Clinical trial NCT02540954
Conditions: Macular Degeneration
Keywords: Age-related macular degeneration (AMD) Eylea treatment Treat and Extend Intravitreal
Sponsor: Bayer
Start date: 2015-09-29; Completion date: 2020-06-04
Enrollment: 336 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare the efficacy of 2 mg aflibercept administered by two different intravitreal (IVT) treatment regimens to subjects with neovascular age-related macular degeneration (nAMD)

Detailed description:
330 Patients who have completed at least one year of treatment with aflibercept will be randomized to two different aflibercept regimens and followed for 76 weeks.

Arms: arm 1: Aflibercept was administered 2mg per injection intravitreal (IVT) in the study eye in Aflibercept extended dosing. Flexible dosing interval is ≥ 8 weeks (no upper limit) based on visual and anatomic outcomes as judged by the investigator. When/if visual and anatomical outcomes indicated that the disease had re-activated, the treatment interval reverted to the last treatment interval in which the disease was inactive (ie, no signs of exudation were observed). arm 2: Aflibercept was administered 2mg per injection IVT in the study eye in Aflibercept 2Q8. Fixed dosing interval is 8 weeks (±3 days), modification of the treatment interval was not allowed.
Interventions: intervention 1: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)
Intervention descriptions: intervention 1: A dose of 2 mg aflibercept injected intravitreally

Protocol documents:
Prot_001.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
An open-label, randomized, active-controlled, parallel-group, Phase-
3b study of the efficacy, safety, and tolerability of 2 mg aflibercept 
administered by intravitreal injections using two different treatment 
regimens to subjects with neovascular age-related macular 
degeneration (nAMD) 
NCT Number: 
NCT02540954 
Document Date: 
10-Dec-2015 
 


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An open-label, randomized, active-controlled, parallel-group, Phase-3b 
study of the efficacy, safety, and tolerability of 2 mg aflibercept 
administered by intravitreal injections using two different treatment 
regimens to subjects with neovascular age-related macular degeneration 
(nAMD)
This protocol version is an integration of the following documents/sections:

Original protocol, Version 1.0, dated 26 March 2015

Amendment 02 (global amendment described in Section 15.1) forming integrated 
protocol Version 2.0, dated 10 December 2015
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
Study title
An open-label, randomized, active-controlled, 
parallel-group, Phase-3b study of the 
efficacy, safety, and tolerability of 2 mg aflibercept
administered by intravitreal injections 
using two different treatment regimens to subjects with 
neovascular age-related macular degeneration (nAMD)
Short title:   Efficacy and safety of two different aflibercept regimens in subjects with nAMD
Test drug:
BAY 86-5321 / VEGF Trap-Eye / aflibercept
Study purpose:
Post-approval commitment
Clinical study phase:
3b
Date:
10 DEC 2015   
Registration:
EudraCT:  2013-000120-33
Version no.:
2.0     
Sponsor’s study no.:
BAY 86-5321 / 16598   
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
, Bayer Pharma AG, Wuppertal, Germany
Phone:
Email:
The study will be conducted in compliance with the protocol, ICH-GCP 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
PPD
PPD


EfJ Bayer HealthCare 
10 DEC 2015 
Integrated Clinical Study Protocol 
No. BAY 86-5321 / 16598 
Signature of the sponsor's medically 
person 
The signatory agrees to the content of the final clinical study protocol as presented. 
N arne: 
 
Role: 
Global Clinical Leader 
Date: 
Signature: 
Page 3 of134 
PPD
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 - amended
Title
An open-label, randomized, active-controlled, parallel-group, Phase-3b 
study of the efficacy, safety, and tolerability of 2 mg aflibercept
administered by intravitreal injections using two different treatment 
regimens to subjects with neovascular age-related macular degeneration 
(nAMD)
Short title
Efficacy and safety of two different aflibercept regimens in subjects with 
nAMD 
Clinical study phase
3b
Study objective(s)
Primary objective
To compare the efficacy of 2 mg aflibercept administered by two different 
intravitreal (IVT) treatment regimens to subjects with nAMD 
Secondary objective
To assess the safety and tolerability of aflibercept in this subject population
Test drug(s)
Name of active ingredient
Intravitreal aflibercept injection (IAI)/ BAY 86-5321 
Dose(s) - amended
Test group: 
2 mg with flexible injection intervals (8 weeks)
(extended-dosing regimen)
Control group: 2 mg with fixed injection intervals (8 weeks) (2Q8)
1
Route of administration
Intravitreal (IVT)
Duration of treatment
72 weeks in the 2Q8 and up to 76 weeks in the extended-dosing group
Reference drug(s)
Not applicable 
Indication
Neovascular age-related macular degeneration (nAMD)
Diagnosis and main criteria 
for inclusion / exclusion -
amended
First set of inclusion criteria:
The following criteria must have been met at the initial start of aflibercept
treatment (i.e. start of aflibercept treatment before this study):

Subject had primary subfoveal choroidal neovascularization (CNV) 
lesions secondary to nAMD, including juxtafoveal lesions that affect 
the fovea, as evidenced by fluorescein angiography (FA) of the study 
eye within 4 weeks before the initiation of aflibercept treatment.
2,3

The area of CNV occupied at least 50% of the total lesion within 
4 weeks before the initiation of aflibercept treatment.3
                                                
1
Time windows were consolidated for all post-baseline visits in both treatment groups to ± 3 days relative to 
baseline per Amendment 2
2
Clarification of inclusion criteria per Amendment 2
3
Extension of the time period per Amendment 2


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
Documented best-corrected visual acuity (BCVA) was 20/40 to 20/320 
(comparable to a letter score of 73 to 25) in the study eye at the 
initiation of treatment (the initial BCVA of the study eye before 
treatment initiation must be documented as Snellen equivalent in the 
electronic case report form [eCRF]).4
Second set of inclusion criteria:
Criteria that must be met at the time of screening include the following 
(incomplete list):

Men and women 51 years of age

The subject’s history of aflibercept treatment meets ALL of the 
following:
a) Treatment in the study eye was initiated with three monthly 
(-1 week/+2 weeks) doses of 2 mg aflibercept and improvements of 
visual and anatomic outcomes were observed
b) Following the above initiation phase, the intervals between 
treatments were between 6 weeks and 12 weeks (one exception will 
be allowed)
c) The interval between the last two pre-study injections was 
≥8 weeks, and visual and anatomic outcomes have been stable over 
this interval.
d) The subject received the last IVT injection of  aflibercept in the 
study eye 2 months (10 days) before the first treatment in this 
study5
e) Total prior treatment duration with aflibercept (i.e. from first 
treatment to randomization into this study) was ≥12 months 
                                                
4 Clarifications of inclusion criteria and removal of reference to study manual per Amendment 2
5 Clarifications in the first and second set of inclusion criteria per Amendment 2


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First set of exclusion criteria:
A subject who has met any of the following criteria at the initial start of 
aflibercept treatment (i.e. start of aflibercept treatment before this study) 
will be excluded from this study.

Any prior or concomitant therapy with an investigational or approved 
agent to treat neovascular AMD in the study eye.

Total lesion size >12 disc areas (30.5 mm2, including blood, scars and 
neovascularization) as assessed by FA in the study eye

Subretinal hemorrhage that was: 
a) 50% or more of the total lesion area, or 
b) if the blood was under the fovea, and
c) the blood under the fovea was 1 or more disc areas in size in the 
study eye. 

Scar or fibrosis making up more than 50% of the total lesion in the 
study eye.

Scar, fibrosis, or atrophy involving the center of the fovea in the study 
eye.

Presence of retinal pigment epithelial tears or rips involving the macula 
in the study eye.

Causes of CNV other than AMD in the study eye.
Second set of exclusion criteria:
Criteria leading to exclusion if met at the time of screening include the 
following (incomplete list):

Subjects who currently meet any of the first set of exclusion criteria 
with the exception of prior treatment with aflibercept

Any prior ocular (in the study eye) or systemic treatment or surgery for 
neovascular AMD, except dietary supplements, vitamins and IVT 
injections of aflibercept, during the time (i.e. at least 12 months) 
between initiation of aflibercept treatment and randomization into this 
study

Any prior treatment with anti-VEGF therapy in the study eye, with the 
exception of IVT injections of aflibercept, during the time (i.e. at least 
12 months) between initiation of aflibercept treatment and 
randomization into this study

Prior systemic anti-VEGF therapy, investigational or approved, within 
the last 15 months prior to randomization 


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Study design -amended
This is a randomized, 2-arm, active-controlled, parallel-group, open-label, 
multicenter, Phase-3b study to assess the non-inferiority of an extended-
dosing regimen of aflibercept to a 2Q8 fixed dosing regimen in subjects 
with nAMD who have completed 1 year of treatment with marketed 
aflibercept according to the approved European Union (EU) drug label. In 
order to be eligible for the study, the subject’s first year of aflibercept
treatment must have (i) been initiated with three monthly
(-1 week/+2 weeks) doses; and (ii) included treatment intervals 
between 6 weeks and 12 weeks (one exception will be allowed). 
This study comprises a screening period of up to 66 days.6
Following screening, eligible subjects will be randomized (1:1) to one of 
two parallel treatment arms. In both arms, aflibercept will be injected IVT 
at a dose of 2 mg per injection. The treatment arms differ in dosing 
intervals:
Extended 
dosing:
Flexible dosing intervals
≥8 weeks (no upper limit) based on visual and anatomic 
outcomes as judged by the investigator.
When/if visual and 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 were observed). 
2Q8:
Fixed dosing intervals
8 weeks7 - modification of the treatment interval is not 
allowed.
For each treatment group, the time window for all post-baseline visits is 
3 days relative to baseline.7
Subjects in both treatment groups will receive the first study treatment on 
Day 1. The treatment period is 72 weeks (in the 2Q8 group) with a final 
study visit at Week 76.
8
The last possible study drug injection in the extended-dosing group can be 
given at Week 76 (i.e. the end of the study) after completion of all 
protocol-specified assessments.9  After Week 76, subjects should be 
returned to standard of care.
The primary efficacy variable is the change in BCVA (as measured by the 
Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting 
at 4 meters) from baseline to Week 52.
                                                
6
Clarification of the period durations per Amendment 2
7
Time windows were consolidated for all post-baseline visits in both treatment groups to ± 3 days relative to 
baseline per Amendment 2
8
Clarification of the period durations per Amendment 2
9
If an extended-dosing subject receives an injection at Week 76, it is the responsibility of the treating 
investigator to follow-up on any adverse events (including ongoing events) that may occur within 4 weeks 
following this treatment. Information regarding such events is to be reported under this protocol (i.e. not as 
spontaneous reports).


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Methodology
This study will be conducted as a 2-arm, open-label study.  
Efficacy will be assessed by the change in ETDRS BCVA letter score from 
study baseline. BCVA will be evaluated at every study visit. Other 
measures of efficacy will include changes from baseline in central retinal 
thickness (CRT) as measured by optical coherence tomography (OCT) at 
each visit, and changes from baseline in quality of life as assessed by the 
National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-
25) at baseline, Week 52 and Week 76.
Assessments of ocular safety will include intraocular pressure (IOP), 
indirect ophthalmoscopy, and slit lamp biomicroscopy at all study visits. 
Under this protocol, mandated FA/FP examinations will be conducted 
during screening and at Weeks 52 and 76 only. However, the treating 
investigator may perform FA/FP at other times during the study based on 
his/her medical judgment and standard of care. 
Overall safety of the subjects will be assessed throughout the study by 
monitoring ophthalmic and systemic adverse events (AEs). All potential 
arterial thrombotic 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 and laboratory tests (hematology 
parameters, blood chemistry parameters, and parameters of urinalysis) will 
be performed at study baseline and at Week 76 only.
Type of control
Different dosing schedules of the test drug
Number of subjects
330 (165 per treatment group)
Primary and secondary 
variable(s)
Primary efficacy variable

Change in ETDRS BCVA letter score for the study eye from baseline 
to Week 52 
Key secondary efficacy variable

Proportion of subjects maintaining vision (i.e. loss of <15 letters) in 
the study eye at Week 52
Secondary efficacy variables 

Proportion of subjects who gained ≥5 letters from baseline to Week 52

Mean change in central retinal thickness (CRT) in the study eye from 
baseline to Week 52

Mean change in CNV area in the study eye from baseline to Week 52

Proportion of subjects who lost ≥30 letters from baseline to Week 52

Mean change from baseline to Week 52 in total score for NEI VFQ-25
Time point/frame of measurement
for primary variable(s)
BCVA will be measured at each visit up to the final visit.


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Plan for statistical analysis
The primary efficacy variable analysis will be conducted on the full 
analysis set (FAS). The FAS is defined as all randomized subjects who 
received any study drug and have a baseline BCVA assessment and at least 
one post-baseline BCVA assessment.
Statistical testing will be conducted to prove the non-inferiority of the 
extended-dosing regimen to the 2Q8 fixed-dosing regimen.  
Null hypothesis 
H0:
μ1 ≤ μ2-D   versus 
Alternative hypothesis 
H1:
μ1 > μ2-D, 
where 
D = non-inferiority margin 
μi = mean change in BCVA letter score for the study eye from baseline 
to Week 52 in treatment group i.
i =
1: extended-dosing regimen
2: fixed-dosing regimen
The non-inferiority margin is 5 letters. The methodological approach will 
be the calculation of two-sided 95% confidence intervals for the difference 
in the least squares means (extended-dosing group minus 2Q8 group) of the 
change in ETDRS letter score from study baseline to Week 52 based on a 
one-way analysis of covariance (ANCOVA) with baseline measure as a 
covariate and treatment group as a fixed factor (last observation carried 
forward [LOCF] will be used for missing values at Week 5210). The 
extended-dosing regimen will be considered to be non-inferior to the fixed 
2Q8 regimen if the confidence interval of the difference lies entirely 
above -5 letters, where a positive difference favors extended dosing. A 
non-inferiority margin of 5 letters is consistent with the margin used in the 
“CATT Study” (Ranibizumab and Bevacizumab for Neovascular Age-
Related Macular Degeneration. N Eng J Med 2011; 365:1897-1908).
                                                
10 LOCF is considered an appropriate method for replacement of missing values in the primary and secondary 
efficacy analyses in the late phase of the study (i.e. carrying forward the last measurement taken between 
Week 36 to Week 48 if the Week-52 measurement is missing), even though nAMD is a progressive disease.


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If, and only if, the extended-dosing regimen is statistically proven to be 
non-inferior to the fixed 2Q8 regimen in the primary efficacy analysis, 
confirmatory testing will be continued to assess the non-inferiority of 
extended dosing to fixed 2Q8 with regard to the key secondary efficacy 
variable (maintenance of vision) in the full analysis set (FAS; with LOCF 
for missing Week-52 ETDRS letter score).  
Null hypothesis
H0:
p1 ≤p2-versus 
Alternative hypothesis
H1:
p1 > p2-where 
pi = proportion of subjects maintaining vision at Week 52 of treatment 
group i 
pre-specified non-inferiority margin of 7%.11  
i =
1: extended-dosing regimen
2: fixed-dosing regimen
The methodological approach will be the calculation of two-sided 95% 
confidence intervals using normal approximation of the difference between 
the proportions (extended-dosing group minus 2Q8 group) of subjects
maintaining vision. The extended-dosing regimen will be considered to be 
non-inferior to the fixed 2Q8 regimen if the confidence interval of the 
difference lies entirely above -7%, where a positive difference favors 
extended dosing. This conditional sequence of statistical hypotheses (a-
priori ordered hypotheses) will control for multiplicity in the confirmatory 
analyses. 
As sensitivity analyses, the primary efficacy and key secondary efficacy 
analyses will be repeated on the per-protocol set (PPS). The PPS is defined 
as all randomized subjects who receive any study drug and have a BCVA 
assessment at study baseline and have at least one BCVA assessment at 
Week 36 or later, and do not have a major protocol deviation.
The other secondary efficacy variables as well as the exploratory efficacy 
variables will be analyzed in a descriptive manner. This may include 95% 
confidence intervals for treatment differences in an exploratory way.
Details regarding the statistical analyses will be provided in the Statistical 
Analysis Plan (SAP).
                                                
11 The non-inferiority margin of 7% was proposed by the 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 pages 22 and 23).


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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 - amended........................................................................................................... 5
Table of contents..................................................................................................................... 12
List of abbreviations............................................................................................................... 17
3.
Introduction..................................................................................................................... 18
3.1
Background - amended........................................................................................... 18
3.2
Rationale of the study ............................................................................................. 19
3.3
Benefit-risk assessment........................................................................................... 19
4.
Study objectives............................................................................................................... 19
5.
Study design - amended.................................................................................................. 20
6.
Study population - amended .......................................................................................... 23
6.1
Inclusion criteria ..................................................................................................... 24
6.1.1
First set of inclusion criteria - amended.................................................... 24
6.1.2
Second set of inclusion criteria - amended ............................................... 24
6.2
Exclusion criteria.................................................................................................... 26
6.2.1
First set of exclusion criteria..................................................................... 26
6.2.2
Second set of exclusion criteria - amended............................................... 26
6.3
Withdrawal of subjects from study......................................................................... 28
6.3.1
Withdrawal - amended.............................................................................. 28
6.3.2
Replacement.............................................................................................. 30
6.4
Subject identification - amended ............................................................................ 30
7.
Treatments....................................................................................................................... 31
7.1
Treatments to be administered - amended.............................................................. 31
7.2
Identity of study treatment - amended.................................................................... 32
7.3
Treatment assignment............................................................................................. 32
7.4
Dosage and administration - amended.................................................................... 33
7.5
Blinding / masking.................................................................................................. 34
7.6
Drug logistics and accountability - amended.......................................................... 34
7.7
Treatment compliance............................................................................................. 35


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8.
Non-study therapy........................................................................................................... 36
8.1
Prior and concomitant therapy................................................................................ 36
8.1.1
Prior therapy.............................................................................................. 36
8.1.2
Concomitant therapy................................................................................. 36
8.1.2.1
Study-eye treatment - amended.............................................. 36
8.1.2.2
Fellow-eye treatment - amended............................................ 36
8.2
Post-study therapy................................................................................................... 37
9.
Procedures and variables - amended............................................................................. 37
9.1
Tabular schedule of evaluations - amended............................................................ 38
9.2
Visit description...................................................................................................... 40
9.2.1
Screening visit (Visit 1) - amended........................................................... 40
9.2.2
Baseline visit (Visit 2) - amended............................................................. 41
9.2.3
Visits between baseline and Week 52 - amended..................................... 42
9.2.4
Primary completion (Week 52) - amended............................................... 43
9.2.5
Visits between primary completion (Week 52) and final visit 
(Week 76) - amended................................................................................ 44
9.2.6
Final visit (Week 76) or early termination- amended............................... 45
9.3
Population characteristics ....................................................................................... 46
9.3.1
Demographic............................................................................................. 46
9.3.2
Medical/surgical and ophthalmic history.................................................. 46
9.4
Efficacy................................................................................................................... 47
9.4.1
Ophthalmic examinations ......................................................................... 47
9.4.1.1
Best corrected visual acuity - amended.................................. 47
9.4.1.2
Optical coherence tomography (OCT) – amended ................ 47
9.4.1.3
Indirect ophthalmoscopy........................................................ 47
9.4.1.4
Slit lamp biomicroscopy ........................................................ 48
9.4.1.5
Intra-ocular pressure (IOP) .................................................... 48
9.4.1.6
Fundus photography (FP) and fluorescein angiography 
(FA) - amended ...................................................................... 48
9.4.2
Efficacy variables...................................................................................... 49
9.5
Pharmacokinetics / pharmacodynamics.................................................................. 49
9.6
Safety ...................................................................................................................... 50
9.6.1
Adverse events .......................................................................................... 50
9.6.1.1
Definitions - amended............................................................ 50
9.6.1.2
Classifications for adverse event assessment......................... 52
9.6.1.2.1
Seriousness.............................................................................52
9.6.1.2.2
Intensity..................................................................................52
9.6.1.2.3
Causal relationship.................................................................52
9.6.1.2.4
Action taken with study treatment - amended........................54
9.6.1.2.5
Other specific treatment(s) of adverse events ........................54
9.6.1.2.6
Outcome.................................................................................55
9.6.1.3
Assessments and documentation of adverse events............... 55
9.6.1.4
Reporting of serious adverse events....................................... 56
9.6.1.5
Expected adverse events - amended....................................... 57


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9.6.2
Pregnancies - amended.............................................................................. 57
9.6.3
Further safety ............................................................................................ 57
9.6.3.1
Laboratory evaluations - amended......................................... 57
9.6.3.2
Physical examination ............................................................. 58
9.6.3.3
Vital signs (temperature, blood pressure and pulse).............. 59
9.7
Patient-reported outcome – amended ..................................................................... 59
9.8
Appropriateness of procedures / measurements ..................................................... 59
10. Statistical methods and determination of sample size ................................................. 59
10.1
General considerations............................................................................................ 59
10.2
Analysis sets ........................................................................................................... 60
10.3
Variables and planned statistical analyses.............................................................. 60
10.3.1
Variables ................................................................................................... 60
10.3.1.1
Efficacy variables................................................................... 60
10.3.1.2
Safety variables ...................................................................... 61
10.3.2
Statistical and analytical plans .................................................................. 61
10.3.2.1
Demography and baseline characteristics.............................. 61
10.3.2.2
Efficacy analyses – amended ................................................. 62
10.3.2.3
Safety variables analysis ........................................................ 63
10.4
Determination of sample size ................................................................................. 64
10.5
Planned interim analyses ........................................................................................ 64
11. Data handling and quality assurance............................................................................ 65
11.1
Data recording......................................................................................................... 65
11.2
Monitoring .............................................................................................................. 66
11.3
Data processing - amended..................................................................................... 67
11.4
Missing data............................................................................................................ 67
11.5
Audit and inspection............................................................................................... 67
11.6
Archiving ................................................................................................................ 68
12. Premature termination of the study.............................................................................. 68
13. Ethical and legal aspects................................................................................................. 69
13.1
Investigator(s) and other study personnel............................................................... 69
13.2
Funding and financial disclosure............................................................................ 70
13.3
Ethical and legal conduct of the study.................................................................... 71
13.4
Subject information and consent - amended........................................................... 71
13.5
Publication policy and use of data.......................................................................... 73
13.6
Compensation for health damage of subjects / insurance....................................... 73
13.7
Confidentiality........................................................................................................ 73
14. Reference list.................................................................................................................... 74


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15. Protocol amendments...................................................................................................... 74
15.1
Amendment 2, dated 10 December 2015................................................................ 75
15.1.1
Overview of changes to the study............................................................. 75
15.1.1.1
Modification 1 – Update of approval status........................... 75
15.1.1.2
Modification 2 – Clarification of duration of the periods...... 75
15.1.1.3
Modification 3 – Time windows and schedule of visits ........ 75
15.1.1.4
Modification 4 – Selection of study eye ................................ 76
15.1.1.5
Modification 5 – Clarifications of inclusion criteria.............. 76
15.1.1.6
Modification 6 – Time periods for inclusion criteria 1 
and 2....................................................................................... 76
15.1.1.7
Modification 7 – Study manual.............................................. 76
15.1.1.8
Modification 8 – Inclusion criterion 8 ................................... 77
15.1.1.9
Modification 9 – Clarifications in second set of 
exclusion criteria.................................................................... 77
15.1.1.10 Modification 10 – Re-screening criteria ................................ 77
15.1.1.11 Modification 11 – Subject identification number .................. 77
15.1.1.12 Modification 12 – Identity of study drug ............................... 78
15.1.1.13 Modification 13 – EU SmPC and other updates for 
safety reasons to dosage and administration.......................... 78
15.1.1.14 Modification 14 – Treatment posology.................................. 78
15.1.1.15 Modification 15 – Drug storage............................................. 78
15.1.1.16 Modification 16 – Final visit or early termination visit......... 79
15.1.1.17 Modification 17 – Specification of pregnancy testing........... 79
15.1.1.18 Modification 18 – Timing of pregnancy testing .................... 79
15.1.1.19 Modification 19 – Order of footnotes and minor 
clarifications in schedule of evaluations ................................ 80
15.1.1.20 Modification 20 – Removal of sample study drug 
injection protocol from appendix........................................... 80
15.1.1.21 Modification 21 – Re-check of eligibility criteria.................. 80
15.1.1.22 Modification 22 – Post-injection ocular assessments ............ 80
15.1.1.23 Modification 23 – Conduct of visits....................................... 81
15.1.1.24 Modification 24 – OCT.......................................................... 81
15.1.1.25 Modification 25 – FA and FP................................................. 81
15.1.1.26 Modification 26 – ECG.......................................................... 82
15.1.1.27 Modification 27 – Actions taken with study treatment.......... 82
15.1.1.28 Modification 28 – Expected adverse events........................... 82
15.1.1.29 Modification 29 – Pregnancies............................................... 82
15.1.1.30 Modification 30 – Time point of blood withdrawal............... 83
15.1.1.31 Modification 31 – NEI VFQ-25 questionnaire ...................... 83
15.1.1.32 Modification 32 – Data processing ........................................ 83
15.1.1.33 Modification 33 – Subject information and consent 
process
83
15.1.1.34 Modification 34 – Fellow eye treatment ................................ 83
15.1.1.35 Modification 35 – Efficacy analyses – sensitivity 
analyses
84


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15.1.2
Changes to the protocol text...................................................................... 84
16. Appendices..................................................................................................................... 124
16.1
National Eye Institute 25-item visual function questionnaire .............................. 124


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List of abbreviations
2Q8
2 mg aflibercept administered every 8 weeks INR
international normalized ratio
AE
adverse event
IOP
intraocular pressure
ALT
alanine aminotransferase
IRB
institutional review board
AMD
age-related macular degeneration
IV
intravenous
ANCOVA analysis of covariance
IVRS
interactive voice response system
APTC
Antiplatelet Trialists' Collaboration
IVT
intravitreal(ly)
AST
aspartate aminotransferase
IWRS
interactive web response system
ATC
Anatomical Therapeutic Chemical
IxRS
Interactive voice/web response system
ATE
arterial thrombotic event
LOCF
last observation carried forward
BCVA
best corrected visual acuity
LSmean
least squares mean
BL
Baseline
MCH
mean corpuscular hemoglobin
BRVO
branch retinal vein occlusion
MCHC
mean corpuscular hemoglobin concentration
BUN
blood urea nitrogen
mCNV
myopic choroidal neovascularization
CIE
Conference on computability in Europe
MCV
mean corpuscular volume
CNV
choroidal neovascularization
MedDRA
Medical Dictionary for Regulatory Activities
CRF
case record form
NaCl
Sodium chloride
CRO
contract research organization
nAMD
neovascular AMD
CRT
central retinal thickness
NEI VFQ-25 National Eye Institute 25-item Visual 
Function Questionnaire
CRVO
central retinal vein occlusion
OCT
optical coherence tomography
CSR
clinical study report
PlGF
placental growth factor
CTFG
Clinical Trials Facilitation group
PID
patient identification number
DME
diabetic macular edema
PPS
per-protocol set
EC
ethics committee
PT
prothrombin time
ECG
Electrocardiogram
PTT
partial thromboplastin time
eCRF
electronic case report form
RAVE
Electronic data capture system
EDC
electronic data capture
SAE
serious adverse event
EMA
European Medicines Agency
SAP
statistical Analysis Plan
ePRO
electronic patient-reported outcome
SAS
Statistical analysis system
ETDRS
Early Treatment Diabetic Retinopathy Study
SC
subcutaneous
EU
European Union
SF-36
Short form health survey 36-item
EudraCT
EU Drug Regulating Authorities Clinical Trials SmPC
Summary of product characteristics
FA
fluorescein angiography
SMT
safety management team
FAS
full analysis set
SOC
system organ class
FP
fundus photography
StM
study manager
GCL
global clinical leader
SUSAR
suspected, unexpected, serious adverse reaction
GCP
Good Clinical Practice
TOSCA
Tools for syntactic corpus analysis
GMP
Good Manufacturing Practice
UPCR
urine protein/creatinine ratio
HR
heart rate
US
United States
HDL
high-density lipoprotein
VA
visual acuity
IA
Interviewer-administered format
VEGF
vascular endothelial growth factor
IAI
intravitreal aflibercept injection
WHO DD
World Health Organisation Drug Dictionary
ICH
International Conference on Harmonisation
YAG
yttrium aluminum garnet
IEC
independent ethics committee


