Clinical trial NCT02581891
Conditions: Macular Degeneration
Keywords: Neovascular age-related macular degeneration nAMD)
Sponsor: Bayer
Start date: 2015-11-19; Completion date: 2019-04-26
Enrollment: 287 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to evaluate the optimal use, efficacy, and safety of a Treat-and-Extend regimen with aflibercept in subjects with nAMD.

Detailed description:
The T\&E dosing regimen for nAMD has emerged as a preferred regimen for many treating physicians aiming at maximizing outcomes by proactively treating the subject at each visit and by extending the treatment interval (if extension criteria are met), thus limiting visits, monitoring, and injections.

To this day, there is limited evidence available addressing the question of what are useful intervals for treating and monitoring, how do they differ among subjects, and how are retreatment criteria applied to achieve long-term desirable outcomes in real-life practice. This study is designed to evaluate the optimal use, efficacy, and safety of the T\&E regimen with intravitreal aflibercept in subjects with nAMD.

Arms: arm 1: Early-start T\&E arm: test group, early treatment individualization arm 2: Late-start T\&E arm; per label, control group, treatment individualization after Year 1
Interventions: intervention 1: Eylea (Intravitreal Aflibercept, VEGF Trap-Eye, BAY86-5321) intervention 2: Eylea (Intravitreal Aflibercept, VEGF Trap-Eye, BAY86-5321)
Intervention descriptions: intervention 1: 3 monthly doses followed by individualized treatment intervals of between 8 to16 weeks based on protocol-defined anatomical criteria intervention 2: 3 monthly doses followed by five 8-weekly doses (5 x 2Q8), then by individualized treatment intervals of between 8 to 16 weeks based on protocol-defined anatomical criteria

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
Managing neovascular age-related macular degeneration (nAMD) 
over 2 years with a Treat and Extend (T&E) regimen of 2 mg 
intravitreal aflibercept - a randomized, open-label, active-controlled, 
parallel-group phase IV/IIIb study (ARIES) 
NCT Number: 
NCT02581891 
Document Date: 
02 Feb 2016 
 


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Managing neovascular age-related macular degeneration (nAMD) over 2 years with a 
Treat and Extend (T&E) regimen of 2 mg intravitreal (IVT) aflibercept - a randomized, 
open-label, active-controlled, parallel-group phase IV/IIIb study (ARIES)
This protocol version is an integration of the following documents/sections:

Original protocol, Version 1.0, dated 30 Jun 2015

Amendment 01 (global amendment described in Section 15.1) forming integrated 
protocol Version 2.0, dated 02 Feb 2016
Amendments not included in the consecutive numbering of amendments are local 
amendments not forming part of this integrated global protocol.


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1.
Title page
Managing neovascular age-related macular degeneration (nAMD) over 2 years with a 
Treat and Extend (T&E) regimen of 2 mg intravitreal (IVT) aflibercept - a 
randomized, open-label, active-controlled, parallel-group phase IV/IIIb study (ARIES)
Managing nAMD with a T&E IVT aflibercept regimen
ARIES
Test drug:
BAY86-5321/aflibercept/ VEGF Trap-Eye (Eylea)
Study purpose:
To assess whether 2 mg IVT aflibercept administered in an early-
start T&E regimen (initiated after the first 8-weekly treatment 
interval) is non-inferior to 2 mg IVT aflibercept administered in a 
late-start T&E regimen (initiated at the end of Year 1, per label) in 
subjects with nAMD.
Clinical study phase:
IV/IIIb
Date:
02 FEB 2016    
Registration:
EudraCT:  2014-003132-39
Version no.:
2.0    
Sponsor’s study no.:
BAY86-5321/17508
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical 
expert:
 
The study will be conducted in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH-GCP) Guidelines, and any applicable regulatory 
requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation, or its use for any other purpose, without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (∀, TM) may not be displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD


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Signature of the sponsor’s medically responsible person
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Role:  
Medical Affairs Responsible 
(MAR)
Date:
_________________________
Signature: _________________________
PPD


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Signature of principal investigator
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
_____________________
Signature: _________________________
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.


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2.
Synopsis
Title
Managing neovascular age-related macular degeneration (nAMD) over 2 years 
with a Treat and Extend (T&E) regimen of 2 mg intravitreal (IVT) aflibercept -
a randomized, open-label, active-controlled, parallel-group phase IV/IIIb study 
(ARIES)
Short title
Managing nAMD with a T&E IVT aflibercept regimen
Acronym
ARIES
Secondary ID
17508
Clinical study phase
IV/IIIb
Study objective(s)
Primary objective
To assess whether 2 mg IVT aflibercept administered in an early-start T&E 
regimen (initiated after the first 8-weekly treatment interval) is non-inferior to 
2 mg IVT aflibercept administered in a late-start T&E regimen (initiated at the 
end of Year 1, per label) in subjects with nAMD
Secondary objectives
To assess the percentage of subjects requiring retreatment with IVT aflibercept 
less frequently than every 8 weeks (2Q8)
To assess the safety and tolerability of IVT aflibercept
Test drug(s)
Name of active ingredient
Aflibercept (Vascular endothelial growth factor [VEGF] Trap-Eye)
Dose(s)
2 mg (0.05 mL)
All subjects during the initiation phase: Three initial monthly doses followed 
by 1 dose 2Q8
Early-start T&E arm (test group, early treatment individualization): 
Individualized treatment intervals of between 8 to16 weeks based on 
anatomical criteria
Late-start T&E arm (per label, control group, treatment individualization after 
Year 1): Four 8-weekly doses (5 x 2Q8), followed by individualized treatment 
intervals of between 8 to 16 weeks based on anatomical criteria
Route of administration
IVT 
Duration of treatment
104 weeks
Reference drug(s)
None
Background treatment
None


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Indication
Neovascular age-related macular degeneration (nAMD)
Diagnosis and main criteria for 
inclusion /exclusion
Subjects ≥50 years of age with active choroidal neovascularization (CNV)
lesions secondary to nAMD
Study design
This is a multicenter, randomized, open-label, active-controlled, 
parallel-group, Phase IV/IIIb study in subjects with nAMD to assess the 
non-inferiority of a 2-mg IVT aflibercept T&E dosing regimen initiated after 
the first 8-weekly treatment interval (3 initial monthly doses followed by 
1 dose 2Q8; then treatment individualization) to a 2-mg IVT aflibercept T&E 
dosing regimen per label (3 initial monthly doses followed by 5 doses 2Q8; 
treatment individualization after Year 1).


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Methodology
This study comprises a screening phase of up to 3 weeks (Visit 1; −3 weeks to 
baseline), a baseline visit (Visit 2, Week 0/Day 1), and a treatment phase of 
104 weeks.  
Only 1 eye will be designated as the study eye.  Starting at baseline 
(Week 0/Day 1), aflibercept 2 mg IVT treatment will be administered to the 
study eye every 4 weeks (3 initial monthly doses at Weeks 0, 4, and 8).  At 
Week 8, the treatment interval will be extended by 4 weeks (i.e. the next 
injection will take place at Week 16). 
At Week 16, subjects will be stratified based on visual outcomes from baseline 
to Week 16 (either <8 or ≥8 letters gain in best-corrected visual acuity 
[BCVA])1 and  randomized 1:1 into 1of the following 2 arms:

In the early-start T&E arm, starting at Week 16, subjects will 
receive treatment in intervals extended by 2 weeks each time (up to a 
maximum of 16 weeks), as long as all anatomical criteria are met.
For subjects who have no intra-retinal fluid (IRF) and no 
subretinal fluid (SRF) at Week 16 (“completely dry”), confirmed 
by the Central Reading Center, the treatment , the treatment interval 
will be extended by 4 weeks for a total of 12 weeks (i.e. schedule next 
visit at Week 28). From week 28 onwards, the normal extension 
algorithm will be applied.

In the late-start T&E arm (per label, control group), subjects will 
receive treatment every 8 weeks to the end of Year 1 (4 x 2Q8 
injections at Weeks 24, 32, 40, and 48).  Then in Year 2 (starting from 
Week 48) the treatment intervals will be extended by 2 weeks each 
time (up to a maximum of 16 weeks), as long as all anatomical 
criteria are met.
The anatomical criteria for extending the treatment intervals, based on optical 
coherence tomography (OCT), are as follows for both study arms:

Absence of intra-retinal fluid (IRF) and

Absence of new neovascularization or hemorrhage and

Subretinal fluid (SRF) not exceeding 50 µm in thickness
If these criteria are not met, the retreatment interval will revert to the last 
treatment interval in which the disease was inactive.  
                                                
1 The threshold for stratification was determined based on the 2Q8 treatment arm from the VIEW 2 study: In this group of 
306 subjects, the median BCVA gains at 16 weeks were 8 letters.


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Methodology
After Week 16 (randomization), the treatment intervals will not be less than 
8 weeks nor more than 16 weeks with the following exception:  If, at any visit 
after Week 16, the subject has lost 15 or more letters from the best previous 
BCVA and the actual BCVA is not better than at baseline; or, if the 
investigator determines, and documents in the eCRF that the subject’s 
condition necessitates more frequent injections than 2Q8, the subject will be 
considered “injection-intensive”.  Such subjects will remain in the study, and 
be treated according to the investigator’s best clinical judgment (i.e. the 
frequency of IVT aflibercept injections is determined by the investigator who 
is free to subsequently adopt a T&E regimen similar to the per-protocol one, if 
deemed appropriate for the subject; however, the treatment intervals should not 
be less than 4 weeks).
Due to the per-protocol variability of treatment intervals, subjects may receive 
their last Year 1 and Year 2 injections at any time between Weeks 42 and 52 
(for Year 1) and Weeks 90 and 104 (for Year 2).  In case these treatment visits 
do not occur at Weeks 52 and/or 104 (±1 week), the subject will return at 
Weeks 52 and/or 104 for mandatory visits without treatment. 
Efficacy will be assessed by the change in BCVA as measured by the Early 
Treatment Diabetic Retinopathy Study (ETDRS) letter score from Week 16 to 
Week 104 (primary efficacy variable) and by the proportion of subjects 
maintaining vision (<3 lines loss) at Week 104 compared with baseline (key-
secondary efficacy variable).  Other secondary measures of efficacy will 
include changes in BCVA to Week 52 (from baseline and Week 16), the 
proportion of subjects maintaining or gaining vision, change in central retinal 
thickness (CRT), and measures related to the number of study drug injections 
and interval duration.  Efficacy will be assessed by BCVA using the ETDRS 
chart, OCT, and fluorescein angiography (FA)/fundus photography (FP).
Assessments of ocular safety will include intraocular pressure (IOP), indirect 
ophthalmoscopy, and slit lamp biomicroscopy.  Overall safety of the subjects 
will be assessed throughout the study by monitoring ocular and non-ocular 
adverse events (AEs).  All potential arterial thromboembolic events (ATEs) 
will be adjudicated according to the Antiplatelet Trialists' Collaboration 
(APTC) endpoints of non-fatal myocardial infarction, non-fatal stroke, and 
fatal vascular events.  Vital signs will be assessed at all study visits.
Type of control
Different start of the test drug T&E dosing regimen (late-start T&E arm, per 
label)
Number of subjects
Approximately 383 screened subjects (254 randomized subjects)
Primary variable(s)
Change in BCVA as measured by the ETDRS letter score from Week 16 to 
Week 104
Time point/frame of 
measurement for primary
variable(s)
Change from Week 16 to Week 104


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Plan for statistical analysis
Primary variable: 
The methodological approach will be the calculation of 2-sided 95% 
confidence intervals (CI) for the difference in the least squares (LS) means 
(early-start T&E regimen minus late-start T&E regimen) of the change in 
ETDRS letter score from Week 16 to Week 104 based on a two-way analysis 
of covariance (ANCOVA) with the BCVA measure at Week 16 as a covariate 
and treatment arm and the stratification variable “visual outcomes” as fixed 
factors (visual outcomes will be determined at Week 16, depending on whether
the subjects reached <8 or ≥8 letters gain in BCVA relative to baseline).
The primary statistical analysis will be performed on the Per-protocol Set 
(PPS).  The early-start T&E regimen will be considered to be non-inferior to 
the late-start T&E regimen if this analysis is statistically significant, i.e. if the 
CI of the difference lies entirely above -5 letters, where a positive difference 
favors the early-start T&E regimen.  
Additionally, the analysis will be performed on the Full Analysis Set (FAS) to 
support the results.  
Key secondary efficacy variable (proportion of subjects maintaining vision 
[<3 lines loss] at Week 104 compared with baseline): 
If, and only if, the early-start T&E regimen is statistically proven to be 
non-inferior to the late-start T&E regimen in the primary efficacy analysis, 
confirmatory testing will be continued on the PPS to assess the non-inferiority 
of the early-start T&E regimen to the late start T&E regimen with regard to the 
key secondary efficacy variable (maintenance of vision).  
The methodological approach will be the calculation of 2-sided 95% CIs of the 
difference between the proportions (early-start T&E regimen minus late-start 
T&E regimen) of subjects maintaining vision at Week 104, taking the 
stratification variable “visual outcomes” into account.  The early-start T&E 
regimen will be considered to be non-inferior to the late-start T&E regimen if 
the CI of the difference lies entirely above -7%, where a positive difference 
favors the early-start T&E regimen.  Additionally, the analysis will be 
performed on the FAS to support the results,  
This hierarchical procedure (a-priori ordered hypotheses) will control for 
multiplicity in the confirmatory analyses on the PPS.
Analyses on secondary and other efficacy variables will be conducted on the 
PPS and FAS in a descriptive manner.  This may include 95% CIs for 
treatment differences in an exploratory way.


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Table of contents
1.
Title page............................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis.............................................................................................................................. 5
Table of contents....................................................................................................................... 9
Table of tables......................................................................................................................... 14
List of abbreviations............................................................................................................... 15
3.
Introduction - amended .................................................................................................. 17
4.
Study objectives............................................................................................................... 19
5.
Study design - amended.................................................................................................. 19
6.
Study population - amended .......................................................................................... 22
6.1
Inclusion criteria - amended........................................................................................... 23
6.2
Exclusion criteria - amended ......................................................................................... 23
6.3
Withdrawal of subjects from the study.......................................................................... 26
6.3.1
Withdrawal - amended................................................................................................ 26
6.3.2
Replacement ............................................................................................................... 28
6.4
Subject identification ..................................................................................................... 28
7.
Treatment(s) .................................................................................................................... 28
7.1
Treatments to be administered - amended ..................................................................... 28
7.2
Identity of study treatment............................................................................................. 29
7.3
Treatment assignment.................................................................................................... 30
7.4
Dosage and administration............................................................................................. 30
7.5
Blinding/masking........................................................................................................... 30
7.6
Drug logistics and accountability - amended................................................................. 31
7.7
Treatment compliance.................................................................................................... 32
8.
Non-study therapy........................................................................................................... 32
8.1
Prior and concomitant therapy - amended ..................................................................... 32
8.2
Post-study therapy.......................................................................................................... 33
9.
Procedures and variables ............................................................................................... 33
9.1
Tabular schedule of evaluations .................................................................................... 33
9.2
Visit description - amended ........................................................................................... 37
9.2.1
Screening visit (Visit 1, Week −3 to baseline [Week 0])........................................... 37
9.2.2
Initiation phase ........................................................................................................... 38
9.2.2.1
Baseline visit (Visit 2, Week 0/Day 1).................................................................... 38
9.2.2.2
Visits 3 and 4 (Weeks 4 and 8) ............................................................................... 38
9.2.3
Randomization visit (Visit 5, Week 16)..................................................................... 39
9.2.4
Proactive extension phase - amended......................................................................... 40


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9.2.4.1
Treatment visits....................................................................................................... 40
9.2.4.2
Mandatory visit at Week 52 .................................................................................... 41
9.2.5
Final visit (Week 104)/early termination.................................................................... 41
9.3
Population characteristics .............................................................................................. 43
9.3.1
Demographic .............................................................................................................. 43
9.3.2
Medical history........................................................................................................... 43
9.4
Efficacy.......................................................................................................................... 43
9.5
Pharmacokinetics/pharmacodynamics........................................................................... 44
9.6
Safety ............................................................................................................................. 44
9.6.1
Adverse events............................................................................................................ 44
9.6.1.1
Definitions............................................................................................................... 44
9.6.1.2
Classifications for adverse event assessment.......................................................... 46
9.6.1.2.1
Seriousness........................................................................................................... 46
9.6.1.2.2
Intensity................................................................................................................ 46
9.6.1.2.3
Causal relationship............................................................................................... 46
9.6.1.2.4
Action taken with study treatment ....................................................................... 48
9.6.1.2.5
Other specific treatment(s) of adverse events...................................................... 48
9.6.1.2.6
Outcome............................................................................................................... 48
9.6.1.3
Assessments and documentation of adverse events ................................................ 49
9.6.1.4
Reporting of serious adverse events........................................................................ 49
9.6.1.5
Expected adverse events.......................................................................................... 50
9.6.2
Pregnancies................................................................................................................. 50
9.6.3
Further safety.............................................................................................................. 51
9.6.3.1
Laboratory evaluations............................................................................................ 51
9.6.3.2
Physical examination............................................................................................... 51
9.6.3.3
Vital signs (temperature, blood pressure, and heart rate)........................................ 51
9.6.3.4
Ocular safety ........................................................................................................... 51
9.7
Other procedures and variables - amended.................................................................... 52
9.8
Appropriateness of procedures / measurements ............................................................ 54
10. Statistical methods and determination of sample size ................................................. 54
10.1
General considerations................................................................................................... 54
10.2
Analysis sets - amended................................................................................................. 54
10.3
Variables and planned statistical analyses..................................................................... 55
10.3.1
Variables..................................................................................................................... 55
10.3.2
Statistical and analytical plans.................................................................................... 55
10.3.2.1
Demography and baseline characteristics - amended ............................................. 55
10.3.2.2
Efficacy analyses..................................................................................................... 55
10.3.2.2.1
Primary efficacy variable analysis....................................................................... 56
10.3.2.2.2
Secondary efficacy variables ............................................................................... 56
10.3.2.2.3
Other efficacy variables ....................................................................................... 57
10.3.2.3
Safety analysis......................................................................................................... 57
10.3.3
Missing data/drop outs ............................................................................................... 58
10.4
Determination of sample size......................................................................................... 58


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10.5
Planned interim analyses - amended.............................................................................. 59
11. Data handling and quality assurance............................................................................ 59
11.1
Data recording................................................................................................................ 59
11.2
Monitoring ..................................................................................................................... 60
11.3
Data processing.............................................................................................................. 61
11.4
Missing data................................................................................................................... 61
11.5
Audit and inspection ...................................................................................................... 61
11.6
Archiving ....................................................................................................................... 61
12. Premature termination of the study .............................................................................. 62
13. Ethical and legal aspects................................................................................................. 63
13.1
Investigator(s) and other study personnel...................................................................... 63
13.2
Funding and financial disclosure ................................................................................... 63
13.3
Ethical and legal conduct of the study........................................................................... 64
13.4
Subject information and consent.................................................................................... 64
13.5
Publication policy and use of data ................................................................................. 65
13.6
Compensation for health damage of subjects/insurance................................................ 66
13.7
Confidentiality ............................................................................................................... 66
14. Reference list.................................................................................................................... 66
15. Protocol amendments...................................................................................................... 68
15.1
Amendment 1, dated 25 Jan 2016.................................................................................. 68
15.1.1
Overview of changes to the study............................................................................... 68
15.1.1.1
Modification 1 – Approved indications for aflibercept........................................... 68
15.1.1.2
Modification 2 – Countries in which aflibercept is approved................................. 68
15.1.1.3
Modification 3 – Time point for disqualifying subjects for randomization............ 69
15.1.1.4
Modification 4 – Diagnosis “completely dry” at Week 16..................................... 69
15.1.1.5
Modification 5 –.Anatomical criteria for extending the treatment intervals........... 69
15.1.1.6
Modification 6 – Option of not extending the treatment interval ........................... 69
15.1.1.7
Modification 7 – Exception for treatment intervals of at least 8 weeks.................. 69
15.1.1.8
Modification 8 – Justification for investigator’s treatment decision....................... 70
15.1.1.9
Modification 9 – Exception for treatment intervals of at least 8 weeks.................. 70
15.1.1.10 Modification 10 – Treatment of underlying disease on the day of the final 
visit and thereafter; AE reporting after the final study visit.................................... 70
15.1.1.11 Modification 11 – Reference point for fluorescein angiography eligibility 
criteria...................................................................................................................... 71
15.1.1.12 Modification 12 – Inclusion criterion 3................................................................... 71
15.1.1.13 Modification 13 – Exclusion criterion 6 ................................................................. 71
15.1.1.14 Modification 14 – Withdrawal criterion 3............................................................... 71
15.1.1.15 Modification 15 – Withdrawal criterion 3............................................................... 72
15.1.1.16 Modification 16 – Screening failure paragraph....................................................... 72
15.1.1.17 Modification 17 – Drug accountability................................................................... 72
15.1.1.18 Modification 18 – Fellow eye treatment ................................................................. 72
15.1.1.19 Modification 19 – Fellow eye treatment ................................................................. 72


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15.1.1.20 Modification 20 – Reference point for visit scheduling.......................................... 73
15.1.1.21 Modification 21 – Specification of AE reporting after 30 days of last 
application of study drug......................................................................................... 73
15.1.1.22 Modification 22 – Time reference for reporting pregnancy as AE or as 
spontaneous report................................................................................................... 73
15.1.1.23 Modification 23 – Observation consistency............................................................ 73
15.1.1.24 Modification 24 – Safety set ................................................................................... 73
15.1.1.25 Modification 25 – Comparability of treatment arms............................................... 74
15.1.1.26 Modification 26 – Efficacy variables analyzed descriptively ................................. 74
15.1.1.27 Modification 27 – Interim analysis ......................................................................... 74
15.1.1.28 Modification 28 – Withdrawable volume ............................................................... 74
15.1.2
Changes to the protocol text....................................................................................... 74
16. Appendices....................................................................................................................... 87
16.1
Aflibercept intravitreal injection procedure - amended................................................. 87


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Table of tables
Table 7-1
Investigational test product ................................................................................... 30
Table 9-1    Schedule of Evaluations and Study Procedures - Amended................................. 34


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List of abbreviations
2Q8
2 mg aflibercept administered every 8 weeks
AE
Adverse event
AMD
Age-related macular degeneration
ANCOVA
Analysis of covariance
APTC
Antiplatelet Trialists’ Collaboration
ATC
Anatomical Therapeutic Chemical
ATE
Arterial thromboembolic event
BCVA
Best-corrected visual acuity
CI
Confidence interval
CNV
Choroidal neovascularization
CRO
Clinical research organization
CRT
Central retinal thickness
CSR
Clinical study report
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
European Medicines Agency
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FA
Fluorescein angiography
FAS
Full Analysis Set
FP
Fundus photography
GCL
Global Clinical Leader
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
ICF
Informed consent form
ICH
International Conference on Harmonisation
i.e.
That is (id est)
IEC
Independent Ethics Committee
IOP
Intraocular pressure
IRB
Institutional Review Board
IRF
Intra-retinal fluid
IVT
Intravitreal
IxRS
Interactive voice/web response system
LOCF
Last observation carried forward
LS
Least squares
MedDRA
Medical Dictionary for Regulatory Activities
nAMD
Neovascular age-related macular degeneration
OCT
Optical coherence tomography
PASS
Power Analysis and Sample Size
PED
Pigment epithelial detachment
PPS
Per-protocol Set
PRN
As needed (pro re nata)
PRP
Panretinal photocoagulation
RETAIN study
Branch retinal vein occlusion or central retinal vein occlusion
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SID
Subject identification
SOC
System organ class
SRF
Subretinal fluid


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StM
Study Manager
SUSAR
Suspected unexpected serious adverse reaction
T&E
Treat and extend
US
United States 
V
Visit
VEGF
Vascular endothelial growth factor
VIEW study
VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD
WHODD
World Health Organization Drug Dictionary
Wk
Week


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3.
Introduction - amended
Background
Age-related macular degeneration (AMD) is a leading cause of adult blindness in the 
developed world (1).  Age-related macular degeneration has a dry and a wet form, the latter of 
which accounts for most AMD-related cases of blindness and is referred to as neovascular 
AMD (nAMD).  Severe vision loss from nAMD is caused by a combination of retinal edema 
and neovascular proliferation.  Vascular endothelial growth factor (VEGF), a protein growth 
factor that both stimulates angiogenesis and increases vascular permeability, is a major 
pathogenic factor in AMD (2).  Anti-VEGF therapy has been shown to provide significant 
therapeutic benefit to patients suffering from nAMD.  
Aflibercept is a potent, specific inhibitor of VEGF with a high affinity for all isoforms of 
VEGF and placental growth factor.  To date, aflibercept has been approved as a treatment for 
nAMD, diabetic macular edema (DME), and macular edema secondary to branch or2 central 
retinal vein occlusion in the United States (US), European Union (EU), Japan, and many3
other countries; as well as for myopic choroidal neovascularization in the EU, Japan and 
several other countries; and for diabetic retinopathy in patients with DME in the US.
Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug.
The approved European Union (EU) labeling for Eylea (aflibercept) states:
The recommended dose for Eylea is 2 mg aflibercept, equivalent to 50 microliters.
Eylea treatment is initiated with 1 injection per month for 3 consecutive doses, 
followed by 1 injection every 2 months.  There is no requirement for monitoring 
between injections.
After the first 12 months of treatment with Eylea, the treatment interval may be 
extended based on visual and anatomic outcomes.  In this case the schedule for 
monitoring should be determined by the treating physician and may be more frequent 
than the schedule of injections.
Rationale of the study
The use of anti-VEGF agents for nAMD has become the standard of care.  The frequency of 
dosing for monthly anti-VEGFs has introduced a burden of illness on patients and caregivers 
as well as capability constraints on physicians in practice.  Physicians have developed a 
practicing trend towards individualizing treatment to reduce the burden and minimize 
reimbursement issues and healthcare costs.  The current individualized treatment gaining 
momentum with practicing physicians is referred to as treat and extend (T&E). In the T&E 
                                                
2 Logical correction of approved indications for aflibercept per Amendment 1 (see Section 15.1.1.1)
3 Quantity of countries in which aflibercept is approved qualified per Amendment 1 (see Section 15.1.1.2


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dosing paradigm, the subject is injected at every visit and the follow-up examination intervals 
are incrementally extended according to the response to treatment.  The T&E regimen for 
nAMD was initially described by Spaide in 2007 (3) and applied in several studies since then 
(4, 5, 6, 7, 8, 9, 10); however, no large-scale studies have examined the use of aflibercept in a 
T&E regimen in any indication.  According to the approved EU label for Eylea, the treatment 
interval may be extended based on visual and anatomic outcomes after the first 12 months of 
treatment with Eylea.  
Optical coherence tomography (OCT) has been used in clinical practice to guide the detection 
of macular fluid in order to direct T&E increase, maintenance, or decrease of follow-up 
intervals. This imaging modality readily permits visualization of anatomic changes common 
to nAMD such as pigment epithelial detachment (PED), subretinal hyper-reflective material 
consistent with choroidal neovascularization (CNV), and pathological fluid accumulation 
(11), as well as anatomic changes.
This study has been designed to assess whether intravitreal (IVT) aflibercept administered in 
an early-start T&E regimen (initiated after the first 8-weekly treatment interval) is non-
inferior to IVT aflibercept administered in a late-start T&E regimen (initiated at the end of 
Year 1, per the approved EU label for Eylea) in subjects with nAMD.  In addition, the 
percentage of subjects requiring retreatment with IVT aflibercept less frequently than every 
8 weeks (2Q8), as well as safety and tolerability, will be assessed.
Benefit-risk assessment
Intravitreal injection of aflibercept in this study of subjects with nAMD is justified and 
supported by the drug’s safety and tolerability profile known from previous studies 
investigating IVT aflibercept in nAMD and other indications.  The beneficial effect on visual 
acuity in patients with nAMD has previously been demonstrated, both with aflibercept 
treatment and with other anti-VEGF therapy.
The risks of the local IVT application are limited to ocular adverse events (AEs).  Due to the 
low systemic level of aflibercept after IVT injection, systemic pharmacodynamic effects such 
as blood pressure changes are unlikely.  Proteinuria and hypertension are potential systemic 
effects from intravenous or subcutaneous administration of this class of drug; however, the 
low systemic blood levels observed in previous IVT studies suggest that direct IVT injection,
at the dose levels proposed for this study, are not expected to have clinically significant 
systemic effects. In addition, arterial thromboembolic events (ATEs) are AEs potentially 
related to systemic VEGF inhibition. The risks associated with IVT administration of 
aflibercept observed in the Phase 3 studies are thought to be similar to those of IVT 
administration of pegaptanib sodium and ranibizumab.
This study will generate evidence regarding the benefits of early T&E regimen initiation (i.e. 
initiation in the first year compared to initiation in the second year per the label) in order to 
provide optimal management of the patient without compromising visual outcomes.  Strict 
extension criteria ensure that the benefit-risk ratio in this study is favorable.  


