Clinical trial NCT04126317
Conditions: Neovascular (Wet) Age-Related Macular Degeneration
Sponsor: Regeneron Pharmaceuticals
Start date: 2019-11-04; Completion date: 2021-11-30
Enrollment: 106 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of the study are to determine the safety of high-dose aflibercept (hereafter referred to as HD) and to determine if HD provides greater intraocular pharmacodynamic (PD) effect and/or longer duration of action compared to intravitreal aflibercept injection (hereafter referred to as IAI).

Detailed description:

Arms: arm 1: Treatment-naïve patients with neovascular "wet" age-related macular degeneration (nAMD) randomized in a 1:1 ratio arm 2: Treatment-naïve patients with nAMD randomized in a 1:1 ratio
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 documents:
Prot_000.pdf: 
Clinical Study Protocol 
VGFTe (HD)-AMD-1905 Amendment 3 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 59 
CONFIDENTIAL 
IND Number:  12462 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, SINGLE-MASKED, ACTIVE-CONTROLLED 
PHASE 2 STUDY OF THE SAFETY, TOLERABILITY, AND EFFICACY 
OF REPEATED DOSES OF HIGH-DOSE AFLIBERCEPT IN PATIENTS 
WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION 
Compound: 
High Dose Aflibercept 
Clinical Phase: 
2 
Protocol Number: 
VGFTe (HD)-AMD-1905 
Protocol Version: 
VGFTe (HD)-AMD-1905 Amendment 3 
Amendment 3 Date of Issue: 
See appended electronic signature page 
Original Date of Issue: 
09 Aug 2019 
Amendment 1 Date of Issue: 
28 Feb 2020 
Amendment 2 Date of Issue 
01 Oct 2020 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
  
 
 
VV-RIM-00159203-1.0 Approved - 26 Jul 2021 GMT-5:00
NCT04126317


Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 2 of 59 
CONFIDENTIAL 
 
 
 
 
  
                                        VV-RIM-00159203-1.0 Approved - 26 Jul 2021 GMT-5:00


Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 3 of 59 
CONFIDENTIAL 
AMENDMENT HISTORY 
AMENDMENT 3 
The purpose of this amendment is to change the time point for evaluation of the primary endpoint 
(proportion of patients without retinal fluid in the center subfield) and certain exploratory 
endpoints from Week 20 to Week 16.  Week 16 is 8 weeks after the third initial loading dose in 
both treatment groups and represents the earliest timepoint to assess anatomic differences in 
treatment effect between 2 mg and 8 mg. Since some patients will receive additional dosing at 
Week 16 while others will not, 20 weeks is less ideal for understanding and comparing treatment 
effects.  This will allow a direct comparison of the 2 treatment groups prior to any 
Additional/Rescue treatment being administered which could potentially confound interpretation 
of the results.  
 
Change  
Rationale for Change 
Sections Changed  
Change of the time point for 
evaluation of the primary endpoint and 
certain exploratory efficacy endpoints 
from Week 20 to Week 16.  
  
To allow head-to-head 
comparison of the 
2 treatment arms without 
potential confounding by 
additional/rescue treatment. 
Week 16 is 8 weeks after the 
third initial loading dose in 
both treatment groups and 
represents the earliest 
timepoint to assess anatomic 
differences in treatment 
effect between 2 mg and 8 
mg. Since some patients will 
receive additional dosing at 
Week 16 while others will 
not, 20 weeks is less ideal 
for understanding and 
comparing treatment effects.   
Synopsis: Study Design, 
Endpoints (Co-primary), 
Statistical Plan (Statistical 
Hypothesis, Efficacy 
Analyses) 
Section 4.1.1 Primary 
Endpoints 
Section 4.1.3 Exploratory 
Endpoints 
Section 6.1 Figure 1  Study 
Flow Diagram 
Section 6.1 Figure 2 
Dosing Schedule 
Section 9.1.3 Early 
Termination Visit 
Section 11.1 Statistical 
Hypothesis 
Section 11.4.3.1 Primary 
Efficacy Analysis 
Section 11.4.3.2 Exploratory 
Efficacy Analysis 
Remove reference to “OC” as a 
method for imputation of missing data. 
Correction for accuracy in 
the 
Statistical 
Analysis 
section.  
Section 11.4.3.2 
, 
Exploratory Efficacy Analysis 
 
Removed mention of absence of 
imputation of missing data in the 
Safety section. 
Correction for accuracy in 
the Safety Analysis section. 
Section 11.4.5 , Safety 
Analysis 
 
 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 4 of 59 
CONFIDENTIAL 
Amendment 2 
The purpose of this amendment is to add the option for dense pharmacokinetic (PK) substudy 
patients to have certain procedures on specified visits performed at a location other than the clinical 
trial site using a mobile nursing service, to possibly enroll additional patients into the PK substudy, 
and to add required language related to the “Coronavirus Disease 2019” (COVID-19) pandemic. 
Change and Rationale for Change 
Sections Changed  
Addition of option for mobile healthcare professional 
service for certain visits for patients in the dense PK 
substudy, to enable the conduct of the trial during the 
COVID-19 pandemic. 
Additional patients may be enrolled in the dense PK 
portion of the study to ensure adequate data are 
captured. 
 
Synopsis: Study Design, Population 
(Sample Size) 
 
Section 3.3 Risk-Benefit 
 
Section 9.1.1.1 Footnotes for the Schedule 
of Events for the Study (#19) 
 
Section 6.1 Study Description and Duration 
 
Section 7.1 Number of Patients Planned 
Section 8.4 Method of Treatment 
Assignment 
 
Section 9.1.2 Table 2 Schedule of Events 
(Dense PK Substudy) 
 
Section 9.1.2.1 Footnotes for the Schedule 
of Events for the Dense PK Substudy (#1, 
#2, #4, #6) 
Additional exclusion criterion to clarify COVID-19 
standards for study inclusion/exclusion, as required 
language related to conduct of trials during the 
pandemic. 
Section 7.2.2 Exclusion Criteria (#33) 
Clarification to state that the timing of blood pressure 
(BP) and PK sample collection should be within 2 hours 
of the time of the injection on day 1 of the study. 
Section 9.1.1.1 Footnotes for the Schedule 
of Events for the Study (#20) 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 5 of 59 
CONFIDENTIAL 
Change and Rationale for Change 
Sections Changed  
Addition of option for mobile healthcare professional 
service for certain visits for patients in the dense PK 
substudy, to enable the conduct of the trial during the 
COVID-19 pandemic. 
Additional patients may be enrolled in the dense PK 
portion of the study to ensure adequate data are 
captured. 
 
Synopsis: Study Design, Population 
(Sample Size) 
 
Section 3.3 Risk-Benefit 
 
Section 9.1.1.1 Footnotes for the Schedule 
of Events for the Study (#19) 
 
Section 6.1 Study Description and Duration 
 
Section 7.1 Number of Patients Planned 
Section 8.4 Method of Treatment 
Assignment 
 
Section 9.1.2 Table 2 Schedule of Events 
(Dense PK Substudy) 
 
Section 9.1.2.1 Footnotes for the Schedule 
of Events for the Dense PK Substudy (#1, 
#2, #4, #6) 
Additional criterion for pro re nata (PRN) treatment, to 
allow for patients experiencing substantial disease 
worsening to receive treatment. 
Section 6.1 Study Description and Duration 
Minor correction of typographical errors. 
Throughout  
Amendment 1  
The primary purpose of this amendment is to update the inclusion criteria to include patients with 
better baseline visual acuity to better align with clinical practice patterns.  
Change and Rationale for Change 
Sections Changed  
Name of Compound corrected to High Dose 
Aflibercept; Medical/Study Director updated 
Title Page 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 6 of 59 
CONFIDENTIAL 
Change and Rationale for Change 
Sections Changed  
Update of pharmacokinetic (PK) data relevant for the 
indication in the rationale for dose selection and 
removal of external references 
Section 3.2.2 Rationale for Dose Selection 
Inclusion criteria updated to include patients with best 
corrected visual acuity (BCVA) between 24 and 78 
letters to better align with clinical practice patterns. 
Section 7.2.1 Inclusion Criteria (#2) 
Minor additions to the exclusion criteria regarding 
participation in an investigational study  
Section 7.2.2 Exclusion Criteria (#28, #29, 
#30, #31, #32; new) 
Inclusion in Schedule of Events of review of 
concomitant medications at Screening visit 2; 
clarification to footnotes to align with table regarding 
timing of research sample collection at Baseline visit 3; 
and provision for additional post-dose intraocular 
pressure (IOP) measurement(s) on day 1 for patients in 
the dense PK substudy as safety measures 
Section 9.1.1 Table 1 Schedule of Events  
Section 9.1.1.1 Footnotes for the Schedule of 
Events for the Study (#4, #21) 
Section 9.1.2 Table 2 Schedule of Events 
(Dense PK Substudy) 
Section 9.1.2.1 Footnotes for the Schedule of 
Events for the Dense PK Substudy (#3, #4; 
new) 
Section 9.2.2.1 Intraocular Pressure 
Addition of time windows for day 1 sample collection 
in the dense PK substudy to facilitate patient follow-up 
Section 9.1.2 Table 2 Schedule of Events 
(Dense PK Substudy) 
Clarification of timing of collection of adverse events 
(AE) to align across studies in the development 
program for high dose (HD) aflibercept 
Section 10.1.1 Safety Evaluation, General 
Guidelines 
Minor edits and formatting changes 
Throughout 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 7 of 59 
CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AOBP 
Automated office blood pressure 
APTC 
Anti-Platelet Trialists’ Collaboration 
AST 
Aspartate aminotransferase 
ATE 
Arterial thromboembolic event 
BCVA 
Best Corrected Visual Acuity 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CNV 
Choroidal neovascularization 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic) 
CRT 
Central retinal thickness 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
FAS 
Full analysis set 
FP 
Fundus photography 
GCP 
Good Clinical Practice 
HD 
High-dose aflibercept injection 
HDL 
High-density lipoprotein 
IAI 
Intravitreal Aflibercept Injection 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRF 
Intraretinal fluid 
IV 
Intravenous 
IVT 
Intravitreal 
IWRS 
Interactive web response system 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 8 of 59 
CONFIDENTIAL 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
nAMD 
Neovascular “wet” age-related macular degeneration 
OCT 
Optical coherence tomography 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PRN 
Pro re nata 
PT 
Preferred term 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RPE 
Sub-retinal pigment epithelium 
RVO 
Retinal vein occlusion 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SBP 
Systolic blood pressure 
SD-OCT 
Spectral domain optical coherence tomography 
SOC 
System organ class 
SRF 
Subretinal fluid 
TEAE 
Treatment-emergent adverse event 
UPCR 
Urine protein:creatinine ratio 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 9 of 59 
CONFIDENTIAL 
TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................14 
1. 
INTRODUCTION ......................................................................................................17 
2. 
STUDY OBJECTIVES ..............................................................................................17 
2.1. 
Primary Objectives .....................................................................................................17 
2.2. 
Secondary Objectives .................................................................................................18 
2.3. 
Exploratory Objectives ...............................................................................................18 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................18 
3.1. 
Hypothesis ..................................................................................................................18 
3.2. 
Rationale .....................................................................................................................18 
3.2.1. 
Rationale for Study Design .........................................................................................18 
3.2.2. 
Rationale for Dose Selection ......................................................................................19 
3.3. 
Risk-Benefit ................................................................................................................20 
4. 
ENDPOINTS ..............................................................................................................21 
4.1. 
Primary and Secondary Endpoints..............................................................................21 
4.1.1. 
Primary Endpoints ......................................................................................................21 
4.1.2. 
Secondary Endpoints ..................................................................................................21 
4.1.3. 
Exploratory Endpoints ................................................................................................21 
5. 
STUDY VARIABLES................................................................................................22 
5.1. 
Demographic and Baseline Characteristics ................................................................22 
5.2. 
Efficacy Variables ......................................................................................................22 
5.3. 
Safety Variables ..........................................................................................................22 
5.4. 
Pharmacokinetic Variables .........................................................................................22 
6. 
STUDY DESIGN .......................................................................................................23 
6.1. 
Study Description and Duration .................................................................................23 
6.1.1. 
End of Study Definition ..............................................................................................24 
6.2. 
Planned Interim Analysis ............................................................................................24 
6.3. 
Study Committees .......................................................................................................25 
6.3.1. 
Adjudication Committee .............................................................................................25 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............25 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 10 of 59 
CONFIDENTIAL 
7.1. 
Number of Patients Planned .......................................................................................25 
7.2. 
Study Population .........................................................................................................25 
7.2.1. 
Inclusion Criteria ........................................................................................................25 
7.2.2. 
Exclusion Criteria .......................................................................................................25 
7.2.3. 
Additional Exclusion Criteria for the Dense PK Substudy ........................................28 
7.3. 
Premature Withdrawal from the Study .......................................................................28 
7.4. 
Replacement of Patients .............................................................................................28 
8. 
STUDY TREATMENTS............................................................................................28 
8.1. 
Investigational and Reference Treatments ..................................................................28 
8.2. 
Additional Treatment ..................................................................................................29 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................29 
8.3.1. 
Dose Modification ......................................................................................................29 
8.3.2. 
Study Drug Discontinuation .......................................................................................29 
8.4. 
Method of Treatment Assignment ..............................................................................29 
8.5. 
Masking ......................................................................................................................29 
8.6. 
Treatment Logistics and Accountability .....................................................................29 
8.6.1. 
Packaging, Labeling, and Storage ..............................................................................29 
8.6.2. 
Supply and Disposition of Treatments .......................................................................30 
8.6.3. 
Treatment Accountability ...........................................................................................30 
8.6.4. 
Treatment Compliance ................................................................................................30 
8.7. 
Concomitant Medications ...........................................................................................30 
8.7.1. 
Prohibited Medications ...............................................................................................30 
8.7.2. 
Permitted Medications ................................................................................................31 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................31 
9.1. 
Schedule of Events .....................................................................................................31 
9.1.1. 
Schedule of Events for the Study ................................................................................31 
9.1.1.1. 
Footnotes for the Schedule of Events for the Study ...................................................34 
9.1.2. 
Schedule of Events for the Dense PK Substudy .........................................................35 
9.1.2.1. 
Footnotes for the Schedule of Events for the Dense PK Substudy.............................35 
9.1.3. 
Early Termination Visit ..............................................................................................36 
9.1.4. 
Unscheduled Visits .....................................................................................................36 
9.2. 
Study Procedures ........................................................................................................36 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
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CONFIDENTIAL 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................36 
9.2.2. 
Ocular Procedures (Efficacy and Safety) ...................................................................36 
9.2.2.1. 
Intraocular Pressure ....................................................................................................36 
9.2.2.2. 
Slit Lamp Examination ...............................................................................................37 
9.2.2.3. 
Indirect Ophthalmoscopy ............................................................................................37 
9.2.2.4. 
Fundus Photography/Fluorescein Angiography .........................................................37 
9.2.2.5. 
Spectral Domain Optical Coherence Tomography .....................................................37 
9.2.2.6. 
Best Corrected Visual Acuity .....................................................................................37 
9.2.3. 
Safety Procedures (Non-ocular) .................................................................................38 
9.2.3.1. 
Vital Signs ..................................................................................................................38 
9.2.3.2. 
Physical Examination .................................................................................................38 
9.2.3.3. 
Electrocardiogram .......................................................................................................38 
9.2.3.4. 
Laboratory Testing ......................................................................................................38 
9.2.4. 
Drug Concentration and Measurements .....................................................................40 
9.2.5. 
Future Biomedical Research .......................................................................................40 
9.2.5.1. 
Pharmacogenomic Analysis (Optional) ......................................................................40 
10. 
SAFETY EVALUATION AND REPORTING .........................................................41 
10.1. 
Recording and Reporting Adverse Events ..................................................................41 
10.1.1. 
General Guidelines .....................................................................................................41 
10.1.2. 
Reporting Procedure ...................................................................................................42 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................42 
10.2. 
Definitions ..................................................................................................................42 
10.2.1. 
Adverse Event .............................................................................................................42 
10.2.2. 
Serious Adverse Event ................................................................................................42 
10.2.3. 
Severity .......................................................................................................................43 
10.2.4. 
Causality .....................................................................................................................43 
10.3. 
Safety Monitoring .......................................................................................................45 
10.4. 
Notifying Health Authorities, Institutional Review Board, and Investigators ...........45 
11. 
STATISTICAL PLAN................................................................................................46 
11.1. 
Statistical Hypothesis ..................................................................................................46 
11.2. 
Justification of Sample Size........................................................................................46 
11.3. 
Analysis Sets ...............................................................................................................46 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
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Page 12 of 59 
CONFIDENTIAL 
11.3.1. 
Efficacy Analysis Sets ................................................................................................46 
11.3.2. 
Safety Analysis Set .....................................................................................................46 
11.3.3. 
Pharmacokinetic Analysis Set ....................................................................................47 
11.4. 
Statistical Methods ......................................................................................................47 
11.4.1. 
Patient Disposition ......................................................................................................47 
11.4.2. 
Demography and Baseline Characteristics .................................................................47 
11.4.3. 
Efficacy Analyses .......................................................................................................47 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................47 
11.4.3.2. 
Exploratory Efficacy Analysis ....................................................................................48 
11.4.4. 
Control of Multiplicity ................................................................................................48 
11.4.5. 
Safety Analysis ...........................................................................................................48 
11.4.5.1. 
Adverse Events ...........................................................................................................48 
11.4.5.2. 
Other Safety ................................................................................................................49 
11.4.5.3. 
Treatment Exposure ....................................................................................................49 
11.4.5.4. 
Treatment Compliance ................................................................................................50 
11.4.6. 
Pharmacokinetics ........................................................................................................50 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................50 
11.5. 
Interim Analysis ..........................................................................................................50 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........51 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................51 
12.1. 
Data Management and Electronic Systems ................................................................51 
12.1.1. 
Data Management .......................................................................................................51 
12.1.2. 
Electronic Systems ......................................................................................................51 
12.2. 
Study Monitoring ........................................................................................................51 
12.2.1. 
Monitoring of Study Sites ...........................................................................................51 
12.2.2. 
Source Document Requirements ................................................................................52 
12.2.3. 
Case Report Form Requirements ................................................................................52 
12.3. 
Audits and Inspections ................................................................................................52 
12.4. 
Study Documentation .................................................................................................53 
12.4.1. 
Certification of Accuracy of Data ...............................................................................53 
12.4.2. 
Retention of Records ..................................................................................................53 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................53 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
13.1. 
Good Clinical Practice Statement ...............................................................................53 
13.2. 
Informed Consent .......................................................................................................54 
13.3. 
Patients Confidentiality and Data Protection ..............................................................54 
13.4. 
Institutional Review Board .........................................................................................54 
13.5. 
Clinical Study Data Transparency ..............................................................................55 
14. 
PROTOCOL AMENDMENTS ..................................................................................55 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................55 
15.1. 
Premature Termination of the Study ...........................................................................55 
15.2. 
Close-out of a Site ......................................................................................................55 
16. 
CONFIDENTIALITY ................................................................................................56 
17. 
FINANCING AND INSURANCE .............................................................................56 
18. 
PUBLICATION POLICY ..........................................................................................56 
19. 
REFERENCES ...........................................................................................................57 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................58 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................59 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................32 
Table 2: 
Schedule of Events (Dense PK Substudy) ..................................................................35 
 