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3.
Introduction
3.1
Background - amended
Age-related macular degeneration (AMD) is a leading cause of adult blindness in the 
developed world (Rahmani et al. 1996). 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 (Aiello et al. 1994). Anti-VEGF therapy has been shown 
to provide significant therapeutic benefit to patients suffering from nAMD.  
To date, aflibercept has been approved as a treatment for nAMD, macular edema secondary to 
central retinal vein occlusion (CRVO), diabetic macular edema (DME), and macular edema 
secondary to branch retinal vein occlusion (BRVO) in the United States (US), European 
Union (EU), Japan, and other countries; as well as for myopic choroidal neovascularization 
(mCNV) in the EU, Japan and other countries; and for diabetic retinopathy in patients with 
DME in the US.12
The approval of aflibercept in the EU (27 November 2012) was based upon the results of two 
randomized, multicenter, double-masked, active-controlled Phase-3 clinical studies — the 
VIEW 1 (US and Canada) and VIEW 2 (EU, Asia/Pacific, and Latin America) studies. Both 
studies demonstrated that aflibercept, dosed every 8 weeks following three initial monthly 
injections, provided efficacy that was clinically equivalent to the former standard of care, 
Lucentis (ranibizumab injection) dosed monthly. The primary endpoint of these studies was
the maintenance of visual acuity (less than 15 letters of vision lost on the Early Treatment 
Diabetic Retinopathy Study [ETDRS] chart) over 52 weeks. During the second year of these 
studies, the treatment interval could be extended (based on protocol-specified re-treatment 
criteria), with no more than 12 weeks allowed between injections. Because the extended 
treatment interval was capped at 12 weeks, the present study is being conducted to assess the 
option to extend the treatment interval with no additional restrictions (i.e. no maximum limit 
to the treatment interval).
The approved EU labeling for 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.
                                                
12 Update of approved indications for aflibercept by country per Amendment 2 (Section 15.1.1.1)


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3.2
Rationale of the study
As a condition for approval, the European Medicines Agency (EMA) has required a study to 
assess every-other-month dosing versus an extended-dosing regimen with no maximum limit 
to the treatment interval. This Phase-3b post-authorization efficacy study has been designed to 
meet this obligation and compares a fixed dosing regimen of 2 mg aflibercept administered 
every 8 weeks (“2Q8 group”) to a flexible extended regimen of 2 mg aflibercept (“extended-
dosing group”) in patients with nAMD who have completed at least 1 year of treatment with 
aflibercept.
3.3
Benefit-risk assessment
Intravitreal injection of VEGF Trap-Eye in this study of subjects with nAMD is justified and 
supported by the drug’s efficacy and safety profile known from previous studies investigating 
VEGF Trap-Eye in nAMD and other indications. The beneficial effect on visual acuity in 
patients with nAMD has previously been demonstrated, both with VEGF Trap-Eye treatment 
and with other anti-VEGF therapy.
The risks of the local IVT application are limited to ocular adverse events (AEs). There is no 
indication that local application causes systemic AEs. Proteinuria and hypertension are 
potential systemic effects from intravenous (IV) or subcutaneous (SC) 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, would not be 
expected to have clinically significant systemic effects. The risks associated with IVT 
administration of VEGF Trap-Eye observed in the Phase-3 studies are thought to be similar to 
those of IVT administration of pegaptanib sodium and ranibizumab.
Taken together, the data indicate that the new therapy (VEGF Trap Eye) has a favorable 
benefit-risk ratio. In particular, subjects enrolled into this study are not seen as being exposed 
to an undue risk.
4.
Study objectives
Primary objective
To compare the efficacy of 2 mg aflibercept administered by two different intravitreal (IVT) 
treatment regimens to subjects with nAMD. 
Secondary objective
To assess the safety and tolerability of aflibercept in this patient population


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5.
Study design - amended
Design overview
This is a randomized, 2-arm, active-controlled, parallel-group, open-label, multicenter, 
Phase-3b study to assess the non-inferiority of an extended-dosing regimen to a 2Q8 fixed
dosing regimen in subjects with nAMD who have completed at least 1 year of treatment with 
aflibercept (from first treatment to randomization into this study) in accordance with the 
constraints as provided in this protocol. 
This study comprises a screening period of up to 66 days (Figure 5–1).13
There will be two parallel treatment arms. In both arms, aflibercept will be injected IVT at a 
dose of 2 mg per injection. The treatment arms differ in dosing intervals:
Extended dosing:
Flexible dosing intervals
≥8 weeks (no upper limit) based on visual and anatomic outcomes as 
judged by the investigator.
When/if visual and 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 were 
observed). 
2Q8:
Fixed dosing intervals
8 weeks - modification of the treatment interval is not allowed.14
                                                
13 Clarification of the period durations per Amendment 2 (Section 15.1.1.2)
14 Time windows were consolidated for all post-baseline visits in both treatment groups to ± 3 days relative to 
baseline per Amendment 2 (Section 15.1.1.3)


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Figure 5–1:
Study flow diagram - amended
Screening
up to 66 
days
15
Treatment
Extended dosing flexible dosing interval (≥8 weeks)
Duration ≤76 weeks
2Q8  fixed dosing interval (8 weeks)
Duration 72 weeks
Day 1
Week 52
Week 72
Week 76
Randomization 
(1:1)
Primary 
completion
End of 
treatment 
for 2Q8
End of 
study
Following screening, eligible subjects will be randomized (1:1) to one of the two parallel 
treatment group. Two post-baseline visits will follow the same strict schedule in both 
treatment groups:  primary completion at Week 52 and the final visit at Week 76. The 
schedule of all other post-baseline visits may differ between the treatment groups as detailed 
in Section 9.15
Subjects in both treatment groups will receive the first study treatment on Day 1. The 
treatment period is 72 weeks (in the 2Q8 group) with a final study visit at Week 76.15
The last possible study drug injection in the extended-dosing group can be given at Week 76 
(i.e. the end of the study) after completion of all protocol-specified assessments.16 After 
Week 76, subjects should be returned to standard of care.
For each treatment group, the time window for all post-baseline visits is ± 3 days relative to 
baseline.17
The primary efficacy variable will be the change in ETDRS BCVA letter score for the study 
eye (starting at 4 meters) from baseline to Week 52. A complete list of all efficacy variables is 
provided in Section 10.3.1.1. Both the primary and secondary efficacy variables will be 
assessed at Week 52/last observation carried forward (LOCF). The primary analysis will be 
based on the Full Analysis Set.  
                                                
15 Clarification of the period durations per Amendment 2 (Section 15.1.1.2)
16 If an extended-dosing subject receives an injection at Week 76, it is the responsibility of the treating 
investigator to follow-up on any adverse events (including ongoing events) that may occur within 4 weeks 
following this treatment. Information regarding such events is to be reported under this protocol (i.e. not as 
spontaneous reports).
17 Time windows were consolidated for all post-baseline visits in both treatment groups to ± 3 days relative to 
baseline per Amendment 2 (Section 15.1.1.3).


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Assessments of ocular safety will include intraocular pressure (IOP), indirect 
ophthalmoscopy, and slit lamp biomicroscopy. Under this protocol, mandatory fluorescein 
angiography (FA)/fundus photography (FP) examinations will be conducted during screening 
as well as at Week 52 and 76 only. However, the treating investigator may perform FA/FP at 
other times during the study based on his/her medical judgment and standard of care.  
Overall safety of the subjects will be assessed throughout the study by recording vital signs 
as well as by monitoring ophthalmic and systemic adverse events (AEs). Laboratory tests 
(hematology panel, chemistry panel, and urinalysis) will be performed at baseline and 
Week 76.  
Justification of the design
Open-label setting:  Since the two treatment groups will be on different visit schedules 
(i.e. a fixed schedule in the 2Q8 group and a variable schedule in the extended-dosing group), 
masking the study would be extremely difficult. Masking the study would require 
harmonizing the schedules in the two groups by having subjects in the extended-dosing group 
attend non-treatment study visits. Doing this, however, would disrupt the intent of an
extended-dosing regimen and, thus, was not considered to be a viable option.
End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last subject for all centers in the respective 
country has occurred.
The end of the study as a whole will be reached as soon as the end of the study according to 
the above definition has been reached in all participating countries (EU and non-EU).


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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.
Two sets of inclusion/exclusion criteria, as described below, will be used to select subjects for 
participation in this study. All inclusion/exclusion criteria will be assessed during the 
screening phase and the subject must sign the informed consent form before any of the 
inclusion/exclusion criteria are assessed. In order to be randomized into this study, a subject 
must meet ALL of the eligibility criteria in both sets of criteria.
Two sets of inclusion and exclusion criteria will be used to select subjects for participation in
this study:  
The first set of inclusion/exclusion criteria will be based on the subject’s medical history 
prior to initiation of treatment with marketed aflibercept and will be assessed by a review 
of the subject’s medical records. This will ensure that the subject’s pre-aflibercept status 
matches, as close as possible, the baseline criteria of the pivotal VIEW program. 
The second set of inclusion/exclusion criteria considers both the subject’s medical 
history (assessed by a review of the subject’s medical records) and the actual status of the 
subject at the time of signing the informed consent form (i.e. at enrollment into the study 
via conduct of study-specific screening procedures).
All inclusion/exclusion criteria will be assessed during the screening phase, and the subject 
must sign the informed consent form before any of the inclusion/exclusion criteria are 
assessed. Fluorescein angiography and fundus photography eligibility criteria will be checked 
against (i) images taken at the time of nAMD diagnosis and initiation of treatment with 
aflibercept and (ii) images obtained during the study screening period. In order to be 
randomized into this study, a subject must meet ALL of the eligibility criteria in both sets of 
criteria.
Only one eye will be designated as the study eye. For subjects who meet eligibility criteria in 
both eyes during the screening phase, the eye with the worse visual acuity (VA) will be 
selected as the study eye.
18  If both eyes have equal VA, 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. 
                                                
18 Clarification of the procedure of selecting the study eye per Amendment 2 (Section 15.1.1.4)


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6.1
Inclusion criteria
6.1.1
First set of inclusion criteria - amended
All of the following criteria must have been met at the initial start of aflibercept treatment 
(i.e. start of aflibercept treatment prior to this study) for a subject to be eligible for this study.
1. Subject had primary subfoveal choroidal neovascularization (CNV) lesions secondary to 
nAMD, including juxtafoveal lesions that affect the fovea, as evidenced by FA of the 
study eye within 4 weeks before the initiation of aflibercept treatment.19,20,21
2. The area of CNV occupied at least 50% of the total lesion within 4 weeks before the 
initiation of aflibercept treatment.21
3. Documented BCVA was 20/40 to 20/320 (comparable to a letter score of 73 to 25) in the 
study eye at the initiation of treatment (the initial BCVA of the study eye before treatment 
initiation must be documented as Snellen equivalent in the electronic case report form 
[eCRF]).22, 23
6.1.2
Second set of inclusion criteria - amended
All of the following criteria must be met at the time of screening for participation in this study 
for a subject to be eligible for this study.
4. Signed written informed consent22
5. Men or women 51 years of age
6. The subject’s history of aflibercept treatment meets ALL of the following:
a) Treatment in the study eye was initiated with three monthly (-1 week/+2 weeks) 
doses of 2 mg aflibercept and improvements of visual and anatomic outcomes were 
observed
b) Following the above initiation phase, the intervals between treatments were 
between 6 weeks and 12 weeks (one exception will be allowed)
c) The interval between the last two pre-study injections was ≥8 weeks, and visual and 
anatomic outcomes have been stable over this interval.
d) The subject received the last IVT injection of aflibercept in the study eye 2 months 
(10 days) before the first treatment in this study22
                                                
19 The reading center acquisition protocol will further specify the standards for FA during the study (replaced 
reference of study manual with reference to reading center acquisition protocol per Amendment 2 
[Section 15.1.1.7])
20 Clarifications of inclusion criteria per Amendment 2 (Section 15.1.1.5)
21 Extension of the time period per Amendment 2 (Section 15.1.1.6)
22 Clarifications of inclusion criteria per Amendment 2 (Section 15.1.1.5)
23 Removal of reference to study manual per Amendment 2 (Section 15.1.1.7)


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e) Total prior treatment duration with aflibercept (i.e. from first treatment to 
randomization into this study) was ≥12 months 
7. Subject is willing, committed, and able to return for ALL clinic visits and complete all 
study-related procedures.
8. Women and men of reproductive potential must agree to a method of highly effective  
contraception (as defined by the Clinical Trial Facilitation Group [CTFG] from 
15 SEP 2014):24  

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o oral
o intravaginal 
o transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o oral
o injectable
o implantable 

Intrauterine device 

Intrauterine hormone-releasing system 

Bilateral tubal occlusion 

Vasectomized partner 

Sexual abstinence
Alternatively women and men of reproductive potential can also use two acceptable 
methods of contraception (as defined by the CTFG from 15 SEP 2014) simultaneously:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action

Male or female condom with or without spermicide 

Cap, diaphragm or sponge with spermicide 
Contraception has to be used from signing the informed consent form until 3 months after 
the last administration of study drug. Postmenopausal women must be amenorrheic for at 
least 12 months in order not to be considered of child bearing potential. 
                                                
24 Use of contraception specified according to the recommendations of the CTFG per Amendment 2
(Section 15.1.1.8).


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6.2
Exclusion criteria
6.2.1
First set of exclusion criteria
A subject who has met any of the following criteria at the initial start of aflibercept treatment 
(i.e. start of aflibercept treatment before this study) will be excluded from this study.
1.
Any prior or concomitant therapy with an investigational or approved agent to treat 
neovascular AMD in the study eye.
2.
Total lesion size >12 disc areas (30.5 mm2, including blood, scars and 
neovascularization) as assessed by FA in the study eye
3.
Subretinal hemorrhage that was: 
a)
50% or more of the total lesion area, or 
b)
if the blood was under the fovea, and
c)
the blood under the fovea was 1 or more disc areas in size in the study eye. 
4.
Scar or fibrosis making up more than 50% of the total lesion in the study eye.
5.
Scar, fibrosis, or atrophy involving the center of the fovea in the study eye.
6.
Presence of retinal pigment epithelial tears or rips involving the macula in the study eye.
7.
Causes of CNV other than AMD in the study eye.
6.2.2
Second set of exclusion criteria - amended
A subject who meets any of the following criteria at the time of screening for participation in 
this study will be excluded from this study.
8.
Subjects who currently meet any of the first set of exclusion criteria with the exception of 
prior treatment with aflibercept
9.
Any prior ocular (in the study eye) or systemic treatment or surgery for neovascular 
AMD, except dietary supplements, vitamins and IVT injections of aflibercept, during the 
time (i.e. at least 12 months) between initiation of aflibercept treatment and 
randomization into this study
10. Any prior treatment with anti-VEGF therapy in the study eye, with the exception of IVT 
injections of aflibercept, during the time (i.e. at least 12 months) between initiation of 
aflibercept treatment and randomization into this study
11. Prior systemic anti-VEGF therapy, investigational or approved, within the last 15 months 
prior to randomization
12. Any vitreous hemorrhage within 4 weeks before randomization in the study eye25
13. Active intraocular, extraocular and periocular inflammation or infection in either eye
                                                
25 Clarifications added per Amendment 2 (Section 15.1.1.9)


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14. Any ocular or periocular infection within 4 weeks of randomization in either eye25
15. Any serious adverse event related to aflibercept during prior treatment (see 
Sections 9.6.1.1 and 9.6.1.2)
16. Any history of allergy or hypersensitivity to povidone iodine25
17. Known serious allergy or hypersensitivity to the fluorescein sodium for injection in 
angiography25
18. Presence of any contraindications indicated in the EU commission/locally approved label 
for aflibercept: Hypersensitivity to the active substance aflibercept or to any of the 
excipients; active or suspected ocular or periocular infection; active severe intraocular 
inflammation
19. Prior vitrectomy in the study eye
20. History of vitreomacular traction in the study eye 25
21. History of retinal detachment or treatment or surgery for retinal detachment in the study 
eye
22. Any history of macular hole of stage 2 and above in the study eye
23. Prior trabeculectomy or other filtration surgery in the study eye
24. Uncontrolled glaucoma (defined as intraocular pressure more than 25 mmHg despite 
treatment with antiglaucoma medication) in the study eye
25. Aphakia or pseudophakia with absence of posterior capsule (unless it occurred as a result 
of an yttrium aluminum garnet [YAG] posterior capsulotomy) in the study eye
26. Previous therapeutic radiation in the region of the study eye
27. History of corneal transplant or corneal dystrophy in the study eye
28. Significant media opacities, including cataract, in the study eye that interferes with visual 
acuity or fundus photography
29. History or clinical evidence of DME or any retinal vascular disease other than AMD in 
either eye
30. Any history of uveitis in either eye
31. Presence of scleromalacia in either eye
32. Pregnancy or breast-feeding (women only)
33. The use of long acting steroids, either systemically or intraocular, in the 18 months before 
initiating study treatment (or Iluvien IVT implant at any time)26
34. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
                                                
26 Clarifications added per Amendment 2 (Section 15.1.1.9)


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contraindicates the use of an investigational drug, might affect interpretation of the results 
of the study, or renders the subject at high risk for treatment complications
35. Previous assignment to treatment during this study
36. Concomitant participation in another clinical study with investigational medicinal 
product(s)
37. 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).
6.3
Withdrawal of subjects from 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 two 
consecutive pre-planned study visits without a major reason agreed upon by the sponsor. 
All attempts to contact the subject must be documented in the subject’s source documents.  
Relevant laboratory abnormality or 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 AMD 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.


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Decision by the investigator or sponsor 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).
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified below:
Screening failure
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 a 
“screening failure”. 
Re-screening of screening failures may be acceptable under the following conditions
27:

The subject had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.

The inclusion / exclusion criteria preventing the subject’s initial attempt to participate 
have been changed (see inclusion criterion 1 and 2 changed via this protocol 
amendment).

The reason for the screening failure was subsequently resolved (e.g. elevated IOP 
decreases, inflammation or infection resolves) 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 has to sign a new informed consent form. To be 
eligible, re-screened subjects must meet all eligibility criteria during the re-screening period.
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been randomized.
                                                
27 Added list of criteria for re-screening per Amendment 2 (Section 15.1.1.10)


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General procedures
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's 
medical records. 
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
6.3.2
Replacement
Subjects who withdraw from the study will not be replaced. 
6.4
Subject identification - amended
The subject number is a 9 digit number consisting of:
Digits 1 to 5 = Unique center number
Digits 6 to 9
= Current subject number within the center
Patient identification numbers (PIDs) will be assigned via interactive voice/web response 
system (IxRS). Once allocated, the subject’s PID number will identify the subject throughout 
the study, and will be entered into the Site Enrollment Log and on the eCRF.
Upon re-screening, a new PID will be assigned.
28
                                                
28 Description of subject identification number changed per Amendment 2 (Section 15.1.1.11)


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7.
Treatments
7.1
Treatments to be administered - amended
There will be two parallel treatment arms, each administering 2 mg aflibercept per injection 
IVT in the study eye. Aflibercept will be administered either on a fixed 2Q8 schedule (i.e. 
2 mg aflibercept every 8 weeks29) or according to an extended-dosing protocol in which the 
dosing interval may be extended beyond 8 weeks based on visual and anatomical outcomes 
and knowledge of the individual subject as judged by the treating investigator (Table 7–1).
Table 7–1:
Treatment groups - amended
Extended-dosing group
2Q8 group
Dose per injection
Aflibercept 2 mg
Aflibercept 2 mg
Administration 
schedulea
Flexible injection intervals:
≥8 weeks
When/if exudation recurs, the treatment 
interval will revert to the last treatment 
interval in which the disease was inactive.
Interval decisions based investigator’s 
judgment. Intervals cannot be less than 
8 weeks (no upper limit).
Fixed injection intervals:
8 weeks throughout the entire treatment 
period29
Duration of treatment up to 76 weeks
72 weeks
Planned number of 
randomized subjects
165
165
a For each treatment group, the time window for all post-baseline visits is ± 3 days relative to baseline29
                                                
29 Time windows were consolidated for all post-baseline visits in both treatment groups to ± 3 days relative to 
baseline per Amendment 2 (Section 15.1.1.3)


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7.2
Identity of study treatment - amended
The identity of the study drug is summarized in Table 7–2.30
Table 7–2:
Identity of study drug
Name
Dose
Concentration
Formulation
Composition
BAY 86-5321
aflibercept
Eylea 
2 mg
40 mg/mL
Solution for 
intravitreal 
injection
40 mg aflibercept/mL
5% sucrose
10mM sodium phosphate
0.03% polysorbate 20
40 mM sodium chloride (NaCl)
Water for injection
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.
For all study drugs, a system of numbering in accordance with all requirements of 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.
7.3
Treatment assignment
Subjects enrolled in the study will be randomized to receive treatment under one of two 
dosing regimens. The two treatment groups will be randomly assigned by the central 
randomization group in a 1:1 ratio to either of the two parallel treatment arms identified in 
Section 7.1. Treatment assignment will be controlled via the IVRS/IWRS.
                                                
30 Table added specifying the identity of study drug per Amendment 2 (Section 15.1.1.12)


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7.4
Dosage and administration - amended
The study drug will be supplied in kits that include the following:

Sterile study drug in sealed glass vials (2 mL) with a withdrawable volume of 0.1 mL
(see Table 7–2 for details on the composition of the study drug)

Filter needle (18 gauge)
Other ancillary components required for the administration of aflibercept (e.g. 30-gauge 
injection needle; 1-ml syringe) will be supplied by the study site.
When aflibercept 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.
After opening the vial, all preparation steps have to take place under aseptic conditions.
The study drug will be withdrawn using aseptic technique through the filter needle attached to 
the 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 by the sterile 
30-gauge needle for the IVT injection. Each patient receives an IVT injection of 50 µl of 
aflibercept. 31
Consideration of special warnings from EU label 
The investigator should consider the special warnings as described in the EU label for 
aflibercept. However, ultimately the investigator should include in his/her treatment decision 
all subject related information and data available and based on this decide what would be best 
for the subject.
The approved EU label for aflibercept includes the following special warnings:
Treatment should be withheld in patients with rhegmatogenous retinal detachment or 
stage 3 or 4 macular holes. In the event of a retinal break, the dose should be withheld 
and treatment should not be resumed until the break is adequately repaired. 
The dose should be withheld and treatment should not be resumed earlier than the next 
scheduled treatment in the event of:

a decrease in BCVA of ≥30 letters compared with the last assessment of visual 
acuity; 

a subretinal haemorrhage involving the centre of the fovea, or, if the size of the 
haemorrhage is ≥50%, of the total lesion area 
The dose should be withheld within the previous or next 28 days in the event of a 
performed or planned intraocular surgery.32
                                                
31 Removed sample study drug injection protocol from the appendix per Amendment 2 (Section 15.1.1.20).
32 Dosage and administration updated and special warnings from EU SmPC added to dosage and administration 
per Amendment 2 (Section 15.1.1.13)


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Posology
Treatment posology is detailed in Table 7–3.33
Table 7–3:
Treatment posology
2Q8 group
Extended-dosing group
Visit
Treatment
Visit
Treatment
Baseline
mandatory Visit 2 
mandatory 
mandatory Visit 2 
mandatory 
Week 8
mandatory visit with treatment
between Week 8 and Week 52, 
visits (including treatment) can be scheduled at any timepoint 
(provided injection intervals are ≥8 weeks)
Week 16
mandatory visit with treatment
Week 24
mandatory visit with treatment
Week 32
mandatory visit with treatment
Week 40
mandatory visit with treatment
Week 48
mandatory visit with treatment
Week 52
mandatory 
no treatment
mandatory 
optional
Week 56
mandatory visit with treatment
between Week 52 and Week 76, 
visits (including treatment) can be scheduled at any timepoint 
(provided injection intervals are ≥8 weeks)
Week 64
mandatory visit with treatment
Week 72
mandatory visit with treatment
Week 76
mandatory 
no treatment
mandatory 
optional
7.5
Blinding / masking
Not applicable - this is an open-label study.  
7.6
Drug logistics and accountability - amended
Packaging
Aflibercept will be supplied by the Sponsor in a 2-mL glass vial. The extractable volume is 
0.1 mL. Each kit will also contain an 18-gauge filter needle. Other ancillary components 
required for the administration of aflibercept (e.g. 30-g x ½ inch injection needle and 
1-mL Luer Lock syringe) will be supplied by the study site.
                                                
33 Added table describing treatment posology per Amendment 2 (Section 15.1.1.14)


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Storage
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate/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’s study file; the site-relevant elements of this information will be available in the 
investigator site file.  
Aflibercept must be stored at the clinical sites in a refrigerator at 2°C to 8°C, protected from 
light, and not frozen. Prior to usage, the unopened vial of aflibercept may be stored at room 
temperature (25 °C / 77°F) for up to 24 hours. After opening the vial or blister pack, proceed 
under aseptic conditions.34
Accountability
On the day of receipt, the responsible site personnel will confirm receipt of study drug via 
IVRS/IWRS. 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.
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned drug will be provided.
7.7
Treatment compliance
As all study drugs will be administered in a medical facility by authorized site personnel, 
compliance with the dosing protocol will be monitored by review of clinic records.
                                                
34 Paragraph added per Amendment 2 (Section 15.1.1.15).


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8.
Non-study therapy
Any relevant previous and concomitant treatments will be recorded in the source 
documentation and then entered into the “Previous and Concomitant Medications” eCRF 
screen using the brand name.   
All recorded previous and concomitant medications will be coded using an internationally 
recognized and accepted coding dictionary.  
8.1
Prior and concomitant therapy
8.1.1
Prior therapy
In particular, any potential previous treatments for AMD will be recorded, including treatment 
with anti VEGF medication, steroids or laser.
Prior treatments that exclude subjects from participation in this study are given in Section 6.2.
8.1.2
Concomitant therapy
Any medication 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 below.
8.1.2.1
Study-eye treatment - amended
Subjects may not receive any standard or investigational agents for treatment of their AMD in 
the study eye other than aflibercept as specified in this protocol until they have completed the 
final or early termination visit assessments.35  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.
8.1.2.2
Fellow-eye treatment - amended
Treatment of the fellow (non-study) eye is not regarded as a study treatment. If the fellow eye 
has AMD, the fellow eye may receive any locally approved non-systemic treatment. If the 
fellow eye shall be treated pharmacologically, the most appropriate treatment option that is 
approved by the governing health authorities may be selected at the investigator’s discretion 
in the subject’s best interest.
                                                
35 Clarified that the final visit procedures should also be conducted in the case of early termination per 
Amendment 2 (Section 15.1.1.16)


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If no drug therapy has been approved for the indication or if the approved therapy is not 
appropriate due to medical reasons, a non-approved pharmacological approach may be 
selected, if it can be considered as local standard of care.36
If it is determined that aflibercept is the most appropriate treatment option for the fellow eye, 
this will still not be regarded as a study treatment and 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.  
8.2
Post-study therapy
After the end of this study, subjects will not be restricted with regard to pursuing available 
treatments for AMD.
9.
Procedures and variables - amended
The study comprises a screening phase (Visit 1; up to 66 days prior to Day 1), Baseline 
(Visit 2, Day 1), a 72-week treatment phase (for the 2Q8 group), and a final study visit at 
Week 76 or an early termination visit.37 All scheduled post-baseline study visits may deviate 
by ± 3 days relative to baseline.38  
                                                
36 Added possibility to treat the fellow eye with any local standard of care per Amendment 2
(Section 15.1.1.34)
37 Clarified that the final visit procedures should also be conducted in the case of early termination per 
Amendment 2 (Section 15.1.1.16)
38 Time windows were consolidated for all post-baseline visits in both treatment groups to ± 3 days relative to 
baseline per Amendment 2 (Section 15.1.1.3) and clarification of the period durations per Amendment 2 
(Section 15.1.1.2)


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9.1
Tabular schedule of evaluations - amended
Table 9–1:
Schedule of assessments and study procedures - amended
Visit number a
Screening
Visit 1
Baseline (BL)
Visit 2
Visits 3 - 8
Prim. compl.
Visit 9
Visits10 -12
Final visit
Visit 1339
or early term.
Time 
pointa 2Q8 group
up to 66 days 
prior
to BL40
(both groups)
Day 1
(both groups)
Weeks 8 – 48
Week 52
(both groups)
Week56, 64, 72
Week 76
(both groups)
Extended-dosing group
Flex. intervals
(≥8 weeks) 
Flex. intervals
(≥8 weeks)
Initiation procedures
Informed consent 