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4.
Study objectives
Primary objective
To assess whether 2 mg IVT aflibercept administered in an early-start T&E regimen (initiated 
after the first 8-weekly treatment interval) is non-inferior to 2 mg IVT aflibercept 
administered in a late-start T&E regimen (initiated at the end of Year 1, per label) in subjects 
with nAMD.
Secondary objectives
To assess the percentage of subjects requiring retreatment with IVT aflibercept less frequently 
than every 8 weeks (2Q8).
To assess the safety and tolerability of IVT aflibercept.
5.
Study design - amended
Design overview
This is a multicenter, randomized, open-label, active-controlled, parallel-group, Phase IV/IIIb
study in subjects with nAMD to assess the non-inferiority of a 2-mg IVT aflibercept T&E 
dosing regimen initiated after the first 8-weekly treatment interval (2Q8) to a 2-mg IVT 
aflibercept T&E dosing regimen per label (treatment individualization after Year 1). In total, 
approximately 268 subjects in Europe, Canada, and Australia will be treated at baseline.   The 
study duration will be 104 weeks plus the recruitment period.  
Subjects must give written informed consent before any data documentation and any study 
procedure.  The study comprises a screening phase of up to 3 weeks (Visit 1; -3 weeks to 
baseline), a baseline visit (Visit 2, Week 0/Day 1), and a treatment phase of 104 weeks.  
Only 1 eye will be designated as the study eye. Starting at baseline (Week 0/Day 1), 
aflibercept 2 mg IVT treatment will be administered to the study eye every 4 weeks during the 
initiation phase (3 initial monthly doses at Weeks 0, 4, and 8).  At Week 8, the treatment 
interval will be extended by 4 weeks (i.e. the next injection will take place at Week 16). If 
subjects require injections at shorter intervals than defined per protocol before or at4 Week 16, 
the subjects will not be randomized but withdrawn from the study (see Section 6.3.1).
At Week 16, subjects will be stratified based on visual outcomes from baseline to Week 16 
(either <8 or ≥8 letters gain in best-corrected visual acuity [BCVA]) and randomized 1:1 into 
1 of the following 2 arms:

In the early-start T&E arm (test group, early treatment individualization), starting at 
Week 16, subjects will receive treatment in intervals extended by 2 weeks each time 
                                                
4 Point in time for disqualifying subjects for randomization defined more exactly per Amendment 1 (see Section 15.1.1.3)


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(up to a maximum of 16 weeks), as long as all anatomical criteria are met.
(Special case “completely dry”: See below, following the 3 anatomical criteria.)5

In the late-start T&E arm (per label, control group, treatment individualization after 
Year 1), subjects will receive treatment every 8 weeks to the end of Year 1 (4 x 2Q8 
injections at Weeks 24, 32, 40, and 48).  Then in Year 2 (starting from Week 48) the 
treatment intervals will be extended by 2 weeks each time (up to a maximum of 
16 weeks), as long as all anatomical criteria are met.
The anatomical criteria for extending the treatment intervals for 6the study eye, based on 
OCT, are as follows for both study arms:

Absence of intra-retinal fluid (IRF) and

Absence of new neovascularization or hemorrhage and

Subretinal fluid (SRF) not exceeding 50 µm in thickness
For subjects who have no IRF and no SRF at Week 16 (“completely dry”), confirmed by 
the Central Reading Center, the treatment interval will be extended by 4 weeks for a total of 
12 weeks (i.e. schedule next visit at Week 28). From Week 28 onward, the normal extension 
algorithm will be applied.7
The investigator assesses whether the subject fulfills the anatomical criteria for treatment 
interval extension and determines the next treatment interval. If the anatomical criteria are 
not met, the retreatment interval will revert to the last treatment interval in which the disease 
was inactive.8  The subject will have all assessments during the proactive extension phase as 
detailed in Section 9.2.
After Week 16 (randomization), the treatment intervals will not be less than 8 weeks nor more 
than 16 weeks with the following exception:9 if, at any visit after Week 16, the subject has 
lost 15 or more letters from the best previous BCVA and the actual BCVA is not better than at 
baseline; or, if the investigator determines10 and documents in the eCRF that the subject’s 
condition necessitates more frequent injections than 2Q8, the subject will be considered 
“injection-intensive”. 11Such subjects will remain in the study, and be treated according to the 
                                                
5 Special case “completely dry” added to the early-start T&E arm per Amendment 1 (see Section 15.1.1.4)
6 Wording added for more clarity per Amendment 1 (See Section 15.1.1.5)
7 Special case “completely dry” added to the early-start T&E arm per Amendment 1 (see Section 15.1.1.4)
8 Option of not extending the treatment interval, even if all anatomical criteria are met, removed per Amendment 1 (see 
Section 15.1.1.6
9 Wording added consistent with synopsis per Amendment 1 (see Section 15.1.1.7)
10 “Justifies” removed per Amendment 1 (see Section 15.1.1.8)
11 Sentence split for better readability per Amendment 1 (see Section 15.1.1.9)


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investigator’s best clinical judgment (i.e. the frequency of IVT aflibercept injections is 
determined by the investigator who is free to subsequently adopt a T&E regimen similar to 
the per-protocol one, if deemed appropriate for the subject; however, the treatment intervals 
should not be less than 4 weeks).
Due to the per-protocol variability of treatment intervals, subjects may receive their last 
Year 1 and Year 2 injections at any time between Weeks 42 and 52 (for Year 1) and 
Weeks 90 and 104 (for Year 2). In case these visits do not occur at Weeks 52 and 104 
(±1 week), subjects will return at Weeks 52 and/or 104 for mandatory visits, where no study 
drug is administered, but where examinations are performed from which the primary and 
secondary outcomes are determined. 
On the day of the final visit (Week 104 ±1 week or early termination) or thereafter, 
administration of study drug is not allowed. Any subsequent treatment of the underlying 
disease of a subject is not part of the study and is at the discretion of the subject’s physician. 
Such treatment should only occur after all study relevant assessments have been performed.
The treating investigator must follow up by phone on any AEs that are ongoing or may occur 
within 30 days of the last administration of study drug.  Information regarding such events 
is to be reported under this protocol (i.e. not as spontaneous reports).12
All ocular assessments are to be conducted in both eyes, unless indicated otherwise. 
Assessments of ocular safety will include intraocular pressure (IOP), indirect 
ophthalmoscopy, and slit lamp biomicroscopy; these will be assessed at all study visits.  Best-
corrected visual acuity and OCT will be conducted at every visit. Mandatory fluorescein 
angiography (FA)/fundus photography (FP) examinations will only be conducted at screening 
and at Weeks 52 and 104/early termination.  However, the treating investigator may perform 
FA/FP at other times of the study based on his/her medical judgment and standard of care.  
Primary variable
The primary efficacy variable is the change in BCVA as measured by the Early Treatment 
Diabetic Retinopathy Study (ETDRS) letter score from Week 16 to Week 104.
A list of all efficacy variables including the key-secondary, secondary, and exploratory 
efficacy variables is provided in Section 9.4.  Safety variables are provided in 
Section 10.3.2.3.
Justification of the design
The use of anti-VEGF agents for nAMD has become the standard of care and the current 
individualized treatment gaining momentum with practicing physicians is referred to as T&E.  
No large-scale studies have examined the use of aflibercept in a T&E regimen in subjects with 
nAMD.  This study in subjects with nAMD aims to assess the non-inferiority of a T&E 
                                                
12 Treatment of underlying disease on the day of the final vist and thereafter; AE reporting after the final study visit (see 
Section 15.1.1.10)


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dosing regimen initiated after the first 8-weekly treatment interval (2Q8) to a T&E dosing 
regimen per label (treatment individualization after Year 1). The non-inferiority design is 
adequate to assess the objectives detailed in Section 4.
Open-label setting:  Since the T&E dosing regimen in the 2 treatment arms will start at 
different time points, masking the study would be extremely difficult and would disrupt the 
intent of a T&E regimen and, thus, was not considered to be a viable option.
For further details on the rationale of the study and the benefit-risk assessment refer to 
Section 3.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (European Union [EU] and non-EU).
Primary completion
The primary completion event for this study is the final study visit at Week 104.
6.
Study population - amended
Eligibility for participation in this study will be based on the inclusion/exclusion criteria.  An 
individual subject may only be randomized once.
Subjects eligible for this study must have active CNV lesions secondary to nAMD with foveal 
involvement.13  The subjects’ eligibility to participate in the study in terms of OCT and FA 
will be determined initially by the investigator and will have to be confirmed by a central 
reading center before the first administration of study treatment at the baseline visit. 
Only one eye will be designated as the study eye. For subjects who meet eligibility criteria in 
both eyes, the eye with the worse visual acuity will be selected as the study eye.  If both eyes 
have equal visual acuity, the eye with the clearest lens and ocular media and least amount of 
subfoveal scar or geographic atrophy will be selected.  If there is no objective basis for 
selecting the study eye, factors such as ocular dominance, other ocular pathology and subject 
preference should be considered in making the selection. 
Ophthalmic eligibility criteria apply to the study eye only unless otherwise specified.
Inclusion and exclusion criteria will be assessed during the screening phase and the subject 
must sign the informed consent form (ICF) before any of the inclusion/exclusion criteria are 
assessed.  Fluorescein angiography eligibility criteria will be checked against (1) images 
taken14 before initiation of treatment with IVT aflibercept and (2) images obtained during the 
study-screening period. 
                                                
13 Specification of  CNV lesions simplified per Amendment 1 (see Section 15.1.1.12)
14 Time point of nAMD diagnosis removed per Amendment 1 (see Section 15.1.1.11)


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6.1
Inclusion criteria - amended
1. Written informed consent.
2. Men and women ≥50 years of age.
3. Active CNV lesions secondary to nAMD with foveal involvement.15 Subjects with 
polypoidal choroidal vasculopathy or retinal angiomatous proliferation are eligible to 
participate in the study, and their condition should be captured in the eCRF.
4. ETDRS BCVA of 73 to 25 letters (20/40 to 20/320 Snellen equivalents) in the study 
eye.
5. Willing, committed, and able to return for all clinic visits and complete all study-
related procedures.
6. Able to read, (or, if unable to read due to visual impairment, be read to verbatim by 
the person administering the informed consent or a family member) understand and 
willing to sign the ICF. 
7. The area of CNV must occupy at least 50% of the total lesion.
8. Women and men of reproductive potential16 must agree to use adequate contraception 
when sexually active. This applies for the time period between signing of the ICF
and 3 months after the last administration of study drug. The definition of adequate 
contraception will be based on the judgment of the investigator and on local 
requirements. Acceptable methods of contraception include, but are not limited to, 
(i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or 
cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based 
contraception. Subjects must agree to utilize two reliable and acceptable methods of 
contraception simultaneously.
6.2
Exclusion criteria - amended
1. Any prior ocular (in the study eye) or systemic treatment or surgery for nAMD, 
except dietary supplements or vitamins.
2. Any prior or concomitant therapy with another investigational agent to treat nAMD in 
the study eye.
3. Prior treatment with anti-VEGF agents as follows:

Prior treatment with anti-VEGF therapy in the study eye is not allowed
                                                
15 Specification of  CNV lesions simplified per Amendment 1 (see Section 15.1.1.12)
16 Women of reproductive or childbearing potential: Postmenopausal women must be amenorrheic for at least 12 
months in order not to be considered of childbearing potential.


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
Prior treatment with anti-VEGF therapy in the fellow eye with an 
investigational agent (not approved, e.g. bevacizumab) within the last 
3 months before the first dose in the study.  Such treatment will also not be 
allowed during the study. Prior treatment with an approved anti-VEGF 
therapy in the fellow eye is allowed.

Prior systemic anti-VEGF therapy, investigational or approved, within the 
last 3 months before the first dose in the study, and such treatment will not 
be allowed during the study.
4. Total lesion size >12 disc areas (30.5 mm2, including blood, scars and 
neovascularization) as assessed by FA in the study eye.
5. Subretinal hemorrhages that are either 50% or more of the total lesion area, or if the 
blood is under the fovea and is 1 or more disc areas in size in the study eye.  (If the 
blood is under the fovea, then the fovea must be surrounded by 270 degrees by visible 
CNV).
6. Scar or fibrosis making up >25%17 of the total lesion in the study eye.
7. Scar, fibrosis, or atrophy involving the center of the fovea in the study eye.
8. Presence of retinal pigment epithelial tears or rips involving the macula in the study 
eye.
9. History of any vitreous hemorrhage within 4 weeks before screening in the study eye.
10. Presence of other causes of CNV in the study eye.
11. Prior vitrectomy in the study eye.
12. History of retinal detachment or treatment or surgery for retinal detachment in the 
study eye.
13. Any history of macular hole of stage 2 and above in the study eye.
14. Any intraocular surgery, periocular surgery, or cataract surgery within 90 days before 
Day 1 in the study eye, except lid surgery, which may not have taken place within 
1 month of screening, as long as it is unlikely to interfere with the injection.
15. Only 1 functional eye even if that eye is otherwise eligible for the study. 
16. Prior trabeculectomy or other filtration surgery in the study eye.
17. Uncontrolled glaucoma (defined as IOP ≥25 mm Hg despite treatment with 
antiglaucoma medication) in the study eye.
18. Aphakia or pseudophakia with absence of posterior capsule (unless it occurred as a 
result of an yttrium aluminum garnet posterior capsulotomy) in the study eye.
                                                
17 Percentage of scar or fibrosis of total lesions reduced per Amendment 1 (see Section 15.1.1.13)


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19. Previous therapeutic radiation in the region of the study eye.
20. History of corneal transplant or corneal dystrophy in the study eye.
21. Significant media opacities, including cataract, in the study eye which might interfere 
with visual acuity, assessment of toxicity or FP.
22. History or clinical evidence of diabetic retinopathy, DME or any retinal vascular 
disease other than AMD in either eye.
23. Active intraocular, extraocular and periocular inflammation or infection in either eye.
24. Any ocular or periocular infection within the last 2 weeks before screening in either 
eye.
25. Any history of ocular or periocular Herpes simplex in either eye.
26. Any history of uveitis in either eye.
27. Presence of scleromalacia in either eye.
28. Any concurrent intraocular condition in the study eye that could require either 
medical or surgical intervention during the 104-week study period.
29. Any concurrent ocular condition in the study eye which, in the opinion of the 
investigator, could either increase the risk to the subject safety or which otherwise 
may interfere with evaluation of efficacy or safety.
30. History of other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that contraindicates the use of an investigational drug.
31. Participation as a subject in any clinical study within 12 weeks before screening.
32. Any systemic or ocular treatment with an investigational agent in the past 3 months 
before screening.
33. The use of long-acting steroids, either systemically or intraocularly, in the past 
6 months before screening.
34. Any history of allergy to the antiseptic used during preparation of the eye for the IVT 
injection in the investigational site (e.g. povidone iodine or chlorhexidine).
35. Known serious allergy to the fluorescein sodium for injection in angiography.
36. Hypersensitivity to the active substance aflibercept or to any of the excipients.
37. Pregnancy or breastfeeding.
38. Close affiliation with the investigational site; e.g. a close relative of the investigator, 
dependent person (e.g. employee or student of the investigational site)
39. Previous assignment to treatment during this study.


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6.3
Withdrawal of subjects from the study
6.3.1
Withdrawal - amended
Note: For this study, premature permanent discontinuation from study medication implies 
premature discontinuation from study participation.
Withdrawal criteria
Subjects must be withdrawn from the study if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further.  The subject will not suffer any disadvantage as a result.

Lost-to-follow-up.  A subject will be considered lost-to-follow-up if he/she misses 
2 consecutive pre-planned study visits without a major reason as agreed upon by the 
sponsor.  All attempts to contact the subject must be documented in the subject’s 
source documents.  

Before or at18 Week 16 (randomization), subjects require injections at shorter intervals 
than defined per protocol, based on the anatomical criteria specified in Section 7.1, 
and on the visual acuity criteria described in Section 9.2.4 for injection-intensive 
subjects.19

Serious adverse events (SAEs), if sponsor or investigator sees this as medical reason 
to warrant withdrawal.

A female subject becomes pregnant.

At the discretion of the treating physician.  The development of conditions which 
would have prevented a subject’s entry into the study according to the selection 
criteria is no reason per se for withdrawal.  However, the withdrawal in such cases 
remains at the discretion of the treating physician.

Determination by the investigator that the subject requires alternate treatment for 
nAMD in the study eye.

AE (decision to be removed from the study made by either the investigator or the 
subject).  The investigator must notify the sponsor immediately if a subject is 
withdrawn because of an AE.
                                                
18 Time point for withdrawing subjects because they need too short injection intervals defined more exactly per Amendment 
1 (see Section 15.1.1.14)
19 Reference to the diagnostic criteria which lead to withdrawal of the subject from the studyadded per Amendment 1 (see 
Section 15.1.1.15


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
Decision by the investigator that termination is in the subject’s best medical interest or 
administrative decision for a reason other than an AE.

Decision by the sponsor to halt the entire study.
Subjects may be withdrawn from the study if any of the following occurs:

If, in the investigator's opinion, continuation of the study would be harmful to the 
subject's well-being.

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).

Decision by the sponsor that termination is in the subject’s best medical interest or 
administrative decision for a reason other than an AE.
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “drop-out” as specified below:
Screening failure20
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “drop-out” (see below) is regarded as a 
“screening failure”. 
Re-screening of screening failures may be acceptable under the following conditions:

The subject had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.

The reason for the screening failure was a transient event, which subsequently 
resolved (e.g. decrease of elevated IOP, controlled arterial hypertension) within 
30 days.
Under any of the above exceptions, a subject may be re-screened once only.  Before a 
re-screening period is initiated, the subject must sign a new informed consent form.  To be 
eligible, re-screened subjects must meet all selection criteria during the re-screening period.
Drop-out
A subject who discontinues study participation prematurely for any reason is defined as a 
“drop-out” if the subject has already received IVT aflibercept.
General procedures
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject's 
medical records. End-of-study/early-termination visit procedures are to be completed at the 
time of discontinuation and subjects who withdraw should have end-of-study/early 
                                                
20 Screening failure paragraph reworded per Amendment 1 (see Section 15.1.1.16)


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termination procedures completed at the time of discontinuation.  The subject may object to 
the generation and processing of post-withdrawal data as specified in Section 13.4.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (premature termination of the study).
6.3.2
Replacement
Withdrawn subjects will not be replaced.
6.4
Subject identification
The subject identification (SID) number is a 9-digit number consisting of a 2-digit country 
code, a 3-digit center number, and a 4-digit subject number (current subject number within the 
center).
Once assigned to a subject, the SID number will not be re-used.
7.
Treatment(s)
7.1
Treatments to be administered - amended
This is an open-label study. The only treatment to be administered to the study eye is 2 mg 
aflibercept administered as an IVT injection.  
Starting at baseline (Week 0/Day 1), after subject eligibility in terms of OCT and FA has been 
confirmed by a central reading center, IVT aflibercept will be administered to the study eye 
every 4 weeks during the initiation phase (3 initial monthly doses at Weeks 0, 4, and 8).  At 
Week 8, the treatment interval will be extended by 4 weeks (1 x 2Q8, i.e. the next injection 
will take place at Week 16). 
At Week 16, after stratification based on visual outcomes from baseline to Week 16 (either 
<8 or ≥8 letters gain in BCVA), subjects will be randomized 1:1 into 1 of the following 
2 arms:

In the early-start T&E arm (test group, early treatment individualization), starting at 
Week 16, subjects will receive treatment in intervals extended by 2 weeks each time 
(up to a maximum of 16 weeks), as long as all anatomical criteria are met.
(Special case “completely dry”: See below, following the 3 anatomical criteria.)21

In the late-start T&E arm (per label, control group, treatment individualization after 
Year 1), subjects will receive treatment every 8 weeks to the end of Year 1 (four 2Q8 
injections).  Then in Year 2 (starting at Week 48), the treatment intervals will be 
extended by 2 weeks each time (up to a maximum of 16 weeks), as long as all 
anatomical criteria are met.  
                                                
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One-hundred twenty-seven (127) subjects are planned to be randomized into each arm. The 
treatment duration will be 104 weeks in both arms.
The anatomical criteria, based on OCT, are as follows for both study arms:

Absence of IRF and

Absence of new neovascularization or hemorrhage and

SRF not exceeding 50 µm in thickness
For subjects who have no IRF and no SRF at Week 16 (“completely dry”), confirmed by 
the Central Reading Center, the treatment interval will be extended by 4 weeks for a total of 
12 weeks (i.e. schedule next visit at Week 28). From Week 28 onward, the normal extension 
algorithm will be applied.22
If these criteria are not met, the retreatment interval will revert to the last treatment interval in 
which the disease was inactive.  In both arms, after Week 8, the treatment intervals will not be 
less than 8 weeks nor more than 16 weeks. 
For further details on determining treatment intervals, see Section 5.
7.2
Identity of study treatment
All study drugs will be labeled according to the requirements of local law and legislation.  
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
The SID number will be recorded on each vial and the SID number and investigator name (if 
locally required) will be recorded on the kit boxes for all the treatment kits.  The kit number 
will be recorded in the subject’s source documentation and also entered into the eCRF.
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk batch of the ingredients.  Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies Quality Assurance group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.  
The study drug, aflibercept, will be manufactured by Bayer Pharma AG, Berlin, Germany and 
supplied by the sponsor in sealed, single-use, sterile 2-mL vials, each with a final extractable 
volume of 0.10 mL.  In accordance with local regulations, each kit may contain one 18-gauge 
filter needle.  Details of the study drug are provided in Table 7-1.
                                                
22 Special case “completely dry” added to the early-start T&E arm per Amendment 1 (see Section 15.1.1.4)


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Table 7-1
Investigational test product
Name
Dose
Concentration
Volume
Formulation
Composition
BAY 86-5321 
/aflibercept/Eylea
2 mg 
40 mg/mL
Injected: 
0.05 mL
For intravitreal 
injection
40 mg aflibercept /mL, 
5% sucrose, 10 mM 
sodium phosphate, pH 
6.3, 0.03% polysorbate 
20, 40 mM sodium 
chloride, water for 
injection
7.3
Treatment assignment
At Week 16, subjects will be stratified based on visual outcomes from baseline to Week 16 
(either <8 or ≥8 letters gain in BCVA) and randomized to receive treatment under 1 of 
2 dosing regimens (see Section 7.1).  
The 2 treatment arms will be randomly assigned in a 1:1 ratio by a randomization list 
generated by the ‘Randomization Management’ department of Bayer using the Bayer standard 
randomization tool ‘RANDOM’.  This randomization list will be uploaded into the interactive 
voice/web response system (IxRS) of the IxRS supplier to control the correct treatment 
assignment of each subject.
7.4
Dosage and administration
The volume of injection will be 50 μL (0.05 mL) for the 2 mg aflibercept dose.  The study 
drug will be withdrawn using aseptic technique through an 18-gauge filter needle attached to 
a 1-mL syringe. The filter needle will be discarded after withdrawal of the vial contents and 
should not be used for IVT injection. The filter needle should be replaced with a sterile 
30-gauge needle for the IVT injection. The contents in the syringe should be expelled until 
the plunger is aligned with the line that marks 0.05 mL on the syringe.
Before administration, the solution for injection needs to be visually inspected. The vial must 
not be used if particulates, cloudiness, or discoloration are visible. 
Before usage, the unopened vial of aflibercept may be stored at room temperature (below 
25°C/77°F) for up to 24 hours.  After opening the vial, procedures have to take place under 
aseptic conditions.  The aflibercept dosing solutions may be kept at room temperature (25°C) 
for up to 2 hours (i.e. once the syringe is filled, the injection must be completed within 
2 hours of the start of dose preparation).
Aflibercept will be administered via IVT injection to the study eye. For the dosing schedule 
and planned duration, see Section 7.1. The study drug injection procedure is detailed in 
Appendix 15.1.2.
7.5
Blinding/masking
Not applicable.


