Clinical trial NCT02581995
Conditions: Macular Edema
Keywords: Diabetic macular edema Intravitreal injection
Sponsor: Bayer
Start date: 2015-11-19; Completion date: 2017-08-09
Enrollment: 560 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the change in quality of life (NEI VFQ 25) in subjects with DME during the first year of treatment with aflibercept according to the EU Label.

Detailed description:

Arms: arm 1: Aflibercept treatment in subjects with diabetic macular edema (DME)
Interventions: intervention 1: Eylea (Aflibercept, VEGF Trap-Eye, BAY86-5321)
Intervention descriptions: intervention 1: 2 mg aflibercept administered every 8 weeks following 5 initial monthly doses Intravitreal (IVT) injection

Protocol documents:
Prot_001.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
Open-label Phase-4 study to examine the change of vision-related 
quality of life in subjects with diabetic macular edema (DME) 
during treatment with intravitreal injections of 2 mg aflibercept 
according to EU label for the first year of treatment 
NCT Number: 
NCT02581995 
Document Date: 
07 September 2015 
 


Integrated Clinical Study Protocol
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Open-label Phase-4 study to examine the change of vision-related quality 
of life in subjects with diabetic macular edema (DME) during treatment 
with intravitreal injections of 2 mg aflibercept according to EU label for 
the first year of treatment
This protocol version is an integration of the following documents/sections:

Original protocol, Version 1.0, dated 10 February 2015

Amendment 01 (global amendment described in Section 15.1) forming integrated 
protocol Version 2.0, dated 07 September 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
Open-label Phase-4 study to examine the change of vision-related quality 
of life in subjects with diabetic macular edema (DME) during treatment 
with intravitreal injections of 2 mg aflibercept according to EU label for 
the first year of treatment
Investigation of the change of vision-related quality of life in subjects treated with 
aflibercept according to EU label for DME
Test drug:
BAY 86-5321;  aflibercept;  Eylea
Study purpose:
Assessment of quality of life
Clinical study phase:
4
Date:
07 September 2015  
Registration:
EudraCT:  2014-005119-17
Version no.:
2.0  
Sponsor’s study no.:
BAY 86-5321 /17850   
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Email:
Phone:
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
PPD


ffi Bayer Health Care 
07 September 2015 
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Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
Role: 
Date: 
Signature: 
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
Title
Open-label Phase-4 study to examine the change of vision-related quality 
of life in subjects with diabetic macular edema (DME) during treatment 
with intravitreal injections of 2 mg aflibercept according to EU label for the 
first year of treatment
Short title
Investigation of the change of vision-related quality of life in subjects 
treated with aflibercept according to EU label for DME
Clinical study phase
4
Study objective(s)
Primary objective
To evaluate the change in quality of life (NEI VFQ-25) in subjects with DME 
during the first year of treatment with aflibercept according to the EU label
for DME
Secondary objectives

To assess further the safety and tolerability of aflibercept in this 
population

To assess the change in the diabetic retinopathy severity score (DRSS) 
from baseline to Week 52

To support subject recruitment for the EMA-requested post-approval 
efficacy study in DME
Test drug(s)
Name of active ingredient
BAY 86-5321 / aflibercept / Eylea
Dose(s)
2 mg aflibercept administered every 8 weeks following 5 initial monthly 
doses
Route of administration
Intravitreal (IVT) injection
Duration of treatment
1 year
Reference drug(s)
None
Indication
Diabetic macular edema (DME)
Diagnosis and main criteria for 
inclusion /exclusion
1.
Type-1 or -2 diabetes mellitus
2.
Diagnosis of DME secondary to diabetes mellitus involving the center of the 
macula (defined as the area of the center subfield on OCT) in the study eye
3.
Decrease in vision determined to be primarily the result of DME in the 
study eye
4.
BCVA in the study eye of ETDRS letter score 73 to 24
(This corresponds to a Snellen equivalent of approximately 20/40 to 20/320.)
Study design
Single-arm, multicenter
Methodology
NEI VFQ-25 questionnaire
Type of control
NA
Data Monitoring Committee
An adjudication committee will perform an additional analysis of arterial 
thrombotic events (ATEs) 
Number of subjects
Total of approximately 450 to 520 subjects planned to be enrolled 
Primary variable(s)
Change from baseline to Week 52 in NEI VFQ-25 total score
Time point/frame of measurement
for primary variable(s)
After 52 weeks of treatment
Plan for statistical analysis
All analyses will be descriptive; no hypothesis testing will be performed.  
95% confidence intervals will be provided as appropriate.


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Table of contents
1.
Title page............................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis.............................................................................................................................. 5
Table of contents....................................................................................................................... 6
List of abbreviations............................................................................................................... 10
3.
Introduction..................................................................................................................... 11
3.1
Background............................................................................................................. 11
3.2
Rationale of the study ............................................................................................. 11
3.3
Benefit-risk assessment........................................................................................... 12
4.
Study objectives............................................................................................................... 13
5.
Study design..................................................................................................................... 13
6.
Study population ............................................................................................................. 14
6.1
Inclusion criteria - amended ................................................................................... 14
6.2
Exclusion criteria - amended .................................................................................. 15
6.3
Withdrawal of subjects from study......................................................................... 17
6.3.1
Withdrawal - amended.............................................................................. 17
6.3.2
Replacement.............................................................................................. 19
6.4
Subject identification - amended ............................................................................ 19
7.
Treatments....................................................................................................................... 20
7.1
Treatments to be administered................................................................................ 20
7.2
Identity of study treatment...................................................................................... 20
7.3
Treatment assignment............................................................................................. 20
7.4
Dosage and administration - amended.................................................................... 21
7.5
Masking .................................................................................................................. 22
7.6
Drug logistics and accountability ........................................................................... 22
7.7
Treatment compliance............................................................................................. 23
8.
Non-study therapy........................................................................................................... 24
8.1
Prior and concomitant therapy................................................................................ 24
8.1.1
Prior therapy.............................................................................................. 24
8.1.2
Concomitant therapy................................................................................. 24
8.1.2.1
Study-eye treatment ............................................................... 24
8.1.2.2
Fellow-eye treatment.............................................................. 24
8.2
Post-study therapy................................................................................................... 25


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9.
Procedures and variables ............................................................................................... 26
9.1
Tabular schedule of evaluations - amended............................................................ 26
9.2
Visit description...................................................................................................... 28
9.2.1
Visit 1  -  Screening - amended................................................................. 28
9.2.2
Visit 2  (Day 1)  -  Baseline - amended..................................................... 29
9.2.3
Visit 3 to Visit 10  (Week 4 to Week 48).................................................. 30
9.2.4
Visit 11  (Week 52)  -  Final visit or early termination............................. 31
9.3
Population characteristics ....................................................................................... 32
9.3.1
Demographic............................................................................................. 32
9.3.2
Medical/surgical and ophthalmic history - amended ................................ 32
9.4
Efficacy - amended................................................................................................. 33
9.4.1
National Eye Institute Visual Functioning Questionnaire-25 
(NEI VFQ-25) - amended ......................................................................... 33
9.4.2
Ophthalmic examinations ......................................................................... 33
9.4.2.1
Best corrected visual acuity (BCVA)..................................... 33
9.4.2.2
Optical coherence tomography (OCT)................................... 34
9.4.2.3
Indirect ophthalmoscopy........................................................ 34
9.4.2.4
Slit lamp biomicroscopy ........................................................ 34
9.4.2.5
Intraocular pressure (IOP)...................................................... 34
9.4.2.6
Fundus photography (FP) and fluorescein angiography 
(FA) - amended ...................................................................... 34
9.4.3
Efficacy variables...................................................................................... 34
9.5
Pharmacokinetics / pharmacodynamics.................................................................. 35
9.6
Safety ...................................................................................................................... 35
9.6.1
Adverse events .......................................................................................... 35
9.6.1.1
Definitions.............................................................................. 35
9.6.1.2
Classifications for adverse event assessment......................... 37
9.6.1.2.1
Seriousness.............................................................................37
9.6.1.2.2
Intensity..................................................................................37
9.6.1.2.3
Causal relationship.................................................................37
9.6.1.2.4
Action taken with study treatment .........................................39
9.6.1.2.5
Other specific treatment(s) of adverse events ........................39
9.6.1.2.6
Outcome.................................................................................40
9.6.1.3
Assessments and documentation of adverse events............... 40
9.6.1.4
Reporting of serious adverse events....................................... 41
9.6.1.5
Expected adverse events - amended....................................... 42
9.6.2
Pregnancies - amended.............................................................................. 42
9.6.3
Further safety ............................................................................................ 43
9.6.3.1
Laboratory evaluations - amended......................................... 43
9.6.3.2
Vital signs (body temperature, blood pressure and pulse)..... 44
9.7
Other procedures and variables............................................................................... 44
9.8
Appropriateness of procedures / measurements ..................................................... 44


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10. Statistical methods and determination of sample size ................................................. 44
10.1
General considerations............................................................................................ 44
10.2
Analysis sets ........................................................................................................... 44
10.3
Variables and planned statistical analyses.............................................................. 45
10.3.1
Variables ................................................................................................... 45
10.3.1.1
Efficacy variables................................................................... 45
10.3.1.2
Safety variables ...................................................................... 45
10.3.2
Statistical and analytical plans .................................................................. 46
10.3.2.1
Demography and baseline characteristics - amended ............ 46
10.3.2.2
Efficacy analyses.................................................................... 46
10.3.2.3
Safety analyses - amended ..................................................... 47
10.4
Determination of sample size ................................................................................. 47
10.5
Planned interim analyses ........................................................................................ 48
11. Data handling and quality assurance............................................................................ 48
11.1
Data recording......................................................................................................... 48
11.2
Monitoring .............................................................................................................. 50
11.3
Data processing....................................................................................................... 50
11.4
Missing data............................................................................................................ 51
11.5
Audit and inspection............................................................................................... 51
11.6
Archiving ................................................................................................................ 51
12. Premature termination of the study .............................................................................. 52
13. Ethical and legal aspects................................................................................................. 53
13.1
Investigator(s) and other study personnel............................................................... 53
13.2
Funding and financial disclosure............................................................................ 53
13.3
Ethical and legal conduct of the study.................................................................... 54
13.4
Subject information and consent - amended........................................................... 54
13.5
Publication policy and use of data.......................................................................... 56
13.6
Compensation for health damage of subjects / insurance....................................... 56
13.7
Confidentiality........................................................................................................ 56
14. Reference list.................................................................................................................... 57


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15. Protocol amendments...................................................................................................... 58
15.1
Amendment 1, dated 07 September 2015............................................................... 58
15.1.1
Overview of changes to the study............................................................. 58
15.1.1.1
Modification 1 - Inclusion criterion 3 .................................... 58
15.1.1.2
Modification 2 –Inclusion criterion 5 .................................... 58
15.1.1.3
Modification 3 – Exclusion criteria........................................ 59
15.1.1.4
Modification 4 – Re-screening criteria .................................. 59
15.1.1.5
Modification 5 – Subject identification number .................... 59
15.1.1.6
Modification 6 – EU SmPC update........................................ 59
15.1.1.7
Modification 7 – Slit lamp biomicroscopy in schedule of 
evaluations.............................................................................. 60
15.1.1.8
Modification 8 – Order of footnotes in schedule of 
evaluations.............................................................................. 60
15.1.1.9
Modification 9 – Specification of pregnancy testing ............. 60
15.1.1.10 Modification 10 – Footnote in schedule of evaluations......... 60
15.1.1.11 Modification 11 – Timing of pregnancy testing .................... 61
15.1.1.12 Modification 12 – Smoking history ....................................... 61
15.1.1.13 Modification 13 – Efficacy variables..................................... 61
15.1.1.14 Modification 14 – NEI VFQ-25 questionnaire ...................... 61
15.1.1.15 Modification 15 – Archiving of FA and PP images............... 62
15.1.1.16 Modification 16 – Expected adverse events........................... 62
15.1.1.17 Modification 17 – Reporting of pregnancies ......................... 62
15.1.1.18 Modification 18 – Laboratory safety parameters................... 62
15.1.1.19 Modification 19 – Analysis sets for demographiy and 
baseline characteristics........................................................... 63
15.1.1.20 Modification 20 – Safety analysis.......................................... 63
15.1.1.21 Modification 21 – Subject information and consent 
process
63
15.1.1.22 Modification 22 – Replacement of patients with subjects ..... 63
15.1.2
Changes to the protocol text...................................................................... 64
16. Appendices....................................................................................................................... 83
16.1
NEI VFQ-25 questionnaire).................................................................................... 84


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List of abbreviations 
2PRN
2 mg aflibercept pro re nata (as needed)
2Q8
2 mg aflibercept administered every 8 weeks
2Q8ext
2 mg aflibercept at injection intervals ≥8 weeks
2Q8fix
2 mg aflibercept at injection intervals of exactly 8weeks
AE
adverse event
ALT
alanine aminotransferase
ANCOVA analysis of covariance
APTC
Antiplatelet Trialists' Collaboration
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
ATE
arterial thrombotic event
BCVA
best corrected visual acuity
BUN
blood urea nitrogen
CHMP
Committee for Medicinal Products for Human Use
CNV
choroidal neovascularization
CRF
case record form
CRO
contract research organization
CRT
central retinal thickness
CSR
clinical study report
DME
diabetic macular edema
DR
diabetic retinopathy
DRSS
diabetic retinopathy severity score (
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
ePRO
electronic patient-reported outcome
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
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HbA1c
glycohemoglobin A1c
HDL
high density lipoprotein
HRQoL
health-related quality of life
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IgG
immunoglobulin G
IOP
intraocular pressure
IRB
institutional review board
IVT
intravitreal(ly)
IxRS
interactive (x) response system
LOCF
last observation carried forward
MAH
marketing authorization holder
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCID
minimal clinically important difference
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation 
nAMD
neovascular age-related  macula degeneration
NEI VFQ
National Eye Institute Visual Function Questionnaire
OCT
optical coherence tomography
PAES
post-approval efficacy study 
PDR
proliferative diabetic retinopathy
PID
patient identification number
PPS
per-protocol set
PRN
Latin: pro re nata (as needed)
PT/INR
prothrombin time
PTT
partial thromboplastin time
QoL
quality of life
SAE
serious adverse event
SAF
safety population
SAP
statistical Analysis Plan
SD
standard deviation
SD-OCT
spectral domain optical coherence tomography
SmPC
Summary of Product Characteristics
SMT
safety management team
SOC
system organ class
SUSAR
suspected, unexpected, serious adverse reaction
UPCR
urine protein/creatinine ratio
VA
visual acuity
VEGF
vascular endothelial growth factor
VIVID 
(DME)
A randomized, double masked, active 
controlled, phase III study of the efficacy and 
safety of repeated doses of intravitreal VEGF 
Trap-Eye in subjects with diabetic macular 
edema
VISTA 
(DME)
A double- masked, randomized, active-
controlled, Phase 3 study of the efficacy and 
safety of intravitreal administration of VEGF 
Trap-Eye in patients with diabetic macular 
edema 
VRQoL
vision-related quality of life
WHODD
World Health Organization Drug Dictionary