Demographic data

Medical / ophthalmic history 

Physical examination

PT / INR and PTT

Inclusion / exclusion criteria


Study medication
Randomization

Administration of 
study treatment 41


extended-
dosing only b

extended-
dosing
only b,c
Ophthalmologic assessments
BCVA (ETDRS chart starting at 4 m) d






Optical coherence tomography






FA, FP



Indirect ophthalmoscopy e






Slit lamp biomicroscopy






Intraocular pressure (IOP) f






a: All post-baseline visits may deviate by ± 3 days relative to baseline. In the 2Q8 group, scheduled visits should not be altered 
due to the deviation of the previous visit.
42
Visit numbers refer to the mandatory visits for treatment administration to subjects in the 2Q8 group. Fewer visits may be 
required for subjects in the extended-dosing group, for whom extended-dosing intervals are indicated.
b: Extended-dosing subjects may receive injections at Week 52 or 76 depending on their individual schedule.
c: If an extended-dosing subject receives an injection at Week 76, follow-up is needed on any adverse events (including 
ongoing events) that may occur within 4 weeks following this treatment (AE reporting under this protocol; i.e. not as 
spontaneous reports)
d: Refraction to be done at each visit
e: Also post-injection at visits with study drug administration
43
f:
Also 30-60 minutes post-injection at visits with study drug administration
43
(Table continued on next page)
                                                
39 Clarified that the final visit procedures should also be conducted in the case of early termination per 
Amendment 2 (Section 15.1.1.16)
40 Clarification of the period duration per Amendment 2 (Section 15.1.1.2)
41 Removed sample study drug injection protocol from the appendix per Amendment 2 (Section 15.1.1.20)
42 Time windows were consolidated for all post-baseline visits in both treatment groups to ± 3 days relative to 
baseline and clarification of the schedule of visits in the 2Q8 group per Amendment 2 (Section 15.1.1.3)
43 Minor clarifications per Amendment 2 (Section 15.1.1.19)


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Table 9–1 (continued) Schedule of assessments and study procedures - amended
Visit number a
Screening
Visit 1
Baseline (BL)
Visit 2
Visits 3 - 8
Prim. compl.
Visit 9
Visits10 -12
Final visit
Visit 1344
or early term.
Time 
pointa 2Q8 group
up to 66 days 
prior
to BL45
(both groups)
Day 1
(both groups)
Weeks 8 – 48
Week 52
(both groups)
Week56, 64, 72
Week 76
(both groups)
Extended-dosing group
Flex. intervals
(≥8 weeks) 
Flex. intervals
(≥8 weeks)
Standard safety
Prior / concomitant medications






Adverse events g





Vital signs (temp., blood pressure, HR)






Hematology / chemistry 


Urinalysis / UPCR


Serum pregnancy test (women of 
childbearing potential only) 46

Urine dipstick pregnancy test 
(women of childbearing potential only) 47 h


Other
NEI VFQ-25 i



BCVA = Best corrected visual acuity;  early term. = early termination; ETDRS = Early Treatment Diabetic Retinopathy Study;  
FA = fluorescein angiography FP = fundus photography; HR = heart rate;  NEI VFQ-25 = National Eye Institute 25-item Visual 
Function Questionnaire;  PT/INR = Prothrombin time / International normalized ratio;  PTT = Partial thromboplastin time;  
UPCR = Urine protein/creatinine ratio
a: All post-baseline visits may deviate by ± 3 days relative to baseline. In the 2Q8 group, scheduled visits should not be altered 
due to the deviation of the previous visit.
48
Visit numbers refer to the mandatory visits for treatment administration to subjects in the 2Q8 group. Fewer visits may be 
required for subjects in the extended-dosing group, for whom extended-dosing intervals are indicated.
g: Any AE occurring up to 4 weeks after the last 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 4 weeks after the last application of aflibercept, the standard procedures that 
are in place for spontaneous reporting will be followed.
h: The urine dipstick pregnancy test is to be repeated as frequently as required following the investigator’s medical judgment 
and local regulations.47
i:
The NEI VFQ-25 is to be administered in a quiet room by a person certified to administer the questionnaire49
                                                
44 Clarified that the final visit procedures should also be conducted in the case of early termination per 
Amendment 2 (Section 15.1.1.16)
45 Clarification of the period duration per Amendment 2 (Section 15.1.1.2)
46 Moved the serum pregnancy test from Initiation procedures to Standard safety per Amendment 2 
(Section 15.1.1.18)
47 Addition of urine dipstick test at the baseline visit per Amendment 2 (Section 15.1.1.17); added foot note h
and added that the urine dipstick test is required at Visit 13 (final visit or early termination) per 
Amendment 2 (Section 15.1.1.18)
48 Time windows were consolidated for all post-baseline visits in both treatment groups to ± 3 days relative to 
baseline and clarification of the schedule of visits in the 2Q8 group per Amendment 2 (Section 15.1.1.3)
49 Footnotes re-arranged and separated table to 2 pages per Amendment 2 (Section 15.1.1.19)


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9.2
Visit description
9.2.1
Screening visit (Visit 1) - amended
Scheduling:  Both treatment groups:  Up to 66 days prior to Day 150
The following procedures will be performed at this visit:

Obtaining signed informed consent form (see Section 13.4 for details).  

Assessment of inclusion and exclusion criteria (see Sections 6.1 and 6.2 for details)

Record of demographic data (see Section 9.3.1 for details)

Record of medical and ophthalmic history (see Section 9.3.2 for details)

Laboratory assessments (see Section 9.6.3.1 for details):

Hematology panel

Chemistry panel, including serum pregnancy test for women of childbearing potential

Prothrombin time/partial thromboplastin time (PT/PTT) and INR

Urinalysis (including urine protein creatinine ratio [UPCR]) – Note: urine sample must 
be obtained before performing FA in order to avoid false elevations in urine protein 
values

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA)51

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)

Record of prior and concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Physical examination (see Section 9.6.3.2 for details)

Vital signs (body temperature, blood pressure and heart rate) 
(see Section 9.6.3.3 for details)
                                                
50 Clarification of the period duration per Amendment 2 (Section 15.1.1.2)
51 The reading center acquisition protocol will further specify the standards for FA/FP during the study 
(replaced reference of study manual with reference to reading center acquisition protocol per Amendment 2
[Section 15.1.1.7]).


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9.2.2
Baseline visit (Visit 2) - amended
Scheduling:  Both treatment groups:  Day 1
The following procedures will be performed at this visit:

Re-check of inclusion and exclusion criteria (see Sections 6.1 and 6.2 for details)52

Including urine dip stick pregnancy test for women of childbearing potential53

Randomization (see Section 7.3 for details)

Record of concomitant medications (see Section 8.1 for details)

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)

Record of NEI VFQ-25 (see Section 9.7 for details)

Record of adverse events (see Section 9.6.1 for details)

Vital signs (body temperature, blood pressure and heart rate) (see Section 9.6.3.3 for 
details)

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):54

Indirect ophthalmoscopy

Intraocular pressure (IOP)
                                                
52 Clarified the re-assessment of inclusion and exclusion criteria per Amendment 2 (Section 15.1.1.21)
53 Addition of urine dipstick test at the baseline visit per Amendment 2 (Section 15.1.1.17)
54 Post-injection ocular assessments added per Amendment 2 (Section 15.1.1.22)


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9.2.3
Visits between baseline and Week 52 - amended
The scheduling of these visits may vary between both treatment groups:
Scheduling:
2Q8 group:
Fixed visit schedule every 8 weeks
Visits 3 to 8
Extended-dosing group:
Individualized flexible schedule with intervals ≥8 weeks
Visits 3 to ≤8
(extended-dosing subjects may have 
fewer visits than 2Q8 subjects)
The following procedures will be performed at any of these visits:

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)

Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Vital signs (body temperature, blood pressure and heart rate) (see Section 9.6.3.3 for 
details)

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):55

Indirect ophthalmoscopy

Intraocular pressure (IOP)
                                                
55 Post-injection ocular assessments added per Amendment 2 (Section 15.1.1.22)


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9.2.4
Primary completion (Week 52) - amended
Scheduling:  Both treatment groups:  Week 52
2Q8 group:
Visit 9
Extended dosing group: Visit ≤9  
Visit number depends on individual schedule
(extended-dosing subjects may have fewer visits than 
2Q8 subjects)
The following procedures will be performed at this visit:

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA)56

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)

Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Vital signs (body temperature, blood pressure and heart rate) (see Section 9.6.3.3 for 
details)

Record of NEI VFQ-25 (see Section 9.7 for details)
Subjects in the extended dosing group if they receive injections at this visit (depending on 
their individual schedule):

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):57

Indirect ophthalmoscopy

Intraocular pressure (IOP)
                                                
56 The reading center acquisition protocol will further specify the standards for FA/FP during the study 
(replaced reference of study manual with reference to reading center acquisition protocol per Amendment 2 
[Section 15.1.1.7]).
57 Post-injection ocular assessments for subjects in the extended dosing group who receive study medication at 
this visit added per Amendment 2 (Section 15.1.1.22)


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9.2.5
Visits between primary completion (Week 52) and final visit (Week 76)
- amended
Scheduling58:
2Q8 group:
Fixed visit schedule every 8 weeks
Visits 10 (Week 56) to 12 (Week 72)
Extended-dosing group:
Individualized flexible schedule with intervals ≥8 weeks
Visit numbers depend on individual schedule
(extended-dosing subjects may have fewer visits than 
2Q8 subjects)
The following procedures will be performed at any of these visits:59

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)

Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Vital signs (body temperature, blood pressure and heart rate) (see Section 9.6.3.3 for 
details)

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):60

Indirect ophthalmoscopy

Intraocular pressure (IOP)
                                                
58 Changed end of study visit to final visit per Amendment 2 (Section 15.1.1.16)
59 Added the full list of study procedures instead of a reference only per Amendment 2 (Section 15.1.1.23)
60 Post-injection ocular assessments added per Amendment 2 (Section 15.1.1.22)


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9.2.6
Final visit (Week 76) or early termination- amended
Scheduling:  Both treatment groups:  Week 76
This visit will also be conducted in case of early termination of a subject.61
The following procedures will be performed at this visit:62

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA)63

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)

Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Vital signs (body temperature, blood pressure and heart rate) (see Section 9.6.3.3 for 
details)

Urine dip stick pregnancy test for women of childbearing potential64

Record of NEI VFQ-25 (see Section 9.7 for details)
Subjects in the extended dosing group if they receive injections at this visit (depending on 
their individual schedule):

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):65

Indirect ophthalmoscopy

Intraocular pressure (IOP)
                                                
61 Clarified that the final visit procedures should also be conducted in the case of early termination per 
Amendment 2 (Section 15.1.1.16)
62 Added the full list of study procedures instead of a reference only per Amendment 2 (Section 15.1.1.23)
63 The reading center acquisition protocol will further specify the standards for FA/FP during the study 
(replaced reference of study manual with reference to reading center acquisition protocol per Amendment 2
[Section 15.1.1.7]).
64 Added that urine dipstick pregnancy test is required at this visit per Amendment 2 (Section 15.1.1.18)
65 Post-injection ocular assessments for subjects in the extended dosing group who receive study medication at
this visit added per Amendment 2 (Section 15.1.1.22)


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9.3
Population characteristics
9.3.1
Demographic
The following demographic parameters will be recorded:

Sex

Year of birth

Race / ethnicity

Weight

Height
9.3.2
Medical/surgical and ophthalmic 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 before signing of the informed consent 

Detailed instructions on the differentiation between (i) medical history and (ii) adverse 
events can be found in Section 9.6.1.1.
In addition, a complete ophthalmic history will be obtained to check the first set of in- and 
exclusion criteria as defined in Sections 6.1.1 and 6.2.1 respectively. To this end, the subjects
must provide informed consent to allow review of medical records from the time of first 
aflibercept treatment. The medical records must be sufficient to allow confirmation of 
eligibility.


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9.4
Efficacy 
9.4.1
Ophthalmic examinations
Note:
In this section, all ophthalmic examinations are described, irrespective of whether 
they are used for efficacy or safety assessments.
All ophthalmic evaluations will be conducted according to the schedule detailed in 
Section 9.1 (Table 9–1).
9.4.1.1
Best corrected visual acuity - amended
Visual function of the study eye and the fellow eye will be assessed using the ETDRS 
protocol (The Early Treatment Diabetic Retinopathy Study Group, 1985) at starting at 
4 meters. Visual Acuity (VA) examiners must be certified to ensure consistent measurement 
of BCVA.66  
9.4.1.2
Optical coherence tomography (OCT) – amended
Retinal and lesion characteristics will be evaluated using OCT. OCT-images of the study eye 
and fellow eye will be captured, transmitted to, and read by the independent reading center. 
All OCTs will be electronically archived at the study sites as part of the source 
documentation. OCT technicians and equipment must be certified by the reading center to 
ensure consistency and quality in image acquisition.67
9.4.1.3
Indirect ophthalmoscopy
Indirect ophthalmoscopy will be performed for both the study eye and fellow eye in a 
standard way (i.e. usually using a head-mounted light source and a 20 dpt lens).  
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.
                                                
66 Removed reference to study manual per Amendment 2 (Section 15.1.1.7)
67 Reworded description of OCT per Amendment 2 (Section 15.1.1.24)


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9.4.1.4
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 2-3 drops of 
phenylephrin-tropicamid (or any other mydriatic) applied topically to the eye.
9.4.1.5
Intra-ocular pressure (IOP)
IOP 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. 
IOP will be assessed for both the study eye and fellow eye.  
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 IVT injection will be carried 
out in the study eye only.
For the measurement of IOP, a local anesthetic combined with fluorescein must be applied 
topically to the eye being tested (e.g. 1 drop of oxybuprocain plus fluorescein).
9.4.1.6
Fundus photography (FP) and fluorescein angiography (FA) -
amended
The anatomical state of the retinal vasculature of the study eye will be evaluated by 
funduscopic examination, FP and FA.  
The study eye will be the transit eye. For all visits where the funduscopic examination, FP, 
and FA procedure are scheduled, FP and FA will be performed on both eyes.  
Fundus and angiographic images will be sent to an independent reading center where images 
will be read. All FA and FP images will be archived electronically at the site as part of the 
source documentation. Although FA is performed on both eyes, only the study eye will be 
evaluated by the independent reading center. Photographers must be certified by the reading 
center to ensure consistency and quality in image acquisition.  
FP and FA from the screening visit (Visit 1) will be captured and transmitted for both eyes to 
an independent reading center where images will be read. A formal check will be done and 
eligibility will be confirmed by the reading center before randomization.


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A detailed protocol for FP and FA image acquisition and assessment can be found in the 
reading center acquisition protocol.68
The treating investigator may perform additional FA/FP at other times during the study based 
on his/her medical judgment and standard of care.69
9.4.2
Efficacy variables
All efficacy variables derived from the ophthalmic examinations are specified in 
Section 10.3.1.1.
9.5
Pharmacokinetics / pharmacodynamics
not applicable
                                                
68 The reading center acquisition protocol will further specify the standards for FA/FP during the study 
(replaced reference of study manual with reference to reading center acquisition protocol per Amendment 2
[Section 15.1.1.7]).
69 Added requirement to archive FA and FP images electronically, clarified the confirmation of eligibility by the 
reading center, and re-ordered paragraphs per Amendment 2 (Section 15.1.1.25)


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9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions - amended
Definition of adverse event (AE)
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.
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.70
Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present at the time of signing the 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 only (e.g. allergic pollinosis).
Conditions that started or deteriorated after signing of informed consent will be
documented as adverse events. This includes intercurrent illnesses.
                                                
70 Removal of reference to ECG per Amendment 2 (Section 15.1.1.26)


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Definition of serious adverse event (SAE)
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 one of the following exceptions is met:
The admission results in a hospital stay of less than 12 hours
The admission is pre-planned 
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2)
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 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator


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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 
In this study, adverse events will be assessed as causally related/not related to (i) the study 
drug, (ii) IVT injection, and (iii) other protocol-specified procedures. The assessment 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 CRF.
The causal relationship will be recorded using the following terms:
Causal relationship to study drug
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
Causal relationship to the injection procedure
The assessment of a possible causal relationship between the AE and the injection procedure 
is based on the question whether there was a “reasonable causal relationship” to protocol-
required procedure(s).
Possible answers are “yes” or “no”
-
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.
-
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.


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Causal relationship to other protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”
-
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 - amended
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.71
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
                                                
71 Removal of “Dose reduced” from possible actions taken with study treatment per Amendment 2
(Section 15.1.1.27)


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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
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 adverse events at all stages of the examination. 
Thus, the subject should be closely observed by the investigator. In case of ongoing drug- or 
injection-related adverse events and medically relevant adverse events at the end of the study, 
the investigator should monitor the subject and document the outcome on the subject’s source 
documents.
The investigator has to record on the respective CRF pages all adverse events (irrespective of 
any causal relationship or seriousness) occurring in the period between the signing of the 
informed consent and the end of the 4-weeks period after the last aflibercept injection.
After the end of this period, there is no requirement to actively collect AEs including deaths.
For any drug-related AE occurring after the end of this period, the standard procedures that 
are in place for spontaneous reporting will be followed.
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 serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug.
The means of obtaining information on an AE (e.g. observed, volunteered, or elicited) is to be 
documented in detail on the eCRF. The following information is required to be recorded:

The specification of the adverse event

The date of onset 

The maximum intensity 

Any study drug action and other action taken by the investigator to resolve the adverse 
events 

Any specific drug or non-drug treatment of the adverse event


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
The drug relationship of the adverse event to aflibercept, the IVT injection, or other 
protocol-specified procedures 

The outcome of the adverse event (for definitions, see above).

If recovered/resolved or fatal – the date ended.
9.6.1.4
Reporting of serious adverse events
The definition of serious adverse events (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.
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.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File. For this, an AE 
page in the CRF as well as the complementary pages provided in the Investigator File must be 
completed for each SAE. Information not available at the time of the initial report must be 
documented on a follow-up SAE form. The sponsor or designee may request substantiating 
data such as relevant hospital or medical records, diagnostic test reports, and death or autopsy 
reports.
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the IECs / 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.


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9.6.1.5
Expected adverse events - amended
Information on AEs with an onset after the first application of the test drug is provided in the 
local label.72
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
9.6.2
Pregnancies - amended
The investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.
The child’s health should be followed up until three months after birth.
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.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE. 
Results from animal studies with high systemic exposure indicate that aflibercept can impair 
male and female fertility. Such effects are not expected after ocular administration with very 
low systemic exposure.73
9.6.3
Further safety
9.6.3.1
Laboratory evaluations - amended
Laboratory evaluation will be conducted according to the schedule provided in Section 9.1
(beyond that schedule, pregnancy tests are to be done in women of childbearing potential as 
frequently as outlined in Table 9–1).74
Blood will be drawn before FA by direct venipuncture.75
Safety laboratory parameters to be evaluated are summarized in Table 9–2.
                                                
72 Reference to summary of product characteristics replaced with reference to local label for information on AEs 
per Amendment 2 (15.1.1.28).
73 New paragraph on fertility and guidance regarding the follow-up after birth per Amendment 2
(Section 15.1.1.29)
74 Specification and timing of pregnancy test changed per Amendment 2 (Sections 15.1.1.17 and 15.1.1.18, 
respectively).
75 Clarification of time point of blood withdrawal with respect to FA per Amendment 2 (Section 115.1.1.30)


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The exact date and time (24-hour clock) of each blood sample obtained will be recorded on 
the appropriate eCRF page. All laboratory tests will be performed at a central laboratory.
A copy of the results will be filed in the source documentation.
Table 9–2:
Laboratory safety parameters
Chemistry
Sodium
Potassium
Chloride
Calcium
Glucose
Albumin
Total Protein, Serum
Creatinine
Blood urea nitrogen (BUN)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Total bilirubin
Amylase
Total cholesterol
HDL cholesterol
Pregnancy test for women of 
childbearing potential (see 
Table 9–1)76
Urinalysis 
Glucose 
Protein
Specific Gravity
Blood
Ketones 
Protein:Creatinine Ratio (UPCR)
Coagulation
Prothrombin time (PT)
Partial thromboplastin time (PTT)
International normalized ratio (INR)
Hematology
Hemoglobin
Hematocrit
Red blood cell count
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin 
concentration (MCHC)
Mean corpuscular hemoglobin (MCH)
Leucocyte count
Differential count
Neutrophils
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
HDL:  high-density lipoprotein
According to current International Conference on Harmonisation (ICH) guidelines, deviations 
from the reference range should be evaluated for clinical significance in each individual case.
The reference ranges and the units and methods for all variables will be provided by the 
central laboratory.
Deviations of laboratory values from the laboratory reference ranges will be flagged on the 
laboratory print-outs.
9.6.3.2
Physical examination
At Screening (Visit 1), a complete physical examination will be performed. Abnormal 
findings should be documented on the eCRF as either medical history or adverse event (see 
Section 9.6.1.1).
                                                
76 Specification and timing of pregnancy test changed per Amendment 2 (Sections 15.1.1.17 and 15.1.1.18, 
respectively).


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9.6.3.3
Vital signs (temperature, blood pressure and pulse)
Temperature, blood pressure, and pulse will be measured at all study visits (and early 
termination if applicable). Temperature and blood pressure should be taken in a consistent and 
standardized way.
9.7
Patient-reported outcome – amended
NEI VFQ-25
Vision-related quality of life will be assessed using the NEI VFQ-25 questionnaire 
(Section 16.1). This questionnaire will be presented in the local language and should be 
administered in a quiet room by a person certified to administer this type of questionnaire, 
preferably before other visit procedures are performed. For subjects unable to read the 
questionnaire owing to vision impairment, a family member, other legal representative of the 
subject, study nurse, or study physician may assist the subject in completing the 
questionnaire. In this case, the name of that person should be documented.77
9.8
Appropriateness of procedures / measurements
All variables and the methods to measure them are standard variables and methods in clinical 
studies, and 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 variables will be analyzed descriptively with appropriate statistical methods: continuous 
variables by sample statistics (i.e. mean, standard deviation, median, quartiles, minimum and 
maximum) and categorical variables by frequency tables (absolute and relative frequencies).
No stratification is planned.
Statistical analysis will be performed using SAS; the version used will be specified in the 
statistical analysis plan.
                                                
77 Documentation of name added per Amendment 2 (Section 15.1.1.31)


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10.2
Analysis sets
Populations for analysis will be defined as follows:
The Full Analysis Set (FAS) will include all randomized subjects who received any study 
drug and have a baseline BCVA assessment and at least one post-baseline BCVA assessment. 
The FAS will be analyzed as randomized.
The Per-Protocol Set (PPS) will include all FAS subjects who have at least one BCVA 
assessment at Week 36 or later and do not have a major protocol deviation. The PPS will be 
analyzed as randomized.
The Safety Analysis Set will include all subjects who receive any study drug under this 
protocol. The safety analysis set will be analyzed as randomized.
10.3
Variables and planned statistical analyses
10.3.1
Variables
10.3.1.1
Efficacy variables
The efficacy variables and the ranking of their statistical analyses at the different timepoints 
(primary, [key] secondary, exploratory) are specified in Table 10–1. A complete list of 
variables to be analyzed for this study will be provided in the statistical analysis plan (SAP).
Table 10–1:
Efficacy variables
Variable
Ranking
Week 52
Week 76
Change from baseline in ETDRS BCVA letter score for the study eye 
Primary
Exploratory
Proportion of subjects maintaining vision (i.e. loss of <15 letters) in the study eye 
Key secondary
Exploratory
Proportion of subjects who gained from baseline ≥5 letters in the study eye
Secondary
Exploratory
Mean change from baseline in CRT in the study eye
Secondary
Exploratory
Mean change from baseline in CNV area in the study eye
Secondary
Exploratory
Proportion of subjects who lost ≥30 letters 
Secondary
Exploratory
Mean change from baseline in total score for NEI VFQ-25 
Secondary
Exploratory
Proportion of subjects for whom the treatment interval was extended
Exploratory
Exploratory
Total number of intravitreal injections required in the study eye
Exploratory
Exploratory
BCVA: best corrected visual acuity;  CNV:  choroidal neovascularization;  CRT:  central retinal thickness;  ETDRS: Early 
Treatment Diabetic Retinopathy Study;  NEI VFQ-25:  National Eye Institute 25-item Visual Function Questionnaire


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10.3.1.2
Safety variables
The following safety variables will be assessed:
Adverse events
Intra-ocular pressure (IOP)
Body temperature
Blood pressure
Pulse
Laboratory evaluations
Ophthalmic safety evaluations are specified in Section 9.4.1
10.3.2
Statistical and analytical plans 
10.3.2.1
Demography and baseline characteristics
Demographic variables and baseline characteristics will be summarized by treatment group 
and all treatment groups combined for all three analysis populations, depending on the type of 
data as described in Section 10.1. Medical history will be coded by MedDRA codes and prior 
and concomitant medications by ATC codes (WHODD). The total score and sub-scores of the 
NEI VFQ-25 will be calculated according to the NEI VFQ-25 scoring algorithm, August 2000 
version.
The treatment group comparability will be checked for each of the analysis populations 
mentioned above. This comparison will be done with respect to age, baseline BCVA letter 
score, baseline NEI VFQ-25 total score, and baseline retinal thickness by a one-way analysis 
of variance main effect model with treatment group as fixed factor. Furthermore, treatment 
groups will be compared with respect to sex by a Chi-squared test.
The number of injections will be tabulated in both treatment groups. The injection data will be 
tabulated in more detail for the extended-dosing group (as specified in the SAP).


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10.3.2.2
Efficacy analyses – amended
The primary efficacy variable analysis will be conducted on the FAS as defined in 
Section 10.2.  
Statistical testing will be conducted to prove the non-inferiority of the extended-dosing 
regimen to the 2Q8 fixed dosing regimen.  
The corresponding null hypothesis is H0: μ1 ≤μ2-D versus 
the alternative hypothesis H1: μ1 > μ2-D, where 
D =
non-inferiority margin 
μi =
mean change in BCVA letter score for the study eye from baseline to Week 52 in 
treatment group i.
i =
1:  extended-dosing regimen
2:  fixed-dosing regimen
The non-inferiority margin is 5 letters.  
The methodological approach will be the calculation of two-sided 95% confidence intervals 
for the difference in the least squares (LS) means (extended-dosing group minus 2Q8 group) 
of the change in ETDRS letter score from study baseline to 52 weeks based on a one-way 
analysis of covariance (ANCOVA) with baseline measure as a covariate and treatment group 
as a fixed factor (LOCF will be used for missing values at 52 weeks78). The extended-dosing
regimen will be considered to be non-inferior to the fixed 2Q8 regimen if the confidence 
interval of the difference lies entirely above -5 letters, where a positive difference favors 
extended dosing. A non-inferiority margin of 5 letters is consistent with margin used in the 
“CATT Study” (CATT Research Group 2011).
If, and only if, the extended-dosing regimen is statistically be proven to be non-inferior to the 
fixed 2Q8 regimen in the primary efficacy analysis, confirmatory testing will be continued to 
prove the non-inferiority of extended dosing to fixed 2Q8 with regard to the key secondary 
efficacy variable (maintenance of vision) in the FAS (with LOCF for missing 52-week 
ETDRS letter score).  
                                                
78 LOCF is considered an appropriate method for replacement of missing values in the primary and secondary 
efficacy analyses in the late phase of the study (i.e. carrying forward the last measurement taken between 
Week 36 to Week 48 if the Week-52 measurement is missing), even though nAMD is a progressive disease.