LIST OF FIGURES 
Figure 1: Study Flow Diagram ......................................................................................................23 
Figure 2: 
Dosing Schedule .........................................................................................................24 
 
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Clinical Study Protocol 
 
VGFTe (HD)-AMD-1905 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 14 of 59 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
 
Title 
A Randomized, Single-Masked, Active-Controlled Phase 2 Study of the 
Safety, Tolerability, and Efficacy of Repeated Doses of High-Dose 
Aflibercept 
in 
Patients 
with 
Neovascular 
Age-Related 
Macular 
Degeneration 
Site Locations 
Principal Investigator 
Approximately 60 sites in the United States 
To be determined 
Objectives 
The primary objectives of the study are: 
• 
To determine the safety of high-dose aflibercept (hereafter 
referred to as HD) 
• 
To 
determine 
if 
HD 
provides 
greater 
intraocular 
pharmacodynamic (PD) effect and/or longer duration of action 
compared to 2 mg intravitreal aflibercept injection (IAI, 
hereafter referred to as IAI) 
There are no secondary objectives. 
Study Design 
This is a phase 2, multi-center, randomized, single-masked study in patients 
with neovascular (wet) age-related macular degeneration (nAMD) that will 
investigate the efficacy, safety, and tolerability of HD versus IAI. 
The study consists of a screening/baseline period, a treatment period, and an 
end of study (EOS) visit at week 44.  Patients will be seen monthly through 
week 44. A total of approximately 100 eligible patients will be randomized 
into 2 groups in a 1:1 ratio.  One group will receive IAI and the other will 
receive HD.  The investigational product will be administered intravitreally 
(IVT) monthly for 3 initial injections (baseline, week 4, and week 8), 
followed by additional doses at weeks 20 and 32.  At weeks 24, 28, 36 and 
40 patients will be evaluated and given a dose (at their randomized dose 
level) if defined retreatment criteria are met. 
The study also includes a pharmacokinetic (PK) substudy, with dense blood 
sampling (dense PK substudy) for systemic drug concentrations and PK 
assessments for approximately 15 patients from each group from selected 
sites.  Blood pressure measurements will also be taken in these patients on 
the same days as for the PK sampling. Additional patients (up to 
approximately 50% more in each treatment group) may be enrolled in the 
dense PK substudy to ensure adequate data are captured. 
The primary safety analysis will take place at week 4.  The primary efficacy 
analysis will take place at week 16, with the exploratory endpoints evaluated 
at week 16 and week 44. 
Study Duration 
The duration of the study for a patient is approximately 44 weeks, excluding 
the screening period. 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
Population 
 
 
Sample Size: 
The study will enroll approximately 100 patients, to be randomized in a 
1:1 ratio. Additional patients may be enrolled in the dense PK portion of the 
study (up to approximately 50% more in each treatment group) to ensure 
adequate data are captured. 
 
Target Population: 
The study population consists of treatment-naïve patients with nAMD 
Treatment(s) 
 
 
Study Drug 
 
 
 
Dose/Route/Schedule: 
The HD will be provided as a liquid formulation in a vial.  The target 
concentration of aflibercept is 114.3 mg/mL.  The dose will be delivered in 
an injection volume of 70 µl. 
The IAI will be provided as a liquid formulation in a vial.  The target 
concentration of aflibercept is 40 mg/mL.  The dose will be delivered in an 
injection volume of 50 µl. 
Endpoints 
 
 
Co-Primary: 
The co-primary endpoints are: 
• 
Safety, which will be evaluated by assessment of treatment-
emergent adverse events (TEAEs) and serious adverse events 
(SAEs) through week 4 
• 
The proportion of patients without retinal fluid in the center 
subfield at week 16 
 
Secondary: 
There are no secondary endpoints in this study. 
Procedures and Assessments 
The efficacy procedures/assessments include:  slit lamp exam, indirect 
ophthalmoscopy, spectral domain optical coherence tomography, fundus 
photography 
and 
fluorescein 
angiography, 
evaluation 
of 
retinal 
characteristics, and Best Corrected Visual Acuity (BCVA). 
The safety procedures/assessments include:  ophthalmic examinations, 
intraocular pressure, assessment of adverse events (AEs), physical 
examination, vital signs, electrocardiogram, and clinical laboratories. 
The study also includes pharmacokinetic analyses and potential analysis 
such as pharmacogenomics, biomarkers, and anti-drug antibodies. 
Statistical Plan 
Statistical Hypothesis: 
No formal hypothesis has been defined for the safety analysis at week 4. 
However, this study will examine the following hypothesis for the 
superiority testing of the primary efficacy variable:  proportion of patients 
without retinal fluid at week 16.  Statistical testing will be conducted to show 
superiority of HD versus IAI. 
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H0:  p1 = p2, against Ha: p1 ≠ p2 
where p1 and p2 are the proportion of patients without retinal fluid at 
week 16 in HD versus IAI, respectively. 
Justification of Sample Size: 
For this phase 2 safety study, 50 patients per group is sufficient to provide 
substantial information regarding safety.  Assume that the proportion of 
patients without fluid in the center subfield in the IAI group is 50% with 
normal approximation and drop out rate is 8%.  Then a total sample size of 
100 patients will allow estimation of the true treatment difference to be 
between (+6.7% to +43.3%) at 95% confidence level, if the observed 
treatment difference is +25% (i.e., observed proportion of patients without 
fluid in the center subfield in HD group is 75%). 
The sample size was estimated based on normal approximation for the 
confidence interval of the difference in proportions using the commercial 
software nQuery nTerm 7.0. 
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. 
Efficacy Analyses: 
Analysis of the primary efficacy variable will take place at week 16.  The 
efficacy analysis for the primary efficacy endpoint will be the comparison 
between the IAI group and the HD group for the proportion of patients 
without fluid in the center subfield at week 16.  The statistical analysis will 
be performed using the chi-square test at the 2-sided 5% significance level. 
For the primary analysis, missing post-baseline values for a given patient 
will be imputed using the last observation carry forward (LOCF) procedure 
to determine the patient’s primary efficacy response. 
Observed case (OC) analysis will be performed for primary efficacy 
endpoint as sensitivity analysis, ie, only observed values will be used for 
analysis. 
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1. 
INTRODUCTION 
Neovascular (wet) AMD (nAMD) is a major health issue in aging populations globally.  Vision 
loss in nAMD results from the abnormal growth and leakage of blood vessels in the macula.  In 
elderly patients affected by nAMD, vision loss frequently has an even greater impact, as it 
substantially reduces the visual compensation of functional impairment by other age-related 
comorbidities, such as arthritis and osteoporosis. 
Intravitreally (IVT) administered anti-vascular endothelial growth factor (VEGF) therapies like 
EYLEA® inhibit neovascular vessel growth and leakage in the retina, and they are currently the 
standard of care for patients with nAMD.  They not only maintain visual function but also provide 
clinically meaningful visual gains.  Treatment of nAMD is chronic and life-long in most patients 
to suppress retinal edema and recurrences of choroidal neovascularization (CNV).  Although the 
currently approved IVT anti-VEGF therapies are efficacious and well-tolerated, the need for IVT 
injections every 4 to 8 weeks, specifically in the initial phase and during maintenance of treatment, 
represents a significant burden to physicians, patients, and caregivers.  While the procedure is 
straightforward and relatively easy to perform, capacity issues for ensuring an appropriate injection 
frequency in order to achieve patient outcomes similar to those seen in the pivotal studies represent 
an increasing challenge to individual practices and the healthcare system, overall. 
While the efficacy and safety of currently approved anti-VEGF therapies have been established 
for the treatment of nAMD, there remains an unmet medical need for the development of therapies 
with the potential to reduce treatment burden while providing at least similar or even improved 
visual outcomes over currently available standard of care. 
Increasing the molar fraction of anti-VEGF therapeutic protein in the dosing formulation is a 
potential way to bring further benefits to patients with chorioretinal vascular diseases, including 
nAMD.  A higher dose of aflibercept administered IVT has the potential to prolong the drug’s 
therapeutic effects.  The resulting extension of treatment intervals early after the initiation of 
treatment to every 12 weeks or 16 weeks would reduce the number of injections in the first 
treatment year.  A potential decrease in injection-related treatment burden and safety events with 
fewer injections could be a significant contribution to patient care and healthcare services. 
Studies will investigate the safety and efficacy of a high-dose aflibercept IVT injection with the 
intent of extending the dosing interval, with at least similar functional and potentially improved 
anatomic outcomes.  EYLEA (2 mg dose, administered at a concentration of 40 mg/mL, also called 
intravitreal aflibercept injection [IAI]) is currently approved in the United States (US) for the 
treatment of nAMD, and is also approved for the treatment of macular edema following retinal 
vein occlusion (RVO), diabetic macular edema (DME), and diabetic retinopathy (DR). 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objectives of the study are: 
• To determine the safety of high-dose aflibercept (hereafter referred to as HD). 
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• To determine if HD provides greater intraocular pharmacodynamic (PD) effect and/or 
longer duration of action compared 2 mg IAI (hereafter referred to as IAI). 
2.2. 
Secondary Objectives 
There are no secondary objectives in this study. 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To generate additional data to determine the effect of HD vs IAI on anatomical 
measures of response and on visual acuity. 
• To characterize the concentrations in plasma over time and corresponding 
pharmacokinetic (PK) parameters for free, bound, and adjusted bound aflibercept 
(collectively referred to as bound) and to conduct exploratory PK/PD and/or dose/PD 
analyses on selected systemic and ocular response variables. 
• To study molecular drivers of nAMD or related diseases, the mechanism of action of 
EYLEA (afIibercept) and the VEGF pathway. 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
A higher dose of aflibercept will extend the interval between doses and/or improve anatomic 
outcomes with comparable efficacy and safety compared to those of the 2 mg dose of aflibercept. 
3.2. 
Rationale 
3.2.1. 
Rationale for Study Design 
Although many patients benefit from treatment with currently available anti-VEGF agents, some 
patients still need frequent injections, and long-term data suggest that in some patients, visual 
benefits may be lost if regular dosing, as frequently as every 4 to 8 weeks, is not maintained.  
Additionally, the treatment paradigm most physicians employ for patients with nAMD after the 
initial dosing period is "treat and extend", which relies primarily on anatomic assessment as a 
pharmacodynamic endpoint to determine a dosing interval for individual patients that is thought 
to optimize benefit/risk and treatment burden.  A therapy that can improve and sustain anatomic 
outcomes with similar safety has the potential to optimize treatment by improving benefit and 
decreasing treatment burden for patients and physicians. 
Increasing the 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 this disease.  This creates the potential for greater 
efficacy and may reduce the overall number of injections by extending the treatment interval, 
thereby reducing burden on both patients and physicians. 
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This study is designed to investigate the effects of HD versus IAI in patients diagnosed with 
nAMD. 
The goal of the study is to investigate the short-term safety of HD.  The study will also investigate 
the efficacy of HD with the intent of improving anatomic outcomes and potentially extending the 
dosing interval for HD vs IAI. 
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 that the concentration at the end of an 8-week dosing interval for a 2 mg IVT dose would 
be achieved 18 days later for an 8 mg IVT dose.  The present study will evaluate whether an 8 mg 
IVT dose can extend the dosing interval in the maintenance phase from 8 to 12 weeks or longer. 
Studies with intravenous (IV) aflibercept indicated that blood pressure (BP) increase was the 
earliest PD 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 approximately 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 approximately 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 84-236x and 34-136x 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. 
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3.3. 
Risk-Benefit 
Benefits of Treatment with HD: 
Nonclinical pharmacology evidence and additional clinical data suggest that an increased molar 
dose could extend the duration of pharmacological effect of IAI.  This would, in turn, reduce the 
overall treatment burden on patients by increasing the dosing interval after the initial monthly 
doses, while maintaining or improving the overall risk/benefit profile. 
High-dose aflibercept may provide improved patient benefit through: 
• longer treatment intervals (≥ every 12 weeks for most patients after initial monthly 
dosing) 
• the potential for improved functional and anatomic efficacy 
• less injection-related risk over time 
• increased compliance due to reduced treatment burden on patients, caregivers, 
physicians, and healthcare systems 
Risks and Risk Management of Treatment with HD: 
The safety profile of HD is considered to be similar to that of IAI, and includes identified risks 
such as intraocular inflammation/infection, retinal tear, retinal detachment, transient increase in 
intraocular pressure (IOP), traumatic cataract, and hypersensitivity. 
Pharmacokinetic and clinical safety data of IAI have indicated that the known potential risks from 
systemic administration of anti-VEGF treatments in oncology indications were not identified with 
local treatment with IAI.  Studies performed with IV administration of aflibercept demonstrated 
that increases in BP were the earliest PD indicator of systemic effects.  Estimated exposure margins 
for free aflibercept after an 8 mg IVT dose, derived from linear extrapolation of available PK data 
for IVT administered 2 mg IAI, suggest adequate margins relative to those concentrations seen 
after systemically administered aflibercept associated with an approximate 5 mm Hg mean SBP 
increase.  Robust generation of safety data is planned in this phase 2 trial to evaluate potential 
systemic exposure-related adverse events (AEs) such as changes in BP and incidence of ocular 
safety events. 
The primary objectives of this study in treatment-naïve nAMD patients are to assess patient safety 
and to generate important data for pharmacovigilance evaluations.  Safety will be assessed by 
collection of vital signs (including heart rate, BP, 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 potential safety concerns 
such as hypersensitivity, pregnancy, ATEs, and uncontrolled arterial hypertension. 
Overall Risk-Benefit Balance: 
Based on the available preclinical and clinical data, the risk-benefit assessment of HD is considered 
to be positive and supports the participation of patients with nAMD in the clinical trial program. 
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COVID-19 Pandemic: 
Recognizing that “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on the 
conduct of clinical trials, the sponsor will only screen patients in this study when the COVID-19 
pandemic is controlled such that patients can safely participate in the study. The sponsor will 
continue initiating study sites for this study, as allowed by local laws and regulations. 
4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoints 
The co-primary endpoints are: 
• Safety, which will be evaluated by assessment of treatment-emergent adverse events 
(TEAEs) and serious adverse events (SAEs) through week 4 
• The proportion of patients without retinal fluid in the center subfield at week 16 
4.1.2. 
Secondary Endpoints 
There are no secondary endpoints in this study. 
4.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• The proportion of patients without retinal fluid in the center subfield at week 44 
• Change in central retinal thickness (CRT) from baseline through week 16 and 
week 44 
• The proportion of patients without intraretinal fluid (IRF) at week 16 and week 44 
• The proportion of patients without subretinal fluid (SRF) at week 16 and week 44 
• The proportion of patients without sub-retinal pigment epithelium (RPE) fluid at 
week 16 and week 44 
• The proportion of patients able to maintain dry retina (total fluid, IRF, and/or SRF) 
through week 16 and week 44 
• The proportion of patients able to maintain a 12-week dosing interval from week 8 
through week 44 
• Change in CRT between dosing visits from week 8 through week 44 
• Change in Best Corrected Visual Acuity (BCVA) from baseline, and proportions of 
patients gaining and losing vision, through week 16 and week 44 
• Change in lesion size and choroidal neovascularization (CNV) size from baseline 
through week 44 
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• Other safety outcomes (eg, TEAEs, SAEs, vital signs, clinical laboratory values, and 
intraocular pressure [IOP]) from baseline through week 16 and week 44 
• Systemic PK of free and bound aflibercept assessed from baseline through week 44 
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 the assessment of retinal fluid. 
The efficacy variables relevant to the exploratory endpoints are: 
• Assessment of retinal fluid levels (total fluid, IRF, and SRF) and retinal thickness on 
spectral domain optical coherence tomography (SD-OCT, or just OCT) 
• Dosing interval 
• Visual acuity 
• Lesion size 
5.3. 
Safety Variables 
The safety variable relevant to the primary safety endpoint is the proportion of patients with 
TEAEs and SAEs. 
The safety variables relevant to the exploratory endpoints are: 
• Ocular exams 
• Vital signs 
• Clinical laboratory values 
• IOP 
5.4. 
Pharmacokinetic Variables 
The PK variables are the concentrations of free and bound aflibercept in plasma and time, using 
both sparse sampling (Table 1) and dense sampling (Table 1 and Table 2). 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This phase 2, multi-center, randomized, single-masked study in patients with nAMD will 
investigate the efficacy, safety, and tolerability of HD versus IAI. 
The study consists of a screening/baseline period, a treatment period, and an end of study (EOS) 
visit at week 44 (Figure 1) (Figure 2).  Patients will be seen monthly through week 44. A total of 
approximately 100 eligible patients will be randomized into 2 groups in a 1:1 ratio.  Additional 
patients may be enrolled in the dense PK substudy (up to approximately 50% more in each 
treatment group in the dense PK substudy) to ensure adequate data are captured. One group will 
receive IAI and the other will receive HD.  The investigational product will be administered 
intravitreally (IVT) monthly for 3 initial injections (baseline, week 4, and week 8), followed by 
additional doses at weeks 20 and 32.  At weeks 24, 28, 36 and 40, patients will be evaluated and 
given a dose (at their randomized dose level) if EITHER of the following criteria are met 
(PRN criteria): 
• Loss of ≥5 letters from week 20 BCVA due to disease progression OR 
• Anatomical findings that are considered vision-threatening, such as worsening or 
persistent retinal fluid, new or worsening retinal pigment epithelial detachment 
(PED), new or persistent hemorrhage, etc. 
 