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3.
Introduction
3.1
Background
Diabetic retinopathy is a major cause of visual impairment.  Diabetic macular edema (DME) 
is a manifestation of DR and is the most frequent cause of blindness in young and mid-aged 
adults (Moss et al. 1998).  It is estimated that 4.8% of the global population has diabetic 
retinopathy, while 3% to 4.1% of Europeans are affected (Prokofyeva & Zrenner 2012).
Vascular endothelial growth factor (VEGF), a protein growth factor that both stimulates 
angiogenesis and increases vascular permeability, plays a key role in the pathophysiology of 
DME (Bhagat et al. 2009).  Hypoxia and other metabolic factors trigger VEGF release.  
VEGF induces vascular leakage and neovascularization.  While neovascularization is the most 
severe manifestation of DR, vascular leakage leading to macular edema is an important cause 
of reduced visual acuity (VA). 
VEGF Trap-Eye is a recombinantly produced fusion protein consisting of the Fc domain of 
human IgG1 fused to portions of the human VEGF receptor extracellular domains.  It has a 
high binding affinity for VEGF and can neutralize VEGF mediated biological activity.  
Therefore, VEGF Trap-Eye may effectively block a key pathway in DME pathophysiology.
Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug.
The detrimental impact on quality of life (QoL) from vision loss compounds any loss in QoL 
due to diabetes or its complications and comorbidities.  This combined with the threat of 
further declines in visual function, or uncertain prospect of an uncomfortable treatment, may 
affect patients’ psychological state or lead to social isolation (Droege et al. 2014; Lloyd et al. 
2013)
Among the several condition-specific measures or instruments which are designed to capture 
the specific impact of vision loss on health-related quality of life (HRQoL) is the National 
Eye Institute Visual Function Questionnaire (NEI VFQ-25).  This is probably the most widely 
used and researched instrument of this type, measuring vision-related quality of life (VRQoL)
(Lloyd 2013, Mangione 2001).  It was used in the pivotal trials for DME (VIVID DME and 
VISTA DME).  The generic HRQoL measure, EQ-5D, also included in VIVID and VISTA, is 
now known to be unable to distinguish between different severity levels in patients with DR
(Tosh et al. 2012).
3.2
Rationale of the study
Little is known about (i) QoL outcomes in DME patients treated with aflibercept per the 
European SmPC, or (ii) the relative influence of the visual acuity of better- and worse-seeing 
eyes on QoL in such patients.
Clinicians and others can use the results of studies in which QoL has been assessed to 
understand better how diabetes and its treatment affects outcomes that are important to 


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patients, and understand motivations for continuing treatment (Speight et al. 2009).  
Therefore, it is important to measure patients’ ability to function and complete their usual 
activities (vision-related quality of life, VRQoL), as this may represent an important element 
of QoL in patients with DME that may be influenced by treatment (Hirneiss 2014).
Vision in the better-seeing eye has been thought to have a stronger influence on VRQoL than 
that in the worse-seeing eye, although the relative strength of influence has recently come into 
question (Hirneiss 2014).  For example, in the RESTORE trial, 12-month gains in the near 
and distance subscales of NEI VFQ 25, and the composite score, were generally higher in 
anti-VEGF-treated patients who received their treatment in their better-seeing eye rather than 
in their worse-seeing eye (Mitchell et al. 2013).  
As per study protocol, most of the VRQoL data in the Phase-3 program (VIVID DME and 
VISTA DME) was obtained from patients whose (treated) study eye was their worse-seeing 
eye.  For subjects who met study eligibility criteria in both eyes, the study protocols specified 
that the eye with the worse visual acuity was to be selected as the study eye.  Because of this, 
VRQoL results may have become confounded and dominated by the vision of the better-
seeing fellow eye, which was permitted to be treated with anti-VEGFs as part of any standard 
care administered.
The minimally difference which can be assessed as being clinically relevant is a 4 to 6 points 
according to Hirneiss (2014). The clinical relevance of VRQoL changes on this instrument in 
DME is not well known, and may differ from 4-6 points above, largely evidenced from 
nAMD studies. This study provides an opportunity to establish what points change in this 
well-used instrument may be clinically relevant for DME (e.g. like Suner et al. [2009] did for 
nAMD).
This study aims to systematically and prospectively collect data on VRQoL outcomes in 
patients with DME treated with aflibercept per the European SmPC.  It also permits 
exploratory analyses of the relative influence of the visual acuity of better- and worse-seeing 
eyes on VRQoL in such patients.
A further rationale for this study is an explicit request by EMA to conduct a long-term post-
approval efficacy study (PAES) with aflibercept in DME; for that study, a sufficiently large 
population of patients IVT pre-treated according to the aflibercept EU label is required.  
Subjects completing the present protocol may subsequently be enrolled into the sponsor’s 
DME PAES.
3.3
Benefit-risk assessment
Throughout the entire study, all subjects enrolled will receive active treatment approved for 
DME with close medical supervision according to established local standard of care in clinical 
practice.
Taken together, participation in this study is not expected to bear an incremental risk for the 
enrolled subjects.


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4.
Study objectives
Primary objective
To evaluate the change in quality of life (NEI VFQ-25) in subjects with DME during the first 
year of treatment with aflibercept according to the EU label for DME
Secondary objectives

To assess further the safety and tolerability of aflibercept in this population

To assess the change in the diabetic retinopathy severity score (DRSS) from baseline 
to Week 52

To support subject recruitment for the EMA-requested post-approval efficacy study in 
DME
5.
Study design
Design overview
Single-arm, multicenter study administering aflibercept according to EU label for the first 
year of treatment, i.e. 2 mg every 4 weeks for 5 consecutive doses, and dosing every 8 weeks 
thereafter.
Primary variable
The primary efficacy variable is the change in NEI VFQ-25 total score from baseline to 
Week 52. 
Justification of the design
Open-label setting: This is a single arm study without masking requirements.  Treatment in 
this study is according to EU label for DME. 
The length of the observation period (1 year) is based on the primary-endpoint results of the 
pivotal DME studies (VISTA DME, VIVID DME), where most of the benefits after start of 
treatment with aflibercept occurred during the initial year of treatment.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (EU and non-EU).


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6.
Study population
Selection of the study eye
At the discretion of the investigator, only one eye will be designated as the study eye.  
6.1
Inclusion criteria - amended
A subject must meet all of the following inclusion criteria at screening and baseline as 
applicable to be eligible for enrollment into this study:
To be met at screening and baseline for this study
1.
Adults of either sex, ≥18 years of age 
2.
Willingness and ability to comply with clinic visits and study-related procedures
3.
Women and men of reproductive potential must agree to a method of highly effective 
contraception (as defined by the Clinical Trials Facilitation group [CTFG] from 15 SEP 2014):

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:
oral
intravaginal 
transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
oral
injectable
implantable 

Intrauterine device (IUD) 

Intrauterine hormone-releasing system (IUS) 

Bilateral tubal occlusion 

Vasectomised partner 

Sexual abstinence
Alternatively women and men of reproductive potential can also use two acceptable 
methods of contraception (as defined  by the Clinical Trials Facilitation group [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. 1
                                                
1
Replacement of text for inclusion criterion 3 per Amendment 1 (see Section 15.1.1.1)


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4.
Negative pregnancy test (urine or serum; women of childbearing potential only)
5.
Signed written informed consent 2
6.
Type-1 or -2 diabetes mellitus
7.
Diagnosis of DME secondary to diabetes mellitus involving the center of the macula 
(defined as the area of the center subfield on OCT) in the study eye
8.
Decrease in vision determined to be primarily the result of DME in the study eye
9.
BCVA in the study eye of ETDRS letter score 73 to 24
(This corresponds to a Snellen equivalent of approximately 20/40 to 20/320)
6.2
Exclusion criteria - amended
A subject must not meet any of the following exclusion criteria, at screening and baseline as 
applicable, to be eligible for enrollment into this study. 3
Ocular exclusion criteria (study eye)
1. Previous treatment with anti-angiogenic drugs in study eye (e.g. pegaptanib sodium, 
bevacizumab, ranibizumab, aflibercept) within the last 12 weeks 
2.
History of vitreoretinal surgery and/or including scleral buckling in the study eye
3. Prior treatment of the study eye with
Long acting steroids, either periocular or intraocular, in the preceding 120 days or 
Iluvien® intravitreal implant at any time
4.
Active proliferative diabetic retinopathy (PDR), current iris neovascularization, vitreous 
hemorrhage, or tractional retinal detachment in the study eye
5.
Aphakia in the study eye 
6. Cataract surgery within 90 days before first study treatment in the study eye
7.
Yttrium-aluminum-garnet capsulotomy in the study eye within 30 days before first study 
treatment
8.
Any other intraocular surgery within 90 days of first study treatment in the study eye
9.
Ocular inflammation (including trace or above) or history of uveitis in the study eye
10. Vitreomacular traction or epiretinal membrane in the study eye evident 
biomicroscopically or on OCT that is thought to affect central vision
11. Pre-retinal fibrosis involving the macula of the study eye 
                                                
2
Inclusion criterion 5 specified per Amendment 1 (see Section 15.1.1.2)
3
Content and order of exclusion criteria changed per Amendment 1 (see Section 15.1.1.3) 


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12. Structural damage to the center of the macula in the study eye that was likely to preclude 
improvement in BCVA following the resolution of macular edema including atrophy of 
the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or 
organized hard exudates
13. Filtration surgery for glaucoma in the past or likely to be needed in the future on the 
study eye
14. Uncontrolled glaucoma (defined as intraocular pressure [IOP] > 25 mmHg despite 
treatment with antiglaucoma medication) in the study eye
15. Concurrent disease in the study eye, other than DME, that could compromise VA, require 
medical or surgical intervention during the study period, or could confound interpretation 
of the results (including advanced glaucoma, retinal vascular occlusion, retinal 
detachment, macular hole, or choroidal neovascularization of any cause)
16. Significant media opacities, including cataract, in the study eye that interferes with visual 
acuity, fundus photography or OCT imaging.
17. Myopia of a spherical equivalent prior to any possible refractive or cataract surgery of 
≥8 diopters in the study eye
Ocular exclusion criteria (either eye)
18. Any ocular or periocular infection in the preceding 4 weeks in either eye
19. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye
Ocular and systemic exclusion criteria
20. Presence of any contraindications indicated in the EU commission/locally approved label 
for aflibercept
Systemic exclusion criteria
21. Administration of systemic anti angiogenic agents within 180 days before first study 
treatment
22. Uncontrolled diabetes mellitus, as defined by hemoglobin (Hb)A1c > 12.0%
23. Uncontrolled blood pressure (defined as systolic blood pressure > 160 mmHg or diastolic 
blood pressure > 95 mmHg while subject is sitting confirmed in two separate 
measurements)
24. Allergy or hypersensitivity to fluorescein
25. Current treatment for a serious systemic infection
26. History of either cerebral vascular accident and/or myocardial infarction within 180 days 
before first study treatment
27. Renal failure requiring dialysis or renal transplant


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28. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug, might affect interpretation of the results 
of the study, or renders the subject at high risk for treatment complications
29. Breast-feeding women
30. Previous receipt of at least 1 dose of study drug under this protocol
31. Concomitant participation in another clinical study with investigational medicinal 
product(s)
32. 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
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 current aflibercept therapy needs to be 
replaced by another treatment for DME.
AE (ocular or non-ocular) that, from the subject’s or the investigator’s view, is serious 
enough to require withdrawal from the study.  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:
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 (via protocol amendment).
The reason for the screening failure was subsequently resolved (e.g. decrease of 
elevated IOP, controlled arterial hypertension) within 30 days.4
Under any of the above exceptions, a subject may be re-screened once only.  To be eligible, 
re-screened subjects must meet all selection criteria at the re-screening visit.
The investigator must ensure that the repeated screening procedures do not expose the subject 
to an unjustifiable health risk.  Also, for re-screening, the subject must re-sign the informed 
consent form, even if it was not changed after the subject’s previous screening.
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already received at least one dose of study medication.
                                                
4
Time frame added per Amendment 1 (see Section 15.1.1.4) 


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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 as medically 
needed.
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: 5
Digits 1 to 5
=  Unique center number
Digits 6 to 9
=  Current subject number within the center
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.
                                                
5
Description of subject identification number changed per Amendment 1 (see Section 15.1.1.5)


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7.
Treatments
7.1
Treatments to be administered
All subjects will receive aflibercept according to the EU label posology, i.e. 5 monthly 
intravitreal injections followed by administrations every 8 weeks.  
7.2
Identity of study treatment
The identity of the study drug is summarized in Table 7–1.
Table 7–1:
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 NaCl
Water for injection
All study drug 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 drug, 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
In this single-arm study, all eligible subjects will receive aflibercept according to the EU label 
for DME.


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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 7–1 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.  
Preparation of the solution
Based on present stability information, the preparation of the solution should be scheduled to 
ensure that the subsequent injection is completed within 2 hours of the start of the preparation.
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 must 
not be used for IVT injection.  The filter needle should be replaced by the sterile 30-gauge 
needle for the IVT injection.  
Dosage
For the 2-mg dose of aflibercept, the volume of injection is 50 L (0.05 mL).  Thus, the 
syringe contents should be expelled until the plunger is aligned with the line that marks 
0.05 mL on the syringe.
Administration
Aflibercept is administered via IVT injection.  The injection must be completed within 
2 hours of the start of dose preparation.
Posology
All subjects enrolled in this single-arm study will be receive aflibercept according to EU label 
for the first year in an open-label fashion, i.e. 5 monthly intravitreal injections followed by 
intravitreal injections every 8 weeks.


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Consideration of special warnings from EU label 6
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 best-corrected visual acuity (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 
7.5
Masking
Not applicable - this is an open-label study.  
7.6
Drug logistics and accountability
Packaging
Aflibercept will be supplied by the sponsor in treatment kits described in Section 7.4. 
Supply
The treatment kits will be shipped to the investigator at regular intervals or as needed during 
the study.  Study drug will be shipped to the site using appropriate methods to maintain 
transport conditions within those recommended by its stability profile.  The investigator, or an 
approved representative (e.g. pharmacist), will ensure that all received study drugs are stored 
in a secured area on site, under recommended storage conditions and in accordance with 
applicable regulatory requirements.
                                                
6
Paragraph added per Amendment 1 (see Section 15.1.1.6)


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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.  
Accountability
On the day of receipt, the responsible site personnel will confirm receipt of study drug via 
IxRS.  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.


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8.
Non-study therapy
8.1
Prior and concomitant therapy
Any relevant previous and concomitant treatments, including surgeries and laser 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.  
8.1.1
Prior therapy
In particular, any potential previous treatments for DME 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 medications 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
Subjects may not receive any standard or investigational pharmacological agents for treatment 
of their DME in the study eye other than aflibercept as specified in this protocol until they 
have completed the assessments scheduled for the Completion / Early Termination visit.  This 
includes medications administered locally (e.g. IVT, by juxtascleral or periorbital routes), as 
well as those administered systemically with the intent of treating either eye.  Ocular laser 
photocoagulation or surgery may be performed if necessary by the investigator.
8.1.2.2
Fellow-eye treatment
If the fellow eye shall be treated pharmacologically, the most applicable 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 the fellow (non-study) eye has DME, the fellow eye may receive any locally approved non-
systemic treatment (note that fellow-eye aflibercept treatment may be used under this 
protocol).


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Even if treated with aflibercept, the fellow eye will not be considered an additional study eye.  
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 standard of care. 
8.2
Post-study therapy
After the end of this study, subjects will not be restricted with regard to pursuing available 
treatments for DME.
After completion of this study, subjects may subsequently be enrolled into the sponsor’s post-
approval efficacy study further investigating the efficacy of aflibercept in DME patients.


