Conditions: Macular Edema
Keywords: Diabetic macular edema DME
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 463
Healthy volunteers: no

Brief summary:
To evaluate the efficacy of long-term treatment with 2 mg aflibercept via different intravitreal (IVT) treatment regimens to participants with DME pretreated with 2 mg aflibercept every 8 weeks after 5 initial monthly injections for approximately 1 year or more (according to the EU label for the first year of treatment)

Detailed description:

Arms:
arm 1: Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks arm 2: Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 week arm 3: Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed)

Interventions: intervention 1: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
An open-label, randomized, active-controlled, parallel-group, Phase-
3b study of the efficacy, safety, and tolerability of three different 
treatment regimens of 2 mg aflibercept administered by intravitreal 
injections to subjects with diabetic macular edema (DME) 
NCT Number: 
NCT02818998 
Document Date: 
07 December 2015 
 


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1.
Title page
An open-label, randomized, active-controlled, parallel-group, Phase-3b 
study of the efficacy, safety, and tolerability of three different treatment 
regimens of 2 mg aflibercept administered by intravitreal injections to 
subjects with diabetic macular edema (DME)
Efficacy and safety of three different aflibercept regimens in subjects with DME
Test drug:
BAY 86-5321; aflibercept; Eylea
Study purpose:
Posology comparison
Clinical study phase:
3b
Date:
07 December 2015  
Registration:
EudraCT: 2014-004938-25
Version no.:
1.0  
Sponsor’s study no.:
BAY 86-5321 / 17613
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
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


Ety Bayer Health Care 
07 December 2015 
Clinical Study Protocol 
No. BAY 86-5321 I 17613 
Version 1.0 
Signature of the sponsor's medically responsible person 
io 
Page: 2 of74 
The signatory agrees to the content of the fmal clinical study protocol as presented. 
Name: 
 
Role: 
Global Clinical Leader 
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
An open-label, randomized, active-controlled, parallel-group, Phase-3b study 
of the efficacy, safety, and tolerability of three different treatment regimens of 
2 mg aflibercept administered by intravitreal injections to subjects with 
diabetic macular edema (DME)
Short title
Efficacy and safety of three different aflibercept regimens in subjects with DME
Clinical study phase
3b
Study objective(s)
Primary objective
To evaluate the efficacy of long-term treatment with 2 mg aflibercept via 
different intravitreal (IVT) treatment regimens to subjects with DME pre-
treated with 2 mg aflibercept every 8 weeks after 5 initial monthly injections 
for approximately 1 year or more (according to the EU label for the first year 
of treatment)
Secondary objective
To assess the safety and tolerability of different treatment regimens of 
aflibercept in this population
Test drug(s)
Name of active ingredient
BAY 86-5321 / aflibercept / Eylea
Dose(s)
For each parallel treatment group 2 mg aflibercept per injection
Posology:
2Q8fix Fixed injection intervals: 8 weeks (reference arm).
No monitoring visits between treatment visits.
Treatment cessation
Usually, treatment should not be ceased in this reference 
arm. However, temporary treatment cessation can be 
considered if the investigator has reason to believe that 
at the respective time point treatment is not in the 
patient’s best interest. The patient should return for 
evaluation as the investigator considers appropriate 
depending on the patient’s condition.
Treatment re-start 
Treatment should be restarted once the condition leading 
to cessation of treatment is resolved. In case of 
recurrence of DME it is proposed to begin with the same 
regimen as a de novo treatment, i.e. five monthly 
injections followed by a 2Q8 regimen.
2Q8ext
Flexible dosing regimen per EU label, injection interval 
≥8 weeks.
No monitoring visits between treatment visits.
Treatment cessation
Cessation of treatment can be considered if the interval 
between two injections reaches or exceeds 16 weeks and 
if this duration can be maintained for at least two 
consecutive intervals without need for shortening of the 
interval, i.e. with stable visual and anatomic outcome 
parameters. If treatment is halted, the patient should 
return for monitoring visits at least every 16 weeks. 
Treatment re-start 
Treatment should be restarted if a deterioration of visual 
and anatomic outcome parameters occurs. If treatment 
has to be restarted due to recurrence of DME, it is 
proposed to begin with the same regimen as a de novo 
treatment, i.e. five monthly injections followed by a 2Q8 
regimen.


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2PRN
Monthly monitoring with dosing as needed
Treatment cessation
If there is no recurrence of active disease, treatment is 
terminated until such time, if ever, that the disease 
recurs. The monthly monitoring is continued throughout.
Treatment re-start 
Treatment will be resumed with single injections each 
time the re-treatment criteria are met.
Route of administration
Intravitreal (IVT) injection
Duration of treatment
2 years
Reference drug(s)
none
Indication
Diabetic macular edema (DME)
Diagnosis and main criteria 
for inclusion /exclusion

Adults of either sex, ≥18 years of age 

The subject’s history of aflibercept treatment meets all of the following:
a. Treatment in the study eye was initiated with five monthly (-1 week / 
+2 weeks) doses of 2 mg aflibercept and improvements of visual and 
anatomic outcomes were observed and documented.
b. Following the above initiation phase, the intervals between treatments 
were between 6 weeks and 12 weeks 
(one exception will be allowed).
c. The interval between the last two pre-study injections was ≥8 weeks, 
and visual and anatomic outcomes have been stable over this interval.
d. The subject received the last IVT injection of aflibercept in the study 
eye 8 weeks (±10 days) before the first planned treatment / 
randomization in this study.
e. Total prior treatment duration with aflibercept (i.e. from first 
aflibercept treatment ever to enrollment into this study) was 1 year or 
longer.
To be met at initiation of pre-study aflibercept treatment:

Type-1 or -2 diabetes mellitus

Diagnosis of DME secondary to diabetes mellitus involving the center of 
the macula (defined as the area of the center subfield of OCT) in the study 
eye

Decrease in vision determined to be primarily the result of DME in the 
study eye

BCVA in the study eye of ETDRS letter score 73 to 24 (corresponding to 
a Snellen equivalent of approximately 20/40 to 20/320)
Study design
Randomized, 3-arm, active-controlled, parallel-group, open-label, multicenter
Methodology
Visual function of the study eye and the fellow eye will be assessed using the 
ETDRS protocol starting at 4 meters. Refraction is to be done at each visit.
Type of control
Active control
Data Monitoring Committee
An adjudication committee will perform an additional analysis of 
arterial thrombotic events (ATEs)
Number of subjects
Total of approximately 490 subjects should be randomized (163 per treatment 
group)
Primary variable(s)
Change in ETDRS BCVA letter score for the study eye 
from baseline to Week 52
Time point/frame of 
measurement for primary 
variable(s)
After 52 weeks of randomized treatment


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Plan for statistical analysis
The primary analysis of the primary efficacy variable will be conducted on 
the full analysis set (FAS). The analyses are repeated on the PPS.
Statistical testing will be conducted to prove the non-inferiority of each of the 
two extended-dosing regimens to the 2Q8 fixed-dosing regimen.
To control the overall type-I error rate for multiple comparisons, Hochberg 
procedure (Hochberg 1988) will be used to adjust for multiplicity.
The hypotheses for the two extended dosing regimen will be based on an 
analysis of covariance (ANCOVA) model with the baseline measure as a 
covariate and treatment group and “10-letter gain from start of aflibercept 
treatment to baseline (yes/no)” as a fixed factor.


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Table of contents
1.
Title page............................................................................................................................ 1
Signature of the sponsor’s medically responsible person..................................................... 2
Signature of principal investigator......................................................................................... 3
2.
Synopsis.............................................................................................................................. 4
Table of contents....................................................................................................................... 7
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............................................................................................................... 12
5.
Study design..................................................................................................................... 12
6.
Study population ............................................................................................................. 16
6.1
Inclusion criteria ..................................................................................................... 16
6.2
Exclusion criteria.................................................................................................... 18
6.3
Withdrawal of subjects from study......................................................................... 20
6.3.1
Withdrawal................................................................................................ 20
6.3.2
Replacement.............................................................................................. 22
6.4
Subject identification.............................................................................................. 22
7.
Treatments....................................................................................................................... 22
7.1
Treatments to be administered................................................................................ 22
7.2
Identity of study treatment...................................................................................... 23
7.3
Treatment assignment............................................................................................. 24
7.4
Dosage and administration...................................................................................... 24
7.5
Masking .................................................................................................................. 26
7.6
Drug logistics and accountability ........................................................................... 26
7.7
Treatment compliance............................................................................................. 27
8.
Non-study therapy........................................................................................................... 27
8.1
Prior and concomitant therapy................................................................................ 27
8.1.1
Prior therapy.............................................................................................. 28
8.1.2
Concomitant therapy................................................................................. 28
8.1.2.1
Study-eye treatment ............................................................... 28
8.1.2.2
Fellow-eye treatment.............................................................. 28
8.2
Post-study therapy................................................................................................... 28