Figure 1: Study Flow Diagram 
 
 
EP=endpoint, pts=patients 
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Figure 2: 
Dosing Schedule 
 
 
The primary safety analysis will take place at week 4.  The primary efficacy analysis will take 
place at week 16, with the exploratory endpoints evaluated at week 16 and week 44. 
Safety will be assessed by collection of vital signs (including heart rate, BP and, temperature), 
AEs, and clinical laboratory assessments.  All AEs reported in this study will be coded using the 
currently available version of the Medical Dictionary for Regulatory Activities (MedDRA®). 
In all patients, blood samples for measurement of drug concentrations 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 
genomic substudy. 
Dense PK Substudy: 
Approximately 15 patients from each group from selected sites will be chosen for a dense PK 
substudy (Table 2).  Additional patients (up to approximately 50% more in each treatment group 
in the dense PK substudy) may be enrolled to ensure adequate data are captured.  Blood pressure 
measurements will also be taken in these patients on the same days as for the PK sampling. This 
may be done at the clinical study site, or on certain visits, by the site personnel or another 
healthcare professional at a remote location (eg, the patient’s home or another appropriate location; 
See Section 9.1.2 , Table 2 ).  
6.1.1. 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
6.2. 
Planned Interim Analysis 
No formal interim analyses will be performed. However, data may be reviewed in this single-
masked study at various time points for safety and/or efficacy. 
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6.3. 
Study Committees 
6.3.1. 
Adjudication Committee 
Potential arterial thromboembolic events (ATEs) will be evaluated by a masked adjudication 
committee, according to criteria formerly applied and published by the Anti-Platelet Trialists’ 
Collaboration (APTC) (Antithrombotic Trialists’ Collaboration, 1994) (Antithrombotic Trialists’ 
Collaboration, 2002).  An ATE is defined as a nonfatal myocardial infarction (MI), nonfatal 
ischemic stroke, nonfatal hemorrhagic stroke, or death resulting from vascular or unknown causes.  
The committee will include 2 to 3 cardiologist-equivalent adjudicators, and the activities of the 
committee will be governed by a charter. 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
The study will enroll approximately 100 patients, to be randomized in a 1:1 ratio.  Additional 
patients may be enrolled in the dense PK portion of the study (up to approximately 50% more in 
each dense PK treatment group) to ensure adequate data are captured. 
7.2. 
Study Population 
The study population consists of treatment-naïve patients with nAMD. 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria at both the screening and/or the randomization visits to 
be eligible for inclusion in the study: 
1. Men or women ≥50 years of age with active subfoveal CNV secondary to nAMD, 
including juxtafoveal lesions that affect the fovea in the study eye as assessed by an 
independent reading center 
2. Best Corrected Visual Acuity (BCVA) Early Treatment Diabetic Retinopathy Study 
(ETDRS) letter score of 78 to 24 (Snellen equivalent of 20/32 to 20/320) in the study eye 
3. Willing and able to comply with clinic visits and study-related procedures 
4. Provide informed consent signed by study patient or legally acceptable representative 
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 CNV due to any cause other than nAMD in either eye 
2. Subretinal hemorrhage in the study eye that is ≥50% of the total lesion area 
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3. Evidence of DME or diabetic retinopathy (defined as more than 1 microaneurysm) in 
either eye in diabetic patients 
4. Prior use of IVT anti-VEGF agents (aflibercept, ranibizumab, bevacizumab, 
brolucizumab, pegaptanib sodium) in the study eye 
5. Prior IVT investigational agents in either eye (eg, anti-ang-2/anti-VEGF bispecific 
monoclonal antibodies, gene therapy) 
6. Previous use of intraocular or periocular corticosteroids within 120 days of screening or 
treatment with an IVT steroid implant at any time in the study eye 
7. Treatment with ocriplasmin in the study eye at any time 
8. Yttrium-aluminium-garnet capsulotomy in the study eye within 14 days of the screening 
visits 
9. History of vitreoretinal surgery (including scleral buckling) in the study eye 
10. Intraocular pressure ≥25 mm Hg in the study eye 
11. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye 
12. Any intraocular inflammation/infection in either eye within 90 days of the screening visit 
13. Any history of macular hole of stage 2 and above in the study eye 
14. Current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment 
visible at the screening assessments in the study eye 
15. 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) 
16. Ocular conditions with poorer prognosis in the fellow eye 
17. Inability to obtain fundus photographs, fluorescein angiography (FA), or OCT (eg, due to 
media opacity, allergy to fluorescein dye or lack of venous access) in the study eye 
18. Any prior systemic anti-VEGF administration 
19. Uncontrolled diabetes mellitus in the opinion of the investigator 
20. Uncontrolled BP (defined as systolic >140 mm Hg or diastolic >90 mm Hg).  Patients may 
be treated with up to 3 agents known to have anti-hypertensive effects for arterial 
hypertension to achieve adequate BP control.  This limit applies to drugs that could be used 
to treat hypertension even if their primary indication in the patient was not for BP control.  
Any recent changes in medications known to affect BP need to be stable for 90 days prior 
to the screening visit. 
21. Variation by more than 10% in the 3 pre-randomization BP measures recorded at the 
screening 1, screening 2, and randomization visits 
22. History of cerebrovascular accident/ transient ischemic attack or myocardial infarction/ 
acute coronary syndrome within 180 days of screening visit 
23. Renal failure, dialysis, or history of renal transplant 
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24. Known sensitivity to any of the compounds of the study formulation 
25. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the sponsor 
26. Pregnant or breastfeeding women 
27. Women of childbearing potential* 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 90 days 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. vasectomized partner 
e. and or sexual abstinence†, ‡ 
*Postmenopausal women must be amenorrhoeic for at least 12 months in order not to be 
considered of childbearing potential.  Pregnancy testing and contraception are not required for 
women with documented hysterectomy or tubal ligation. 
†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.  
‡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. 
28. Participation in an investigational study within 30 days prior to screening visit that involved 
treatment with any drug (excluding vitamins and minerals) or device 
29.  Any other intraocular surgery within 12 weeks (84 days) before the screening visit 
(see Exclusion Criterion #9) 
30. History of corneal transplant or corneal dystrophy in study eye 
31. 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 
32. 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 
33. Any active, unresolved systemic infectious disease that, in the opinion of the investigator, 
would interfere with the patient’s ability to complete the study.  NOTE: A patient who has 
a documented, positive PCR or serology test for SARS-CoV-2 may be enrolled provided 
the patient has:  
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1) Recovered from COVID-19 (all COVID-19-related symptoms and major clinical 
findings which can potentially affect the safety of the patient should be resolved to 
baseline), and  
2) Had 2 negative results from a health authority-authorized nucleic acid amplification 
(PCR) test for COVID-19 taken at least 48 hours apart. 
7.2.3. 
Additional Exclusion Criteria for the Dense PK Substudy 
1. Prior IAI in the fellow eye 
2. Patients on more than 2 anti-hypertensive medications 
3. Patients with known cardiac arrhythmia 
4. Patients who, in the opinion of the investigator, are unlikely to have stable BP over the 
course of the study (eg, due to known non-compliance with medication) 
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, as described in Section 9.1.3. 
Rules for discontinuation of study treatment are discussed in Section 8.3.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from study will not be replaced.  However, if a patient from the 
dense PK substudy discontinues before providing the PK sample at visit 7, an additional patient 
may be enrolled in the dense PK substudy. 
8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
The HD will be provided as a liquid formulation in a vial.  The target concentration of aflibercept 
is 114.3 mg/mL.  The dose will be delivered in an injection volume of 70 µl. 
The IAI will be provided as a liquid formulation in a vial.  The target concentration of aflibercept 
is 40 mg/mL.  The dose will be delivered in an injection volume of 50 µl. 
Instructions on dose preparation are provided in the pharmacy manual. 
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8.2. 
Additional Treatment 
Deviation from the treatment schedule defined in the protocol is discouraged.  Efforts should be 
made to ensure adherence to the protocol-specified dosing intervals.  If, however, in the 
investigator’s judgement, a patient cannot adhere to the protocol-specified dosing interval due to 
persistent or worsening disease and requires an interim injection, the patient may receive additional 
treatment at week 16.  The investigator must make reasonable efforts to consult with the study 
director or sponsor designee prior to additional treatment being allowed.  Patients will receive their 
randomized dose of aflibercept if it is determined that additional treatment will be administered. 
Patients who receive additional treatment will continue to receive their randomized treatment at 
future visits and will remain masked to treatment assignment.  Data from patients receiving 
additional treatment will be censored from the time additional treatment is administered.  Reasons 
for the decision to give additional treatment will be captured in the CRF. 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
8.3.2. 
Study Drug Discontinuation 
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 100 patients will be randomized in a 1:1 ratio to receive either IAI or HD according 
to a central randomization scheme provided by an interactive web response system (IWRS) to the 
designated study pharmacist (or qualified designee). Additional patients may be enrolled in the 
dense PK portion of the study (up to approximately 50% more in each treatment group) to ensure 
adequate data are captured. 
8.5. 
Masking 
This is a single-masked study.  The patients, visual acuity examiners, and reading center will be 
masked to treatment assignment. 
8.6. 
Treatment Logistics and Accountability 
8.6.1. 
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. 
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Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.6.2. 
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. 
8.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
• 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. 
8.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.7. 
Concomitant Medications 
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication.  This includes medications that were started before the study 
and are ongoing during the study. 
If a pretreatment concomitant medication is administered in the study eye before injection 
(eg, antibiotic or anesthetic), it must be administered for fellow eye treatment as well. 
8.7.1. 
Prohibited Medications 
Introduction of new anti-hypertensive medications or changes to current regimens for the 
management of chronic hypertension are not anticipated during the course of the study, and any 
changes in regimen must be captured in the electronic data capture (EDC).  If a patient reports new 
or increased use of anti-hypertensive medications, the principal investigator (PI) should discuss 
with the patient’s provider whether or not investigational treatment should be discontinued. 
Study Eye: 
Patients are not allowed to receive any standard or investigational treatment for nAMD in the study 
eye other than their assigned study treatment with HD or IAI, as specified in the protocol.  This 
includes medications administered locally (eg, IVT, topical, juxtascleral, or periorbital routes), as 
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well as those administered systemically, with the intent of treating nAMD in the study eye or 
fellow eye. 
Fellow Eye: 
If the fellow eye has nAMD, or any other approved indication, IAI (2 mg) will be allowed and 
supplied through the IWRS.  Patients are not allowed to receive any other anti-VEGF agent in the 
fellow eye. 
Patients enrolled in the dense PK substudy cannot receive IAI (2 mg) in the fellow eye before 
week 12. 
Non-Ocular (Systemic): 
Non-ocular (systemic) standard or investigational treatments for nAMD of the study or fellow eye 
are not permitted.  Systemic anti-angiogenic agents and anti-Ang2 inhibitors are not permitted 
during the study. 
8.7.2. 
Permitted Medications 
Any other medications that are considered necessary for the patient’s welfare, and that are not 
expected to interfere with the evaluation of the study drug, are allowed. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
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 in response to 
COVID-19, are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency. 
9.1. 
Schedule of Events 
9.1.1. 
Schedule of Events for the Study 
The study assessments and procedures for the study are presented by study period and visit in 
Table 1. 
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Table 1: 
Schedule of Events 
Study Procedure 
Screenin
g 
Visit 1 
Screen
ing 
Visit 2 
Baseli
ne 
Visit 3 
Visit 
4 
Visit 
5 
Visi
t 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
EOS 
Visit 15 
Month 
 