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9.
Procedures and variables
9.1
Tabular schedule of evaluations - amended
Table 9–1:
Schedule of assessments and procedures – amended
Screening
Visit 1
Baseline
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7 to 
Visit 10
End of study 
/ early termin.
Visit 11
4 weeks 
before BL
Day 1
Week 4
Week 8
Week 12
Week 16
Week 24 to 
Week 48 Week 52c
Acceptable deviations relative to BL
± 5 days
± 5 days
± 5 days
± 5 days
±10 days a ± 10 days
Initiation procedures
Informed consent 

Demographic data

Medical / ophthalmic history 

Check of enrollment criteria


Study medication
Administration of study drug 






no 
treatment
Ophthalmologic assessments
(= bilaterally; ●○= study eye only [additional assessments may occur outside of this protocol])
BCVA (ETDRS chart starting at 4 m) b

●○
●○
●○
●○
●○
●○

Optical coherence tomography 
●○
●○
●○
Fluorescein angiography
●○
●○
Fundus photography


Indirect ophthalmoscopy c
●○
●○
●○
●○
●○
●○
●○
●○
Slit lamp biomicroscopy 7


●○
●○
●○
●○
●○
●○
Intraocular pressure (IOP) c
●○
●○
●○
●○
●○
●○
●○
●○
Patient-reported outcomes
NEI VFQ-25








Standard safety
Prior / concomitant medications








Adverse events d








Hematology / chemistry 


Urinalysis / UPCR


Pregnancy test - serum e 8
(women of childbearing potential only)

Pregnancy test – urine dipstick
(women of childbearing potential only) f


Vital signs (body temperature, 
blood pressure, pulse)



BCVA = best corrected visual acuity;  BL = baseline;  ETDRS = Early Treatment Diabetic Retinopathy Study;  
UPCR = urine protein / creatinine ratio
Footnotes to table on next page
                                                
7
Changed to bilaterally for screening and baseline per Amendment 1 (see Section 15.1.1.7)
8
Urine dipstick no alternative to serum test per Amendment 1 (see Section 15.1.1.9)


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Footnotes to Table 9–1 9
a
The intervals between Visits 6 to 9 are 8 weeks ±10 days.
The interval between Visit 9 and Visit 10 must be ≥56 days (8 weeks).
b
Refraction to be done at each visit
c
Also post injection
d
Any AE occurring up to 4 weeks after the last injection of aflibercept has to be documented, regardless of the causal 
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.  All potential arterial thrombotic events (ATEs) will 
be adjudicated according to the Antiplatelet Trialists' Collaboration (APTC).
e
The test is to take place within 7 days before the first injection of study medication 10
f
The test is to be repeated as frequently as required 11
                                                
9
Footnotes re-arranged per Amendment 1 (see Section 15.1.1.8)
10 Footnote added per Amendment 1 (see Section 15.1.1.10)
11 Footnote changed per Amendment 1 (see Section 15.1.1.11)


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9.2
Visit description
9.2.1
Visit 1  -  Screening - amended
Scheduling
The Screening visit must occur within 4 weeks of the baseline visit (Day 1).
Conduct
The following procedures will be performed at this visit:

Collection of signed informed consent form (see Section 13.4 for details)

Record of demographic data (see Section 9.3.1 for details)

Record of prior and concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Record of medical and ophthalmic history (see Section 9.3.2 for details)

Assessment of inclusion and exclusion criteria (see Sections 6.1 and 9 for details)

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart starting at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA)

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intraocular pressure (IOP)

NEI VFQ-25 (see Section 9.4.1 for details)

Laboratory assessments (see Section 9.6.3.1 for details):

Hematology panel

Chemistry panel

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

Serum pregnancy test in women of childbearing potential 12

Vital signs (body temperature, blood pressure and pulse) (see Section 9.6.3.2 for details)
                                                
12 Urine dipstick test no alternative to serum test at screening per in Amendment 1 (see Section 15.1.1.9)


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9.2.2
Visit 2  (Day 1)  -  Baseline - amended
Scheduling
This visit should take place within 4 weeks of the screening visit.
Conduct
The following procedures will be performed at this visit:

Assessment of inclusion and exclusion criteria (see Sections 6.1 and 9 for details)

Including urine dip stick pregnancy test for women of childbearing potential 13

Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Pre-injection ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart starting at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intraocular pressure (IOP)

NEI VFQ-25 (see Section 9.4.1 for details)

Vital signs (body temperature, blood pressure and pulse) (see Section 9.6.3.2 for details)

First application of study medication (see Section 7.4 for details)
Injections are to take place after completion of the procedures listed above.

Post-injection ocular assessments (see Section 9.4.1 for details):

Indirect ophthalmoscopy

Intraocular pressure (IOP)
                                                
13 Urine dipstick test added for baseline visit per Amendment 1 (see Section 15.1.1.9)


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9.2.3
Visit 3 to Visit 10  (Week 4 to Week 48)
Scheduling
For the scheduling of these visits, the following deviations relative to baseline are acceptable:
Monthly post-baseline visits through week 16 (Visits 3 to 6):
± 5 days
Regular Q8 schedule (Visits 7 to 9)
± 10 days
The interval between Visit 9 and Visit 10 must be at least 56 days (8 weeks).
Conduct
The conduct of Visit 3 to Visit 10 will be identical.  The following procedures will be 
performed at these visits:

Record of concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Pre-injection ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart starting at 4 m (refraction is to be done at each visit)

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intraocular pressure (IOP)

NEI VFQ-25 (see Section 9.4.1 for details)

Application of study medication (see Section 7.4 for details)
Injections are to take place after completion of the procedures listed above.

Post-injection ocular assessments (see Section 9.4.1 for details):

Indirect ophthalmoscopy

Intraocular pressure (IOP)


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9.2.4
Visit 11  (Week 52)  -  Final visit or early termination
Scheduling
This visit will be the last scheduled visit under this protocol.  It is to be scheduled at Week 52 
(± 10 days) after baseline.
This visit will also be conducted in case of premature termination of a subject.
Conduct
At this visit, no study medication under this protocol will be administered.
The following procedures will be performed:

Record of prior and concomitant medications (see Section 8.1 for details)

Record of adverse events (see Section 9.6.1 for details)

Ocular assessments (see Section 9.4.1 for details):

BCVA using ETDRS chart starting at 4 m (refraction is to be done at each visit)

Optical coherence tomography (OCT)

Fundus photography (FP) and fluorescein angiography (FA)

Indirect ophthalmoscopy

Slit lamp biomicroscopy 

Intraocular pressure (IOP)

Laboratory assessments (see Section 9.6.3.1 for details):

Hematology panel

Chemistry panel

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

Pregnancy test in women of childbearing potential (urine dipstick test) 14

Vital signs (body temperature, blood pressure and pulse) (see Section 9.6.3.2 for details)

NEI VFQ-25 (see Section 9.4.1 for details)
                                                
14 Urine dipstick test only per Amendment 1 (see Section 15.1.1.11)


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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 - amended
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility.
In particular, the following will be asked for:

Duration of diabetes

Type of diabetes (Type 1/2)

Diabetic retinopathy (including first diagnosis, intensity)

First diagnosis of DME 
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 selection criteria as 
defined in Section 6 and life style details including smoking history will be recorded. 15
                                                
15 Recording of smoking history added per Amendment 1 (see Section 15.1.1.12)


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9.4
Efficacy - amended
9.4.1
National Eye Institute Visual Functioning Questionnaire-25 
(NEI VFQ-25) - amended
Vision-related QoL will be assessed using the NEI VFQ-25 questionnaire (see Section 16.1
for details).  
This questionnaire will be presented in the local language and should be administered in a 
quiet room by a study-related person qualified to administer this type of questionnaire, 
preferably before other visit procedures are performed.  For subjects unable to read the 
questionnaire due to vision impairment, a family member, other legal representative of the 
subject, study nurse, or study physician may assist the subject in completing the 
questionnaires.  In this case, the name of that person should be documented. 16
9.4.2
Ophthalmic examinations
Note:
In this section, all ophthalmic examinations are described, irrespective of whether 
they are used for efficacy or safety assessments.
Unless otherwise specified, all ophthalmic evaluations under this protocol will be conducted 
on the study eye only according to the schedule detailed in Section 9.1 (Table 9–1).  At any 
visit, ophthalmic examinations not stipulated by this protocol may take place outside of this 
protocol at the discretion of the investigator.
All ophthalmic evaluations are to be performed before study drug injection.  In addition, 
indirect ophthalmoscopy and IOP measurement are also to be performed post injection.
The investigator will record all variables as specified in the CRF.
All efficacy variables derived from the ophthalmic examinations are specified in 
Section 10.3.1.1.
9.4.2.1
Best corrected visual acuity (BCVA)
Visual function will be assessed using the ETDRS protocol (Early Treatment Diabetic 
Retinopathy Study Research Group 1985) starting at 4 meters.  Refraction is to be done at 
each visit.  Examiners of visual acuity (VA) must be certified to ensure consistent 
measurement of BCVA.  Unilateral versus bilateral examinations are specified in Table 9–1
for each visit.  A detailed protocol for conducting VA testing and refraction can be found in 
the Study Manual.  
                                                
16 Documentation of name added per Amendment 1 (see Section 15.1.1.14)


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9.4.2.2
Optical coherence tomography (OCT)
Retinal and lesion characteristics will be evaluated using SD-OCT.  For all visits where the 
OCT procedure is scheduled, images will be captured and read by the investigator. All OCTs 
will be electronically archived at the study sites as part of the source documentation.  
9.4.2.3
Indirect ophthalmoscopy
Indirect ophthalmoscopy will be performed according to local medical practice and applicable 
medical standards at the site.  
9.4.2.4
Slit lamp biomicroscopy
The slit lamp examination will be performed according to local medical practice and 
applicable medical standards at the site.
9.4.2.5
Intraocular pressure (IOP)
IOP is to be measured using applanation tonometry (Goldmann, Tonopen or approved 
alternative).  The same method of IOP measurement must be used in each subject throughout 
the study.  
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).
9.4.2.6
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.  Fundus and angiographic images will be read by the 
investigator.  All FA and FP images will be archived electronically 17 at the site as part of the 
source documentation.  
In addition, the 7-Field-FP for both eyes will be transmitted to central reading center for 
ETDRS diabetic retinopathy severity scale (DRSS) grading and storage.
9.4.3
Efficacy variables
All efficacy variables derived from the ophthalmic examinations are specified in 
Section 10.3.1.1. 18
                                                
17 Clarification for archiving as electronic archiving added per Amendment 1 (see Section 15.1.1.15)
18 Section added per Amendment 1 (see Section 15.1.1.13)


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9.5
Pharmacokinetics / pharmacodynamics
Not applicable
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
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 
patient 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).
Medical history versus adverse event 
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.
Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present until signing of informed consent are recorded as 
medical history (e.g. seasonal allergy without acute complaints).
Conditions that started before signing of informed consent and for which symptoms 
or treatment are present after signing of informed consent, at unchanged intensity, 
are recorded as medical history (e.g. allergic pollinosis).
Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  This includes intercurrent illnesses.


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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 the injection 
procedure.
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 
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
9.6.1.2.5
Other specific treatment(s) of adverse events
None
Remedial drug therapy
Other


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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 
“fatal” 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 


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
Any specific drug or non-drug treatment of the adverse event

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.
ATE analysis
Potential arterial thrombotic events (ATEs) will be evaluated by an adjudication committee 
according to criteria formerly applied and published by the Anti-Platelet Trialists’ 
Collaboration (APTC) (Antithrombotic Trialists' Collaboration 2002).  The definition of 
ATEs as well as further details are described in the adjudication committee charter.
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.


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Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.
9.6.1.5
Expected adverse events - amended
Information on AEs with an onset after the first application of the test drug is provided in the 
local label. 19
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. 20
                                                
19 Sentence revised per Amendment 1 (see Section 15.1.1.16)
20 Paragraph added per Amendment 1 (see Section 15.1.1.17)


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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 
outlined in Table 9–1). 21
Blood will be drawn before FA by direct venipuncture.  
Safety laboratory parameters to be evaluated are summarized in Table 9–2.
The date of each blood sample obtained will be recorded on the appropriate eCRF page.  
A copy of the laboratory results will be filed in the source documentation.
Table 9–2:
Laboratory safety parameters - amended
Chemistry
Sodium
Potassium
Chloride
Calcium
Glucose
HbA1c
Albumin
Total Protein, Serum
Creatinine
Blood urea nitrogen (BUN)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Total bilirubin
Amylase
Total cholesterol 22
HDL cholesterol
Urinalysis 
Glucose 
Protein
Specific Gravity
Blood
Ketones 
Protein:Creatinine Ratio (UPCR)
Pregnancy test for women of 
childbearing potential 
(see Table 9–1)
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 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 laboratory.
Deviations of laboratory values from the laboratory reference ranges will be flagged on the 
laboratory print-outs.
                                                
21 Scheduling of serum and urine pregnancy test changed per Amendment 1 (see Section 15.1.1.11)
22 Total and HDL cholesterol added per Amendment 1 (see Section 15.1.1.18)


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9.6.3.2
Vital signs (body temperature, blood pressure and pulse)
Vital signs include body temperature, blood pressure (diastolic and systolic), and pulse.  They 
will be taken according to the schedule provided in Section 9.1.  Measurements should be 
done in a consistent and standardized way according to locally established practice.
9.7
Other procedures and variables
Not applicable
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. 
Statistical analysis will be performed using SAS; the version used as well as further details of 
the analysis will be specified in the statistical analysis plan.
10.2
Analysis sets
Populations for analysis will be defined as follows:
The Full Analysis Set (FAS) will include all subjects who received at least one injection of 
study drug and have completed the baseline and at least one post-baseline NEI VFQ-25 
questionnaire.
The Safety Analysis Set will include all subjects who have received at least one injection of 
study drug.