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7.6
Drug logistics and accountability - amended
Packaging and labeling
For information on packaging and labeling see Section 7.2.
Storage
All study drugs will be stored at the investigational site in accordance with Good Clinical
Practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
department of the sponsor (or its affiliate/clinical research organization [CRO]), and will be 
inaccessible to unauthorized personnel.  Special storage conditions and a complete record of 
batch numbers and expiry dates can be found in the sponsor study file; the site-relevant 
elements of this information will be available in the investigator site file.
Aflibercept vials are to be stored at 2°C to 8°C.  The drug must not be frozen.  Before usage, 
the unopened aflibercept vial may be stored at room temperature (25°C / 77°F) for up to 
24 hours.  The temperature in the storage refrigerator has to be measured daily on working 
days with a min/max thermometer (continuous temperature monitoring is also allowed). 
Records of actual storage conditions (i.e. temperature log) at the study site must be 
maintained.  These must include a record of the dates on which the storage refrigerator was 
checked, the initials of the person checking the temperature, and the temperature at that time.
Accountability
The responsible site personnel will confirm receipt of study drug via IxRS (on the day of 
receipt or the earliest possible time point). The personnel will use the study drug only within 
the framework of this clinical study and in accordance with this protocol.  Receipt, 
distribution, return, and destruction (if any) of the study drug must be properly documented 
according to the sponsor’s agreed and specified procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
The physician or designated medical or pharmacy personnel handling the drug product are 
responsible for the accountability of all used 23 and unused study drug. Drug accountability 
records must be kept current and should contain the dates, quantities, kit numbers, and batch 
numbers (or lot numbers) of study drug received by the investigator, dispensed or 
administered to specified subjects, disposed of at the site (disposal at the site may occur only 
with a sponsor approval), or returned to the sponsor or a specified designee for disposal.  
Drug accountability will be overseen by study site personnel.  All inventories, along with 
shipment receipts, shipment temperature recordings (if applicable), storage temperature logs, 
pharmacy dose preparation logs, and IxRS confirmation reports must be made available for 
inspection.  At the conclusion of the study, photocopies of all drug accountability records will 
be provided by each site to the sponsor.
                                                
23 “Partially used” removed per Amendment 1 (see Section 15.1.1.17


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Supply and return
The treatment kits will be shipped to the investigator at regular intervals or as needed during 
the study.  Study drug will be shipped to the site using appropriate methods to maintain 
transport conditions within those recommended by its stability profile.  The investigator, or an 
approved representative (e.g. pharmacist), will ensure that all received study drugs are stored 
in a secured area on site, under recommended storage conditions and in accordance with 
applicable regulatory requirements.
At the end of the study and following reconciliation and documentation by the site monitor, 
all used, partially used, and unused vials of aflibercept will either be destroyed at the site or 
returned to a specified designee for disposal. 
7.7
Treatment compliance
All injections will be given at the clinical site.  Study personnel will monitor and document 
treatment compliance.
8.
Non-study therapy
8.1
Prior and concomitant therapy - amended
For prohibited drugs and procedures before the study, see Section 6.2.
Subjects may not receive any standard or investigational agents for treatment of their AMD in 
the study eye other than IVT aflibercept as specified in this protocol until they have 
completed the end of study/early termination visit assessments.  This includes medications 
administered locally (e.g. IVT, by juxtascleral or periorbital routes), as well as those 
administered systemically with the intent of treating the fellow eye.
If the fellow (non-study) eye has a condition approved to be treated by IVT anti-VEGF, the 
fellow eye may receive any locally approved non-systemic treatment (Note that fellow-eye 
IVT aflibercept treatment may be reimbursed24 in consultation with the sponsor); off-label 
treatment of the fellow eye with bevacizumab is prohibited.  If the fellow eye receives 
treatment, it is not advised that this occurs on the same day25 as when the study eye is treated.  
Even if treated with IVT aflibercept, the fellow eye will not be considered an additional study 
eye.  Subjects who receive treatment for the fellow eye should remain in the study.  Safety for 
the fellow eye, regardless of whether the fellow eye receives treatment, will be monitored at 
all study visits.  
                                                
24 Study drug must not be used for treatment of the fellow eye (if needed), but may be reimbursed per Amentment 1 (see 
Section 15.1.1.18
25 Time point of the fellow eye treatment reworded per Amendment 1 (see Section 15.1.1.19


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Any previous and concomitant treatments administered to the non-study eye will be recorded 
in the source documentation and then entered into the “Previous and Concomitant 
Medications” eCRF screen using the brand name.  
Any other medications that are considered necessary for the subject’s welfare, and that are not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of 
the investigator, with the exceptions noted above.
All previous and concomitant medications will be coded using an internationally recognized 
and accepted coding dictionary.  
8.2
Post-study therapy
After the end of the study, subjects will be treated with either IVT aflibercept or other 
treatment according to their physician's decision and standard of care. Such further treatment 
will occur at the subject’s expense and outside the purview of this study.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
A tabular schedule of study evaluations and procedures is provided in Table 9-1.


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Table 9-1 Schedule of Evaluations and Study Procedures - Amended
Study Phase
Initiation phase
Random.
Proactive extension phase
Treatment Arms
All Subjects
Early-start T&E Arma
Late-start T&E Arma
All Subjects
Visitb/Wkc
Screening
V1
Wk -3 to 0
Baseline
V2
Wk 0 (Day 1)
V3, 4
Wk 4, 8
V5
Wk 16
Visits extended by
anatomical criteriad
Year 1: Wk 24, 32, 40, 48
Year 2: Visits extended by
anatomical criteriad
End of study/
Wk 104 or
Early termination
Mandatory visits
Wk -3 to 0
Wk 0
Wk 4, 8
Wk 16
Wk 52e
Wk 52e
Wk 104e
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographic data
X
Medical/ophthalmic history
X
Physical examination
X
Pregnancy testf
X
X
(X)g
(X)g
(X)g
(X)g
(X)g
BCVA using ETDRS charth
X
X
X
X
X
X
X
OCT
X
X
X
X
X
X
X
FA/FPi
X
X (Wk 52 only)
X (Wk 52 only)
X
AEsjk
X
X
X
X
X
X
X
Indirect ophthalmoscopyk
X
X
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
X
X
IOPk
X
X
X
X
X
X
X
Vital signsl
X
X
X
X
X
X
X
Prior/concomitant medications
X
X
X
X
X
X
X
Randomization
X
Administration of study treatmentm
X
X
X
X
X
n26
Determination of next treatment 
intervalo
Xp
X
Xq
Telephone safety checkr
X
X
X
X
X
X
2Q8 = 2 mg aflibercept administered every 8 weeks; AE = adverse event; BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; 
FA = fluorescein angiography; FP = fundus photography; IOP = intraocular pressure; IVT = intravitreal; OCT = optical coherence tomography; random. = randomization; 
T&E = treat and extend; V = visit; Wk = week.
Note: All ocular assessments are to be conducted in both eyes, unless indicated otherwise.
                                                
26 Treatment of underlying disease on the day of the final vist and thereafter; AE reporting after the final study visit per Amendment 1 (see Section 15.1.1.10


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Table 9–1 Schedule of Evaluations and Study Procedures (continued)
a: Three initial monthly IVT aflibercept injections (initiation phase) followed either by one 8-weekly dose (2Q8) in the early-start T&E arm or by five 8-weekly doses (2Q8) in the late-
start T&E arm. The treatment interval may then be extended by 2 weeks each time (individualized treatment intervals of between 8 to16 weeks) based on anatomical outcomes.  
When/if anatomical outcomes indicate that the disease has re-activated, the treatment interval will revert to the last treatment interval in which the disease was inactive (i.e. no 
signs of exudation). For details on treatment intervals see Section 5.  
b: Visit numbers refer to the mandatory visits for treatment administration to subjects for the 3 initial monthly doses at Weeks 0, 4, and 8, followed by one 8-weekly dose (2Q8) at the 
randomization visit.
c: Visit schedules may deviate by ±7 days. Set schedule visits and fixed dosing arms use baseline for the calculation. Flexible visits always use the planned week number of the 
current visit to calculate the week number of the next visit.27 The procedures required at each visit have to be complete within 3 days, i.e. split visits are allowed.  Additionally, 
all procedures have to be complete within the 7-day window.  Slit lamp (anterior segment), IOP measurement, and indirect ophthalmoscopy are recommended to take place on 
the same day as the IVT injection.
d: Anatomical criteria:  No intraretinal fluid (IRF), no new neovascularization or hemorrhage, and subretinal fluid (SRF) not exceeding 50 µm in thickness.28 For further details on
determining treatment intervals see Section 5.
e: All subjects will have mandatory visits at Weeks 52 and 104.  In case the scheduled retreatment visit does not occur at Weeks 52 and 104 (±1 week), subjects in both treatment 
arms will still have mandatory visits without treatment at Weeks 52 and 104.
f: Urine test, for women of child-bearing potential only; a positive result should be confirmed by a serum pregnancy test. Postmenopausal women must be amenorrheic for at least 
12 months in order not to be considered of childbearing potential.
g: After the first treatment, a urine pregnancy test is mandatory at every treatment visit (prior to injection) in all countries where it is required by local regulations. If required by 
national /institutional regulations, a pregnancy test should be performed for women of childbearing potential at the end of study visit.
h: Refraction and BCVA using the ETDRS chart is to be performed at each visit.
i: Mandatory at screening, Week 52, and Week 104/early termination, but may be performed at other times based on the investigator’s medical judgment and standard of care.
j: The treating investigator must follow up by phone on any AEs that are ongoing or may occur or within 30 days of the last administration of study drug. Information regarding 
such events is to be reported under this protocol (i.e. not as a spontaneous report).29 For any drug-related AE occurring after 30 days of the last IVT application of 
aflibercept, the standard procedures that are in place for spontaneous reporting will be followed. If a subject prematurely withdraws from the study, AEs should be recorded 
until withdrawal or 30 days after the last dose of study drug, whichever is later.
k: Pre- and post-dose, as applicable. If a subject receives a study injection, indirect ophthalmoscopy should be conducted post-dose and IOP should be assessed in the study eye 30 
to 60 minutes post-dosing.
l: Temperature, blood pressure, and heart rate
m: See Appendix 15.1.2 for an example study drug injection procedure.
n: On the day of the final visit (Week 104 ±1 week or early termination) or thereafter, administration of study drug is not allowed. Any subsequent treatment of a subject’s underlying 
disease is not part of the study and is at the discretion of subject’s physician. Such treatment should only occur after all study relevant assessments have been performed..30
p: For subjects in the early-start T&E arm only.
(Footnotes continued)
                                                
27 Reference point for visit scheduling reworded per Amendment 1 (see Section 15.1.1.20)
28 Option of not extending the treatment interval, even if all anatomical criteria are met, removed per Amendment 1 (see Section 15.1.1.6)
29 Treatment of underlying disease on the day of the final vist and thereafter; AE reporting after the final study visit per Amendment 1 (see Section 15.1.1.10)
30 Treatment of underlying disease on the day of the final vist and thereafter; AE reporting after the final study visit per Amendment 1 (see Section 15.1.1.10)


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(Footnotes continued
o: Investigator assessment of whether the subject fulfills the anatomical criteria based on OCT for treatment interval extension (see Section 5 for details) and determination of next 
treatment interval.
q: In Year 2 only (starting from Week 48).
r: A mandatory safety telephone call will be made approximately 3 days after treatment to ensure no signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred.


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9.2
Visit description - amended
Visit schedules may deviate by ±7 days.  Set schedule visits and fixed dosing arms use 
baseline for the calculation. Flexible visits always use the planned week number of the 
current visit to calculate the week number of the next visit.31.  The procedures required at each 
visit have to be complete within 3 days, i.e. split visits are allowed.  Additionally, all 
procedures have to be complete within the 7-day window.  Slit lamp (anterior segment), IOP 
measurement, and indirect ophthalmoscopy are recommended to take place on the same day 
as the IVT injection.
Note: After the first treatment, a urine pregnancy test is mandatory at every treatment visit 
(prior to injection) in all countries where it is required by local regulations; a positive result 
should be confirmed by a serum pregnancy test. If required by national /institutional 
regulations, a pregnancy test should be performed for women of childbearing potential at the 
end of study visit.
9.2.1
Screening visit (Visit 1, Week −3 to baseline [Week 0])

Signed ICF (see Section 13.4 for details)

Allocation of unique SID number (see Section 13.4 for details)

AEs (see Section 9.6.1 for details)

Inclusion and exclusion criteria (see Sections 6.1 and 6.2 for details)

Demographic data (see Section 9.3.1 for details)

Medical and ophthalmic history (see Section 9.3.2 for details)

Prior and concomitant medications (see Section 8.1 for details)

Physical examination (see Section 9.6.3.2 for details)

Vital signs (temperature, blood pressure and heart rate) (see Section 9.6.3.3 for details)

Urine pregnancy test for women of childbearing potential; a positive result should be 
confirmed by a serum pregnancy test.   Postmenopausal women must be amenorrheic 
for at least 12 months in order not to be considered of childbearing potential (see 
Section 9.6.3.1 for details).

Ocular assessments (see Section 9.7 for details):

Refraction and BCVA using the ETDRS chart 

OCT
                                                
31 Reference point for visit scheduling redefined per Amendment 1 (see Section 15.1.1.20)


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
FP and FA (the study manual will further specify the standards for FA/FP 
during the study as well as for the historic evaluation of pre-existing 
images)

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

IOP
9.2.2
Initiation phase
9.2.2.1
Baseline visit (Visit 2, Week 0/Day 1)

Inclusion and exclusion criteria (see Sections 6.1 and 6.2 for details). This includes a 
negative urine pregnancy test for women of childbearing potential; a positive result 
should be confirmed by a serum pregnancy test. Postmenopausal women must be 
amenorrheic for at least 12 months in order not to be considered of childbearing 
potential. 

AEs (pre- and post-dose) (see Section 9.6.1 for details)

Prior and concomitant medications (see Section 8.1 for details) 

Vital signs (temperature, blood pressure and heart rate) (see Section 9.6.3.3 for details)

Ocular assessment (see Section 9.7 for details) before IVT aflibercept injection:

Refraction and BCVA using the ETDRS chart 

OCT

Indirect ophthalmoscopy 

Slit lamp biomicroscopy

IOP

IVT injection of study drug (see Section 7.4 for details and Appendix 15.1.2 for an 
example study drug injection procedure), followed by a 30- to 60-min observation 
period

IOP in the study eye 30 to 60 min following IVT injection

Indirect ophthalmoscopy (postdose)

Mandatory safety telephone call approximately 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred
9.2.2.2
Visits 3 and 4 (Weeks 4 and 8)

AEs (pre- and post-dose) (see Section 9.6.1 for details)

Prior and concomitant medications (see Section 8.1 for details)

Vital signs (temperature, blood pressure and heart rate) (see Section 9.6.3.3 for details)


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
Ocular assessment (see Section 9.7 for details) before IVT aflibercept injection:

Refraction and BCVA using the ETDRS chart 

OCT

Indirect ophthalmoscopy 

Slit lamp biomicroscopy

IOP

IVT injection of study drug (see Section 7.4 for details and Appendix 15.1.2 for an 
example study drug injection procedure), followed by a 30- to 60-min observation 
period

IOP in the study eye 30 to 60 min following IVT injection

Indirect ophthalmoscopy (postdose)

Mandatory safety telephone call approximately 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred
9.2.3
Randomization visit (Visit 5, Week 16)

Stratification based on visual outcomes from baseline to Week 16 (either <8 or 
≥8 letters gain in BCVA) and randomization of subjects via IxRS into the late-start 
T&E arm or the early-start T&E arm (see Section 7.3 for details)

AEs (pre- and post-dose) (see Section 9.6.1 for details)

Prior and concomitant medications (see Section 8.1 for details)

Vital signs (temperature, blood pressure and heart rate) (see Section 9.6.3.3 for details)

Ocular assessment (see Section 9.7 for details) before IVT aflibercept injection:

Refraction and BCVA using the ETDRS chart 

OCT

Indirect ophthalmoscopy 

Slit lamp biomicroscopy

IOP

IVT injection of study drug (see Section 7.4 for details and Appendix 15.1.2 for an 
example study drug injection procedure), followed by a 30- to 60-min observation 
period

IOP in the study eye 30 to 60 min following IVT injection

Indirect ophthalmoscopy (postdose)


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
For subjects in the early-start T&E arm only: The investigator assesses whether the 
subject fulfills the anatomical criteria based on OCT (see Section 5 for details) for 
treatment interval extension and determines the next treatment interval.

Mandatory safety telephone call approximately 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred
9.2.4
Proactive extension phase - amended
In the early-start T&E arm, starting at Week 16, subjects will receive treatment in intervals 
extended by 2 weeks each time (up to a maximum of 16 weeks), as long as all anatomical 
criteria are met. For subjects who have no IRF and no SRF at Week 16 (“completely dry”) 
confirmed by the Central Reading Center, the treatment interval will be extended by 4 weeks 
for a total of 12 weeks (i.e. schedule next visit at Week 28). From Week 28 onward, the 
normal extension algorithm will be applied.32
In the late-start T&E arm, subjects will receive treatment per label, every 8 weeks to the end 
of Year 1 (2Q8 injections at Weeks 24, 32, 40, 48).  Baseline will be used for calculation of 
fixed visits.  Then in Year 2 (starting from Week 48) the treatment intervals will be extended 
by 2 weeks each time (up to a maximum of 16 weeks), as long as all anatomical criteria are 
met.  Date of the next visit during Year 2 will be calculated based on the actual visit date.33
After Week 16 (randomization), the treatment intervals will not be less than 8 weeks nor more 
than 16 weeks with the following exception:  If, at any visit after Week 16, the subject has 
lost 15 or more letters from the best previous BCVA and the actual BCVA is not better than at 
baseline; or, if the investigator determines34 and documents in the eCRF that the subject’s 
condition necessitates more frequent injections than 2Q8, the subject will be considered 
“injection-intensive”, remain in the study, and be treated according to the investigator’s best 
clinical judgment (i.e. the frequency of IVT aflibercept injections is determined by the 
investigator who is free to subsequently adopt a T&E regimen similar to the per-protocol one, 
if deemed appropriate for the subject; however, the treatment intervals should not be less than 
4 weeks).
All subjects will have a mandatory visit at Week 52.  In case a scheduled retreatment visit 
does not occur at Week 52 (±1 week), subjects in both treatment arms will still have a 
mandatory visit without treatment at Week 52. With the exception of these mandatory 
Week-52 and 104 visits, subjects MUST receive a treatment when they attend a scheduled 
study visit (based on their individualized treatment schedule/treatment interval).  
9.2.4.1
Treatment visits
The following assessments will be conducted for subjects in both treatment arms:
                                                
32 Special case “completely dry” added to the early-start T&E arm per Amendment 1 (see Section 15.1.1.4)
33 Reference point for visit scheduling redefined per Amendment 1 (see Section 15.1.1.20)
34 “Justifies” removed per Amendment 1 (see Section 15.1.1.8)


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
AEs (pre- and post-dose) (see Section 9.6.1 for details)

Prior and concomitant medications (see Section 8.1 for details)

Ocular assessment (see Section 9.7 for details) before IVT aflibercept injection:

Refraction and BCVA using the ETDRS chart 

OCT

Indirect ophthalmoscopy 

Slit lamp biomicroscopy

IOP

Vital signs (temperature, blood pressure and heart rate) (see Section 9.6.3.3 for details)

IVT injection of study drug (see Section 7.4 for details and Appendix 15.1.2 for an 
example study drug injection procedure), followed by a 30- to 60-min observation 
period. 

IOP in the study eye 30 to 60 min following IVT injection

Indirect ophthalmoscopy (post-dose)

Mandatory safety telephone call approximately 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred
At all visits for subjects in the early-start T&E arm and at all Visits in Year 2 (starting from 
Week 48) for subjects in the late-start T&E arm:

The investigator assesses whether the subject fulfills the anatomical criteria based on 
OCT (see Section 5 for details) for treatment interval extension and determines the 
next treatment interval.
9.2.4.2
Mandatory visit at Week 52
The following assessments will be conducted for subjects in both treatment arms:

all assessments as described for the treatment visits in Section 9.2.4.1 will be 
conducted, except that no study drug will be injected and in consequence, there will be 
no post-dose assessments of IOP, indirect ophthalmoscopy, AEs, and no safety 
telephone call (unless the visit coincides with a scheduled treatment visit [±1 week]). 

FP and FA will be conducted (the study manual will further specify the standards for 
FA/FP during the study as well as for the historic evaluation of pre-existing images).
9.2.5
Final visit (Week 104)/early termination
All subjects will have a mandatory final visit at Week 104 ±1 week or early termination.  
Administration of the study drug is not allowed at this visit. Any subsequent treatment of a 
subject’s underlying disease is not part of the study and is at the discretion of the subject’s


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physician.  Such treatment should only occur after all study- relevant assessments have been 
performed.
The treating investigator must follow up by phone on any AEs that are ongoing or may occur 
within 30 days of the last administration of study drug.  Information regarding such events 
is to be reported under this protocol (i.e. not as spontaneous reports).35
If a pregnancy occurs more than 30 days after the last visit or the last IVT injection (whatever 
is earlier), this report will be processed as a spontaneous report.

AEs (pre- and post-dose, if applicable) (see Section 9.6.1 for details)

Prior and concomitant medications (see Section 8.1 for details) 

Vital signs (temperature, blood pressure and heart rate) (see Section 9.6.3.3 for details)

Ocular assessment (see Section 9.7 for details; if an injection is given at this visit, 
ocular assessments must be completed before administering the injection)

Refraction and BCVA using the ETDRS chart 

OCT

FP and FA (the study manual will further specify the standards for FA/FP 
during the study as well as for the historic evaluation of pre-existing 
images)

Indirect ophthalmoscopy

Slit lamp biomicroscopy

IOP

IVT injection of study drug if the visit coincides with a scheduled treatment visit 
(±1 week; see Section 7.4 for details and Appendix 15.1.2 for an example study drug 
injection procedure), followed by a 30- to 60-min observation period. 

IOP in the study eye 30 to 60 min following IVT injection (as applicable)

Indirect ophthalmoscopy (post-dose as applicable)

Mandatory safety telephone call approximately 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred
                                                
35 Treatment of underlying disease on the day of the final vist and thereafter; AE reporting after the final study visit per 
Amendment 1 per Amendment 1 (see Section 15.1.1.10)


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9.3
Population characteristics
9.3.1
Demographic
Subjects will be recruited from men and women ≥50 years of age.  The following 
demographic parameters will be recorded:

Gender

Year of birth

Weight

Height

Race/ethnicity (collection may be restricted per local regulations)
9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases, or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Not pertaining to the study indication

Start date before signing of the informed consent 

Considered relevant for the subject’s study eligibility
In addition, a complete medical and ophthalmic history will be obtained at screening (Visit 1)
to check the in- and exclusion criteria as defined in Sections 6.1 and 6.2, respectively.  
Detailed instructions on the differentiation between (1) medical history and (2) AEs can be 
found in Section 9.6.1.1.
9.4
Efficacy 
Primary efficacy variable:  

Change in BCVA as measured by the ETDRS letter score from Week 16 to Week 104
Key-secondary efficacy variable:  

Proportion of subjects maintaining vision (<3 lines loss) at Week 104 compared with 
baseline
Secondary efficacy variables:

Change in BCVA as measured by the ETDRS letter score from baseline to Weeks 52 
and 104 and from Week 16 to Week 52

Change in central retinal thickness (CRT) from baseline to Weeks 52 and 104 and 
from Week 16 to Weeks 52 and 104

Number of study drug injections from baseline to Weeks 52 and 104

Duration of last treatment interval


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
Proportion of subjects requiring retreatment at 8, 10, 12, 14, and 16 weeks as the last 
treatment interval

Proportion of 3-line gainers at Weeks 52 and 104 compared with baseline 

Proportion of subjects maintaining vision (<3 lines loss) at Week 52 compared with 
baseline
Exploratory efficacy variables: 

Change in CNV size and total lesion size from baseline to Weeks 52 and 104

Proportion of subjects with non-deteriorating OCT morphology (as assessed by the 
central reading center) at Weeks 52 and 104 compared with baseline

Proportion of subjects showing no IRF and no SRF at Weeks 8, 16, 52, and 104

Proportion of subjects showing no IRF and no SRF exceeding 50 µm in thickness at 
Weeks 52 and 104 

Percentage of subjects requiring retreatment with IVT aflibercept less frequently than 
every 8 weeks (2Q8)
A complete list of variables to be analyzed for this study will be provided in the statistical 
analysis plan (SAP).
Note: As each line on the ETDRS chart has 5 letters, subjects maintaining vision (<3 lines 
loss) are subjects who gain any number of letters, subjects without gain or loss of letters, and 
subjects who lose less than 15 letters in BCVA; 3-line gainers are subjects who gain at least 
15 letters in BCVA.
Ophthalmic procedures to assess efficacy (BCVA using the ETDRS chart, OCT, and FA/FP) 
are described in Section 9.7.
9.5
Pharmacokinetics/pharmacodynamics
Not applicable.
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom, or disease) in a subject
or clinical investigation subject after providing written informed consent for participation in 
the study.  Therefore, an AE may or may not be temporally or causally associated with the use 
of a medicinal (investigational) product.


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A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory findings, or 
other abnormal findings.

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs.  This includes intercurrent illnesses.
Definition of serious adverse event 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least 1 of the following exceptions is met:
The admission results in a hospital stay of less than 12 hours
The admission is pre-planned 
(i.e. elective or scheduled surgery arranged prior to the start of the study)
The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability/incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 


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functions.
e.
Is a congenital anomaly/birth defect
f.
Is another serious or important medical event as judged by the investigator
9.6.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.  
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:

Mild

Moderate

Severe
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the eCRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”.
An assessment of “no” would include:
1.
The existence of a highly likely alternative explanation, e. g. mechanical bleeding at 
surgical site.
or
2.
Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment.


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Important factors to be considered in assessing the relationship of the AE to study treatment 
include:

The temporal sequence from drug administration:  the event should occur after the 
drug is given.  The length of time from drug exposure to event should be evaluated in 
the clinical context of the event.

Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge):  subject’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question.

Underlying, concomitant, intercurrent diseases: each event should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have.

Concomitant medication or treatment: the other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them 
might have caused the event in question.

Known response pattern for this class of drug: Clinical/preclinical

Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.

The pharmacology and pharmacokinetics of the study treatment: the pharmacokinetic 
properties (absorption, distribution, metabolism, and excretion) of the study treatment, 
coupled with the individual subject’s pharmacodynamics should be considered.

The assessment is not possible
In this study, AEs will be assessed as related/not related to the study drug, IVT injection, and 
other protocol-specified procedures.  The causal relationship will be recorded using the 
following terms:
Evaluation of relationship to the study drug

Not related: AEs that were clearly and incontrovertibly due to causes other than the 
study drug (e.g. disease, environment), or were felt with a reasonable degree of 
certainty to be unrelated to the study drug.

Related: AEs for which a connection with the study drug could not be ruled out with 
certainty, or were felt with a reasonable degree of certainty to be related to the study 
drug, or were incontrovertibly related to the study drug.
A possible example of a drug-related AE would be a hypersensitivity reaction.
Evaluation of relationship to the injection procedure

Not related: AEs that were clearly and incontrovertibly due to causes other than the 
IVT injection procedure (e.g. disease, environment), or were felt with a reasonable 
degree of certainty to be unrelated to the IVT injection procedure.


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
Related: AEs for which a connection with the IVT injection procedure could not be 
ruled out with certainty, or which were felt with a reasonable degree of certainty to be 
related to the IVT injection procedure, or which were incontrovertibly related to the 
IVT injection procedure.
A possible example of an injection-related AE would be eye pain at the site of the injection.
Evaluation of relationship to study conduct

Not related: AEs that were clearly and incontrovertibly due to causes other than a 
protocol-specified procedure (e.g. disease, environment), or were felt with a 
reasonable degree of certainty to be unrelated to a protocol-specified procedure other 
than the IVT injection.

Related: AEs for which a connection to a protocol-specified procedure other than the 
IVT injection could not be ruled out with certainty, or which were felt with a 
reasonable degree of certainty to be related to a protocol-specified procedure other 
than the IVT injection, or which were incontrovertibly related to a protocol-specified 
procedure other than the IVT injection.
A possible example of a procedure-related AE would be bruising at the site of a blood draw.
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.