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9.
Procedures and variables ............................................................................................... 28
9.1
Tabular schedule of evaluations ............................................................................. 28
9.2
Visit description...................................................................................................... 30
9.2.1
Screening................................................................................................... 30
9.2.2
Baseline..................................................................................................... 31
9.2.3
Visits after baseline and before Week 52.................................................. 32
9.2.4
Week 52 .................................................................................................... 33
9.2.5
Visits after Week 52 and before Week 100 .............................................. 33
9.2.6
Week 100 (final visit or early termination)............................................... 34
9.3
Population characteristics ....................................................................................... 35
9.3.1
Demographic............................................................................................. 35
9.3.2
Medical/surgical and ophthalmic history.................................................. 35
9.4
Efficacy................................................................................................................... 36
9.4.1
Ophthalmic examinations ......................................................................... 36
9.4.1.1
Best corrected visual acuity ................................................... 36
9.4.1.2
Optical coherence tomography (OCT)................................... 36
9.4.1.3
Indirect ophthalmoscopy........................................................ 36
9.4.1.4
Slit lamp biomicroscopy ........................................................ 36
9.4.1.5
Intraocular pressure (IOP)...................................................... 37
9.4.1.6
Fundus photography (FP) and fluorescein angiography 
(FA)........................................................................................ 37
9.4.2
Efficacy variables...................................................................................... 37
9.4.3
National Eye Institute Visual Functioning Questionnaire 25 (NEI 
VFQ-25).................................................................................................... 37
9.5
Pharmacokinetics / pharmacodynamics.................................................................. 37
9.6
Safety ...................................................................................................................... 38
9.6.1
Adverse events .......................................................................................... 38
9.6.1.1
Definitions.............................................................................. 38
9.6.1.2
Classifications for adverse event assessment......................... 39
9.6.1.2.1
Seriousness.............................................................................39
9.6.1.2.2
Intensity..................................................................................40
9.6.1.2.3
Causal relationship.................................................................40
9.6.1.2.4
Action taken with study treatment .........................................42
9.6.1.2.5
Other specific treatment(s) of adverse events ........................42
9.6.1.2.6
Outcome.................................................................................43
9.6.1.3
Assessments and documentation of adverse events............... 43
9.6.1.4
Reporting of serious adverse events....................................... 44
9.6.1.5
Expected adverse events ........................................................ 45
9.6.2
Pregnancies ............................................................................................... 45
9.6.3
Further safety ............................................................................................ 46
9.6.3.1
Laboratory evaluations........................................................... 46
9.6.3.2
Vital signs (temperature, blood pressure and pulse).............. 47
9.7
Other procedures and variables............................................................................... 47
9.8
Appropriateness of procedures / measurements ..................................................... 47


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10. Statistical methods and determination of sample size ................................................. 47
10.1
General considerations............................................................................................ 47
10.2
Analysis sets ........................................................................................................... 48
10.3
Variables and planned statistical analyses.............................................................. 48
10.3.1
Variables ................................................................................................... 48
10.3.1.1
Efficacy variables................................................................... 48
10.3.1.2
Safety variables ...................................................................... 49
10.3.2
Statistical and analytical plans .................................................................. 49
10.3.2.1
Demography and baseline characteristics.............................. 49
10.3.2.2
Efficacy analyses.................................................................... 49
10.3.2.2.1
Primary efficacy variable .......................................................49
10.3.2.2.2
Secondary efficacy variables..................................................51
10.3.2.2.3
Exploratory efficacy variables ...............................................51
10.3.2.3
Safety analyses....................................................................... 51
10.3.2.3.1
Adverse events .......................................................................52
10.3.2.3.2
Other safety variables.............................................................52
10.4
Determination of sample size ................................................................................. 52
10.5
Planned interim analyses ........................................................................................ 53
11. Data handling and quality assurance............................................................................ 53
11.1
Data recording......................................................................................................... 53
11.2
Monitoring .............................................................................................................. 55
11.3
Data processing....................................................................................................... 55
11.4
Missing data............................................................................................................ 55
11.5
Audit and inspection............................................................................................... 56
11.6
Archiving ................................................................................................................ 56
12. Premature termination of the study .............................................................................. 57
13. Ethical and legal aspects................................................................................................. 58
13.1
Investigator(s) and other study personnel............................................................... 58
13.2
Funding and financial disclosure............................................................................ 59
13.3
Ethical and legal conduct of the study.................................................................... 59
13.4
Subject information and consent............................................................................. 60
13.5
Publication policy and use of data.......................................................................... 61
13.6
Compensation for health damage of subjects / insurance....................................... 62
13.7
Confidentiality........................................................................................................ 62
14. Reference list.................................................................................................................... 62
15. Protocol amendments...................................................................................................... 63
16. Appendices....................................................................................................................... 64
16.1
NEI VFQ-25 Questionnaire.................................................................................... 64


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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 8 weeks
AE
adverse event
ALT
alanine aminotransferase
AMD
age-related macular degeneration
ANCOVA
analysis of covariance
APTC
Antiplatelet Trialists' Collaboration
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical 
Classification System
ATE
arterial thrombotic event
BCVA
best corrected visual acuity
BUN
blood urea nitrogen
CNV
choroidal neovascularization
CRF
case record form
CRO
contract research organization
CRT
central retinal thickness
CSR
clinical study report
CTFG
Clinical Trials Facilitation Group
DME
diabetic macular edema
DR
diabetic retinopathy
DRSS
diabetic retinopathy severity scale
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
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IgG
immunoglobulin G
IOP
intraocular pressure
IRB
institutional review board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
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
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
NEI VFQ-25 National Eye Institute Visual Functioning 
Questionnaire 25
OCT
optical coherence tomography
PDR
proliferative diabetic retinopathy
PID
subject 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
SAS
statistical analysis software
SD-OCT
spectral domain optical coherence 
tomography
SMT
safety management team
SOC
system organ class
SUSARs
suspected, unexpected, serious adverse 
reaction
UPCR
urine protein/creatinine ratio
VA
visual acuity
VEGF
vascular endothelial growth factor
WHO-DD
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.
The approval of aflibercept in the EU (August 2014) was based upon the results of two 
randomized, multicenter, double-masked, active-controlled Phase-3 clinical studies, VISTA 
DME and VIVID DME. The primary endpoint of these studies was the change from baseline 
to Week 52 in BCVA in ETDRS letter score. Both studies demonstrated that aflibercept, 
dosed every 8 weeks following five initial monthly injections, provided efficacy that was 
superior to laser treatment, the former standard of care.
The approved EU label for aflibercept states:
The recommended dose for Eylea is 2 mg aflibercept equivalent to 50 microlitres.
Eylea treatment is initiated with one injection per month for five consecutive doses, 
followed by one injection every two months. There is no requirement for monitoring 
between injections. 
After the first 12 months of treatment with Eylea, the treatment interval may be extended 
based on visual and anatomic outcomes. The schedule for monitoring should be 
determined by the treating physician.
If visual and anatomic outcomes indicate that the subject is not benefiting from 
continued treatment, Eylea should be discontinued.
3.2
Rationale of the study
The approved dosing schedule for the first year of DME treatment has been thoroughly 
studied during the clinical development program and is well supported by the available data 
as originally submitted.


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For additional support of the approved dosing schedule for the second year of treatment and 
beyond, the MAH seeks to collect further data including information on treatment cessation 
and restart. To this end, the present study is initiated. It is designed to meet requests made by 
EMA as part of a post-approval commitment.
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.
Taken together, participation in this study is not expected to bear an undue risk for the 
enrolled subjects.
4.
Study objectives
Primary objective
To evaluate the efficacy of long-term treatment with 2 mg aflibercept via different intravitreal 
(IVT) treatment regimens to subjects with DME pre-treated with 2 mg aflibercept every 
8 weeks after 5 initial monthly injections for approximately 1 year or more (according to the 
EU label for the first year of treatment)
Secondary objective
To assess the safety and tolerability of different treatment regimens of aflibercept in this 
population
5.
Study design
Design overview
This is a randomized, 3-arm, active-controlled, parallel-group, open-label, multicenter, 
Phase-3b study to be conducted in subjects pre-treated with aflibercept for 1 year or more.
Aflibercept 2 mg administered at a fixed schedule every 8 weeks (2Q8fix) is regarded as the 
reference arm. Two alternative regimens will be compared to the reference arm: A regimen 
with a gradually extended dosing interval according to the current EU label (2Q8ext) and a 
pro re nata dosing scheme (2PRN) with monthly monitoring (Figure 1).


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Figure 1:
Overall study design
Screening
Treatment
3-arm, randomized, open-label 
2Q8fix: Fixed dosing regimen, injection intervals 8 weeks
No monitoring visits between treatment visits
2Q8ext: Extended dosing regimen, injection intervals ≥8 weeks
No monitoring visits between treatment visits
2PRN:
Monthly monitoring visits 
Injections as frequently as needed
Screening
Enrollment
Randomization (1:1:1)
Baseline
Primary 
completion
Week 52
End of 
study
Week 100
Table 1 shows the detailed treatment schedules and procedures for temporary cessation of 
treatment.