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10.3
Variables and planned statistical analyses
10.3.1
Variables
10.3.1.1
Efficacy variables
Primary efficacy variables
The primary efficacy variable is 

The change from baseline to Week 52 in the NEI VFQ-25 total score
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”.
Secondary efficacy variables
The secondary efficacy variables include

The change from baseline to Week 52 in the NEI VFQ-25 near activities subscale

The change from baseline to Week 52 in the NEI VFQ-25 distant activities subscale

The change from baseline to Week 52 in BCVA (ETDRS letter score)

The change from baseline to Week 52 in CRT measured by OCT

Proportion of subjects progressing to ≥ 61 ETDRS diabetic retinopathy severity scale
(DRSS) as assessed by FP
Exploratory efficacy variables
A complete list of variables to be analyzed for this study will be provided in the statistical 
analysis plan (SAP).
10.3.1.2
Safety variables
The following safety variables will be assessed:
Adverse events (see Section 9.6.1)
Vital signs (see Section 9.6.3.2)
Ophthalmologic safety variables (see Section 9.4.1)


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10.3.2
Statistical and analytical plans 
10.3.2.1
Demography and baseline characteristics - amended
Demographic variables and baseline characteristics will be summarized for both 23 analysis 
sets, 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 (WHO DD). 
The number of injections will be tabulated.  
10.3.2.2
Efficacy analyses
All efficacy variables will be analyzed on the FAS.
Primary efficacy variable
The analyses of the primary efficacy variable will be descriptively.  95% confidence intervals 
will be provided based on the t-distribution assuming that the changes from baseline are 
normally distributed. 
To be comparable with publications of other studies in this indication, missing values will be 
imputed with the last observed post-baseline value collected before the missing value 
(LOCF). 
Frequencies of subjects worsening or improving (separately for not achieving, achieving or 
exceeding the clinically meaningful difference specified in Section 10.4) will be computed for 
each time point.
With regard to the classification of clinical meaningfulness of QoL at Week 52, mean change 
in BCVA will be calculated for each of the two categories.  The difference in mean change in 
BCVA between the two categories of clinically meaningfulness of QoL will be evaluated, 
together with t-distribution-based 95% confidence intervals.
As sensitivity analysis a multiple imputation (MI) analysis will be provided.  The imputations 
will be based on the baseline value as well as all observed changes from baseline.
Furthermore, a repeated-measurements-model analysis will be conducted including the visit 
as fixed factor and the baseline value and the baseline*visit interaction as covariate.
In addition, the effect of the choice of the study eye on the quality of life (better seeing eye vs. 
worse seeing eye) will be investigated.
Further exploratory analyses will be conducted to investigate the intra-individual variability in 
the score over time and the correlation between the BCVA value in both eyes and the score.
                                                
23 Correction from 3 to 2 analysis sets per Amendment 1 (see Section 15.1.1.19)


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Secondary efficacy variables
The secondary efficacy variables will be analyzed descriptively in analogy to the primary 
efficacy variables.
Exploratory efficacy variables
All exploratory variables will be analyzed descriptively.
10.3.2.3
Safety analyses - amended
All safety variables will be summarized descriptively on the SAF.
Adverse events
Treatment-emergent AEs will be presented by MedDRA preferred term within primary 
system organ class (SOC). 24  Intensity and causal relationship to the investigational product 
will be analyzed descriptively.  Non-ocular, ocular AEs in the study eye, and non-ocular AEs 
in the fellow eye will be displayed separately.
Potential arterial thrombotic events (ATEs) as described in Section 9.6.1.3 will be presented 
separately.
Other safety variables
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 calculation of incidence rates for treatment emergent laboratory abnormalities by 
treatment group.
10.4
Determination of sample size
A total of approximately 450 to 520 subjects is planned to be enrolled.  This takes the
sponsor’s planned subsequent post-approval efficacy study into consideration.
In a previously conducted study with aflibercept in DME, the standard deviation observed for
the change from baseline to Week 52 in the NEI VFQ-25 total score was 11.
Assuming a similar variability (SD = 11), with a sample size of 450 subjects (520 subjects), 
the difference between the mean and the limits of the 95% confidence intervals will not 
exceed 1.1 (1.0) with a probability of 90%. 
                                                
24 No summary by treatment groups per Amendment 1 (see Section 15.1.1.20)


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As the minimal clinically important difference (MCID) has been reported to be in the range of 
4 to 6 (Hirneiss 2014), for the context of this study, it was decided to use the value of 5 as 
MCID.  The change in QoL will be classified according to the two categories 

Change ≥MCID

Change < MCID (this includes no change or deteriorations).  
In both categories, the mean change from baseline in BCVA will be evaluated, and a 95% 
confidence interval for the difference between both categories will be calculated.  Taken the 
sample size range specified above and assumptions25 for the distribution of subjects on the 
two MCID categories, the length of this respective confidence interval will not exceed 1.8 to 
1.9 letters with a probability of 90% (with SD = 10 for change in BCVA based on previously 
conducted studies with aflibercept in DME). 
This precision is considered to be sufficient to assess the relevance of change in QoL over 
time, and in relation to BCVA measurements.
Sample size calculated with PASS (Power Analysis & Sample Size) v. 11 (Confidence 
Intervals for One Mean with Tolerance Probability and Confidence Intervals for the 
Difference Between Two Means with Tolerance Probability).
10.5
Planned interim analyses
No formal interim analysis will be conducted.  
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 (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/CRO has 
licensed from Medidata Solutions Worldwide.  RAVE has been validated by Medidata 
Solutions Worldwide and Bayer/CRO 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/CRO extensively 
                                                
25 Based on former aflibercept in DME studies, and considering the slightly different population in this study, a proportion 
between 50:50 and 70:30 is assumed.


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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 the sponsor'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.
Data recorded from screening failures
Data of 'only screened subjects' will be recorded at least as source data.  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 screen failure
Date of last visit.  
These data will be transferred to the respective database.


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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.
11.3
Data processing
Data will be collected as described in Section 11.1.  Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures.  This is applicable for data recorded on CRF as well as for data from other 
sources (e.g. IxRS, adjudication committees).
For data coding (e.g. AEs, medication, medical history, surgeries), internationally recognized 
and accepted dictionaries will be used.


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11.4
Missing data 
All efforts will be made to minimize the amount of missing data.  Measures for this include 
investigators’ training and timely monitoring of CRF entries for completeness (see 
Section 11.2).
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
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.


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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 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.
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.


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13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
The sponsor’s medical expert is identified on the title page (including contact details).
The co-ordinating investigator responsible for signing the final clinical study report (CSR) 
will be assigned by the sponsor after finalization of this protocol.
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.
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 IEC/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 are recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.


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Each subject will be informed about the following aspects of premature withdrawal:
Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
The subject’s consent covers early-termination examinations as specified in the visit 
description described in Section 9.2.4 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.  Each subject / legal representative
or proxy consenter will have ample time and opportunity to ask questions. 26
Only if the subject / legal representative or proxy consenter 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 may read 
the document to the subject and may assist the subject in signing the form.  In this case, the 
name of that person should be documented. 27
If the subject is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the sponsor and the 
investigator).  This is to be documented by a signature from the informing physician as well 
as by a signature from the witness.
The informed consent form and any other written information provided to subjects / legal 
representatives or proxy consenters 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 / legal representative or proxy consenter 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.
                                                
26 Paragraph revised to align with sponsor internal standards per Amendment 1 (see Section 15.1.1.21)
27 Paragraph added to align with sponsor internal standards per Amendment 1 (Section 15.1.1.21)


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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 
Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of 
antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk 
patients.  Br Med J. 2002; 324: 71-86.
Bhagat N, Grigorian RA, Tutela A et al.  Diabetic macular edema: pathogenesis and 
treatment.  Surv Ophthalmol 2009; 54(1): 1-32.
Campochiaro PA, Sophie R, Pearlman J.  Long-term outcomes in patients with retinal vein 
occlusion treated with ranibizumab - The RETAIN study.  Ophthalmology 2014; 121: 209-
219
CATT Research Group.  Ranibizumab and bevacizumab for neovascular age-related macular 
degeneration.  N Eng J Med 2011; 365:1897-1908
Droege et al. Graefes Arch Clin Exp Ophthalmol. 2014; 252: 31-34.
Early Treatment Diabetic Retinopathy Study Research Group.  Photocoagulation for diabetic 
macular edema.  Arch Ophthalmol 1985; 103: 1796-1806
Hirneiss C.  The impact of a better-seeing eye and a worse-seeing eye on vision-related 
quality of life.  Clinical Ophthalmology 2014; 8: 1703–1709
Ho AC, Busbee BG, Regillo CD et al.  Twenty-four-month efficacy and safety of 0.5 mg or 
2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular 
degeneration.   Ophthalmology 2014 Jul 9. pii: S0161-6420(14)00429-1. doi: 
10.1016/j.ophtha.2014.05.009. [Epub ahead of print]
Lloyd et al. Health and Quality of Life Outcomes 2013, 11:10
Mangione et al. Clinical Ophthalmology 2014:8 1703–1709
Mitchell et al. JAMA Ophthalmol. 2013;131(10):1339-1347.
Moss SE, Klein R, Klein BE.  The 14-year incidence of visual loss in a diabetic population.  
Ophthalmology 1998; 105(6):  998-1003.
Prokofyeva E & Zrenner E.  Epidemiology of Major Eye Diseases Leading to Blindness in 
Europe: A Literature Review.  Ophthalmic Res 2012; 47: 171–188
Speight et al. Diabet Med. 2009 Apr;26(4):315-27
Suner IJ, Kokame GT, Yu E, Ward J et al.  Responsiveness of NEI VFQ-25 to changes in 
visual acuity in neovascular AMD: validation studies from two phase 3 clinical trials. 
Invest Ophthalmol Vis Sci. 2009;50:3629–3635.
Tosh et al. Value in Health 2012; 15(11): 118-127.


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15.
Protocol amendments
Editorial note
In the sections on changes to the protocol text, all protocol sections affected by the respective
amendment are detailed; the sequence of the sections follows the structure of the most recent
previous protocol version. As applicable, changes to the protocol text are highlighted as
follows:

Addition of a whole new portion: Brief identification of the new portion

Removal of a whole portion: Complete display of the removed portion, formatted as
crossed out

Editing of an existing portion: Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent previous protocol version. 
Deletions are crossed out in the “old text”. Additions are underlined in the “new 
text”.

Tables / figures: The term “amended” is added to the caption.

Terminological changes: Brief specification of the terminological change
Correction of typos or omissions are not highlighted.
15.1
Amendment 1, dated 07 September 2015
15.1.1
Overview of changes to the study
15.1.1.1
Modification 1 - Inclusion criterion 3
Inclusion criterion 3 - use of adequate contraception (definition based on the judgment of the 
investigator) replaced with use of highly effective contraception (definition based on CTFG 
from 15 SEP 2014).
Rationale: For subject safety reasons
The following protocol sections are affected by this modification:
Section 6.1 Inclusion criteria
15.1.1.2
Modification 2 –Inclusion criterion 5
‘Written informed consent’ complemented by ‘signed’
Rationale: Specification of informed consent
The following protocol sections are affected by this modification:
Section 6.1 Inclusion criteria


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15.1.1.3
Modification 3 – Exclusion criteria
Content and order of exclusion criteria changed.
Rationale: More detailed specification, clearer overview
The following protocol sections are affected by this modification:
Section 6.2 Exclusion criteria
15.1.1.4
Modification 4 – Re-screening criteria
Time frame for resolution of reason for screening failure (to allow re-screening) added to list 
of criteria for re-screening.
Rationale: Clarification
The following protocol sections are affected by this modification:
Section 6.3.1 Withdrawal
15.1.1.5
Modification 5 – 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
15.1.1.6
Modification 6 – EU SmPC update
Special warnings from EU SmPC (most recent version number) added to dosage and 
administration.
Rationale: For subject safety reasons
The following protocol sections are affected by this modification:
Section 7.4 Dosage and administration


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15.1.1.7
Modification 7 – Slit lamp biomicroscopy in schedule of evaluations
Description of slit lamp biomicroscopy updated.
Rationale: In agreement with exclusion criteria 18 and 19 to be performed bilaterally at
screening and baseline
The following protocol sections are affected by this modification:
Section 9.1 Tabular schedule of evaluations
15.1.1.8
Modification 8 – Order of footnotes in schedule of evaluations
Arranging the footnotes in the order the table is read, line by line
Rationale: More reader friendly
The following protocol sections are affected by this modification:
Section 9.1 Tabular schedule of evaluations
15.1.1.9
Modification 9 – Specification of pregnancy testing
Serum test binding for screening visit (urine dipstick is no alternative); urine dipstick test 
added for baseline visit
Rationale: A subject 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 9.2.1 Visit 1  -  Screening
Section 9.2.2 Visit 2 (Day 1)  -  Baseline
15.1.1.10 Modification 10 – Footnote in schedule of evaluations

Footnote e (part of former d, see Modification 9, Section 15.1.1.9) Serum pregnancy test 
within 7 days before first injection of study medication
Rationale: For subject safety reasons
The following protocol sections are affected by this modification:
Section 9.1 Tabular schedule of evaluations


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15.1.1.11 Modification 11 – Timing of pregnancy testing
Footnote f (part of former d, see Modification 9, Section 15.1.1.9) ‘The [urine dipstick 
pregnancy] test is to be repeated as frequently as required’ and is required at Visit 11 (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 9.2.4 Visit 11  (Week 52)  -  Final visit or early termination
Section 9.6.3.1 Laboratory evaluations
15.1.1.12 Modification 12 – Smoking history
Addition of smoking history to the medical history
Rationale: The smoking history was added to allow analysis of the general cardiovascular risk
The following protocol sections are affected by this modification:
Section 9.3.2 Medical/surgical and ophthalmic history
15.1.1.13 Modification 13 – Efficacy variables 
New sub-section 9.4.3 Efficacy variables added to Section 9.4 Efficacy
Rationale: Reference to Section 10.3.1.1 regarding efficacy variables derived from the 
ophthalmic examinations
The following protocol sections are affected by this modification:
Section 9.4 Efficacy
15.1.1.14 Modification 14 – 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 9.4.1 National Eye Institute Visual Functioning Questionnaire-25 
(NEI VFQ-25)


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15.1.1.15 Modification 15 – Archiving of FA and PP images
Requirement to archive FA and FP images electronically added.
Rationale: Clarification
The following protocol sections are affected by this modification:
Section 9.4.2.6 Fundus photography (FP) and fluorescein angiography (FA)
15.1.1.16 Modification 16 – 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
15.1.1.17 Modification 17 – Reporting of pregnancies
New paragraph on fertility added to Section 9.6.2 Pregnancies
Rationale: To include guidance in a specific adverse event situation
The following protocol sections are affected by this modification:
Section 9.6.2 Pregnancies
15.1.1.18 Modification 18 – Laboratory safety parameters
Addition of total and HDL cholesterol to the laboratory safety parameters.
Rationale: Total cholesterol and HDL cholesterol were added to allow analysis of the general 
cardiovascular risk
The following protocol sections are affected by this modification:
Section 9.6.3.1 Laboratory evaluations


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15.1.1.19 Modification 19 – Analysis sets for demographiy and baseline 
characteristics
Three analysis sets changed to two
Rationale: Correction
The following protocol sections are affected by this modification:
Section 10.3.2.1 Demography and baseline characteristics
15.1.1.20 Modification 20 – Safety analysis
Summary by treatment groups removed.
Rationale: Only 1 treatment group
The following protocol sections are affected by this modification:
Section 10.3.2.3 Safety analyses
15.1.1.21 Modification 21 – 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
15.1.1.22 Modification 22 – Replacement of patients with subjects
“Patients” replaced with “subjects” where applicable 
Rationale: To establish consistency in wording throughout the text
This terminological change is not marked as change in the text.


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15.1.2
Changes to the protocol text
Changes to the protocol text are highlighted as specified at the beginning of Section 15.
The addition of HDL and HRQoL to the list of abbreviations is not highlighted additionally in 
this section.
Section 6.1 Inclusion criteria
Inclusion criterion 3 replaced per Modification 1 (Section 15.1.1.1).
Old text:
3.
Women and men of reproductive potential must agree to use adequate contraception 
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. 
The definition of adequate contraception will be based on the judgment of the 
investigator and on local requirements.
Acceptable methods of contraception include, but are not limited to: (i) condoms (male or 
female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with 
spermicide; (iii) intra-uterine device; (iv) hormone-based contraception.
Subjects must agree to utilize two reliable and acceptable methods of contraception 
simultaneously. 
Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of child bearing potential. 