Drug withdrawn

Drug interrupted

Dose not changed

Not applicable

Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events

None

Remedial drug therapy

Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae


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
Not recovered/not resolved

Fatal

Unknown
9.6.1.3
Assessments and documentation of adverse events
Attention is to be paid to the occurrence of AEs at all stages of the examination.  Thus, the 
subject should be closely observed by the investigator.  In case of ongoing drug- or 
injection-related AEs and medically relevant AEs at the end of the study, the investigator 
should monitor the subject and document the outcome on the subject’s source documents.
The treating investigator must follow up by phone on any AEs that are ongoing or may occur 
within 30 days of the last administration of study drug. Information regarding such events 
is to be reported under this protocol (i.e. not as a spontaneous report). 36
For any drug related37 AE occurring after 30 days of the last application of study drug, the 
standard procedures that are in place for spontaneous reporting of adverse drug reactions will 
be followed.38
The investigator has to record on the respective eCRF pages all AEs occurring in the period 
between the signing of the informed consent and the end of the follow-up phase; after the end 
of the follow-up phase there is no requirement to actively collect AEs including deaths.  The 
type of information that should be assessed and recorded by the investigator for each AE is 
listed in Section 9.6.1.2. 
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s).
For all AEs and SAEs, the sponsor has to carry out a separate assessment for expectedness, 
seriousness, and causal relationship to study drug.
If a subject prematurely withdraws from the study, AEs should be recorded until withdrawal 
or 30 days after the last dose of study drug, whichever is later.
9.6.1.4
Reporting of serious adverse events
The definition of SAEs is given in Section 9.6.1.1. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.
                                                
36 Treatment of underlying disease on the day of the final vist and thereafter; AE reporting after the final study visit per 
Amendment 1  (see Section 15.1.1.10)
37 Specification of AE reporting after 30 days of last application of study drug per Amendment 1 (see Section 15.1.1.21
38Treatment of underlying disease on the day of the final vist and thereafter; AE reporting after the final study visit per 
Amendment 1 (see Section 15.1.1.10)


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Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as 
needed.
All SAEs occurring during the observation period defined in Section 9.6.1.3 must 
immediately (within 24 hours of the investigator’s awareness) be reported to the recipient 
detailed in the manual.  An SAE form must also be completed within 24 hours of the 
investigator awareness and forwarded to the designated recipient.  Each SAE must be 
followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.  For this, an AE page in the eCRF as well as the complementary pages 
provided in the Investigator File must be completed for each SAE.
Serious adverse events will be collected up until 30 days after the last dose of study drug or 
the termination visit, whichever is later.
Serious adverse events occurring after the protocol-defined observation period will be 
processed by the sponsor according to all applicable regulations.
Notification of the Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs)
Notification of the IECs/IRBs about all relevant events (e.g. SAEs, suspected unexpected
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.
9.6.1.5
Expected adverse events
For the EU, the Summary of product characteristics is considered the most appropriate 
relevant reference safety information.  The local label is considered an appropriate reference 
safety information in other countries.
The expectedness of AEs will be determined by the sponsor according to the Company Core 
Data Sheet and according to all local regulations.
9.6.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a study subject during 
her participation in this study, although a pregnancy per se is not considered an SAE.  The 
outcome of the pregnancy should be followed up carefully, and any outcome of the mother 


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and the child at delivery should be reported.  If a pregnancy occurs more than 30 days after 
the last visit or the last IVT injection of study drug39 (whatever is earlier), this report will be 
processed as a spontaneous report.
For all reports, the forms provided are to be used.  The investigator should submit them within 
the same timelines as an SAE.
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
The child’s health should be followed up until 3 months after birth.
9.6.3
Further safety
9.6.3.1
Laboratory evaluations
A urine pregnancy test for women of childbearing potential will be performed at screening 
and baseline.  Postmenopausal women must be amenorrheic for at least 12 months in order 
not to be considered of childbearing potential.  After the first treatment, a urine pregnancy test 
is mandatory at every treatment visit (prior to injection) in all countries where it is required by 
local regulations. A positive result should be confirmed by a serum pregnancy test. If 
required by national /institutional regulations, a pregnancy test should be performed for 
women of childbearing potential at the end of study visit.
The date of each sample obtained and the result will be recorded on the appropriate eCRF 
page. Pregnancy tests will be performed at a local laboratory. A copy of the results will be 
filed in the source documentation.
9.6.3.2
Physical examination
Abnormal physical examination findings are recorded either as medical history or AEs (see 
Section 9.6.1.1).
9.6.3.3
Vital signs (temperature, blood pressure, and heart rate)
Temperature, blood pressure, and heart rate will be measured at all study visits (and early 
termination if applicable).  Temperature and blood pressure should be taken in a consistent 
manner.
9.6.3.4
Ocular safety
Assessments of ocular safety will include IOP, indirect ophthalmoscopy, and slit lamp 
biomicroscopy (see Section 9.7).
                                                
39 “Study drug” added per Amendment 1 (see Section 15.1.1.21


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9.7
Other procedures and variables - amended
All potential ATEs will be adjudicated by a masked adjudication committee according to the 
APTC endpoints of non-fatal myocardial infarction, non-fatal stroke, and fatal vascular events 
(see also Section 13.1).  
All ophthalmic examinations are to be conducted in both eyes, unless indicated otherwise.  
The following ophthalmic examinations (except for FP/FA) will be conducted at every visit 
throughout the study.  Fundus photography/FA will be conducted at screening (Visit 1), 
Week 52, and the end of the study (Week 104 visit/early termination visit). The study manual 
will further specify the standards for FA/FP during the study as well as for the historic 
evaluation of pre-existing images.  The treating investigator may perform additional FA/FP at 
other times during the 104 weeks of the study based on his/her medical judgment and 
standard of care.
Care should be taken as much as possible to use the same equipment for all examinations for a 
certain subject.40
Indirect ophthalmoscopy
Indirect ophthalmoscopy is to be obtained in a standard manner (i.e. usually using a head-
mounted light source and a 20-diopter lens).
Slit lamp biomicroscopy
The slit lamp examination is to be performed in both the study eye and the fellow eye 
irrespective of whether the fellow eye has AMD.  If the fellow eye is not diagnosed with 
AMD, it will be followed to determine whether AMD develops.

Anterior segment assessment: the examination of the anterior segment is to be 
performed only with the slit lamp without any additive drugs or lenses.

Posterior segment assessment: the posterior segment should be examined with the slit 
lamp and the appropriate lens.  For this examination, the pupil of the eye must be 
dilated (mydriasis) with 2 to 3 drops of phenylephrin-tropicamid (or any other 
mydriatic) applied topically to the eye.
Intraocular pressure measurement
Intraocular pressure is to be measured using applanation tonometry (Goldmann or Tonopen).  
The same method of IOP measurement must be used in each subject throughout the study.  
Pre-injection IOP will be assessed for both the study eye and fellow eye.  Assessment of IOP 
30 to 60 min following IVT injection will be carried out only in the study eye.
For the measurement of IOP, a local anesthetic must be topically applied to the eye being 
tested (e.g. 1 drop of oxybuprocain).
                                                
40 Principle of observation consistency pointed out per Amendment 1 (see Section 15.1.1.23)


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Best-corrected visual acuity 
Visual function of the study eye and the fellow eye will be assessed using the ETDRS 
protocol starting at 4 meters.  Visual acuity examiners must be certified to ensure consistent 
measurement of BCVA, and a refraction will be performed at each visit.  Per subject, the 
same examiner must perform all assessments whenever possible.41  A detailed protocol for 
conducting visual acuity testing and refraction can be found in the study manual. 
Optical coherence tomography
Retinal and lesion characteristics such as CRT will be evaluated using spectral domain OCT.  
Images on the study eye and the fellow eye will be captured and assessed by study-site 
personnel specifically trained and certified for this assessment in order to ensure consistency 
and quality in image acquisition.  All OCT assessments will be electronically archived at the 
study site as part of the subject’s source documentation. 
Initially, the OCT images taken at the study site of up to 2 volunteers per site may be assessed 
by the central reading center to certify the site for central reading. During the study, all OCT 
images of the study eye will be read by the central reading center as part of this protocol.  The 
subjects’ eligibility to participate in the study in terms of OCT will be determined initially by 
the investigator, but will have to be confirmed by a central reading center before the first 
administration of study treatment at the baseline visit. Only centrally assessed images for the 
study eye will be used in the assessment of eligibility for the study and in the analysis of 
efficacy data. Treatment decisions (i.e. deciding whether a treatment interval can be 
extended) will be made by the investigator.
A detailed protocol for OCT image acquisition and assessment can be found in the OCT study 
manual.
Fundus photography and fluorescein angiography 
The anatomical state of the retinal vasculature will be evaluated by funduscopic examination, 
FP, and FA at screening, Week 52, and Week 104/early termination. The treating investigator 
may perform additional FA/FP at other times during the study based on his/her medical 
judgment and standard of care. Photographers must be certified by the reading center to 
ensure consistency and quality in image acquisition; for certification, images taken at the 
study site of up to 2 volunteers per site may be assessed by the central reading center.  All FA 
and FP images will be archived at the study site as part of the subject’s source documentation.  
Fundus photography and FA at the screening visit, Week 52, and Week 104/early termination, 
and any unscheduled FP or FA imaging will be assessed by the investigator and sent to an 
independent reading center where images will be read by masked readers.  The subjects’ 
eligibility to participate in the study in terms of FA will be determined initially by the 
investigator, but will have to be confirmed by a central reading center before the first 
administration of study treatment at the baseline visit.  Although FA is performed on both 
                                                
41 Principle of observation consistency pointed out per Amendment 1 (see Section 15.1.1.23)


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eyes and both eyes may be evaluated by the investigator, only the study eye will be evaluated 
by the independent reading center.  
The study manual will further specify the standards for FA/FP during the study as well as for 
the historic evaluation of pre-existing images.  
9.8
Appropriateness of procedures / measurements
All efficacy and safety variables and the methods by which they are assessed are standard 
variables and methods in clinical studies, as well as in ophthalmic practice. They are widely 
used and generally recognized as reliable, accurate, and relevant.
10.
Statistical methods and determination of sample size
10.1
General considerations
All statistical issues including definitions and proposed analyses of variables, format and 
content of tables, and listings and figures will be detailed in the SAP.  The SAP will be 
finalized before enrollment of subjects in the study.
All variables will be analyzed descriptively with appropriate statistical methods: continuous 
variables by sample statistics (i.e. mean, standard deviation, median, quartiles, and minimum 
and maximum), and categorical variables by frequency tables (absolute and relative 
frequencies).
A stratification by visual outcomes at Week 16 is planned, to ensure equal allocation of 
subgroups, thereby making it easier to interpret the results.  Visual outcomes will be 
determined at Week 16, depending on whether the subjects reached <8 or ≥8 letters gain in 
BCVA relative to baseline. The threshold for stratification was determined based on the 2Q8 
treatment arm from the VIEW 2 study: In this group of 306 subjects, the median BCVA gains 
at 16 weeks were 8 letters.
Statistical analysis will be performed using Statistical Analysis System (SAS); the version 
used will be specified in the SAP.
10.2
Analysis sets - amended
Populations for analysis are defined as follows:
The Full Analysis Set (FAS) will include all randomized subjects who received any study 
drug and have a BCVA assessment at Week 16 and at least 1 additional post-Week-16 BCVA 
assessment.  The FAS will be analyzed “as randomized”.
The Per-protocol Set (PPS) will include all subjects in the FAS without any major protocol 
deviation. Major protocol deviations are any violation of in- or exclusion criteria, a treatment 
duration shorter than 52 weeks, and no BCVA assessment at Week 52 or later.  Additionally, 
injection-intensive subjects who need injections at shorter intervals than 2Q8 between 
Week 16 and Week 52 will be excluded from the PPS. The PPS will be analyzed “as 
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The Safety Analysis Set (SAF) will include all subjects who received any study drug under 
this protocol. In the safety analysis, subjects who dropped out after start of treatment before 
randomization will be described only in ‘total’, since no allocation of such subjects to a 
treatment arm is possible. Randomized subjects will be analyzed ‘as randomized’.42
10.3
Variables and planned statistical analyses
10.3.1
Variables
For a preliminary list of efficacy and safety variables see Section 9.4 and Section 10.3.2.3, 
respectively. The complete list and details regarding the derivations of the variables will be 
provided in the SAP, before enrollment of the first subject.
10.3.2
Statistical and analytical plans 
10.3.2.1
Demography and baseline characteristics - amended
Demographic and baseline characteristics will be summarized by treatment arm (overall and 
stratified by “visual outcomes”) and all treatment arms combined for all 3 analysis 
populations (overall and stratified by visual outcome at Week 16).  Medical history will be 
coded by Medical Dictionary for Regulatory Activities (MedDRA) codes and prior and 
concomitant medications by Anatomical Therapeutic Chemical (ATC) codes (World Health 
Organization Drug Dictionary [WHODD]).  
The treatment arm comparability will be checked for each of the analysis populations (FAS, 
PPS, SAF). This comparison will be done for age, baseline, and Week 16 BCVA letter score 
and baseline and Week 16 CRT by a one-way analysis of variance comparing both treatment 
arms. The test statistics are reliable for variables not normally distributed as well, given the 
large sample sizes available here. Furthermore, treatment arms will be compared with respect 
to gender by Chi-squared test.43
10.3.2.2
Efficacy analyses
Details regarding the statistical analyses will be provided in the SAP.
Generally, in non-inferiority studies the most interesting population for efficacy analysis is 
the PPS, and the FAS should support the results for a valid interpretation. Therefore, the 
primary efficacy variable will be analyzed for both analysis sets with the PPS as the primary 
population and the FAS as the supportive one.  The key secondary variable will also be 
analyzed for both analysis sets in the same order. 
The other44 efficacy variables will be analyzed descriptively.
Efficacy data for the treated but non-randomized subjects will be described.
                                                
42 Paragraph describing the Safety Analysis Set reworded per Amendment 1 (see Section 15.1.1.24)
43 Paragraph on comparability of treatment arms reworded per Amendment 1 (see Section 15.1.1.25)
44  “Secondary” deleted per Amendment 1 (see Section 15.1.1.26)


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10.3.2.2.1
Primary efficacy variable analysis
The primary efficacy variable analysis will be conducted on the PPS and FAS as defined in 
Section 10.2.  
Statistical testing will be conducted to prove the non-inferiority of the early-start T&E 
regimen to the late-start T&E regimen.
Null hypothesis 
H0:
μ1 ≤ μ2-D  versus 
Alternative hypothesis 
H1:
μ1 > μ2-D, where 
D =
non-inferiority margin 
μi =
mean change in BCVA as measured by the ETDRS letter score for the study 
eye from Week 16 to Week 104 in treatment arm i.
i =
1: early-start T&E regimen
2: late-start T&E regimen
The non-inferiority margin D is set to 5 letters.  A non-inferiority margin of 5 letters is 
consistent with margin used in the “CATT Study” (12).
The methodological approach will be the calculation of 2-sided 95% confidence intervals (CI)
for the difference in the least squares (LS) means (early-start T&E regimen minus late-start 
T&E regimen) of the change in ETDRS letter score from Week 16 to Week 104 based on a 
two-way analysis of covariance (ANCOVA) with the BCVA measure at Week 16 as a 
covariate, and treatment arm and the stratification variable “visual outcomes” as fixed factors.
The primary statistical analysis will be performed on the PPS. The early-start T&E regimen 
will be considered to be non-inferior to the late-start T&E regimen if this analysis is
statistically significant, i.e. if the CI of the difference lies entirely above -5 letters, where a 
positive difference favors the early-start T&E regimen.  Additionally, the analysis will be 
performed on the FAS to support the results.
10.3.2.2.2
Secondary efficacy variables
The key secondary efficacy variable analysis will be conducted on the PPS and FAS as 
defined in Section 10.2.  
If, and only if, the early-start T&E regimen is statistically proven to be non-inferior to the 
late-start T&E regimen in the primary efficacy analysis, confirmatory testing will be 
continued on the PPS to assess the non-inferiority of the early-start T&E regimen to the 
late-start T&E regimen with regard to the key secondary efficacy variable (“maintenance of 
vision”).  


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Null hypothesis
H0:
p1 ≤ p2-∆ versus
Alternative hypothesis
H1:
p1 > p2-∆ where
pi =
proportion of subjects maintaining vision at Week 104 of treatment arm i 
∆ =
pre-specified non-inferiority margin of 7%45.   
i =
1:  early-start T&E regimen
2:  late-start T&E regimen
The methodological approach will be the calculation of 2-sided 95% CIs of the difference 
between the proportions (early-start T&E regimen minus late-start T&E regimen) of subjects 
maintaining vision at Week 104 taking the stratification variable “visual outcomes” into 
account.  The early-start T&E regimen will be considered to be non-inferior to the late-start 
T&E regimen if the CI of the difference lies entirely above -7%, where a positive difference 
favors the early-start T&E regimen.  Additionally, the analysis will be performed on the FAS 
to support the results.
This hierarchical procedure (a-priori ordered hypotheses) will control for multiplicity in the 
confirmatory analyses on the PPS.
Analyses on the other secondary efficacy variables will be conducted on the PPS and FAS as 
defined in Section 10.2 in a descriptive manner, with and without using “visual outcomes” as 
factor.  This may include 95% CIs for treatment differences in an exploratory way.
10.3.2.2.3
Other efficacy variables
The number of injections will be tabulated in both treatment arms. The injection interval data 
will be tabulated in detail for both treatment arms.
Analyses on exploratory efficacy variables will be conducted on the PPS and FAS in a 
descriptive manner.  This may include 95% CIs for treatment differences in an exploratory 
way.
10.3.2.3
Safety analysis
The safety analysis will be conducted in the SAF for intervals from baseline to Week 104, 
baseline to Week 52, and Week 52 to Week 104 by treatment arm.  
Treatment-emergent ocular AEs (study eye and fellow eye separately) and non-ocular AEs 
will be presented by MedDRA preferred term within primary system organ class (SOC) and 
summarized by treatment arms. Intensity and causal relationship to the investigational 
product will be analyzed descriptively. Serious AEs, including narratives, will be 
documented separately.  
                                                
45 The non-inferiority margin of 7% was proposed by the European Medicines Agency (EMA) in their scientific advice of 
May 2007 during the discussion of the proposed 10% non-inferiority margin in the VIEW studies (EMEA/CHMP/SAWP/ 
310870/ 2007 pp 22 & 23).


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In addition, the incidence of treatment-emergent systemic AEs will be summarized by 
treatment arm and by treatment arm and concomitant treatment of the fellow eye.
Other safety variables (e.g. IOP measurements and vital signs) will be analyzed descriptively 
including changes from baseline. 
10.3.3
Missing data/drop outs 
Data from subjects who drop out of the study will be included in all summaries where 
possible.
Missing values regarding the primary and key-secondary efficacy variables will be replaced 
by “last observation carried forward” (LOCF) using the last available post-baseline values.  
Last observation carried forward is considered an appropriate method especially in the late 
phase of the study (i.e. after Week 52), even though untreated nAMD is a progressive disease.  
Sensitivity analyses (complete cases, maximum-likelihood and/or multiple imputations; see 
the SAP for details) will be performed to investigate the influence of the missing values.
The handling of other missing or incomplete data will be detailed in the SAP.  Methods for 
avoiding missing values are described in Section 11.4.  
10.4
Determination of sample size
Based on the assumptions of 
(i)
a standard deviation of 13 for the mean change in BCVA from Week 16 to 
Week 104, 
(ii)
a non-inferiority margin of 5 letters, 
(iii)
an equal mean change in BCVA from Week 16 to Week 104 in the 2 treatment 
groups, 
(iv)
a power of 80%, and 
(v)
a 1-sided α of 2.5%, 
the sample size estimation resulted in 108 evaluable subjects per treatment arm (calculated 
with Power Analysis and Sample Size (PASS) software, version 11, non-inferiority of 
2 means).  
With an expected dropout rate of 15% from Week 16 to Week 104, a total of 254 subjects 
(127 per treatment arm) should be randomized. 
With an additional expected dropout rate of 5% until Week 16, approximately 268 subjects 
have to be treated at baseline.
Approximately 383 subjects have to be screened, assuming that 30% of them will be 
screening failures.


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10.5
Planned interim analyses - amended
An interim analysis is planned after all subjects have finished the 52-week visit (or withdrew). 
No data after visit Week 52 will be used in the interim analysis. Primary and secondary 
efficacy variables cannot be calculated, as no values from Week 104 will be analyzed.  The
analysis is only descriptive, no inferential tests will be performed, no decisions on the 
outcome will be made (e.g. terminating the study or changing the design) and it is planned to 
publish the descriptive results of this interim analysis.  Therefore, no α-adjustment seems 
necessary.
Analysis details will be given in the SAP.46
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be an eCRF; a validated electronic data capture 
(EDC) system called RAVE.  Subject data necessary for analysis and reporting will be 
entered/transmitted into a validated database or data system.
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer/the CRO has 
licensed from Medidata Solutions Worldwide.  RAVE has been validated by Medidata 
Solutions Worldwide for use in clinical studies.  RAVE allows for the application of software 
logic to set-up data entry screens and data checks to ensure the completeness and accuracy of 
the data entered by the site personnel.  The CRO extensively applies the logic to ensure data 
are complete and reflect the clinical data requirements of the study.  Data queries resulting 
from the application of the software logic are resolved by the site personnel.  The data are 
stored at a secure host facility maintained by Medidata Solutions Worldwide and transferred 
on a periodic basis to Bayer's internal computer system via a secure Virtual Private Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software.  All internal Bayer, CRO, and external investigator site personnel 
seeking access must go through a thorough RAVE training process before they are granted 
access to RAVE for use in Bayer's clinical studies.  Training records are to be maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made.  This information is available both at the investigator’s site and at Bayer.  Data 
                                                
46 Description of interim analysis revised per Amendment 1 (see Section 15.1.1.27)


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entries made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.
Source documentation
It is the expectation of the sponsor that data entered into the eCRF has source documentation 
available at the site. All data must be available in source documents before entry into eCRFs.  
The site must implement processes to ensure availability of all required source 
documentation.  A source document checklist (not part of this protocol) will be used at the 
site to identify the source data for key data points collected and the monitor will work with the 
site to complete this.
Data recorded from screening failures
Data of 'only screened subjects' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable.  At minimum, the following data should be 
recorded in the eCRF:

Demographic information (subject number; year of birth/age; gender; if applicable 
race/ethnicity)

Date of informed consent

Reason for premature discontinuation

Date of last visit.  
These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the eCRF in 
addition to the data specified above:

All information related to the SAE such as: 

Concomitant medication

Medical history

Other information needed for SAE complementary page
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate, and complete.  
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 


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
Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s/ CRO’s standards and data cleaning 
procedures.  This is applicable for data recorded on eCRF as well as for data from other 
sources (e.g. IxRS and adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
11.4
Missing data 
Most important is to avoid missing data, e.g. by monitoring in time for completeness (see 
Section 11.2) and investigators’ training, especially to motivate subjects to be compliant with 
the study protocol.  The risk of bias to the efficacy results due to missing data may be 
decreased in this study, since all subjects will receive IVT aflibercept during the study.
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Subject (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution, or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 


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alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change (e.g.
relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due to but not limited to 
the following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,

Safety findings from this study (e.g. SAEs)

Results of parallel clinical studies

Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
It should be noted that the results of the interim analysis cannot lead to a study closure and 
that no study closure after the interim analysis is possible as no α-adjustment was planned.
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for an individual subject's withdrawal can be found in Section 6.3.1.


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13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
The Global Clinical Leader (GCL) in cooperation with the Study Manager (StM) will assign 
the coordinating investigator responsible for signing the final clinical study report (CSR).
All other study personnel are identified in a separate personnel list (not part of this clinical 
study protocol) as appropriate.  This list will be updated as needed; an abbreviated version 
with personnel relevant for the centers will be available in each center’s investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before subject recruitment may start at the respective center.  Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study and the study medical expert are identified on the title page 
of this protocol.  If required by local law, local co-sponsors will be nominated; they will be 
identified on the respective country-specific signature pages.
Key institutions such as the central reading center and external data evaluation bodies are 
identified in separate documents as well.
Central reading center for images
An independent central reading center will evaluate the ophthalmic images obtained by OCT 
and FP/FA (see Section 9.7).
External data evaluation bodies
The sponsor will institute a steering committee to guide the trial in all aspects of efficacy and 
must ensure that all relevant information is provided by investigators.  The composition of the 
team, the functional roles, and responsibilities will be specified in the charter.
A masked adjudication committee will perform an additional analysis of ATEs based on the 
APTC endpoints of non-fatal myocardial infarction, non-fatal stroke, and fatal vascular 
events, including fatal hemorrhages and sudden unexplained death.  Details will be described 
in the adjudication committee charter.
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.


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Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
GCP guidelines and the guiding principles detailed in the Declaration of Helsinki.  The study 
will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations, and 
organizations.  When necessary, an extension, amendment, or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor.  The responsible unit (e.g.
IEC/IRB, head of the study center/medical institution) must supply to the sponsor, upon 
request, a list of the EC/IRB members involved in the vote and a statement to confirm that the 
IEC/IRB is organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
All relevant information on the study will be summarized in an integrated subject information 
sheet and ICF provided by the sponsor. A sample subject information and ICF is provided as 
a document separate to this protocol.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject prior to his/her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.


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Each subject will be informed about the following aspects of premature withdrawal:

Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 

The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2.5 to be conducted after withdrawal of consent. 

The subject’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the SAP. 

Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading); these data would also be retained and 
statistically analyzed in accordance with the SAP.  The subject has the right to object 
to the generation and processing of this post-withdrawal data.  For this, he/she needs 
to sign a corresponding declaration of objection; alternatively, the subject’s oral 
objection may be documented in the subject’s source data.
Each subject will have ample time and opportunity to ask questions.
Only if the subject voluntarily agrees to sign the ICF and has done so, may he/she enter the 
study.  Additionally, the investigator will personally sign and date the form.  The subject will 
receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the subject’s note/file of the medical institution.
In the event that informed consent is obtained on the date that screening study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
If the subject is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the sponsor and the 
investigator).  This is to be documented by a signature from the informing investigator as well 
as by a signature from the witness.
The ICF and any other written information provided to subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the subject
information and/or the written ICF.  The investigator will inform the subject of changes in a 
timely manner and will ask the subject to confirm his/her participation in the study by signing 
the revised ICF.  Any revised written ICF and written information must receive the IEC/IRB’s 
approval/favorable opinion in advance of use.
13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 


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All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs and intends to also publish the results of the interim analysis 
of the study.
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.
13.6
Compensation for health damage of subjects/insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the eCRF, and if the subject name appears on any other document (e.g. pathologist report), 
it must be obliterated before a copy of the document is supplied to the sponsor.  Study 
findings stored on a computer will be stored in accordance with local data protection laws.  As 
part of the informed consent process, the subjects will be informed in writing that 
representatives of the sponsor, IEC/IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available 
for inspection will be handled in strictest confidence and in accordance with local data 
protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.
14.
Reference list 
1. Rahmani B, Tielsch JM, Katz J, Gottsch J, Quigley H, Javitt J, et al. The cause-specific 
prevalence of visual impairment in an urban population. The Baltimore Eye Survey. 
Ophthalmology. 1996 Nov;103(11):1721-6.


