseline ≥ 10 mmHg 
≥110 mmHg and increase from baseline ≥ 10 mmHg 
 
 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 86 of 95 
10.6. 
Process to Derive Week 48 Data Cut-off 
For week 48 evaluations, a strategy for performing the data cut-off for the clinical database was 
developed, as described in the following: 
10.6.1. 
Visit Independent Data 
Visit independent data (or event-based data) include adverse events, concomitant/prior 
medication, and surgeries. 
Patients that discontinued study prematurely before or at week 48 (Visit 14) 
These patients are defined as having their end of study CRF page filled, and have either: 
• a dropout date earlier or equal to date of first injection + 336 days + 5 days (to account 
for the visit window) or 
• a dropout date equal to week 48 visit date 
For such patients, all event-based records are kept in the clinical database for week 48 analysis 
without any change. 
Patients who stayed longer than week 48 (visit 14) in the study 
These patients are the patients who did not discontinue study prematurely at/before week 48 
(visit 14). Therefore, these patients are either: 
• still ongoing after week 48 (visit 14) 
• discontinued the study prematurely, but were in the study for longer than week 48 (visit 
14) 
For such patients, the following will be applied: 
All event records with a start date later than the date of the week 48 (visit 14) will be censored. 
This includes the case where the incomplete date is without any doubt later than the week 48 
visit date, eg, week 48 (visit 14) is 10 April 2020 and the incomplete date is May 2020 or only 
2021. If the week 48 visit date is missing, then the date of first injection + 336 days will be used 
instead. 
Records with a start date earlier or equal to the date of week 48 (first injection + 336 days if date 
of week 48 visit is missing) will be kept. This includes records with incomplete dates when the 
incomplete date is earlier than the week 48 date or in cases where it is not clear if the record 
occurred before or after week 48 (eg, week 48 [visit 14] is 10 April 2020 and the incomplete date 
is March 2020, April 2020 or only 2020 or even a missing date). If the date is incomplete, the 
following adaptions to the data will be made.  
Concomitant medication: 
If a stop date is reported which is earlier than the date of week 48 (visit 14) (first 
injection + 336 days if date of week 48 is missing), the record will not be changed. 
If a stop date is reported which is later than the date of week 48 (visit 14) (first 
injection + 336 days if date of week 48 is missing), the stop date will be set to missing and the 
variable CMONG will be set to 1 (yes). 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 87 of 95 
Adverse Events: 
AEs with a start date on or after the date of the week 48 (visit 14) will be censored. Cut-off date 
will be first injection + 336 days if date of week 48 is missing. 
If a stop date of adverse event is specified and earlier or equal to date of week 48 (visit 14) (first 
injection + 336 days if date of week 48 missing), then the record will not be changed. 
If a stop date of adverse event is specified and later than the date of week 48 (visit 14) (first 
injection + 336 days if date of week 48 is missing), then the stop date will be set to missing and 
the outcome of the adverse event (SAS variable AEOUT) will be set to missing. 
If no stop date is specified and the outcome is either not yet reported (AEOUT is blank) or is 
reported (AEOUT is 3 - recovering/resolving, 4 - not recovered/not resolved, 6 - unknown), then 
the outcome will be set to missing (AEOUT is blank). 
Surgeries: 
All surgeries with a date of surgery later than week 48 (visit 14) date will not be included in the 
analysis. Cut-off date will be first injection + 336 days if date of week 48 is missing. 
10.6.2. 
Study Medication Data 
Study medication data in the study eye up to week 44 (visit 13) will be kept for the week 48 
analysis. Study medication data in the fellow eye prior to week 48 (week 14) will be included for 
the week 48 analysis.   
10.6.3. 
Visit Dependent Data 
All visit dependent data up to week 48 (visit 14) will be kept for the week 48 analysis except for 
post-dose IOP at the week 48 visit. All visit dependent data later than week 48 (visit 14) will not 
be included for the week 48 analysis. Unscheduled visits with a date prior to the week 48 (visit 
14) visit date will be kept for the week 48 analysis. If a patient did not have a week 48 (visit 14) 
visit, unscheduled visit will be kept up to date of first injection + 336 days for the week 48 
analysis. 
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Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 88 of 95 
10.7. 
Process to Derive Week 60 Data Cut-off 
For week 60 evaluations, the same strategy for performing the data cut-off for the clinical 
database as described in Appendix 10.6 will be followed. Instead of “first injection + 336 days” 
for week 48, missing dates for week 60 will be imputed by first injection + 420 days. 
10.8. 
SAS Procedures 
10.8.1. 
MMRM 
 