 
0 
1 
2 
- 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Week 
 
 
0 
4 
8 
~9 
12 
16 
20 
24 
28 
32 
36 
40 
44 
Day 
-21 to 
 -1 
-20 to 
-1 
1 
29 
57 
61 
85 
113 
141 
169 
197 
225 
253 
281 
309 
Window (day) 
 
 
 
±51 
±51 
±2 
±52 
±52 
±52 
±52 
±5 
±52 
±5 
±5 
±52 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dense PK sampling informed 
consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic substudy/ FBR 
substudy informed consent 
form 4 
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 
 
 
X 
X 
X 
 
 
 
X 
X 
PRN6 
X 
PRN6 
X 
 
X 
PRN6 
X 
PRN6 
 
Ocular Efficacy and Safety (bilateral 
unless indicated): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refraction and BCVA 
(ETDRS)7 
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 
Slit lamp examination 
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 
FA, FP10 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
SD-OCT10 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-ocular Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs11, 12, 13  
X 
X14 
X 
X 
X 
X14 
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 
Laboratory Testing15: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
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Study Procedure 
Screenin
g 
Visit 1 
Screen
ing 
Visit 2 
Baseli
ne 
Visit 3 
Visit 
4 
Visit 
5 
Visi
t 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
EOS 
Visit 15 
Month 
 
 
0 
1 
2 
- 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Week 
 
 
0 
4 
8 
~9 
12 
16 
20 
24 
28 
32 
36 
40 
44 
Day 
-21 to 
 -1 
-20 to 
-1 
1 
29 
57 
61 
85 
113 
141 
169 
197 
225 
253 
281 
309 
Blood chemistry 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Pregnancy test (women of 
childbearing potential)16 
X 
Serum 
 
X 
Urine 
X 
Urin
e 
X 
Urin
e 
 
 
 
X 
Urin
e 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
 
Urinalysis/UPCR17 
X 
 
 
X18 
 
 
X 
 
 
 
 
 
 
 
X 
Pharmacokinetics and 
Research Sampling: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples (dense)19 
 
 
See 
sched
ule 
below 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
PK samples (sparse)20 
 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
Research sample21 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Genomic DNA sample 
(optional) 4 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BCVA=Best Corrected Visual Acuity, ECG=electrocardiogram, EOS=end of study, ETDRS=Early Treatment Diabetic Retinopathy Study, FA=fluorescein 
angiography, FBR=future biomedical research, FP=fundus photography, IOP=Intraocular pressure, PK=pharmacokinetics, PRN=pro re nata (as needed), 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 for the Study 
1. For patients in the dense PK substudy, the visit window is ± 0 days. 
2. For patients in the dense PK substudy, the visit window is ± 2 days. 
3. Signed only by patients participating in the dense PK substudy and in addition to the study 
ICF. 
4. The optional genomic and FBR 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.   
5. Refer to pharmacy manual for study drug injection guidelines.  Following study drug 
injection, patients will be observed for approximately 30 minutes. 
6. Patients will be dosed as needed per criteria 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 bilaterally at all study visits.  On days when study 
drug is administered, IOP should also be measured approximately 30 minutes after 
administration of study drug, in the study eye only.  Intraocular pressure will be measured 
using Goldman applanation tonometry or Tono-pen™ and the same method of 
measurement must be used in each patient throughout the study. 
9. Indirect ophthalmoscopy should be performed bilaterally at all visits.  On days when study 
drug is administered, it should also be performed immediately after administration of study 
drug (study eye only). 
10. The same SD-OCT/FA/FP imaging system used at screening and day 1 must be used at all 
subsequent visits in each patient.  Images will be taken in both eyes before dosing at each 
required visit. 
11. Vital signs (temperature, BP, heart rate) should be measured pre-injection, per the 
procedure outlined in the study procedure manual.  Blood pressure assessments will be 
taken using automated office blood pressure (AOBP) 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. 
12. Timing of BP assessment at all visits must be within 2 hours of planned time of dosing on 
day 1 for patients in the dense PK substudy.  For all other patients, this window should be 
adhered to as closely as possible. 
13. For patients participating in the dense PK substudy, HR and BP also will be collected 
according to the schedule in Table 2. 
14. Only BP and heart rate will be measured at these visits.  No temperature measures are 
required. 
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15. All samples collected for laboratory assessments should be obtained prior to administration 
of fluorescein and prior to administration of study drug. 
16. 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. 
17. For patients participating in the dense PK substudy, urinalysis/UPCR will also be collected 
according to the schedule in Table 2. 
18. Week 4 collection of urinalysis/UPCR only for patients in the dense PK substudy. 
19. Dense PK sampling will be performed in approximately 30 patients (15 in each group) 
drawn according to the schedule in Table 2.  On dosing days, BP and PK samples must be 
collected prior to study drug administration. Additional patients (up to approximately 
50% more in each treatment group) may be enrolled in the dense PK substudy to ensure 
adequate data are captured. 
20. Sparse PK sampling will be performed in all patients not enrolled in the dense PK substudy 
according to the schedule defined in Table 1.  On dosing days, BP and PK samples should 
be collected prior to study drug administration, and the timing of BP and PK sample 
collection should be within ±2 hours of the time of the injection on day 1 of the study. 
21. Exploratory research serum sample should be drawn prior to the administration of study 
drug at baseline (visit 3, day 1) and week 44. 
9.1.2. 
Schedule of Events for the Dense PK Substudy 
The additional study assessments and procedures for the dense PK substudy are presented by study 
period and visit in Table 2. 
Table 2: 
Schedule of Events (Dense PK Substudy) 
Visit 
Dose 
Assessment Day 
and Time (h) 
Dense PK 
Sample 
Collection 
Heart Rate 
and Blood 
Pressure1,2  
Urinalysis 
/ UPCR 
Visit 3 
(Baseline) 
X 
1 
Time of first dose 
X (pre-dose) 
X 
 
4h post-dose (±30 min)3 
X 
 
 
8h post-dose (±2 h)4 
X 
 
 
 
 
2 
±2h5 
X 
X 
 
 
3 
±2h5 
X 
X 
 
 
5 
±2h5 
X 
X 
 
 
8 
±2h5 
X 
X 
X6 
 
15 
±2h5 
X 
X 
X6 
 
22 
±2h5 
X 
X 
 
9.1.2.1. 
Footnotes for the Schedule of Events for the Dense PK Substudy 
1. Timing of all BP assessments must be within ±2 hours of the time of dosing on day 1. 
This may be done at the clinical study site or by the site personnel or another healthcare 
professional at a remote location (eg, the patient’s home or other appropriate location).  
Regardless of where BP measurements are taken, the procedure described in 
Section 9.2.3.1 must be followed. 
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2. Blood pressure assessments will be taken using automated office blood pressure 
(AOBP) 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. 
3. Intraocular pressure will be measured at approximately 4 hours post-dose only if the 
IOP measurement from approximately 30 minutes to 60 minutes post-dose remains 
clinically significantly higher than the pre-injection reading.  
4. Intraocular pressure will be measured at approximately 8 hours post-dose only if the 
IOP measurements from approximately 30 minutes to 60 minutes and approximately 
4 hours post-dose remain clinically significantly higher than the pre-injection reading. 
5. PK draw for all assessment days are to be performed within ±2 hours to the time of 
dosing on day 1. 
6. This may be done at the clinical study site or by the site personnel or another healthcare 
professional at a remote location (eg, the patient’s home or other appropriate location). 
9.1.3. 
Early Termination Visit 
Patients who are withdrawn from the study before the primary efficacy endpoint visit (week 16) 
will be asked to return to the clinic for 2 additional visits:  once for an early termination visit 
consisting of the end of study (EOS, Visit 15) assessments described in Table 1 and again at the 
approximate time for visit 8 (week 16/day 113). 
9.1.4. 
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. 
9.2.2. 
Ocular Procedures (Efficacy and Safety) 
9.2.2.1. 
Intraocular Pressure 
Intraocular pressure will be measured in both eyes at every visit using Goldmann applanation 
tonometry or Tono pen™, as specified in Table 1.  The same method of IOP measurement must 
be used throughout the study for each individual patient.  On dosing visits, IOP will also be 
measured approximately 30 minutes post-dose (study eye). 
For patients in the dense PK substudy, IOP will also be measured 4 hours post-dose if the reading 
from approximately 30 minutes to 60 minutes post-dose remains clinically significantly higher 
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than the pre-dose reading, and again at approximately 8 hours post-dose if the reading from 
approximately 4 hours post-dose remains clinically significantly higher than the pre-dose reading. 
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 (see study procedure manual) by the investigator, as specified in 
Table 1. 
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) and post-dose (study eye) by the investigator, as specified in 
Table 1.  Post-dose evaluation must be performed immediately after injection. 
9.2.2.4. 
Fundus Photography/Fluorescein Angiography 
The anatomical state of the retinal vasculature will be evaluated by FP and FA as specified in 
Table 1.  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. 
Fundus and angiographic images will be sent to an independent reading center where images will 
be read by masked readers.  All FPs and FAs will be archived at the site as part of the source 
documentation.  Photographers must be certified by the reading center to ensure consistency and 
quality in image acquisition.  A detailed protocol for image acquisition and transmission can be 
found in the study procedure manual.  Imaging technicians should remain masked to treatment 
assignment. 
9.2.2.5. 
Spectral Domain Optical Coherence Tomography 
Retinal characteristics will be evaluated at every visit using SD-OCT.  Images will be captured 
and transmitted for both eyes.  Images will be sent to an independent reading center where they 
will be read by masked readers.  All OCTs will be electronically archived at the study site as part 
of the source documentation.  Optical coherence tomography technicians must be certified by the 
reading center to ensure consistency and quality in image acquisition.  A detailed protocol for 
acceptable OCT machines and OCT image acquisition/transmission can be found in the study 
procedure manual.  Imaging technicians should remain masked to treatment assignment. 
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, as specified in Table 1.  Visual acuity examiners must be certified to ensure consistent 
measurement of BCVA, and must remain masked to treatment assignment, treatment schedule and 
study eye.  Best corrected visual acuity should be done before any other ocular procedures are 
performed (see study procedure manual).  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. See study 
procedure manual for details. 
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9.2.3. 
Safety Procedures (Non-ocular) 
9.2.3.1. 
Vital Signs 
Vital signs, including temperature, BP, and heart rate will be collected pre-dose at designated time 
points according to Table 1. 
For all patients, BP assessments at designated time points (see Table 1 and Table 2) will be taken 
using automated office blood pressure (AOBP) 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.  Vital sign measurements will be taken once the patient has 
been sitting down for a minimum of 5 minutes.  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 1. 
9.2.3.3. 
Electrocardiogram 
A standard 12 lead ECG measurement will be measured at visits specified in Table 1.  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, urinalysis, and pregnancy testing samples will be analyzed by a 
central laboratory.  All samples collected for laboratory assessments will be obtained prior to 
administration of study drug.  At visits at which FA is performed, urinalysis samples must be 
collected before FA to avoid false elevations in urine protein values.  Detailed instructions for 
blood sample collection are in the laboratory manual provided to study sites. 
Samples for laboratory testing will be collected at time points according to Table 1.  Tests will 
include: 
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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) 
 
* Low-density lipoprotein (LDL) + high-density lipoprotein (HDL) 
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) 
 