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2. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular 
endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other 
retinal disorders. N Engl J Med. 1994 Dec 01;331:1480-7.
3. Spaide R. Ranibizumab according to need: a treatment for age-related macular 
degeneration. Am J Ophthalmol. 2007 Apr;143(4):679-80.
4. Engelbert M, Zweifel SA, Freund KB. Long-term follow-up for type 1 (subretinal 
pigment epithelium) neovascularization using a modified ‘treat and extend’ dosing 
regimen of intravitreal antivascular endothelial growth factor therapy. Retina. 
2010 Oct;30(9):1368-75.
5. Gupta OP, Shienbaum G, Patel AH, Fecarotta C, Kaiser RS, Regillo CD. A treat and 
extend regimen using ranibizumab for neovascular age-related macular degeneration 
clinical and economic impact. Ophthalmology. 2010 Nov;117(11):2134-40. 
6. Oubraham H, Cohen SY, Samimi S, Marotte D, Bouzaher I, Bonicel P, et al. Inject and 
extend dosing versus dosing as needed: a comparative retrospective study of ranibizumab 
in exudative age-related macular degeneration. Retina. 2011 Jan;31(1):26-30.
7. Shienbaum G, Gupta OP, Fecarotta C, Patel AH, Kaiser RS, Regillo CD. Bevacizumab 
for neovascular age-related macular degeneration using a treat-and-extend regimen: 
clinical and economic impact. Am J Ophthalmol. 2012 Mar;153(3):468-73.
8. Toalster N, Russell M, Ng P. A 12-month prospective trial of inject and extend regimen 
for ranibizumab treatment of age-related macular degeneration. Retina. 
2013 Jul-Aug;33(7):1351-8.
9. Pruente C. Efficacy and Safety of Ranibizumab in "Treat and Extend" Treatment 
Algorithms Versus Ranibizumab As Needed in Patients With Macular Edema and Visual 
Impairment Secondary to Diabetes Mellitus (RETAIN). Presented at AAO 2013.
10. Mrejen S, Jung J, Gallego-Pinazo R, et al. Long-Term Visual Outcomes for a Treat and 
Extend Anti-VEGF Regimen in Eyes with Neovascular Age-Related Macular 
Degeneration. Poster presented at ARVO 2013.
11. Hee MR, Baumal CR, Puliafito CA, Duker JS, Reichel E, Wilkins JR, et al. Optical 
coherence tomography of age-related macular degeneration and choroidal 
neovascularization. Ophthalmology. 1996 Aug;103(8):1260-70.
12. Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, et al. for the 
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research 
Group. Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related 
Macular Degeneration Two-Year Results. Ophthalmology. 2012 Jul;119(7):1388–98.
13. Aiello LP, Brucker AJ, Chang S, Cunningham ET Jr, D’Amico DJ, Flynn HW Jr, et al. 
Evolving guidelines for intravitreous injections. Retina. 2004 Oct;24(5 Suppl):S3-19.


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15.
Protocol amendments
Editorial note
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version.  As applicable, changes to the protocol text are highlighted as 
follows:

Addition of a whole new portion: Brief identification of the new portion

Removal of a whole portion: Complete display of the removed portion, formatted as 
crossed out

Editing of an existing portion: Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent previous protocol version.  Deletions 
are crossed out in the “old text”.  Additions are underlined in the “new text”.

Tables / figures: The term “amended” is added to the caption.

Terminological changes: Brief specification of the terminological change
Correction of typos or omissions are not highlighted.
15.1
Amendment 1, dated 25 Jan 2016
15.1.1
Overview of changes to the study
15.1.1.1
Modification 1 – Approved indications for aflibercept
Logical correction of approved indications for aflibercept.
Rationale: Previous version logically incorrect.
The following protocol sections are affected by this modification:
Section 3 Introduction
15.1.1.2
Modification 2 – Countries in which aflibercept is approved
Countries in which aflibercept is approved qualified.
Rationale: Previous version suggested fewer number of countries.
The following protocol sections are affected by this modification:
Section 3 Introduction


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15.1.1.3
Modification 3 – Time point for disqualifying subjects for 
randomization
Time point for disqualifying subjects for randomization defined more exactly.
Rationale: For clarity
The following protocol sections are affected by this modification:
Section 5 Study design
15.1.1.4
Modification 4 – Diagnosis “completely dry” at Week 16
Special case “completely dry” added to the early-start T&E arm.
Rationale: Gain results on subjects responding to the treatment very quickly.
The following protocol sections are affected by this modification:
Section 5 Study design
Section 7.1 Treatments to be administered 
Section 9.2.4 Proactive extension phase
15.1.1.5
Modification 5 –.Anatomical criteria for extending the treatment 
intervals
Wording added for more clarity.
Rationale: For clarity.
The following protocol sections are affected by this modification:
Section 5 Study design
15.1.1.6
Modification 6 – Option of not extending the treatment interval
Option of not extending the treatment interval, even if all anatomical criteria are met, 
removed.
Rationale: On advice of Steering Committee to ensure uniformity of subject management in 
keeping with protocol and consistency of data.
The following protocol sections are affected by this modification:
Section 5 Study design
Table 9-1 Schedule of Evaluations and Study Procedures
15.1.1.7
Modification 7 – Exception for treatment intervals of at least 8 weeks
Wording added consistent with synopsis.


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Rationale: For consistency and clarity.
The following protocol sections are affected by this modification:
Section 5 Study design
15.1.1.8
Modification 8 – Justification for investigator’s treatment decision
“Justifies” removed.
Rationale: For clarity, to avoid implication that investigator’s treatment decision needs to be 
approved by an adjudication panel or authority
The following protocol sections are affected by this modification:
Section 5 Study design
Section 9.2.4 Proactive extension phase
15.1.1.9
Modification 9 – Exception for treatment intervals of at least 8 weeks
Sentence split for better readability.
Rationale: Better readability
The following protocol sections are affected by this modification:
Section 5 Study design
15.1.1.10 Modification 10 – Treatment of underlying disease on the day of the 
final visit and thereafter; AE reporting after the final study visit
If subjects need treatment of their underlying disease on the day of the final visit (or 
thereafter), this is not part of the study and is at the discretion of the subjects’ physician.
AEs ongoing after the final visit or occurring within 30 days of the last injection of study drug 
must be followed up by phone and be reported under the study protocol (i.e. not as 
spontaneous reports).
For drug-related AEs occurring after 30 days of the last application of study drug the standard 
procedures that are in place for spontaneous reporting of adverse drug reactions will be 
followed.
Rationale: To clarify that the final per protocol study procedures are the pre-injection 
assessment at week 104 (or early termination). If it is determined, based on these evaluations, 
that a subject requires an injection at this last visit, this falls outside the scope of the protocol 
and must therefore be performed according to the physician’s discretion. 
Specificiation of the method of contact for the 30 day safety follow up (i.e. by phone) 
following the last injection of study drug
The following protocol sections are affected by this modification:


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Section 5 Study design
Section 9.1 Tabular schedule of evaluations (Table 9-1 Schedule of Evaluations and 
Study Procedures
Section 9.2.5 Final visit (Week 104)/early termination
Section 9.6.1.3 Assessments and documentation of adverse events
15.1.1.11
Modification 11 – Reference point for fluorescein angiography eligibility 
criteria
Time of nAMD diagnosis removed
Rationale: Checking of FA/FP eligibility criterion against images at time of diagnosis is not 
required for the trial
The following protocol sections are affected by this modification:
Section 6 Study population
15.1.1.12 Modification 12 – Inclusion criterion 3
Specification of CNV lesions simplified.
Rationale: As per Steering Committee suggestion; to simplify and broaden the inclusion 
criterion by removing the quantitative definition of ‘juxtafoveal’
The following protocol sections are affected by this modification:
Section 6 Study population
Section 6.1 Inclusion criteria
15.1.1.13 Modification 13 – Exclusion criterion 6
Percentage of total lesions for scar or fibrosis reduced.
Rationale: On advice of  steering committee to reflect current medical best practice trends.
The following protocol sections are affected by this modification:
Section 6.2 Exclusion criteria
15.1.1.14 Modification 14 – Withdrawal criterion 3
Time point for withdrawing subjects from the study defined more exactly
Rationale: For clarity
The following protocol sections are affected by this modification:
Section 6.3.1 Withdrawal


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15.1.1.15 Modification 15 – Withdrawal criterion 3
Reference to the diagnostic criteria that lead to withdrawal of the subject from the study added 
Rationale: For completeness
The following protocol sections are affected by this modification:
Section 6.3.1 Withdrawal
15.1.1.16 Modification 16 – Screening failure paragraph
Text reworded.
Rationale: Updated to be in line with other aflibercept protocols and specify that subject s 
may only be rescreened once
The following protocol sections are affected by this modification:
Section 6.3.1 Withdrawal
15.1.1.17 Modification 17 – Drug accountability
“Partially used” removed from the types of drugs the study site must account for.
Rationale: For clarity and to ensure that vials are only used a single time.
The following protocol sections are affected by this modification:
Section 7.6 Drug logistics and accountability
15.1.1.18 Modification 18 – Fellow eye treatment
If aflibercept treatment of the fellow eye is warranted, commercial drug should be used.
Rationale: Clarification that the drug will not be supplied by Bayer but may be reimbursed
upon consultation with the study team.
The following protocol sections are affected by this modification:
Section 8.1 Prior and concomitant therapy
15.1.1.19 Modification 19 – Fellow eye treatment
Time point of the fellow eye treatment reworded.
Rationale: Less stringent wording, which provides guidance (and protocol preference) but 
allows for local/ investigator practice patterns
The following protocol sections are affected by this modification:
Section 8.1 Prior and concomitant therapy


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15.1.1.20 Modification 20 – Reference point for visit scheduling 
Reference point for visit scheduling reworded in more detail.
Rationale: For clarity and to ensure alignment with structure of database
The following protocol sections are affected by this modification:
Section 9.1 Tabular schedule of evaluations (Table 9-1 Schedule of Evaluations and 
Study Procedures)
Section 9.2 Visit description
Section 9.2.4 Proactive extension phase
15.1.1.21 Modification 21 – Specification of AE reporting after 30 days of last 
application of study drug 
Procedure for spontaneous reporting of adverse drug reactions applies for drug related AEs 
occurring after 30 days of the last administration of the study drug.
Rationale: For clarity and consistency with Footnote j to Table 9-1.
The following protocol sections are affected by this modification:
Section 9.6.1.3 Assessments and documentation of adverse events
15.1.1.22 Modification 22 – Time reference for reporting pregnancy as AE or as 
spontaneous report
Addition of “study drug”
Rationale: Clarification that spontaneous reporting applies after dose of study drug.
The following protocol sections are affected by this modification:
Section 9.6.2 Pregnancies
15.1.1.23 Modification 23 – Observation consistency
Principle of observation consistency pointed out.
Rationale: Good scientific practice.
The following protocol sections are affected by this modification:
Section 9.7 Other procedures and variables 
15.1.1.24 Modification 24 – Safety set
Paragraph describing the Safety Analysis Set reworded.


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Rationale: For clarity.
The following protocol sections are affected by this modification:
Section 10.2 Analysis sets
15.1.1.25 Modification 25 – Comparability of treatment arms
Paragraph on comparability of treatment arms reworded.
Rationale: Harmonization of text between study protocol and statistical plan.
The following protocol sections are affected by this modification:
Section 10.3.2.1 Demography and baseline characteristics
15.1.1.26 Modification 26 – Efficacy variables analyzed descriptively
“Secondary” deleted.
Rationale: The key secondary variable will be analyzed confirmatively.
The following protocol sections are affected by this modification:
Section 10.3.2.2 Efficacy analyses
15.1.1.27 Modification 27 – Interim analysis
Description of interim analysis revised.
Rationale: Clarification and harmonization of text between study protocol and statistical plan.
The following protocol sections are affected by this modification:
Section 10.5 Planned interim analyses
15.1.1.28 Modification 28 – Withdrawable volume
Withdrawable volume corrected
Rationale: Error in original protocol version
The following protocol sections are affected by this modification:
Section 16.1 Aflibercept intravitreal injection procedure
15.1.2
Changes to the protocol text
Changes to the protocol text are highlighted as specified at the beginning of Section 15


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Approved indications for aflibercept - Section 3 Introduction
Logical correction of approved indications for aflibercept per Modification 1 (Section 
15.1.1.1)
Old text
To date, aflibercept has been approved as a treatment for nAMD, diabetic macular edema 
(DME), and macular edema secondary to branch and central retinal vein occlusion in …
New text
To date, aflibercept has been approved as a treatment for nAMD, diabetic macular edema 
(DME), and macular edema secondary to branch or central retinal vein occlusion in …
Countries in which aflibercept is approved - Section 3 Introduction
Quantification of countries in which aflibercept is approved qualified per Modification 2 
(Section15.1.1.2)
Old text
To date, aflibercept has been approved as a treatment for … in the United States (US), 
European Union (EU), Japan and several other countries;
New text
To date, aflibercept has been approved as a treatment for … in the United States (US), 
European Union (EU), Japan and many other countries;
Time point for disqualifying subjects for randomization - Section 5 Study design
Point in time for disqualifying subjects for randomization defined more exactly per 
Modification 3 (Section 15.1.1.3)
Old text
If subjects require injections at shorter intervals than defined per protocol before Week 16, the 
subjects will not be randomized but withdrawn from the study
New text
If subjects require injections at shorter intervals than defined per protocol before or at 
Week 16, the subjects will not be randomized but withdrawn from the study


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Diagnosis “completely dry” 
Section 5 Study design
Section 7.1 Treatments to be administered
Section 9.2.4 Proactive extension phase
Special case “completely dry” added to the early-start T&E arm per Modification 4 
(Section 15.1.1.4)
Old text
In the early-start T&E arm (test group, early treatment individualization), starting at Week 
16, subjects will receive treatment in intervals extended by 2 weeks each time (up to a 
maximum of 16 weeks), as long as all anatomical criteria are met.
New text
In the early-start T&E arm (test group, early treatment individualization), starting at Week 
16, subjects will receive treatment in intervals extended by 2 weeks each time (up to a 
maximum of 16 weeks), as long as all anatomical criteria are met.
(Special case “completely dry”: See below, following the 3 anatomical criteria.)
And definition added:
The anatomical criteria for extending the treatment intervals for the study eye, based on OCT, 
are as follows for both study arms:

Absence of intra-retinal fluid (IRF) and

Absence of new neovascularization or hemorrhage and

Subretinal fluid (SRF) not exceeding 50 µm in thickness
For subjects who have no IRF and no SRF at Week 16 (“completely dry”) confirmed by the 
Central Reading Center, the treatment interval will be extended by 4 weeks for a total of 12 
weeks (i.e. schedule next visit at Week 28). From Week 28 onward, the normal extension 
algorithm will be applied.
Anatomical criteria for extending the treatment intervals - Section 5 Study design
Wording added for more clarity per Modification 5 (Section 15.1.1.5)
Old text
The anatomical criteria for the study eye, based on OCT, are as follows for both study arms:


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New text
The anatomical criteria for extending the treatment intervals for the study eye, based on OCT, 
are as follows for both study arms:
Option of not extending treatment interval
Section 5 Study design
Section 9.1 Tabular schedule of evaluations (Table 9-1 Schedule of Evaluations and 
Study Procedures)
Option of not extending the treatment interval, even if all anatomical criteria are met, 
removed per Modification 6 (Section 15.1.1.6)
Old text
The investigator assesses whether the subject fulfills the anatomical criteria for treatment 
interval extension and determines the next treatment interval.  If the anatomical criteria are 
not met, the retreatment interval will revert to the last treatment interval in which the disease 
was inactive.  Even if all anatomical criteria are met (including the presence of SRF not 
exceeding 50 µm in thickness), the investigator will have the option of not extending the 
treatment interval provided that this decision is adequately medically justified and 
documented in the electronic case report form (eCRF). The subject will have all assessments 
during the proactive extension phase as detailed in Section 9.2.
New text
The investigator assesses whether the subject fulfills the anatomical criteria for treatment 
interval extension and determines the next treatment interval.  If the anatomical criteria are 
not met, the retreatment interval will revert to the last treatment interval in which the disease 
was inactive.  The subject will have all assessments during the proactive extension phase as 
detailed in Section 9.2.
Exception for treatment intervals of at least 8 weeks - Section 5 Study design
Wording added consistent with synopsis per Modification 7 (Section 15.1.1.7)
Old text
After Week 16 (randomization), the treatment intervals will not be less than 8 weeks nor more 
than 16 weeks.  If, at any visit after Week 16, the subject has …, the subject will be 
considered “injection-intensive”.


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New text
After Week 16 (randomization), the treatment intervals will not be less than 8 weeks nor more 
than 16 weeks with the following exception:  If, at any visit after Week 16, the subject has …, 
the subject will be considered “injection-intensive”.
Justification for investigator’s treatment decision 
Section 5 Study design
Section 9.2.4 Proactive extension phase
“Justifies” removed per Modification 8 (Section 15.1.1.8)
Old text
After week 16 … or, if the investigator determines, justifies, and documents in the eCRF that 
the subject’s condition necessitates more frequent injections than 2Q8, the subject will be 
considered “injection-intensive” (and remain in the study)
New text
After week 16 …or, if the investigator determines and documents in the eCRF that the 
subject’s condition necessitates more frequent injections than 2Q8, the subject will be 
considered “injection-intensive” (and remain in the study)
Exception for treatment intervals of at least 8 weeks – Section 5 Study design
Sentence split for better readability per Modification 9 (Section 15.1.1.9)
Old text
After Week 16 (randomization), the treatment intervals will not be less than 8 weeks nor more 
than 16 weeks with the following exception:  If, at any visit after Week 16, the subject has 
lost 15 or more letters from the best previous BCVA and the actual BCVA is not better than 
at baseline; or, if the investigator determines and documents in the eCRF that the subject’s 
condition necessitates more frequent injections than 2Q8, the subject will be considered 
“injection-intensive”, remain in the study, and be treated according to the investigator’s best 
clinical judgment (i.e. the frequency of IVT aflibercept injections is determined by the 
investigator who is free to subsequently adopt a T&E regimen similar to the per-protocol one, 
if deemed appropriate for the subject; however, the treatment intervals should not be less than 
4 weeks).
New text
After Week 16 (randomization), the treatment intervals will not be less than 8 weeks nor more 
than 16 weeks with the following exception:  If, at any visit after Week 16, the subject has 


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lost 15 or more letters from the best previous BCVA and the actual BCVA is not better than 
at baseline; or, if the investigator determines and documents in the eCRF that the subject’s 
condition necessitates more frequent injections than 2Q8, the subject will be considered 
“injection-intensive”. Such subjects will remain in the study, and be treated according to the 
investigator’s best clinical judgment (i.e. the frequency of IVT aflibercept injections is 
determined by the investigator who is free to subsequently adopt a T&E regimen similar to 
the per-protocol one, if deemed appropriate for the subject; however, the treatment intervals 
should not be less than 4 weeks).
Treatment of underlying disease on the day of the final visit and thereafter; AE 
reporting after the final study visit
Section 5 Study design
Section 9.1 Tabular schedule of evaluations (Table 9-1 Schedule of Evaluations and 
Study Procedures)
Section 9.2.5 Final visit (Week 104)/early termination
Section 9.6.1.3 Assessments and documentation of adverse events
If a subjects needs an injection of aflibercept on the day of the final visit, commercial drug is 
to be used. Pertaining AEs are reported as spontaneous AEs. AEs occurring within 30 days of 
the last injection of study drug must be followed up by phone. – Per Modification 10 
(Section 15.1.1.10)
Old text
If a subject receives an injection at Week 104, it is the responsibility of the treating 
investigator to follow-up on any AEs (including ongoing events) that may occur within 
30 days following this treatment.  Information regarding such events is to be reported under
this protocol (i.e. not as spontaneous reports).  After Week 104, subjects will return to 
standard of care.
New text
On the day of the final visit (Week 104 ±1 week or early termination) or thereafter, 
administration of study drug is not allowed. Any subsequent treatment of the underlying 
disease of a subject is not part of the study and is at the discretion of the subject’s physician. 
Such treatment should only occur after all study relevant assessments have been performed.
The treating investigator must follow up by phone on any AEs that are ongoing or may occur 
within 30 days of the last administration of study drug.  Information regarding such events 
is to be reported under this protocol (i.e. not as spontaneous reports).  AEs assigned to the 
injection of commercial drug at Week 104 are to be reported as spontaneous reports.


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Reference point for fluorescein angiography eligibility criteria – Section 6 Study 
Population
Time of nAMD diagnosis removed per Modification 11 (Section 15.1.1.11)
Old text
Fluorescein angiography eligibility criteria will be checked against (1) images taken at the 
time of nAMD diagnosis and before initiation of treatment with IVT aflibercept and 
(2) images obtained during the study-screening period.
New text
Fluorescein angiography eligibility criteria will be checked against (1) images taken before 
initiation of treatment with IVT aflibercept and (2) images obtained during the study-
screening period.
Inclusion criterion 3
Specification of CNV lesions simplified per Modification 12 (Section 15.1.1.12)
Section 6 Study population
Old text
Subjects eligible for this study must have subfoveal CNV secondary to nAMD.  “Subfoveal” 
CNV shall be defined as the presence of subfoveal neovascularization, including juxtafoveal 
lesions that affect the fovea
New text
Subjects eligible for this study must have active CNV lesions secondary to nAMD with foveal 
involvement.
Section 6.1 Inclusion criteria
Old text
3.
Active primary subfoveal CNV lesions secondary to nAMD, including juxtafoveal 
lesions that affect the fovea as evidenced by FA in the study eye.  Subjects with 
polypoidal choroidal vasculopathy or retinal angiomatous proliferation are eligible to 
participate in the study, and their condition should be captured in the eCRF.
New text
3.
Active CNV lesions secondary to nAMD with foveal involvement.  Subjects with 
polypoidal choroidal vasculopathy or retinal angiomatous proliferation are eligible to 
participate in the study, and their condition should be captured in the eCRF.


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Exclusion criterion 6 - Section 6.2 Exclusion criteria
Percentage of total lesions for scar or fibrosis reduced per Modification 13 (Section 15.1.1.13)
Old text
6.
Scar or fibrosis making up >50% of the total lesion in the study eye.
New text
6.
Scar or fibrosis making up >25% of the total lesion in the study eye.
Withdrawal criterion 3 – Section 6.3.1 Withdrawal
Time point for withdrawing subjects from the study defined more exactly per Modification 14
(Section 15.1.1.14)
Reference to the diagnostic criteria that lead to withdrawal of the subject from the study added 
per Modification 15 (Section 15.1.1.15)
Old text

Before Week 16 (randomization), subjects require injections at shorter intervals than 
defined per protocol.
New text

Before or at Week 16 (randomization), subjects require injections at shorter intervals 
than defined per protocol, based on the anatomical criteria specified in Section 7.1, 
and on the visual acuity criteria described in Section 9.2.4 for injection-intensive 
subjects.
Screening failure paragraph – Section 6.3.1 Withdrawal
Text reworded per Modification 16 (Section 15.1.1.16)
Old text
Restarting the defined set of screening procedures to enable the “screening failure” subject’s 
participation at a later time point is not allowed – with the following exceptions:

The subject had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.

Initial screening occurred too early to complete the required washout period after prior 
therapy.

The in-/exclusion criteria preventing the subject’s initial attempt to participate have 
been changed (via protocol amendment).


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Thus, participation of an initial “screening failure” subject at a later time point even if he/she 
meets all selection criteria upon re-screening is not acceptable.
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk.  In addition, for re-screening, the subject has 
to re-sign the ICF, even if it was not changed after the subject’s previous screening.
New text
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see below) is regarded as a 
“screening failure”. 
Re-screening of screening failures may be acceptable under the following conditions:

The subject had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.

The reason for the screening failure was a transient event, which subsequently 
resolved (e.g. decrease of elevated IOP, controlled arterial hypertension) within 
30 days.
Under any of the above exceptions, a subject may be re-screened once only.  Before a 
re-screening period is initiated, the subject must sign a new informed consent form.  To be 
eligible, re-screened subjects must meet all selection criteria during the re-screening period.
Drug accountability – Section 7.6 Drug logistics and accountability
“Partially used” removed from the types of drugs the study site must account for per 
Modification 17 (Section 15.1.1.17).
Old text
The physician or designated medical or pharmacy personnel handling the drug product are 
responsible for the accountability of all used, partially used, and unused study drug.
New text
The physician or designated medical or pharmacy personnel handling the drug product are 
responsible for the accountability of all used and unused study drug.
Fellow eye treatment – Section 8.1 Prior and concomitant therapy
Study drug must not be used for treatment of the fellow eye (if needed), but may be 
reimbursed per Modification 18 (Section 15.1.1.18)
Time point of the fellow eye treatment reworded per Modification 19 (Section 15.1.1.19)


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Old text
If the fellow (non-study) eye has a condition approved to be treated by IVT anti-VEGF, the 
fellow eye may receive any locally approved non-systemic treatment (Note that fellow-eye 
IVT aflibercept treatment may be supplied under this protocol in consultation with the 
sponsor); off-label treatment of the fellow eye with bevacizumab is prohibited.  If the fellow 
eye receives treatment, this should not occur at the same visit as when the study eye is treated.
New text
If the fellow (non-study) eye has a condition approved to be treated by IVT anti-VEGF, the 
fellow eye may receive any locally approved non-systemic treatment (Note that fellow-eye 
IVT aflibercept treatment may be reimbursed in consultation with the sponsor); off-label 
treatment of the fellow eye with bevacizumab is prohibited.  If the fellow eye receives 
treatment, it is not advised that this occurs on the same day as when the study eye is treated.
Reference point for visit scheduling 
Section 9.1 Tabular schedule of evaluations (Table 9-1 Schedule of Evaluations and 
Study Procedures)
Section 9.2 Visit description
Reference point for visit scheduling reworded in more detail per Modification 20 (Section 
15.1.1.20)
Old text
Visit schedules may deviate by ±7 days.  Scheduled visits should not be altered due to the 
deviation of the previous visit.
New text
Visit schedules may deviate by ±7 days.  Set schedule visits and fixed dosing arms use 
baseline for the calculation. Flexible visits always use the planned week number of the current 
visit to calculate the week number of the next visit. 
Section 9.2.4 Proactive extension phase
Old text
In the late-start T&E arm, subjects will receive treatment per label, every 8 weeks to the end 
of Year 1 (2Q8 injections at Weeks 24, 32, 40, 48).  Then in Year 2 (starting from Week 48) 
the treatment intervals will be extended by 2 weeks each time (up to a maximum of 
16 weeks), as long as all anatomical criteria are met.
New text
In the late-start T&E arm, subjects will receive treatment per label, every 8 weeks to the end 
of Year 1 (2Q8 injections at Weeks 24, 32, 40, 48).  Baseline will be used for calculation of 


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fixed visits.  Then in Year 2 (starting from Week 48) the treatment intervals will be extended 
by 2 weeks each time (up to a maximum of 16 weeks), as long as all anatomical criteria are 
met..  Date of the next visit during Year 2 will be calculated based on the actual visit date.
Time reference for reporting pregnancy as AE or as spontaneous report – Section 9.6.2 
Pregnancies
Addition of “study drug” per Modification 21 (Section 15.1.1.21)
Old text
If a pregnancy occurs more than 30 days after the last visit or the last IVT injection (whatever 
is earlier), this report will be processed as a spontaneous report.
New text
If a pregnancy occurs more than 30 days after the last visit or the last IVT injection of study 
drug (whatever is earlier), this report will be processed as a spontaneous report.
Observation consistency - Section 9.7 Other procedures and variables (medical 
examinations)
Principle of observation consistency pointed out per Modification 23 (Section 15.1.1.23)
Old text
All ophthalmic examinations are to be conducted in both eyes, unless indicated otherwise.  
The following ophthalmic examinations (except for FP/FA) will be conducted at every visit 
throughout the study.  Fundus photography/FA will be conducted at screening (Visit 1), 
Week 52, and the end of the study (Week 104 visit/early termination visit).  The study manual 
will further specify the standards for FA/FP during the study as well as for the historic 
evaluation of pre-existing images.  The treating investigator may perform additional FA/FP at 
other times during the 104 weeks of the study based on his/her medical judgment and 
standard of care.
New text
All ophthalmic examinations are to be conducted in both eyes, unless indicated otherwise.  
The following ophthalmic examinations (except for FP/FA) will be conducted at every visit 
throughout the study.  Fundus photography/FA will be conducted at screening (Visit 1), 
Week 52, and the end of the study (Week 104 visit/early termination visit).  The study manual 
will further specify the standards for FA/FP during the study as well as for the historic 
evaluation of pre-existing images.  The treating investigator may perform additional FA/FP at 
other times during the 104 weeks of the study based on his/her medical judgment and 
standard of care.