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New text:
3.
Women and men of reproductive potential must agree to a method of highly effective   
contraception (as defined by the Clinical Trials Facilitation group [CTFG] from 15 SEP 
2014):   

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:

oral

intravaginal 

transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

oral

injectable

implantable 

Intrauterine device (IUD) 

Intrauterine hormone-releasing system (IUS) 

Bilateral tubal occlusion 

Vasectomised partner 

Sexual abstinence
Alternatively women and men of reproductive potential can also use two acceptable 
methods of contraception (as defined  by the Clinical Trials Facilitation group [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. 
Section 6.1 Inclusion criteria
Inclusion criterion 5 changed per Modification 2 (Section 15.1.1.2).
Old text:
5.
Written informed consent
New text:
5.
Signed written informed consent


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Section 6.2 Exclusion criteria
Content and order of exclusion criteria changed per Modification 3 (Section 15.1.1.3).
Old text:
A subject must not meet any of the following exclusion criteria, at screening and baseline as 
applicable, to be eligible for enrollment into this study. 
1. Previous treatment with anti-angiogenic drugs in study eye (e.g. pegaptanib sodium, 
bevacizumab, ranibizumab) within the last 12 weeks 
2.
History of vitreoretinal surgery and/or including scleral buckling in the study eye
3.
Use of long acting steroids, either periocular or intraocular, in the preceding 120 days
4.
Any ocular or periocular infection in the preceding 4 weeks
5.
Active proliferative diabetic retinopathy (PDR), current iris neovascularization, vitreous
hemorrhage, or tractional retinal detachment in the study eye
6.
Aphakia in the study eye 
7.
Cataract surgery within 90 days 
8.
Yttrium-aluminum-garnet capsulotomy in the study eye within 30 days 
9.
Any other intraocular surgery within 90 days 
10. Ocular inflammation (including trace or above) or history of uveitis in the study eye
11. Vitreomacular traction or epiretinal membrane in the study eye evident 
biomicroscopically or on OCT that is thought to affect central vision
12. Pre-retinal fibrosis involving the macula of the study eye 
13. Structural damage to the center of the macula in the study eye that was likely to preclude 
improvement in BCVA following the resolution of macular edema including atrophy of 
the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or 
organized hard exudates
14. Filtration surgery for glaucoma in the past or likely to be needed in the future on the 
study eye
15. Intraocular pressure (IOP) ≥25 mmHg in the study eye
16. Concurrent disease in the study eye, other than DME, that could compromise VA, require 
medical or surgical intervention during the study period, or could confound interpretation 
of the results (including retinal vascular occlusion, retinal detachment, macular hole, or 
choroidal neovascularization of any cause)
17. Myopia of a spherical equivalent prior to any possible refractive or cataract surgery of 
≥8 diopters
18. Administration of systemic anti angiogenic agents within 180 days 


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Uncontrolled diabetes mellitus in the opinion of the investigator
19. Uncontrolled blood pressure (defined as systolic blood pressure > 160 mmHg or diastolic 
blood pressure > 95 mmHg while subject is sitting confirmed in two separate 
measurements)
20. Presence of any contraindications indicated in the EU commission/locally approved label 
for aflibercept
21. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye
22. Allergy to fluorescein
23. Current treatment for a serious systemic infection
24. History of either cerebral vascular accident and/or myocardial infarction within 180 days 
25. Renal failure requiring dialysis or renal transplant
26. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug, might affect interpretation of the results 
of the study, or renders the subject at high risk for treatment complications
27. Significant media opacities, including cataract, in the study eye that interferes with visual 
acuity, fundus photography or OCT imaging.
28. Breast-feeding women
29. Previous assignment to treatment during this study
30. Concomitant participation in another clinical study with investigational medicinal 
product(s).  
31. 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)
New text:
A subject must not meet any of the following exclusion criteria, at screening and baseline as 
applicable, to be eligible for enrollment into this study. 
Ocular exclusion criteria (study eye)
1. Previous treatment with anti-angiogenic drugs in study eye (e.g. pegaptanib sodium, 
bevacizumab, ranibizumab) within the last 12 weeks 
2.
History of vitreoretinal surgery and/or including scleral buckling in the study eye
3.
Prior treatment of the study eye with
Long acting steroids, either periocular or intraocular, in the preceding 120 days or 
Iluvien® intravitreal implant at any time
4.
Active proliferative diabetic retinopathy (PDR), current iris neovascularization, vitreous 
hemorrhage, or tractional retinal detachment in the study eye


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5.
Aphakia in the study eye 
6.
Cataract surgery within 90 days before first study treatment in the study eye
7.
Yttrium-aluminum-garnet capsulotomy in the study eye within 30 days before first study 
treatment
8.
Any other intraocular surgery within 90 days of first study treatment in the study eye
9.
Ocular inflammation (including trace or above) or history of uveitis in the study eye
10. Vitreomacular traction or epiretinal membrane in the study eye evident 
biomicroscopically or on OCT that is thought to affect central vision
11. Pre-retinal fibrosis involving the macula of the study eye 
12. Structural damage to the center of the macula in the study eye that was likely to preclude 
improvement in BCVA following the resolution of macular edema including atrophy of 
the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or 
organized hard exudates
13. Filtration surgery for glaucoma in the past or likely to be needed in the future on the 
study eye
14. Uncontrolled glaucoma (defined as intraocular pressure [IOP] > 25 mmHg despite 
treatment with antiglaucoma medication) in the study eye
15. Concurrent disease in the study eye, other than DME, that could compromise VA, require 
medical or surgical intervention during the study period, or could confound interpretation 
of the results (including advanced glaucoma, retinal vascular occlusion, retinal 
detachment, macular hole, or choroidal neovascularization of any cause)
16. Significant media opacities, including cataract, in the study eye that interferes with visual 
acuity, fundus photography or OCT imaging.
17. Myopia of a spherical equivalent prior to any possible refractive or cataract surgery of 
≥8 diopters in the study eye
Ocular exclusion criteria (either eye)
18. Any ocular or periocular infection in the preceding 4 weeks in either eye
19. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye
Ocular and systemic exclusion criteria
20. Presence of any contraindications indicated in the EU commission/locally approved label 
for aflibercept


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Systemic exclusion criteria
21. Administration of systemic anti angiogenic agents within 180 days before first study 
treatment
22. Uncontrolled diabetes mellitus as defined by hemoglobin (Hb)A1c > 12.0%
23. Uncontrolled blood pressure (defined as systolic blood pressure > 160 mmHg or diastolic 
blood pressure > 95 mmHg while subject is sitting confirmed in two separate 
measurements)
24. Allergy or hypersensitivity to fluorescein
25. Current treatment for a serious systemic infection
26. History of either cerebral vascular accident and/or myocardial infarction within 180 days 
before first study treatment
27. Renal failure requiring dialysis or renal transplant
28. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug, might affect interpretation of the results 
of the study, or renders the subject at high risk for treatment complications
29. Breast-feeding women
30. Previous receipt of at least 1 dose of study drug under this protocol
31. Concomitant participation in another clinical study with investigational medicinal 
product(s).  
32. 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)


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Section 6.3.1 Withdrawal
Criteria for re-screening clarified as per Modification 4 (Section 15.1.1.4)
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”. 
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 (via protocol amendment).
The reason for the screening failure was subsequently resolved (e.g. decrease of elevated IOP, 
controlled arterial hypertension). 
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 (via protocol amendment).
The reason for the screening failure was subsequently resolved (e.g. decrease of elevated IOP, 
controlled arterial hypertension) within 30 days.


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Section 6.4 Subject identification
Description of subject identification number changed per Modification 5 (Section 15.1.1.5).
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
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.
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
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 7.4 Dosage and administration
Following paragraph added below ‘Posology’ per Modification 6 (Section 15.1.1.6).
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 best-corrected visual acuity (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 
Section 9.1 Tabular schedule of evaluations
Slit lamp biomicroscopy updated as per Modification 7 (Section 15.1.1.7).
Footnotes re-arranged per Modification 8 (Section 15.1.1.8).
Pregnancy test: Serum test binding for screening visit, urine dipstick test added for baseline 
visit per Modification 9 (Section 15.1.1.9).
Footnote e, serum pregnancy test within 7 days before first injection of study medication 
added per Modification 10 (Section 15.1.1.10).
Footnote f (former d, see Modification 8, Section 15.1.1.8) urine dipstick pregnancy test is to 
be repeated as frequently as required changed per Modification 11 (Section 15.1.1.11)


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Old text:
Table 9-1:
Schedule of assessments and procedures
Screening
Visit 1
Baseline
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7 to 
Visit 10
End of study 
/ early termin.
Visit 11
4 weeks 
before BL
Day 1
Week 4
Week 8
Week 12
Week 16
Week 24 to 
Week 48 Week 52c
Acceptable deviations relative to BL
± 5 days
± 5 days
± 5 days
± 5 days
±10 dayse ± 10 days
Initiation procedures
Informed consent 

Demographic data

Medical / ophthalmic history 

Check of enrollment criteria


Study medication
Administration of study drug 






no 
treatment
Ophthalmologic assessments
(= bilaterally; ●○= study eye only [additional assessments may occur outside of this protocol])
BCVA (ETDRS chart starting at 4 m) a

●○
●○
●○
●○
●○
●○

Optical coherence tomography 
●○
●○
●○
Fluorescein angiography
●○
●○
Fundus photography


Indirect ophthalmoscopy b
●○
●○
●○
●○
●○
●○
●○
●○
Slit lamp biomicroscopy
●○
●○
●○
●○
●○
●○
●○
●○
Intraocular pressure (IOP) b
●○
●○
●○
●○
●○
●○
●○
●○
Patient-reported outcomes
NEI VFQ-25








Standard safety
Prior / concomitant medications








Adverse events c








Hematology / chemistry 


Urinalysis / UPCR


Pregnancy test – urine or serum d


Vital signs (body temperature, 
blood pressure, pulse)



BCVA = best corrected visual acuity;  BL = baseline;  ETDRS = Early Treatment Diabetic Retinopathy Study;  UPCR = urine 
protein / creatinine ratio
a:
Refraction to be done at each visit
b
Also post injection
c:
Any AE occurring up to 4 weeks after the last injection of aflibercept has to be documented, regardless of the causal 
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.  All potential arterial thrombotic events (ATEs) will 
be adjudicated according to the Antiplatelet Trialists' Collaboration (APTC).
d:
In women of childbearing potential only.  The first test is to be done as close as possible before the first injection of study 
medication.  The test is to be repeated as frequently as demanded by local requirements.
e
The intervals between Visits 6 to 9 are 8 weeks ±10 days.
The interval between Visit 9 and Visit 10 must be ≥56 days (8 weeks).


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New text:
Table 9-1:
Schedule of assessments and procedures – amended
Screening
Visit 1
Baseline
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7 to 
Visit 10
End of study 
/ early termin.
Visit 11
4 weeks 
before BL
Day 1
Week 4
Week 8
Week 12
Week 16
Week 24 to 
Week 48 Week 52c
Acceptable deviations relative to BL
± 5 days
± 5 days
± 5 days
± 5 days
±10 daysa ± 10 days
Initiation procedures
Informed consent 

Demographic data

Medical / ophthalmic history 

Check of enrollment criteria


Study medication
Administration of study drug 






no 
treatment
Ophthalmologic assessments
(= bilaterally; ●○= study eye only [additional assessments may occur outside of this protocol])
BCVA (ETDRS chart starting at 4 m) b

●○
●○
●○
●○
●○
●○

Optical coherence tomography 
●○
●○
●○
Fluorescein angiography
●○
●○
Fundus photography


Indirect ophthalmoscopy c
●○
●○
●○
●○
●○
●○
●○
●○
Slit lamp biomicroscopy


●○
●○
●○
●○
●○
●○
Intraocular pressure (IOP) c
●○
●○
●○
●○
●○
●○
●○
●○
Patient-reported outcomes
NEI VFQ-25








Standard safety
Prior / concomitant medications








Adverse events d








Hematology / chemistry 


Urinalysis / UPCR


Pregnancy test – serum e
(women of childbearing potential only)

Pregnancy test – urine dipstick
(women of childbearing potential only) f


Vital signs (body temperature, 
blood pressure, pulse)



BCVA = best corrected visual acuity;  BL = baseline;  ETDRS = Early Treatment Diabetic Retinopathy Study;  UPCR = urine 
protein / creatinine ratio
a
The intervals between Visits 6 to 9 are 8 weeks ±10 days.
The interval between Visit 9 and Visit 10 must be ≥56 days (8 weeks).
b
Refraction to be done at each visit
c
Also post injection
d
Any AE occurring up to 4 weeks after the last injection of aflibercept has to be documented, regardless of the causal 
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.  All potential arterial thrombotic events (ATEs) will 
be adjudicated according to the Antiplatelet Trialists' Collaboration (APTC).
e
The test is to take place within 7 days before the first injection of the study medication
f
The test is to be repeated as frequently as required


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Section 9.2.1 Visit 1  -  Screening 
Urine dipstick pregnancy test no alternative to serum test in screening visit per Modification 9
(Section 15.1.1.9).
Old text:
Conduct
The following procedures will be performed at this visit:
…

Pregnancy test in women of childbearing potential (urine or serum test)
New text:
Conduct
The following procedures will be performed at this visit:
…

Serum pregnancy test in women of childbearing potential 
Section 9.2.2 Visit 2 (Day 1)  -  Baseline
Urine dipstick pregnancy test added for baseline visit per Modification 9 (Section 15.1.1.9)
Old text:
Conduct
The following procedures will be performed at this visit:

Assessment of inclusion and exclusion criteria (see Sections 6.1 and 9 for details)
New text:
Conduct
The following procedures will be performed at this visit:

Assessment of inclusion and exclusion criteria (see Sections 6.1 and 9 for details)

Including urine dip stick pregnancy test for women of childbearing potential 


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Section 9.2.4 Visit 11  (Week 52)  -  Final visit or early termination
Urine dipstick test required for pregnancy testing at this visit as per Modification 11
(Section 15.1.1.11).
Old text:
Conduct
…

Pregnancy test in women of childbearing potential (urine or serum test)
New text:
Conduct
…

Pregnancy test in women of childbearing potential (urine dipstick test)
Section 9.3.2 Medical/surgical and ophthalmic history
Addition of smoking history to the medical history per Modification 12 (Section 15.1.1.12).
Old text:
In addition, a complete ophthalmic history will be obtained to check the selection criteria as 
defined in Section 6.
New text:
In addition, a complete ophthalmic history will be obtained to check the selection criteria as 
defined in Section 6 and life style details including smoking history will be recorded.
Section 9.4 Efficacy
New Section 9.4.3 added per Modification 13 (Section 15.1.1.13)
Section 9.4.3 Efficacy variables
All efficacy variables derived from the ophthalmic examinations are specified in 
Section 10.3.1.1.


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Section 9.4.1 National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ 25)
Requirement to document the name of the person assisting the subject in completing the NEI 
VFQ-25 questionnaire added per Modification 14 (Section 15.1.1.14).
Old text:
...
This questionnaire will be presented in the local language and should be administered in a 
quiet room by a study-related person qualified to administer this type of questionnaire, 
preferably before other visit procedures are performed.  For subjects unable to read the 
questionnaire due to vision impairment, a family member, other legal representative of the 
subject, study nurse, or study physician may assist the subject in completing the 
questionnaires.
New text:
...
This questionnaire will be presented in the local language and should be administered in a 
quiet room by a study-related person qualified to administer this type of questionnaire, 
preferably before other visit procedures are performed.  For subjects unable to read the 
questionnaire due to vision impairment, a family member, other legal representative of the 
subject, study nurse, or study physician may assist the subject in completing the 
questionnaires.  In this case, the name of that person should be documented.
Section 9.4.2.6 Fundus photography (FP) and fluorescein angiography (FA)
Clarification for archiving as electronic archiving added per Modification 15
(Section 15.1.1.15).
Old text:
The anatomical state of the retinal vasculature of the study eye will be evaluated by 
funduscopic examination, FP and FA.  Fundus and angiographic images will be read by the 
investigator.  All FA and FP images will be archived at the site as part of the source 
documentation.  
...
New text:
The anatomical state of the retinal vasculature of the study eye will be evaluated by 
funduscopic examination, FP and FA.  Fundus and angiographic images will be read by the 
investigator.  All FA and FP images will be archived electronically at the site as part of the 
source documentation.  
...