Women of childbearing potential must have a documented negative serum pregnancy test before 
randomization at visit 3.  Urine pregnancy tests will be performed prior to any treatment 
administration (in study eye or fellow eye) at any regular or unscheduled visit. 
A negative result must be documented before a dose can be given in the study eye or in the fellow 
eye. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the 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 
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 investigator. 
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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 drug concentration will be collected at the visits listed in Table 1 and at the time 
points listed in Table 1 and Table 2 for sparse and dense PK sampling.  Instructions for PK blood 
sample collection will be included in the laboratory manual provided to study sites. 
For all patients, a research serum sample will be collected at baseline and week 44 for potential 
analyses (such as biomarkers or anti-drug antibody assessments). 
9.2.5. 
Future Biomedical Research 
Additional analyses may be performed on leftover samples as well as PK samples from patients 
who consent to participate in the optional future biomedical research substudy.  Samples will be 
banked in long term storage. The leftover samples will be stored for up to 15 years after the final 
date of the database lock. The leftover samples may be utilized for future biomedical research of 
nAMD, related diseases or pathways blocked by study treatment, and any adverse reactions that 
may emerge.  These samples may also be used for unrelated assay development and 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 (CSR). 
9.2.5.1. 
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 (pre-dose), 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 nAMD 
and related diseases.  These samples will be single-coded as defined by the International Council 
for Harmonisation (ICH) guideline E15.  Samples will be stored for up to 15 years after the final 
date of the database lock. 
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to nAMD, other nAMD clinical outcome measures and possible AEs.  In 
addition, associations between genomic variants and prognosis or progression of nAMD 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 nAMD 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 
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. 
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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 the ICF to the end of on-treatment period (see Section 11.4.5.1).  
Medical conditions that existed or were diagnosed prior to the signing of the Informed Consent 
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 Investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2.  
The Investigator’s assessment must be clearly documented in the site’s source documentation with 
the Investigator’s signature.  The Investigator should follow up on treatment-emergent serious 
adverse events (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 
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, 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 serious adverse event (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 
signing the Informed Consent Form) 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). 
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 (end of the on-treatment period) that 
the Investigator assesses as related to study drug should also be reported. 
All SAEs, and pregnancy reports are to be reported according to the procedures in Section 10.1.3. 
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10.1.2. 
Reporting Procedure 
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the study drug.  For SAEs, a detailed narrative summarizing 
the course of the event, including its evaluation, treatment, and outcome should be provided on the 
AE 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). 
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). 
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• 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 a hospital admission (any duration) or an 
emergency room visit 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 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. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
10.2.4. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
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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 & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
• Patient’s medical and social history  
Causality to the Study Drug 
• 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 
(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: 
− 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. 
Causality to the Injection Procedure 
The relationship of AEs to the injection procedure is assessed by the investigator, and is a clinical 
decision based on all available information.  The following question is addressed: 
Is there a reasonable possibility that the AE may have been caused by the injection procedure? 
The possible answers are: 
Not Related: There is a reasonable possibility that the event may have been caused by the 
injection procedure 
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Related: 
There is a reasonable possibility that the event may have been caused by the 
injection procedure 
Causality to the Study Conduct (Protocol-Specified 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 (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. 
10.4. 
Notifying Health Authorities, Institutional Review Board, and 
Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, 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 
(aflibercept), 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 IRB unless delegated to the sponsor. 
Event expectedness for study drug (aflibercept) is assessed against the Reference Safety 
Information section of the 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 IRBs as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to make 
changes to adapt to unexpected issues in study execution and data that may affect the planned 
analyses.  The final SAP will be issued before the first database lock. 
Endpoints are listed in Section 4.  Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis 
No formal hypothesis has been defined for the safety analysis at week 4. 
However, the study will examine the following hypothesis for the superiority testing of the primary 
efficacy variable:  proportion of patients without retinal fluid at week 16.  Statistical testing will 
be conducted to show superiority of HD versus IAI. 
H0:  p1 = p2, against Ha: p1 ≠ p2 
where p1 and p2 are the proportion of patients without retinal fluid at week 16 in HD versus IAI, 
respectively. 
11.2. 
Justification of Sample Size 
For this phase 2 safety study, 50 patients per group is sufficient to provide substantial information 
regarding safety.  Assume that the proportion of patients without fluid in the center subfield in the 
IAI group is 50% with normal approximation and drop out rate is 8%.  Then a total sample size of 
100 patients will allow estimation of the true treatment difference to be between (+6.7% to 
+43.3%) at 95% confidence level, if the observed treatment difference is +25% (ie, observed 
proportion of patients without fluid in the center subfield in HD group is 75%). 
The sample size was estimated based on normal approximation for the confidence interval of the 
difference in proportions using the commercial software nQuery nTerm 7.0. 
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients; it is based on the treatment allocated 
(as randomized).  Efficacy endpoints will be analyzed using the FAS. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF.  Additional safety analyses will be performed on 
patients included in the dense PK substudy. 
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11.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all patients who received any study drug and who had a at 
least 1 non-missing result following the first dose of study drug.  Patients will be analyzed based 
on actual treatment received. 
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. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of randomized patients: received a randomization number 
• The total number of patients in each analysis set 
• 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 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
Analysis of the primary efficacy variable will take place at week 16.  The efficacy analysis for the 
primary efficacy endpoint will be the comparison between the IAI group and the HD group for the 
proportion of patients without fluid in the center subfield at week 16.  The statistical analysis will 
be performed using the chi-square test at the 2-sided 5% significance level. 
For the primary analysis, missing post-baseline values for a given patient will be imputed using 
the last observation carry forward (LOCF) procedure to determine the patient’s primary efficacy 
response. 
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Observed case (OC) analysis will be performed for primary efficacy endpoint as sensitivity 
analysis, ie, only observed values will be used for analysis. 
11.4.3.2. Exploratory Efficacy Analysis 
For the following categorical exploratory endpoints, analyses will be performed in the same 
manner as for the primary efficacy analysis: 
• The proportion of patients without retinal fluid in the center subfield at week 44 
• The proportion of patients without intraretinal fluid (IRF) at week 16 and week 44 
• The proportion of patients without subretinal fluid (SRF) at week 16 and week 44 
• The proportion of patients without RPE fluid at week 16 and week 44 
• The proportion of patients able to maintain dry retina (total fluid, IRF, and/or SRF) 
through week 16 and week 44 
• The proportion of patients able to maintain a 12-week dosing interval from week 8 
through week 44 
The continuous exploratory endpoints (such as mean change in CRT, mean change in BCVA, 
mean change in lesion size and CNV size) will be summarized descriptively. They will also be 
analyzed using an analysis of covariance model with treatment as the main effect and baseline 
measurement as covariate.  Missing data will be imputed using the LOCF method. In addition, 
supportive analyses may be conducted using mixed-model repeated measures (MMRM) analysis 
model (of which missing values will not be imputed explicitly) using treatment group, visit and 
baseline measurements as factors. 
11.4.4. 
Control of Multiplicity 
There will be no control for multiplicity. 
11.4.5. 
Safety Analysis 
The safety variables will be analyzed on the SAF for the on-treatment period from baseline/day 1 
through week 4 (primary analysis) and the end of study (week 44).   
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 TEAEs) is defined as the time from the first dose 
of study drug to the last dose of study drug plus 30 days, or to the last study visit 
(week 44), whichever is later.  
• The posttreatment period is defined as after the end of the on-treatment period. 
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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 the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.3), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
Deaths and other SAEs will be listed and summarized 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 (temperature, pulse, and BP) will be summarized by baseline and change from baseline 
to each scheduled assessment time with descriptive statistics.  Blood pressure will be measured in 
all patients at the time points indicated in Table 1 and Table 2.  Changes in BP will be assessed 
using a time-weighted average change from baseline at select visits and the mean change from 
baseline at all visits. 
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. 
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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) x 100%. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
Main Study: 
The concentrations of free and bound aflibercept over time will be summarized by descriptive 
statistics for each treatment group.  No formal statistical hypothesis testing will be performed. 
Dense PK Substudy: 
The PK parameters to be determined after the first dose for free and bound aflibercept may include, 
but are not limited to: 
• Cmax 
• Cmax/Dose 
• tmax 
• tlast 
• Clast 
• 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. 
The concentrations of free and bound aflibercept over time and selected PK parameters will be 
summarized by descriptive statistics by treatment group.  This descriptive statistical assessment 
will 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. 
11.5. 
Interim Analysis 
No formal interim analyses will be performed. However, data may be reviewed in this single-
masked study at various time points for safety and/or efficacy. 
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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. 
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 (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, contract research organization [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. 
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The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
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 Case Report 
Forms (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 
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Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
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 CRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
CRF 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.  
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. 
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13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB.  A copy of the IRB-approved ICF and documentation of 
approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient.   
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, 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. 
13.3. 
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. 
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 
An appropriately constituted IRB, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB should be informed as soon as possible  
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• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB should be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical study. 
A copy of the IRB approval letter with a current list of the IRB members and their functions must 
be received by the sponsor prior to shipment of drug supplies to the investigator.  The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Treatment codes will be disseminated to each investigation site approximately 8 weeks following 
the final study data base lock.  Final study results will be published on a public clinical trial website 
according to applicable local guidelines and regulations. 
14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB-
approved amendment.  Where required per local legislation, regulatory authority approval will also 
be sought.  
15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
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Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB and Health Authorities must be informed according to applicable 
regulatory requirements, and adequate consideration must be given to the protection of the 
patients’ interests. 
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 
Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of 
antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. 
Br Med J 2002; 324:71-86. 
Antithrombotic Trialists’ Collaboration. Collaborative overview of randomized trial of antiplatelet 
therapy – II: Maintenance of vascular graft or arterial patency by antiplatelet therapy.  Br Med J 
1994; 308:168-171. 
Early Treatment Diabetic Retinopathy Study research group.  Photocoagulation for diabetic 
macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 
1985 Dec;103(12):1796-806. 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol:  A Randomized, Single-Masked, Active-Controlled Phase 2 
Study of the Safety, Tolerability, and Efficacy of Repeated Doses of High-Dose Aflibercept in 
Patients with Neovascular Age-Related Macular Degeneration and agree to abide by all provisions 
set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
 (Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the intended conduct of the study. 
Study Title: 
 A Randomized, Single-Masked, Active-Controlled Phase 2 Study of the Safety, 
Tolerability, and Efficacy of Repeated Doses of High-Dose Aflibercept in Patients with 
Neovascular Age-Related Macular Degeneration 
Protocol Number: 
VGFTe (HD)-AMD-1905  
Protocol Version:  
VGFTe (HD)-AMD-1905 Amendment 3 
 
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-00159203 v1.0
Signature Page for VV-RIM-00159203 v1.0 Approved
ESig Approval
ESig Approval
ESig Approval
ESig Approval
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 48 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: 2.0 
Clinical Study Protocol 
Title: 
A Randomized, Single-Masked, Active-Controlled Phase 2 
Study of the Safety, Tolerability, and Efficacy of Repeated 
Doses of High-Dose Aflibercept in Patients with Neovascular 
Age-Related Macular Degeneration 
Compound: 
Intravitreal Aflibercept Injection 
Protocol Number: 
VGFTe (HD)-AMD-1905 
Clinical Phase: 
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date: 
Version 2.0 / 26JUL2021 
Original Statistical Analysis Plan / 16JUL2020 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: VGFTe (HD)-AMD-1905 
Statistical Analysis Plan Version 2.0 
 
Date: 26JUL2021 
 
CONFIDENTIAL 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
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
 
Designee: 
  
 
See appended electronic signature page 
Head of BDM or designee 
 
 
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Protocol: VGFTe (HD)-AMD-1905 
Statistical Analysis Plan Version 2.0 
 
Date: 26JUL2021 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale ..................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Exploratory Objectives .................................................................................................9 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ..................................9 
1.2.5. 
Revision History for SAP Amendments .......................................................................9 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................14 
3. 
ANALYSIS POPULATIONS ....................................................................................15 
3.1. 
Full Analysis Set .........................................................................................................15 
3.2. 
Safety Analysis Set .....................................................................................................15 
3.3. 
Pharmacokinetic Analysis Set ....................................................................................15 
4. 
ANALYSIS VARIABLES .........................................................................................16 
4.1. 
Demographic and Baseline Characteristics ................................................................16 
4.2. 
Medical History ..........................................................................................................16 
4.3. 
Prior/Concomitant Medication ...................................................................................16 
4.4. 
Treatment Exposure/Compliance ...............................................................................17 
4.4.1. 
Exposure to Study Drug ..............................................................................................17 
4.4.2. 
Measurement of Compliance ......................................................................................18 
4.5. 
Efficacy Variables ......................................................................................................18 
4.5.1. 
Primary Efficacy Variable ..........................................................................................18 
4.5.2. 
Secondary Efficacy Variable ......................................................................................18 
4.5.3. 
Exploratory Efficacy Variables ..................................................................................18 
4.6. 
Safety Variables ..........................................................................................................19 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................19 
4.6.2. 
Surgeries .....................................................................................................................19 
4.6.3. 
Laboratory Safety Variables .......................................................................................19 
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4.6.4. 
Vital Signs ..................................................................................................................20 
4.6.5. 
12-Lead ECG ..............................................................................................................20 
4.6.6. 
Ocular Safety Variables ..............................................................................................20 
4.7. 
Pharmacokinetic Variables .........................................................................................20 
5. 
STATISTICAL METHODS .......................................................................................21 
5.1. 
Demographics and Baseline Characteristics ...............................................................21 
5.2. 
Medical History ..........................................................................................................21 
5.3. 
Prior/Concomitant Medications ..................................................................................21 
5.4. 
Subject Disposition .....................................................................................................21 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................22 
5.6. 
Analyses of Efficacy Variables ..................................................................................22 
5.6.1. 
Analysis of Primary Efficacy Variable(s) ...................................................................22 
5.6.2. 
Analysis of Exploratory Efficacy Variables ...............................................................23 
5.6.3. 
Subgroup Analyses .....................................................................................................23 
5.6.4. 
Control of Multiplicity ................................................................................................23 
5.7. 
Analysis of Safety Data ..............................................................................................24 
5.7.1. 
Adverse Events ...........................................................................................................24 
5.7.2. 
Surgeries .....................................................................................................................25 
5.7.3. 
Clinical Laboratory Measurements.............................................................................25 
5.7.4. 
Analysis of Vital Signs ...............................................................................................25 
5.7.5. 
Analysis of 12-Lead ECG ...........................................................................................27 
5.7.6. 
Analysis of Ocular Safety Variables ...........................................................................27 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................28 
5.8.1. 
Analysis of Drug Concentration Data .........................................................................28 
5.8.2. 
Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses ....................28 
6. 
DATA CONVENTIONS ............................................................................................29 
6.1. 
Definition of Baseline .................................................................................................29 
6.2. 
Visit Windows ............................................................................................................29 
6.3. 
Unscheduled Assessments ..........................................................................................29 
6.4. 
Handling of Patients who Discontinue .......................................................................29 
6.5. 
Data Handling Convention for Missing Data .............................................................29 
7. 
INTERIM ANALYSIS ...............................................................................................30 
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Statistical Analysis Plan Version 2.0 
 
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8. 
SOFTWARE ...............................................................................................................31 
9. 
SUMMARY OF MEASURES AND ANALYSES ADDRESSING IMPACT 
OF COVID-19 ............................................................................................................32 
10. 
REFERENCES ...........................................................................................................34 
11. 
APPENDIX.................................................................................................................35 
11.1. 
Schedule of Time and Events .....................................................................................35 
11.1.1. 
Schedule of Events for the Study ................................................................................35 
11.1.2. 
Schedule of Events for the Dense PK Substudy .........................................................39 
11.2. 
Detailed Definition of special AEs .............................................................................40 
11.2.1. 
Hypertension ...............................................................................................................40 
11.2.2. 
Intraocular inflammation ............................................................................................42 
11.2.3. 
Nasal mucosal events ..................................................................................................42 
11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................44 
11.4. 
Process to Derive Week 16 Data Cut-off ...................................................................46 
11.4.1. 
Visit Dependent Data ..................................................................................................46 
11.4.2. 
Visit Independent Data ...............................................................................................46 
11.4.3. 
Study Medication Data ...............................................................................................47 
11.5. 
Process to Derive Week 4 Data Cut-off .....................................................................48 
 
LIST OF TABLES 
Table 1: 
Revision History for SAP Amendments .....................................................................10 
Table 2: 
Schedule of Events .....................................................................................................35 
Table 3: 
Schedule of Events (Dense PK Substudy) ..................................................................39 
Table 4: 
Criteria for Potentially Clinically Significant Values .................................................44 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................13 
Figure 2: 
Dosing Schedule .........................................................................................................14 
 
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Statistical Analysis Plan Version 2.0 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AOBP 
Automated office blood pressure 
APTC 
Anti-Platelet Trialists' Collaboration 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutically Chemical 
AUC 
Area under the curve 
BCVA 
Best Corrected Visual Acuity 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CMH 
Cochran-Mantel-Haenszel 
CNV 
Choroidal neovascularization 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic) 
CRT 
Central retinal thickness 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
FAS 
Full analysis set 
FP 
Fundus photography 
HD 
High-dose aflibercept injection 
HDL 
High-density lipoprotein 
IAI 
Intravitreal Aflibercept Injection 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IOP 
Intraocular pressure 
IRF 
Intraretinal fluid 
IVT 
Intravitreal 
IWRS 
Interactive web response system 
LOCF 
Last observation carry forward 
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Statistical Analysis Plan Version 2.0 
 