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The null hypothesis is H0: p1 ≤p2-versus 
the alternative hypothesis H1: p1 > p2-where 
pi =
proportion of subjects maintaining vision at 52 weeks of treatment group i 
=
pre-specified non-inferiority margin of 7%.79  
i =
1:  extended-dosing regimen
2:  fixed-dosing regimen
The methodological approach will be the calculation of two-sided 95% confidence intervals 
using normal approximation of the difference between the proportions (extended-dosing
group minus 2Q8 group) of subjects maintaining vision. The extended-dosing regimen will be 
considered to be non-inferior to the fixed 2Q8 regimen if the confidence interval of the 
difference lies entirely above -7%, where a positive difference favors extended dosing. This 
conditional sequence of statistical hypotheses (a-priori ordered hypotheses) will control for 
multiplicity in the confirmatory analyses. 
As sensitivity analyses, the primary efficacy and key secondary efficacy analyses will be 
repeated on the Per-Protocol Set as defined in Section 10.2.  
The analysis can also include, if applicable, BCVA evolution over the course of pre-study 
aflibercept treatment, starting with the initial BCVA value as captured in the first set of 
inclusion criteria. Snellen-equivalents may therefore be converted into ETDRS letter scores.80
The other secondary efficacy variables as well as the exploratory efficacy variables will be 
analyzed in a descriptive manner. This may include 95 % confidence intervals for treatment 
differences in an exploratory way. 
Details regarding the statistical analysis of the other efficacy variables will be provided in the 
SAP.
10.3.2.3
Safety variables analysis
The safety analysis will be conducted in the safety analysis set. Treatment-emergent AEs will 
be presented by MedDRA preferred term within primary system organ class (SOC) and 
summarized by treatment groups. Intensity and causal relationship to the investigational 
product will be analyzed descriptively. SAEs, including narratives, will be documented 
separately.  
Other safety variables (e.g. IOP measurements, vital signs and laboratory tests) will be 
analyzed descriptively including changes from baseline. The descriptive analysis of laboratory 
data will include a listing of laboratory data that fall outside of normal range, and the 
                                                
79 The non-inferiority margin of 7% was proposed by the 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 pages 22 and 23).
80 Added example of possible analysis per Amendment 2 (Section 15.1.1.35)


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calculation of incidence rates for treatment emergent laboratory abnormalities by treatment 
group.
10.4
Determination of sample size
Based on the assumptions of (i) a standard deviation of 13 for the mean change in BCVA 
from study baseline to Week 52, (ii) a non-inferiority margin of 5 letters, (iii) an equal mean 
change in BCVA from study baseline to Week 52 in the two treatment groups, (iv) a power of 
90%, and (v) a one-sided alpha of 2.5%, the samples size estimation resulted in 144 evaluable 
subjects per treatment group (calculated with PASS 11, non-inferiority of two means). With
an expected drop-out rate of 13%, a total of 330 subjects should be randomized (165 per 
treatment group) to ensure the power also in the PPS analysis.
The sample size of 144 evaluable subjects per treatment group will have, in the analysis of the 
key secondary efficacy variable, power of 0.78 with an assumed proportion of 95% of 
subjects maintaining vision at Week 52 in both treatment groups, and a power of 0.86 with an 
assumed proportion of 96% of subjects maintaining vision at Week 52 in both treatment 
groups (with a two-sided alpha of 5% and a non-inferiority margin of 7%, calculated with 
PASS 11, non-inferiority of two proportions [differences]). 
10.5
Planned interim analyses
Not applicable – no interim analysis is planned.


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11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Subject data necessary for analysis and reporting will be entered/transmitted into a 
validated database or data system (CIE/TOSCA; SAS). 
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 has licensed 
from Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its 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. Bayer 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 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 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 
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 key data entered into the CRF has source 
documentation available at the site. 
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.


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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 CRF:
Demographic information (subject number; year of birth / age; sex; 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 CRF 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). 
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.


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11.3
Data processing - amended
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 CRF as well as for data from other sources 
(e.g. IVRS, laboratory, reading center, adjudication committees).81
For data coding (e.g. AEs, medication, surgeries), internationally recognized and accepted 
dictionaries will be used.82
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.
Moreover, the risk of missing data may be decreased in this study, since all subjects must 
have been treated with the study drug aflibercept for one year to be enrolled in this study and 
all subjects will receive active aflibercept during the course of this 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.
                                                
81  Removal of reference to ECG per Amendment 2 (Section 15.1.1.26)
82  Changed examples per Amendment 2 (Section 15.1.1.32)


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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.
Patient (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, 
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 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 any interim analysis
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.
The investigator has the right to close his/her center at any time.


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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 individual subject's withdrawal can be found in Section 6.3.1.
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 not included in this section 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 is 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.


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Central reading center for images
An independent central reading center will evaluate the ophthalmic images obtained by OCT 
(see Section 9.4.1.2) and FP / FA (see Section 9.4.1.6).
External data evaluation bodies
The sponsor may decide to institute a Steering Committee to guide the trial in all aspects of 
safety and 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.
In addition, a Safety Management Team (SMT), led by the sponsor’s Global Safety Leader, 
will meet periodically to review safety data. Members of the SMT can include representatives 
from Global Pharmacovigilance, Pharmacoepidemiology, Clinical Development, Biostatistics, 
Data Management, Clinical Pharmacology, Preclinical Development, Regulatory Affairs, and 
Medical Affairs as appropriate.
Finally, an adjudication committee will perform an additional analysis of arterial thrombotic 
events (ATEs) based on the Antiplatelet Trialists' Collaboration (APTC) endpoint 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.
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.


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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 
Good Clinical Practice (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 - amended
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center. A sample 
subject information and informed consent form 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.
Each subject will be informed about the following aspects of premature withdrawal:


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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 9.2.6 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 statistical analysis plan. 
Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan. The subject has the right to object to the 
generation and processing of this post-withdrawal data.83  
Each subject will have ample time and opportunity to ask questions.
Only if the subject voluntarily agrees to sign the informed consent form and has done so, may 
he/she enter the study. Additionally, the investigator will personally sign and date the form. 
The subject / legal representative or proxy consenter 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 patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline 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 unable to read the informed consent form due to vision impairment, a family 
member, other legal representative of the subject, study nurse, or study physician should read 
the document verbatim to the subject. A discussion and explanation, including answering all 
questions from the subject, should also occur prior to the subject or their legal representative 
signing the form. An impartial witness should be present during the entire informed consent 
discussion. The witness must be unaffiliated with the conduct of the study, and will also sign 
and date the document along with the subject or their legal representative. 83
The informed consent form 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 informed consent form. 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 informed consent form. Any 
revised written informed consent form and written information must receive the IEC/IRB`s 
approval / favorable opinion in advance of use.
                                                
83  Paragraph revised to align with sponsor internal standards per Amendment 2 (Section 15.1.1.33)


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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. 
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. 
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 CRF, 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.


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14.
Reference list 
Aiello LP, Avery RL, Arrigg PG et al. Vascular endothelial growth factor in ocular fluid of 
patients with diabetic retinopathy and other retinal disorders. N Eng J Med 1994; 331:1480-
1487.
Rahmani B, Tielsch JM, Katz J et al. The cause-specific prevalence of visual impairment in 
an urban population. The Baltimore Eye Survey. Ophthalmology. 1996; 103:1721-1726.
The CATT Research Group. Ranibizumab and Bevacizumab for Neovascular Age-Related 
Macular Degeneration. N Eng J Med 2011; 365:1897-1908.
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.


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15.1
Amendment 2, dated 10 December 2015
15.1.1
Overview of changes to the study
15.1.1.1
Modification 1 – Update of approval status
Update of approved indications for aflibercept by country
Rationale: Update
The following protocol sections are affected by this modification:

Section 3.1 Background
15.1.1.2
Modification 2 – Clarification of duration of the periods
Clarification of the duration of the screening period (change from expression in weeks to 
expression in days) and other periods
Rationale: Clarification
The following protocol sections are affected by this modification:

Synopsis – Study design

Section 5 Study design

Section 9 Procedures and variables

Section 9.1 Tabular schedule of evaluations

Section 9.2.1 Screening visit (Visit 1)
15.1.1.3
Modification 3 – Time windows and schedule of visits 
Consistency throughout the protocol: Different time windows (± 3 and ± 7 days given at 
different protocol sections) were consolidated for all post-baseline visits in both treatment 
groups to ± 3 days relative to baseline and clarification of the schedule of visits in the 2Q8 
group.
Rationale: Clarification and consistency
The following protocol sections are affected by this modification:

Synopsis – Test drugs – Doses

Synopsis – Study design

Section 5 Study design

Section 7.1 Treatments to be administered

Section 9  Procedures and variables

Section 9.1 Tabular schedule of evaluations


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15.1.1.4
Modification 4 – Selection of study eye
Clarification of the procedure of selecting the study eye
Rationale: Clarification
The following protocol sections are affected by this modification:

Section 6 Study population
15.1.1.5
Modification 5 – Clarifications of inclusion criteria
Clarified the following in the first and second set of inclusion criteria: 

FA is sufficient for inclusion criterion 1 - removal of FP (inclusion criterion 1)

Clarification of the conversion from BCVA to letter score (inclusion criterion 3)

‘Written informed consent’ complemented by ‘signed’ (Inclusion criterion 4)

Clarification of timepoint of the last allowed aflibercept injection before first treatment 
in the study
Rationale: Clarification
The following protocol sections are affected by this modification:

Synopsis – Diagnosis and main criteria for inclusion / exclusion

Section 6.1 Inclusion criteria
15.1.1.6
Modification 6 – Time periods for inclusion criteria 1 and 2
Extension of the time periods from 3 weeks to 4 weeks 
Rationale: Update to reflect clinical practice
The following protocol sections are affected by this modification:

Section 6.1 Inclusion criteria

Synopsis – Diagnosis and main criteria for inclusion / exclusion
15.1.1.7
Modification 7 – Study manual
Removed references to study manual and added references to reading center acquisition 
protocol for FA and FP
Rationale: Correction
The following protocol sections are affected by this modification:

Synopsis – Diagnosis and main criteria for inclusion / exclusion

Section 6.1 Inclusion criteria

Section 9.2.1 Screening visit (Visit 1)


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
Section 9.2.4 Primary completion (Week 52)

Section 9.4.1.1 Best corrected visual acuity

Section 9.4.1.6 Fundus photography (FP) and fluorescein angiography (FA)
15.1.1.8
Modification 8 – Inclusion criterion 8
Use of contraception specified according to the recommendations of the CTFG from 15 SEP 
2014.
Rationale: For subject safety reasons
The following protocol sections are affected by this modification:

Section 6.1.2 Second set of inclusion criteria
15.1.1.9
Modification 9 – Clarifications in second set of exclusion criteria
Clarifications added
Rationale: Clarification
The following protocol sections are affected by this modification:

Section 6.2.2 Second set of exclusion criteria
15.1.1.10 Modification 10 – Re-screening criteria
Added list of criteria for re-screening
Rationale: Correction (omission in the original protocol)
The following protocol sections are affected by this modification:

Section 6.3.1 Withdrawal
15.1.1.11 Modification 11 – Subject identification number
Description of subject identification number changed
Rationale: Correction
The following protocol sections are affected by this modification:

Section 6.4 Subject identification


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15.1.1.12 Modification 12 – Identity of study drug
Added table specifying the identity of study drug
Rationale: Correction (omission in the original protocol)
The following protocol sections are affected by this modification:

Section 7.2 Identity of study drug
15.1.1.13 Modification 13 – EU SmPC and other updates for safety reasons to 
dosage and administration 
Special warnings from EU Summary of product characteristics (SmPC) (most recent version 
number) added to dosage and administration and dosage and administration updated
Rationale: For subject safety reasons
The following protocol sections are affected by this modification:

Section 7.4 Dosage and administration
15.1.1.14 Modification 14 – Treatment posology
Added table describing treatment posology
Rationale: Clarification
The following protocol sections are affected by this modification:

Section 7.4 Dosage and administration
15.1.1.15
Modification 15 – Drug storage
Added description of storage conditions
Rationale: More detailed specification
The following protocol sections are affected by this modification:

Section 7.6 Drug logistics and accountability


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15.1.1.16 Modification 16 – Final visit or early termination visit
Clarified throughout the protocol that the final visit procedures should also be conducted in 
the case of early termination and changed end of study visit to final visit
Rationale: Clarification
The following protocol sections are affected by this modification:

Section 8.1.2.1 Study-eye treatment

Section 9 Procedures and variables

Section 9.1 Tabular schedule of evaluations

Section 9.2.5 Visits between primary completion (Week 52) and end of study visit 
(Week 76)

Section 9.2.6 End of study (Week 76)
15.1.1.17 Modification 17 – Specification of pregnancy testing 
Added a urine dipstick pregnancy test to the baseline visit
Rationale: A patient could become pregnant between screening and baseline. To confirm that 
the subject is not pregnant before the start of treatment, a urine dipstick pregnancy test is to be 
performed at the baseline visit.
The following protocol sections are affected by this modification:

Section 9.1 Tabular schedule of evaluations

Section 9.2.2 Baseline visit (Visit 2)

Section 9.6.3.1 Laboratory evaluations
15.1.1.18 Modification 18 – Timing of pregnancy testing
Moved the serum pregnancy test in the Schedule of assessments and study procedures from 
Initiation procedures to Standard safety. Added foot note ‘The urine dipstick pregnancy test is 
to be repeated as frequently as required following the investigator’s medical judgment and 
local regulations’ to the Tabular schedule of evaluations. Added that a urine dipstick 
pregnancy test is required at the final visit or early termination.
Rationale: For subject safety reasons 
The following protocol sections are affected by this modification:

Section 9.1 Tabular schedule of evaluations

Section 9.2.6 End of study visit (Week 76) 

Section 9.6.3.1 Laboratory evaluations


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15.1.1.19 Modification 19 – Order of footnotes and minor clarifications in 
schedule of evaluations 
Arranging the footnotes in the order the table is read, line by line, and separated the table to 
2 pages; and minor clarifications regarding pre-and post-dose assessments for indirect 
ophthalmoscopy and IOP
Rationale: More reader friendly
The following protocol sections are affected by this modification:

Section 9.1 Tabular schedule of evaluations
15.1.1.20 Modification 20 – Removal of sample study drug injection protocol 
from appendix
Removed sample study drug injection protocol (Drug administration protocol) from the 
appendix 
Rationale: Harmonization with other post-authorization efficacy studies
The following protocol sections are affected by this modification:

Section 7.4 Dosage and administration

Section 9.1 Tabular schedule of evaluations

Appendix 16.1 Drug administration protocol
15.1.1.21 Modification 21 – Re-check of eligibility criteria
Clarified the re-check of inclusion and exclusion criteria at the Baseline visit
Rationale: Clarification
The following protocol sections are affected by this modification:

Section 9.2.2 Baseline Visit (Visit 2)
15.1.1.22 Modification 22 – Post-injection ocular assessments
Added post-injection ocular assessments to all treatment visits
Rationale: Clarification (omitted in some sections in the original protocol)
The following protocol sections are affected by this modification:

Section 9.2.2 Baseline Visit (Visit 2)

Section 9.2.3 Visits between baseline and Week 52

Section 9.2.4 Primary completion (Week 52)


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
Section 9.2.5 Visits between primary completion (Week 52) and end of study 
(Week 76)

Section 9.2.6 End of study (Week 76)
15.1.1.23 Modification 23 – Conduct of visits
Added the full list of study procedures to the visits between primary completion (Week 52) 
and the final visit (Week 76) or early termination instead of a reference only
Rationale: More reader friendly
The following protocol sections are affected by this modification:

Section 9.2.5 Visits between primary completion (Week 52) and end of study 
(Week 76)

Section 9.2.6 End of study (Week 76)
15.1.1.24 Modification 24 – OCT
Reworded description of OCT in efficacy section
Rationale: Harmonization with other post-authorization efficacy studies
The following protocol sections are affected by this modification:

Section 9.4.1.2 Optical coherence tomography (OCT)
15.1.1.25 Modification 25 – FA and FP
Added requirement to archive FA and FP images electronically, clarified the confirmation of 
eligibility by the reading center, and re-ordered paragraphs
Rationale: Clarification and more reader friendly
The following protocol sections are affected by this modification:

Section 9.4.1.6 Fundus photography (FP) and fluorescein angiography (FA)


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15.1.1.26 Modification 26 – ECG
Removal of references to electrocardiogram (ECG)
Rationale: Correction
The following protocol sections are affected by this modification:

Section 9.6.1.1 Definitions

Section 11.3 Data processing
15.1.1.27 Modification 27 – Actions taken with study treatment
Removal of “Dose reduced” from possible actions taken with study treatment
Rationale: Correction
The following protocol sections are affected by this modification:

Section 9.6.1.2.4 Action taken with study treatment
15.1.1.28 Modification 28 – Expected adverse events
Reference to summary of product characteristics replaced with reference to local label for 
information on AEs.
Rationale: Editorial clarification of the process
The following protocol sections are affected by this modification:

Section 9.6.1.5 Expected adverse events
15.1.1.29 Modification 29 – Pregnancies
New paragraph on fertility and guidance regarding the follow-up after birth added to the 
pregnancy section
Rationale: Addition of guidance
The following protocol sections are affected by this modification:

Section 9.6.2 Pregnancies


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15.1.1.30 Modification 30 – Time point of blood withdrawal
Clarification of time point of blood withdrawal with respect to FA
Rationale: Clarification
The following protocol sections are affected by this modification:

Section 9.6.3.1 Laboratory evaluations
15.1.1.31 Modification 31 – NEI VFQ-25 questionnaire
Requirement to document the name of the person assisting the subject in completing the 
NEI VFQ-25 questionnaire added.
Rationale: Clarification of process
The following protocol sections are affected by this modification:

Section 9.7 Patient-reported outcome - NEI VFQ 25
15.1.1.32 Modification 32 – Data processing
Minor rewording (changed examples)
Rationale: Clarification
The following protocol sections are affected by this modification:

Section 11.3 Data processing
15.1.1.33 Modification 33 – Subject information and consent process 
Revision of text describing the subject information and informed consent process
Rationale: Alignment with sponsor internal standards
The following protocol sections are affected by this modification:

Section 13.4  Subject information and consent
15.1.1.34 Modification 34 – Fellow eye treatment
Added possibility to treat the fellow eye with any local standard of care
Rationale: More detailed specification
The following protocol sections are affected by this modification:

Section 8.1.2.2 Fellow eye treatment


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15.1.1.35 Modification 35 – Efficacy analyses – sensitivity analyses
Added example of possible analysis
Rationale: More detailed specification
The following protocol sections are affected by this modification:

Section 10.3.2.2 Efficacy analyses
15.1.2
Changes to the protocol text
Changes to the protocol text are highlighted as specified at the beginning of Section15.
Changes to abbreviations (i.e. the location where the abbreviation is first used changed) are 
not highlighted.
Synopsis – Test drugs – Doses
Time windows were consolidated for all post-baseline visits in both treatment groups to 
± 3 days relative to baseline per Modification 3 (Section 15.1.1.3)
Old text:
Dose(s)
Test group: 
2 mg with flexible injection intervals (8 weeks)
(extended-dosing regimen)
Control group: 2 mg with fixed injection intervals (8 weeks ± 7 days)
(2Q8)
New text:
Dose(s)
Test group: 
2 mg with flexible injection intervals (8 weeks)
(extended-dosing regimen)
Control group: 2 mg with fixed injection intervals (8 weeks) (2Q8)


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Synopsis – Diagnosis and main criteria for inclusion / exclusion
Clarifications in the inclusion criteria per Modification 5 (Section 15.1.1.5)
Extension of the time periods from 3 weeks to 4 weeks for the first 2 criteria of the first set of 
inclusion criteria per Modification 6 (Section 15.1.1.6)
Removed references to study manual (Section 15.1.1.7)
Old text:
Diagnosis and main criteria 
for inclusion / exclusion
First set of inclusion criteria:
The following criteria must have been met at the initial start of aflibercept 
treatment (i.e. start of aflibercept treatment before this study):

Subject had primary subfoveal choroidal neovascularization (CNV) 
lesions secondary to nAMD, including juxtafoveal lesions that affect 
the fovea, as evidenced by fluorescein angiography/photography 
(FA/FP) of the study eye within 3 weeks before the initiation of 
aflibercept treatment.

The area of CNV occupied at least 50% of the total lesion within 
3 weeks before the initiation of aflibercept treatment. 

Documented best-corrected visual acuity (BCVA) was 20/40 to 20/320 
(letter score of 73 to 25) in the study eye at the initiation of treatment. 
Because BCVA may not have been assessed by the Early Treatment 
Diabetic Retinopathy Study (ETDRS) protocol, guidance for 
conversion of Snellen visual acuity assessments will be provided in the 
study manual.
New text:
Diagnosis and main criteria 
for inclusion / exclusion
First set of inclusion criteria:
The following criteria must have been met at the initial start of aflibercept 
treatment (i.e. start of aflibercept treatment before this study):

Subject had primary subfoveal choroidal neovascularization (CNV) 
lesions secondary to nAMD, including juxtafoveal lesions that affect 
the fovea, as evidenced by fluorescein angiography (FA) of the study 
eye within 4 weeks before the initiation of aflibercept treatment.

The area of CNV occupied at least 50% of the total lesion within
4 weeks before the initiation of aflibercept treatment. 

Documented best-corrected visual acuity (BCVA) was 20/40 to 20/320 
(comparable to a letter score of 73 to 25) in the study eye at the 
initiation of treatment (the initial BCVA of the study eye before 
treatment initiation must be documented as Snellen equivalent in the 
electronic case report form [eCRF]).


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Synopsis – Study design
Clarification of the period durations per Modification 2 (Section 15.1.1.2)
Time windows were consolidated for all post-baseline visits in both treatment groups to 
± 3 days relative to baseline per Modification 3 (Section 15.1.1.3)
Old text:
This study comprises a screening period of up to 8 weeks (+ 10 days) and a treatment period of 72 weeks (up to 
76 weeks in the extended-dosing group). A final study visit for all subjects will be conducted at Week 76.
…
2Q8:
Fixed dosing intervals
8 weeks (±7 days) - modification of the treatment interval is not allowed.
Subjects in both treatment groups will receive the first study treatment on Day 1. The treatment period is 
72 weeks (or up to 76 weeks in the extended-dosing group) with a final study visit at Week 76.
New text:
This study comprises a screening period of up to 66 days.
…
2Q8:
Fixed dosing intervals
8 weeks - modification of the treatment interval is not allowed.
For each treatment group, the time window for all post-baseline visits is 3 days relative to baseline.
Subjects in both treatment groups will receive the first study treatment on Day 1. The treatment period is 
72 weeks (in the 2Q8 group) with a final study visit at Week 76 


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Section 3.1 Background
Update of approved indications for aflibercept by country per Modification 1 
(Section 15.1.1.1)
Old text:
… To date, aflibercept has been approved as a treatment for nAMD in the United States (US), 
European Union (EU), Japan and several other countries and for the treatment of macular 
edema secondary to central retinal vein occlusion (CRVO) in the US and several other 
countries. Phase-3 studies of aflibercept in diabetic macular edema (DME), branch retinal 
vein occlusion (BRVO), and myopic choroidal neovascularization (mCNV) are ongoing.
Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug.
New text:
… To date, aflibercept has been approved as a treatment for nAMD, macular edema 
secondary to central retinal vein occlusion (CRVO), diabetic macular edema (DME), and 
macular edema secondary to branch retinal vein occlusion (BRVO) and CRVO in the United 
States (US), European Union (EU), Japan, and other countries; as well as for myopic 
choroidal neovascularization (mCNV) in the EU, Japan and other countries; and for diabetic 
retinopathy in patients with DME in the US.
Section 5 Study design
Clarification of the period durations per Modification 2 (Section 15.1.1.2)
Time windows were consolidated for all post-baseline visits in both treatment groups to 
± 3 days relative to baseline per Modification 3 (15.1.1.3).
Old text:
This study comprises a screening period of up to 8 weeks (+ 10 days) and a treatment period 
of 72 weeks (up to 76 weeks in the extended-dosing group) (Figure 5-1).  
There will be two parallel treatment arms. In both arms, aflibercept will be injected IVT at a 
dose of 2 mg per injection. The treatment arms differ in dosing intervals:
Extended dosing:
Flexible dosing intervals
≥8 weeks (no upper limit) based on visual and anatomic outcomes as 
judged by the investigator.
When/if visual and 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 were 
observed). 


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2Q8:
Fixed dosing intervals
8 weeks (±7 days) - modification of the treatment interval is not allowed.
Figure 5-1:
Study flow diagram 
Screening
up to 8 weeks 
(+10 days)
Treatment
Extended dosing flexible dosing interval (≥8 weeks)
Duration ≤76 weeks
2Q8  fixed dosing interval (8 weeks)
Duration 72 weeks
Day 1
Week 52
Week 72
Week 76
Randomization 
(1:1)
Primary 
completion
End of 
treatment 
for 2Q8
End of 
study
Following screening, eligible subjects will be randomized (1:1) to one of the two parallel 
treatment group. Subjects in both treatment groups will receive the first study treatment on 
Day 1. The treatment period is 72 weeks (or up to 76 weeks in the extended-dosing group) 
with a final study visit at Week 76.
Two post-baseline visits will follow the same strict schedule in both treatment groups:  
primary completion at Week 52 and the final visit at Week 76. All other post-baseline visits 
may differ between the treatment groups as detailed in Section 9.
The last possible study drug injection in the extended-dosing group can be given at Week 76 
(i.e. the end of the study) after completion of all protocol-specified assessments. After 
Week 76, subjects should be returned to standard of care.
New text:
This study comprises a screening period of up to 66 days (Figure 5-1).  
There will be two parallel treatment arms. In both arms, aflibercept will be injected IVT at a 
dose of 2 mg per injection. The treatment arms differ in dosing intervals:
Extended dosing:
Flexible dosing intervals
≥8 weeks (no upper limit) based on visual and anatomic outcomes as 
judged by the investigator.
When/if visual and 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 were 
observed). 


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2Q8:
Fixed dosing intervals
8 weeks - modification of the treatment interval is not allowed.
Figure 5-1:
Study flow diagram - amended
Screening
up to 66 days
Treatment
Extended dosing flexible dosing interval (≥8 weeks)
Duration ≤76 weeks
2Q8  fixed dosing interval (8 weeks)
Duration 72 weeks
Day 1
Week 52
Week 72
Week 76
Randomization 
(1:1)
Primary 
completion
End of 
treatment 
for 2Q8
End of 
study
Following screening, eligible subjects will be randomized (1:1) to one of the two parallel 
treatment group. Two post-baseline visits will follow the same strict schedule in both 
treatment groups:  primary completion at Week 52 and the final visit at Week 76. The 
schedule of all other post-baseline visits may differ between the treatment groups as detailed 
in Section 9.
Subjects in both treatment groups will receive the first study treatment on Day 1. The 
treatment period is 72 weeks (in the 2Q8 group) with a final study visit at Week 76.
The last possible study drug injection in the extended-dosing group can be given at Week 76 
(i.e. the end of the study) after completion of all protocol-specified assessments. After 
Week 76, subjects should be returned to standard of care.
For each treatment group, the time window for all post-baseline visits is ± 3 days relative to 
baseline.
Section 6 Study population
Clarification of the procedure of selecting the study eye per Modification 4 (Section 15.1.1.4)
Old text:
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 (VA) will be selected as the study eye. If both 
eyes have equal VA, 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. 


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New text:
Only one eye will be designated as the study eye. For subjects who meet eligibility criteria in 
both eyes during the screening phase, the eye with the worse visual acuity (VA) will be 
selected as the study eye. If both eyes have equal VA, 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. 
Section 6.1 Inclusion criteria
Clarifications in the first and second set of inclusion criteria per Modification 5 
(Section 15.1.1.5)
Extension of the time periods from 3 weeks to 4 weeks for inclusion criteria 1 and 2 per 
Modification 6 (Section 15.1.1.6)
Removed reference to study manual per Modification 7 (Section 15.1.1.7)
Use of contraception specified according to the recommendations of the CTFG per 
Modification 8 (Section 15.1.1.8)
Old text:
Section 6.1.1 First set of inclusion criteria
All of the following criteria must have been met at the initial start of aflibercept treatment 
(i.e. start of aflibercept treatment prior to this study) for a subject to be eligible for this study.
1. Subject had primary subfoveal choroidal neovascularization (CNV) lesions secondary to 
nAMD, including juxtafoveal lesions that affect the fovea, as evidenced by FA/FP of the 
study eye within 3 weeks before the initiation of aflibercept treatment.84
2. The area of CNV occupied at least 50% of the total lesion within 3 weeks before the 
initiation of aflibercept treatment. 
3. Documented BCVA was 20/40 to 20/320 (letter score of 73 to 25) in the study eye at the 
initiation of treatment. Because BCVA may not have been assessed by the ETDRS 
protocol at initiation of aflibercept treatment, guidance for conversion of data (e.g. Snellen 
to approximate ETDRS) will be provided in the study manual.
Section 6.1.2 Second set of inclusion criteria
All of the following criteria must be met at the time of screening for participation in this study 
for a subject to be eligible for this study.
4. Written informed consent
5. Men or women 51 years of age
                                                
84 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.