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Table 1:
Treatment administration and cessation
Detailed administration schedule
Treatment cessation and re-start
2Q8fix
Fixed injection intervals: 8 weeks throughout the entire 
treatment period
After the baseline visit, the subjects return every 8 weeks 
to the investigational site. Starting at the baseline visit, 
they receive an injection at each visit. The last injection 
will be at Week 96. The final safety and efficacy 
assessments are done at Week 100 (final visit). There 
will be no pure monitoring visits, i.e. without treatment 
(with the exception of Week 52 [primary completion] and 
Week 100 [final visit]).
Treatment cessation
Usually, treatment should not be ceased 
in this reference arm. However, temporary 
treatment cessation can be considered if 
the investigator has reason to believe that 
at the respective time point treatment is 
not in the patient’s best interest. The 
patient should return for evaluation as the 
investigator considers appropriate 
depending on the patient’s condition.  
Treatment re-start 
Treatment should be restarted once the 
condition leading to cessation of 
treatment is resolved. In case of 
recurrence of DME it is proposed to begin 
with the same regimen as a de novo 
treatment, i.e. five monthly injections 
followed by a 2Q8 regimen. 
2Q8ext
Flexible injection intervals: ≥8 weeks (no upper limit)
At the baseline visit and at each subsequent visit, the 
investigator will determine the duration until the subject’s 
next injection, based on visual and anatomic outcomes at 
the current visit. Injection intervals can be extended if 
visual and anatomic measures are stable. When/if 
edema recurs, the treatment interval should be reverted 
to the last treatment interval when the disease was 
inactive. The increments and decrements for the injection 
intervals are at the investigator’s discretion; typically, 
increments of 2 weeks are recommended. There will be 
no pure monitoring visits, i.e. an injection will be given at 
each visit with the (potential) exception of Weeks 52 and 
100. At Weeks 52 and 100, an injection can be given if 
this visit coincides with a scheduled injection visit.
All subjects return for efficacy and safety assessments at 
Week 52 (primary endpoint assessment). The final safety 
and efficacy assessments will be done at Week 100 (final 
visit).*
Treatment cessation
Cessation of treatment can be considered 
if the interval between two injections 
reaches or exceeds 16 weeks and if this 
duration can be maintained for at least 
two consecutive intervals without need for 
shortening of the interval, i.e. with stable 
visual and anatomic outcome parameters. 
If treatment is halted, the patient should 
return for monitoring visits at least every 
16 weeks.
Treatment re-start 
Treatment should be restarted if a 
deterioration of visual and anatomic 
outcome parameters occurs. If treatment 
has to be restarted due to recurrence of 
DME, it is proposed to begin with the 
same regimen as a de novo treatment, 
i.e. five monthly injections followed by a 
2Q8 regimen.
2PRN
After randomization, the subjects return every 4 weeks to 
the investigational site. At each visit, the investigator will 
determine, based on pre-specified re-treatment criteria, 
whether an injection is to be given or not.
Injection decision will be based on the investigator’s 
judgment using the following re-treatment criteria:
• Leakage as sign of active DME (e.g. CRT as assessed 
by SD-OCT > 300 µm and/or an increase of > 50 µm 
from best previous measurement)
• Increase of ≥5 letters in BCVA between current and 
most recent previous visit
• Loss of ≥5 letters from the previous BCVA 
measurement with any increase in SD-OCT CRT
The last visit with an option for treatment under this 
protocol is at Week 96. The final safety and efficacy 
assessments will be done at Week 100 (final visit).
Treatment cessation
If there is no recurrence of active disease, 
treatment is terminated until such time, if 
ever, that the disease recurs. The monthly 
monitoring is continued throughout.
Treatment re-start 
Treatment will be resumed with single 
injections each time the re-treatment 
criteria are met.
*If an extended-dosing subject receives an injection at Week 100, it is the responsibility of the treating investigator to follow 
up on any adverse events (including ongoing events) that may occur within 4 weeks following this treatment. Information 
regarding such events is to be reported under this protocol (i.e. not as spontaneous reports).
For all treatment groups, the time window for all 
visits is 3 days relative to baseline.
BCVA:
best corrected visual acuity
CRT: 
central retinal thickness
PRN: 
Latin: pro re nata (as needed)
SD OCT: spectral domain optical coherence 
tomography


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Randomization will be stratified by 10-letter gain from start of aflibercept treatment 
(“yes”/”no” as obtained from available medical documentation). For each group, the first 
injection of study medication will be given at the baseline visit.
Owing to the nature of the different dosing regimens, the three arms will not have the same 
visit and treatment schedule. Therefore, masking of the treatments is not feasible.
For each treatment group, the assessment of the primary endpoint will be performed at 
Week 52.
For each treatment group, the time window for all visits is 3 days relative to baseline. After 
the final visit or after early termination, all subjects return to standard-of-care treatment 
outside of this study. 
Efficacy and safety assessments will be performed throughout the study as detailed in the 
schedule of evaluations in Section 9.
Primary variable
The primary efficacy variable is the change in best corrected visual acuity (BCVA; as 
measured by the ETDRS letter score) from baseline (i.e. randomization) to Week 52. 
Justification of the design
Open-label setting: Since all treatment groups will be on different visit schedules, masking the 
study is impossible. Masking the study would require harmonizing the visit schedules in all 
groups by having subjects in the 2Q8 groups attend non-treatment study visits. Doing this, 
however, would disrupt the intent of an extended-dosing regimen and, thus, was not 
considered to be a viable option.
The primary endpoint will be assessed at the end of the first year of treatment under this 
protocol. As the protocol is designed, subjects completing one year in the study will have also 
completed the end of their second year of treatment given that subjects entering this study will 
have received a first year of treatment outside of this study. The results of the primary 
endpoint at week 52 of this study (after at least two years of treatment with aflibercept) will 
be reported in a stand-alone clinical study report to make this important information available 
to the community as soon as possible.
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
Only one eye will be designated as the study eye.
6.1
Inclusion criteria
A subject must meet all of the following inclusion criteria 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.
The subject’s history of aflibercept treatment meets all of the following:
a. Treatment in the study eye was initiated with five monthly (-1 week / +2 weeks) doses 
of 2 mg aflibercept and improvements of visual and anatomic outcomes were observed 
and documented.
b. Following the above initiation phase, the intervals between treatments were between 
6 weeks and 12 weeks (one exception will be allowed).
c. The interval between the last two pre-study injections was ≥8 weeks, and visual and 
anatomic outcomes have been stable over this interval.
d. The subject received the last IVT injection of aflibercept in the study eye 8 weeks 
(±10 days) before the first planned treatment / randomization in this study.
e. Total prior treatment duration with aflibercept (i.e. from first aflibercept treatment 
ever to enrollment into this study) was 1 year or longer.
Adherence to Criterion 2 will be checked on the basis of the available medical 
documentation. If no information is available, this inclusion criterion is considered as not 
fulfilled and the subject cannot be included in the study.
3.
Willingness and ability to comply with clinic visits and study-related procedures
4.
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


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Progestogen-only hormonal contraception associated with inhibition of ovulation:

Oral

Injectable

Implantable 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partner 
Sexual abstinence
Alternatively women and men of reproductive potential can also use two acceptable 
methods of contraception (as defined by the 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.
5.
Negative pregnancy test (serum test at screening; urine dip stick test at baseline; women 
of childbearing potential only)
6.
Signed written informed consent
To be met at initiation of pre-study aflibercept treatment
The check of adherence to these criteria will be based on available medical documentation.
If no information is available, the respective inclusion criterion is considered as not fulfilled 
and the subject cannot be included in the study.
7.
Type-1 or -2 diabetes mellitus
8.
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
9.
Decrease in vision determined to be primarily the result of DME in the study eye
10. 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.


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6.2
Exclusion criteria
A subject must not meet any of the following exclusion criteria as applicable to be eligible for 
enrollment into this study. The check of these criteria at initiation of pre-study aflibercept 
treatment (referred to as “first aflibercept injection”) will be based on available medical 
documentation. If no information is available, the exclusion criterion is considered fulfilled 
and the subject cannot be included in the study. 
At initiation of pre-study aflibercept treatment
1.
Previous treatment with anti-angiogenic drugs in study eye (e.g. pegaptanib sodium, 
bevacizumab, ranibizumab or aflibercept) within the last 12 weeks before initiation of 
aflibercept pre-study treatment 
At all of the following time points

Initiation of pre-study aflibercept treatment 

Screening for this study 

Baseline for this study
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 aflibercept treatment in the study eye
7.
Yttrium-aluminum-garnet capsulotomy in the study eye within 30 days before aflibercept 
treatment
8.
Any other intraocular surgery within 90 days of aflibercept 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 was 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 
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13. 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)
14. Myopia of a spherical equivalent prior to any possible refractive or cataract surgery of 
≥8 diopters in the study eye
15. Administration of systemic anti angiogenic agents within 180 days before aflibercept 
treatment
16. Uncontrolled diabetes mellitus as defined by hemoglobin (Hb)A1c > 12.0%
17. 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)
18. Presence of any contraindications indicated in the EU commission/locally approved label 
for aflibercept
At all of the following time points

Screening for this study 

Baseline for this study.
19. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye
20. Any ocular or periocular infection in the preceding 4 weeks in either eye
21. Filtration surgery for glaucoma in the past or likely to be needed in the future on the 
study eye
22. Uncontrolled glaucoma (defined as intraocular pressure [IOP] > 25 mmHg despite 
treatment with antiglaucoma medication) in the study eye
23. Allergy or hypersensitivity to fluorescein
24. Current treatment for a serious systemic infection
25. History of either cerebral vascular accident and/or myocardial infarction within 180 days 
before aflibercept treatment
26. Renal failure requiring dialysis or renal transplant
27. 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
28. Significant media opacities, including cataract, in the study eye that interferes with visual 
acuity, fundus photography or OCT imaging.
29. Breast-feeding women
30. Previous receipt of at least 1 dose of study drug under this protocol


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31. Concomitant participation in another clinical study with investigational medicinal 
product(s). Exception: A temporal overlap with participation in Bayer study 
protocol 17850 is acceptable.
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
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 potent 
enough to require withdrawal from the study. The investigator must notify the sponsor 
immediately if a subject is withdrawn because of an AE.
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. 


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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”. 
In general, re-starting the defined set of screening procedures to enable the “screening failure” 
subject’s participation at a later time point is not allowed. Thus, in general, participation of an 
initial “screening failure” subject at a later time point is not acceptable even if he/she meets 
all selection criteria upon re-screening.
However, as an exception, re-screening may be acceptable under the following conditions:
The subject had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.
The in- / 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.
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.
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk. Also, for re-screening, the subject has to 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 been randomized.


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General procedures
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's 
medical records. 
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (Premature termination of the study).
6.3.2
Replacement
Subjects who withdraw from the study will not be replaced. 
6.4
Subject identification
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.
7.
Treatments
7.1
Treatments to be administered
As detailed in the inclusion criterion 2 (Section 6.1), all subjects to be randomized into this 
study are required to have received at least 1 year of treatment with aflibercept.
Each eligible subject will be randomized (1:1:1) to one of three parallel treatment groups 
specified in Table 2.