PROC MIXED DATA = <data at Week48>; 
 
CLASS subjid trtpn avisitn basecrt pdme region; 
 
MODEL chg = base basecrt pdme region trtpn avisitn base*avisitn trtpn*avisitn /DDFM=kr; 
 
REPEATED avisitn / SUBJECT=subjid TYPE=un GROUP=trtpn; 
 
LSMESTIMATE trtpn*avisitn "HDq12 - 2q8 " XXX /  cl upper testvalue=-4;  
        *for non-inferiority test with margin = 4; 
LSMESTIMATE trtpn*avisitn "HDq16 - 2q8 " XXX /  cl upper testvalue=-4;  
        *for non-inferiority test with margin = 4; 
 
LSMESTIMATE trtpn*avisitn "HDq12 - 2q8 " XXX /  cl upper testvalue=0; 
        *for superiority test;  
 
LSMESTIMATE trtpn*avisitn "HDq16 - 2q8 " XXX /  cl upper testvalue=0; 
        *for superiority test;  
RUN; 
10.8.2. 
ANCOVA 
 
PROC MIXED DATA = <data until Week48>; 
 
CLASS trtpn basecrt pdme region ; 
 
MODEL chg = base basecrt pdme region trtpn; 
LSMESTIMATE trtpn "HDq12 - 2q8" xxx /cl upper testvalue=-4;  
*for non-inferiority test with margin = 4; 
LSMESTIMATE trtpn "HDq16 - 2q8" xxx /cl upper testvalue=-4;  
*for non-inferiority test with margin = 4; 
RUN; 
10.8.3. 
Multiple Imputation 
Step 1. Imputation: Impute missing value using MCMC method and subsequently impute 
missing data by a regression model. 
PROC MI DATA=<indata> SEED=01934 OUT=mi01 NIMPUTE=50; * seed = 01934;minimum = 0 0 0 0 0  
 
maximum = 100 100 100 100 100; * BCVA feasible range is 0 to 100; 
 
mcmc impute=monotone; 
 
VAR base v2 v3 v4 v5;  
RUN; 
 
PROC MI DATA=mi01 SEED=01934 out = full NIMPUTE=1; * seed = 01934; 
 
minimum = . . . . 0 0 0 0 0 0 
 
maximum = . . . . 100 100 100 100 100; 
       CLASS basecrt pdme region trtpn 
  
BY _imputation_; 
 
MONOTONE REG; 
 
VAR basecrt pdme region trtpn base v2 v3 v4 v5;  
RUN; 
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Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 89 of 95 
Step 2. Analysis: Each complete dataset is analyzed by ANCOVA model. 
PROC MIXED DATA = full; 
 
by _imputation_; 
 
CLASS trtpn basecrt pdme region; 
 
MODEL chg = base basecrt pdme region trtpn; 
LSMESTIMATE trtpn "HDq12 - 2q8" xxx /cl upper testvalue=-4;  
LSMESTIMATE trtpn "HDq16 - 2q8" xxx /cl upper testvalue=-4;  
 
ods output lsmestimates=lsme; 
RUN; 
Step 3. Pooling: The MIANALYZE procedure is used to combine results.  
PROC MIANALYZE DATA=lsme theta0=-4; 
 
by label; 
 
modeleffects estimate; 
 
stderr stderr; 
 
ods output parameterestimates=parameterest1 VarianceInfo=varinfo1; 
 
run; 
10.8.4. 
Tipping Point Analysis 
Step 1 to Step 3 below are repeated for a range of feasible &delta values. The tipping point will 
be determined as the &delta value for which the conclusion under MAR is reversed. 
Step 1. Imputation: Impute missing value using MCMC method and subsequently impute 
missing data by a regression model with MNAR adjustment. 
PROC MI DATA=<indata> SEED=01934 OUT=mi01 NIMPUTE=50; * seed = 01934;minimum = 0 0 0 0 0  
       maximum = 100 100 100 100 100; * BCVA feasible range is 0 to 100; 
       mcmc impute=monotone; 
       VAR base v2 v3 v4 v5;  
RUN; 
 