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LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-model repeated measures 
nAMD 
Neovascular “wet” age-related macular degeneration 
OC 
Observed case 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PRN 
Pro re nata 
PT 
Preferred term 
RBC 
Red blood cell 
RPE 
Sub-retinal pigment epithelium 
RVO 
Retinal vein occlusion 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
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 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
WHODD 
WHO Drug Dictionary 
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Statistical Analysis Plan Version 2.0 
 
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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 VGFTe (HD)-AMD-1905 study. 
1.1. 
Background/Rationale 
Neovascular “wet” age-related macular degeneration (nAMD) is a major health issue in aging 
populations globally. Vision loss in nAMD results from the abnormal growth and leakage of 
blood vessels in the macula. In elderly patients affected by nAMD, vision loss frequently has an 
even greater impact, as it substantially reduces the visual compensation of functional impairment 
by other age-related comorbidities, such as arthritis and osteoporosis. 
Intravitreally (IVT) administered anti-vascular endothelial growth factor (VEGF) therapies like 
EYLEA® inhibit neovascular vessel growth and leakage in the retina, and they are currently the 
standard of care for patients with nAMD. Anti-VEGF agents not only maintain visual function 
but can also provide clinically meaningful visual gains. Treatment of nAMD must generally be 
continued throughout a patient's lifetime in order to suppress retinal edema and recurrences of 
choroidal neovascularization (CNV). Although the currently approved IVT anti-VEGF therapies 
are efficacious and well-tolerated, the need for IVT injections every 4 to 8 weeks, both in the 
initial phase and during maintenance of treatment, represents a significant burden to physicians, 
patients, and caregivers. While the procedure is straightforward and relatively easy to perform, 
capacity issues for ensuring an appropriate injection frequency in order to achieve patient 
outcomes similar to those seen in the pivotal studies represent an increasing challenge to 
individual practices and the healthcare system, overall. 
While the efficacy and safety of currently approved anti-VEGF therapies have been established 
for the treatment of nAMD, there remains an unmet medical need for the development of 
therapies with the potential to reduce treatment burden while providing at least similar or even 
improved visual outcomes over currently available standard of care. 
Increasing the molar fraction of anti-VEGF therapeutic protein in the dosing formulation is a 
potential way to bring further benefits to patients with chorioretinal vascular diseases, including 
nAMD. A higher dose of aflibercept administered IVT has the potential to prolong the drug’s 
therapeutic effects. The resulting extension of treatment intervals early after the initiation of 
treatment to every 12 weeks or 16 weeks would reduce the number of injections in the first 
treatment year. A potential decrease in injection-related treatment burden and safety events with 
fewer injections could be a significant contribution to patient care and healthcare services. 
This study will investigate the safety and efficacy of a high-dose aflibercept IVT injection with 
the intent of extending the dosing interval, with at least similar functional and potentially 
improved anatomic outcomes. EYLEA® (2 mg dose, administered at a concentration of 
40 mg/mL, also called intravitreal aflibercept injection [IAI]) is currently approved in the United 
States for the treatment of nAMD, and is also approved for the treatment of macular edema 
following retinal vein occlusion (RVO), diabetic macular edema (DME), and diabetic 
retinopathy (DR). Multiple indications have also received regulatory approval in countries 
outside the US. 
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1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objectives of the study are: 
• To determine the safety of high-dose aflibercept (hereafter referred to as HD). 
• To determine if HD provides greater intraocular pharmacodynamic (PD) effect and/or 
longer duration of action compared 2 mg IAI (hereafter referred to as IAI). 
1.2.2. 
Secondary Objectives 
There are no secondary objectives in this study. 
1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To generate additional data to determine the effect of HD vs IAI on anatomical 
measures of response and on visual acuity. 
• To characterize the concentrations in plasma over time and corresponding 
pharmacokinetic (PK) parameters for free, bound, and adjusted bound aflibercept 
(collectively referred to as bound) and to conduct exploratory PK/PD and/or dose/PD 
analyses on selected systemic and ocular response variables. 
• To study molecular drivers of nAMD or related diseases, the mechanism of action of 
EYLEA® (afIibercept) and the VEGF pathway. 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
Not applicable. 
1.2.5. 
Revision History for SAP Amendments 
Version 2.0  
The purpose of this amendment is to change the time point for evaluation of the primary endpoint 
(proportion of patients without retinal fluid in the center subfield) and certain exploratory 
endpoints from Week 20 to Week 16.  This will allow a direct comparison of the 2 treatment groups 
prior to any Additional/Rescue treatment being administered which could potentially confound 
interpretation of the results. 
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Table 1: 
Revision History for SAP Amendments 
Change  
Rationale for Change 
Section(s) 
Change of the time point for evaluation of the 
primary endpoint and certain exploratory efficacy 
endpoints from Week 20 to Week 16  
To allow head-to-head 
comparison of the 2 treatment 
arms without potential 
confounding by 
additional/rescue treatment. 
Week 16 is 8 weeks after the 
third initial loading dose in both 
treatment groups and represents 
the earliest timepoint to assess 
anatomic differences in 
treatment effect between 2 mg 
and 8 mg. Since some patients 
will receive additional dosing at 
Week 16 while others will not, 
20 weeks is less ideal for 
understanding and comparing 
treatment effects.  
2.1 Study Design and 
Randomization 
2.2 Sample Size 
4.5 Efficacy Variables 
4.6.6 Ocular Safety 
Variables 
5.6 Analysis of 
Efficacy Variable(s) 
7 Interim Analysis 
11.4 and 11.5 Process 
to derive data cut-off 
date 
Added a clarifying note: 
Note: up to and including week 16, aLOCF and 
LOCF analysis are identical, and so are aOC and 
OC. 
Clarification needed for the 
new primary timepoint of 
analysis. 
5.6.1 Analysis of 
Primary Efficacy 
Variable(s) 
 
Deleted the following typographical error: 
“Patients who have received additional 
treatment’ 
Typographical error 
5.6.1. Analysis of 
Primary Efficacy 
Variable(s) 
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Change  
Rationale for Change 
Section(s) 
Changed: For the primary analysis, missing post-
baseline values for a given patient will be 
imputed using the last observation carry forward 
(LOCF) procedure to determine the patient’s 
primary efficacy response. For any patient who 
receives additional treatment at week 16, 
measurements after additional treatment is given 
will be imputed using the last observation prior 
to additional treatment. Patients will be 
considered as non-responders if all post-baseline 
observations are missing. LOCF procedure has 
been used in previous ophthalmology studies. 
Therefore, LOCF method will be used in this HD 
phase 2 study.  
To: 
For the primary analysis, missing post-
baseline values for a given patient will be 
imputed using the last observation carry 
forward (LOCF) procedure to determine the 
patient’s primary efficacy response.  
• LOCF analysis: 
Missing observations are imputed by 
the last non-missing post-baseline 
observation. Patients will be 
considered as non-responders if all 
post-baseline observations are 
missing. For any patient who receives 
additional treatment at week 16, i.e., 
rescue, upon discussion with the 
Sponsor, their measurements at time 
points past week 16 will be imputed 
using the last observation prior to 
additional treatment at week 16.  For 
remaining patients, their observed 
data at time points past week 16 will 
be included as usual. 
Rationale: The analysis 
timepoint is week 16, so no 
“carry forward” of data from 
week 16 is necessary. 
5.6.1. Analysis of 
Primary Efficacy 
Variable(s) 
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Change  
Rationale for Change 
Section(s) 
Deleted statement: “Observed case (OC) analysis 
will be performed for primary efficacy endpoint 
as sensitivity analysis, i.e., only observed values 
will be used for analysis.” As a OC and OC are 
identical for week 16 timepoint and aOC is being 
refered to later on in this paragraph. 
aOC and OC are identical 
for week 16 timepoint and 
aOC is being refered to later 
on in this paragraph. 
5.6.1. Analysis of 
Primary Efficacy 
Variable(s) 
Deleted statement: “Data will not be imputed for 
the safety analysis.”. 
Missing dates imputations 
are described in this SAP. 
5.7 Analysis of Safety 
Data 
Changed: TEAEs by relationship to 
treatment (related, not related), presented by 
SOC and PT 
To: Treatment related TEAEs presented by 
SOC and PT 
 
We will present TEAEs 
regardless of relationship, 
and also, separately, 
treatment-related TEAEs. 
"Not related” TEAEs will 
not be summarized 
separately. 
5.7 Analysis of Safety 
Data 
Changed: In addition, the review of safety 
and efficacy will occur at the following 
timepoints:  
• When all patients in the PK substudy 
(n=~30) have reached week 4, in 
order to assess safety in a 
subpopulation after the initial dose 
• When all patients in the PK substudy 
(n=~30) have reached week 12, in 
order to assess safety and efficacy in 
a subpopulation of patients after the 
loading phase 
• When all patients have reached week 
12, in order to assess safety and 
efficacy in the total population at the 
end of the loading phase 
To: In addition, a review of the safety and 
efficacy data will occur periodically 
throughout the conduct of the study. 
 
Periodic reviews of safety 
and efficacy data are 
being completed more 
frequently than the 
specific visit cutoffs 
described in this section. 
7 Interim Analysis 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This phase 2, multi-center, randomized, single-masked study in patients with nAMD will 
investigate the efficacy, safety, and tolerability of HD versus IAI.  
The study consists of a screening/baseline period, a treatment period, and an end of study (EOS) 
visit at week 44 (Figure 1) (Figure 2). Patients will be seen monthly through week 44. A total of 
approximately 100 eligible patients will be randomized into 2 groups in a 1:1 ratio. One group 
will receive IAI and the other will receive HD. The investigational product will be administered 
IVT monthly for 3 initial injections (baseline, week 4, and week 8), followed by additional doses 
at weeks 20 and 32. At weeks 24, 28, 36 and 40, patients will be evaluated and given a dose (at 
their randomized dose level) if both of the following criteria are met (pro re nata [PRN] criteria): 
• Loss of ≥5 letters from week 20 Best Corrected Visual Acuity (BCVA) due to disease 
progression 
• Persistence or recurrence of disease activity indicated by worsening or persistent 
retinal fluid, or new or persistent hemorrhage 
Figure 1: 
Study Flow Diagram 
 
EP=endpoint, pts=patients 
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Figure 2: 
Dosing Schedule 
 
 
 