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6. The subject’s history of aflibercept treatment meets ALL of the following:
a) Treatment in the study eye was initiated with three monthly (-1 week/+2 weeks) 
doses of 2 mg aflibercept and improvements of visual and anatomic outcomes were 
observed
b) Following the above initiation phase, the intervals between treatments were 
between 6 weeks and 12 weeks (one exception will be allowed)
c) The interval between the last two pre-study injections was ≥8 weeks, and visual and 
anatomic outcomes have been stable over this interval.
d) The subject received the last IVT injection of aflibercept in the study eye ≥2 months 
(10 days) before the first treatment in this study
e) Total prior treatment duration with aflibercept (i.e. from first treatment to 
randomization into this study) was ≥12 months 
7. Subject is willing, committed, and able to return for ALL clinic visits and complete all 
study-related procedures.
8. Women and men of reproductive potential must agree to utilize two reliable and 
acceptable methods of contraception simultaneously when sexually active. This applies 
for the time period between signing of the informed consent form and 3 months after the 
last administration of study drug.  
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.
Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of child bearing potential.
New text:
Section 6.1.1 First set of inclusion criteria
All of the following criteria must have been met at the initial start of aflibercept treatment 
(i.e. start of aflibercept treatment prior to this study) for a subject to be eligible for this study.
1. Subject had primary subfoveal choroidal neovascularization (CNV) lesions secondary to 
nAMD, including juxtafoveal lesions that affect the fovea, as evidenced by FA of the 
study eye within 4 weeks before the initiation of aflibercept treatment.85
2. The area of CNV occupied at least 50% of the total lesion within 4 weeks before the 
initiation of aflibercept treatment. 
3. Documented BCVA was 20/40 to 20/320 (comparable to a letter score of 73 to 25) in the 
study eye at the initiation of treatment (the initial BCVA of the study eye before treatment 
initiation must be documented as Snellen equivalent in the electronic case report form 
[eCRF]).  
                                                
85 The reading center acquisition protocol will further specify the standards for FA during the study.


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Section 6.1.2 Second set of inclusion criteria
All of the following criteria must be met at the time of screening for participation in this study 
for a subject to be eligible for this study.
4. Signed written informed consent
5. Men or women 51 years of age
6. The subject’s history of aflibercept treatment meets ALL of the following:
a) Treatment in the study eye was initiated with three monthly (-1 week/+2 weeks) 
doses of 2 mg aflibercept and improvements of visual and anatomic outcomes were 
observed
b) Following the above initiation phase, the intervals between treatments were 
between 6 weeks and 12 weeks (one exception will be allowed)
c) The interval between the last two pre-study injections was ≥8 weeks, and visual and 
anatomic outcomes have been stable over this interval.
d) The subject received the last IVT injection of aflibercept in the study eye 2 months 
(10 days) before the first treatment in this study
e) Total prior treatment duration with aflibercept (i.e. from first treatment to 
randomization into this study) was ≥12 months 
7. Subject is willing, committed, and able to return for ALL clinic visits and complete all 
study-related procedures.
8.
Women and men of reproductive potential must agree to a method of highly effective  
contraception (as defined by the Clinical Trial Facilitation Group [CTFG] from 15 SEP 
2014):  

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o oral
o intravaginal 
o transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o oral
o injectable
o implantable 

Intrauterine device 

Intrauterine hormone-releasing system 

Bilateral tubal occlusion 

Vasectomized partner 

Sexual abstinence
Alternatively women and men of reproductive potential can also use two acceptable 
methods of contraception (as defined by the CTFG from 15 SEP 2014) simultaneously:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action


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
Male or female condom with or without spermicide 

Cap, diaphragm or sponge with spermicide 
Contraception has to be used from signing the informed consent form until 3 months after 
the last administration of study drug. Postmenopausal women must be amenorrheic for at 
least 12 months in order not to be considered of child bearing potential. 
Section 6.2.2 Second set of exclusion criteria
Clarifications added per Modification 9 (Section 15.1.1.9)
Old text:
…
12. Any vitreous hemorrhage within 4 weeks before randomization 
13. Active intraocular, extraocular and periocular inflammation or infection in either eye.
14. Any ocular or periocular infection within 4 weeks of randomization
15. Any serious adverse event related to aflibercept during prior treatment (see Sections
9.6.1.1 and 9.6.1.2)
16. Any history of allergy to povidone iodine
17. Known serious allergy to the fluorescein sodium for injection in angiography
18. Presence of any contraindications indicated in the EU commission/locally approved label 
for aflibercept: Hypersensitivity to the active substance aflibercept or to any of the 
excipients; active or suspected ocular or periocular infection; active severe intraocular 
inflammation
19. Prior vitrectomy in the study eye
20. History of vitreomacular traction
…
33. The use of long acting steroids, either systemically or intraocular, in the 18 months 
before initiating study treatment
…
New text:
…
12. Any vitreous hemorrhage within 4 weeks before randomization in the study eye
13. Active intraocular, extraocular and periocular inflammation or infection in either eye.
14. Any ocular or periocular infection within 4 weeks of randomization in either eye


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15. Any serious adverse event related to aflibercept during prior treatment (see Sections
9.6.1.1 and 9.6.1.2
16. Any history of allergy or hypersensitivity to povidone iodine.
17. Known serious allergy or hypersensitivity to the fluorescein sodium for injection in 
angiography
18. Presence of any contraindications indicated in the EU commission/locally approved label 
for aflibercept: Hypersensitivity to the active substance aflibercept or to any of the 
excipients; active or suspected ocular or periocular infection; active severe intraocular 
inflammation
19. Prior vitrectomy in the study eye
20. History of vitreomacular traction in the study eye
…
33. The use of long acting steroids, either systemically or intraocular, in the 18 months 
before initiating study treatment (or Iluvien IVT implant at any time)
…
Section 6.3.1 Withdrawal
Added list of criteria for re-screening per Modification 10 (Section 15.1.1.10)
Old text:
Screening failure
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 a 
“screening failure”. 
New text:
Screening failure
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 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 inclusion / exclusion criteria preventing the subject’s initial attempt to participate 
have been changed (see inclusion criterion 1 and 2 changed via this protocol 
amendment).


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
The reason for the screening failure was subsequently resolved (e.g. elevated IOP 
decreases, inflammation or infection resolves) 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 has to sign a new informed consent form. To be 
eligible, re-screened subjects must meet all eligibility criteria during the re-screening period.
Section 6.4 Subject identification
Description of subject identification number changed per Modification 11 (Section 15.1.1.11)
Old text:
The subject number is a 9 digit number consisting of:
Digits 1 to 2 
=  Country code
Digits 3 to 5
=  Center number within the country
(Digits 1 to 5
=  Trial unit)
Digits 6 to 9
=  Current subject number within the center
The sponsor or designee will provide the centers with a sufficient number of center-specific 
PIDs to cover all potential subjects. Once allocated, the subject’s PID number will identify the 
subject throughout the study, and will be entered into the Site Enrollment Log and on the 
eCRF.
New text:
The subject number is a 9 digit number consisting of:
Digits 1 to 5 
= Unique center number
Digits 6 to 9
= Current subject number within the center
Patient identification numbers (PIDs) will be assigned via IxRS. Once allocated, the subject’s 
PID number will identify the subject throughout the study, and will be entered into the Site 
Enrollment Log and on the eCRF.
Upon re-screening, a new PID will be assigned.


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Section 7.1 Treatments to be administered
Time windows were consolidated for all post-baseline visits in both treatment groups to 
± 3 days relative to baseline per Modification 3 (Section 15.1.1.3)
Old text:
There will be two parallel treatment arms, each administering 2 mg aflibercept per injection 
IVT in the study eye. Aflibercept will be administered either on a fixed 2Q8 schedule (i.e. 
2 mg aflibercept every 8 weeks [±7 days]) or according to an extended-dosing protocol in 
which the dosing interval may be extended beyond 8 weeks based on visual and anatomical 
outcomes and knowledge of the individual subject as judged by the treating investigator 
(Table 7-1).
Table 7-1:
Treatment groups
Extended-dosing group
2Q8 group
Dose per injection
Aflibercept 2 mg
Aflibercept 2 mg
Administration 
schedule
Flexible injection intervals:
≥8 weeks
When/if exudation recurs, the treatment 
interval will revert to the last treatment 
interval in which the disease was inactive.
Interval decisions based investigator’s 
judgment. Intervals cannot be less than 
8 weeks (no upper limit).
Fixed injection intervals:
8 weeks ±7 days throughout the entire 
treatment period
Duration of treatment up to 76 weeks
72 weeks
Planned number of 
randomized subjects
165
165


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New text:
There will be two parallel treatment arms, each administering 2 mg aflibercept per injection 
IVT in the study eye. Aflibercept will be administered either on a fixed 2Q8 schedule (i.e. 
2 mg aflibercept every 8 weeks) or according to an extended-dosing protocol in which the 
dosing interval may be extended beyond 8 weeks based on visual and anatomical outcomes 
and knowledge of the individual subject as judged by the treating investigator (Table 7-1).
Table 7-1:
Treatment groups - amended
Extended-dosing group
2Q8 group
Dose per injection
Aflibercept 2 mg
Aflibercept 2 mg
Administration 
schedulea
Flexible injection intervals:
≥8 weeks
When/if exudation recurs, the treatment 
interval will revert to the last treatment 
interval in which the disease was inactive.
Interval decisions based investigator’s 
judgment. Intervals cannot be less than 
8 weeks (no upper limit).
Fixed injection intervals:
8 weeks throughout the entire treatment 
period
Duration of treatment up to 76 weeks
72 weeks
Planned number of 
randomized subjects
165
165
a For each treatment group, the time window for all post-baseline visits is ± 3 days relative to baseline
Section 7.2 Identity of study treatment
Following table added specifying the identity of study drug per Modification 12 
(Section 15.1.1.12)
The identity of the study drug is summarized in Table 7-2.
Table 7-2:
Identity of study drug - added
Name
Dose
Concentration
Formulation
Composition
BAY 86-5321
aflibercept
Eylea 
2 mg
40 mg/mL
Solution for 
intravitreal 
injection
40 mg aflibercept/mL
5% sucrose
10mM sodium phosphate
0.03% polysorbate 20
40 mM NaCl
Water for injection


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Section 7.4 Dosage and administration
Dosage and administration updated and special warnings from EU SmPC (most recent version 
number) added to dosage and administration per Modification 13 (Section 15.1.1.13)
Added table describing treatment posology per Modification 14 (Section 15.1.1.14)
Removed sample study drug injection protocol from the appendix per Modification 20 
(Section 15.1.1.20).
Old text:
The volume of injection will be 50 μL (0.05 mL) for the 2 mg aflibercept dose. The study 
drug will be withdrawn from the glass vial 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.
Prior to administration, visually inspect the solution for injection. Do not use the vial if 
particulates, cloudiness, or discoloration are visible.
Prior to usage, the unopened vial of aflibercept may be stored at room temperature 
(25°C/77°F) for up to 24 hours. After opening the vial, proceed under aseptic conditions.
An example of a drug administration protocol is provided in Section 16.1.
New text:
The study drug will be supplied in kits that include the following:

Sterile study drug in sealed glass vials (2 mL) with a withdrawable volume of 0.1 mL
(see Table 7-2 for details on the composition of the study drug)

Filter needle (18 gauge)
Other ancillary components required for the administration of aflibercept (e.g. 30-gauge 
injection needle; 1-ml syringe) will be supplied by the study site. 
When aflibercept 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. 
After opening the vial, all preparation steps have to take place under aseptic conditions.
The study drug will be withdrawn using aseptic technique through the filter needle attached to 
the 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 by the sterile 
30-gauge needle for the IVT injection. Each patient receives an IVT injection of 50 µl of 
aflibercept. 


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Consideration of special warnings from EU label 
The investigator should consider the special warnings as described in the EU label for 
aflibercept. However, ultimately the investigator should include in his/her treatment decision 
all subject related information and data available and based on this decide what would be best 
for the subject.
The approved EU label for aflibercept includes the following special warnings:
Treatment should be withheld in patients with rhegmatogenous retinal detachment or 
stage 3 or 4 macular holes. In the event of a retinal break, the dose should be withheld 
and treatment should not be resumed until the break is adequately repaired. 
The dose should be withheld and treatment should not be resumed earlier than the next 
scheduled treatment in the event of:

a decrease in BCVA of ≥30 letters compared with the last assessment of visual 
acuity; 

a subretinal haemorrhage involving the centre of the fovea, or, if the size of the 
haemorrhage is ≥50%, of the total lesion area 
The dose should be withheld within the previous or next 28 days in the event of a 
performed or planned intraocular surgery 


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Posology
Treatment posology is detailed in Table 7-3.
Table 7-3:
Treatment posology - added
2Q8 group
Extended-dosing group
Visit
Treatment
Visit
Treatment
Baseline
mandatory Visit 2 
mandatory 
mandatory Visit 2 
mandatory 
Week 8
mandatory visit with treatment
between Week 8 and Week 52, 
visits (including treatment) can be scheduled at any timepoint 
(provided injection intervals are ≥8 weeks)
Week 16
mandatory visit with treatment
Week 24
mandatory visit with treatment
Week 32
mandatory visit with treatment
Week 40
mandatory visit with treatment
Week 48
mandatory visit with treatment
Week 52
mandatory 
no treatment
mandatory 
optional
Week 56
mandatory visit with treatment
between Week 52 and Week 76, 
visits (including treatment) can be scheduled at any timepoint 
(provided injection intervals are ≥8 weeks)
Week 64
mandatory visit with treatment
Week 72
mandatory visit with treatment
Week 76
mandatory 
no treatment
mandatory 
optional
Section 7.6 Drug logistics and accountability
Added the following paragraph to ‘Storage’ per Modification 15 (Section 15.1.1.15):
Aflibercept must be stored at the clinical sites in a refrigerator at 2C to 8C, protected from 
light, and not frozen. Prior to usage, the unopened vial of aflibercept may be stored at room 
temperature (25 °C / 77°F) for up to 24 hours. After opening the vial or blister pack, proceed 
under aseptic conditions.
Section 8.1.2.1 Study eye treatment
Clarification that the final visit procedures should also be conducted in the case of early 
termination per Modification 16 (Section 15.1.1.16)
Old text:
Subjects may not receive any standard or investigational agents for treatment of their AMD in 
the study eye other than aflibercept as specified in this protocol until they have completed the 
completion/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.


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New text:
Subjects may not receive any standard or investigational agents for treatment of their AMD in 
the study eye other than aflibercept as specified in this protocol until they have completed the 
final or 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.
Section 8.1.2.2 Fellow eye treatment
Added possibility to treat the fellow eye with any local standard of care per Modification 34
(Section 15.1.1.34)
Old text:
Treatment of the fellow (non-study) eye is not regarded as a study treatment. If the fellow eye 
has AMD, the fellow eye may receive any locally approved non-systemic treatment. If the 
fellow eye shall be treated pharmacologically, the most appropriate treatment option that is 
approved by the governing health authorities may be selected at the investigator’s discretion 
in the subject’s best interest.
If it is determined that aflibercept is the most appropriate treatment option for the fellow eye, 
this will still not be regarded as a study treatment and 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.  
New text:
Treatment of the fellow (non-study) eye is not regarded as a study treatment. If the fellow eye 
has AMD, the fellow eye may receive any locally approved non-systemic treatment. If the 
fellow eye shall be treated pharmacologically, the most appropriate treatment option that is 
approved by the governing health authorities may be selected at the investigator’s discretion 
in the subject’s best interest.
If no drug therapy has been approved for the indication or if the approved therapy is not 
appropriate due to medical reasons, a non-approved pharmacological approach may be 
selected, if it can be considered as local standard of care.
If it is determined that aflibercept is the most appropriate treatment option for the fellow eye, 
this will still not be regarded as a study treatment and 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.  


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Section 9 Procedures and variables
Clarification of the period durations per Modification 2 (Section 15.1.1.2)
Time windows were consolidated for all post-baseline visits in both treatment groups to 
± 3 days relative to baseline per Modification 3 (Section 15.1.1.3)
Old text:
The study comprises a screening phase (Visit 1; -8 weeks [10 days] to Day 1), Baseline 
(Visit 2, Day 1), a 72-week treatment phase for the 2Q8 group, and up to 76 weeks for the 
extended-dosing group. All post-baseline study visits may deviate by ± 3 days.  
New text:
The study comprises a screening phase (Visit 1; up to 66 days prior to Day 1), Baseline 
(Visit 2, Day 1), a 72-week treatment phase (for the 2Q8 group), and a final study visit at 
Week 76 or an early termination visit. All scheduled post-baseline study visits may deviate by 
± 3 days relative to baseline.  
Section 9.1 Tabular schedule of evaluations
Clarification of the period durations per Modification 2 (Section 15.1.1.2)
Time windows were consolidated for all post-baseline visits in both treatment groups to 
± 3 days relative to baseline per Modification 3 (Section 15.1.1.3)
Clarification that the final visit procedures should also be conducted in the case of early 
termination per Modification 16 (Section 15.1.1.16)
Addition of urine dipstick test at the baseline visit per Modification 17 (Section 15.1.1.17)
Added foot note (numbered now as h) ‘The urine dipstick pregnancy test is to be repeated as 
frequently as required following the investigator’s medical judgment and local regulations’ to 
the Tabular schedule of evaluations; added that it is required at Visit 13 (final visit or early 
termination);  and moved the pregnancy test in the Schedule of assessments and study 
procedures from Initiation procedures to Standard safety per Modification 18 
(Section 15.1.1.18).
Arranging the footnotes in the order the table is read, line by line; and minor clarifications 
regarding pre-and post-dose assessments for indirect ophthalmoscopy and IOP per 
Modification 19 (Section 15.1.1.19)
Removed sample study drug injection protocol from the appendix per Modification 20 
(Section 15.1.1.20).


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Old text:
Table 9-1:
Schedule of assessments and study procedures 
Visit number a
Screening
Visit 1
Baseline (BL)
Visit 2
Visits 3 - 8
Prim. compl.
Visit 9
Visits10 -12
Final visit
Visit 13h
Time 
pointa 2Q8 group
-8 weeks to 
BL (10 days)
(both groups)
Day 1
(both groups)
Weeks 8 – 48
Week 52
(both groups)
Week56, 64, 72
Week 76
(both groups)
Extended-dosing group
Flex. intervals
(≥8 weeks) 
Flex. intervals
(≥8 weeks) 
Initiation procedures
Informed consent 

Demographic data

Medical / ophthalmic history 

Physical examination

Serum pregnancy test 
(women of childbearing potential only)

PT / INR and PTT

Inclusion / exclusion criteria


Study medication
Randomization

Administration of study treatment f


extended-
dosing only i

extended-
dosing only i,j
Ophthalmologic assessments
BCVA (ETDRS chart starting at 4 m) g






Optical coherence tomography






Fluorescein angiogr., fundus photogr.



Indirect ophthalmoscopy d






Slit lamp biomicroscopy






Intraocular pressure (IOP) e






Standard safety
Prior / concomitant medications






Adverse events c





Vital signs (temp., blood pressure, HR)






Hematology / chemistry 


Urinalysis / UPCR


Other
NEI VFQ-25 b



BCVA = Best corrected visual acuity;  ETDRS = Early Treatment Diabetic Retinopathy Study; HR = heart rate;  
NEI VFQ-25 = National Eye Institute 25-item Visual Function Questionnaire;  PT/INR = Prothrombin time / International 
normalized ratio;  PTT = Partial thromboplastin time;  UPCR = Urine protein/creatinine ratio
a: Visit schedules may deviate by ± 3 days relative to baseline. Scheduled visits should not be altered due to the deviation of 
the previous visit.  
Visit numbers refer to the mandatory visits for treatment administration to subjects in the 2Q8 group. Fewer visits may be 
required for subjects in the extended-dosing group, for whom extended-dosing intervals are indicated.
b: The NEI VFQ-25 is to be administered in a quiet room by a person certified to administer the questionnaire
c: Any AE occurring up to 4 weeks after the last 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 4 weeks after the last application of aflibercept, the standard procedures that 
are in place for spontaneous reporting will be followed.
d: Pre- and post-dose at visits with study drug administration
e: Pre-dose and 30-60 minutes post-injection at visits with study drug administration
f:
See Section 16.1 for an example study drug injection protocol.
g: Refraction to be done at each visit
h: Also to be conducted in case of premature discontinuation of study participation
i:
Extended-dosing subjects may receive injections at Week 52 or 76 depending on their individual schedule.
j:
If an extended-dosing subject receives an injection at Week 76, follow-up is needed on any adverse events (including ongoing 
events) that may occur within 4 weeks following this treatment (AE reporting under this protocol; i.e. not as spontaneous reports)


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New text:
Table 9-1:
Schedule of assessments and study procedures 
Visit number a
Screening
Visit 1
Baseline (BL)
Visit 2
Visits 3 - 8
Prim. compl.
Visit 9
Visits10 -12
Final visit 
Visit 13
or early term.
Time 
pointa 2Q8 group
Up to 66 
days prior
to BL
(both groups)
Day 1
(both groups)
Weeks 8 – 48
Week 52
(both groups)
Week56, 64, 72
Week 76
(both groups)
Extended-dosing group
Flex. intervals
(≥8 weeks) 
Flex. intervals
(≥8 weeks) 
Initiation procedures
Informed consent 

Demographic data

Medical / ophthalmic history 

Physical examination

PT / INR and PTT

Inclusion / exclusion criteria


Study medication
Randomization

Administration of study treatment


extended-
dosing only b

extended-
dosing 
only b,c
Ophthalmologic assessments
BCVA (ETDRS chart starting at 4 m) d






Optical coherence tomography






FA, FP



Indirect ophthalmoscopy e






Slit lamp biomicroscopy






Intraocular pressure (IOP) f






a: All post-baseline visits may deviate by ± 3 days relative to baseline. In the 2Q8 group, scheduled visits should not be altered 
due to the deviation of the previous visit.  
Visit numbers refer to the mandatory visits for treatment administration to subjects in the 2Q8 group. Fewer visits may be 
required for subjects in the extended-dosing group, for whom extended-dosing intervals are indicated.
b: Extended-dosing subjects may receive injections at Week 52 or 76 depending on their individual schedule.
c: If an extended-dosing subject receives an injection at Week 76, follow-up is needed on any adverse events (including 
ongoing events) that may occur within 4 weeks following this treatment (AE reporting under this protocol; i.e. not as 
spontaneous reports)
d: Refraction to be done at each visit
e: Also post-injection at visits with study drug administration
f:
Also 30-60 minutes post-injection at visits with study drug administration 
(Table continued on next page)


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Table 9-1 (continued): Schedule of assessments and study procedures 
Visit number a
Screening
Visit 1
Baseline (BL)
Visit 2
Visits 3 - 8
Prim. compl.
Visit 9
Visits10 -12
Final visit 
Visit 13
or early term.
Time 
pointa 2Q8 group
Up to 66 
days prior
to BL
(both groups)
Day 1
(both groups)
Weeks 8 – 48
Week 52
(both groups)
Week56, 64, 72
Week 76
(both groups)
Extended-dosing group
Flex. intervals
(≥8 weeks) 
Flex. intervals
(≥8 weeks) 
Standard safety
Prior / concomitant medications






Adverse events g





Vital signs (temp., blood pressure, HR)






Hematology / chemistry 


Urinalysis / UPCR


Serum pregnancy test (women of 
childbearing potential only)

Urine dipstick pregnancy test 
(women of childbearing potential only) h


Other
NEI VFQ-25 i



BCVA = Best corrected visual acuity;  early term. = early termination; ETDRS = Early Treatment Diabetic Retinopathy Study;  
FA = fluorescein angiography;  FP = fundus photography; HR = heart rate;  NEI VFQ-25 = National Eye Institute 25-item Visual 
Function Questionnaire;  PT/INR = Prothrombin time / International normalized ratio;  PTT = Partial thromboplastin time;  
UPCR = Urine protein/creatinine ratio
a: All post-baseline visits may deviate by ± 3 days relative to baseline. In the 2Q8 group, scheduled visits should not be altered 
due to the deviation of the previous visit.  
Visit numbers refer to the mandatory visits for treatment administration to subjects in the 2Q8 group. Fewer visits may be 
required for subjects in the extended-dosing group, for whom extended-dosing intervals are indicated.
g: Any AE occurring up to 4 weeks after the last 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 4 weeks after the last application of aflibercept, the standard procedures that 
are in place for spontaneous reporting will be followed.
h: The urine dipstick pregnancy test is to be repeated as frequently as required following the investigator’s medical judgment 
and local regulations.
i:
The NEI VFQ-25 is to be administered in a quiet room by a person certified to administer the questionnaire


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Section 9.2.1 Screening visit (Visit 1)
Clarification of the period durations per Modification 2 (Section 15.1.1.2); replaced reference 
of study manual with reference to reading center acquisition protocol per Modification 7 
(Section 15.1.1.7)
Old text:
Scheduling:  Both treatment groups:  Week -8 (10 days) to Day 1
…

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA) 86

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)
New text:
Scheduling:  Both treatment groups:  Up to 66 days prior to Day 1
…

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA) 87

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)
                                                
86 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.
87 The reading center acquisition protocol will further specify the standards for FA/FP during the study.


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Section 9.2.2 Baseline visit (Visit 2)
Added a urine dipstick pregnancy test to the baseline visit per Modification 17 
(Section 15.1.1.17)
Clarified the re-assessment of inclusion and exclusion criteria at the Baseline visit per 
Modification 21 (Section 15.1.1.21)
Post-injection ocular assessments added per Modification 22 (Section 15.1.1.22)
Old text:
Scheduling:  Both treatment groups:  Day 1
The following procedures will be performed at this visit:

Assessment of inclusion and exclusion criteria (see Sections 6.1 and 6.2 for details)

Randomization (see Section 7.3 for details)

…

Application of study medication (see Section 7.4 for details)
New text:
Scheduling:  Both treatment groups: Day 1
The following procedures will be performed at this visit:

Re-check of inclusion and exclusion criteria (see Sections 6.1 and 6.2 for details)

Including urine dip stick pregnancy test for women of childbearing potential 

Randomization (see Section 7.3 for details)

…

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):

Indirect ophthalmoscopy

Intraocular pressure (IOP)


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Section 9.2.3 Visits between baseline and Week 52
Post-injection ocular assessments added per Modification 22 (Section 15.1.1.22)
Old text:
…

Application of study medication (see Section 7.4 for details)
New text:
…

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):

Indirect ophthalmoscopy

Intraocular pressure (IOP)
Section 9.2.4 Primary completion (Week 52)
Replaced reference of study manual with reference to reading center acquisition protocol per 
Modification 7 (Section 15.1.1.7)
Post-injection ocular assessments for subjects in the extended dosing group who receive study 
medication at this visit added per Modification 22 (Section 15.1.1.22)
Old text:
The following procedures will be performed at this visit:

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA) 88

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Vital signs (body temperature, blood pressure and heart rate) (see Section 9.6.3.3 for details)

Record of NEI VFQ-25 (see Section 9.7 for details)
                                                
88 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.