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Section 9.6.1.5 Expected adverse events
Reference to summary of product characteristics replaced with reference to local label for 
information on AEs as per Modification 16 (Section 15.1.1.16).
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.
Section 9.6.2 Pregnancies
New paragraph on fertility added per Modification 17 (Section 15.1.1.17).
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.
Section 9.6.3.1 Laboratory evaluations
Scheduling of serum and urine pregnancy test changed as per Modification 11
(Section 15.1.1.11) and addition of total and HDL cholesterol to the laboratory safety 
parameters per Modification 18 (Section 15.1.1.18).


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Old 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 demanded by local requirements.
Table 9-2:
Laboratory safety parameters
Chemistry
Sodium
Potassium
Chloride
Calcium
Glucose
HbA1c
Albumin
Total Protein, Serum
Creatinine
Blood urea nitrogen (BUN)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Total bilirubin
Amylase
Urinalysis 
Glucose 
Protein
Specific Gravity
Blood
Ketones 
Protein:Creatinine Ratio (UPCR)
Pregnancy test for women of 
childbearing potential 
(urine or serum test is acceptable)
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
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).
Table 9-2:
Laboratory safety parameters - amended
Chemistry
Sodium
Potassium
Chloride
Calcium
Glucose
HbA1c
Albumin
Total Protein, Serum
Creatinine
Blood urea nitrogen (BUN)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Total bilirubin
Amylase
Total cholesterol
HDL cholesterol
Urinalysis 
Glucose 
Protein
Specific Gravity
Blood
Ketones 
Protein:Creatinine Ratio (UPCR)
Pregnancy test for women of 
childbearing potential 
(urine or serum see Table 9-1)
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 10.3.2.1 Demography and baseline characteristics
Three analysis sets changed to two per Modification 19 (Section 15.1.1.19).
Old text:
Demographic variables and baseline characteristics will be summarized for all three analysis 
sets, 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 (WHO DD). 
New text:
Demographic variables and baseline characteristics will be summarized for both analysis sets, 
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 (WHO DD). 
Section 10.3.2.3 Safety analyses
Summary of treatment groups removed per Modification 20 (Section 15.1.1.20).
Old text:
Adverse events
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.  Non-ocular, ocular 
AEs in the study eye, and non-ocular AEs in the fellow eye will be displayed separately.
New text:
Adverse events
Treatment-emergent AEs will be presented by MedDRA preferred term within primary 
system organ class (SOC).  Intensity and causal relationship to the investigational product will 
be analyzed descriptively.  Non-ocular, ocular AEs in the study eye, and non-ocular AEs in 
the fellow eye will be displayed separately.


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Section 13.4 Subject information and consent
Revised to align with sponsor standards per Modification 21 (Section 15.1.1.21).
Old text:
Each subject will be informed about the following aspects of premature withdrawal:
Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
The subject’s consent covers early-termination examinations as specified in the visit 
description described in Section 9.2.4 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.  For this, he/she needs to sign a 
corresponding declaration of objection; alternatively, the subject’s oral objection may 
be documented in the subject’s source data.  Each subject / legal representative or 
proxy consenter will have ample time and opportunity to ask questions.
Only if the subject / legal representative or proxy consenter 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.


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New text:
Each subject will be informed about the following aspects of premature withdrawal:
Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
The subject’s consent covers early-termination examinations as specified in the visit 
description described in Section 9.2.4 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.  Each subject / legal 
representative or proxy consenter will have ample time and opportunity to ask 
questions.
Only if the subject / legal representative or proxy consenter 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 may read 
the document to the subject and may assist the subject in signing the form.  In this case, the 
name of that person should be documented.


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16.
Appendices


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16.1
NEI VFQ-25 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


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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.


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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


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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


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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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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


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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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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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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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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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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: 
Open-label Phase-4 study to examine the change of vision-related 
quality of life in subjects with diabetic macular edema (DME) 
during treatment with intravitreal injections of 2 mg aflibercept 
according to EU label for the first year of treatment 
NCT Number: 
NCT02581995 
Document Date: 
04 May 2017 
 


Statistical Analysis Plan
          
Protocol No.: BAY86-5321/ 17850
Page:
1 of
29
Reference Number: BHC-RD-OI-119
Supplement Version: 7
Open-label Phase-4 study to examine the change of vision-related quality of life in 
subjects with diabetic macular edema (DME) during treatment with intravitreal 
injections of 2 mg aflibercept according to EU label for the first year of treatment 
Investigation of the change of vision-related quality of life in subjects treated with aflibercept 
according to EU label for DME (AQUA)
Bayer study drug
BAY86-5321/ aflibercept / VEGF Trap-Eye (Eylea)
Study purpose:
Assessment of quality of life
Clinical study
phase:
4
Date:
04 May 2017
Study No.:
BAY86-5321/ 17850
Version:
3.0
Author:
INC Research
Germany
INC Project Code:
04.6000.1005565
EUDRAC:
2014-005119-17
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
PPD


Statistical Analysis Plan
          
Protocol No.: BAY86-5321/ 17850
Page:
2 of
29
Reference Number: BHC-RD-OI-119
Supplement Version: 7
Table of Contents
Table of Contents......................................................................................................................2
Table of Tables..........................................................................................................................3
Abbreviations ............................................................................................................................4
1.
Introduction........................................................................................................................6
1.1
Background.......................................................................................................................6
1.2
Rationale of the study.......................................................................................................6
1.3
List of documents used.....................................................................................................6
2.
Study Objectives ................................................................................................................6
3.
Study Design.......................................................................................................................6
4.
General Statistical Considerations...................................................................................9
4.1
General Principles ............................................................................................................9
4.2
Handling of Dropouts.......................................................................................................9
4.3
Handling of Missing Data ................................................................................................9
4.4
Interim Analyses and Data Monitoring ..........................................................................10
4.5
Data Rules ......................................................................................................................10
4.6
Validity Review..............................................................................................................12
5.
Analysis Sets.....................................................................................................................13
5.1
Assignment of analysis sets............................................................................................13
6.
Statistical Methodology...................................................................................................13
6.1
Population characteristics...............................................................................................13
6.1.1
Screening Failures and protocol deviations ................................................................13
6.1.2
Subject validity status .................................................................................................13
6.1.3
Subject disposition ......................................................................................................14
6.1.4
Demography and baseline characteristics ...................................................................14
6.1.5
Medical history............................................................................................................14
6.1.6
Medical history of diabetes, diabetic retinopathy and DME.......................................15
6.1.7
Prior and concomitant medication ..............................................................................15
6.1.8
Exposure......................................................................................................................16
6.1.9
Smoking History .........................................................................................................16
6.2
Efficacy...........................................................................................................................16
6.2.1
Primary Efficacy Variable – NEI VFQ-25 total score................................................16
6.2.2
Secondary Efficacy Variables.....................................................................................20
6.2.2.1
NEI VFQ-25 near activities subscale.......................................................................20
6.2.2.2
NEI VFQ-25 distant activities subscale...................................................................20
6.2.2.3
Best corrected visual acuity (BCVA) ......................................................................21
6.2.2.4
Central retinal thickness (CRT) measured by OCT.................................................21
6.2.2.5
ETDRS diabetic retinopathy severity scale (DRSS)................................................21
6.2.3
Exploratory Efficacy Variables...................................................................................22


Statistical Analysis Plan
          
Protocol No.: BAY86-5321/ 17850
Page:
3 of
29
Reference Number: BHC-RD-OI-119
Supplement Version: 7
6.2.3.1
Average changes of NEI VFQ-25 during the study.................................................22
6.2.3.2
Indirect ophthalmoscopy..........................................................................................22
6.2.3.3
Fluorescein angiography (FA) .................................................................................22
6.2.3.4
Fundus photography (FP) ........................................................................................22
6.2.3.5
Refraction.................................................................................................................23
6.2.3.6
Optical coherence tomography (OCT).....................................................................23
6.2.3.7
Classification of the study eye .................................................................................23
6.3
Safety..............................................................................................................................23
6.3.1
Adverse Events (AEs).................................................................................................23
6.3.2
Pregnancy test .............................................................................................................25
6.3.3
Laboratory Tests..........................................................................................................25
6.3.4
Vital Signs...................................................................................................................26
6.3.5
Intraocular Pressure (IOP)...........................................................................................26
6.3.6
Slit lamp biomicroscopy .............................................................................................26
7.
Document history and changes in the planned statistical analysis..............................26
8.
References.........................................................................................................................26
9.
Appendix...........................................................................................................................27
9.1
Calculation of the NEI VFQ-25 scores ..........................................................................27
Table of Tables
Table 1: Schedule of assessments and procedures......................................................................8
Table 2: Definition of Better-seeing eye, Worse-seeing eye and equal vision.........................12
Table 3: Laboratory safety parameters .....................................................................................25
Table 4: Scoring Key: Recoding of Items.................................................................................28
Table 5: Averaging of Items to Generate VFQ-25 Sub-Scales.................................................29


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Abbreviations
AE
adverse event 
ANCOVA
analysis of covariance 
APTC
Antiplatelet Trialists' Collaboration 
ATC
Anatomical Therapeutic Chemical 
ATE
Arterial thrombotic event 
BCVA
Best corrected visual acuity 
BMI
Body mass index
BSE
Better-seeing eye
CRF
case record form 
CRT
central retinal thickness 
DME
diabetic macular edema 
DR
diabetic retinopathy
DRSS
diabetic retinopathy severity score
EMA
European Medicines Agency 
EoS
end of study/early termination
ET
early termination
ETDRS
Early Treatment Diabetic Retinopathy Study 
EU
European Union 
EV
equal vision
FA 
fluorescein angiography 
FAS
full analysis set 
FP
fundus photography 
IOP 
intraocular pressure
IVT 
intravitreal(ly)
LOCF 
last observation carried forward
MCID
minimal clinically important difference
MedDRA 
Medical Dictionary for Regulatory Activities


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MI
multiple imputation
NEI VFQ-25
The National Eye Institute 25-Item Visual Function Questionnaire
OCT 
optical coherence tomography
PAES
postapproval efficacy study
PDR 
proliferative diabetic retinopathy
PT
Preferred term
SAE 
serious adverse event
SAF 
safety population
SAP 
statistical analysis plan
SmPC
summary of Product Characteristics 
SOC 
system organ class
SOP
standard operating procedure
UPCR 
urine protein/creatinine ratio
VA 
visual acuity
VEGF 
vascular endothelial growth factor
VIVID
(DME)
A randomized, double masked, active controlled, phase III study of the efficacy 
and safety of repeated doses of intravitreal VEGF Trap-Eye in subjects with 
diabetic macular edema
VISTA
(DME)
A double- masked, randomized, active-controlled, Phase 3 study of the efficacy 
and safety of intravitreal administration of VEGF Trap-Eye in patients with 
diabetic macular edema
VRM
Validity Review Meeting
WHO-DD
World Health Organization Drug Dictionary
WSE
worse-seeing eye


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1.
Introduction
1.1
Background
Diabetic retinopathy (DR) is a major cause of visual impairment. Diabetic macular edema 
(DME) is a manifestation of DR and is the most frequent cause of blindness in young and 
mid-aged adults. It is estimated that 4.8% of the global population has diabetic retinopathy, 
while 3% to 4.1% of Europeans are affected.
Details of background information are available in the study protocol.
1.2
Rationale of the study
Little is known about QoL outcomes in DME patients treated with aflibercept per the 
European Summary of Product Characteristics (SmPC), or the relative influence of the visual 
acuity of better- and worse-seeing eyes on QoL in such patients. 
Details of the study rationale are available in the study protocol.
1.3
List of documents used

Clinical Study Protocol No. BAY 86-5321 /17850, version 1.0, 10 February 2015

Clinical Study Protocol No. BAY 86-5321 /17850, version 2.0, 07 September 2015
2.
Study Objectives
Primary objective
To evaluate the change in quality of life (NEI VFQ-25) in subjects with DME during the first 
year of treatment with aflibercept according to the EU label for DME.
Secondary objectives

To assess further the safety and tolerability of aflibercept in this population

To assess the change in the diabetic retinopathy severity score (DRSS) from baseline 
to Week 52

To support subject recruitment for the EMA-requested post-approval efficacy study in 
DME
3.
Study Design
Design overview
Single-arm, multicenter study administering aflibercept according to EU label for the first 
year of treatment, i.e. 2 mg every 4 weeks for 5 consecutive doses, and dosing every 8 weeks 
thereafter.
Justification of the design


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Open-label setting: This is a single arm study without masking requirements. Treatment in 
this study is according to EU label for DME.
The length of the observation period (1 year) is based on the primary-endpoint results of the
pivotal DME studies (VISTA DME, VIVID DME), where most of the benefits after start of
treatment with aflibercept occurred during the initial year of treatment.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (EU and non-EU).
Visit overview
The scheduled assessments and procedures are displayed in the following Table 1.