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Table 2:
Treatment groups
2Q8fix
2Q8ext
2PRN
Dose per injection
Aflibercept 2 mg
Aflibercept 2 mg
Aflibercept 2 mg
Regimen
Fixed dosing regimen, 
injection interval: 8 weeks 
(reference arm).
No monitoring visits 
between treatment visits.
Flexible dosing regimen per 
EU label, injection interval: 
≥8 weeks.
No monitoring visits between 
treatment visits.
Monthly monitoring with dosing 
as needed.
Last study 
treatment
Week 96
Week 100 or earlier b
Week 96 or earlier
Final safety and 
efficacy 
assessments
Week 100
Week 100 c
Week 100
Planned number of 
randomized 
subjects
163
163
163
Detailed 
administration 
schedule a
See Section 5, Table 1
Treatment 
cessation
See Section 5, Table 1
BCVA: best corrected visual acuity; CRT: central retinal thickness; PRN: Latin: pro re nata (as needed);
SD-OCT: spectral domain optical coherence tomography
a
For each treatment group, the time window for all visits is 3 days relative to baseline.
b
At Week 100, subjects receive an injection if this visit coincides with a scheduled injection visit.
c.   If an extended-dosing subject receives an injection at Week 100, it is the responsibility of the treating investigator to follow 
up     on any adverse events (including ongoing events) that may occur within 4 weeks following this treatment. Information 
regarding such events is to be reported under this protocol (i.e. not as spontaneous reports).
7.2
Identity of study treatment
The identity of the study drug is summarized in Table 3.
Table 3:
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
10 mM sodium phosphate
0.03% polysorbate 20
40 mM NaCl
Water for injection
All study drugs will be labeled according to the requirements of local law and legislation.
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.


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For all study drugs, a system of numbering in accordance with all requirements of GMP will 
be used, ensuring that each dose of study drug can be traced back to the respective bulk batch 
of the ingredients. Lists linking all numbering levels will be maintained by the sponsor’s 
clinical supplies Quality Assurance group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.
7.3
Treatment assignment
Subjects enrolled in the study will be randomized to receive treatment under one of three 
dosing regimens. The three treatment groups will be randomly assigned by the central 
randomization group in a 1:1:1 ratio to one of the three parallel treatment arms identified in 
Section 7.1. Treatment assignment will be controlled via the IxRS.
Randomization will be stratified by 10-letter gain from start of aflibercept treatment 
(“yes”/”no” as obtained from available medical documentation).
7.4
Dosage and administration
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 Section 7.2, Table 3 for details on the composition of the study drug)

Filter needle (18 gauge)
Other ancillary components required for the administration of aflibercept (e.g. 30-gauge 
injection needle; 1-ml syringe) will be supplied by the study site.
When aflibercept vials are removed from the refrigerator, the solution should be visually 
inspected and it should have no evidence of turbidity. If particulates, cloudiness, or 
discoloration are visible, the vial must not be used.
After opening the vial, all preparation steps have to take place under aseptic conditions.
The study drug will be withdrawn using aseptic technique through the filter needle attached to 
the syringe. The filter needle will be discarded after withdrawal of the vial contents and 
should not be used for IVT injection. The filter needle should be replaced by the sterile 
30-gauge needle for the IVT injection. Each patient receives an IVT injection of 50 µl of 
aflibercept.


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Posology
Treatment posology is detailed in Table 4. Re-treatment criteria for the 2PRN arm are 
specified in Section 7.1, Table 2.
Table 4:
Treatment posology
2Q8fix
2Q8ext
2PRN
Visit
Treatment
Visit
Treatment
Visit
Treatment
Screening mandatory Visit 1 no treatment
mandatory Visit 1 
no treatment
mandatory Visit 1 
no treatment
Baseline
mandatory Visit 2 mandatory 
mandatory Visit 2 
mandatory 
mandatory Visit 2 
mandatory 
Week 4
no visit
no visit
mandatory Visit 3
throughout all 
visits between 
Week 4 and 
Week 96, 
treatment is 
optional according 
to the 
re-treatment 
criteria given in 
Section 7.1, 
Table 2
Week 8
mandatory visit with treatment
between 
Week 8 and Week 52, 
visits (incl. treatment) can be 
scheduled at any time point
(provided injection intervals 
are ≥8 weeks)
mandatory Visit 4
Week 12
no visit
mandatory Visit 5
Week 16
mandatory visit with treatment
mandatory Visit 6
Week 20
no visit
mandatory Visit 7
Week 24
mandatory visit with treatment
mandatory Visit 8
Week 28
no visit
mandatory Visit 9
Week 32
mandatory visit with treatment
mandatory Visit 10
Week 36
no visit
mandatory Visit 11
Week 40
mandatory visit with treatment
mandatory Visit 12
Week 44
no visit
mandatory Visit 13
Week 48
mandatory visit with treatment
mandatory Visit 14
Week 52
mandatory 
no treatment
mandatory 
optional
mandatory Visit 15 
Week 56
mandatory visit with treatment
between 
Week 52 and Week 100, 
visits (incl. treatment) can be 
scheduled at any time point
(provided injection intervals 
are ≥8 weeks)
mandatory Visit 16
Week 60
no visit
mandatory Visit 17
Week 64
mandatory visit with treatment
mandatory Visit 18
Week 68
no visit
mandatory Visit 19
Week 72
mandatory visit with treatment
mandatory Visit 20
Week 76
no visit
mandatory Visit 21
Week 80
mandatory visit with treatment
mandatory Visit 22
Week 84
no visit
mandatory Visit 23
Week 88
mandatory visit with treatment
mandatory Visit 24
Week 92
no visit
mandatory Visit 25
Week 96
mandatory visit with treatment
mandatory Visit 26
Week 100
mandatory 
no treatment
mandatory 
optional
mandatory Visit 27
no treatment
The reasons for treatment cessation – and if applicable re-start – will be documented. The 
treatment schedule in the 2Q8fix and 2Q8ext groups may deviate from the schedule proposed 
in Section 7.4, Table 4 if cessation and re-start become necessary (see Section 5, Table 1). 
However, the visits at week 52 and 100 since baseline are mandatory for all subjects 
regardless of any temporary cessation of treatment.


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Consideration of special warnings based on 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 
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.


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Storage
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate/CRO), and will be inaccessible to unauthorized personnel. Special storage 
conditions and a complete record of batch numbers and expiry dates can be found in the 
sponsor’s study file; the site-relevant elements of this information will be available in the 
investigator site file.
Aflibercept must be stored at the clinical sites in a refrigerator at 2C to 8C, protected from 
light, and not frozen. Prior to usage, the unopened vial or blister pack of aflibercept may be 
stored at room temperature (25 °C / 77°F) for up to 24 hours. After opening the vial or blister 
pack, proceed under aseptic conditions.
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.
8.
Non-study therapy
8.1
Prior and concomitant therapy
Any relevant previous and concomitant treatments will be recorded in the source 
documentation and then entered into the “Previous and Concomitant Medications” eCRF 
screen using the brand name.
All recorded previous and concomitant medications will be coded using an internationally 
recognized and accepted coding dictionary.


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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 medication considered necessary for the subject’s welfare, and that are not expected to 
interfere with the evaluation of the study drug, may be given at the discretion of the 
investigator, with the exceptions noted below.
8.1.2.1
Study-eye treatment
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 deemed 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).
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.
9.
Procedures and variables
9.1
Tabular schedule of evaluations


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Table 5:
Schedule of assessments and procedures 
Screening b
Baseline b
Primary 
completion
Final visit / 
early termination
Visit number a
Visit 1
Visit 2
Visits 3 - 14
Visit 15
Visits 16 - 26
Visit 27
Timing 2PRN c
individualized
for all 
treatment 
groups
Day 1
for all 
treatment 
groups
Week 4 - 48
Week 52
for all 
treatment 
groups
Week 56 -
96
Week 100
for all 
treatment 
groups
2Q8fix c
Week 8 - 48
2Q8ext c
individualized
individualized
Initiation procedures
Informed consent 

Demographic data

Medical / ophthalmic history 

Check of in-/exclusion criteria


Randomization

Study medication
Administration of study treatment 

○d
○d
○d
○d
Ophthalmologic assessments
(all assessments bilaterally [additional assessments may occur outside of this protocol])
BCVA (ETDRS chart starting at 4 m) e






Optical coherence tomography 

mand./option.f

mand./option.f

Fluorescein angiogr., fundus photogr.

optional g

optional g

Indirect ophthalmoscopy






Slit lamp biomicroscopy






Intraocular pressure (IOP)






Patient-reported outcomes
NEI VFQ-25



Standard safety
Prior / concomitant medications






Adverse events h






Hematology / chemistry 



Urinalysis / UPCR



Pregnancy test i
Serum

Urine

○i

○i

Vital signs (temp., blood pressure, pulse)



BCVA = best corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; PT/INR = prothrombin time / 
international normalized ratio; PTT = partial thromboplastin time; UPCR = urine protein / creatinine ratio
a.
Visit numbers refer to the mandatory visits for treatment administration to subjects in the 2PRN group. Fewer visits are 
required for subjects in the 2Q8fix or 2Q8ext groups.
b.
If all data needed for enrollment are available, the screening visit and the baseline visit may take place on the same day. In 
such a case, procedures scheduled for both visits will be conducted only once.
Scheduling of screening and baseline visit(s) has to ensure that the first injection of study medication under this protocol 
meets the respective criteria for the pre-study treatment as specified in Section 6.1, inclusion criterion 2.d.
c.
Scheduling of the post-baseline visits (except Week 52 and Week 100): 2PRN, fixed schedule every 4 weeks; 2Q8fix: fixed 
schedule every 8 weeks; 2Q8ext: individualized. Visits at Week 52 and Week 100 are mandatory for all treatment groups.
Visit schedules may deviate by ± 3 days relative to baseline.
d.
Treatment schedules differ across treatment groups; details are provided in Section 7.4, Table 4.
e.
Refraction to be done at each visit
f.
Mandatory for 2PRN subjects. Otherwise to be done only if deemed necessary by the investigator or required by local 
medical practice.
g.
To be done only if deemed necessary by the investigator or required by local medical practice.
h.
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).
If a 2Q8ext subject receives an injection at Week 100, follow-up is needed on any AEs (including ongoing events) that may 
occur within 4 weeks following this treatment (AE reporting under this protocol; i.e. not as spontaneous reports)
i.
In women of childbearing potential only. The test is to be repeated as frequently as requested.