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Care should be taken as much as possible to use the same equipment for all examinations for a 
certain subject.
And:
Old text
Visual function of the study eye and the fellow eye will be assessed using the ETDRS 
protocol starting at 4 meters.  Visual acuity examiners must be certified to ensure consistent 
measurement of BCVA, and a refraction will be performed at each visit.  A detailed protocol 
for conducting visual acuity testing and refraction can be found in the study manual. 
New text
Visual function of the study eye and the fellow eye will be assessed using the ETDRS 
protocol starting at 4 meters.  Visual acuity examiners must be certified to ensure consistent 
measurement of BCVA, and a refraction will be performed at each visit.  Per subject, the 
same examiner must perform all assessments whenever possible.  A detailed protocol for 
conducting visual acuity testing and refraction can be found in the study manual.
Safety set - Section 10.2 Analysis sets
Paragraph describing the Safety Analysis Set reworded per Modification 24 (Section 
15.1.1.24)
Old text
The Safety Analysis Set (SAF) will include all subjects who receive any study drug under this 
protocol.  The SAF will be analyzed “as received”.  
New text
The Safety Analysis Set (SAF) will include all subjects who received any study drug under 
this protocol. In the safety analysis, subjects who dropped out after start of treatment before 
randomization will be described only in ‘total’, since no allocation of such subjects to a 
treatment arm is possible. Randomized subjects will be analyzed ‘as randomized’.
Comparability of treatment arms – Section 10.3.2.1 Demography and baseline 
characteristics
Paragraph on comparability of treatment arms reworded per Modification 25
(Section 15.1.1.25)
Old text
The treatment arm comparability will be checked for each of the analysis populations (FAS, 
PPS, SAF).  This comparison will be done for age, baseline and Week 16 BCVA letter score 


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and baseline and Week 16 CRT by a 2-tailed student t-test comparing both treatment arms.  
The test statistics are reliable for variables not normally distributed as well, given the large 
sample sizes available here.  Furthermore, treatment arms will be compared with respect to 
gender by Fisher’s exact test
New text
The treatment arm comparability will be checked for each of the analysis populations (FAS, 
PPS, SAF). This comparison will be done for age, baseline and Week 16 BCVA letter score 
and baseline and Week 16 CRT by a one-way analysis of variance comparing both treatment 
arms. The test statistics are reliable for variables not normally distributed as well, given the 
large sample sizes available here. Furthermore, treatment arms will be compared with respect 
to gender by Chi-squared test.
Efficacy variables analyzed descriptively - Section 10.3.2.2 Efficacy analyses
“Secondary” deleted per Modification 26 (Section 15.1.1.26)
Old text
The other secondary efficacy variables will be analyzed descriptively. 
New text
The other efficacy variables will be analyzed descriptively. 
Interim analysis - Section 10.5 Planned interim analyses
Description of interim analysis revised per Modification 27 (Section 15.1.1.27)
Old text
An interim analysis is planned after all subjects have finished the 52-week visit (or withdrew).  
Only efficacy data up to Week 52 will be used in the interim analysis.  Primary and secondary 
efficacy variables cannot be calculated, as no values from Week 104 will be analyzed.  The 
analysis is only descriptive, no decisions on the outcome will be made (e.g. terminating the 
study or changing the design) and it is planned to publish the results of this interim analysis.  
Therefore, no α-adjustment seems necessary.
New text
An interim analysis is planned after all subjects have finished the 52-week visit (or withdrew).  
No data after visit Week 52 will be used in the interim analysis.  Primary and secondary 
efficacy variables cannot be calculated, as no values from Week 104 will be analyzed.  The 
analysis is only descriptive, no inferential tests will be performed, no decisions on the 
outcome will be made (e.g. terminating the study or changing the design) and it is planned to 


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publish the descriptive results of this interim analysis.  Therefore, no α-adjustment seems 
necessary.
Analysis details will be given in the SAP.
Withdrawable volume - Section 16.1 Aflibercept intravitreal injection procedure
Withdrawable volume corrected per Modification 28 (Section 15.1.1.28)
Old text
VEGF Trap-Eye study drug will be supplied by the sponsor in sealed, sterile 2 mL-vials, each 
with a “withdrawable” volume of approximately 0.5 mL.
New text
VEGF Trap-Eye study drug will be supplied by the sponsor in sealed, sterile 2 mL-vials, each 
with a “withdrawable” volume of approximately 0.1 mL.
16.
Appendices
16.1
Aflibercept intravitreal injection procedure - amended
Study drug dose and volume for administration
VEGF Trap-Eye is formulated as a sterile liquid to a final concentration of 40 mg/mL VEGF 
Trap-Eye in 5% sucrose, 10 mM sodium phosphate pH 6.3, 0.03% polysorbate 20, and 
40 mM NaCl.  VEGF Trap-Eye study drug will be supplied by the sponsor in sealed, sterile 
2 mL-vials, each with a “withdrawable” volume of approximately 0.1 mL47.  The volume of 
injection will be 50 μL (0.05 mL) for the 2-mg dose of VEGF Trap-Eye.  The study drug will 
be withdrawn using aseptic technique through an 18-gauge filtered needle attached to a 1-mL 
syringe.  The needle will be discarded after withdrawal of the vial contents and should not be 
used for IVT injection.  The needle should be replaced with a sterile 30-gauge needle for the 
IVT injection.  The contents should be expelled until the plunger is aligned with the line that 
marks 0.05 mL on the syringe.
When VEGF Trap-Eye vials are removed from the refrigerator, the solution should be 
visually inspected, and it should have no evidence of turbidity.  If particulates, cloudiness, or 
discoloration are visible, the vial must not be used.  
                                                
47 Withdrawable volume corrected per Amendment 1 (see Section 15.1.1.28)


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Based on present stability data and the fact that the dosing solution contains no bacteriostatic 
agents, VEGF Trap-Eye dosing solutions may be kept at room temperature (25°C) for up to 
2 hours (i.e. once the syringe is filled, the injection of VEGF Trap-Eye must be completed 
within 2 hours of the start of dose preparation).
Subject preparation for injection
The physician or designee will prepare the subject for injection. 
Use of topical antibiotic agents
At the time of this study, the use of topical antibiotics as prophylaxis in intravitreal injections, 
both in the preparation and post injection, varies considerably between different practices.  
There is no consensus on the use of topical antibiotics, the agent to be used, and the dose 
administered.  In this protocol, it is recommended that a broad spectrum topical antibiotic be 
used as part of the preparation for the intravitreal injection procedure, and as prophylaxis in 
the days immediately following the injection.
The use of a topical antibiotic is recommended, but is at the discretion of the investigator.
Suggested use:

Instruct the subject to self-administer 1-2 drops of the antibiotic to the study eye, 
3 times a day, for 3 days before the injection day

On the injection day, as part of the preparation for injection, instill 1 drop to the eye 
1 hour before the injection, and another drop 15 minutes before the injection

After the injection, instruct the subject to self-administer 1-2 drops of the topical 
antibiotic to the injected eye, 3 times a day, for additional 3 days
Study drug preparation
The mandatory sequence of steps required for preparation must be followed for 
administration of the dose in this clinical trial, as described below.  This drug administration 
protocol is based upon the recent guideline published in Retina (13) and current standard of 
practice.
Preparatory steps:
1. Preparation
a.
Apply topical anesthetic.
b. Apply povidone-iodine to eyelid margins, eyelashes, and conjunctival surface
c.
Place 1 or 2 drops of 5% povidone-iodine on the ocular surface at the intended 
injection site.
d. Use sterilized forceps and calipers (speculum) to stabilize the globe and 
measure the injection site.
e.
Optional: Inject 0.5 mL of 2% xylocaine without epinephrine 
subconjunctivally at the intended injection site (the entry site of the needle for 


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the intravitreous injection should be in the inferotemporal quadrant, 3.0 to 
3.5 mm from the limbus in aphakic/pseudophakic subjects, and 3.5 to 4.0 mm 
in the phakic subjects).
f.
Use sterile fluorescein strips and single use proparacaine bottles for all 
subjects.  Fluoracaine or other combination fluorescein sodium and 
proparacaine HCl mixtures should NOT be used.
g. Drape
h. Apply additional drop of povidone iodine to site of injection.
2. Study drug (VEGF Trap-Eye) administration
a.
Insert needle at marked injection point.
b. Gently inject study drug.
c.
As the needle is withdrawn, a sterile cotton tip applicator should be rolled over 
the entry site to minimize the risk of drug reflux.  This should be held in place 
for a full 10 seconds.
Further guidance can be found in The Royal College of Ophthalmologists Intravitreal 
Injections Procedure Guideline 
(http://www.rcophth.ac.uk/docs/publications/publishedguidelines/IntravitrealInjectionsJuly20
06.pdf).
Post-injection procedures
1. Indirect ophthalmoscopy in the study eye only
2. Measure IOP approximately 30 minutes after injection in the study eye only.
3. A mandatory safety telephone call should be made approximately 3 days after 
treatment to ensure no signs or symptoms of retinal detachment, endophthalmitis, or 
other AEs have occurred.
Additional post-injection management procedures as recommended by the guidelines are as 
follows:
1. After the injection, instruct the subject to self-administer 1-2 drops of a topical 
antibiotic to the injected eye, 3 times a day, for an additional 3 days.
2. Post-injection reperfusion of the optic nerve:
a.
Visualize the optic nerve to verify reperfusion of the central retinal artery in 
the immediate post-injection period.
b. Verify IVT location of therapeutic agent when possible.
c.
Verify that the retina is attached and that there is no new intraocular 
hemorrhage.
3. Intraocular pressure


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Intraocular pressure may be lowered by pharmaceutical or surgical intervention, if 
required.  If a tonopen is used to check pressure, a clean tonopen condom should be 
placed on the tip before taking each measurement.  If applanation tonometry is used, the 
applanator tip should be swabbed with alcohol and allowed to dry before using it to 
measure IOP.
a.
Monitor IOP approximately 30 minutes after each injection.
b. Check IOP while maintaining a clean field.
c.
Monitor IOP closely until it is below 25 mm Hg.
d. Treatment should be initiated whenever IOP is increased to the extent that the 
central retinal artery remains closed and the subject has no light perception for 
more than 1 to 2 minutes.
e.
Transient graying or obscuration of vision following injection is expected and 
should not be treated.
f.
Paracentesis should be used only in extreme circumstances when the degree of 
pressure elevation poses an imminent and irreversible threat to vision.  In the 
rare situation when a paracentesis is warranted, IOP should be recorded both 
before and after the procedure.  A 0.1- to 0.2-mL paracentesis may be 
performed at the temporal limbus using a 27- or 30-gauge needle or surgical 
knife, if judged to be necessary by the investigator.
g. Record all IOP measurements and related treatments in the source document 
and on the appropriate eCRF page.
Discharge
No special precautions are required before discharge of a subject who has had an uneventful 
recovery from IVT injection, but subjects and/or caregivers should be educated to avoid 
rubbing the eye and to recognize the signs and symptoms of endophthalmitis, retinal 
detachment, or intraocular hemorrhage.  These signs and symptoms include eye pain or 
increased discomfort, increased redness of the eye (compared to immediately after injection), 
blurred or decreased vision, and increased ocular sensitivity to light.

Subjects should be informed that some blurring of vision is common after an injection, 
which is often described as seeing spots floating in the eye.  Floaters usually resolve 
after a few days or weeks.

Subjects who experience AEs after injection that require additional monitoring should 
remain in the clinic until the condition is resolved, and should be treated according to 
the investigator’s medical judgment.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Managing neovascular age-related macular degeneration (nAMD) 
over 2 years with a Treat and Extend (T&E) regimen of 2 mg 
intravitreal aflibercept - a randomized, open-label, active-controlled, 
parallel-group phase IV/IIIb study (ARIES) 
NCT Number: 
NCT02581891 
Document Date: 
17 May 2019 
 


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PPD


Statistical Analysis Plan  
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Reference Number: BPD-SOP-060 
Supplement Version: 6 
Table of Contents 
1. 
Introduction ....................................................................................................................... 6 
1.1 
Background ...................................................................................................................... 6 
1.2 
Rationale of the study ...................................................................................................... 7 
1.3 
Benefit-risk assessment .................................................................................................... 7 
1.4 
List of documents used .................................................................................................... 7 
2. 
Study Objectives ................................................................................................................ 8 
3. 
Study Design ...................................................................................................................... 8 
3.1 
Design overview .............................................................................................................. 8 
3.2 
Visit overview .................................................................................................................. 8 
3.3 
Assessments overview ................................................................................................... 10 
4. 
General Statistical Considerations ................................................................................ 13 
4.1 
General Principles .......................................................................................................... 13 
4.2 
Handling of Dropouts .................................................................................................... 13 
4.3 
Handling of Mis-Stratification ....................................................................................... 14 
4.4 
Handling of Missing Data .............................................................................................. 14 
4.4.1 
General rules ............................................................................................................... 14 
4.4.2 
Adverse events ............................................................................................................ 14 
4.4.3 
Prior and concomitant medication .............................................................................. 15 
4.4.4 
Efficacy analysis ......................................................................................................... 15 
4.5 
Interim Analyses and Data Monitoring ......................................................................... 16 
4.5.1 
Data Monitoring ......................................................................................................... 16 
4.5.2 
Interim Analyses ......................................................................................................... 16 
4.6 
Data Rules ...................................................................................................................... 17 
4.7 
Validity Review ............................................................................................................. 21 
5. 
Analysis Sets .................................................................................................................... 21 
6. 
Statistical Methodology .................................................................................................. 22 
6.1 
Population characteristics .............................................................................................. 22 
6.1.1 
Screening Failures ...................................................................................................... 22 
6.1.2 
Disposition .................................................................................................................. 22 
6.1.3 
Demography ............................................................................................................... 24 
6.1.4 
Baseline Characteristics .............................................................................................. 24 
6.1.5 
Medical/ophthalmic history ........................................................................................ 25 
6.1.6 
Medical History of neovascular age-related macular degeneration (nAMD) ............ 25 
6.1.7 
Prior and Concomitant Medications ........................................................................... 26 
6.1.8 
Compliance, drug concentration data and/or related data .......................................... 26 
6.2 
Efficacy .......................................................................................................................... 27 
6.2.1 
Primary efficacy variable............................................................................................ 27 
6.2.2 
Key-secondary efficacy variable ................................................................................ 28 
6.2.3 
Other secondary efficacy variables ............................................................................. 29 
6.2.4 
Exploratory efficacy variables .................................................................................... 29 


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6.2.5 
Fluorescein Angiography (FA)/ Fundus Photography (FP) ....................................... 30 
6.3 
Pharmacokinetics / pharmacodynamics ......................................................................... 30 
6.4 
Safety ............................................................................................................................. 30 
6.4.1 
Ocular Safety .............................................................................................................. 30 
6.4.2 
Overall Safety ............................................................................................................. 31 
7. 
Document history and changes in the planned statistical analysis ............................. 33 
7.1 
Changes with respect to SAP version 1.0, 2. November 2015 ...................................... 33 
7.2 
Changes with respect to SAP version 2.0, 24. November 2017 .................................... 34 
8. 
References ........................................................................................................................ 34 
9. 
Appendix .......................................................................................................................... 35 
9.1 
Cut-Off Specification Clarifications .............................................................................. 35 
 


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Reference Number: BPD-SOP-060 
Supplement Version: 6 
Abbreviations 
 
2Q8 
2 mg aflibercept administered every 8 weeks 
AE 
Adverse event 
AMD 
Age-related macular degeneration 
ANCOVA 
Analysis of covariance 
APTC 
Antiplatelet Trialists’ Collaboration 
ATC 
Anatomical Therapeutic Chemical 
ATE 
Arterial thromboembolic event 
BCVA 
Best-corrected visual acuity 
CI 
Confidence interval 
CNV 
Choroidal neovascularization 
CRT 
Central retinal thickness 
eCRF 
Electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
FA 
Fluorescein angiography 
FAS 
Full Analysis Set 
FP 
Fundus photography 
IOP 
Intraocular pressure 
IRF 
Intraretinal fluid 
IVT 
Intravitreal 
LOCF 
Last observation carried forward 
LS 
Least squares 
MI 
Multiple imputations 
MedDRA 
Medical Dictionary for Regulatory Activities 
nAMD 
Neovascular age-related macular degeneration 
OCT 
Optical coherence tomography 
PPS 
Per-protocol Set 
PRN 
As needed (pro re nata) 
PT 
Preferred term 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SF 
Screening Failure 
SOC 
System organ class 
SRF 
Subretinal fluid 
T&E 
Treat and extend 


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Reference Number: BPD-SOP-060 
Supplement Version: 6 
TEAE 
Treatment-emergent adverse event 
US 
United States  
V 
Visit 
VEGF 
Vascular endothelial growth factor 
VRM 
Validity Review Meeting 
WHO-DD 
World Health Organization Drug classification Dictionary 
Wk 
Week 
 


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Reference Number: BPD-SOP-060 
Supplement Version: 6 
1. 
Introduction 
This SAP describes both the analyses described for final analysis after all patients have 
completed the study (Year 2), which is the time point of the primary and secondary endpoints, 
as well as the analyses planned for the exploratory interim analyses after the first year of 
treatment. Wherever appropriate, analyses that had been planned for the final analysis after 
year two will be performed analogously for the interim analysis. All analyses at the interim 
time point are purely exploratory.  
1.1 
Background 
Age-related macular degeneration (AMD) is a leading cause of adult blindness in the 
developed world. Age-related macular degeneration has a dry and a wet form, the latter of 
which accounts for most AMD-related cases of blindness and is referred to as neovascular 
AMD (nAMD). Severe vision loss from nAMD is caused by a combination of retinal edema 
and neovascular proliferation. Vascular endothelial growth factor (VEGF), a protein growth 
factor that both stimulates angiogenesis and increases vascular permeability, is a major 
pathogenic factor in AMD. Anti-VEGF therapy has been shown to provide significant 
therapeutic benefit to patients suffering from nAMD.   
Aflibercept is a potent, specific inhibitor of VEGF with a high affinity for all isoforms of 
VEGF and placental growth factor. To date, aflibercept has been approved as a treatment for 
nAMD, diabetic macular edema, and macular edema secondary to branch or central retinal 
vein occlusion in the United States (US), European Union (EU), Japan and many other 
countries; as well as for myopic choroidal neovascularization in the EU, Japan and several 
other countries; and for diabetic retinopathy in patients with diabetic macular edema in the 
US.  
Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug. 
The approved European Union (EU) labeling for Eylea (aflibercept) states: 
The recommended dose for Eylea is 2 mg aflibercept, equivalent to 50 microliters. 
Eylea treatment is initiated with one injection per month for three consecutive doses, followed by one 
injection every two months. There is no requirement for monitoring between injections. 
After the first 12 months of treatment with Eylea, the treatment interval may be extended based on 
visual and anatomic outcomes. In this case the schedule for monitoring should be determined by the 
treating physician and may be more frequent than the schedule of injections. 


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1.2 
Rationale of the study 
The use of anti-VEGF agents for nAMD has become the standard of care. The frequency of 
dosing for monthly anti-VEGFs has introduced a burden of illness on patients and caregivers 
as well as capability constraints on physicians in practice.  
Physicians have developed a practicing trend towards individualizing treatment to reduce the 
burden and minimize reimbursement issues and healthcare costs. The current individualized 
treatment gaining momentum with practicing physicians is referred to as treat and extend 
(T&E). In the T&E dosing paradigm, the subject is injected at every visit and the follow-up 
examination intervals are incrementally extended according to the response to treatment.  
This study has been designed to assess whether intravitreal (IVT) aflibercept administered in 
an early-start T&E regimen (initiated after the first 8-weekly treatment interval) is non-
inferior to IVT aflibercept administered in a late-start T&E regimen (initiated at the end of 
Year 1, per the approved EU label for Eylea) in subjects with nAMD. In addition, the 
percentage of subjects requiring retreatment with IVT aflibercept less frequently than every 
8 weeks (2Q8), as well as safety and tolerability, will be assessed. 
1.3 
Benefit-risk assessment 
The risks of the local IVT application are limited to ocular adverse events (AEs).  
Due to the low systemic level of aflibercept after IVT injection, systemic pharmacodynamic 
effects such as blood pressure changes are unlikely. 
Proteinuria and hypertension are potential systemic effects from intravenous or subcutaneous 
administration of this class of drug; however, the low systemic blood levels observed in 
previous IVT studies suggest that direct IVT injection, at the dose levels proposed for this 
study, are not expected to have clinically significant systemic effects.  
In addition, arterial thromboembolic events (ATEs) are AEs potentially related to systemic 
VEGF inhibition. The risks associated with IVT administration of aflibercept observed in the 
Phase 3 studies are thought to be similar to those of IVT administration of pegaptanib sodium 
and ranibizumab. 
This study will generate evidence regarding the benefits of early T&E regimen initiation (i.e. 
initiation in the first year compared to initiation in the second year per the label) in order to 
provide optimal management of the patient without compromising visual outcomes.  Strict 
extension criteria ensure that the benefit-risk ratio in this study is favorable.   
1.4 
List of documents used 
 Clinical Study Protocol No. BAY86-5321/17508, version 2.0, 02 February 2016 


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2. 
Study Objectives 
Primary objective 
To assess whether 2 mg IVT aflibercept administered in an early-start T&E regimen (initiated 
after the first 8-weekly treatment interval) is non-inferior to 2 mg IVT aflibercept 
administered in a late-start T&E regimen (initiated at the end of Year 1, per label) in subjects 
with nAMD 
Secondary objectives 
 To assess the percentage of subjects requiring retreatment with aflibercept less 
frequently than every 8 weeks (2Q8) 
 To assess the safety and tolerability of aflibercept 
3. 
Study Design 
3.1 
Design overview 
This is a multicenter, randomized, open-label, active-controlled, parallel-group, Phase IV/IIIb 
study in subjects with nAMD to assess the non-inferiority of a 2-mg IVT aflibercept T&E 
dosing regimen initiated after the first 8-weekly treatment interval (2Q8) to a 2-mg IVT 
aflibercept T&E dosing regimen per label (treatment individualization after Year 1).  
In total, approximately 268 subjects in Europe, Canada, and Australia will be treated at 
baseline. The study duration will be 104 weeks plus the recruitment period.   
3.2 
Visit overview 
The study comprises a screening phase of up to 3 weeks (Visit 1; -3 weeks to baseline), a 
baseline visit (Visit 2, Week 0/Day 1), and a treatment phase of 104 weeks. 
Only 1 eye will be designated as the study eye. Starting at baseline (Week 0/Day 1), 
aflibercept 2 mg IVT treatment will be administered to the study eye every 4 weeks during the 
initiation phase (3 initial monthly doses at Weeks 0, 4, and 8). At Week 8, the treatment 
interval will be extended by 4 weeks (i.e. the next injection will take place at Week 16). If 
subjects require injections at shorter intervals before or at Week 16 than defined per protocol, 
the subjects will not be randomized at Week 16 but withdrawn from the study. 
At Week 16, subjects will be stratified based on visual outcomes from baseline to Week 16 
(either <8 or ≥8 letters gain in best-corrected visual acuity [BCVA]) and randomized 1:1 into 
1 of the following 2 arms: 
 In the early-start T&E arm (test group, early treatment individualization), starting at 
Week 16, subjects will receive treatment in intervals extended by 2 weeks each time 


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(up to a maximum of 16 weeks), as long as all anatomical criteria are met. For subjects 
who have no intraretinal fluid (IRF) and no subretinal fluid (SRF) at Week 16 
(“completely dry at Week 16”), confirmed by the Central Reading Center, the 
treatment interval will be extended by 4 weeks for a total of 12 weeks (i.e. schedule 
next visit at Week 28). From Week 28 onwards, the normal extension algorithm will 
be applied.  
 In the late-start T&E arm (per label, control group, treatment individualization after 
Year 1), subjects will receive treatment every 8 weeks to the end of Year 1 (4 x 2Q8 
injections at Weeks 24, 32, 40, and 48).  Then in Year 2 (starting from Week 48) the 
treatment intervals will be extended by 2 weeks each time (up to a maximum of 
16 weeks), as long as all anatomical criteria are met.  
The anatomical criteria for extending the treatment intervals for the study eye, based on 
optical coherence tomography (OCT), are as follows for both study arms: 
 Absence of intraretinal fluid (IRF) and 
 Absence of new neovascularization or hemorrhage and 
 Subretinal fluid (SRF) not exceeding 50 µm in thickness 
The investigator assesses whether the subject fulfills the anatomical criteria for treatment 
interval extension and determines the next treatment interval.  If the anatomical criteria are 
not met, the retreatment interval will revert to the last treatment interval in which the disease 
was inactive. The subject will have all assessments during the proactive extension phase as 
described in Section 3.3. 
After Week 16 (randomization), the treatment intervals will not be less than 8 weeks nor more 
than 16 weeks with the following exception:  
 if, at any visit after Week 16, the subject has lost 15 or more letters from the best 
previous BCVA and the actual BCVA is not better than at baseline; or,  
 if the investigator determines and documents that the subject’s condition necessitates 
more frequent injections than 2Q8. 
Such subjects will be considered “injection-intensive”, remain in the study, and be treated 
according to the investigator’s best clinical judgment (i.e. the frequency of IVT aflibercept 
injections is determined by the investigator who is free to subsequently adopt a T&E regimen 
similar to the per-protocol one, if deemed appropriate for the subject; however, the treatment 
intervals should not be less than 4 weeks). 
Due to the per-protocol variability of treatment intervals, subjects may receive their last 
Year 1 and Year 2 injections at any time between Weeks 42 and 52 (for Year 1) and 
Weeks 90 and 104 (for Year 2).  In case these visits do not occur at Weeks 52 and 104 


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(±1 week), subjects will return at Weeks 52 and/or 104 for mandatory visits, where no study 
drug is administered, but where examinations are performed from which the primary and 
secondary outcomes are determined.  
If a subject receives an injection at Week 104, it is the responsibility of the treating 
investigator to follow-up on any AEs (including ongoing events) that may occur within 
30 days following this treatment.  
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (European Union [EU] and non-EU). 
The primary completion event for this study is the final study visit at Week 104. 
3.3 
Assessments overview 
Overall safety of the subjects will be assessed throughout the study by monitoring ocular and 
non-ocular adverse events (AEs).  All potential ATEs will be adjudicated according to the 
Antiplatelet Trialists' Collaboration (APTC) endpoints of non-fatal myocardial infarction, 
non-fatal stroke, and fatal vascular events. For the interim analysis APTC-adjudication will 
not be performed. 
Vital signs will be assessed at all study visits. 
All ocular assessments are to be conducted in both eyes, unless indicated otherwise.   
Assessments of ocular safety will include  
 intraocular pressure (IOP),  
 indirect ophthalmoscopy, and  
 slit lamp biomicroscopy;  
these will be assessed at all study visits.   
Assessments of efficacy are  
 BCVA  
 OCT 
 Fluorescein angiography (FA)/fundus photography (FP)  
 
BCVA and OCT will be performed at every visit, whereas mandatory FA-/FP-examinations 
will only be conducted at screening and at Weeks 52 and 104/early termination. However, the 
treating investigator may perform FA/FP at other times of the study based on his/her medical 
judgment and standard of care.   
 