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New text:
The following procedures will be performed at this visit:

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA) 89

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Vital signs (body temperature, blood pressure and heart rate) (see Section 9.6.3.3 for 
details)

Record of NEI VFQ-25 (see Section 9.7 for details)
Subjects in the extended dosing group if they receive injections at this visit (depending on 
their individual schedule):

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):

Indirect ophthalmoscopy

Intraocular pressure (IOP)
                                                
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Section 9.2.5 Visits between primary completion (Week 52) and end of study (Week 76)
Changed end of study visit to final visit per Modification 16 (Section 15.1.1.16)
Added the full list of study procedures instead of a reference only per Modification 23 
(Section 15.1.1.23)
Post-injection ocular assessments added per Modification 22 (Section 15.1.1.22)
Old text:
Section 9.2.5 Visits between primary completion (Week 52) and end of study visit 
(Week 76)  
Scheduling:
2Q8 group:
Fixed visit schedule every 8 weeks
Visits 10 (Week 56) to 12 (Week 72)
Extended-dosing group:
Individualized flexible schedule with intervals ≥8 weeks
Visit numbers depend on individual schedule
(extended-dosing subjects may have fewer visits than 
2Q8 subjects)
The conduct of any of these visits will be identical to the visits between baseline and Week 52 
as described in Section 9.2.3.
New text:
Section 9.2.5 Visits between primary completion (Week 52) and final visit (Week 76)  
Scheduling:
2Q8 group:
Fixed visit schedule every 8 weeks
Visits 10 (Week 56) to 12 (Week 72)
Extended-dosing group:
Individualized flexible schedule with intervals ≥8 weeks
Visit numbers depend on individual schedule
(extended-dosing subjects may have fewer visits than 
2Q8 subjects)
The following procedures will be performed at any of these visits:

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)


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
Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Vital signs (body temperature, blood pressure and heart rate) (see Section 9.6.3.3 for 
details)

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):

Indirect ophthalmoscopy

Intraocular pressure (IOP)
Section 9.2.6 End of study (Week 76)
Clarified that the final visit procedures should also be conducted in the case of early 
termination per Modification 16 (Section 15.1.1.16)
Added that a urine dipstick pregnancy test is required at the final visit or early termination per 
Modification 18 (Section 15.1.1.18)
Post-injection ocular assessments for subjects in the extended dosing group who receive study 
medication at this visit added per Modification 22 (Section 15.1.1.22)
Added the full list of study procedures instead of a reference only per Modification 23 
(Section 15.1.1.23)
Old text:
Section 9.2.6 End of study (Week 76) 
Scheduling:  Both treatment groups:  Week 76 
The conduct of any of this visit will be identical to the visit at Week 52 as described in 
Section 9.2.4.


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New text:
Section 9.2.6 Final visit (Week 76) or early termination
Scheduling:  Both treatment groups:  Week 76 
This visit will also be conducted in case of early termination of a subject.
The following procedures will be performed at this visit:

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA) 90

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intra-ocular pressure (IOP)

Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Vital signs (body temperature, blood pressure and heart rate) (see Section 9.6.3.3 for 
details)

Urine dip stick pregnancy test for women of childbearing potential

Record of NEI VFQ-25 (see Section 9.7 for details)
Subjects in the extended dosing group if they receive injections at this visit (depending on 
their individual schedule):

Application of study medication (see Section 7.4 for details)

Post-injection ocular assessments (see Section 9.4.1 for details):

Indirect ophthalmoscopy

Intraocular pressure (IOP)
                                                
90 The reading center acquisition protocol will further specify the standards for FA/FP during the study.


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Section 9.4.1.1 Best corrected visual acuity
Removed reference to study manual and added references to reading center acquisition 
protocol for FA and FP per Modification 7 (Section 15.1.1.7)
Old text:
Visual function of the study eye and the fellow eye will be assessed using the ETDRS 
protocol (The Early Treatment Diabetic Retinopathy Study Group, 1985) at starting at 
4 meters. Visual Acuity (VA) examiners must be certified to ensure consistent measurement 
of BCVA. A detailed protocol for conducting VA 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 (The Early Treatment Diabetic Retinopathy Study Group, 1985) at starting at 
4 meters. Visual Acuity (VA) examiners must be certified to ensure consistent measurement 
of BCVA.  
Section 9.4.1.2 Optical coherence tomography (OCT)
Reworded description of OCT in efficacy section per Modification 24 (Section 15.1.1.24).
Old text:
Retinal and lesion characteristics will be evaluated using OCT on the study eye. For all visits 
where the OCT procedure is scheduled, images on the study eye and fellow eye will be 
captured, transmitted to, and read by the independent reading center; at screening, OCT 
images will be captured on both eyes. All OCTs will be electronically archived at the study 
sites as part of the source documentation. OCT technicians must be certified by the reading 
center to ensure consistency and quality in image acquisition.
New text:
Retinal and lesion characteristics will be evaluated using OCT. OCT-images of the study eye 
and fellow eye will be captured, transmitted to, and read by the independent reading center.
All OCTs will be electronically archived at the study sites as part of the source 
documentation. OCT technicians and equipment must be certified by the reading center to 
ensure consistency and quality in image acquisition.


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Section 9.4.1.6 Fundus photography (FP) and fluorescein angiography (FA)
Replaced reference of study manual with reference to reading center acquisition protocol per 
Modification 7 (Section 15.1.1.7)
Added requirement to archive FA and FP images electronically, clarified the confirmation of 
eligibility by the reading center, and re-ordered paragraphs per Modification 25 
(Section 15.1.1.25)
Old text:
The anatomical state of the retinal vasculature of the study eye will be evaluated by 
funduscopic examination, FP and FA.  
The study eye will be the transit eye. For all visits where the funduscopic examination, FP, 
and FA procedure are scheduled, FP and FA will be performed on both eyes. FP and FA from 
the screening visit (Visit 1) will be captured and transmitted for both eyes and reviewed 
before randomization.  
Fundus and angiographic images will be sent to an independent reading center where images 
will be read. All FA and FP images will be archived at the site as part of the source 
documentation. Although FA is performed on both eyes, only the study eye will be evaluated 
by the independent reading center. Photographers must be certified by the reading center to
ensure consistency and quality in image acquisition.  
A detailed protocol for FP and FA image acquisition and assessment can be found in the FA 
Study Manual 91.
The treating investigator may perform additional FA/FP at other times during the study based 
on his/her medical judgment and standard of care.
New text:
The anatomical state of the retinal vasculature of the study eye will be evaluated by 
funduscopic examination, FP and FA.  
The study eye will be the transit eye. For all visits where the funduscopic examination, FP, 
and FA procedure are scheduled, FP and FA will be performed on both eyes. 
Fundus and angiographic images will be sent to an independent reading center where images 
will be read. All FA and FP images will be archived electronically at the site as part of the 
source documentation. Although FA is performed on both eyes, only the study eye will be 
evaluated by the independent reading center. Photographers must be certified by the reading 
center to ensure consistency and quality in image acquisition.  
                                                
91 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.


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FP and FA from the screening visit (Visit 1) will be captured and transmitted for both eyes to 
an independent reading center where images will be read. A formal check will be done and 
eligibility will be confirmed by the reading center before randomization.
A detailed protocol for FP and FA image acquisition and assessment can be found in the 
reading center acquisition protocol92.
The treating investigator may perform additional FA/FP at other times during the study based 
on his/her medical judgment and standard of care.
Section 9.6.1.1 Definitions
Removal of reference to ECG per Modification 26 (Section 15.1.1.26)
Old text:
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory findings, 
ECG findings, or other abnormal findings.
New text:
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.
Section 9.6.1.2.4 Action taken with study treatment
Removal of “Dose reduced” from possible actions taken with study treatment per 
Modification 27 (Section 15.1.1.27)
Old text:
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.
Drug withdrawn
Drug interrupted
Dose reduced
Dose not changed
Not applicable
Unknown
                                                
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New text:
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
Section 9.6.1.5 Expected adverse events
Reference to summary of product characteristics replaced with reference to local label for 
information on AEs per Modification 28 (Section 15.1.1.28).
Old text:
For this study, the applicable reference document is the most current version of the summary 
of product characteristics.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
New text:
Information on AEs with an onset after the first application of the test drug is provided in the 
local label.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.


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Section 9.6.2 Pregnancies
New paragraph on fertility and guidance regarding the follow-up after birth added to the 
pregnancy section per Modification 29 (Section 15.1.1.29)
Old text:
The investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.
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.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE. 
New text:
The investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.
The child’s health should be followed up until three months after birth.
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.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE. 
Results from animal studies with high systemic exposure indicate that aflibercept can impair 
male and female fertility. Such effects are not expected after ocular administration with very 
low systemic exposure.


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Section 9.6.3.1 Laboratory evaluations
Specification and timing of pregnancy test changed per Modification 17 (Section 15.1.1.17) 
and Modification 18 (Section 15.1.1.18)
Clarification of time point of blood withdrawal with respect to FA per Modification 30 
(Section 15.1.1.30)
Old text:
Laboratory evaluation will be conducted according to the schedule provided in Section 9.1.
Blood will be drawn by direct venipuncture. 
Safety laboratory parameters to be evaluated are summarized in Table 9-2.
The exact date and time (24-hour clock) of each blood sample obtained will be recorded on 
the appropriate eCRF page. All laboratory tests will be performed at a central laboratory.
A copy of the results will be filed in the source documentation.
Table 9-2:
Laboratory safety parameters
Chemistry
Sodium
Potassium
Chloride
Calcium
Glucose
Albumin
Total Protein, Serum
Creatinine
Blood urea nitrogen (BUN)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Total bilirubin
Amylase
Total cholesterol
HDL cholesterol
Serum pregnancy test for women 
of childbearing potential
Urinalysis 
Glucose 
Protein
Specific Gravity
Blood
Ketones 
Protein:Creatinine Ratio (UPCR)
Coagulation
Prothrombin time (PT)
Partial thromboplastin time (PTT)
International normalized ratio (INR)
Hematology
Hemoglobin
Hematocrit
Red blood cell count
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin 
concentration (MCHC)
Mean corpuscular hemoglobin (MCH)
Leucocyte count
Differential count
Neutrophils
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
HDL:  high-density lipoprotein


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New text:
Laboratory evaluation will be conducted according to the schedule provided in Section 9.1
(beyond that schedule, pregnancy tests are to be done in women of childbearing potential as 
frequently as outlined in Table 9-1).
Blood will be drawn before FA by direct venipuncture. 
Safety laboratory parameters to be evaluated are summarized in Table 9-2.
The exact date and time (24-hour clock) of each blood sample obtained will be recorded on 
the appropriate eCRF page. All laboratory tests will be performed at a central laboratory.
A copy of the results will be filed in the source documentation.
Table 9-2:
Laboratory safety parameters - amended
Chemistry
Sodium
Potassium
Chloride
Calcium
Glucose
Albumin
Total Protein, Serum
Creatinine
Blood urea nitrogen (BUN)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Total bilirubin
Amylase
Total cholesterol
HDL cholesterol
Pregnancy test for women of 
childbearing potential (see 
Table 9-1)
Urinalysis 
Glucose 
Protein
Specific Gravity
Blood
Ketones 
Protein:Creatinine Ratio (UPCR)
Coagulation
Prothrombin time (PT)
Partial thromboplastin time (PTT)
International normalized ratio (INR)
Hematology
Hemoglobin
Hematocrit
Red blood cell count
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin 
concentration (MCHC)
Mean corpuscular hemoglobin (MCH)
Leucocyte count
Differential count
Neutrophils
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
HDL:  high-density lipoprotein


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Section 9.7 Patient-reported outcome -NEI VFQ-25
Requirement to document the name of the person assisting the subject in completing the 
NEI VFQ-25 questionnaire added per Modification 31 (Section 15.1.1.31)
Old text:
Vision-related quality of life will be assessed using the NEI VFQ-25 questionnaire 
(Section 16.1). This questionnaire will be presented in the local language and should be 
administered in a quiet room by a person certified to administer this type of questionnaire, 
preferably before other visit procedures are performed. For subjects unable to read the 
questionnaire owing to vision impairment, a family member, other legal representative of the 
subject, study nurse, or study physician may assist the subject in completing the 
questionnaire.
New text:
Vision-related quality of life will be assessed using the NEI VFQ-25 questionnaire 
(Section 16.1). This questionnaire will be presented in the local language and should be 
administered in a quiet room by a person certified to administer this type of questionnaire, 
preferably before other visit procedures are performed. For subjects unable to read the 
questionnaire owing to vision impairment, a family member, other legal representative of the 
subject, study nurse, or study physician may assist the subject in completing the 
questionnaire. In this case, the name of that person should be documented.
Section 10.3.2.2 Efficacy analyses
Added example of possible analysis per Modification 35 (Section 15.1.1.35)
Old text:
As sensitivity analyses, the primary efficacy and key secondary efficacy analyses will be 
repeated on the Per-Protocol Set as defined in Section 10.2.  
New text:
As sensitivity analyses, the primary efficacy and key secondary efficacy analyses will be 
repeated on the Per-Protocol Set as defined in Section 10.2.  
The analysis can also include, if applicable, BCVA evolution over the course of pre-study 
aflibercept treatment, starting with the initial BCVA value as captured in the first set of 
inclusion criteria. Snellen-equivalents may therefore be converted into ETDRS letter scores.


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Section 11.3 Data processing
Removal of reference to ECG per Modification 26 (Section 15.1.1.26)
Minor rewording (changed examples) per Modification 32 (Section 15.1.1.32)
Old text:
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 CRF as well as for data from other sources 
(e.g. IVRS, laboratory, ECG, ePRO, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
New text:
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 CRF as well as for data from other sources 
(e.g. IVRS, laboratory, reading center, adjudication committees).
For data coding (e.g. AEs, medication, surgeries), internationally recognized and accepted 
dictionaries will be used.


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Section 13.4 Subject information and informed consent
Revised to align with sponsor standards per Modification 33 (Section 15.1.1.33).
Old text:
Each subject will be informed about the following aspects of premature withdrawal:
…
Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan. 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.
…
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
New text:
Each subject will be informed about the following aspects of premature withdrawal:
…
Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan. The subject has the right to object to the 
generation and processing of this post-withdrawal data.  
…
In the event that informed consent is obtained on the date that baseline 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 unable to read the informed consent form due to vision impairment, a family 
member, other legal representative of the subject, study nurse, or study physician should read 
the document verbatim to the subject. A discussion and explanation, including answering all 
questions from the subject, should also occur prior to the subject or their legal representative 
signing the form. An impartial witness should be present during the entire informed consent 
discussion. The witness must be unaffiliated with the conduct of the study, and will also sign 
and date the document along with the subject or their legal representative.


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Section 16.1 Drug administration protocol
Removal of the Appendix Drug administration protocol per Modification 20 
(Section 15.1.1.20).
Section 16.1 Drug administration protocol
Study Drug Dose and Volume for Administration.  
The supplied kits include a fill needle, injection needle and 1 syringe.
VEGF Trap-Eye is formulated as a sterile liquid to a final concentration of 40 mg/mL VEGF 
Trap in 5% sucrose, 10 mM sodium phosphate pH 6.3, 0.03% polysorbate 20, and 40 mM 
NaCl in water for injection. VEGF Trap-Eye study drug will be supplied by the sponsor in 
sealed, sterile 2-mL vials each with a withdrawable volume of 0.5 mL. The volume of 
injection will be 50 L (0.05 mL) for the 2 mg dose of VEGF Trap. The study drug will be 
withdrawn using aseptic technique through an 18 gauge fill 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.
VEGF Trap-Eye vials are to be stored at 2C to 8C. Freezing of the drug is to be avoided. 
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. Exposure of the material to temperatures 
outside these limits, except for warming prior to administration, is not recommended and may 
result in loss of activity. Records of actual storage conditions (i.e. temperature log) at the 
study site must be maintained; and must include a record of the dates, when the refrigerator 
was checked, the initials of person checking, and the temperature.
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; the injection of VEGF Trap-Eye must be completed within 2 hours of the start of 
dose preparation.


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16.
Appendices
16.1
National Eye Institute 25-item visual function questionnaire
PB/IA
National Eye Institute 
Visual Functioning Questionnaire - 25
(VFQ-25)
version 2000
(INTERVIEWER ADMINISTERED FORMAT)
January 2000
RAND hereby grants permission to use the "National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25) July 1996, in accordance 
with the following conditions which shall be assumed by all to have been agreed to as a consequence of accepting and using this document:
1. Changes to the NEI VFQ-25 - July 1996 may be made without the written permission of RAND. However, all such changes shall be 
clearly identified as having been made by the recipient.
2. The user of this NEI VFQ-25 - July 1996 accepts full responsibility, and agrees to hold RAND harmless, for the accuracy of any 
translations of the NEI VFQ-25 Test Version - July 1996 into another language and for any errors, omissions, misinterpretations, or 
consequences thereof.
3. The user of this NEI VFQ-25 - July 1996 accepts full responsibility, and agrees to hold RAND harmless, for any consequences resulting 
from the use of the NEI VFQ-25.
4. The user of the NEI VFQ-25 - July 1996 will provide a credit line when printing and distributing this document or in publications of 
results or analyses based on this instrument acknowledging that it was developed at RAND under the sponsorship of the National Eye 
Institute.
5. No further written permission is needed for use of this NEI VFQ-25 - July 1996. 
7/29/96
© R 1996
Per Amendment 2 (Section 15.1.1.20,) the Drug administration protocol was removed from the appendix.


Integrated Clinical Study Protocol
No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 125 of 134
Instructions:
I’m going to read you some statements about problems which involve your vision or 
feelings that you have about your vision condition. After each question I will read you a 
list of possible answers. Please choose the response that best describes your situation.
Please answer all the questions as if you were wearing your glasses or contact lenses (if 
any).
Please take as much time as you need to answer each question. All your answers are 
confidential. In order for this survey to improve our knowledge about vision problems 
and how they affect your quality of life, your answers must be as accurate as possible.
Remember, if you wear glasses or contact lenses for a particular activity, please answer 
all of the following questions as though you were wearing them.


Integrated Clinical Study Protocol
No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 126 of 134
Visual Functioning Questionnaire - 25
PART 1 - GENERAL HEALTH AND VISION
1.
In general, would you say your overall health is*: 
(Circle One)
READ CATEGORIES:
Excellent................................... 1
Very Good................................ 2
Good......................................... 3
Fair ........................................... 4
Poor .......................................... 5
2.
At the present time, would you say your eyesight using both eyes (with glasses or 
contact lenses, if you wear them) is excellent, good, fair, poor, or very poor or are you 
completely blind?
(Circle One)
READ CATEGORIES:
Excellent................................... 1
Good......................................... 2
Fair ........................................... 3
Poor .......................................... 4
Very Poor ................................. 5
Completely Blind ..................... 6
______________________
* Skip Question 1 when the VFQ-25 is administered at the same time as the SF-36 or RAND 36-Item Health 
Survey 1.0


Integrated Clinical Study Protocol
No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 127 of 134
3.
How much of the time do you worry about your eyesight?
(Circle One)
READ CATEGORIES:
None of the time................................... 1
A little of the time ................................ 2
Some of the time .................................. 3
Most of the time ................................... 4
All of the time?..................................... 5
4.
How much pain or discomfort have you had in and around your eyes (for example, 
burning, itching, or aching)? Would you say it is:
(Circle One)
READ CATEGORIES:
None ......................................... 1
Mild.......................................... 2
Moderate................................... 3
Severe, or.................................. 4
Very severe?............................. 5
PART 2 - DIFFICULTY WITH ACTIVITIES
The next questions are about how much difficulty, if any, you have doing certain activities 
wearing your glasses or contact lenses if you use them for that activity.
5.
How much difficulty do you have reading ordinary print in newspapers? Would you say 
you have:
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6


Integrated Clinical Study Protocol
No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 128 of 134
6.
How much difficulty do you have doing work or hobbies that require you to see well up 
close, such as cooking, sewing, fixing things around the house, or using hand tools? 
Would you say:
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6
7.
Because of your eyesight, how much difficulty do you have finding something on a 
crowded shelf?
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6
8.
How much difficulty do you have reading street signs or the names of stores?
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6


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No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 129 of 134
9.
Because of your eyesight, how much difficulty do you have going down steps, stairs, or 
curbs in dim light or at night? 
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6
10.
Because of your eyesight, how much difficulty do you have noticing objects off to the 
side while you are walking along?
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6
11.
Because of your eyesight, how much difficulty do you have seeing how people react to 
things you say?
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6


Integrated Clinical Study Protocol
No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 130 of 134
12.
Because of your eyesight, how much difficulty do you have picking out and matching 
your own clothes?
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6
13.
Because of your eyesight, how much difficulty do you have visiting with people in their 
homes, at parties, or in restaurants?
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6
14.
Because of your eyesight, how much difficulty do you have going out to see movies, 
plays, or sports events?
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all .............................................................. 1
A little difficulty................................................................. 2
Moderate difficulty............................................................. 3
Extreme difficulty .............................................................. 4
Stopped doing this because of your eyesight ..................... 5
Stopped doing this for other reasons or not 
interested in doing this ....................................................... 6


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No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 131 of 134
15.
Now, I’d like to ask about driving a car. Are you currently driving, at least once in a 
while?
(Circle One)
Yes.......................... 1
Skip To Q 15c
No........................... 2
15a.
IF NO, ASK: Have you never driven a car or have you given up driving?
(Circle One)
Never drove............ 1
Skip To Part 3, Q 17
Gave up .................. 2
15b.
IF GAVE UP DRIVING: Was that mainly because of your eyesight, mainly for 
some other reason, or because of both your eyesight and other reasons?
(Circle One)
Mainly eyesight.......................................... 1
Skip To Part 3, Q 17
Mainly other reasons .................................. 2
Skip To Part 3, Q 17
Both eyesight and other reasons................. 3
Skip To Part 3, Q 17
15c.
IF CURRENTLY DRIVING: How much difficulty do you have driving during 
the daytime in familiar places? Would you say you have:
(Circle One)
No difficulty at all ...................................... 1
A little difficulty......................................... 2
Moderate difficulty..................................... 3
Extreme difficulty ...................................... 4


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No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 132 of 134
16.
How much difficulty do you have driving at night? Would you say you have: (READ 
CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all ............................................ 1
A little difficulty............................................... 2
Moderate difficulty........................................... 3
Extreme difficulty ............................................ 4
Have you stopped doing this because
of your eyesight................................................ 5
Have you stopped doing this for other 
reasons or are you not interested in 
doing this.......................................................... 6
16a. How much difficulty do you have driving in difficult conditions, such as in bad weather, 
during rush hour, on the freeway, or in city traffic? Would you say you have:
(READ CATEGORIES AS NEEDED)
(Circle One)
No difficulty at all ............................................ 1
A little difficulty............................................... 2
Moderate difficulty........................................... 3
Extreme difficulty ............................................ 4
Have you stopped doing this because
of your eyesight................................................ 5
Have you stopped doing this for other 
reasons or are you not interested in 
doing this.......................................................... 6


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No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 133 of 134
PART 3: RESPONSES TO VISION PROBLEMS
The next questions are about how things you do may be affected by your vision. For each one, 
I’d like you to tell me if this is true for you all, most, some, a little, or none of the time.
(Circle One On Each Line)
READ CATEGORIES:
All of the 
time
Most of 
the time
Some of 
the time
A little 
of the 
time
None of 
the time
17. Do you accomplish 
less than you would 
like because of your vision?.
1
2
3
4
5
18. Are you limited in how long 
you can work or do other 
activities because 
of your vision? .....................
1
2
3
4
5
19. How much does pain or 
discomfort in or around your 
eyes, for example, burning, 
itching, or aching, keep you 
from doing what you’d like to 
be doing?
Would you say: ....................
1
2
3
4
5


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No. BAY 86-5321 / 16598   
10 DEC 2015   
Page 134 of 134
For each of the following statements, please tell me if it is definitely true, mostly true, mostly 
false, or definitely false for you or you are not sure.
(Circle One On Each Line)
Definitely
Mostly
Not
Mostly
Definitely
True
True
Sure
False
False
20.
I stay home most of the time
because of my eyesight. ...........
1
2
3
4
5
21.
I feel frustrated a lot of the 
time because of my 
eyesight.....................................
1
2
3
4
5
22.
I have much less control 
over what I do, because of 
my eyesight. .............................
1
2
3
4
5
23.
Because of my eyesight, 
I have to rely too much 
on what other people 
tell me.......................................
1
2
3
4
5
24.
I need a lot of help from 
others because of my 
eyesight.....................................
1
2
3
4
5
25.
I worry about doing things
that will embarrass myself
or others, because of my
eyesight.....................................
1
2
3
4
5
That’s the end of the interview. Thank you very much for your time and your help. 

SAP_000.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
An open-label, randomized, active-controlled, parallel-group, Phase-
3b study of the efficacy, safety, and tolerability of 2 mg aflibercept 
administered by intravitreal injections using two different treatment 
regimens to subjects with neovascular agerelated macular 
degeneration (nAMD) 
NCT Number: 
NCT02540954 
Document Date: 
31-Jan-2020 
 


Statistical Analysis Plan
Protocol No.: BAY86-5321/ 16598
Page:
1 of
42
An open-label, randomized, active-controlled, parallel-group, Phase-3b study of the 
efficacy, safety, and tolerability of 2 mg aflibercept administered by intravitreal 
injections using two different treatment regimens to subjects with neovascular age-
related macular degeneration (nAMD)
Efficacy and safety of two different aflibercept regimens in subjects with nAMD
Bayer study drug
BAY86-5321/ aflibercept / VEGF Trap-Eye (Eylea)
Study purpose:
Post-approval commitment
Clinical study 
phase:
3b
Date:
31 Jan 2020
Study No.:
BAY86-5321 / 16598
Version:
3.0
Author:
Syneos Health
81929 Munich
Germany
Syneos Health 
Project Code:
04.6000.1005563
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) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
Protocol No.: BAY86-5321/ 16598
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Table of Contents
Abbreviations............................................................................................................................ 4
1
Introduction....................................................................................................................... 6
1.1
Objective.......................................................................................................................... 6
1.2
Background...................................................................................................................... 6
1.3
Rationale of the Study...................................................................................................... 7
1.4
List of Documents used ................................................................................................... 7
2
Study Objectives................................................................................................................ 7
3
Study Design ...................................................................................................................... 8
3.1
Design Overview ............................................................................................................. 8
3.2
Inclusion/Exclusion ......................................................................................................... 8
3.3
Visit Overview................................................................................................................. 9
3.4
Efficacy and Safety variables........................................................................................... 9
4
General Statistical Considerations ................................................................................ 12
4.1
General Principles.......................................................................................................... 12
4.2
Handling of Dropouts .................................................................................................... 12
4.3
Handling of Missing Data.............................................................................................. 13
4.3.1
Adverse Events........................................................................................................... 13
4.3.2
Efficacy Analysis........................................................................................................ 13
4.3.2.1
Last Observation Carried Forward.......................................................................... 14
4.3.2.2
Multiple Imputation................................................................................................. 14
4.3.2.3
Repeated Measurements Model .............................................................................. 15
4.3.2.4
Observed Cases ....................................................................................................... 15
4.3.3
Prior and Concomitant Medication / Medical History ............................................... 15
4.4
Interim Analyses and Data Monitoring ......................................................................... 15
4.5
Data Rules...................................................................................................................... 16
4.6
Validity Review ............................................................................................................. 18
5
Analysis Sets and Subgroups.......................................................................................... 18
5.1
Analysis Sets.................................................................................................................. 18
5.2
Definition of Subgroups................................................................................................. 19
6
Statistical Methodology .................................................................................................. 20
6.1
Population Characteristics ............................................................................................. 20
6.1.1
Study Periods and Sample Sizes................................................................................. 20
6.1.2
Subject Validity Status ............................................................................................... 20
6.1.3
Subject Disposition..................................................................................................... 20
6.1.4
Demographics and Baseline Characteristics............................................................... 21
6.1.5
Medical and Ophthalmological History ..................................................................... 23
6.1.6
Prior and Concomitant Medications........................................................................... 23
6.1.7
Exposure..................................................................................................................... 24