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9.2
Visit description
9.2.1
Screening 
Scheduling (identical for all subjects of all treatment groups)
If all data needed for enrollment are available, the screening visit and the baseline visit may 
take place on the same day. In such a case, procedures scheduled for both visits will be 
conducted only once.
Scheduling of screening and baseline visit(s) has to ensure that the first injection of study 
medication under this protocol meets the respective criteria for the pre-study treatment as 
specified in inclusion criterion 2.d (Section 6.1).
Conduct
The following procedures will be performed at this visit:

Obtaining 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 10 for details)
(If screening and baseline visits take place on different days, the assessable selection 
criteria are to be met on both days.)

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 (serum test)

Vital signs (body temperature, blood pressure and pulse) (see Section 9.6.3.2 for details)


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
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).
9.2.2
Baseline 
Scheduling (identical for all subjects of all treatment groups)
If all data needed for enrollment are available, the screening visit and the baseline visit may 
take place on the same day. In such a case, procedures scheduled for both visits will be 
conducted only once.
Scheduling of screening and baseline visit(s) has to ensure that the first injection of study 
medication under this protocol meets the respective criteria for the pre-study treatment as 
specified in inclusion criterion 2.d (Section 6.1).
Conduct
The following procedures will be performed at this visit:

Assessment of inclusion and exclusion criteria (see Sections 6.1 and 10 for details)
(If screening and baseline visits take place on different days, all selection criteria are to be 
met on both days.)

Randomization (see Section 7.3 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)

NEI VFQ-25 (see Section 9.4.3 for details)

Pregnancy test in women of childbearing potential (urine dip stick test)

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 (also post injection)

Slit lamp biomicroscopy 

Intraocular pressure (IOP) (also post injection)

First application of study medication (see Section 7.4 for details).
Injections are to take place after completion of the procedures listed above.


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9.2.3
Visits after baseline and before Week 52
Scheduling
The scheduling of visits after baseline and before Week 52 differs among treatment groups 
(see Section 5):
2Q8fix
Fixed schedule for each subject in this treatment group:
Visits take place in strict accordance with the Q8 schedule, i.e. at Weeks 8, 
16, 24 etc.
2Q8ext
Individualized visit schedule. Visit interval ≥8 weeks
2PRN
Fixed schedule for each subject in this treatment group:
Visits every 4 weeks
The treatment schedule in the 2Q8fix and 2Q8ext groups may deviate from the schedule 
proposed in Section 7.4, Table 4 if cessation and re-start become necessary (see Section 5,
Table 1). If a subject returns for a monitoring visit during temporary treatment cessation, the 
procedures described for a visit in the PRN treatment group should be performed. If treatment 
is re-started, the paradigms described in Section 5, Table 1 should be followed in accordance 
with the subject’s assigned treatment group.
Conduct
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) - mandatory for PRN, otherwise optional

Optional: Fundus photography (FP) and fluorescein angiography (FA)

Indirect ophthalmoscopy (also post injection if applicable)

Slit lamp biomicroscopy 

Intraocular pressure (IOP) (also post injection if applicable)

Application of study medication (see Section 7.4 for details) as follows:

2Q8fix:
Treatment at each visit 

2Q8ext:
Treatment at each visit

2PRN:
Treatment only if re-treatment criteria (see Section 7.1, Table 2) are met

Record reason for cessation/restart of treatment if applicable
Injections are to take place after completion of the procedures listed above.


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9.2.4
Week 52
Scheduling (identical for all subjects of all treatment groups)
All subjects of all treatment groups will have this visit; it will be scheduled for Week 52 
(± 3 days) after baseline.
Conduct
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)

NEI VFQ-25 (see Section 9.4.3 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

Pregnancy test in women of childbearing potential (urine dip stick test)

Vital signs (body temperature, blood pressure and pulse) (see Section 9.6.3.2 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 (also post injection if applicable)

Slit lamp biomicroscopy 

Intraocular pressure (IOP) (also post injection if applicable)

Application of study medication (see Section 7.4 for details) as follows:

2Q8fix:
No treatment

2Q8ext:
Treatment only if according to individualized treatment schedule

2PRN:
Treatment only if re-treatment criteria (see Section 7.1, Table 2) are met.
Injections are to take place after completion of the procedures listed above.
9.2.5
Visits after Week 52 and before Week 100
Scheduling and conduct of the visits after Week 52 and before Week 100 will follow the 
specifications for visits after baseline and before Week 52 as described in Section 9.2.3.


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9.2.6
Week 100 (final visit or early termination)
Scheduling (identical for all subjects of all treatment groups)
All subjects of all treatment groups will have this visit; it will be scheduled for Week 100 
(± 3 days) after baseline.
This visit will also be conducted in case of premature termination of a subject.
Conduct
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)

NEI VFQ-25 (see Section 9.4.3 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

Pregnancy test in women of childbearing potential (urine dip stick test)

Vital signs (body temperature, blood pressure and pulse) (see Section 9.6.3.2 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).

Application of study medication (see Section 7.4 for details) as follows:

2Q8ext:
Treatment only if according to individualized treatment schedule
If treated at this visit, subjects are to be followed up for AEs as specified in
Section 9.1, Table 5 Footnote h.
The other treatment groups do not receive study drug at this visit.


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9.3
Population characteristics
9.3.1
Demographic
The following demographic parameters will be recorded:

Sex

Year of birth

Race / ethnicity

Weight

Height
9.3.2
Medical/surgical and ophthalmic history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

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 

Smoking history
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. To this end, the subjects must provide informed consent to allow review 
of medical records from the time of first aflibercept treatment.


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9.4
Efficacy 
9.4.1
Ophthalmic examinations
Note:
In this section, all ophthalmic examinations are described, irrespective of whether 
they are used for efficacy or safety assessments.
All ophthalmic evaluations will be conducted according to the schedule detailed in 
Section 9.1, Table 5. Ophthalmic examinations will be conducted on both eyes. At any visit, 
ophthalmic examinations not stipulated by this protocol may take place outside of this 
protocol at the discretion of the investigator.
If applicable, all ophthalmic evaluations are to be performed before study drug injection.
9.4.1.1
Best corrected visual acuity
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. Visual Acuity (VA) examiners must be certified to ensure consistent measurement of 
BCVA.
9.4.1.2
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 archived electronically at the study sites as part of the source 
documentation. All protocol-mandated OCTs will be sent to the central reading center for 
evaluation and storage.
9.4.1.3
Indirect ophthalmoscopy
Indirect ophthalmoscopy will be performed according to local medical practice and applicable 
medical standards at the site.
9.4.1.4
Slit lamp biomicroscopy
The slit lamp examination will be performed according to local medical practice and 
applicable medical standards at the site.


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9.4.1.5
Intraocular pressure (IOP)
IOP is to be measured using applanation tonometry (Goldmann, Tonopen or other approved 
alternatives). 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).
9.4.1.6
Fundus photography (FP) and fluorescein angiography (FA)
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 for the individual treatment decisions. All FA and FP images will be archived 
electronically at the site as part of the source documentation. All protocol-mandated FA and 
FP images will be sent to the central reading center for evaluation and storage.
The 7-Field-FP for both eyes will be transmitted to the central reading center for ETDRS 
diabetic retinopathy severity scale (DRSS) grading and storage.
9.4.2
Efficacy variables
All efficacy variables derived from the ophthalmic examinations are specified in 
Section 10.3.2.2.
9.4.3
National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-
25)
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.
9.5
Pharmacokinetics / pharmacodynamics
not applicable


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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
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.


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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 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 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 AE

The date of onset

The maximum intensity 

Any study drug action and other action taken by the investigator to resolve the AE 

Any specific drug or non-drug treatment of the AE


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
The drug relationship of the AE to aflibercept, the IVT injection, or other protocol-
specified procedures 

The outcome of the AE (for definitions, see above).

If recovered/resolved or fatal – the date ended.
ATE analysis
Potential arterial thrombotic events (ATEs) will be evaluated by a masked adjudication 
committee according to criteria formerly applied and published by the Anti-Platelet Trialists’ 
Collaboration (APTC) (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
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.
9.6.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.
The child’s health should be followed up until three months after birth.
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE. 
Results from animal studies with high systemic exposure indicate that aflibercept can impair 
male and female fertility. Such effects are not expected after ocular administration with very 
low systemic exposure.


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9.6.3
Further safety
9.6.3.1
Laboratory evaluations
Laboratory evaluations 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 requested).
Blood will be drawn by direct venipuncture.
Safety laboratory parameters to be evaluated are summarized in Table 6.
The exact date and time (24-hour clock) 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 6:
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 
Total cholesterol
HDL cholesterol
Urinalysis 
Glucose 
Protein
Specific Gravity
Blood
Ketones 
Protein:Creatinine Ratio (UPCR)
Pregnancy test for women of 
childbearing potential 
(either urine or serum test as specified 
and Section 9.1 and 9.2)
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.


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9.6.3.2
Vital signs (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 will be specified in the 
statistical analysis plan.