PROC MI DATA=mi01 SEED=01934 out = full NIMPUTE=1; * seed = 01934; 
       minimum = . . . . 0 0 0 0 0 0 
       maximum = . . . . 100 100 100 100 100; 
       CLASS basecrt pdme region trtpn 
      BY _imputation_; 
       MONOTONE REG; 
       MNAR ADJUST( v5 / SHIFT= &delta ADJUSTOBS=(TRT01PN ='HDq12') );* v5 is the outcome at the 
visits of interest, e.g. BCVA at week 48; 
       MNAR ADJUST( v5 / SHIFT= &delta ADJUSTOBS=(TRT01PN ='HDq16') ); 
       VAR basecrt pdme region trtpn base v2 v3 v4 v5;  
RUN; 
Step 2. Analysis: Each complete dataset with MNAR adjustment is analyzed by ANCOVA 
model. 
PROC MIXED DATA = full; 
       by _imputation_; 
       CLASS trtpn basecrt pdme region; 
       MODEL chg = base basecrt pdme region trtpn; 
LSMESTIMATE trtpn "HDq12 - 2q8" xxx /cl upper testvalue=-4;  
LSMESTIMATE trtpn "HDq16 - 2q8" xxx /cl upper testvalue=-4;  
       ods output lsmestimates=lsme; 
RUN; 
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Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 90 of 95 
Step 3. Pooling: The MIANALYZE procedure is used to combine results. 
PROC MIANALYZE DATA=lsme theta0=-4; 
       by label; 
       modeleffects estimate; 
       stderr stderr; 
       ods output parameterestimates=parameterest1 VarianceInfo=varinfo1; 
       run; 
 
 
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Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 91 of 95 
10.9. 
Additional Secondary Efficacy Variables and Analyses 
This section pre-specifies the statistical approaches for defining and analyzing additional 
secondary efficacy variables at week 48, for submission to the US FDA (based on the G-SAP 
that constitutes the primary analysis for the study). 
10.9.1. 
Analysis Populations 
The following populations of analysis will be used for the additional secondary efficacy 
analyses. 
10.9.1.1. Full Analysis Set (FAS) 
Refer to Section 3.1  
10.9.1.2. Modified Full Analysis Set (mFAS) 
The modified full analysis set 1 (mFAS1) includes all randomized patients who completed initial 
treatment phase and maintained their dosing interval (i.e., 
• maintained post 3-dose loading on a q12 interval for HDq12 group and never having 
their dosing interval shortened to less than q12w;  
• maintained post 3-dose loading on a q16 interval for the HDq16 group and never 
having their dosing interval shortened to less than q16w; and 
• all patients in the 2q8 group receive fixed q8 dosing).   
The modified full analysis set 2 (mFAS2) includes all randomized patients who completed initial 
treatment phase and maintained their dosing interval (i.e., 
• maintained post 3-dose loading for All HD group (pooled HDq12 and HDq16 groups) 
on either q12 or q16 interval and never having their dosing interval shortened to less 
than q12w; and 
• all patients in the 2q8 group receive fixed q8 dosing). 
Both analysis sets, mFAS1 and mFAS2, are based on the treatment assigned to the patient at 
baseline (as randomized).   
10.9.2. 
Additional Secondary Efficacy Variable(s) 
Additional secondary efficacy analyses will be conducted for the following variables: 
• Change from baseline in BCVA (as measured by ETDRS letter score) at week 48 
(previously defined primary efficacy variable; see Section 4.5.1) 
• Change from 8-weeks post initial treatment phase in BCVA (as measured by ETDRS 
letter score) at week 48 (additional secondary efficacy variable). 
Note that per the dosing schedule shown in Figure 2,  the initial treatment phase is through week 
8 (3 doses) for both HDq12 and HDq16 treatment groups, and through week 16 (5 doses) for the 
2q8 treatment group.  Hence 8-weeks post initial treatment phase is Week 16 for both HDq12 
and HDq16 treatment groups and Week 24 for the 2q8 treatment group. 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 92 of 95 
 
10.9.3. 
Additional Secondary Efficacy Analyses 
The additional secondary efficacy analyses will be an alternative tipping point analysis on the 
efficacy variables in Section 10.9.2. 
For analysis set (FAS and mFAS) and each variable, the following algorithm will be applied: 
1. Within each treatment group, for patients with data at both week 48 and at the designated 
baseline for the analysis, sort the patient level data for change in BCVA at week 48 from 
smallest to largest, e.g., ranging from -60, -59, …, -1, 0, +1, …to +50 ETDRS letter 
score.  Patients without data at both week 48 and designated baseline are removed from 
numerator and denominator calculations described below. 
2. For the analysis (sub)set, compare mean change in BCVA at week 48 between HDq12 
with the mean change in BCVA at week 48 for the 2q8 control group.   
3. If the mean change in BCVA for HDq12 group ≥ [mean change in BCVA for 2q8 group 
+ Δ] where Δ=0 or -2, then  
a. report the number, percentage of patients in the (sub)set relative to the original 
analysis set, and 2-sided 95% CI (continuity-corrected Wilson (score) method) for 
HDq12 group, 
b. report the tipping point value in the HDq12 group analysis subset that is the lowest 
letter change in BCVA, and  
c. stop. 
4. Otherwise, exclude patients with the next worst score in HDq12 group to obtain a new 
subset.  Retain original analysis set in 2q8 control group. Repeat steps 2 and 3, until 
stopping condition is reached or all patient level data is used in the HDq12 group.  
Repeat the above algorithm for HDq16 group and the All HD group. 
The above analyses specified for completers may also be repeated using the estimand framework 
(see Section 5.6). 
The reported results from these additional analyses will be as follows (see Table 6). 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 93 of 95 
Table 6: Additional Secondary Efficacy Analyses – Alternative Tipping Point Analyses 
 