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6.2
Efficacy.......................................................................................................................... 25
6.2.1
Primary Efficacy Variable Analysis........................................................................... 26
6.2.2
Key Secondary Efficacy Variable .............................................................................. 27
6.2.3
Other Secondary Efficacy Variables .......................................................................... 28
6.2.3.1
Proportion of Subjects who gained from BL ≥5 Letters in the Study Eye.............. 28
6.2.3.2
Mean Change from BL in CRT in the Study Eye ................................................... 28
6.2.3.3
Mean Change from BL in CNV Area in the Study Eye.......................................... 28
6.2.3.4
Proportion of Subjects who lost ≥30 Letters in the Study Eye ............................... 29
6.2.3.5
Mean Change from BL in Total Score for NEI VFQ-25 ........................................ 29
6.2.4
Exploratory Efficacy Variables .................................................................................. 29
6.2.4.1
Proportion of Subjects for whom the Treatment Interval was extended................. 29
6.2.4.2
Total number of ivt Injections required in the Study Eye....................................... 30
6.2.4.3
Week 76 Analysis.................................................................................................... 30
6.3
Pharmacokinetics / Pharmacodynamics......................................................................... 30
6.4
Safety ............................................................................................................................. 31
6.4.1
Adverse Events (AEs) ................................................................................................ 31
6.4.2
Laboratory Evaluations and Pregnancy Tests ............................................................ 33
6.4.3
Further Safety ............................................................................................................. 34
6.4.3.1
Vital Signs............................................................................................................... 34
6.4.3.2
Surgeries after Start of Study .................................................................................. 34
6.4.3.3
Intra-Ocular Pressure (IOP) .................................................................................... 34
6.4.3.4
Slit Lamp Biomicroscopy........................................................................................ 35
6.4.3.5
Indirect Ophthalmoscopy........................................................................................ 35
7
References ........................................................................................................................ 38
8
Appendix.......................................................................................................................... 39
8.1
Calculation of the NEI VFQ-25 Scores ......................................................................... 39
8.2
Calculation of Confidence Intervals for Treatment Differences.................................... 42
8.2.1
Rates and Proportions................................................................................................. 42
8.2.2
Means ......................................................................................................................... 42


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Abbreviations
2Q8
2 mg aflibercept administered every 8 weeks 
AE
adverse event 
ALT
alanine aminotransferase 
AMD
age-related macular degeneration
ANCOVA
analysis of covariance 
APTC
Antiplatelet Trialists' Collaboration 
AST
aspartate aminotransferase 
ATC
Anatomical Therapeutic Chemical 
ATE
arterial thrombotic event 
BCVA
best corrected visual acuity 
BHC
Bayer HealthCare
BL
baseline
BMI
body mass index
BRVO
branch retinal vein occlusion
BUN
blood urea nitrogen 
CI
confidence interval
CNV
choroidal neovascularization 
CRF
case record form 
CRT
central retinal thickness 
CRVO
central retinal vein occlusion
DME
diabetic macular edema 
DMP
data monitoring plan 
eCRF
electronic case report form 
EMA
European Medicines Agency 
ETDRS
Early Treatment Diabetic Retinopathy Study 
EU
European Union 
EudraCT
EU Drug Regulating Authorities Clinical Trials 
FA 
fluorescein angiography 
FAS
full analysis set 
FP
fundus photography 
FPFV
First-Patient-First-Visit
HDL
high-density lipoprotein
INR
international normalized ratio
IOP 
intraocular pressure


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IVT 
intravitreal(ly)
LDM
Lead Data Manager
LOCF 
last observation carried forward
LS
least squares
MI
Multiple Imputations
MCH 
mean corpuscular hemoglobin
MCHC 
mean corpuscular hemoglobin concentration
mCNV
myopic choroidal neovascularization
MCV 
mean corpuscular volume
MedDRA 
Medical Dictionary for Regulatory Activities
nAMD
Neovascular macular degeneration
NEI VFQ-25
National Eye Institute 25-item Visual Function Questionnaire
OC 
observed cases
OCT 
optical coherence tomography
PDD
protocol deviation document
PPS 
per-protocol set
PT/INR 
prothrombin time
PT
preferred term
PTT 
partial thromboplastin time
RMM
repeated measurements model
SAE 
serious adverse event
SAF 
safety population
SAP 
statistical analysis plan
SOC 
system organ class
SOP
standard operating procedure
TEAE
treatment-emergent AE
UPCR 
urine protein/creatinine ratio
US
United States
VEGF 
vascular endothelial growth factor
VIEW 1
Vascular Endothelial Growth Factor VEGF Trap-Eye: Investigation of 
Efficacy and Safety in Wet Age-Related Macular Degeneration (AMD)
VIEW 2
A randomized, double masked, active controlled, phase 3 study of the 
efficacy, safety, and tolerability of repeated doses of intravitreal VEGF 
Trap-Eye in subjects with neovascular age-related macular degeneration 
(AMD)
VRM
Validity Review Meeting
VTE
VEGF Trap-Eye
WHODD
World Health Organization Drug Dictionary


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1
Introduction
1.1
Objective
This statistical analysis plan (SAP) describes the statistical methods and data presentations to 
be used in the summary and analyses of data from an open-label, randomized, active-
controlled, parallel-group, Phase-3b study of the efficacy, safety, and tolerability of 2 mg 
aflibercept administered by intravitreal injections using two different treatment regimens to 
subjects with neovascular age-related macular degeneration (nAMD).
This document is based on the Clinical Study Protocol No. BAY 86-5321 /16598, version 2.0, 
dated 10 December 2015. It describes the plans for the final analyses.
1.2
Background
Age-related macular degeneration (AMD) is a leading cause of adult blindness in the
developed world (5). 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 (1). 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 in the United States (US), European Union (EU), Japan and several other countries 
and for the treatment of macular edema secondary to central retinal vein occlusion (CRVO) in 
the US and several other countries. Phase-3 studies of aflibercept in diabetic macular edema 
(DME), branch retinal vein occlusion (BRVO), and myopic choroidal neovascularization 
(mCNV) are ongoing.
Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug.
The approval of aflibercept in the EU (22 November 2012) was based upon the results of two 
randomized, multicenter, double-masked, active-controlled Phase-3 clinical studies — the 
VIEW 1 (US and Canada) and VIEW 2 (EU, Asia/Pacific, and Latin America) studies. Both 
studies demonstrated after 52 weeks that aflibercept, dosed every 8 weeks following three 
initial monthly injections, provided efficacy that was non-inferior to monthly dosing of 
ranibizumab. The primary endpoint of these studies was the proportion of patients who 
maintained visual acuity (less than 15 letters of vision lost on the Early Treatment Diabetic 


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Retinopathy Study [ETDRS] chart) over 52 weeks. During the second year of these studies, 
the treatment interval could be extended (based on protocol-specified re-treatment criteria), 
with no more than 12 weeks allowed between injections, while the label allows an extension 
of the treatment interval beyond 12 weeks. To address the remaining issue regarding the 
optimal dosing frequency after 1 year of treatment with aflibercept, EMA requested a post-
authorization randomized study with primary objective of comparing the proactive 8-weekly 
injections to a reactive regimen based on visual and anatomic outcomes.
The approved EU labeling for aflibercept at the time-point of study design stated:
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.
1.3
Rationale of the Study
As a condition for approval, the European Medicines Agency (EMA) has required a study to 
assess every-other-month dosing versus an extended-dosing regimen with no maximum limit 
to the treatment interval. This Phase-3b post-authorization efficacy study has been designed to 
meet this obligation and compares a fixed dosing regimen of 2 mg aflibercept administered 
every 8 weeks (“2Q8 group”) to a flexible extended regimen of 2 mg aflibercept (“extended 
dosing group”) in patients with nAMD who have completed at least 1 year of treatment with 
aflibercept.
1.4
List of Documents used

Clinical Study Protocol No. BAY 86-5321 /16598, version 2.0, dated 10 December 2015

Protocol deviation document, version 8.0, dated 06 November 2018
2
Study Objectives
Primary objective
To compare the efficacy of 2 mg aflibercept administered by two different intravitreal (IVT) 
treatment regimens to subjects with nAMD.
Secondary objective


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To assess the safety and tolerability of aflibercept in this patient population
3
Study Design
3.1
Design Overview
This is a randomized, 2-arm, active-controlled, parallel-group, open-label, multicenter, Phase-
3b study to assess the non-inferiority of an extended-dosing regimen to a 2Q8 fixed dosing
regimen in subjects with nAMD who have completed at least 1 year of treatment with
aflibercept (from first treatment to randomization into this study) in accordance with the
constraints as provided in this protocol.
This study comprises a screening period of up to 66 days. There will be two parallel treatment 
arms. In both arms, aflibercept will be injected IVT at a dose of 2 mg per injection. The 
treatment arms differ in dosing intervals:
VTE extended 
dosing:  
Flexible dosing intervals of ≥8 weeks (no upper limit) based on visual 
and anatomic outcomes as judged by the investigator. When/if visual 
and anatomical outcomes indicate that the disease has reactivated, the 
treatment interval will revert to the last treatment interval in which the 
disease was inactive (i.e. no signs of exudation were observed).
VTE 2Q8: 
Fixed dosing intervals of 8 weeks (± 3 days) - modification of the 
treatment interval is not allowed. VTE 2Q8 will serve as the control-
group.
3.2
Inclusion/Exclusion
Two sets of inclusion and exclusion criteria will be used to select subjects for participation in
this study:
The first set of inclusion/exclusion criteria will be based on the subject’s medical history prior 
to initiation of treatment with marketed aflibercept and will be assessed by a review of the 
subject’s medical records. This will ensure that the subject’s pre-aflibercept status matches, as 
close as possible, the baseline (BL) criteria of the pivotal VIEW program.

1st set of inclusion-criteria: incl. 1 to incl. 3

1st set of exclusion-criteria: excl. 1 to excl. 7
The second set of inclusion/exclusion criteria considers both the subject’s medical history 
(assessed by a review of the subject’s medical records) and the actual status of the subject at 
the time of signing the informed consent form (i.e. at enrollment into the study via conduct of 
study-specific screening procedures).


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
2nd set of inclusion-criteria: incl. 4 to incl. 8

2nd set of exclusion-criteria: excl. 8 to excl. 37
Details are available in the clinical study protocol, Section 6.1 and 6.2.
3.3
Visit Overview
Following screening, eligible subjects will be randomized (1:1) to one of the two parallel 
treatment group. Subjects in both treatment groups will receive the first study treatment on 
Day 1. The treatment period in the 2Q8 group is 72 weeks with a final study visit at Week 76, 
the treatment period in the VTE extended dosing group is 76 weeks.
Two post-baseline visits will follow the same strict schedule in both treatment groups: 
primary completion at Week 52 and the final visit at Week 76. All other post-baseline visits 
may differ between the treatment groups as detailed in study-protocol, Section 9.
The last possible study drug injection in the extended-dosing group can be given at Week 76 
(i.e. the end of the study) after completion of all protocol-specified assessments1. After Week 
76, subjects should be returned to standard of care.
For each treatment group, the time window for all post-baseline visits is ± 3 days relative to 
baseline
Table 1 gives a description of the planned assessments and study procedures.
3.4
Efficacy and Safety variables
The primary efficacy variable will be the change in best corrected visual acuity (BCVA) using 
ETDRS chart letter score for the study eye (starting at 4 meters) from baseline to Week 52. A 
complete list of all efficacy variables is provided in Section 6.1.6. 
Both the primary and secondary efficacy variables will be assessed at Week 52/last 
observation carried forward (LOCF). The primary analysis will be based on the Full Analysis 
Set.
Efficacy will be assessed by the change in ETDRS BCVA letter score from study baseline. 
BCVA will be evaluated at every study visit. Other measures of efficacy will include changes 
from baseline in central retinal thickness (CRT) and choroidal neovascularization (CNV) as 
measured by optical coherence tomography (OCT) at each visit, and changes from baseline in 
                                                
1 If an extended-dosing subject receives an injection at Week 76, it is the responsibility of the treating 
investigator to follow-up on any adverse events (including ongoing events) that may occur within 4 weeks 
following this treatment. Information regarding such events is to be reported under this protocol (i.e. not as 
spontaneous reports).


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quality of life as assessed by the National Eye Institute 25-item Visual Function 
Questionnaire (NEI VFQ-25) at baseline, Week 52 and Week 76. Proportion of subjects with 
extended treatment interval and number of injections are also considered as efficacy 
measures,
Assessments of ocular safety will include intraocular pressure (IOP), indirect
ophthalmoscopy, and slit lamp biomicroscopy at all study visits. Under this protocol, 
mandatory fluorescein angiography (FA)/fundus photography (FP) examinations will be 
conducted during screening and at Weeks 52 and 76 only. However, the treating investigator 
may perform FA/FP at other times during the study based on his/her medical judgment and 
standard of care.
Overall safety of the subjects will be assessed throughout the study by monitoring ophthalmic 
and systemic adverse events (AEs). All potential arterial thrombotic 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 and laboratory tests (hematology parameters, blood chemistry 
parameters, and parameters of urinalysis) will be performed at study baseline and at Week 76 
only.


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Table 1: Schedule of assessments and study procedures
Visit number a
Screening
Visit 1
Baseline (BL)
Visit 2
Visits 3 - 8
Prim. compl.
Visit 9
Visits 10 - 12
Final visit
Visit 13h
Time 
pointa 2Q8 group
up to 66
days prior
to BL
(both groups)
Day 1
(both groups)
Weeks 8 – 48
Week 52
(both groups)
Week56, 64, 72
Week 76
(both groups)
Extended-dosing group
Flex. intervals
(≥8 weeks) 
Flex. intervals
(≥8 weeks) 
Initiation procedures
Informed consent 

Demographic data

Medical / ophthalmic history 

Physical examination

PT / INR and PTT

Inclusion / exclusion criteria


Study medication
Randomization

Administration of study treatment f


extended-
dosing only i

extended-
dosing only i,j
Ophthalmologic assessments
BCVA (ETDRS chart starting at 4 m) g






Optical coherence tomography






Fluorescein angiogr., fundus photogr.



Indirect ophthalmoscopy d






Slit lamp biomicroscopy






Intraocular pressure (IOP) e






Standard safety
Prior / concomitant medications






Adverse events c





Vital signs (temp., blood pressure, HR)






Hematology / chemistry 


Urinalysis / UPCR


Serum pregnancy test 
(women of childbearing potential only)

Urine dipstick pregnancy test 
(women of childbearing potential only)


Other
NEI VFQ-25 b



BCVA = Best corrected visual acuity;  ETDRS = Early Treatment Diabetic Retinopathy Study;  HR = heart rate;  
NEI VFQ-25 = National Eye Institute 25-item Visual Function Questionnaire;  PT/INR = Prothrombin time / International 
normalized ratio;  PTT = Partial thromboplastin time;  UPCR = Urine protein/creatinine ratio
a: Visit schedules may deviate by ± 3 days relative to baseline.  Scheduled visits should not be altered due to the deviation of 
the previous visit.  
Visit numbers refer to the mandatory visits for treatment administration to subjects in the 2Q8 group.  Fewer visits may be 
required for subjects in the extended-dosing group, for whom extended-dosing intervals are indicated.
b: The NEI VFQ-25 is to be administered in a quiet room by a person certified to administer the questionnaire
c: Any AE occurring up to 4 weeks after the last 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 4 weeks after the last application of aflibercept, the standard procedures that 
are in place for spontaneous reporting will be followed.
d: Pre- and post-dose at visits with study drug administration
e: Pre-dose and 30-60 minutes post-injection at visits with study drug administration


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f:
See Section 16.1 of the study protocol for an example study drug injection protocol.
g: Refraction to be done at each visit
h: Also to be conducted in case of premature discontinuation of study participation
i:
Extended-dosing subjects may receive injections at Week 52 or 76 depending on their individual schedule.
j:
If an extended-dosing subject receives an injection at Week 76, follow-up is needed on any adverse events (including 
ongoing events) that may occur within 4 weeks following this treatment (AE reporting under this protocol; i.e. not as 
spontaneous reports)
4
General Statistical Considerations
The statistical evaluation will be performed by using the software package SAS release 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA). 
The statistical analysis plan (SAP) version 1.0 of this open-label study is finalized before 
First-Patient-First-Visit (FPFV) to avoid additional reporting bias.
4.1
General Principles
The 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-group, and the percentage values will be reported to one decimal 
place.
If not stated otherwise, ANCOVA-tables will include the least squares (LS) means at baseline,
the LS mean changes relative to BL for both treatment groups, and the difference in the LS
means (extended-dosing group minus 2Q8 group) as point estimate and as 95%-CI.
4.2
Handling of Dropouts
Subjects must or might be withdrawn from study for different reasons, which are specified in 
the 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 “dropout” as specified below:
Screening failure


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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 “dropout” (see below) is regarded a 
“screening failure”.
Re-screening of screening failures may be acceptable under the specific conditions described 
in Section 6.3.1 of the study-protocol.
Drop-out
A subject who discontinues study participation prematurely for any reason is defined as a 
“drop-out” if the subject has already been randomized.
The number of screening failures and drop-outs as well as the respective reasons will be 
summarized.
4.3
Handling of Missing Data
All missing or incomplete data will be presented in the subject data listings as they are 
recorded on the Case Report Form (CRF). In general they will not be substituted or replaced, 
except for the parameters described below and in Section 6.1.6 for efficacy analysis.
When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data:
4.3.1
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 
not the event is treatment-emergent is questionable, the event will be presumed to be 
treatment-emergent. If it is clear from the (partially missing date) that the adverse event 
occurred prior to first dose of study drug or more than 30 days after the last dose of study 
drug, it will be treated as not treatment emergent.
4.3.2
Efficacy Analysis
The primary method for replacing missing values for all efficacy analyses will be “last 
observation carried forward” (LOCF), see Section 4.3.2.1. 
The following other methods will be applied to account for missing data for the primary 
endpoint (assuming that the missing values are missing at random):

Multiple imputations (MI), see Section 4.3.2.2.

Repeated measurements model (RMM), see Section 4.3.2.3.
Moreover, an observed case analysis (OC), see Section 4.3.2.4, will be provided.


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4.3.2.1 Last Observation Carried Forward
Missing ETDRS BCVA letter scores will be imputed by LOCF using the last available 
scheduled post-baseline values.
After the imputation the respective dataset will be filled and the data will be analyzed as if the 
missing values had been observed (as the last available value). For example, the primary 
efficacy variable will be analyzed as described in Section Error! Reference source not 
found.. 
4.3.2.2 Multiple Imputation
Multiple imputations (MI) for missing values will additionally performed on the primary and 
key secondary efficacy variables.   
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=3818 OUT=out1 NIMPUTE=20; 
MCMC impute=monotone;
VAR base t1 t2 … ;
RUN;
b. Subsequently missing data will be imputed by a regression model.
PROC MI DATA=out1 SEED=4144 OUT=full nimpute=1;
BY _Imputation_;
CLASS treatment;
MONOTONE method=reg;
VAR treatment base t1 t2 … ;
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 is no need to bother with any missing data. On each imputed dataset 
the primary and key secondary analysis will be performed as described in Sections 0
and 6.2.2. It should be clarified, that classifications (loss of < 15 letters) will be 
performed after the imputation of the missing BCV-values.


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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.
4.3.2.3 Repeated Measurements Model
The repeated measurements model (RMM) does not employ formal imputation. RMM has 
been extensively used in the analysis of longitudinal data especially when missing data is a 
concern and missing at random (MAR) is assumed.
For RMM, if SAS mixed model is used, the sample SAS codes will be like the following: 
PROC MIXED DATA=<indata>; 
CLASS subject treatment(ref=VTE2Q8) time-window; 
MODEL chg = base treatment time-window treatment*time-
window /ddfm=kr; 
repeated time-window / sub = subject type = un; 
lsmeans treatment / cl diff pdiff=CONTROL(2Q8fix);
RUN;
Where the treatment difference is obtained with the lsmeans statement for the treatment 
differences at time Week52. 
4.3.2.4 Observed Cases
The primary analysis will be repeated on observed cases, without any imputation.
4.3.3
Prior and Concomitant Medication / Medical History
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”.
The following algorithm will be used for the calculation of durations and/or to flag 
medications: 
-
for incomplete start dates:  if only day is missing - first of month, if day and month 
missing - first day (1st January) of year. 
-
for incomplete stop dates:  if only day is missing - last of month, if day and month 
missing - last day (31st December) of year or “ongoing”, when last day of year is after 
last study-day of the subject.


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4.4
Interim Analyses and Data Monitoring
No formal interim analysis will be conducted.
4.5
Data Rules
Determination of baseline values
Generally, pre-treatment values recorded at Visit 2 (Day 1) will be used as baseline values. 
This visit should take place within 8 weeks of the screening visit. If no baseline value is 
available then last available 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.
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 measurement is before start of treatment, 
and

First non-missing repeated measurement, if measurement 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 scheduled time-windows
The screening visit must occur within 8 weeks of the baseline visit (Day 1). Screening values 
collected more than 8 weeks before baseline will be flagged in the patient listings, but might 
be used for summary tables and analysis.
For the scheduling of Visit 3 to Visit 13 (Week 4 to Week 76) ± 3 days relative to baseline are 
foreseen.
Values outside these windows will not be dropped from summary tables and analysis, but
flagged as “outside time-window” in the patient listings.
Defining time-windows for the visit wise summaries
The visits for the control-group (VTE 2Q8) are fixed, therefore the respective results will be 
summarized as scheduled – i.e. Screening, Baseline, Week 8, Week 16, Week 24, Week 32, 
Week 40, Week 48, Week 52, Week 56, Week 64, Week 72 and Week 76, if applicable.
For the VTE extended dosing group the following time-windows after BL will be defined: 

Screening:
study-days - 66 to -1

Baseline:
study-day 1

Week 1-8: 
study-days 2 to 59

Week 9-16: 
study-days 60 to 116


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
Week 17-24: study-days 117 to 172

Week 25-32: study-days 173 to 228

Week 33-40: study-days 229 to 284

Week 41-48: study-days 285 to 340

Week 49-51: study-days 341 to 361

Week 52:
study-days 362 to 368

Week 53-60: study-days 369 to 424

Week 61-68: study-days 425 to 480

Week 69-75: study-days 481 to 529

Week 76:
study days 530 to 536

> Week 76:
study days > 536
The last measurement before or at the upper bound of the time interval will be displayed in 
each time interval.
These rules especially apply for all assessments at End of Study / End of treatment in both 
treatment-groups.
Pooling centers
Two types of pooling will be performed:
a) All centers combined
b) Geographic region
Calculation of durations and study-days
Durations and study-days 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 database lock.
Presentation
Listings will be sorted by treatment, 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.


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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.
4.6
Validity Review
Validity Review Meetings (VRMs) are performed according to Bayer HealthCare (BHC) 
Standard Operating Procedures (SOP) and will be led by the Syneos Health Lead Data 
Manager (LDM). Details are available in the DMP.
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 validity review meeting will be documented in an amendment 
and, if applicable, in a supplement to this SAP.
5
Analysis Sets and Subgroups
5.1
Analysis Sets
Populations for analysis will be defined as follows:
Full analysis set (FAS)
The FAS will include all randomized subjects who received any study drug and have a 
baseline BCVA assessment and at least one post-baseline BCVA assessment. 
The FAS will be analysed as randomized.
Per-protocol set (PPS)
The PPS will include all FAS subjects who have at least one BCVA assessment at Week 36 or 
later and do not have a major protocol deviation. Major protocol deviations will be defined in 
the  protocol deviation document (PDD). In version 8.0 of the PDD from November 6th, 2018 
the following major protocol deviations are listed for FAS-subjects:

In-/Exclusion criteria not met but subject entered treatment phase

Excluded concomitant medication treatment

Procedure deviations
o
Visit 2 has not been performed


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o
Planned BCVA-examination in study eye has not been performed at any Post 
Baseline Visit  >= Week 36
o
Patient missed two or more consecutive study drug injections prior to week 52
PPS will be defined at the last VRM i.e. prior to database lock. The PPS will be analysed as 
randomized.
Safety analysis set (SAF)
The SAF will include all subjects who receive any study drug under this protocol. 
The safety analysis set will be analysed as randomized. Subjects treated other than 
randomized will be marked in the listings.
5.2
Definition of Subgroups
Subgroups are
-
Sex (f/m)
-
Geographic region
o
Canada and Western Europe:  Canada , France and UK
o
Middle Europe:  Austria, Germany and Switzerland
o
Eastern Europe: Czech Republic, Hungary, Poland, Slovakia and Lithuania
o
Southern Europe: Spain, Portugal and Italy
-
Change of BCVA from first aflibercept administration to AZURE baseline (< 10
letters, >= 10 letters)
The rationale for this subgroup definition is to have roughly 50 % of the subjects in 
each of the two subgroups of change from first aflibercept administration to AZURE 
baseline. In the VIEW2 study the median change from first injection to week 52 was 9 
letters.


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6
Statistical Methodology
6.1
Population Characteristics
6.1.1
Study Periods and Sample Sizes
Study sample sizes will be provided by trial unit and overall for all enrolled subjects. 
The number of minor and major protocol deviations will be summarized by trial unit and 
overall for all enrolled subjects. 
The number of major protocol deviations will be summarized by category and overall for all 
randomized subjects.
Screening Failures will only be listed together with the reason for their failure and all 
available disposition data (Date of informed consent, Reason for screen failure, Date of last 
visit).
For screening failures with an SAE all information related to the SAE will be listed.
6.1.2
Subject Validity Status
An overview-table for all randomized subjects will be given, displaying in each treatment 
group and overall the number and percentages of subjects: 

Subjects valid for safety analysis

Subjects valid for FAS analysis

Subjects valid for per protocol analysis

Excluded from safety analysis
o
Never took study drug

SAF, but excluded from FAS analysis
o
[Reason, category from PDD]

FAS, but excluded from per protocol analysis
o
[Reason, category from PDD]
6.1.3
Subject Disposition
All enrolled subjects will be summarized together with the reason(s) for not entering the 
treatment period. Possible reasons are:

Adverse event

Death

Withdrawal by subject

Lost to follow-up


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
Screen failure

Other
An overview-table for all randomized subjects will be given, displaying in each treatment 
group and overall the number and percentages of subjects at end of treatment: 

Completed treatment period

Not completed treatment period
o
withdrawn up to week 36 
o
withdrawn after week 36 up to week 52 
o
withdrawn after week 52 up to week 76

Primary reason for not completing treatment
o
Adverse Event
o
Death
o
Withdrawal by subject
o
Lost to follow-up
o
Protocol Violation
o
Study terminated by sponsor
o
Treatment failure
o
Physician decision
o
Pregnancy
o
Other
A similar table will be provided displaying the result at end of study.
The subject disposition will be displayed for all enrolled subjects in a summary table showing 
the number of subjects randomized but not treated.
6.1.4
Demographics and Baseline Characteristics
Demographic variables will be summarized by treatment group and all treatment groups 
combined for all three analysis populations, depending on the type of data as described in
Section 4.1.
The following demographic variables are recorded at screening. In case of repeated measures 
the last available value before randomization will be used for summary tables.

sex (m/f/childbearing potential)

race

ethnicity

age 

age (classified)

weight 

height

body mass index (BMI)


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
study eye (left or right)

cigarettes smoking (never/former/current)

other tobacco smoking (never/former/current)
The treatment group comparability will be checked for each of the analysis populations
mentioned above. This comparison will be done with respect to age by a one-way analysis of 
variance with treatment group as fixed factor and with respect to gender by a Chi-squared test.
Baseline characteristics will be summarized by treatment group and all treatment groups 
combined for all three analysis populations, depending on the type of data as described in
Section 4.1.
The total score and sub-scores of the National Eye Institute 25-item Visual Function 
Questionnaire (NEI VFQ-25) will be calculated according to the NEI VFQ-25 scoring 
algorithm, August 2000 version. The most important instructions are displayed in appendix
8.1.
The following baseline characteristics will be summarized:

Baseline BCVA letter scores (study eye)

Baseline central retinal thickness (CRT) (study eye)

Baseline choroidal neovascularization (CNV) area (study eye)

Baseline CNV lesion type (study eye)

Baseline total CNV lesion area (study eye)

Baseline NEI VFQ-25 total score 
The treatment group comparability will be checked for each of the analysis populations
mentioned above. This comparison will be done with respect to 

Baseline BCVA letter score

Baseline NEI VFQ-25 total score

Baseline CRT

Baseline CNV area
by a one-way analysis of variance with treatment group as fixed factor. 
Results from prothrombin time (PT/INR) and partial thromboplastin time (PTT)
measurements and physical examination at screening will only be listed. 
The subgroups 

sex, 

geographic region and 

change of ETDRS BCVA letter score from first aflibercept administration to AZURE 
baseline


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will be displayed for all three analysis populations by treatment group and overall.
6.1.5
Medical and Ophthalmological History
The number and percentages of subjects with the respective medical history will be displayed 
for SAF and FAS by treatment group and overall, stratified for ocular medical history in the 
study/fellow eye.
For the tables, subjects may be counted under multiple system organ classes (SOC) and 
preferred terms (PT), but for each SOC and PT, subjects are only counted once. Medical 
histories will be sorted by descending frequency, in all treatment groups combined, by the 
SOCs and within each SOC by PT. 
The duration of nAMD (years) will be calculated per eye as described in Section 4.5. The
variables recorded on the respective page of the CRF will be summarized by treatment group
and all treatment groups combined for SAF and FAS, depending on the type of data as 
described in Section 4.1.
6.1.6
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 World Health Organization Drug classification Dictionary 
(WHO-DD), latest version available before database lock, for SAF.
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, stratified by 

ocular medication (yes/no) and 

eye (study eye/fellow eye) 
consisting of medication class and preferred name, sorted by descending frequencies. Bilateral 
medications are counted as medications for the study as well as the fellow eye. 
Subjects may be counted under multiple medication classes and preferred names but within
each category subjects are only counted once. However, multiple ATC codes per drug are 


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possible. Therefore, the same drug may be counted in more than one category for the same 
subject.
6.1.7
Exposure
The number of injections (counts and metrics) will be displayed for all three analysis 
populations by treatment group and overall.
Treatment duration is calculated as (date of ‘end of treatment’ - date of ‘first injection after 
randomization’ + 56)/7. The rationale for this is that the minimal time between aflibercept
injections is 8 weeks that means 56 days. It will be summarized by treatment group and total
for all three analysis populations.
The last actual injection interval will be calculated as (last injection – previous injection +1)/7
tabulated in both treatment groups and total for all three analysis populations – as counts, 
classified and metric variable as described in Section 4.1. The last intended injection interval 
as documented by the investigator will be summarized similarly.