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10.2
Analysis sets
Populations for analysis will be defined as follows:
The Full Analysis Set (FAS) will include all randomized subjects who received any study 
drug and have a baseline BCVA assessment and at least one post-baseline BCVA assessment. 
The FAS will be analyzed as randomized.
The Per-Protocol Set (PPS) will include all FAS subjects who have at least one BCVA 
assessment at Week 36 or later and do not have a major protocol deviation until Week 52.
The PPS will be analyzed as randomized.
The Safety Analysis Set will include all subjects who receive any study drug under this 
protocol. The safety analysis set will be analyzed as randomized.
10.3
Variables and planned statistical analyses
10.3.1
Variables
10.3.1.1
Efficacy variables
The efficacy variables and the ranking of their statistical analyses at the different time points 
(primary, secondary, exploratory) are specified in Table 7.
Table 7: Efficacy variables
Variable
Ranking
Week 52
Week 100
Change from baseline in ETDRS BCVA letter score for the study eye 
Primary
Secondary
Change from baseline in CRT in the study eye
Secondary
Secondary
Proportion of subjects who gained ≥10, ≥15 letters
Secondary
Secondary
Proportion of subjects who lost ≥30 letters
Secondary
Secondary
Total number of intravitreal injections required in the study eye
Exploratory
Exploratory
Total number of visits
Exploratory
Exploratory
Proportion of subjects who lost ≥0, ≥5, ≥10, ≥15 letters 
Exploratory
Exploratory
Proportion of subjects who gained ≥0, ≥5 letters
Exploratory
Exploratory
Total number of OCT / FA / FP procedures
Exploratory
Exploratory
Mean change from baseline in NEI VFQ-25 total score
Exploratory
Exploratory
BCVA: best corrected visual acuity; CNV: choroidal neovascularization; CRT: central retinal thickness;
ETDRS: Early Treatment Diabetic Retinopathy Study


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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
Vital signs
Ophthalmological safety variables (see Section 9.4.1)
10.3.2
Statistical and analytical plans 
10.3.2.1
Demography and baseline characteristics
Demographic variables and baseline characteristics will be summarized by treatment group 
and all treatment groups combined for all three analysis populations, depending on the type of 
data as described in Section 10.1. Medical history will be coded by MedDRA codes and prior 
and concomitant medications by ATC codes (WHO-DD). 
The number of injections will be tabulated in all treatment groups. The injection data will be 
tabulated in more detail for the extended-dosing group (as specified in the SAP).
10.3.2.2
Efficacy analyses
10.3.2.2.1
Primary efficacy variable
The primary efficacy variable is the (absolute) change from baseline in ETDRS BCVA letter 
score for the study eye to Week 52.
The primary analysis of the primary efficacy variable will be conducted on the full analysis 
set (FAS). The analyses will be repeated on the PPS to provide supportive evidence 
(sensitivity analysis).


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Statistical testing will be conducted to prove the non-inferiority of each of the two extended-
dosing regimens to the 2Q8 fixed-dosing regimen. The corresponding hypotheses are
1.
P2Q8ext:
Null hypothesis 
H01: μ2Q8ext ≤ μ2Q8fix-D
versus
Alternative hypothesis H1: μ2Q8ext > μ2Q8fix -D, 
2.
P2PRN:
Null hypothesis 
H01: μ2PRN ≤ μ2Q8fix –D
versus
Alternative hypothesis H1: μ2PRN > μ2Q8fix -D, 
where 
D
= non-inferiority margin chosen as 4 letters (see below for a justification)
μ2Q8ext = true mean change in BCVA letter score for the study eye from baseline to 
Week 52 in the 2Q8ext treatment regimen
μ2Q8fix = true mean change in BCVA letter score for the study eye from baseline to 
Week 52 in the 2Q8fix dosing treatment regimen
μ2PRN = true mean change in BCVA letter score for the study eye from baseline to 
Week 52 in the 2PRN treatment regimen
To control the overall type-I error rate for multiple comparisons, Hochberg procedure 
(Hochberg 1988) as implemented in PROC Multtest in SAS will be used to adjust for 
multiplicity. The two hypotheses stated above will be tested based on an analysis of 
covariance (ANCOVA) model with the baseline measure as a covariate and treatment group 
and “10-letter gain from start of aflibercept treatment to baseline (yes/no)” as a fixed factor:
The observation of subject i receiving treatment t can be written as follows:
it
i
j
t
itr
x
Y








with
t
denoting the treatment effect for treatment t (2Q8ext, 2Q8fix, 2PRN),
γj
denoting the effect of the stratification variable “10-letter gain from start 
of aflibercept treatment (yes/no)”
ix
denoting the baseline BCVA of subject i,
β
denoting the coefficient associated with baseline BCVA and
)
,0
(
~
2
t
it
N


denoting the residual error.
Justification of the non-inferiority margin
Previous studies with anti-VEGF therapies in other indications regarded a difference of 
5 letters as clinically relevant. For example, the CATT study in AMD, comparing 
ranibizumab and bevacizumab in a setting close to real life, used a non-inferiority margin of 
5 letters in the in BCVA (CATT Research Group 2011).


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Recently, controlled Phase-3 clinical trials studying AMD (HARBOR study [Ho et al. 2014]) 
or DME (RETAIN study [Campochiaro et al. 2014]) were based on a reduced margin of 
4 letters.
In line with this consideration, the present study uses a non-inferiority margin of 4 letters. It 
should be noted that the RETAIN trial used a slightly different primary endpoint (mean 
average change of BCVA) than this study. Using the same margin for this study which 
employs the mean change of BCVA at Week 52 as primary endpoint, is more conservative 
than the precedence set by RETAIN.
Missing data / drop outs 
To be consistent with the pivotal Phase-3 studies for this indication, missing BCVA values 
will be imputed using the (last observation carried forward [LOCF]) approach. 
The following other methods will be applied to account for missing data (assuming that the 
missing values are missing at random):
1. Multiple imputations 
2. Repeated measurements model
Moreover, an observed-case analysis will be provided.
10.3.2.2.2
Secondary efficacy variables
The secondary efficacy variables are:

Change from baseline in ETDRS BCVA letter score for the study eye to Week 100

Change from baseline in CRT in the study eye to Week 52

Change from baseline in CRT in the study eye to Week 100
The secondary variables will be analyzed descriptively only, i.e. no confirmatory hypothesis 
testing will be performed. However, the same model as outlined for the primary efficacy 
variable will be applied to calculate confidence intervals for the differences between the 
flexible regimen and the 2Q8fix group.
10.3.2.2.3
Exploratory efficacy variables
All exploratory efficacy variables will be analyzed descriptively. Confidence intervals for the 
differences between the flexible regimen and the 2Q8fix group will be provided where 
appropriate.
10.3.2.3
Safety analyses
All safety variables will be summarized descriptively on the SAF.


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10.3.2.3.1
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.
Potential arterial thrombotic events (ATEs) as described in Section 9.6.1.3 will be presented 
separately.
10.3.2.3.2
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
Sample size determination is based on the following assumptions:
(i)
The following standard deviations for the change in BCVA from randomization to 
Week 52
2Q8fix regimen:
9
2Q8ext regimen: 11
2PRN regimen:
11
(ii)
Non-inferiority margin of 4 letters
(iii)
Equal mean change in BCVA from study baseline to Week 52 in the treatment 
groups
(iv)
Family wise error rate (for the two comparisons) alpha of 2.5% (one-sided tests).
The sample size estimation resulted in 135 evaluable subjects per treatment group (calculated
with PASS 11, non-inferiority of two means) to reach a power of ~90% to obtain a significant 
result for the comparison of 2Q8ext vs. 2Q8fix (for the comparison of 2PRN vs. 2Q8fix). 
With an expected drop-out rate of approximately 17%, a total of approximately 490 subjects 
should be randomized (163 per treatment group) to ensure a sufficient power also in the PPS 
analysis.


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10.5
Planned interim analyses
No formal interim analysis will be conducted.
The primary endpoint data will be analyzed at Week 52 and will serve as basis for the clinical 
study report to be written at this point, while the final analysis of the Week-100 data will be 
conducted at that point. 
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Subject data necessary for analysis and reporting will be entered/transmitted into a 
validated database or data system (CIE/TOSCA; SAS). 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 
from Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies. RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel. Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study. Data queries 
resulting from the application of the software logic are resolved by the site personnel. The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual Private 
Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.


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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, as far as the reason for 
the premature discontinuation is identifiable. At minimum, the following data should be 
recorded in the CRF:
Demographic information 
(subject number; year of birth / age; sex; if applicable race / ethnicity)
Date of informed consent
Reason for premature discontinuation
Date of last visit.
These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the CRF in 
addition to the data specified above:
All information related to the SAE such as: 

Concomitant medication

Medical history

Other information needed for SAE complementary page


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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, laboratory, adjudication committees, reading center).
For data coding (e.g. AEs, medication, surgeries), internationally recognized and accepted 
dictionaries will be used.
11.4
Missing data 
Most important is to avoid missing data, e.g. by monitoring in time for completeness (see 
Section 11.2) and investigators’ training, especially to motivate subjects to be compliant with 
the study protocol.
Moreover, the risk of missing data may be decreased in this study, since all subjects must 
have been treated with the study drug aflibercept for one year to be enrolled in this study and 
all subjects will receive active aflibercept during the course of this study.


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11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Subject (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
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 any interim analysis
Results of parallel clinical studies
Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).
If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The investigator has the right to close his/her center at any time.
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.
Central reading center for images
An independent central reading center will evaluate ophthalmic images obtained by OCT and 
FP / FA, as described in Section 9.4.1.2 and Section 9.4.1.6, respectively.
External data evaluation bodies
The sponsor may decide to institute a Steering Committee to guide the trial in all aspects of 
safety and efficacy and must ensure that all relevant information is provided by investigators.
The composition of the committee, the functional roles, and responsibilities will be specified 
in its charter.
In addition, a Safety Management Team (SMT), led by the sponsor’s Global Safety Leader, 
will meet periodically to review safety data. Members of the SMT can include representatives 
from Global Pharmacovigilance, Pharmacoepidemiology, Clinical Development, Biostatistics, 
Data Management, Clinical Pharmacology, Preclinical Development and Regulatory Affairs 
as appropriate.