 
 
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Table 1: Schedule of Evaluations and Study Procedures  
Study Phase 
 
Initiation phase 
Random. 
Proactive extension phase 
 
Treatment Arms 
All Subjects 
Early-start T&E Arma 
Late-start T&E Arma 
All Subjects 
Visitb/Wkc 
Screening 
V1 
Wk -3 to 0 
Baseline  
V2 
Wk 0 (Day 1) 
 
V3, 4 
Wk 4, 8 
 
V5 
Wk 16 
Visits extended by 
anatomical criteriad 
Year 1: Wk 24, 32, 40, 48 
Year 2: Visits extended by 
anatomical criteriad 
End of study/ 
Wk 104 or  
Early termination  
Mandatory visits 
Wk -3 to 0 
Wk 0 
Wk 4, 8 
Wk 16 
Wk 52e 
Wk 52e 
Wk 104e 
Informed consent  
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
Medical/ophthalmic history 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
Pregnancy testf 
X 
X 
(X)g 
(X)g 
(X)g 
(X)g 
(X)g 
BCVA using ETDRS charth 
X  
X 
X 
X 
X 
X 
X 
OCT 
X  
X 
X 
X 
X 
X 
X 
FA/FPi 
X  
 
 
 
X (Wk 52 only) 
X (Wk 52 only) 
X 
AEsjk 
X 
X 
X 
X 
X 
X 
X 
Indirect ophthalmoscopyk  
X  
X 
X 
X 
X 
X 
X 
Slit lamp biomicroscopy 
X  
X 
X 
X 
X 
X 
X 
IOPk 
X  
X 
X 
X 
X 
X 
X 
Vital signsl 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
 
X 
 
 
 
Administration of study treatmentm 
 
X 
X 
X 
X 
X 
Xn 
Determination of next treatment 
intervalo 
 
 
 
Xp 
X 
Xq 
 
Telephone safety checkr 
 
X 
X 
X 
X 
X 
X 
2Q8 = 2 mg aflibercept administered every 8 weeks; AE = adverse event; BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; 
FA = fluorescein angiography; FP = fundus photography; IOP = intraocular pressure; IVT = intravitreal; OCT = optical coherence tomography; random. = randomization; 
T&E = treat and extend; V = visit; Wk = week. 
Note: All ocular assessments are to be conducted in both eyes, unless indicated otherwise. 


 
 
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a: Three initial monthly IVT aflibercept injections (initiation phase) followed either by one 8-weekly dose (2Q8) in the early-start T&E arm or by five 8-weekly doses (2Q8) in the late-
start T&E arm. The treatment interval may then be extended by 2 weeks each time (individualized treatment intervals of between 8 to16 weeks) based on anatomical outcomes.  
When/if anatomical outcomes indicate that the disease has re-activated, the treatment interval will revert to the last treatment interval in which the disease was inactive (i.e. no 
signs of exudation). For details on treatment intervals see Section 5 of study protocol version 2.0, 02 Feb 2016.   
b: Visit numbers refer to the mandatory visits for treatment administration to subjects for the 3 initial monthly doses at Weeks 0, 4, and 8, followed by one 8-weekly dose (2Q8) at the 
randomization visit. 
c: Visit schedules may deviate by ±7 days. Scheduled visits should not be altered due to the deviation of the previous visit. The procedures required at each visit have to be complete 
within 3 days, i.e. split visits are allowed. Additionally, all procedures have to be complete within the 7-day window. Slit lamp (anterior segment), IOP measurement, and indirect 
ophthalmoscopy are recommended to take place on the same day as the IVT injection. 
d: Anatomical criteria: No intraretinal fluid (IRF), no new neovascularization or hemorrhage, and subretinal fluid (SRF) not exceeding 50 µm in thickness. Even if all anatomical criteria  
        are met, including the presence of SRF not exceeding 50 μm in thickness, the investigator has the option not to extend if, based on best clinical judgment the disease is 
        considered active. This decision has to be justified and documented in the electronic case report form (eCRF). For further details on determining treatment intervals see  
        Section 5 of study protocol version 2.0, 02 Feb 2016. 
e: All subjects will have mandatory visits at Weeks 52 and 104. In case the scheduled retreatment visit does not occur at Weeks 52 and 104 (±1 week), subjects in both treatment 
arms will still have mandatory visits without treatment at Weeks 52 and 104. 
f: Urine test, for women of child-bearing potential only; a positive result should be confirmed by a serum pregnancy test. Postmenopausal women must be amenorrheic for at least 
12 months in order not to be considered of childbearing potential.  
g: After the first treatment, a urine pregnancy test is mandatory at every treatment visit (prior to injection) in all countries where it is required by local regulations. If required by 
national /institutional regulations, a pregnancy test should be performed for women of childbearing potential at the end of study visit. 
h: Refraction and BCVA using the ETDRS chart is to be performed at each visit. 
i: Mandatory at screening, Week 52, and Week 104/early termination, but may be performed at other times based on the investigator’s medical judgment and standard of care. 
j: Any AE occurring up to 30 days after the last IVT injection of aflibercept has to be documented, regardless of the relationship to the study drug or the seriousness of the event and 
reported in accordance with this protocol (i.e. not as a spontaneous report). For any drug-related AE occurring after 30 days after the last IVT application of aflibercept, the 
standard procedures that are in place for spontaneous reporting will be followed. If a subject prematurely withdraws from the study, AEs should be recorded until withdrawal or 
30 days after the last dose of study drug, whichever is later. 
k: Pre- and post-dose, as applicable. If a subject receives a study injection, indirect ophthalmoscopy should be conducted post-dose and IOP should be assessed in the study eye 30 
to 60 minutes post-dosing. 
l: Temperature, blood pressure, and heart rate 
m: See Appendix 16.1 of study protocol version 2.0, 02 Feb 2016. for an example study drug injection procedure. 
n: IVT injection of study drug if the visit coincides with a scheduled treatment visit (±1 week) at Week 104, but only after all assessment have been performed. If a subject receives an 
injection at Week 104, it is the responsibility of the treating investigator to follow-up on any AEs (including ongoing events) that may occur within 30 days following this treatment.  
Information regarding such events is to be reported under this protocol (i.e. not as spontaneous reports). 
o: Investigator assessment of whether the subject fulfills the anatomical criteria based on OCT for treatment interval extension (see Section 5 of study protocol version 2.0, 02 Feb 
2016. for details) and determination of next treatment interval. 
p: For subjects in the early-start T&E arm only. 
q: In Year 2 only (starting from Week 48). 
r: A mandatory safety telephone call will be made approximately 3 days after treatment to ensure no signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred. 
 


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4. 
General Statistical Considerations 
The Statistical Analysis Plan (SAP) version 1.0 of this open-label study was finalized and 
signed before the first subject received any study drug, to avoid additional reporting bias. 
A summary of the updates of the SAP is given in Section 7. 
The statistical evaluation will be performed by using the software package Statistical Analysis 
System (SAS) release 9.3 or higher (SAS Institute Inc., Cary, NC, USA).  
4.1 
General Principles 
All variables will be analyzed by descriptive statistical methods. The number of data available 
and missing data, mean, standard deviation, minimum, quartiles, median, and maximum will 
be calculated for metric data. Mean and standard deviation will be reported to one decimal 
place greater than the data were collected. Quartiles, median, minimum and maximum values 
will be reported with the same precision as they were collected. 
Frequency tables will be generated for categorical data. These include the counts and 
percentages of each category including the category ‘missing’ as a separate category, if 
applicable. Percentages will be calculated using a denominator of all subjects in the specified 
population and treatment arm, and the percentage values will be reported to one decimal 
place. 
If not stated otherwise, ANCOVA tables will include the least squares (LS) means and the LS 
mean changes relative to Week 16 for both treatment arms, and the difference in the LS 
means (early-start T&E arm minus late-start T&E arm) as point estimate and as 95% CI. 
In general and if applicable, all analysis that had been planned for the final analysis time point 
after two years of treatment will be conducted analogously for the interim time point at Week 
52, if appropriate. All analyses at the interim time point are to be considered exploratory. 
4.2 
Handling of Dropouts 
Subjects must or might be withdrawn from the study for different reasons, which are specified 
in the study protocol in Section 6.3.1. Subjects who withdraw from the study will not be 
replaced. Premature permanent discontinuation from study medication implies premature 
discontinuation from study participation. 
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“Screening Failure” or “Drop-Out” as specified below.  
Screening failure (SF) 


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A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “drop-out” (see below) is considered a 
“screening failure”. Re-screening is only allowed under special conditions, specified in the 
study protocol, Section 6.3.1. 
The number of Screening Failures will be summarized and the reasons will be listed.  
Drop-out 
A subject who discontinues study participation prematurely for any reason is defined as a 
“drop-out” if the subject has already received IVT aflibercept. Drop-outs before Week 16 are 
treated but not randomized.  
The number of subjects who withdrew, as well as the reasons for drop-out of study treatment 
will be summarized. 
4.3 
Handling of Mis-Stratification 
Subjects are randomized at Week 16, stratified by visual outcome at Week 16 into “< 8 letters 
BCVA gain from baseline” and “≥ 8 letters BCVA gain from baseline“. Possible mis-
stratifications will not exclude the respective patients from the PPS. 
In general in the statistical models and in the subgroup analyses the true change from baseline 
to Week 16 will be used. In order to assess a potential impact of mis-stratifications on the 
primary efficacy endpoint a sensitivity analysis will be conducted using the stratification 
variable as collected in the IxRS instead of the potentially different correct one recorded on 
the eCRF.  
4.4 
Handling of Missing Data 
4.4.1 
General rules  
Data from subjects who drop out of the study will be included in all summaries where 
possible. 
All missing or incomplete data will be presented in the subject data listings as they are 
recorded on the eCRF.  
When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data: 
4.4.2 
Adverse events 
In general, data will not be imputed for safety analysis. If dates of adverse experiences 
(clinical or laboratory untoward events) are missing so that the determination of whether or 


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not the event is treatment emergent is questionable, the event will be presumed to be 
treatment emergent. If it is clearly stated, that the Adverse Event occurs prior to first dose of 
study drug then it will be treated as not treatment emergent. 
Adverse Events starting later than 30 days after last study-drug injection will be considered as 
non-treatment emergent. 
4.4.3 
Prior and concomitant medication 
Completely missing start and stop dates of medication are considered missing and no 
replacement is generated. A medication with a complete missing start-date will be assumed to 
start before first application of the study drug. A complete missing stop-date will be handled 
as “ongoing”.  
4.4.4 
Efficacy analysis 
The primary method for replacing missing values will be “last observation carried forward” 
(LOCF), see Section 4.4.4.1. Sensitivity analyses (observed cases and multiple imputations 
(MI), see Section 4.4.4.2), will be performed to investigate the influence of the missing 
values. 
4.4.4.1 
Last Observation Carried Forward 
Missing values regarding the primary and key-secondary efficacy variable will be replaced by 
LOCF using the last available post-baseline values.  Last observation carried forward is 
considered an appropriate method especially in the late phase of the study (i.e. after Week 
52), even though untreated nAMD is a progressive disease. 
4.4.4.2 
Multiple Imputation (MI) 
Multiple imputation methods involve three steps: 
I. 
Imputation  
i.e., the generation of multiple copies of the original dataset by replacing missing 
values using an appropriate stochastic model.  
a. First missing data will be imputed in order to achieve a monotone missing 
pattern using the MCMC (Markov Chain Monte Carlo) method, using SAS-
procedure proc MI similarly as below. 
 
PROC MI DATA=<indata> SEED=2345 OUT=out1 NIMPUTE=20;  
MCMC impute=monotone; 
VAR base Week4 Week8 Week 16 <time-windows>; 
RUN; 
 
b. Subsequently missing data will be imputed by a regression model. 
 
PROC MI DATA=out1 SEED=6789 OUT=full NIMPUTE=1; 
BY _Imputation_; 


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CLASS treatment; 
MONOTONE method=reg; 
VAR treatment base Week4 Week8 Week 16 <time-windows>; 
RUN; 
 
II. 
Analysis,  
i.e., the analysis of the multiple imputed datasets as complete sets. The analysis step is 
performed for each of the multiply imputed datasets. Since all imputed datasets are 
complete there are no issues with missing data. On each imputed dataset the primary 
and key-secondary analysis will be performed as described in Sections 6.2.1 and 6.2.2. 
It should be clarified that classifications (e.g. loss of < 15 letters / 3 lines) will be 
performed after the imputation of the missing BCVA-values. 
 
III. 
Pooling,  
i.e., the combination of the different parameter estimates across the multiple datasets 
based on Rubin’s rules to produce a unique point estimate and standard error taking 
into account the uncertainty of the imputation process using SAS procedure proc 
MIANALYZE. 
4.5 
Interim Analyses and Data Monitoring 
4.5.1 
Data Monitoring  
Data monitoring procedures are described in the data management plan and in Section 11.2 of 
the study protocol. 
4.5.2 
Interim Analyses  
An interim analysis is planned after all subjects have finished the 52-Week visit (or withdrew 
prior to Week 52). No data after the date of visit at Week 52 will be used in the interim 
analysis. 
Primary and key secondary efficacy variables cannot be calculated, as no values from 
Week 104 will be analyzed. The analysis is only descriptive, no inferential tests will be 
performed, no decisions on the outcome will be made (e.g. terminating the study or changing 
the design) and it is planned to publish the descriptive results of this interim analysis. 
Therefore, no α-adjustment is necessary. 
In general all analyses described below for the final analysis time point will be analogously 
conducted for the Week 52 time point, if applicable. Any analyses are to be regarded 
exploratory. For subjects who received a planned injection at their 52-Week visit, the 
injection time point represents a hard cut, i.e. no post-injection measurements and 
assessments contribute to the interim analysis.  
The process of cut-off will follow the general specifications as decribed in the guideline 
“Database Cutoff Specification v1.0, 15Sept2017” and the ARIES-specific given in Section 
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The efficacy endpoints will be analyzed in the Full Analysis Set (FAS) – LOCF and observed 
cases, where applicable –, safety endpoints in the Safety Analysis Set (SAF), and the 
description of the study population (including disposition, demography, baseline 
characteristics, medical history, concomitant medication, study exposure) in FAS and SAF, if 
not stated otherwise. Details can be found in the specifications of Tables, Listings and Figures 
for the interim analysis. 
For definitions of the populations see Section 5. 
4.6 
Data Rules 
Generally, pre-treatment values recorded at Visit 2 (Week 0/Day 1), will be used as baseline 
values. This visit should take place within 3 weeks of the screening visit. If no baseline value 
is available then last available scheduled screening values are used.  
Change from baseline is calculated as the value at the post-baseline time point minus the 
baseline value, i.e. value at time point – value at baseline,  change from Week 16 
(=randomization) is calculated similarly. 
Handling of repeated measurements at the same visit 
If measurements were repeated at the same scheduled visit, the value actually flagged as 
scheduled will be the 
 Last non-missing repeated measurement, if visit is before start of treatment, and 
 First non-missing repeated measurement, if visit is after start of treatment. 
Generally, only scheduled measurements will be used for statistical summaries and analysis. 
Unscheduled measurements will not be used for analysis; however, they will be listed.  
Handling of time-windows 
Visit schedules may deviate by ±7 days.  Scheduled visits should not be altered due to the 
deviation of the previous visit.  
The procedures required at each visit have to be complete within 3 days, i.e. split visits are 
allowed. Additionally, all procedures have to be complete within the 7-day window. 
Screening 
Screening visit must occur within 3 weeks of the baseline visit (Visit 2, Week 0/Day 1).  
Initiation Phase and Randomization 
Three initial monthly doses at baseline visit (Visit 2, Week 0/Day 1), Visit 3 (Week 4) and 
Visit 4 (Week 8) will be administered.  
At the randomization visit (Visit 5, Week 16) the subjects will be stratified based on visual 
outcomes (either <8 or ≥8 letters gain in BCVA) and randomized in the early-start or the 
late-start T&E arm. Afterwards the subjects will receive their IVT injection of the study drug. 


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Proactive Extension Phase 
In the early-start T&E arm, starting at Week 16, subjects will receive treatment in intervals 
extended by 2 weeks each time (up to a maximum of 16 weeks), as long as all anatomical 
criteria are met. For subjects who have no IRF and no SRF at Week 16 (“completely dry at 
Week 16”) confirmed by the Central Reading Center, the treatment interval will be extended 
by 4 weeks for a total of 12 weeks (i.e. schedule next visit at Week 28). From Week 28 
onward, the normal extension algorithm will be applied. 
In the late-start T&E arm, subjects will receive treatment per label, every 8 weeks to the end 
of Year 1 (2Q8 injections at Weeks 24, 32, 40, 48). Baseline will be used for calculation of 
fixed visits. Then in Year 2 (starting from Week 48) the treatment intervals will be extended 
by 2 weeks each time (up to a maximum of 16 weeks), as long as all anatomical criteria are 
met. Date of the next visit during Year 2 will be calculated based on the actual visit date. 
In both arms, the treatment intervals will not be less than 8 weeks nor more than 16 weeks.  
All subjects will have mandatory visits at Week 52 and Week 104. In case a scheduled 
treatment visit does not occur at Week 52 (±1 week), subjects in both treatment arms will still 
have a mandatory visit without treatment at Week 52.  
With the exception of these mandatory Week 52 and 104 visits, subjects MUST receive a 
treatment when they attend a scheduled study visit (based on their individualized treatment 
schedule/treatment interval).   
Extended Visits 
In the early-start T&E arm, starting at Week 16, and the second year of the late-start T&E 
arm, starting from Week 48, visits might be extended by anatomical criteria. A deviation of 
± 1 week relative to baseline is acceptable. 
Visit-wise summaries 
The following visits are displayed in the summaries: 
Screening, Baseline, Week 4, Week 8, Week 16, Week 52 and Week 104. 
In general, the efficacy variables (Section 6.2.1 to 6.2.4) will be summarized according to 
these mandatory visits, if applicable.   
Defining time-windows for the summaries 
Study days will be calculated relative to baseline. Study days prior to first injection date are 
calculated as (actual date – first injection date), after first injection date as (actual date – first 
injection date)+1. 
The following time-windows will be used for summaries of the efficacy (Section 6.2.1 to 
6.2.4) and the safety variables from Section 6.4.1 to 6.4.2, except for the Adverse Events:  
Pre-randomisation: Screening, Baseline, Week 4, Week 8, Week 16,  


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Interim Analysis:  
Week 17-24 (days 117-172) 
Week 25-32 (days 173-228) 
Week 33-40 (days 229-284) 
Week 41-48 (days 285-340) 
Week 49-51 (days 341-361) 
Week 52 
 
Main Analysis - second year (both treatment arms):  
Week 53-60 (days 368-423) 
Week 61-68 (days 424-479) 
Week 69-76 (days 480-535) 
Week 77-84 (days 536-591) 
Week 85-92 (days 592-647) 
Week 93-100 (days 648-703) 
Week 101-103 (days 704-724) 
Week 104 
 
In case of multiple scheduled visits in a specific time-window the following procedures will 
be performed to get only one value per subject in a window: 
  Efficacy variables: the measurement of the last scheduled visit before or at the upper 
bound of the time interval will be displayed in each time interval. 
 Safety variables:  
o Intra-ocular pressure (IOP): The highest values will be used. 
o Indirect ophthalmoscopy: “Abnormal” values and their descriptions will be 
used, if available, and the highest stage/numbers of vitreous cells. 
o Slit lamp biomicroscopy: “Abnormal” values and their descriptions will be 
used, if available, and the highest stage/numbers of anterior chamber flare or 
cells. 
o Vital signs: The highest values will be used. 
 
Telephone Calls 


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Mandatory safety telephone call will be made approximately 3 days after treatment to ensure 
no signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred. Up 
to 2 days delay will be accepted. 
Early termination 
If a patient is terminated early, data from the early termination visit will be mapped to the 
next mandatory visit, if the visit falls in the respective time-window.   
In addition, efficacy-data from the early termination visit will be mapped to the time-windows 
defined above. 
Pooling centers 
All centers will be combined for the purposes of the analysis. 
Calculation of durations 
Durations are calculated relative to baseline, if not specified otherwise.  
Coding 
The verbatim of the following panels will be coded by the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) available before database lock 
 Medical history  
 Adverse Events  
 Surgeries after start of study 
Prior and concomitant medications will be coded by the latest version of World Health 
Organization Drug classification Dictionary (WHO-DD) available before (interim) database 
lock. 
Presentation 
Listings will be sorted by treatment arm, unique subject identifier and date if applicable. 
Dates will be formatted as DDMMMYYYY. Partial dates will be presented on data listings as 
recorded on CRFs. 
Rounding for all variables will occur only as the last step, immediately prior to presentation in 
listings and tables. No intermediate rounding will be performed on derived variables. The 
standard rounding practice of rounding numbers ending in 0-4 down and numbers ending 5-9 
up will be employed. 
Every table, listing and figure will be produced with an electronic date stamp to document 
when it was produced. 


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4.7 
Validity Review 
Validity Review Meetings (VRMs) are performed according to Bayer AG Standard Operating 
Procedures and will be led by the INC Research Lead Data Manager. Details are available in 
the data management plan. 
The results of the VRM will be documented in the Validity Review Report and may comprise 
decisions and details relevant for statistical evaluation. Any changes to the statistical analysis 
prompted by the results of the VRM will be documented in an amendment and, if applicable, 
in a supplement to this SAP. 
5. 
Analysis Sets 
Populations for analysis are defined as follows: 
Full Analysis Set (FAS) 
The FAS will include all randomized subjects who received any study drug and have a BCVA 
assessment at Week 16 and at least 1 additional post-Week 16 BCVA assessment.   
The FAS will be analyzed “as randomized”. 
Per-protocol Set (PPS) 
The PPS will include all subjects in the FAS without any major protocol deviation.   
Major protocol deviations are  
 any violation of in- or exclusion criteria,  
 a treatment duration shorter than 52 weeks,  
 no BCVA assessment at Week 52 or later. 
Additionally, injection-intensive subjects who need injections at shorter intervals than 2Q8 
between Week 16 and Week 52 will be excluded from the PPS.  
Additional reasons for exclusion from the PPS are defined in the final Study Protocol 
Deviation Document and includes  
 Subject received medication expected to interfere with the evaluation of the study 
drug. 
 Subjects received investigational pharmacological agents (not specified) to treat AMD 
in the study eye  
 Subject received  injection of study drug  solution showing evidence of turbidity 
(particulates, cloudiness, or discoloration) after visual inspection of aflibercept 
solution.   