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Table 1: Schedule of assessments and procedures
Screening
Visit 1
Baseline
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7 to 
Visit 10
End of study 
/ early termin.
Visit 11
4 weeks 
before BL
Day 1
Week 4
Week 8
Week 12
Week 16
Week 24 to 
Week 48 Week 52c
Acceptable deviations relative to BL
± 5 days
± 5 days
± 5 days
± 5 days
±10 daysa ± 10 days
Initiation procedures
Informed consent 

Demographic data

Medical / ophthalmic history 

Check of enrollment criteria


Study medication
Administration of study drug 






no 
treatment
Ophthalmologic assessments
(= bilaterally; ●○= study eye only [additional assessments may occur outside of this protocol])
BCVA (ETDRS chart starting at 4 m) b

●○
●○
●○
●○
●○
●○

Optical coherence tomography 
●○
●○
●○
Fluorescein angiography
●○
●○
Fundus photography


Indirect ophthalmoscopy c
●○
●○
●○
●○
●○
●○
●○
●○
Slit lamp biomicroscopy
●●
●●
●○
●○
●○
●○
●○
●○
Intraocular pressure (IOP) c
●○
●○
●○
●○
●○
●○
●○
●○
Patient-reported outcomes
NEI VFQ-25








Standard safety
Prior / concomitant medications








Adverse events d








Hematology / chemistry 


Urinalysis / UPCR


Pregnancy test – serum e
   (women of childbearing potential only)

Pregnancy test – urine dipstick
(women of childbearing potential only) f


Vital signs (body temperature, 
blood pressure, pulse)



BCVA = best corrected visual acuity;  BL = baseline;  ETDRS = Early Treatment Diabetic Retinopathy Study;  UPCR = urine 
protein / creatinine ratio
a
The intervals between Visits 6 to 9 are 8 weeks ±10 days.
The interval between Visit 9 and Visit 10 must be ≥56 days (8 weeks).
b:
Refraction to be done at each visit
c
Also post injection
d:
Any AE occurring up to 4 weeks after the last injection of aflibercept has to be documented, regardless of the causal 
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.  All potential arterial thrombotic events (ATEs) will 
be adjudicated according to the Antiplatelet Trialists' Collaboration (APTC).
e
The test is to take place within 7 days before the first injection of study medication
f
The test is to be repeated as frequently as required


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4.
General Statistical Considerations
The Statistical Analysis Plan (SAP) for this open-label study was finalized before First-
Patient-First-Visit to avoid additional reporting bias. Later updates afterwards are of cosmetic
type and/or rely on updates of other core documents.
The statistical evaluation will be performed using the software package SAS release 9.3 or 
higher (SAS Institute Inc., Cary, NC, USA). 
4.1
General Principles
All variables will be analyzed by descriptive statistical methods. 
The number of data available and missing data, mean, standard deviation, minimum, 
quartiles, median, and maximum will be calculated for metric data. 
Frequency tables will be generated for categorical data.
4.2
Handling of Dropouts
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “dropout”
A subject who discontinues study participation and/or study drug prematurely for any reason 
is defined as a dropout, if the subject has already received at least one dose of study 
medication.
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. The 
number of subjects who withdrew, as well as the reasons for drop-out of study treatment will 
be summarized. 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before first study drug application is regarded as a screening failure. Re-screening of 
screening failures may be acceptable under the specific conditions, which are specified in the 
protocol in Section 6.3.1. A subject may be re-screened once only. To be eligible, re-screened 
subjects must meet all selection criteria at the re-screening visit.
The number of screening failures will be summarized, the reasons will be listed.
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 parameter described in this Section, Sections 4.5 and 6.2.
General rules
When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data:


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In case of missing data from safety variables all replacements will be performed according to 
a worst case scenario. Missing drug relationship will be replaced by drug related and missing 
intensity will be replaced by severe intensity.
Adverse events
In case the AE onset date is missing or incomplete, the date will be imputed for the 
calculation according to the worst case approach. If the AE onset date is missing it will be 
imputed with the start of treatment date. For incomplete AE onset dates the missing day will 
be imputed as the first day of the month and the missing month will be imputed as January. If 
the replaced starting date is prior to the start of treatment date, the starting date will be set to 
the start of treatment date. Exceptions are given where the partial dates would allow to state 
otherwise.
In case the AE end date is completely missing it will not be imputed. If the AE end date is 
partially missing, the missing day will be imputed with the last day of the month, and the 
missing month will be imputed with December.
Prior and concomitant medication / medical history
Completely missing start and stop dates of medication / medical history event are considered 
missing and no replacement is generated. A medication / medical history event 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”.
If only the day is missing, it will be replaced with the first day of the month for start dates, 
and with the last of the month for stop dates. If day and month are missing, and the year is 
non-missing, the date will be completed with ‘01 January’ for start dates and with ’31 
December’ for stop dates. 
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 4 weeks of the screening visit. If no baseline value is 
available then last available scheduled screening values are used. Change from baseline is 
calculated as the value at the post-baseline time point minus the baseline value, i.e. value at 
time point – value at baseline.
Handling of repeated measurements at the same visit
If measurements were repeated at the same scheduled visit, the value actually flagged as 
scheduled will be the

Last non-missing repeated measurement, if visit is before start of treatment, and


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
First non-missing repeated measurement, if visit is after start of treatment.
Generally, only scheduled measurements will be used for statistical summaries and analysis. 
Unscheduled measurements will not used for analysis, but only listed.
Handling time-windows
The screening visit must occur within 4 weeks of the baseline visit (Day 1). Screening values 
collected more than 4 weeks before baseline will be flagged in the patient listings, but used 
for summary tables and analysis, if no unscheduled screening measurement are available.
For the scheduling of Visit 3 to Visit 10 (Week 4 to Week 48), the following deviations 
relative to baseline are foreseen:

Monthly post-baseline visits through week 16 (Visits 3 to 6): ± 5 days

Regular Q8 schedule (Visits 7 to 10) ± 10 days

The interval between Visit 9 and Visit 10 must be at least 56 days (8 weeks).
Visit 11 (Week 52) will be the last scheduled visit under this protocol. It is to be scheduled at 
Week 52 (± 10 days) after baseline.
Values outside these windows will not be dropped from summary tables and analysis, but 
flagged as “outside time-window” in the patient listings.
Early termination (ET)
Visit based information of the early termination visit will be mapped to the closest missing 
visit according to the visit schedule. This can result in data for visits at which this variable 
was not scheduled to be collected. This data will nevertheless be included into the (LOCF-) 
analyses and be reported as observed value for the respective visit.
Pooling centers
No pooling of centers will be performed.
Calculation of durations
Durations are calculated relative to baseline, if not specified otherwise. Durations will be 
presented and used (e.g. in summary tables) as integer values.
The integer value of the durations will be listed and summarized, if not specified otherwise.
Classification of the study eye
It is up to the investigator to decide which eye will be treated with the study drug (study eye) 
and which not (fellow eye). At baseline and at end of study/early termination (EoS) the  
BCVA assessment will be performed in both eyes. In the other scheduled visits only the study 
will be examined.
The following classification of the study eye (Table 2), first published from Bressler et al (2) 
and recommended from Hirneiss (3) will be performed:


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Table 2: Definition of Better-seeing eye, Worse-seeing eye and equal vision
Better-seeing eye (BSE)
Worse-seeing eye (WSE)
Equal vision (EV)
Baseline VA letter 
score in both eyes >
(20/100)*
Baseline VA of the study 
eye is better than that of 
the fellow eye by > 5 
letters
Baseline VA of the study 
eye is worse than that of 
the fellow eye by > 5 
letters
Baseline VA of the study 
eye is within +/- 4 letters 
of that of the fellow eye
Baseline VA letter 
score in one or both
eyes < (20/100)*
Baseline VA of the study 
eye is better than that of 
the fellow eye by > 10
letters
Baseline VA of the study 
eye is worse than that of 
the fellow eye by > 10
letters
Baseline VA of the study 
eye is within +/- 9 letters 
of that of the fellow eye
* A Snellen score of 20/100 is equivalent to an ETDRS letter of 50.
This classification, which takes the variability of VA measurements through implementing 
the EV-category into account, will equivalently used for EoS. 
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 unique subject identifier and date if applicable.
Dates will be formatted as DDMMMYYYY. Partial dates will be presented on data listings 
as recorded on CRFs.
Rounding for all variables will occur only as the last step, immediately prior to presentation 
in listings and tables. No intermediate rounding will be performed on derived variables. The 
standard rounding practice of rounding numbers ending in 0-4 down and numbers ending 5-9 
up will be employed.
Every table, listing and figure will be produced with an electronic date stamp to document 
when it was produced.
4.6
Validity Review
Validity Review Meetings (VRMs) are performed according to Bayer’s Standard Operating 
Procedures (SOP) and will be led by the INC Research Lead Data Manager. Details are 
available in the Data-Management-Plan.
The results of the VRM will be documented in the Validity Review Report and may comprise 
decisions and details relevant for statistical evaluation. Any changes to the statistical analysis 


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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
5.1
Assignment of analysis sets
Populations for analysis will be defined as follows:
Full Analysis Set (FAS)
The Full Analysis Set (FAS) will include all subjects who received at least one injection of 
study drug and have completed the baseline and at least one post-baseline NEI VFQ-25 
questionnaire. The FAS will be the primary dataset for all efficacy parameter.
Safety analysis set (SAF)
The Safety Analysis Set will include all subjects who have received at least one injection of 
study drug. The SAF will be the primary dataset for all safety variables. 
6.
Statistical Methodology
No hypothesis testing will be performed. 95% confidence intervals will be provided as 
appropriate. No stratification is planned. 
6.1
Population characteristics
If not mentioned otherwise, the population characteristics will be summarized in FAS and 
SAF depending on the type of data as described in Section 4.1.
6.1.1
Screening Failures and protocol deviations
Screening Failures will be listed together with the reason for their exclusion from study and 
all available data (Date of informed consent, Reason for screening failure, Date of last visit).
For screening failures with an SAE all information related to the SAE will be listed.
Protocol deviations will be summarized for all enrolled subjects.
6.1.2
Subject validity status
An overview-table will summarize the subject validity and primary reasons for exclusion 
from analysis for all subjects assigned to treatment, displaying the number and percentages 
of: 

subjects valid for safety analysis

subjects valid for FAS analysis

excluded from SAF (by reason)

excluded from FAS (by reason)


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6.1.3
Subject disposition
The number and reason for withdrawal will be obtained and summarized in a frequency table
referring to 
-
end of screening (all enrolled subjects), 
-
end of treatment (all randomized subjects), and
-
end of study (all randomized subjects) 
In addition, subjects disposition (all enrolled subjects) will be summarized to get the number 
of subjects enrolled, with screening failures, randomized, treated, and completed the study.
6.1.4
Demography and baseline characteristics
Demographic variables will be summarized for FAS and SAF and listed for all subjects, with 
screening failures on a separate page, and patients excluded from FAS flagged.
The following demographic parameters will be summarized:

Gender

Age

Race

Ethnicity

Weight

Height

Body mass index (BMI)

Smoking history – never, former, current

Study eye – left or right

Study eye – BSE, WSE or EV
The following baseline characteristics are observed at screening and/or baseline and will be 
tabulated for FAS and SAF. In case of repeated measures the last available value before 1st 
application of the study drug will be used for summary tables.

baseline NEI VFQ-25 total score 

baseline BCVA letter scores (study eye)

baseline DRSS (study eye)

baseline CRT (study eye)
Baseline HbA1c will be classified (> 8%, <=8%), and summarized as categorized and as 
metric variable.
6.1.5
Medical history
Medical history will be summarized for FAS and SAF and listed for all subjects, with 
screening failures on a separate page.


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Overall medical history will be summarized based on the MedDRA version available before 
database lock. The number and percentages of subjects affected as well as the number of 
events will be displayed. The following variables are of interest:

Any medical history

System Organ Classes (SOCs)

Preferred Terms (PTs)
The SOCs will be sorted by descending frequency of subjects, within each SOC the PTs will 
be sorted by descending frequency of subjects affected.
The table will be repeated for ocular medical history by eye (study eye, fellow eye). Bilateral 
findings are counted as findings of the study eye as well as the fellow eye.   
6.1.6
Medical history of diabetes, diabetic retinopathy and DME
Medical history of diabetes, diabetic retinopathy and DME will be summarized for FAS and
SAF, and listed for all subjects, with screening failures on a separate page.
For the following variables number of patients (percentage) and duration of the disease will 
be summarized.

Diabetes Mellitus Type 1

Diabetes Mellitus Type 2

Diabetic Retinopathy – Study Eye

Diabetic Retinopathy – Fellow Eye

Diabetic Macular Edema – Study Eye

Diabetic Macular Edema – Fellow Eye
6.1.7
Prior and concomitant medication
Summaries will be presented in tabular form using 3-digit Anatomical Therapeutic Chemical 
Classification (ATC) classification codes and subclass via the World Health Organization 
Drug classification Dictionary (WHO-DD), latest version available before database lock.
The medications will be classified as follows

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 for the SAF-population will be created overall and 
stratified by ocular medication (yes/no) and study eye (study eye vs. fellow eye) consisting of 
ATC class and subclass used by the subjects, sorted by descending frequencies. Bilateral 
medications are counted as medications for the study as well as the fellow eye.   


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6.1.8
Exposure
The number of injections, total amount of aflibercept and the duration of exposure will be 
tabulated for the FAS and the SAF.
6.1.9
Smoking History
History of cigarette smoking (never, former, current) will be tabled as baseline 
characteristics.
The following parameters will be listed only.

Number of cigarettes per day

Age at start of habitual cigarette use

Duration of habitual cigarette use

Any other tobacco smoking type (never, former, current)
6.2
Efficacy
Efficacy parameter will be listed for all subjects summarized for the FAS and listed for all 
subjects, with patients excluded from FAS flagged.
6.2.1
Primary Efficacy Variable – NEI VFQ-25 total score
The primary efficacy variable is

The change from baseline to Week 52 in the NEI VFQ-25 total score.
The NEI VFQ-25 total score will be evaluated at each visit (Visit 1 to Visit 11). 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 in appendix 9.1.
The scores and their changes from baseline to all post-baseline visits in the NEI VFQ-25 total 
score will be summarized descriptively, including 95% confidence intervals for the changes.
Primary analysis
The primary efficacy variable will be summarized descriptively. Ninety-five percent 
confidence intervals will be provided based on the t-distribution assuming that the changes 
from baseline are normally distributed. 
To be comparable with publications of other studies in this indication, missing values will be
imputed with the last observed post-baseline value collected before the missing value
(LOCF).
Sensitivity analysis
Several sensitivity analyses will be performed to support results of the primary analysis. 
Non-parametric analysis


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The Central Limit Theorem implies that the limiting distribution of the sample mean is 
normal regardless of the distribution of the original data (under some conditions), so that the 
normal approximation is quite accurate in large sample sizes. 
Nevertheless, the assumption of normality of the primary efficacy variable will be described 
and checked with the Shapiro-Wilk test. If the assumption of normality can be rejected a non-
parametric 95%-CI, consisting of 2.5%- and 97.5%-quartiles as confidence limits, will be 
calculated and Hodges-Lehmann estimations will be performed.
The primary method (LOCF) is not necessarily conservative because subjects dropping out 
due to lack of efficacy are considered as stable. Therefore, several further sensitivity analyses 
will be provided, which are described below
Observed Cases (OC)
The primary analysis will be repeated on the observed values, i.e., only including patients 
that have a NEI VFQ-25 total score result at Week 52 (+/- 10 days), i.e. without LOCF-
imputation.
Categorized Analysis
Frequencies of subjects worsening or improving, additionally for not achieving, achieving or 
exceeding the minimally clinically important difference (MCID) will be computed for each 
time point. MCID is defined as 5. 
The change in QoL will be classified according to the two categories, change ≥or < MCID. 
The category < MCID includes no change in QoL or deteriorations.  
Multiple Imputation (MI)
MI Instead of LOCF-imputation will be performed to estimate the missing values. The 
imputations will be based on the baseline value as well as all observed changes from baseline. 
Subsequently, the primary efficacy analysis will be repeated. 
It is assumed that any systematic difference between the missing values and the observed 
values can be explained by differences in observed data, i.e. the missing efficacy data are 
“Missing at random”. 
Multiple imputation aims to allow for the uncertainty about the missing data by creating 
several different plausible imputed data sets and appropriately combining results obtained 
from each of them. The validity of results from multiple imputation depends on such 
modeling being done carefully and appropriately. 
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. The missing data will be imputed by a 
two step procedure. 