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Finally, an adjudication committee will perform an additional analysis of arterial thrombotic 
events (ATEs) as described in Section 10.3.2.3.1. The composition of the committee, the 
functional roles, and responsibilities are specified in its charter.
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
Financial disclosure
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements. All relevant documentation will be filed in the 
trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the sponsor. The responsible unit (e.g. IEC/IRB, head 
of the study center/medical institution) must supply to the sponsor, upon request, a list of the 
EC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 


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institution/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center. A sample 
subject information and informed consent form is provided as a document separate to this 
protocol.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject, prior to his/her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.
Each subject will be informed about the following aspects of premature withdrawal:
Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2.6 to be conducted after withdrawal of consent. 
The subject’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan. 
Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan. The subject has the right to object to the 
generation and processing of this post-withdrawal data.
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 subject’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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If the subject is unable to read the informed consent form due to vision impairment, a family 
member, other legal representative of the subject, study nurse, or study physician should read 
the document verbatim to the subject. A discussion and explanation, including answering all 
questions from the subject, should also occur prior to the subject or their legal representative 
signing the form. An impartial witness should be present during the entire informed consent 
discussion. The witness must be unaffiliated with the conduct of the study, and will also sign 
and date the document along with the subject or their legal representative.
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.
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. 


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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.
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.
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema.
Arch Ophthalmol 1985; 103: 1796-1806.
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 Nov;121(11):
2181-92.
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988; 75: 800-802.
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.


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15.
Protocol amendments
not applicable for the original protocol


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16.
Appendices
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 Nationa l 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_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
An open-label, randomized, active-controlled, parallel-group, Phase-
3b study of the efficacy, safety, and tolerability of three different 
treatment regimens of 2 mg aflibercept administered by intravitreal 
injections to subjects with diabetic macular edema (DME) 
NCT Number: 
NCT02818998 
Document Date: 
08 November 2018 
 


 
Statistical Analysis Plan 
 
Protocol No.: BAY86-5321 / 17613 
Page: 
1 of 
42
 
Reference Number: BHC-RD-OI-119 
Supplement Version: 7 
An open-label, randomized, active-controlled, parallel-group, Phase-3b study of 
the efficacy, safety, and tolerability of three different treatment regimens of 2 mg 
aflibercept administered by intravitreal injections to subjects with diabetic 
macular edema (DME) 
Efficacy and safety of three different aflibercept regimens in subjects with DME 
Bayer study drug 
BAY86-5321/aflibercept / VEGF Trap-Eye (Eylea)  
Study purpose: 
Posology comparison  
Clinical study phase: IIIb 
Date: 
08 Nov 2018 
Study No.: 
 
 BAY86-5321/17613 
Version: 
4.0 
Author: 
  
Syneos Health 
81929 Munich, Germany  
 
 
INC Project Code: 
04.6000.1005566A 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document, whether in 
part or in full, to parties not associated with the clinical investigation or its use for any other 
purpose without the prior written consent of the sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate Signature Document. 
 
 
PPD


 
Statistical Analysis Plan 
 
Protocol No.: BAY86-5321 / 17613 
Page: 
2 of 
42
 
Reference Number: BHC-RD-OI-119 
Supplement Version: 7 
 
Table of Contents 
1 
Introduction ........................................................................................................................ 6 
1.1 
Background ....................................................................................................................... 6 
1.2 
Rationale of the study ....................................................................................................... 6 
1.3 
Benefit-risk assessment .................................................................................................... 6 
1.4 
List of documents used ..................................................................................................... 7 
2 
Study Objectives ................................................................................................................. 7 
3 
Study Design ....................................................................................................................... 7 
3.1 
Design overview ............................................................................................................... 7 
3.2 
Administration schedule ................................................................................................... 7 
3.3 
Treatment cessation .......................................................................................................... 8 
3.4 
Treatment re-start ............................................................................................................. 8 
3.5 
Randomization .................................................................................................................. 9 
3.6 
Visit overview ................................................................................................................... 9 
3.7 
Assessments overview .................................................................................................... 10 
4 
General Statistical Considerations ................................................................................. 11 
4.1 
General Principles ........................................................................................................... 11 
4.2 
Handling of Dropouts ..................................................................................................... 11 
4.3 
Handling of Missing Data ............................................................................................... 12 
4.3.1 
Adverse events ............................................................................................................ 12 
4.3.2 
Prior and concomitant medication ............................................................................... 12 
4.3.3 
Efficacy analysis ......................................................................................................... 13 
4.4 
Interim Analyses and Data Monitoring .......................................................................... 15 
4.5 
Data Rules ....................................................................................................................... 15 
4.6 
Validity Review .............................................................................................................. 18 
5 
Analysis Sets and Subgroups .......................................................................................... 19 
5.1 
Analysis Sets ................................................................................................................... 19 
5.2 
Definition of subgroups .................................................................................................. 19 
5.2.1 
Subgroups for efficacy and safety analyses ................................................................ 19 
5.2.2 
Subgroups for efficacy analyses only .......................................................................... 20 
5.2.3 
Subgroups for safety analyses only ............................................................................. 20 
6 
Statistical Methodology ................................................................................................... 21 
6.1 
Population characteristics ............................................................................................... 21 
6.1.1 
Screening failures ........................................................................................................ 21 
6.1.2 
Disposition .................................................................................................................. 21 
6.1.3 
Demography ................................................................................................................ 22 
6.1.4 
Baseline characteristics ............................................................................................... 23 
6.1.5 
Medical/ophthalmic history ......................................................................................... 23 
6.1.6 
Medical history of diabetes and DME ......................................................................... 24 
6.1.7 
Prior and concomitant medications ............................................................................. 24 


 
Statistical Analysis Plan 
 
Protocol No.: BAY86-5321 / 17613 
Page: 
3 of 
42
 
Reference Number: BHC-RD-OI-119 
Supplement Version: 7 
6.1.8 
Exposure ...................................................................................................................... 25 
6.2 Efficacy .............................................................................................................................. 26 
6.2.1 
Primary efficacy variable ............................................................................................ 26 
6.2.2 
Secondary efficacy variables ....................................................................................... 28 
6.2.3 
Exploratory efficacy variables..................................................................................... 28 
6.2.4 
Further exploratory efficacy analyses ......................................................................... 29 
6.2.5 
Subgroup analyses ....................................................................................................... 31 
6.3 Pharmacokinetics/pharmacodynamics .......................................................................... 31 
6.4 
Safety .............................................................................................................................. 32 
6.4.1 
Adverse events (AEs) .................................................................................................. 32 
6.4.2 
Laboratory evaluations and pregnancy tests ............................................................... 34 
6.4.3 
Further Safety .............................................................................................................. 35 
7 
Document history and changes in the planned statistical analysis .............................. 37 
8 
References ......................................................................................................................... 38 
9 
Appendix ........................................................................................................................... 39 
9.1 Calculation of the NEI VFQ-25 scores ........................................................................... 39 
9.2 Process to derive cut-off data for the Week 52 analysis from the global study database
 ............................................................................................................................................ 41 
 
 
 
 


 
Statistical Analysis Plan 
 
Protocol No.: BAY86-5321 / 17613 
Page: 
4 of 
42
 
Reference Number: BHC-RD-OI-119 
Supplement Version: 7 
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 8 weeks 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
APTC 
Antiplatelet Trialists’ Collaboration 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
ATE 
Arterial Thromboembolic Event 
AUC 
Area under the Curve 
BCVA 
Best-Corrected Visual Acuity 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CNV 
Choroidal neovascularization 
CRF 
Case Report Form 
CRT 
Central Retinal Thickness 
DME 
Diabetic Macular Edema 
DMP 
Data-Management-Plan 
DR 
Diabetic Retinopathy 
DRSS 
Diabetic Retinopathy Severity Scale 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
FA 
Fluorescein Angiography 
FAS 
Full Analysis Set 
FP 
Fundus Photography 
HbA1c 
Glycohemoglobin A1c 
HDL 
High Density Lipoprotein 
HL 
Normal Range Higher Limit 
IOP 
Intraocular Pressure 
IVT 
Intravitreal(ly) 
IxRS 
Interactive Voice / Web (either/both) Response System 
LDM 
Lead Data Manager 
LOCF 
Last Observation Carried Forward 
LL 
Normal Range Lower Limit 
LS 
Least Squares 
MAH 
Marketing Authorization Holder 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputations 
MMRM 
Mixed-Effect Model Repeated Measure 
MSSO 
Maintenance and Support Services Orgainisation 
NEI VFQ-25 
National Eye Institute Visual Functioning Questionnaire 25 
NPDR 
Non-Proliferative Diabetic Retinopathy 
OAD 
Operational Acquisition Data 
OCT 
Optical Coherence Tomography 


 
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PDR 
Proliferative Diabetic Retinopathy 
PPS 
Per-Protocol Set 
PRN 
As needed (pro re nata) 
QoL 
Quality of Life 
SMQ 
Standardised MedDRA Querie 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SF 
Screening Failure 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States  
V 
Visit 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
VRM 
Validity Review Meeting 
WHO-DD 
World Health Organization Drug Dictionary 
Wk 
Week 
 
 
 
 
 
 
 
 


 
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1 
Introduction 
This analysis plan describes the planned analyses for the study reports that will be prepared  
 after all subjects have finalized their first year of treatment (Week 52) and  
 after the end of the study (Week 100).  
The analyses will be mainly described for the Week 52 report. Details for cut-off of the data for the 
Week 52 analysis are given in the Appendix 9.2. 
All analyses will then be repeated for the Week 100 CSR using Week 100 as the respective analysis 
time point, if not specified otherwise. 
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.  
Vascular endothelial growth factor (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 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. 
The approved European Union (EU) labeling for Eylea (aflibercept) states: 
The recommended dose for Eylea is 2 mg aflibercept, equivalent to 50 microliters. 
Eylea treatment is initiated with one injection per month for five consecutive doses, followed by one injection 
every two months. There is no requirement for monitoring between injections. 
After the first 12 months of treatment with Eylea, the treatment interval may be extended based on visual and 
anatomic outcomes. The schedule for monitoring should be determined by the treating physician. 
If visual and anatomic outcomes indicate that the subject is not benefiting from continued treatment, Eylea 
should be discontinued. 
More background information is available in the study protocol section 3.1. 
1.2 
Rationale of the study 
The approved dosing schedule for the first year of DME treatment has been thoroughly studied 
during the clinical development program and is well supported by the available data as originally 
submitted. 
For additional support of the approved dosing schedule for the second year of treatment and beyond, 
the marketing authorization holder (MAH) seeks to collect further data including information on 
treatment cessation and restart. To this end, the present study is initiated. It is designed to meet 
requests made by European Medicines Agency (EMA) as part of a post-approval commitment. 
1.3 
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. 