The primary safety analysis will take place at week 4. The primary efficacy analysis will take 
place at week 16, with the exploratory endpoints evaluated at week 16 and week 44. 
Approximately 100 patients will be recruited and randomized from approximately 60 sites in a 
1:1 ratio to receive either IAI or HD according to a central randomization scheme provided by an 
interactive web response system (IWRS) to the designated study pharmacist (or qualified 
designee). Randomization will be stratified according to whether patients enter into dense PK 
substudy, to allow for equal allocation in both treatment groups (n~15 patients per group in 
dense PK substudy).  
The Study event table is presented in Appendix 11.1. 
Dense PK Substudy 
Approximately 15 patients eligible for the dense PK substudy will be randomized to each 
treatment group. Schedule of study assessments for patients in the PK substudy is given in 
Table 3 (Section 11.1). 
2.2. 
Sample Size and Power Considerations  
For this phase 2 safety study, 50 patients per group are sufficient to provide information 
regarding safety. Assuming that the proportion of patients without fluid in the center subfield at 
week 16 in the IAI group is 50% and drop out rate is 8%, then a total sample size of 100 patients 
will allow estimation of the true treatment difference to be between +6.7% to +43.3% at 95% 
confidence level (normal approximation), if the observed treatment difference is +25% (i.e., 
observed proportion of patients without fluid in the center subfield at week 16 in HD group is 
75%). 
The sample size was estimated based on normal approximation for the confidence interval of the 
difference in proportions using the commercial software nQuery nTerm 7.0. 
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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. 
Full Analysis Set 
The full analysis set (FAS) includes all randomized patients; it is based on the treatment 
allocated (as randomized). 
FAS is the primary analysis set for efficacy endpoints, unless specified otherwise.  
3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF. Additional safety analyses may be 
performed on patients included in the dense PK substudy. 
3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set includes all patients who received any study drug and who had at least 1 
non-missing drug concentration result following the first dose of study drug. Patients will be 
analyzed based on actual treatment received. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic variables will be summarized:  
• Age (year) 
• Age category:>=50-<65y; >=65y  
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic/Latino) 
• Baseline Weight 
• Baseline Height 
• Baseline Body mass index (BMI) calculated from weight and height 
• Categorized BMI: BMI<=30 kg/m², BMI >30- <=35 kg/m², BMI >35 kg/m² 
• Baseline blood pressure (systolic and diastolic), heart rate, temperature 
• Smoking History: Current, Past, Never 
The following baseline characteristics will be included: 
• BCVA 
• Central retinal thickness (CRT) 
• Intraocular pressure (IOP) 
• CNV size 
• Total Lesion Area 
• Lesion sub-type 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
4.3. 
Prior/Concomitant Medication 
Medications will be recorded from the time of informed consent to the final study visit. 
Medications will be coded to the Anatomical Therapeutic Chemical level 2 (ATC, therapeutic 
main group) and ATC level 4 (chemical/therapeutic subgroup), according to the latest available 
version of WHO Drug Dictionary (WHODD). Patients will be counted once in all ATC 
categories linked to the medication. 
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Mediations will be summarized as follows: 
• Prior medications: medications started and ended prior to administration of the study 
drug 
• Concomitant medications: medications that are ongoing at, or begin after the 
administration of the study drug 
• New medications: medications that begin after the start of study treatment 
The prior, concomitant and new medication will be summarized by ATC class (ATC level 1) and 
subclass (ATC level 2). 
Variables for concomitant medication description and analysis will include Generic name, ATC 
level codes, Indication, Dose/Dose Unit, Frequency, Route, start/end date and study day, 
Duration, Ongoing. 
4.4. 
Treatment Exposure/Compliance 
4.4.1. 
Exposure to Study Drug 
The following variables regarding exposure to study drug in the Study Eye for each patient will 
be summarized: 
• The total number of injections administered (including PRN injections and the 
additional treatment at week 16) 
• The total number of injections administered adjusted for additional treatment, that is, 
including only planned injections for patients who receive additional treatment at 
week 16, and including planned injections and PRN injections for patients who don’t 
receive additional treatment at week 16 
• Proportion of patients who only receive planned injections 
• Proportion of patients who receive PRN and the total number of PRN injection 
administered 
• Proportion of patients who receive PRN and the total number of PRN injection 
administered for patients who do not receive additional treatment at week 16 
• Proportion of patients who receive PRN and the total number of PRN injection 
administered for patients who receive additional treatment at week 16  
• Duration of treatment calculated (Weeks) as: [(last study treatment date) - (first study 
treatment date) + 28]/7 (28 days are added because of the minimum 4 week dosing 
interval in the study) 
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4.4.2. 
Measurement of Compliance 
Compliance with protocol-defined study medication will be calculated as follows: 
Treatment compliance = (number of received injections through the analysis time)/(number of 
planned injections during the period of participation in the study through the analysis time) × 
100%.Compliance will be summarized as both continuous and categorical variables (<60% vs. 
>=60%), as well as number of patients receiving 100% injections. 
The planned injections above do not include PRN or additional treatment at week 16. 
4.5. 
Efficacy Variables 
4.5.1. 
Primary Efficacy Variable 
The proportion of patients without retinal fluid in the center subfield at week 16. Here, without 
retinal fluid means absence of both IRF and SRF. 
4.5.2. 
Secondary Efficacy Variable 
There is no secondary efficacy variable in this study. 
4.5.3. 
Exploratory Efficacy Variables 
The exploratory endpoints are: 
• The proportion of patients without retinal fluid in the center subfield at week 44 
• Change in CRT from baseline through week 16 and week 44 
• The proportion of patients without intraretinal fluid (IRF) at week 16 and week 44 
• The proportion of patients without subretinal fluid (SRF) at week 16 and week 44 
• The proportion of patients without sub-retinal pigment epithelium (RPE) fluid at 
week 16 and week 44 
• The proportion of patients able to maintain dry retina (absence of IRF and/or SRF) 
through week 16 and week 44 (Maintain dry is defined as reaching dry and 
maintaining dry for all subsequent study visits and at least two consecutive visits) 
• The proportion of patients able to maintain a 12-week dosing interval from week 8 
through week 44, i.e., the proportion of patients who do not receive PRN injections or 
additional injection at week 16. The denominator is based on the number of patients 
who complete the study 
• Change in CRT between dosing visits from week 8 through week 44 will be 
summarized in the following intervals: 
− change from week 8 through week 12; 
− change from week 12 through week 16; 
− change from week 16 through week 20; 
− for visit after week 20, change between the dosing visits; 
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• Change in BCVA from baseline, and proportions of patients gaining and losing 
vision, through week 16 and week 44 
• Change in lesion size and CNV size from baseline through week 44 
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. 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). 
A Serious Adverse Event (SAE) is an AE that is classified as serious according to the criteria 
specified in the protocol. 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded to a 
PT and associated primary SOC according to the MedDRA® (the Version 22.0 or the latest 
current available version). 
Other variables for AE description and analysis will include AE Verbatim Term, AE start date 
and end date/ongoing and corresponding study day, AE duration, relationship of AE to study 
drug, relationship of AE to study procedure, seriousness, severity, action due to AE, treatment of 
AE and outcome. 
In addition to standard AE summaries, adjudicated Anti-Platelet Trialists' Collaboration (APTC) 
events, intraocular inflammation, hypertension and nasal mucosa events will be summarized as 
described in Section 5.7.1. 
4.6.2. 
Surgeries 
All the surgeries after informed consent are collected on the CRF and are coded by MedDRA. 
Treatment emergent surgery is defined as surgery performed on or after the start of study 
treatment. 
4.6.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, and other. 
Clinical laboratory values will be converted to standard international (SI) units and grouped by 
function in summary tables. Conventional unit may be provided. 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 
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(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 
4.6.4. 
Vital Signs 
Variables of analysis for vital signs include temperature, blood pressure (BP, systolic and 
diastolic) and heart rate. 
4.6.5. 
12-Lead ECG 
Variables of 12-Lead Electrocardiogram (ECG) include PR interval, QRS interval, RR interval, 
QT interval, Ventricular rate and Heart rate. 
4.6.6. 
Ocular Safety Variables 
Ocular AEs (including IOI) will be summarized as described in Section 4.6.1 and Section 5.7.1. 
In addition, other variables of analysis for ocular safety measures include IOP. Variables of 
analysis in Study Eye from baseline through week 16 and week 44 include proportion of patients 
with increased IOP: 
• ≥ 10 mmHg increase in IOP measurement from baseline to any pre-dose 
measurement 
• > 21 mmHg for any pre-dose measurement 
• ≥ 25 mmHg for any pre-dose measurement 
• ≥ 35 mmHg at any time 
Post dose IOP measurement should be the last IOP recorded. 
4.7. 
Pharmacokinetic Variables  
The PK variables are the concentrations of free, bound, adjusted bound, and total aflibercept in 
plasma at each time point, using both sparse and dense sampling. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following information: the 
number of patients reflected in the calculation (n), mean, standard deviation, 1st quartile, median, 
3rd quartile, minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined for SAF and FAS. Parameters to be summarized include those 
described in Section 4.1. 
5.2. 
Medical History 
Medical history will be descriptively summarized for FAS. Summaries will show number and 
percentage of patients by primary SOC and PT. The tables will be sorted by decreasing 
frequency of primary SOC. Within each primary SOC, PTs will be sorted by decreasing 
frequency. 
5.3. 
Prior/Concomitant Medications 
All prior/concomitant/new 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 ATC followed by ATC level 2, ATC level 4 and PT. 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, hence 
may be counted several times for the same medication. 
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. 
Subject Disposition 
The disposition of patients in the study will be summarized by treatment group and overall for 
FAS. 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 met the inclusion criteria regarding the 
target indication and signed the Informed consent form (ICF) 
•  The total number of randomized patients who received a randomization number 
• The total number of patients in each analysis set 
• 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 
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The following listings will also be provided: 
• 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 
5.5. 
Extent of Study Treatment Exposure and Compliance 
Exposure to study drug and compliance 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. 
5.6. 
Analyses of Efficacy Variables 
5.6.1. 
Analysis of Primary Efficacy Variable(s) 
Analysis of the primary efficacy variable will take place at week 16. The efficacy analysis for the 
primary efficacy endpoint will be the comparison between the IAI group and the HD group for 
the proportion of patients without retinal fluid in the center subfield at week 16. The statistical 
analysis will be performed using chi-square test at the 2-sided 5% significance level. The 95% 
CIs will be provided based on normal approximation. P-value will also be provided for 
comparing the proportion of patients without retinal fluid at week 16 in HD versus IAI. 
For the primary analysis, missing post-baseline values for a given patient will be imputed using 
the last observation carry forward (LOCF) procedure to determine the patient’s primary efficacy 
response.  
• LOCF analysis: 
Missing observations are imputed by the last non-missing post-baseline observation. 
Patients will be considered as non-responders if all post-baseline observations are 
missing. For any patient who receives additional treatment at week 16, i.e., rescue, upon 
discussion with the Sponsor, their measurements at time points past week 16 will be 
imputed using the last observation prior to additional treatment at week 16.  For 
remaining patients, their observed data at time points past week 16 will be included as 
usual. 
LOCF procedure has been used in previous ophthalmology studies. Therefore, LOCF method 
will be used in this HD phase 2 study.  
The following sensitivity analyses are used for the primary efficacy variable: 
• Observed case (OC) analysis 
Measurements taken after the initiation of additional treatment at week 16 will be 
censored; only observed and non-censored values will be used for analysis, (i.e. missing 
data will not be imputed). 
In the following analyses, the value at the given timepoint will be used regardless of whether the 
patient received additional treatment or not. Two different analyses will be conducted: 
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• Ancillary LOCF (aLOCF) – Data obtained after the initiation of additional treatment 
will be included; missing data will be imputed by LOCF. Patients will be considered 
as non-responders if all post-baseline observations are missing. The data will be 
analyzed in the same way as described for the primary analysis.  
• Ancillary observed case (aOC) - All observed values will be used for analysis, 
including measurements taken after the initiation of additional treatment is given. 
Missing data will not be imputed. The data will be analyzed in the same way as 
described for the primary analysis. 
Note: up to and including week 16, aLOCF and LOCF analyses are identical, and so are aOC and 
OC. 
5.6.2. 
Analysis of Exploratory Efficacy Variables 
For the following binary exploratory endpoints, analyses will be performed in the same manner 
as for the primary efficacy analysis: 
• The proportion of patients without retinal fluid in the center subfield at week 44 
• The proportion of patients without IRF at week 16 and week 44 
• The proportion of patients without SRF at week 16 and week 44 
• The proportion of patients without Sub-RPE fluid at week 16 and week 44 
• The proportion of patients able to maintain (defined as meeting the criteria for "dry" 
at least two consecutive visits and for all subsequent visits) dry retina (IRF, and/or 
SRF) through week 16 and week 44 
• The proportion of patients able to maintain a 12-week dosing interval from week 8 
through week 44 
The continuous exploratory endpoints (such as mean change in CRT, mean change in BCVA, 
mean change in lesion size and CNV size) will be summarized descriptively. They will also be 
analyzed using an analysis of covariance model with treatment as the main effect and baseline 
measurement as a covariate. Missing data will be imputed using LOCF procedure. The following 
sensitivity analyses will be done for efficacy endpoints: OC, aLOCF, and aOC as defined in 
Section 5.6.1. In addition, supportive analyses will be conducted for change in BCVA from 
baseline using mixed-model repeated measures (MMRM) analysis model (of which missing 
values will not be imputed explicitly). The model will include treatment group, visit as fixed 
factors as well as terms for the interaction between baseline and the visit and for the interaction 
between treatment and visit and baseline BCVA measurements as covariate. 
5.6.3. 
Subgroup Analyses 
There will be no pre-defined subgroup analyses in this study. 
5.6.4. 
Control of Multiplicity 
There will be no control for multiplicity. 
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5.7. 
Analysis of Safety Data 
The safety variables as defined in Section 4.6 will be analyzed on the SAF for the on-treatment 
period from baseline/day 1 through week 4 (primary analysis) and the end of study (week 44).  
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs, 12-lead ECG and physical exams). 
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Appendix 11.3. 
The summary of safety results will be presented for each treatment group. 
5.7.1. 
Adverse Events 
All AEs reported in this study will be coded using the currently available version of the 
MedDRA®. Coding will be to lowest level terms. The verbatim text, the PT, and SOC will be 
listed. 
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 
plus 30 days, or to the last study visit (week 44), whichever is later 
• The posttreatment period is defined as after the end of the on-treatment period 
TEAEs are defined as those that are not present at baseline or represent the exacerbation of a pre-
existing condition during the on-treatment period. 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, presented by SOC and PT (regardless of relationship to 
treatment) 
• Treatment-related TEAEs presented by SOC and PT 
TEAEs leading to permanent treatment discontinuation will be listed and summarized by 
treatment group. 
TEAEs in the study eye related to the injection procedure and those related to the study drug, 
injection procedure and study conduct will be summarized separately. 
Deaths will be listed and summarized by treatment group. 
SAEs, drug-related TEAEs, drug-related SAEs, and TEAEs leading to discontinuation will be 
summarized in the same way as described for TEAE. 
TEAEs will further be summarized by the following categories: 
• Ocular TEAEs in the study eye  
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• Ocular TEAEs in the fellow eye 
• Non-ocular TEAEs 
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 decreasing frequency. Within each primary SOC, PTs 
will be sorted by decreasing frequency. For tables presenting severity of events, the worst 
severity will be chosen for patients with multiple instances of the same event. 
APTC events, intraocular inflammation, hypertension and nasal mucosa events will be tabulated and 
listed. The detailed definitions of these special AEs are presented in Appendix 11.2. Please refer to 
APTC charter for more information for APTC events. 
5.7.2. 
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 
5.7.3. 
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. Summary 
statistics will include the number of patients, mean, median, standard deviation, quartiles, 
minimum, and maximum. The graphs of mean (or median) value of some lab parameters vs. visit 
will also be plotted. 
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.  
A treatment-emergent PCSV is a laboratory value that was normal at Baseline but met PCSV 
criteria after treatment with study drug. Definition of PCSV is listed in Appendix 11.3. 
Treatment Emergent PCSVs will be summarized based on the SAF and in the subgroup of SAF 
patients who do not meet the PCSV criterion at baseline. 
5.7.4. 
Analysis of Vital Signs 
Repeated post-dose blood pressure measurement are taken at week 4, week 8, week 9 
(approximately 1 week after the third initial monthly dose), and then every 4 weeks from week 
12 to week 44 for SAF. For the patients in the PK substudy, additional BP measures are taken at 
post dose days 2, 3, 5, 8, 15 and 22. 
Vital signs (heart rate, systolic/diastolic BP, and temperature) will be summarized by Baseline 
and change from Baseline to each scheduled assessment time with descriptive statistics. The 
Baseline for BP is defined as the average of all 3 valid measurements taken prior to 
administration of study drug. The Baseline for other vital signs endpoints will be the latest 
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available valid measurement taken prior to the administration of study drug, as specified in 
Section 6.1. The graphs of mean (or median) value of some vital sign parameters vs. visit will 
also be plotted. For additional BP analysis, please see the paragraphs below. 
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Blood Pressure (main study) 
In addition to the descriptive analysis above, changes in systolic BP and diastolic BP will be 
assessed using a time-weighted average for all timepoints up to week 9. All available BP 
measurements up to week 9 will be included for patients in the SAF (whether in PK substudy or 
not). The time-weighted average change from baseline in systolic BP and diastolic BP will be 
calculated as the Area Under the Curve (AUC) divided by the total duration in days. For patients 
who do not have available measurement at last visit, AUC will be calculated up to the last 
available measurements. AUC = 0 for patients who have no post-baseline measurements or 
changes from baseline were all 0 at all visits. 
One-sided 95% confidence intervals will be created using normal approximation for changes in 
systolic BP and diastolic BP based on time-weighted average change from baseline, separately 
for each treatment group (IAI and HD). A nominal p-value for a one sample t-test for an 
alternative hypothesis of mean time-weighted average change from baseline <= 3 mm Hg will be 
presented for exploratory purpose. 
Blood Pressure (PK substudy) 
For the patients in the PK substudy, changes in systolic and diastolic BP will be assessed as 
described above (change from baseline to each scheduled assessment and time-weighted average 
from baseline to week 9). Like the main study, one-sided 95% confidence intervals and a 
nominal p-value will be presented. 
In addition, adverse events of hypertension will be tabulated and listed (see Appendix 11.2) and 
changes in anti-hypertensive medications including changes in dose for these medications over 
the course of the study will be evaluated. 
5.7.5. 
Analysis of 12-Lead ECG 
ECG parameters (PR interval, QT interval, QRS interval, Ventricular rate and Heart rate) will be 
summarized by Baseline and change from Baseline to each scheduled and collected assessment 
time. PCSV summary of ECG parameters will be provided for the SAF. 
ECG status (i.e. normal, abnormal) will be reported. Shift tables will be provided to present the 
post-baseline status according to the baseline status (normal or missing / abnormal) by treatment 
group. 
5.7.6. 
Analysis of Ocular Safety Variables 
Baseline IOP and change from Baseline in IOP to each scheduled assessment visit will be 
summarized with descriptive statistics for study eye and fellow eye. Assessment of significant 
values or increases will be made and summarized for the proportion of patients with increased 
IOP in the study eye or fellow eye with the categories defined in Section 4.6.6. 
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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. 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 
• 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. 
Selected PK parameters will be summarized by descriptive statistics by treatment group. This 
descriptive statistical assessment will 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 and Pharmacokinetics/Pharmacodynamics Analyses 
Exposure-response analyses for systemic and ocular response variables may be performed, as 
appropriate. 
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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, i.e., 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. 
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 window (±1 week) of the next scheduled 
visit after the last previous visit, the efficacy assessment 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 exploratory efficacy variables, missing observations will be imputed using 
LOCF. The details are described in the efficacy analysis section (Section 5.6). 
Pretreatment/concomitant medication 
For the tabulation of pretreatment 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 
For some AEs it is important to determine whether the AE started before or after the first active 
aflibercept injection. If the AE start date is partially missing, it will be imputed by the latest 
possible date (considering other available data, e.g., stop date) to be conservative. 
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7. 
INTERIM ANALYSIS 
No formal interim analyses will be performed. However, data will be reviewed in this 
single-masked study at various time points for safety and/or efficacy.  
Analysis of data will be conducted for the prespecified primary analyses at the following 
timepoints: 
• When all patients have reached week 4 (primary safety endpoint) 
• When all patients have reached week 16 (primary efficacy endpoint) 
In addition, a review of the safety and efficacy data will occur periodically throughout the 
conduct of the study. 
 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
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9. 
SUMMARY OF MEASURES AND ANALYSES ADDRESSING 
IMPACT OF COVID-19 
In light of the public health emergency related to COVID-19, in accordance with the regulatory 
guidance (2020) and in order to ensure the clinical study patient’s safety and the continuity of 
clinical study conduct and oversight, the following measures are explored and implemented for 
this study conduct and analysis: 
1. A Regeneron-standard CRF is implemented to collect COVID-19 related information: 
• Subject's Visit Impact due to COVID-19: 
− Entire visit not performed 
− Partial face to face visit 
− Remote Visit (Phone, Tele-medicine/Skype etc.) 
− Hybrid Visit (Partial face to face AND Remote Visit) 
− Home Visit by site staff or home health services 
•  Reasons: 
− Subject unable to travel due to COVID-19 
− Subject/Guardian under quarantine due to COVID-19 
− Limited site personnel availability due to COVID-19 
− Site closure due to COVID-19  
− Other 
• Discontinuation of treatment due to COVID-19 
• Reasons: 
− Subject has COVID-19  
− Subject decided to stop due to COVID-19 
− Subject can no longer travel due to COVID-19 
− Physician decision due to COVID-19 
− Sponsor decision due to COVID-19 
− Other 
• Discontinuation of study due to COVID-19 
• Reasons: 
− Subject has COVID-19  
− Subject decided to stop due to COVID-19 
− Subject can no longer travel due to COVID-19 
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− Physician decision due to COVID-19 
− Sponsor decision due to COVID-19 
− Other 
• Complete the AE form if subject tested positive or has symptoms of COVID-19 
Missed visits and discontinuation treatment/study due to COVID-19 will be summarized 
by treatment group and overall for FAS. 
2. An updated version of MedDRA version 23.0 is to be released on 19 April 2020 to 
include new COVID-19 terms. The study team is to implement this re-released version 
9823.0 by 4 May 2020, in line with the currently established procedure 
3. Since some sites may suspend onsite study visits or patients may opt not to attend, to 
address the impact of missing data due to COVID-19 on efficacy analysis, additional 
subgroup analyses (such as including only patients who have received all 3 loading 
doses) may be performed as sensitivity analysis to evaluate the robustness of the efficacy 
results. 
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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10. 
REFERENCES 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic, 
Guidance for Industry, Investigators, and Institutional Review Boards, March 2020
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11. 
APPENDIX 
11.1. 
Schedule of Time and Events 
11.1.1. 
Schedule of Events for the Study 
The study assessments and procedures for the study are presented by study period and visit in Table 2. 
Table 2: 
Schedule of Events 
Study Procedure 
Screening 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
EOS 
Visit 15 
Month 
 