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Safety Analysis Set (SAF) 
The SAF will include all subjects who received any study drug under this protocol. In the 
safety analysis subjects who dropped out after start of treatment before randomization will be 
described only in “total”, since no allocation of such subjects to a treatment arm is possible.  
6. 
Statistical Methodology 
If not specified otherwise, all tables will be summarized by treatment arms and stratified by 
visual outcomes from baseline to Week 16 (either <8 or ≥8 letters gain in BCVA). Important 
efficacy and safety tables, as well as demographics and baseline characteristics and exposure 
data is in addition displayed broken down by the dryness status of the study eye at Week 16 
(“completely dry at Week 16” versus “not completely dry at Week 16”).  
Tables for the safety population will account for the treated, but not randomized subjects 
supplementary to the two treatment arms.  
6.1 
Population characteristics 
Population characteristics (except Screening Failures and Disposition) will be summarized by 
treatment arm and all treatment arms combined for all 3 analysis populations (overall and 
stratified by visual outcome at Week 16 as well as by the dryness status of the study eye at 
randomization), depending on the type of data as described in Section 4.1.  
6.1.1 
Screening Failures 
All available data from Screening Failures (SF) will be listed. At minimum, the following 
data from SF should be displayed:   
 demographic information,  
 date of informed consent,  
 reason for premature discontinuation,  
 date of last visit 
For SF with an SAE, the following data will be listed in addition to the data specified above: 
 All information related to the SAE such as: 
 Concomitant medication 
 Medical history 
 Other information needed for SAE complementary page 
6.1.2 
Disposition 
The screened but not treated subjects (screening failures) will be summarized together with 
the reason(s) for non-treatment. Possible reasons are: 
 Adverse Event 


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 Death 
 Informed consent withdrawn 
 Lost to follow-up 
 Not met inclusion criteria 
 Met exclusion criteria 
The treated but not randomized subjects (drop-outs) will be summarized together with the 
reason(s) for non-randomization. Possible reasons are: 
 Adverse Event 
 Death 
 Informed consent withdrawn 
 Lost to follow-up 
 Not met inclusion criteria 
 Met exclusion criteria 
 Determination of the treating physician/investigator/sponsor 
 Less than 3 injections 
 Injection-intensive (subjects require injections at shorter intervals than defined per 
protocol) 
An overview table for all randomized subjects will be given, displaying in each treatment arm 
and overall the number and percentages of subjects:  
 Completed 
 Not completed  
o withdrawn after Week 16 up/including to Week 52  
o withdrawn after Week 52 up/including to Week 104  
o withdrawn during study (by primary reason) 
Another overview table for all screened subjects will be given, displaying in each treatment 
arm and overall the number and percentages of subjects:  
 Enrolled 
 Screening failures 
 Safety analysis set (SAF) 
 Randomized 
 FAS 
 PPS 
 SAF, but not randomized 
 Randomized, but not FAS 
o missing BCVA-assessment at Week 16 
o baseline, but no post- randomization BCVA-assessment  
 FAS, but not PPS 
o any violation of in- or exclusion criteria  
o treatment duration shorter than 52 weeks 


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o no BCVA assessment at Week 52 or later 
o prohibited medication. 
o pharmacological agents to treat AMD in the study eye  
o injection of turbid solution   
o injection-intensive (shorter intervals than 2Q8 between Week 16 and Week 52) 
6.1.3 
Demography 
The following demographic variables are recorded at screening. In case of repeated measures 
the last available value before baseline will be used for summary tables. This table will also 
be presented by dryness status at Week 16. 
 Gender 
 Age 
 Race 
 Ethnicity 
 Height 
 Weight 
 Body Mass Index 
 Study eye - left or right 
The treatment arm comparability will be checked for each of the analysis populations (FAS, 
PPS, SAF). This comparison will be done for age by a 2-tailed student’s t-test comparing both 
treatment arms. The test statistics are reliable for variables not normally distributed as well, 
given the large sample sizes available here.  
Furthermore, treatment arms will be compared with respect to gender by Fisher’s exact test.  
6.1.4 
Baseline Characteristics 
The following baseline characteristics are observed at screening, during the initiation phase 
and at randomization (Week 16). In case of repeated measures the last available value at the 
respective visit will be used for summary tables. This table will also be presented by dryness 
status at Week 16. 
 BCVA letter scores (study eye) 
 Categorized BCVA (5-letter intervals) (study eye) 
 Central retinal thickness (CRT) (study eye) 
 CNV size (study eye) 
 Lesion size (study eye) 
The treatment arm comparability will be checked for each of the analysis populations (FAS, 
PPS, SAF). This comparison will be done for baseline and Week 16 values of BCVA letter 
score and of CRT by a 2-tailed student’s t-test comparing both treatment arms. The test 
statistics are reliable for variables not normally distributed as well, given the large sample 
sizes available here.  


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Furthermore, treatment arms will be compared with respect to gender by Fisher’s exact test.  
Additionally, the BCVA gain (<8 or ≥8 letters) from baseline at Week 16 will be presented as 
actual and as stratified via IVRS. A Fisher’s exact test will be added to evaluate the treatment 
arm comparability (early T&E versus late T&E).  
The dryness proportion will also be shown per treatment arm. 
6.1.5 
Medical/ophthalmic history 
Medical history findings (i.e. previous diagnoses, diseases, or surgeries) meeting all criteria 
listed below will be collected: 
 Not pertaining to the study indication 
 Start date before signing of the informed consent 
 Considered relevant for the subject’s study eligibility 
Detailed instructions on the differentiation between medical history and AEs can be found in 
Section 9.6.1.1 of the study protocol. 
The number and percentages of subjects affected as well as the number of events will be 
displayed for the safety and the full analysis population by BCVA gain and dryness status. 
The following variables are of interest: 
 Any medical history 
 System Organ Classes (SOCs) 
 Preferred Terms (PT) 
The SOCs will be sorted by descending frequency of subjects, within each SOC the PTs will 
be sorted by descending frequency of subjects affected. 
The tables will be repeated for ocular medical history (i.e. ocular medical history ticked as 
Yes) by eye (study eye, fellow eye and both eyes).  
6.1.6 
Medical History of neovascular age-related macular degeneration 
(nAMD) 
The medical history of nAMD will be collected for both eyes and presented per study eye and 
per fellow eye. The duration of nAMD (years) will be calculated as described in Section 4.6. 
The following parameter will be summarized: 
 Duration of nAMD (years) 
 Typical age-related macular degeneration (yes/no) 
 Polypoidal Choroidal Vasculopathy (yes/no) 
 Retinal Angiomatous Proliferation (yes/no) 
In addition, a complete ophthalmic history will be obtained to check the selection criteria. 
Inconsistencies will be flagged in the respective patient listings. 


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6.1.7 
Prior and Concomitant Medications 
Summaries of all prior and concomitant medications recorded will be presented in tabular 
form using 3-digit Anatomical Therapeutic Chemical (ATC) classification codes and 
preferred drug name via the WHO-DD, latest version available before database lock. 
The medications will be classified as 
 Concomitant: Medications that are ongoing at, began after the start of study drug, or 
medications that were started after end of study drug. 
 New Concomitant: Medications that began after the start of study drug, and those that 
were started after end of study drug. 
 Prior: Medications that started and stopped before the start of study drug. 
For each of these categories a table will be created for each of the analysis populations (FAS, 
PPS, SAF), stratified by  
 ocular medication (yes/no) and  
 eye (study eye vs. fellow eye)  
consisting of medication class and preferred name, sorted by descending frequencies. 
6.1.8 
Compliance, drug concentration data and/or related data 
Treatment duration is calculated as (date of ‘end of treatment’ - date of first injection at/after 
baseline +1). 
Treatment duration after randomization is calculated as (date of ‘end of treatment’ - date of 
first injection after randomization +1). 
The total number of intravitreal injections in the study eye is defined as the number of 
administered injections per subject, computed at Week 52 and Week 104, respectively.  
This will be accompanied by the proportion of subjects with at least one extension and, 
thereof, the maximum extension per subject. 
Compliance (%) is calculated as the number of intravitreal injections in the study eye at the 
scheduled injection visits (+/- 10 days) divided by number of scheduled injection visits 
(multiplied by 100). 
Treatment duration, treatment duration after randomization, number of injections, proportion 
of subjects with at least one extension, maximum number of extensions and compliance (%) 
will be summarized for all 3 analysis populations.  


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The proportions of subjects with last treatment interval of 8, 10, 12, 14, and 16 weeks up to 
Week 52 and up to Week 104 are presented together with summary statistics for the length of 
the last treatment interval up to Week 52 and up to Week 104 for the different treatment arms. 
An analogous analysis comprises the intended treatment interval after the last injection at the 
visit up to Week 52 and Week 104.   
6.2 
Efficacy 
Generally, in non-inferiority studies the most interesting population for efficacy analysis is 
the PPS, and the FAS should support the results for a valid interpretation. Therefore, the 
primary efficacy variable will be analyzed for both analysis sets with the PPS as the primary 
population and the FAS as the supportive one. The key-secondary variable will also be 
analyzed for both analysis sets in the same order. 
The other efficacy variables will be analyzed descriptively. 
Efficacy analysis will use LOCF-imputed datasets as the datasets of first choice. To support 
these results, “Observed Cases” and MI for missing values will be performed on the primary 
and key-secondary efficacy variables (see Section 4.4).  
An additional sensitivity analysis addresses the influence of mis-stratification with subsequent 
mis-randomization on the primary endpoint. This will be performed on the LOCF-imputed 
PPS with subjects stratified as actual and stratified as via IVRS. 
Efficacy data for the treated but non-randomized subjects will be listed only. 
6.2.1 
Primary efficacy variable 
The primary efficacy variable is the change in BCVA as measured by the Early Treatment 
Diabetic Retinopathy Study (ETDRS) letter score from Week 16 to Week 104.  
Statistical testing will be conducted to prove the non-inferiority of the early-start T&E regimen to 
the late-start T&E regimen. 
Null hypothesis  
 
H0: μ1 ≤ μ2-D versus 
Alternative hypothesis   
H1: μ1 > μ2-D, where 
D =  
non-inferiority margin 
μi =  
mean change in BCVA as measured by the ETDRS letter score for the study eye 
from Week 16 to Week 104 in treatment arm i. 
i =  
1: early-start T&E regimen 
2: late-start T&E regimen 
The non-inferiority margin D is set to 5 letters. 
The methodological approach will be the calculation of 2-sided 95% confidence intervals (CI) for 
the difference in the LS means (early-start T&E regimen minus late-start T&E regimen) of the 
change in ETDRS letter score from Week 16 to Week 104 based on a two-way analysis of 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o.: B A Y 8 6 -5 3 2 1/ 1 7 5 0 8  
 
 
 
Pa ge:  
2 8  of  
3 5  
 
Refere nce N u m ber: B P D- S O P- 0 6 0  
S u p ple me nt Versi o n: 6 
c o varia nce ( A N C O V A) wit h t he B C V A meas ure at Wee k 1 6 as a c o variate a n d treat me nt ar m a n d 
t he stratificati o n varia ble “ vis ual o utc o mes” (act ual val ues) as fi xe d fact or s.  
T he pri mar y statistical a nal ysis will be perf or me d o n t he P P S. T he earl y-start T & E re gi me n will 
be c o nsi dere d t o be n o n-i nferi or t o t he late-start T & E re gi me n if t his a nal ysis is statisticall y 
si g nifica nt, i.e. if t he CI of t he differe nce lies e ntirel y a b o ve - 5 letters, w here a p ositi ve differe nce 
fa v ors t he earl y-start T & E re gi me n.  
A d diti o nall y, t he a nal ysis will be perf or me d o n t he F ull A nal ysis Set ( F A S), a n d wit h o ut t he 
fact or “ vis ual o utc o mes” t o s u p p ort t he res ults.  
L O C F is t he mai n a nal ysis wit h o bser ve d cases a n d MI as s u p p orti ve.  
6. 2. 2  
Ke y-sec o n d ar y effic ac y v ari a ble  
T he ke y-sec o n dar y efficac y varia ble de n otes t he pr o p orti o n of s u bjects mai ntai ni n g visi o n ( < 3 
li nes l oss1 ) at Wee k 1 0 4 c o m pare d wit h baseli ne.  
If, a n d o nl y if, t he earl y-start T & E re gi me n is statisticall y pr o ve n t o be n o n-i nferi or t o t he late-
start T & E re gi me n i n t he pri mar y efficac y a nal ysis, c o nfir mat or y testi n g will be c o nti n ue d o n t he 
P P S t o assess t he n o n-i nferi orit y of t he earl y-start T & E re gi me n t o t he late start T & E re gi me n 
wit h re gar d t o t he ke y -sec o n dar y efficac y varia ble ( mai nte na nce of visi o n).  
N ull h y p ot hesis  
 
H 0: p1 ≤ p 2-Δ  vers us  
Alte r nati ve h y p ot hesis   
H 1: p1 > p 2-Δ  w here  
p i =  
pr o p orti o n of s u bjects mai ntai ni n g visi o n at Wee k 1 0 4 of treat me nt ar m i  
Δ =  
pre -s pecifie d n o n -i nferi orit y mar gi n of 7 %. 
i =  
1: earl y -start T & E re gi me n 
2: late-start T & E re gi me n 
T he met h o d ol o gical a p pr oac h will be t he calc ulati o n of 2-si de d 9 5 % CIs of t he differe nce 
bet wee n t he pr o p orti o ns (earl y-start T & E re gi me n mi n us late-start T & E re gi me n) of s u bjects 
mai ntai ni n g visi o n at Wee k 1 0 4, ta ki n g t he act ual stratificati o n varia ble “ vis ual o utc o mes” i nt o 
acc o u nt ( C M H). T he earl y -start T & E re gi me n will be c o nsi dere d t o be n o n-i nferi or t o t he late-
start T & E re gi me n if t he CI of t he differe nce lies e ntirel y a b o ve -7 %, w here a p ositi ve differe nce 
fa v ors t he earl y-start T & E re gi me n. A d diti o nall y, t he a nal ysis will be perf or me d o n t he F A S t o 
s u p p ort t he res ults, a n d wit h o ut “ vis ual o utc o mes” as a d diti o nal fact or.  
L O C F is t he mai n a nal ysis wit h o bser ve d cases a n d MI as s u p p orti ve.  
T his hierarc hical pr oce d ure  (a-pri ori or dere d h y p ot heses) will c o ntr ol f or m ulti plicit y i n t he 
c o nfir mat or y a nal yses o n t he P P S.  
                                                 
1  As eac h li ne o n t he E T D R S c hart has 5 letters, s u bjects mai ntai ni n g visi o n ( < 3 li nes l oss) are 
s u bjects w h o gai n a n y n u m ber of letters, s u bjects wit h o ut gai n or l oss of letters, a n d s u bjects w h o 
l ose less t ha n 1 5 letters i n B C V A  


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6.2.3 
Other secondary efficacy variables 
Analyses on other secondary efficacy variables will be conducted on the PPS and FAS in a 
descriptive manner, with and without stratified by “visual outcomes”, depending on the type of 
data as described in Section 4.1. This may include 95% CIs for treatment differences in an 
exploratory way.  
The following variables are identified to be other secondary: 
 
Change in BCVA as measured by the ETDRS letter score from baseline to Weeks 52 and 
104 and from Week 16 to Week 52 by mandatory visit and by time-window 
 
Change in central retinal thickness (CRT) from baseline to Weeks 52 and 104 and from 
Week 16 to Weeks 52 and 104 by mandatory visit and by time-window 
 
Number of study drug injections from baseline to Weeks 52 and 104  
 
Duration of last treatment interval 
 
Proportion of subjects requiring retreatment at 8, 10, 12, 14, and 16 weeks as the last 
treatment interval  
 
Proportion of 3-line gainers at Weeks 52 and 104 compared with baseline  
 
Proportion of subjects maintaining vision (<3 lines loss) at Week 52 compared with 
baseline  
6.2.4 
Exploratory efficacy variables  
Analyses on other efficacy variables will be conducted on the PPS and FAS in a descriptive 
manner, with and without stratified by “visual outcomes”, depending on the type of data as 
described in Section 4.1. This may include 95% CIs for treatment differences in an exploratory 
way. 
 
Change in CNV size and total lesion size from baseline to Weeks 52 and 104  
 
Proportion of subjects with non-deteriorating OCT morphology (as assessed by the central 
reading center) at Weeks 52 and 104 compared with baseline  
 
Proportion of subjects showing no IRF and no SRF at Weeks 8, 16, 52 and 104  
 
Proportion of subjects showing no intraretinal cysts, no IRF and no SRF at Weeks 8, 16, 
52 and 104  
 
Proportion of subjects showing no IRF and no SRF exceeding 50 μm in thickness at 
Weeks 52 and 104 
 
Proportion of subjects showing no intraretinal cysts, no IRF and no SRF exceeding 50 μm 
in thickness at Weeks 52 and 104 
 
Percentage of subjects requiring retreatment with IVT aflibercept less frequently than 
every 8 weeks (2Q8)  


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6.2.5 
Fluorescein Angiography (FA)/ Fundus Photography (FP)  
For all visits where FP and FA procedures are scheduled, they will be performed on both 
eyes, but only the study eye will be evaluated by the independent reading center. 
FA/FP measurements (except CNV and total lesion size) of the study eye will be listed only. 
6.3 
Pharmacokinetics / pharmacodynamics 
Not applicable. 
6.4 
Safety 
The safety analysis will be conducted on the SAF (as defined in Section 5).  
6.4.1 
Ocular Safety 
6.4.1.1 
Intra-ocular Pressure (IOP) 
IOP will be assessed for both the study eye and fellow eye at all visits.  
At visits with study drug administration, pre-injection IOP will be assessed for both the study 
eye and fellow eye. Assessment of IOP 30-60 minutes following the IVT injection will be 
carried out in the study eye only. 
All IOP measurements will be classified as follows: 
 > 25 mmHg  
 ≥ 30 mmHg 
 ≥ 35 mmHg  
 ≥ 40 mmHg  
Any increase from pre-injection/baseline/Week 16 of ≥ 10 mmHg will be flagged.  
The IOP analysis will include 
 original measurements 
 changes from pre-injection/baseline/Week 16 
 classified measurements 
 flagged measurements  
This analysis will be performed descriptively at all visits, stratified by study eye vs. fellow 
eye, depending on the type of data as described in Section 4.1. 
Additionally for the study eye, the changes of the measurements between pre- and post-
injection will be analyzed descriptively depending on the type of data as described in 
Section 4.1.  


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6.4.1.2 
Indirect Ophthalmoscopy 
At visits with study drug administration, pre-injection indirect ophthalmoscopy will be 
assessed for both the study eye and fellow eye. Post-injection assessments will be carried out 
in the study eye only 30-60 minutes following the IVT injection. 
All indirect ophthalmoscopy variables from the respective eCRF-pages (i.e., Indirect 
ophthalmoscopy: posterior segment examination, Indirect ophthalmoscopy: study eye - post 
injection) will only be listed.  
6.4.1.3 
Slit Lamp Biomicroscopy 
The slit lamp examination is to be performed at all visits in both the study eye and the fellow 
eye irrespective of whether the fellow eye has AMD.  
Slit lamp biomicroscopy measurements form the respective eCRF-pages (Slit lamp 
biomicroscopy) will only be listed, except for the assessments of the anterior chamber and the 
lens in the study eye.  
6.4.2 
Overall Safety 
6.4.2.1 
Adverse Events (AEs) 
The definitions of AEs and serious AEs (SAEs) are provided in the study protocol, Section 
9.6.1.1. The classifications according to seriousness, intensity, causality, action taken, other 
specific treatment and outcome are provided in the study protocol, Section 9.6.1.2. 
Treatment-emergent adverse events (TEAEs) are AEs that start after the first application of 
aflibercept in the study.  
Potential ATEs will be evaluated by a masked adjudication committee according to criteria 
formerly applied and published by the APTC. Further details are described in the adjudication 
committee charter.  
If not specified otherwise the following tables will be prepared for  
 All AE 
 Ocular AE in the study eye 
 Ocular AE in the fellow eye  
 Non-ocular AE 
Summary tables by treatment and overall will be produced for the following categories for 
AEs, treatment-emergent AEs and non-treatment AEs: 
 Subjects with at least one AE 
 Subjects with at least one AE causally related to study drug  
 Subjects with at least one AE causally related to intravitreal injection procedures 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o.: B A Y 8 6 -5 3 2 1/ 1 7 5 0 8  
 
 
 
Pa ge:  
3 2  of  
3 5  
 
Refere nce N u m ber: B P D- S O P- 0 6 0  
S u p ple me nt Versi o n: 6 
 S u bjects wit h at least o ne A E  ca usall y relate d t o ot her pr oce d ures re q uire d b y t he 
pr ot oc ol 
 Ma xi m u m i nte nsit y f or a n y A E  
 Ma xi m u m i nte nsit y f or st u d y dr u g-relate d A Es 
 A E  wit h o utc o me deat h  
 S u bjec ts wit h a n y seri o us A E  
 S u bjec ts wit h a n y seri o us A E ca usall y relate d t o st u d y dr u g 
 S u bjec ts wit h a ny seri o us A E ca usall y relate d t o i ntra vitreal i njecti o n pr oce d ure 
 S u bjec ts wit h a n y seri o us A E ca usall y relate d t o ot her pr oce d ures re q uire d b y t he 
pr ot oc ol 
 S u bjects wit h at least o ne A P T C e ve nt 2  
 Disc o nti n uati o n of st u d y dr u g d ue t o A Es  
 Disc o nt i n uati o n of st u d y dr u g d ue t o seri o us A Es      
T he f oll o wi n g ta bles will prese nt t he res pecti ve A Es b y Me d D R A preferre d ter m ( P T) wit hi n 
pri mar y s yste m or ga n class ( S O C) a n d s u m marize d b y treat me nt ar ms. S u bjects ma y be 
c o u nte d u n der m ulti ple s yste m or ga n classes a n d preferre d ter ms, b ut f or eac h s yste m or ga n 
class a n d preferre d ter m, s u bjects are o nl y c o u nte d o nce.   
 T E A Es 
 T E A Es ca usal l y relate d t o st u d y dr u g or i v i njecti o n pr oce d ure     
 T E A Es ca usal l y relate d t o st u d y dr u g  
 T E A Es ca usal l y relate d t o i v i njecti o n pr oce d ure3      
 Seri o us T E A Es 
 Seri o us T E A Es ca usal l y relate d t o st u d y- dr u g or i v i njecti o n pr oce d ure     
 Seri o us T E A Es ca usal l y relate d t o st u d y- dr u g     
 T E A E s res ulti n g i n disc o nti n uati o n of st u d y dr u g  
 T E A Es b y ma xi m u m se verit y 
 St u d y dr u g-relate d T E A Es b y ma xi m u m se verit y 
 N o n- seri o us A E s 
 T E A Es b y w orst o utc o me 
 Treat me nt-e mer ge nt A P T Cs 4  
T he n u m ber a n d perce nta ges of s u bjects affecte d as well as t he n u m ber of e ve nts will be 
dis pla ye d. S O Cs will be s orte d b y desce n di n g fre q ue nc y of s u bjects, wit hi n eac h S O C t he P T 
will be s orte d b y desce n di n g n u m ber of e ve nts.  
                                                 
2  n ot a p plica ble f or t he i nteri m a nal ysis 
3  O nl y f or “ All A E” 
4  n ot a p plica ble f or t he i nteri m a nal ysis 


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6.4.2.2 
Vital Signs 
Vital signs (body temperature, blood pressure, heart-rate including changes from baseline will 
be displayed for each treatment arm and overall. 
6.4.2.3 
Laboratory Evaluations / Pregnancy Tests 
A urine pregnancy test for women of childbearing potential will be performed at screening 
and baseline. After the first treatment, a urine pregnancy test is mandatory at every treatment 
visit (prior to injection) in all countries where it is required by local regulations. 
 A positive result should be confirmed by a serum pregnancy test. If required by national 
/institutional regulations, a pregnancy test should be performed for women of childbearing 
potential at the end of study visit. 
Results of the pregnancy tests for women of childbearing potential will be listed only. 
7. 
Document history and changes in the planned statistical analysis 
7.1 
Changes with respect to SAP version 1.0, 2. November 2015 
1) Adopted the changes from the study protocol amendment v2.0. 
2) Added introductory paragraph in Section 1 to underline validity of the SAP for interim 
as well as final analysis.  
3) Added Section 4.3 on handling of mis-stratifications. Related consequences and 
sensitivity analyses are mentioned in the respective sections.   
4) Interim analysis section (now Section 4.5): Described the interim analysis more 
concisely; added comment on the data cut-off date specification including the 
reference to the generic document. Replaced subsections on listings, tables and figures 
to be conducted for the interim analysis with an instructive  reference to the final 
analysis to avoid redundancy. 
5) Statistical Methodology section (Section 6) extended for subgroup analyses 
(completely dry vs. not completely dry) and the consideration of treated but not 
randomized subjects in the safety analyses. 
6) Demography  and baseline characteristics (Sections 6.1.3 and 6.1.4): updated the 
descriptive analyses to 2-tailed student’s t-test and Fisher’s exact test for consistency 
with the study protocol. Categorized BCVA and gain in BCVA with respect to mis-
stratification is added. 
7) Section 6.1.8 on compliance and exposure added 


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8) Intraocular pressure and slit lamp biomicroscopy (Sections 6.4.1.2 and 6.4.1.3): 
Planned descriptive analyses replaced by listings. 
9) Safety analyses (Section 6.4.2.1): Added five tables on TEAEs by SOC and PT. 
10) Appendix 9.1 Cut-Off Specification Clarifications added 
Formal changes comprise the update of the header with the new company logo and name, 
the update of reference documents and the correction of minor mistakes, such as the 
abbreviation of PT as prothrombin time (SAP v1.0) instead of preferred term (SAP v2.0).  
7.2 
Changes with respect to SAP version 2.0, 24. November 2017 
Beside some editorial changes and minor clarifications the following updates were 
implemented in ths vesion 
1. Definition of “treatment emergent AE”:  
Adverse Events starting later than 30 days after last study-drug injection will be 
considered as non-treatment emergent. 
2. Definition of “Compliance” adapted, enlarging the interval  to +/- 10 days. 
3. Two exploratory endpoints were added 
4. Tables for Adverse Events are updated to be consistent with other Bayer studies. 
8. 
References 
 Clinical Study Protocol No. BAY86-5321/17508, version 2.0, 02 February 2016 
 Study Protocol Deviation Document, version 1.0, 21 October 2015 
 Database Cutoff Specification v1.0, 15Sept2017 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o.: B A Y 8 6 -5 3 2 1/ 1 7 5 0 8  
 
 
 
Pa ge:  
3 5  of  
3 5  
 
Refere nce N u m ber: B P D- S O P- 0 6 0  
S u p ple me nt Versi o n: 6 
9.  
A p pe n di x  
9. 1  
C ut - Off S pecific ati o n Cl arific ati o ns 
Ge neral r ules fr o m t he g ui deli nes “ Data base C ut off S pecificati o n v 1. 0, 1 5 Se pt 2 0 1 7” will be 
f oll o we d: 
 All va ria bles w hic h are set b y t he ti mi n g c o nce pt, e. g., relati ve da ys,  as well as t he 
treat me nt e mer ge nt fla g will be re-calc ulate d after t he c ut off is d o ne.  
 If t here is a d o mai n, w hic h de pe n ds o n a n ot her, t he pare nt d o mai n is al wa ys c ut first, 
t he depe n de nt d o mai n will t he n be c ut acc or di n gl y 5 .  
 If a n o bser vati o n has a partial date, t he o bser vati o n will be c ut o nl y if t he partial date 
is wit h o ut a n y d o u bt after t he c ut off date. 
T here are s o me e xce pti o ns wit h re gar d t o t he g ui deli ne me nti o ne d a b o ve.: 
Sect i o n 5. 1: C ut off Visit: T he visit w hic h i n dic at es a ny d at a c ollecte d by t his visit will be use d 
f or a n alysis 
As descri be d i n Secti o n 6, t he i nteri m data release will be base d o n a pla n ne d 
o bser vati o n ti me f or eac h patie nts, i.e., a visit- base d c ut- off will be use d . In a d diti o n t o 
t he defi niti o ns gi ve n a b o ve,  st u d y dr u g i njecti o ns gi ve n at t he c ut- off visit as well as 
data  of a n y assess me nts sc he d ule d p ost-i njecti o n at t his visit will n ot be i ncl u de d. 
Secti o n 7. 1; D ate b ase d c ut off: S pecific ati o n f or differe nt O A D D o m ai ns  
Us u ally a ut h orities re q uest a s peci al listi n g of all s u bjects w h o die d after c ut off 
d ate. F or t his p ur p ose t he i nf or m ati o n rel ate d t o “ de at h ” ( pri m ary c a use of de at h, 
de at h d ate, etc.) s h o ul d n ot be re m ove d eve n if after t he c ut off d ate.   
T his r ule is a p plica ble f or o nc ol o gical st u dies a n d will n ot be use d here. T heref ore, i n 
t his st u d y fatal A Es are n ot treate d differe nt t o ot her seri o us A Es.  
                                                 
5  F or e xa m ple, after re m o val of a n A E after c ut- off, t he res pecti ve c o nc o mita nt me dicati o n f or t his A E s hall als o 
be re m o ve d