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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=3456 OUT=full NIMPUTE=20; 
*(=number of imputations m)*;
BY <...>;
mcmc impute=monotone;
VAR y1 y2 y3 y4 y5; 
*(results depend on order);
RUN;
b. Subsequently missing data will be imputed by a regression model.
PROC MI DATA=out1 SEED=5678 OUT=full nimpute=1;
BY <imputation_ ...>;
MONOTONE reg;
VAR y1 y2 y3 y4 y5;
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.
proc means data=full alpha=0.05 clm mean std;
VAR y1 y2 y3 y4 y5;
run;
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, if applicable.
Repeated Measurement Analysis
The effect of the type of eye treated (better-seeing or worse-seeing at baseline) during the 
study shall be described within a repeated-measurements-model including  

visit

baseline value

baseline*visit interaction and

eye 
as fixed factors. “Eye” denotes the study eye class (BSE, EV or WSE) at baseline. The model 
is:
Yi = Xi+ ; with


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i  = 1, …, n (subjects)
~ N(0,2)
Y = changes from baseline
X = vector of fixed effects (visit, baseline, interaction, eye) 
The analysis will be performed for OC and LOCF. SAS code similar to the following will be 
used.
PROC MIXED DATA = <indata>;
CLASS avisitn subjid eye;
MODEL chg = base avisitn avisitn*base eye/ DDFM=kr;
REPEATED avisitn / SUBJECT = subjid TYPE=un;
RUN;
Exploratory analysis
Subgroups
The effect of the choice of the study eye (BSE, WSE or EV), gender and prior use of anti-
VEGF on the quality of life will be investigated at each post-baseline visit as follows. 
The change to baseline in the NEI VFQ-25 total score will be summarized descriptively in 
each subgroup at each visit. 
Ninety-five percent confidence intervals will be provided based on the t-distribution 
assuming that the changes from baseline are normally distributed. LOCF and OC will be 
analyzed.
Intra-individual Variability
Further exploratory analyses will be conducted to investigate the intra-individual variability 
in the score over time. This will be done graphically displaying the distribution of the 
standard deviation of the individual changes from baseline over time with a box-plot or 
scatter-plot.
Correlation BCVA and QoL
The correlations between the BCVA-changes to baseline for the following eyes and the NEI 
VFQ-25 total score-changes to baseline will be performed using Pearson’s Correlation 
Coefficient and displayed graphically using scatter-plots on the LOCF-data.

Study eye

BSE at baseline

WSE eye at baseline

BSE at EoS

WSE at EoS
Furthermore the correlation between the change in NEI VFQ-25 total score and

‘Minimum of BCVA in left eye and BCVA in right eye at EOS’ minus ‘Minimum of 
BCVA in left eye and BCVA in right eye at Baseline’


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
‘Maximum of BCVA in left eye and BCVA in right eye at EOS’ minus ‘Maximum of 
BCVA in left eye and BCVA in right eye at Baseline’
will be investigated.
In addition, the mean change from baseline in BCVA will be evaluated, and a 95% 
confidence interval for the difference between both MCID-categories, change ≥or < MCID,
will be calculated.
Possible confounder
The effect of the following parameters on the NEI VFQ-25 total score-changes to baseline the 
will be analyzed, using Pearson’s Correlation Coefficient and displayed graphically using 
scatter-plots

duration of diabetes mellitus (years), 

duration of diabetic retinopathy (years), 

duration of diabetic macular edema (years), 

age (years). 
To describe the influence of gender the distribution (mean, SD) of  the NEI VFQ-25 total 
score-changes to baseline will be displayed graphically over time, overall and stratified by 
gender. The same will be done regarding the prior use of anti-VEGF (Y/N).
6.2.2
Secondary Efficacy Variables
In general, the secondary efficacy variables will be analyzed descriptively in analogy to the 
primary efficacy variables, if applicable. 
The secondary efficacy variables are
-
The change from baseline to Week 52 in the NEI VFQ-25 near activities subscale
-
The change from baseline to Week 52 in the NEI VFQ-25 distant activities subscale
-
The change from baseline to Week 52 in BCVA (ETDRS letter score)
-
The change from baseline to Week 52 in CRT measured by optical coherence 
tomography (OCT)
-
Proportion of subjects progressing to ≥61 ETDRS diabetic retinopathy severity scale 
(DRSS) as assessed by fundus photography (FP)
6.2.2.1
NEI VFQ-25 near activities subscale
The NEI VFQ-25 near activities subscale will be calculated according to Table 5 (see 
Appendix 9.1). The statistical analysis strategy will be performed equivalently to those of the 
primary endpoint (Section 6.2.1), except the exploratory analysis.
6.2.2.2
NEI VFQ-25 distant activities subscale
The NEI VFQ-25 distant activities subscale will be calculated according to Table 5 (see 
Appendix 9.1). The statistical analysis strategy will be performed equivalently to those of the 
primary endpoint (Section 6.2.1), except the exploratory analysis.


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6.2.2.3
Best corrected visual acuity (BCVA)
The values might range from 0 to 100. Primary and sensitivity analysis will be performed 
according to the analysis of the primary endpoint, if applicable.
The categorized analysis will be performed with regard to the following classes during the 
course of time:

≥15 letter gain (Yes/No)

≥10 letter gain (Yes/No)

≥   5 letter gain (Yes/No)

≥  0 letter gain (Yes/No)

≥   0 letter loss (Yes/No)

≥  5 letter loss (Yes/No)

≥10 letter loss (Yes/No)

≥15 letter loss (Yes/No)
The exploratory analysis described in 6.2.1 is fitted to the QoL-scores and might not be 
applicable. 
6.2.2.4
Central retinal thickness (CRT) measured by OCT
The retinal thickness will be recorded at screening, baseline and end of study/early 
termination (EoS) at the study eye only. Absolute changes to baseline will be calculated. 
Missing post-baseline values will not be imputed. No additional analysis except the 
descriptive summaries will be performed.
6.2.2.5
ETDRS diabetic retinopathy severity scale (DRSS)
The ETDRS DRSS will be assessed by FP at screening and at EoS according to the following 
scale for both eyes.
-
10 – DR absent 
-
14 – DR questionable 
-
15 – DR questionable 
-
20 – Micro-aneurysms only 
-
35 – Mild NPDR 
-
43 – Moderate NPDR 
-
47 – Moderately severe NPDR 
-
53 – Severe NPDR 
-
61 – Mild PDR 
-
65 – Moderate PDR 
-
71 – High-risk PDR 
-
75 – High-risk PDR 
-
81 – Advanced PDR: fundus partially obscured, center of macula attached 
-
85 – Advanced PDR: posterior fundus obscured, or center of macula detached 
-
90 – Cannot grade, even sufficiently for level 81 or 85 


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In general, a value of “90” will be treated as missing in the summary tables and statistical 
analysis, though it will be listed as “90”.
Shift tables will be created, displaying the number and percentages of subjects in each class at 
baseline and at Week 52, stratified by study eye vs. fellow eye.
A “≥2 step improvers” is defined as a subject whose DRSS-category will decrease 2 classes, 
e.g. from “65 – Moderate PDR” to “53 – Severe NPDR”. The definition of “≥3 step 
improvers” is equivalent. Both variables will be displayed as described in Section 4.1, 
stratified by study eye vs. fellow eye.
According to exclusion criterion 5 subjects suffering on an active proliferative diabetic 
retinopathy (PDR) in the study eye will be screening failures and excluded from analysis. 
Therefore, regarding the study eye, subjects progressing to ≥61 in ETDRS DRSS is 
equivalent to subjects getting a PDR during the study. Some subjects might be dropped from 
this analysis of progression in the fellow eye, because they already start at baseline with 
active PDR (exclusion criterion only valid for the study eye). .
The proportion of subjects progressing to ≥61 in ETDRS DRSS will be displayed together 
with exact binomial 95% confidence intervals in both eyes separately. The comparison of 
both proportions and their CI will be provided. 
Because of the type of this parameter (classified, only one post-baseline measurement) the 
analyses regarding the primary endpoint (Section 6.2.1) are not applicable.
6.2.3
Exploratory Efficacy Variables
6.2.3.1
Average changes of NEI VFQ-25 during the study
The average of the changes with regard to baseline will be calculated for OC and LOCF in 
the total score and both sub-scores (NEI VFQ-25 near activities subscale and NEI VFQ-25 
distant activities subscale) for each subject in the FAS. These average changes will be 
displayed as described in Section 4.1.
6.2.3.2
Indirect ophthalmoscopy
Pre- and post-injection results of the indirect ophthalmoscopy in the both eyes (vitreous body, 
optic nerve head, macula, peripheral retina and retinal tear, break, detachment or hemorrhage)
will only be listed.
6.2.3.3
Fluorescein angiography (FA)
The FA parameters (leakage, central ischaemia, neovascularization elsewhere and 
neovasularization disc) will only be listed.
6.2.3.4
Fundus photography (FP)
Results of the FP will be listed for the following parameters

microaneurysms,

hemorrhages and microaneurysms,


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
hard exudates entire field,

hard exudates center of macula,

soft exudates,

intraretinal micro-vascular abnormalities ,

neovascularization disc,

fibrous proliferation on disc,

neovascularization elsewhere,

fibrous proliferation elsewhere,

pre-retinal hemorrhage, 

venous beading,

venous loops and/or reduplication, 

prior pan-retinal photocoagulation and/or

vitreous hemorrhage
6.2.3.5
Refraction
Results of the Refraction will be listed only.
6.2.3.6
Optical coherence tomography (OCT)
With the exception of CRT (see Section 6.2.2.4) results of the OCT for the study eye (
macular edema, cysts visible, subretinal fluid, vitro-macular traction, macular 
hole/pseudohole/lamellar hole fluid) will only be listed.
6.2.3.7
Classification of the study eye
At Baseline and EoS the study eye can be categorized in BSE, WSE or EV (see Table 2). A 
shift table will be provided for Week 52 (using LOCF data) to summarize the change in the 
classification from Baseline to Week 52.Pharmacokinetics / pharmacodynamics
Not  applicable
6.3
Safety
Safety parameters will be analyzed and listed for the Safety analysis set (SAF).
6.3.1
Adverse Events (AEs)
Treatment emergent AEs are defined as AEs that started after the first injection of study-
treatment but not more than 30 days after the last injection of study-treatment under this
protocol. A summary table of number of subjects with AEs and another one with treatment
emergent AEs (TEAE) will be produced displaying the following categories:

Subjects reporting at least one (TE)AE

Subjects reporting at least one ocular (TE)AE in the study eye

Subjects reporting at least one ocular (TE)AE in the fellow eye

Subjects reporting at least one non-ocular (TE)AE 

Subjects reporting at least (treatment emergent) APTC event


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
Subjects reporting at least one causal related to aflibercept (TE)AE     

Subjects reporting at least one causal related to iv injection (TE)AE     

Subjects reporting at least one causal related to other procedures (TE)AE 

Maximum intensity for any (TE)AE    

Maximum intensity for any study drug-related (TE)AE

(Treatment emergent) deaths

Subjects reporting at least one serious (TE)AE

Subjects reporting at least one study-drug related serious (TE)AE

SAEs related to procedures required by the protocol

Discontinuation of study drug due to (TE)AEs

Discontinuation of study drug due to SAEs
Treatment emergent AEs will be presented by MedDRA preferred term within primary
system organ class (SOC) and summarized. Intensity and causal relationship to the 
investigational product will be analyzed descriptively.
The following tables are foreseen: 

TEAEs

Ocular TEAEs

Ocular TEAEs in the study eye

Ocular TEAEs in the fellow eye

Non-ocular TEAEs

Serious TEAEs

Serious ocular TEAEs

Serious ocular TEAEs in the study eye

Serious ocular TEAEs in the fellow eye

Serious non-ocular TEAEs

TEAEs by maximum severity

Treatment emergent APTC events

Causal related to aflibercept TEAE     

Causal related to iv injection TEAE     

Causal related to other procedures TEAE     

Serious study-drug related TEAEs

Serious TEAEs by maximum severity

Study-drug related TEAEs by maximum severity

TEAEs by worst outcome

Serious TEAEs by worst outcome

Treatment emergent deaths

TEAEs resulting in discontinuation of aflibercept

Non-serious AEs
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.


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The number and percentages of subjects affected as well as the number of events will be 
displayed. SOCs will be sorted by descending frequency of subjects, within each SOC the 
PTs will be sorted by descending frequency of subjects affected.
Potential arterial thrombotic events (ATEs) will be evaluated by an adjudication committee 
according to criteria formerly applied and published by the Anti-Platelet Trialists’
Collaboration (APTC) (1). The definition of ATEs as well as further details are described in 
the adjudication committee charter. They will be presented separately.
In the tables, 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.     
In addition, subject listings will be performed for all deaths, serious AEs and AEs resulting in 
discontinuation of aflibercept. These specific and mandatory listings will be included in the 
tables section of the statistical output.  
6.3.2
Pregnancy test
Results of the pregnancy tests (serum and urine dipstick) will be listed only.
6.3.3
Laboratory Tests
The following hematology, chemistry and urinalysis parameter will be summarized by visit.
They will be converted to the Bayer Standard Units given in brackets.
Table 3: Laboratory safety parameters
Chemistry
Urinalysis 
Hematology
Sodium (MMOL/DL)
Potassium (MMOL/DL)
Chloride (MMOL/DL)
Calcium (MG/DL)
Glucose (MG/DL)
HbA1c (%)
Albumin (G/DL)
Total Protein, Serum (G/L)
Creatinine (MG/DL)
Blood urea nitrogen (MG/DL)
Aspartate aminotransferase (U/L)
Alanine aminotransferase (U/L)
Alkaline phosphatase (U/L)
Total bilirubin (MG/DL)
Amylase (U/L)
Total cholesterol (MG/DL)
High density lipoprotein
cholesterol (MG/DL)
Protein (MG/DL)
Specific Gravity (G/ML)
Protein : Creatinine Ratio (MG/G 
CRE)
Hemoglobin (G/DL)
Hematocrit (%)
Red blood cell count (T/L)
Mean corpuscular volume (FL)
Mean corpuscular hemoglobin 
concentration (G/DL)
Mean corpuscular hemoglobin (PG)
Leucocytes count (GIGA/L)
Differential count
Neutrophils (GIGA/L)
Neutrophils/Leukocytes (%)
Lymphocytes (GIGA/L)
Lymphophils/Leukocytes (%)
Monocytes (GIGA/L)
Monophils/Leukocytes (%)
Basophils (GIGA/L)
Basophils/Leukocytes (%)
Eosinophils (GIGA/L)
Eosinophils/Leukocytes (%)
Platelet count (GIGA/L)


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Shift tables will be performed for the categorical parameters, glucose, blood and ketones 
from the urinalysis.
Additionally, treatment emergent high or low laboratory values will be tabled.
6.3.4
Vital Signs 
Vital signs (body temperature, blood pressure [diastolic and systolic], pulse) will be 
summarized by visit.
6.3.5
Intraocular Pressure (IOP)
Pre- and post- injection IOP and change from baseline in IOP will be summarized by visit. 
Classified pre- and post- injection IOP (> 25 mmHg, ≥ 30 mmHg, ≥ 35 mmHg, ≥ 40 mmHg) 
in the study eye will be summarized by visit.
6.3.6
Slit lamp biomicroscopy
Slit lamp biomicroscopy data for the study eye (Frequency of abnormal findings regarding 
anterior chamber and lens) will be summarized as shift tables (baseline vs. Week 52). 
Specifications of all slit lamp biomicroscopy –related findings will be listed.
7.
Document history and changes in the planned statistical analysis
•
SAP final draft version 1.0, dated 19 Mar 2015 (not finalized)
•
SAP final version 2.0, dated 20 May 2015
8.
References
1. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials 
of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high 
risk patients. Br Med J. 2002; 324: 71-86.
2. Bressler NM, Chang TS, Suner IJ, et al. Vision-related function after ranibizumab 
treatment by better- or worse-seeing eye: clinical trial results from MARINA and 
ANCHOR. Ophthalmology. 2010;117:747–756. 
3. Hirneiss C. The impact of a better-seeing eye and a worse-seeing eye on vision-related
quality of life. Clinical Ophthalmology 2014; 8: 1703–1709
4. Mangione, CM. NEI VFQ-25 Scoring Algorithm – August 2000, Version 2000, The 
National Eye Institute 25-Item, Visual Function Questionnaire (VFQ-25)


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9.
Appendix 
9.1
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 16.1.
The NEI VFQ-25 generates the following vision-targeted subscales (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 
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.


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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."
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.


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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 4)
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 5). 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.