 
0 
1 
2 
- 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Week 
 
 
0 
4 
8 
~9 
12 
16 
20 
24 
28 
32 
36 
40 
44 
Day 
-21 to 
 -1 
-20 to -1 
1 
29 
57 
61 
85 
113 
141 
169 
197 
225 
253 
281 
309 
Window (day) 
 
 
 
±51 
±51 
±2 
±52 
±52 
±52 
±52 
±5 
±52 
±5 
±5 
±52 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dense PK sampling informed 
consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic substudy/ FBR 
informed consent 4 
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 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
 
 
X 
X 
X 
 
 
 
X 
X 
PRN6 
X 
PRN6 
X 
 
X 
PRN6 
X 
PRN6 
 
Ocular Efficacy and Safety (bilateral 
unless indicated): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refraction and BCVA 
(ETDRS)7 
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 
Slit lamp examination 
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 
FA, FP10 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
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Study Procedure 
Screening 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
EOS 
Visit 15 
Month 
 
 
0 
1 
2 
- 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Week 
 
 
0 
4 
8 
~9 
12 
16 
20 
24 
28 
32 
36 
40 
44 
Day 
-21 to 
 -1 
-20 to -1 
1 
29 
57 
61 
85 
113 
141 
169 
197 
225 
253 
281 
309 
SD-OCT10 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-ocular Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs11, 12, 13  
X 
X14 
X 
X 
X 
X14 
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 
Laboratory Testing15: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Blood chemistry 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Pregnancy test (women of 
childbearing potential)16 
X 
Serum 
 
X 
Urine 
X 
Urine 
X 
Urine 
 
 
 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
 
Urinalysis/UPCR17 
X 
 
 
X18 
 
 
X 
 
 
 
 
 
 
 
X 
Pharmacokinetics and 
Research Sampling: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples (dense)19 
 
 
See 
schedule 
below 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
PK samples (sparse)20 
 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
Research sample21 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Genomic DNA sample 
(optional) 4 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BCVA=Best Corrected Visual Acuity, ECG=electrocardiogram, EOS=end of study, ETDRS=Early Treatment Diabetic Retinopathy Study, FA=fluorescein 
angiography, FBR=future biomedical research, FP=fundus photography, IOP=Intraocular pressure, PK=pharmacokinetics, PRN=pro re nata (as needed), SD-
OCT=spectral domain optical coherence tomography, UPCR=urine protein:creatinine ratio 
1. For patients in the dense PK substudy, the visit window is ± 0 days. 
2. For patients in the dense PK substudy, the visit window is ± 2 days. 
3. Signed only by patients participating in the dense PK substudy and in addition to the study ICF. 
4. The optional genomic sub-study 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 sub-study ICF. This ICF will also include 
language for patients to consent to participate in the optional FBR study. 
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5. Refer to pharmacy manual for study drug injection guidelines. Following study drug injection, patients will be observed for 
approximately 30 minutes. 
6. Patients will be dosed as needed per criteria in Section 2.1. 
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 bilaterally at all study visits. On days when study drug is administered, IOP should also 
be measured approximately 30 minutes after administration of study drug, in the study eye only. Intraocular pressure will be 
measured using Goldman applanation tonometry or Tono-pen™ and the same method of measurement must be used in each 
patient throughout the study. 
9. Indirect ophthalmoscopy should be performed bilaterally at all visits. On days when study drug is administered, it should also 
be performed immediately after administration of study drug (study eye only). 
10. The same SD-OCT/FA/FP imaging system used at screening and day 1 must be used at all subsequent visits in each patient. 
Images will be taken in both eyes before dosing at each required visit. 
11. Vital signs (temperature, BP, heart rate) should be measured pre-injection, per the procedure outlined in the study procedure 
manual. Blood pressure assessments will be taken using automated office blood pressure (AOBP) 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 electronic data capture (EDC). Detailed instructions can be found in the study procedure manual. 
12. Timing of BP assessment at all visits must be within 2 hours of planned time of dosing on day 1 for patients in the dense PK 
substudy. For all other patients, this window should be adhered to as closely as possible. 
13. For patients participating in the dense PK substudy, HR and BP also will be collected according to the schedule in Table 3. 
14. Only BP and heart rate will be measured at these visits. No temperature measures are required. 
15. All samples collected for laboratory assessments should be obtained prior to administration of fluorescein and prior to 
administration of study drug. 
16. 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. 
17. For patients participating in the dense PK substudy, urinalysis/UPCR will also be collected according to the schedule in 
Table 3. 
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18. Week 4 collection of urinalysis/UPCR only for patients in the dense PK substudy. 
19. Dense PK sampling will be performed in 30 patients (15 in each group) drawn according to the schedule in Table 3. On dosing 
days, PK samples must be collected prior to study drug administration. 
20. Sparse PK sampling will be performed in all patients not enrolled in the dense PK substudy according to the schedule defined 
in Table 2. On dosing days, PK samples should be collected prior to study drug administration. 
21. Exploratory research serum sample should be drawn prior to the administration of study drug at screening and week 44. 
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11.1.2. 
Schedule of Events for the Dense PK Substudy 
The 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 
and Time (h) 
Dense PK Sample 
Collection 
Heart Rate and 
Blood 
Pressure1,2  
Urinalysis / 
UPCR 
Visit 3 
(Baseline) 
X 
1 
Time of first dose 
X (pre-dose) 
X 
 
4 (post-dose) 
X 
 
 
8 (post-dose) 
X 
 
 
 
 
2 
±2h3 
X 
X 
 
 
3 
±2h3 
X 
X 
 
 
5 
±2h3 
X 
X 
 
 
8 
±2h3 
X 
X 
X 
 
15 
±2h3 
X 
X 
X 
 
22 
±2h3 
X 
X 
 
1. Timing of all BP assessment must be within 2 hours of the time of dosing on day 1. 
2. Blood pressure assessments will be taken using automated office blood pressure (AOBP) 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. 
3. PK draw for all assessment days are to be performed within ±2 hours of to the time of dosing on day 1. 
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11.2. 
Detailed Definition of special AEs  
11.2.1. 
Hypertension 
Preferred term 
Accelerated hypertension 
Blood pressure ambulatory increased 
Blood pressure diastolic increased 
Blood pressure inadequately controlled 
Blood pressure increased 
Blood pressure systolic increased 
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 
Prehypertension 
Renal hypertension 
Renovascular hypertension 
Retinopathy hypertensive 
Supine hypertension 
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Preferred term 
Systolic hypertension 
White coat hypertension 
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11.2.2. 
Intraocular inflammation  
Preferred term 
Anterior chamber cell 
Anterior chamber flare 
Anterior chamber inflammation 
Anterior chamber fibrin 
Aqueous fibrin 
Autoimmune uveitis 
Candida endophthalmitis 
Chorioretinitis 
Choroiditis 
Cyclitis 
Endophthalmitis 
Eye infection intraocular 
Eye inflammation 
Hypopyon 
Infective iritis 
Infective uveitis 
Infectious iridocyclitis 
Iridocyclitis 
Iritis 
Mycotic endophthalmitis 
Non-infectious endophthalmitis 
Non-infective chorioretinitis 
Pseudoendophthalmitis 
Serpiginous choroiditis 
Uveitis 
Vitreal cells 
Vitreous fibrin 
Vitritis 
11.2.3. 
Nasal mucosal events 
 Epistaxis 
Nasal mucosa atrophy 
Nasal mucosa blistering 
Nasal mucosa discolouration 
Nasal mucosa disorder 
Nasal mucosa erosion 
Nasal mucosa hypertrophy 
Nasal mucosa ulcer 
Nasal turbinate abnormality 
Nasal turbinate hypertrophy 
                                        VV-RIM-00162855-1.0 Approved - 28 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe (HD)-AMD-1905 
Statistical Analysis Plan Version 2.0 
Date: 26JUL2021 
 
CONFIDENTIAL 
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Nasal septum haematoma 
Nasal septum perforation 
Nasal septum ulceration 
Nasal cavity toxicity 
Nasal necrosis 
Nasal ulcer 
Cautery to nose 
                                        VV-RIM-00162855-1.0 Approved - 28 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe (HD)-AMD-1905 
Statistical Analysis Plan Version 2.0 
Date: 26JUL2021 
 
CONFIDENTIAL 
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11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Table 4: 
Criteria for Potentially Clinically Significant Values 
Parameter 
Potentially clinically significant value (PCSV)  
Clinical Chemistry 
 
ALT 
By distribution analysis : 
> 3 ULN 
AST 
By distribution analysis : 
> 3 ULN 
Alkaline Phosphatase 
> 1.5 ULN 
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) 
Lipasemia 
≥ 3 ULN 
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 
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 
                                        VV-RIM-00162855-1.0 Approved - 28 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe (HD)-AMD-1905 
Statistical Analysis Plan Version 2.0 
Date: 26JUL2021 
 
CONFIDENTIAL 
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Parameter 
Potentially clinically significant value (PCSV)  
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 
≥ 700 GIGA/L 
                                        VV-RIM-00162855-1.0 Approved - 28 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe (HD)-AMD-1905 
Statistical Analysis Plan Version 2.0 
Date: 26JUL2021 
 
CONFIDENTIAL 
Page 46 of 48 
11.4. 
Process to Derive Week 16 Data Cut-off 
For week 16 evaluations, a strategy for performing the data cut-off for the clinical database was 
developed, as described in the following: 
11.4.1. 
Visit Dependent Data 
All visit dependent data up to week 16 (visit 8 will be kept for the week 16 analysis. All visit 
dependent data later than week 16 (visit 8) will not be included for the week 16 analysis. 
Unscheduled visits with a date prior to the week 16 (visit 8) visit date will be kept for the week 
16 analysis. If a patient did not have a week 16 (visit 8) visit, unscheduled visit will be kept up to 
date of first injection + 112 days for the week 16 analysis. 
11.4.2. 
Visit Independent Data 
Visit independent data (or event based data) include adverse events, concomitant/prior 
medication, and surgical/medical history. 
Patients that discontinued study prematurely before or at week 16 (Visit 8) 
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 + 112 days or 
• a dropout date earlier or equal to week 16 visit date 
For such patients, all event based records are kept in the clinical database for week 16 analysis 
without any change. 
Patients who stayed longer than week 16 (Visit 8) in the study 
These patients are the patients who did not discontinue study prematurely at/before week 16 
(visit 8). Therefore, these patients are either: 
• still ongoing after week 16 (visit 8), 
• discontinued the study prematurely, but were in the study for longer than week 16 
(visit 8). 
For such patients, the following will be applied: 
All event records with a start date later than the date of the week 16 (visit 8) will be censored. 
This includes the case where the incomplete date is without any doubt later than the week 16 
visit date, e.g. week 16 (visit 8) is 10 April 2020 and the incomplete date is May 2020 or only 
2021. If the week 16 visit date is missing, then the date of first injection + 112 days will be used 
instead. 
Records with a start date earlier or equal to the date of week 16 (first injection + 112 days if date 
of week 16 is missing) will be kept (this includes incomplete dates when the incomplete date is 
earlier than the week 16 date or in cases where it is not clear if the record occurred before or after 
week 16, e.g., week 16 (visit 8) is 10 April 2020 and the incomplete date is March 2020, 
April 2020 or only 2020 or even a missing date, but several adaptions to the data will be made): 
                                        VV-RIM-00162855-1.0 Approved - 28 Jul 2021 GMT-5:00


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Statistical Analysis Plan Version 2.0 
Date: 26JUL2021 
 
CONFIDENTIAL 
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Concomitant medication: 
If a stop date is reported which is earlier than the date of week 16 (visit 8) (first 
injection + 112 days if date of week 16 is missing), the record will not be changed. 
If a stop date is reported which is later than the date of week 16 (visit 8) (first 
injection + 112 days if date of week 16 is missing), the stop date will be set to missing and the 
variable CMONG will be set to 1 (yes). 
Adverse Events: 
AEs with a start date on or after the date of the week 16 (visit 8) will be censored. Cut-off date 
will be first injection + 112 days if date of week 16 is missing. 
If a stop date of adverse event is specified and earlier or equal to date of week 16 (visit 8) (first 
injection + 112 days if date of week 16 missing), then the record will not be changed. 
If a stop date of adverse event is specified and later than the date of week 16 (visit 8) (first 
injection + 112 days if date of week 16 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 16 (visit 8) date will be deleted. 
11.4.3. 
Study Medication Data 
Study medication data up to week 12 (visit 7) will be kept for the week 16 analysis. 
                                        VV-RIM-00162855-1.0 Approved - 28 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: VGFTe (HD)-AMD-1905 
Statistical Analysis Plan Version 2.0 
Date: 26JUL2021 
 
CONFIDENTIAL 
Page 48 of 48 
11.5. 
Process to Derive Week 4 Data Cut-off 
For week 4 evaluations, same strategy for performing the data cut-off for the clinical database as 
described in Appendix 11.4 will be followed. Instead of “first injection + 112 days” for week 16, 
missing dates for week 4 will be imputed by first injection + 28 days. 
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