Population Variable 
Analysis Results 
Δ 
Tipping 
Point in 
HD group 
1a FASa 
Change from 
baseline in 
BCVA at week 
48 
• Number and Percentage of patients in the 
HDq12 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
HDq16 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
All HD analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
0 
 
 
 
0 
 
 
 
0 
 
x1 letters 
 
 
 
y1 letters 
 
 
 
z1 letters 
1b FASa 
Change from 
baseline in 
BCVA at week 
48 
• Number and Percentage of patients in the 
HDq12 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
HDq16 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
All HD analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
-2 
 
 
 
-2 
 
 
 
-2 
x2 letters 
 
 
 
y2 letters 
 
 
 
z2 letters 
 
2a FASa 
Change from 
8-weeks post 
initial treatment 
in BCVA at 
week 48 
• Number and Percentage of patients in the 
HDq12 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
HDq16 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
All HD analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
0 
 
 
 
0 
 
 
 
0 
 
x3 letters 
 
 
 
y3 letters 
 
 
 
z3 letters 
                                        VV-RIM-00208112-1.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 94 of 95 
 
Population Variable 
Analysis Results 
Δ 
Tipping 
Point in 
HD group 
2b FASa 
Change from 
8-weeks post 
initial treatment 
in BCVA at 
week 48 
• Number and Percentage of patients in the 
HDq12 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
HDq16 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
All HD analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
-2 
 
 
 
-2 
 
 
 
-2 
x4 letters 
 
 
 
y4 letters 
 
 
 
z4 letters 
3a mFAS1b; 
mFAS2c 
Change from 
baseline in 
BCVA at week 
48 
• Number and Percentage of patients in the 
HDq12 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
HDq16 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
0 
 
 
 
0 
 
x5 letters 
 
 
 
y5 letters 
3b mFAS1b; 
mFAS2c 
Change from 
baseline in 
BCVA at week 
48 
• Number and Percentage of patients in the 
HDq12 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
HDq16 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
All HD analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
-2 
 
 
 
-2 
 
 
 
-2 
x6 letters 
 
 
 
y6 letters 
 
 
 
z6 letters 
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Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe-HD-DME-1934 
Statistical Analysis Plan 
Date: 19 AUGUST 2022 
 
CONFIDENTIAL 
Page 95 of 95 
 
Population Variable 
Analysis Results 
Δ 
Tipping 
Point in 
HD group 
4a mFAS1b; 
mFAS2c 
Change from 
8-weeks post 
initial treatment 
in BCVA at 
week 48 
• Number and Percentage of patients in the 
HDq12 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
HDq16 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
All HD analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
0 
 
 
 
0 
 
 
 
0 
 
x7 letters 
 
 
 
y7 letters 
 
 
 
z7 letters 
4b mFAS1b; 
mFAS2c 
Change from 
8-weeks post 
initial treatment 
in BCVA at 
week 48 
• Number and Percentage of patients in the 
HDq12 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
HDq16 analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
• Number and Percentage of patients in the 
All HD analysis subset for whom mean 
change in BCVA ≥ [mean change in 
BCVA for 2q8 group – Δ] 
-2 
 
 
 
-2 
 
 
 
-2 
x8 letters 
 
 
 
y8 letters 
 
 
 
z8 letters 
a FAS = Full Analysis Set, which includes all randomized patients who received at least 1 dose of study medication. 
b mFAS1 = Modified Full Analysis Set 1, which includes all randomized patients who completed the initial 
treatment phase and maintained dosing interval (HDq12, HDq16, and 2q8 groups). 
c mFAS2 = Modified Full Analysis Set 2, which includes all randomized patients who completed the initial 
treatment phase and maintained dosing interval (All HD group and 2q8 group). 
 
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