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6.2
Efficacy
Efficacy variables will be summarized by treatment group for each visit depending on the 
type of data as described in Section 4.1 for the FAS.
The analysis of the primary, key secondary, and secondary variables will be based on the 
results at Week 52. LOCF will be used for missing post-baseline values at 52 weeks2. 
Sensitivity analysis using RMM, OC and MI will be performed on the primary efficacy 
variable on the FAS. Analyses on the PPS and on subgroups will be considered as 
supplementary.
The efficacy variables and the ranking of their statistical analyses at the different timepoints 
(primary, [key] secondary, exploratory) are specified in Table 2. The first 9 efficacy variables 
and the ranking of their statistical analyses were specified in the study protocol. Additionally,
“time to withdrawal“ will be analysed in an exploratory manner.
Table 2: Efficacy variables
Ranking
Item
Variable 
Week 52
Week 76
1
Change from baseline in ETDRS BCVA letter score for the study eye
Primary
Exploratory
2
Proportion of subjects maintaining vision (i.e. loss of < 15 letters) in 
the study eye
Key secondary
Exploratory
3
Proportion of subjects who gained from baseline 5 letters in the 
study eye
Secondary
Exploratory
4
Mean change from baseline in CRT in the study eye
Secondary
Exploratory
5
Mean change from baseline in CNV area in the study eye
Secondary
Exploratory
6
Proportion of subjects who lost ≥ 30 letters
Secondary
Exploratory
7
Mean change from baseline in total score for NEI VFQ-25
Secondary
Exploratory
8
Proportion of subjects for whom the treatment interval was extended
Exploratory
Exploratory
9
Total number of intravitreal injections required in the study eye
Exploratory
Exploratory
10
Time to withdrawal 
Exploratory
Exploratory
BCVA = best corrected visual acuity; CNV: choroidal neovascularization; 
CRT = central retinal thickness; 
ETDRS = Early Treatment Diabetic Retinopathy Study; 
NEI VFQ-25 = National Eye Institute 25-item Visual Function Questionnaire
                                                
2 LOCF is considered an appropriate method for replacement of missing values in the primary and secondary
efficacy analyses in the late phase of the study (i.e. carrying forward the last measurement taken between
Week 36 to Week 48 if the Week-52 measurement is missing), even though nAMD is a progressive disease.


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Subgroup analysis will be performed by sex, geographic region and change of ETDRS BCVA 
letter score from first aflibercept administration to AZURE baseline for 

Item 1: Change from baseline in ETDRS BCVA letter score for the study eye (LOCF), 

Item 2: Proportion of subjects maintaining vision (LOCF), and

Item 7: Mean change from baseline in total score for NEI VFQ-25 (OC)
at Week 52 on FAS.
6.2.1
Primary Efficacy Variable Analysis
The primary efficacy variable is the change from baseline in ETDRS BCVA letter score for 
the study eye. The primary efficacy variable analysis will be performed on the FAS (defined 
in Section 5).
Statistical testing will be conducted to prove the non-inferiority of the extended-dosing
regimen to the 2Q8 fixed dosing regimen.
The corresponding null hypothesis is H0: μ1 ≤μ2-D versus the alternative hypothesis H1: μ1 > 
μ2-D, where
D = 
non-inferiority margin
μi = 
mean change in BCVA letter score for the study eye from baseline to Week 52 
in treatment group i.
i = 
1: extended-dosing regimen
2: fixed-dosing regimen
The non-inferiority margin is 5 letters.
The methodological approach will be the calculation of a two-sided 95% confidence interval
for the difference in the least squares (LS) means (extended-dosing group minus 2Q8 group)
of the change in ETDRS letter score from study baseline to 52 weeks based on a one-way
analysis of covariance (ANCOVA) with baseline measure as a covariate and treatment group
as a fixed factor. 
In the data analysis, ANCOVA can be performed using SAS PROC MIXED procedure with 
the following key SAS statements:
PROC MIXED DATA=<input dataset>;
CLASS <treatment group> 
MODEL <change from baseline in BCVA>
=<treatment group> <baseline BCVA>/DDFM=KenwardRoger;
LSMEANS <treatment group>/
PDIFF=CONTROLU(‘<Fixed dosing regimen>’) CL 
ALPHA=0.025;
RUN;


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The extended-dosing regimen will be considered to be non-inferior to the fixed 2Q8 regimen 
if the confidence interval of the difference lies entirely above -5 letters, where a positive 
difference favours extended dosing. A non-inferiority margin of 5 letters is consistent with 
margin used in the “CATT Study” (3).
If, and only if, the extended-dosing regimen is statistically proven to be non-inferior to the
fixed 2Q8 regimen in the primary efficacy analysis, confirmatory testing will be continued to
prove the non-inferiority of extended dosing to fixed 2Q8 with regard to the key secondary
efficacy variable (maintenance of vision) in the FAS (with LOCF for missing 52-week
ETDRS letter score).
As supplemental analysis the primary efficacy analyses will be repeated on the PPS (defined 
in Section 5) using LOCF. RMM, MI and OC in the FAS will serve as sensitivity analysis.
Subgroup analysis are supplementary.
For illustrational purposes figures containing the mean ETDRS BCVA letter score changes 
from baseline together with their standard deviations over the course of time will be presented 
for LOCF in FAS. 
6.2.2
Key Secondary Efficacy Variable
The key secondary efficacy variable is the proportion of subjects maintaining vision (i.e. loss 
of < 15 letters) in the study eye. The key secondary efficacy variable analysis will be 
performed on the FAS.
The corresponding null hypothesis is H0: p1 ≤p2-versus the alternative hypothesis H1: p1 > 
p2-, where
pi = 
proportion of subjects maintaining vision at Week 52 of treatment group i

pre-specified non-inferiority margin of 7%3
i = 
1: extended-dosing regimen, 
2: fixed-dosing regimen
The methodological approach will be the calculation of two-sided 95% confidence intervals 
using normal approximation of the difference between the proportions (extended-dosing 
group minus 2Q8 group) of subjects maintaining vision. 
The extended-dosing regimen will be considered to be non-inferior to the fixed 2Q8 regimen 
if the confidence interval of the difference lies entirely above -7%, where a positive difference 
                                                
3 The non-inferiority margin of 7% was proposed by the 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 pages 22 and 23).


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favours extended dosing. This conditional sequence of statistical hypotheses (a-priori ordered 
hypotheses) will control for multiplicity in the confirmatory analyses.
The analyses will be repeated on the PPS. 
6.2.3
Other Secondary Efficacy Variables
The other secondary efficacy variables will be analysed in a descriptive manner. This may 
include 95% confidence intervals (CI) for treatment differences at Weeks 52 in an exploratory 
way. Details for calculation are given in Section 8.2.
The LOCF-analyses will be carried out on the FAS.
6.2.3.1
Proportion of Subjects who gained from BL ≥5 Letters in the Study Eye
BCVA will be measured at each visit up to the final visit. The changes from baseline will be
calculated and summarized as described in Section 4.1, together with the respective 95%-CI 
(normal approximation) in each visit.
Subsequently, the BCVA results will be dichotomized in gain from baseline in the study eye
of 5 letters or < 5 letters. The numbers and proportions of subjects with a gain 5 letters
will be displayed at each visit together with the respective 95% CI (exact binomial) for both 
treatment groups and overall.
6.2.3.2
Mean Change from BL in CRT in the Study Eye 
Optical coherence tomography (OCT) to measure the CRT will be performed at each visit up 
to the final visit.
The changes to baseline will be calculated and summarized together with the respective 95%-
CI (normal approximation) at each visit.
For illustrational purposes figures containing the mean values of the changes from baseline 
together with their standard deviations over the course of time will be presented. 
6.2.3.3
Mean Change from BL in CNV Area in the Study Eye
OCT to measure the CNV area will be performed at each visit up to the final visit. The 
changes to baseline will be calculated and summarized together with the respective 95%-CI 
(normal approximation) at each visit. 
For illustrational purposes figures containing the mean values of the changes from baseline 
together with their standard deviations over the course of time will be presented. 


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6.2.3.4
Proportion of Subjects who lost ≥30 Letters in the Study Eye
The changes from baseline of the BCVA will be dichotomized in loss 30 letters in the study 
eye, and < 30 letters. The numbers and proportions of subjects with a loss 30 letters will be 
displayed at each visit together with the respective 95% CI (exact binomial) for both 
treatment groups. 
6.2.3.5
Mean Change from BL in Total Score for NEI VFQ-25 
NEI VFQ-25 will be evaluated at baseline, visit Week 52 and Week 76/final visit. LOCF will 
not be performed. From the 25 questions a total score and up to twelve sub-scores can be 
derived (see Section 8.1,Table 5). The (sub-) scores range from 0 to 100.
The changes from baseline of the total score will be summarized together with the respective 
95%-CI (normal approximation). 
For illustrational purposes figures containing the mean total values of the changes from 
baseline together with their standard deviations over the course of time will be presented. 
6.2.4
Exploratory Efficacy Variables
The exploratory efficacy variables from  will be analysed in a descriptive manner. This may 
include 95% confidence intervals for treatment differences at Weeks 52 and 76 in an 
exploratory way. 
If not stated otherwise, the analyses will be carried out on the FAS and only observed cases 
(without LOCF) will be analysed. 
6.2.4.1
Proportion of Subjects for whom the Treatment Interval was extended
A scheduled extended treatment interval (=extension) is defined as a scheduled interval of at 
least 9 weeks (+/- 3 days) between two injection visits, regardless of the real treatment 
interval. 
An extension based on actual values is defined as an interval of at least 9 weeks between two 
injection visits.
A subject year will be calculated as the individual treatment duration divided by 365 days.
The following data will be tabulated for the extended-dosing group.

Number of scheduled extensions at Weeks 52 and 76

Number of scheduled extensions for study completers
The following data will be summarized on both treatment groups. 


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
Number of extensions based on actual values at Weeks 52 and 76

Number of extensions based on actual values for study completers

Number of extensions based on actual values, per subject year
6.2.4.2
Total number of ivt Injections required in the Study Eye 
The total number of ivt injections required in the Study Eye is defined as the number of 
administered injections per subject.
Compliance (%) is calculated as the number of ivt injections in the study eye at the scheduled 
injection visits (+/- 3 days) divided by number of scheduled injection visits (multiplied by 
100).
The following variables will be tabulated in both treatment groups:

Number of injections at Weeks 52 and 76

Number of observed injections at Weeks 52 and 76, per subject year 

Compliance at Weeks 52 and 76

Number of injections per study completer
6.2.4.3
Week 76 Analysis
As described in Sections 0 to 6.2.3.5 the results at Week 52 are used to analyze the primary, 
key secondary or secondary variables. 
If not specified otherwise, the analyses with respect to Week 76 will be performed in the same 
way as for Week 52 (except subgroup analysis), however in a descriptive manner.
6.3
Pharmacokinetics / Pharmacodynamics
Not  applicable


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6.4
Safety
The safety analysis will be conducted in the safety analysis set (as defined in Section 5).
6.4.1
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 and less or equal than 30 days after the last dose of study drug. 
Potential arterial thrombotic events (ATEs) will be evaluated by a masked adjudication 
committee according to criteria formerly applied and published by the Anti-Platelet Trialists’
Collaboration (APTC) (2). Further details are described in the adjudication committee 
charter.
Overview tables by treatment and overall will be produced for the following categories for all 
AE and TEAE, presenting number of subjects and events:

Subjects with at least one AE/TEAE

Subjects with at least one ocular AE/TEAE 

Subjects with at least one ocular AE/TEAE in the study eye

Subjects with at least one ocular AE/TEAE in the fellow eye

Subjects with at least one non-ocular AE/TEAE 

Subjects with at least one (treatment emergent) APTC event

Subjects with at least one AE/TEAE causally related to aflibercept 

Subjects with at least one AE/TEAE causally related to ivt injection     

Subjects with at least one AE/TEAE causally related to other protocol- required
procedures

Maximum intensity for any AE/TEAE

Maximum intensity for any TEAE causally related to aflibercept

AE/TEAE with outcome Death     

Subjects with at least one serious AE/TEAE

Subjects with at least one serious TEAE causally related to aflibercept

Subjects with at least one serious TEAE causally related to ivt injection procedures

Subjects with at least one serious TEAE causally related to protocol- required
procedures

Discontinuation of study drug due to TEAE

Discontinuation of study drug due to (treatment emergent) SAE

Subjects with at least one non-treatment emergent AE (pre-treatment)


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
Subjects with at least one non-treatment emergent AE (post-treatment)
The overview table for TEAEs will also be displayed stratified for the subgroups. 
The following tables will present the respective AEs or TEAEs by MedDRA preferred term 
(PT) within primary system organ class (SOC) and summarized by treatment groups. Subjects 
may be counted under multiple system organ classes and preferred terms, but for each system 
organ class and preferred term, subjects are only counted once.

TEAEs

Ocular TEAEs

Ocular TEAEs in the study eye

Ocular TEAEs in the fellow eye

Non-ocular TEAEs 

Serious TEAEs

Serious ocular TEAEs in the study eye

Serious ocular TEAEs in the fellow eye

Serious non-ocular TEAEs

TEAEs causally related to aflibercept     

TEAEs causally related to injection procedure    

TEAEs causally related to other procedures required by the protocol 

Serious TEAEs causally related to aflibercept     

TEAEs by maximum intensity

Serious TEAEs by maximum intensity

Serious TEAEs causally related to aflibercept by maximum intensity

TEAEs by worst outcome    

Serious TEAEs by worst outcome    

Treatment emergent ATPC events4

TEAEs resulting in discontinuation of aflibercept

Treatment emergent Deaths

Non-Serious TEAEs

Non-treatment-emergent AEs

Non-treatment-emergent AEs (pre-treatment)

Non-treatment-emergent AEs (post-treatment)
The number and percentages of subjects affected as well as the number of events (except for 
those by maximum severity or worst outcome) will be displayed. SOCs will be sorted by 
descending frequency of all subjects, within each SOC the PT will be sorted by descending 
frequency of all subjects affected.
                                                
4 APTCs are summarized by APTC-term and preferred term. 


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Additional the following subject listings will be provided.

Serious adverse events

Adverse events resulting in discontinuation of study drug

Deaths
6.4.2 Laboratory Evaluations and Pregnancy Tests
All laboratory tests will be performed at a central laboratory at screening and final visit. The 
last measurement before first application of study-drug in this study will be used as baseline-
value. Safety laboratory parameters to be evaluated are shown in Table 3.
Table 3: Laboratory safety parameters
Chemistry
Sodium
Potassium
Chloride
Calcium
Glucose
Albumin
Total Protein, Serum
Creatinine
Blood urea nitrogen (BUN)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Total bilirubin
Amylase
Serum pregnancy test for women 
of childbearing potential
Urinalysis 
Glucose 
Protein
Specific Gravity
Blood
Ketones 
Protein: Creatinine Ratio (UPCR)
Coagulation
Prothrombin time (PT)
Partial thromboplastin time (PTT)
International normalized ratio (INR)
Hematology
Hemoglobin
Hematocrit
Red blood cell count
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin 
concentration (MCHC)
Mean corpuscular hemoglobin (MCH)
Leucocyte count
Differential count
Neutrophils
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
According to current International Conference on Harmonization guidelines, deviations from 
the reference range should be evaluated for clinical significance in each individual case. The 
reference ranges and the units and methods for all variables will be provided by the central 
laboratory.
Deviations of laboratory values from the laboratory reference ranges will be flagged on the 
laboratory listings.


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Treatment-emergent laboratory abnormalities, defined as laboratory abnormalities after
randomization under this study protocol, will be summarized by laboratory category and 
treatment group.
Summary statistics for the laboratory values will only be provided, when they are converted in 
comparable SI values. Values below “Normal Range Lower Limit” (LL) will be set to 0.5*LL 
for the calculation of summary statistics. Values above “Normal Range Higher Limit” (HL) 
will be set to HL.
Pregnancy tests will be performed for women of childbearing potential; a serum pregnancy
test will be performed at screening and urine tests will be performed at baseline and Week 76. 
Beyond that schedule, pregnancy tests are to be done in women of childbearing potential as 
frequently as requested.
Results of the pregnancy tests for women of childbearing potential will be listed only.
6.4.3
Further Safety
6.4.3.1
Vital Signs
Vital signs (body temperature, blood pressure, pulse) including changes from baseline will be
displayed for each treatment group.
6.4.3.2
Surgeries after Start of Study
Separate tables for treatment-emergent surgeries will be presented, overall and split by study 
eye and fellow eye.
6.4.3.3 Intra-Ocular Pressure (IOP)
At visits with study drug administration, pre-injection and 30 to 60-min post-injection IOP 
will be assessed for the study eye. All IOP measurements will be classified as follows:

> 25 mmHg 

≥ 30 mmHg

≥ 35 mmHg 

≥ 40 mmHg 
Any increase from pre-injection/baseline of ≥10 mmHg will be flagged. 
The IOP analysis will include

original measurements

changes from pre-injection 

changes from baseline

classified measurements


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
flagged measurements 
This analysis will be performed descriptively at all visits depending on the type of data as 
described in Section Error! Reference source not found..
Additionally, 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. 
6.4.3.4 Slit Lamp Biomicroscopy
The slit lamp examination will be performed according to local medical practice and 
applicable medical standards at the site.
Frequency tables for normal/abnormal slit lamp biomicroscopy findings as well as for the 
grading of  ‘anterior chamber flare’, ‘anterior chamber cells’ and ‘anterior vitreous cells’ will 
be provided. 
6.4.3.5 Indirect Ophthalmoscopy
At visits with study drug administration, pre-injection indirect ophthalmoscopy will be 
assessed for the study eye. Post-injection assessments will be carried out 30-60 minutes 
following the IVT injection.
Frequency tables for normal/abnormal findings in the pre-injection assessment will be 
provided. The cup-to-disc ratio will presented by summary statistics. All other data will be 
listed.


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Document History and Changes in the Planned Statistical Analysis
Main changes to „SAP final version 1.0, dated 29 May 2015“:

In Section 4.5, the time-windows are corrected and pooling rules are added. Definition 
of geographic region 

In Section 6.1.4, diabetic status (yes/no), anti-hypertensive medication (yes/no) are 
deleted, because these parameter will not be collected, geographic region was added.

In Section 6.1.6, subgroup analysis was added.
Main changes to „SAP final version 2.0, dated 08 September 2015“:

Section 4.3.1: Adverse Events started later than 30 days after last dose of study-drug 
are not considered as treatment emergent.

Section 4.3.2: RMM and OC were added. SAS-Code for MI-procedure was clarified.

Section 4.3.3: An algorithm was given, to derive the flags for incomplete start- and 
stop-dates for concomitant medications.

Section 4.5: Time-windows are slightly updated to be consistent with VIOLET. 

Section 5.1: Major protocol deviations have been adapted to version 8.0 of the PDD.

Section 5.2: Definition of subgroups was added, including the additional subgroup 
“Change of the ETDRS BCVA letter score from first aflibercept administration to 
AZURE baseline (< 10 letters or >= 10 letters)”.

Section 6.1: Clarifications and updates for analyses according to Bayer standards.

Section 6.2.1: Clarifications and updates for analyses: 
o
Updating SAS-Code for primary analysis
o
Adding sensitivity analyses RMM and OC

Section 6.2.2: Clarifications and updates for analyses: 
o
Dropping sensitivity analyses for key secondary parameter

Section 6.2.3: Clarifications and updates for analyses: 
o
Dropping sensitivity and PPS-analyses for other secondary parameter
o
Clarifying analyses for NEI-VFQ-25, especially dropping sub-score analysis

Section 6.2.4: Clarifications and updates for analyses: 
o
Clarifying analysis of treatment-extension


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o
Adding Compliance (%)

Section 6.4: Clarifications and updates for analyses according to Bayer standards.

Section 6.4.1: Adding overview TEAE tables stratified for subgroups.

The analysis of the further safety measurements were described. The summaries of the 
fellow-eye was dropped.

Formula for calculation of confidence intervals are given in the Appendix 8.1.


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7
References
1. Aiello LP, Avery RL, Arrigg PG et al. Vascular endothelial growth factor in ocular fluid 
of patients with diabetic retinopathy and other retinal disorders. N Eng J Med 1994; 
331:1480-1487.
2. Antiplatelet Trialists’ Collaboration (2002) Collaborative meta-analysis of randomised 
trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in 
high risk patients. BMJ, 324,71–86.
3. CATT Research Group. Ranibizumab and Bevacizumab for Neovascular Age-Related
Macular Degeneration. N Eng J Med 2011; 365:1897-1908.
4. Mangione CM, MD NEI VFQ-25 Scoring Algorithm – August 2000, Version 2000, The 
National Eye Institute 25-Item, Visual Function Questionnaire (VFQ-25)
5. Rahmani B, Tielsch JM, Katz J et al. The cause-specific prevalence of visual impairment 
in an urban population. The Baltimore Eye Survey. Ophthalmology. 1996; 103:1721-
1726.


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8
Appendix 
8.1
Calculation of the NEI VFQ-25 Scores
The calculation for NEI VFQ-25 sub-scale scores and total score will be performed according
to the “NEI VFQ-25 Scoring Algorithm – August 2000 (4). The most important instructions 
are displayed below:
The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-
related constructs, plus an additional single-item general health rating question, which are also 
presented in the protocol in Section 16.2.
The NEI VFQ-25 generates the following vision-targeted sub-scales (number of questions):

global vision rating (1), 

difficulty with near vision activities (3), 

difficulty with distance vision activities (3), 

limitations in social functioning due to vision (2), 

role limitations due to vision (2),

dependency on others due to vision (3), 

mental health symptoms due to vision (4), 

driving difficulties (3), 

limitations with peripheral (1),

color vision (1), and 

ocular pain (2). 
Additionally, the VFQ-25 contains the single general health rating question which has been 
shown to be a robust predictor of future health and mortality in population-based studies. 
Scoring VFQ-25 is a two-step process:
1. First, original numeric values from the survey are re-coded following the scoring rules 
outlined in Table 4. All items are scored so that a high score represents better 
functioning. Each item is then converted to a 0 to 100 scale so that the lowest and 
highest possible scores are set at 0 and 100 points, respectively. In this format scores 
represent the achieved percentage of the total possible score, e.g. a score of 50
represents 50% of the highest possible score. 
2. In step 2, items within each sub-scale are averaged together to create the 12 sub-scale 
scores. Table 5 indicates which items contribute to each specific sub-scale. Items that 
are left blank (missing data) are not taken into account when calculating the scale 


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scores. Sub-scales with at least one item answered can be used to generate a sub-scale 
score. Hence, scores represent the average for all items in the subscale that the 
respondent answered.
To calculate an overall composite score for the VFQ-25, simply average the vision-targeted 
subscale scores, excluding the general health rating question. By averaging the sub-scale 
scores rather than the individual items we have given equal weight to each sub-scale, whereas 
averaging the items would give more weight to scales with more items.
Table 4: Scoring Key: Recoding of Items
Item Numbers
Change original 
response category(a)
To recoded value 
of:
1,3,4,15c(b)
1
2
3
4
5
100
75
50
25
0
2
1
2
3
4
5
6
100
80
60
40
20
0
5,6,7,8,9,10,11,
12,13,14,16,16a
1
2
3
4
5
6
100
75
50
25
0
*
17,18,19,20,21,
22,23,24,25
1
2
3
4
5
0
25
50
75
100
(a) Pre-coded response choices as printed in the questionnaire.
(b) Item 15c has four-response levels, but is expanded to a five-levels using item 15b.
Note: 
If 15b=1, then 15c should be recoded to “0”
If 15b=2, then 15c should be recoded to missing.
If 15b=3, then 15c should be recoded to missing
* Response choice "6" indicates that the person does not perform the activity because of non-vision 
related problems. If this choice is selected, the item is coded as "missing."


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Table 5: Averaging of Items to Generate VFQ-25 Sub-Scales
Scale
Number of items
Items to be averaged  
(after recoding per Table 3)
General Health
1
1
General Vision
1
2
Ocular Pain
2
4, 19
Near Activities
3
5, 6, 7
Distance Activities
3
8, 9, 14
Vision Specific:
    Social Functioning
    Mental Health
    Role Difficulties    
    Dependency
2
4
2
3
11, 13
3, 21, 22, 25
17, 18
20, 23, 24
Driving
3
15c, 16, 16a
Color Vision
1
12
Peripheral Vision
1
10
Scoring example
Items 5, 6, and 7 are used to generate the near activities sub-scale score (Table 4). Each of the 
items has 6 response choices. 

Response choice 6 indicates that the respondent does not perform the activity because of 
reasons that are unrelated to vision. If a respondent selects this choice, the answer is 
treated as missing and an average of the remaining items is calculated.

Response choice 5 indicates that an activity is so difficult that the participant no longer 
performs the activity. This extremely poor near vision response choice is recoded to “0” 
points before taking an average of all three items. 

To score all items in the same direction, Table 4 shows that responses 1 through 5 for 
items 5, 6, and 7 should be recoded to values of 100, 75, 50, 25, and 0 respectively. 

If the respondent is missing one of the items, the person's score will be equal to the 
average of the two non-missing items.
Formula:                      Mean = (Score for each item with a non-missing answer)
Total number of items with non-missing answers
Example:
With responses converted: = (25 + 100 + 25) / 3= 50
Note: 100 = Best, 0 = Worst possible score.


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8.2
Calculation of Confidence Intervals for Treatment Differences
8.2.1
Rates and Proportions
The confidence interval using normal approximation is defined as
   CI = pext – pfix ± zα/2*SQRT(pext(1-pext)/next +pfix(1-pfix)/nfix)
where  
SQRT is the square root function
        
pext
= success rate in the extended dosing group
pfix
= success rate in the fixed dosing group
next
= number of subjects in the extended dosing group
nfix
= number of subjects in the fixed dosing group
zα 
= α quantile of the standard normal distribution.
No continuity correction is used in this normal approximation. 
This confidence interval can be calculated with SAS PROC FREQ using the table options 
‘RISKDIFF’ and ‘ALPHA=0.05’.
8.2.2
Means
The 95% confidence interval for the mean is defined as
   CI = mext – mfix ± t1-α/2,n*SE
where under the assumption of equal variances:
        
mext = mean (difference to baseline) in the extended dosing group
        
mfix = mean (difference to baseline) in the fixed dosing group
t1-α,n = α quantile of the t-distribution.
n 
= next + nfix
next
= number of subjects in the extended dosing group
nfix = number of subjects in the fixed dosing group
SE 
= pooled Standard Error
Under the assumption of unequal variances (Behrens-Fisher-Problem) Satterthwaite’s formula 
for calculating the CI is available. 
Both confidence intervals can be calculated with SAS PROC TTEST using the option 
‘ALPHA=0.05’. There the assumption of equal variances in both dsoing-groups will be 
automatically tested using an F-test. If the respective p-value is below 0.05 than 
Satterthwaite’s formula will be used, otherwise the CI using the pooled Standard Error, 
described above more detailed detail.