 
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Taken together, participation in this study is not expected to bear an undue risk for the enrolled 
subjects. 
 
1.4 
List of documents used 
 Clinical Study Protocol: No. BAY86-5321/17613, version 1.0, dated 07 Dec 2015 
 Case Report Form (CRF) : 17613 VIOLET aCRF final version 1.0, dated 05FEB2016 
 Study Protocol Deviation Document (PDD): PDD 17613  Final Version 1.0, dated 26Apr16  
 Database Cutoff Specification v1.0, 15Sept2017  
 
2 
Study Objectives 
Primary objective 
To evaluate the efficacy of long-term treatment with 2 mg aflibercept via different intravitreal (IVT) 
treatment regimens to subjects with DME pre-treated with 2 mg aflibercept every 8 weeks after 
5 initial monthly injections for approximately 1 year or more (according to the EU label for the first 
year of treatment) 
Secondary objectives 
To assess the safety and tolerability of different treatment regimens of aflibercept in this population 
 
3 
Study Design 
 
3.1 
Design overview 
This is a randomized, 3-arm, active-controlled, parallel-group, open-label, multicenter, Phase-3b 
study to be conducted in subjects pre-treated with aflibercept for 1 year or more.  
Aflibercept 2 mg administered at a fixed schedule every 8 weeks (2Q8fix) is regarded as the 
reference arm.  
Two alternative regimens will be compared to the reference arm: a regimen with a gradually 
extended dosing interval according to the current EU label (2Q8ext) and a pro re nata dosing scheme 
(2PRN) with monthly monitoring (see Figure 1). 
 
3.2 
Administration schedule 
2Q8fix: Fixed injection intervals: 8 weeks throughout the entire treatment period 
After the baseline visit, the subjects return every 8 weeks to the investigational site. Starting at 
the baseline visit, they receive an injection at each visit. The last injection will be at Week 96. 
The final safety and efficacy assessments are done at Week 100 (final visit).  


 
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2Q8ext: Flexible injection intervals ≥ 8 weeks (no upper limit) 
At the baseline visit and at each subsequent visit, the investigator will determine the duration 
until the subject’s next injection, based on visual and anatomic outcomes at the current visit.  
Injection intervals can be extended if visual and anatomic measures are stable. When/if edema 
recurs, the treatment interval should be reverted to the last treatment interval when the disease 
was inactive. The increments and decrements for the injection intervals are at the 
investigator’s discretion; typically, increments of 2 weeks are recommended.  
2PRN: 2 mg aflibercept pro re nata (as needed) 
After randomization, the subjects return every 4 weeks to the investigational site. At each 
visit, the investigator will determine, based on pre-specified re-treatment criteria, whether an 
injection is to be given or not. Injection decision will be based on the investigator’s judgment.  
Further details regarding the scheduled administrations are given in the study protocol Section 5, 
Table 1. 
 
3.3 
Treatment cessation 
2Q8fix: Fixed injection intervals - 8 weeks throughout the entire treatment period 
Usually, treatment should not be ceased in this reference arm. However, temporary treatment 
cessation can be considered upon investigator’s discretion.   
2Q8ext: Flexible injection intervals ≥ 8 weeks (no upper limit) 
Cessation of treatment can be considered if the interval between two injections reaches or 
exceeds 16 weeks and if this duration can be maintained for at least two consecutive intervals 
without need for shortening of the interval. If treatment is halted, the subject should return for 
monitoring visits at least every 16 weeks. 
2PRN: 2 mg aflibercept pro re nata (as needed) 
If there is no recurrence of active disease, treatment is terminated until such time, if ever, that 
the disease recurs. The monthly monitoring is continued throughout. 
Further details regarding the cessation of the treatments are given in the study protocol Section 5, 
Table 1. 
 
3.4 
Treatment re-start 
2Q8fix: Fixed injection intervals - 8 weeks throughout the entire treatment period 
Treatment should be restarted once the condition leading to cessation of treatment is resolved. 
In case of recurrence of DME it is proposed to begin with the same regimen as a de novo 
treatment, i.e. five monthly injections followed by a 2Q8 regimen.  
2Q8ext: Flexible injection intervals ≥ 8 weeks (no upper limit) 


 
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Treatment should be restarted if a deterioration of visual and anatomic outcome parameters 
occurs. If treatment has to be restarted due to recurrence of DME, it is proposed to begin with 
the same regimen as a de novo treatment, i.e. five monthly injections followed by a 2Q8 
regimen. 
 
2PRN: 2 mg aflibercept pro re nata (as needed) 
Treatment will be resumed with single injections each time the re-treatment criteria are met. 
Further details regarding the re-start of the treatments are given in the study protocol Section 5, 
Table 1. 
 
3.5 
Randomization  
Randomization will be stratified by 10-letter gain from start of aflibercept treatment (“yes”/”no” as 
obtained from available medical documentation). For each group, the first injection of study 
medication will be given at the baseline visit. 
Owing to the nature of the different dosing regimens, the three arms will not have the same visit and 
treatment schedule. Therefore, masking of the treatments is not feasible.  
 
Figure 1: Overall study design 
Screening 
Treatment 
3-arm, randomized, open-label  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2Q8fix: Fixed dosing regimen, injection intervals 8 weeks 
No monitoring visits between treatment visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2Q8ext: Extended dosing regimen, injection intervals ≥ 8 weeks 
No monitoring visits between treatment visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2PRN: Monthly monitoring visits  
Injections as frequently as needed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Enrollment 
Randomization (1:1:1) 
Baseline 
 
 
 
 
 
Primary  
completion 
Week 52 
 
 
 
 
 
 
End of 
study 
Week 100 
 
3.6 
Visit overview 
In general, the time window for all visits is  3 days relative to baseline. An overview of visits and 
assessments is given  in Table 5 of the study protocol. In Section 9.2 of the study protocol 
scheduling and conduct of the following visits are described in detail: 
 Screening  


 
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 Baseline  
 Visits after baseline and before Week 52 
 Week 52  
 Visits after Week 52 and before Week 100 
 Week 100 (final visit or early termination) 
If all data needed for enrollment are available, the screening visit and the baseline visit may take 
place on the same day. In such a case, procedures scheduled for both visits will be conducted only 
once. 
The scheduling of visits „after baseline and before Week 52“ and „after Week 52 and before 
Week 100“ differs among treatment groups: 
 2Q8fix: Fixed schedule for each subject in this treatment group: Visits take place in strict 
accordance with the Q8 schedule, i.e. at Weeks 8, 16, 24 etc. 
 2Q8ext: Individualized visit schedule: Visit interval ≥ 8 weeks 
 2PRN: Fixed schedule for each subject in this treatment group: Visits every 4 weeks 
The treatment schedule in the 2Q8fix and 2Q8ext groups may deviate from the schedule if cessation 
and re-start become necessary.  If a subject returns for a monitoring visit during temporary treatment 
cessation, the procedures described for a visit in the 2PRN treatment group should be performed. If 
treatment is re-started, the paradigms described in Section 3.4 should be followed.  
For each treatment group, the assessment of the primary endpoint will be performed at the 
mandatory visit at Week 52 (± 3 days) after baseline.  
The Week 100 visit (± 3 days) after baseline is a mandatory visit, too. After the final visit or after 
early termination, all subjects return to standard-of-care treatment outside of this 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). 
 
3.7 
Assessments overview 
Overall safety of the subjects will be assessed by monitoring 
 ocular and non-ocular adverse events (AEs)1 and 
 prior and concomitant medications throughout the study 
 vital signs assessed at all study visits and 
 laboratory (haematology, chemistry, urinalysis) at screening, Week 52 and Week 100. 
 
                                                     
1 All potential arterial thromboembolic events (ATEs) will be adjudicated according to the Antiplatelet Trialists' 
Collaboration (APTC) endpoints of non-fatal myocardial infarction, non-fatal stroke, and fatal vascular events. 


 
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The following ophthalmic examinations will be assessed at all study visits: 
 Best-Corrected Visual Acuity (BCVA) 
 Optical Coherence Tomography (OCT) 
 intraocular pressure (IOP)  
 indirect ophthalmoscopy  
 slit lamp biomicroscopy 
 Fluorescein angiography (FA) 
 Fundus photography (FP) 
 
4 
General Statistical Considerations 
The Statistical Analysis Plan (SAP) of this open-label study was finalized before the first subject 
received any study drug, to avoid additional reporting bias. 
The statistical evaluation will be performed by using the software package Statistical Analysis 
System (SAS) release 9.3 or higher (SAS Institute Inc., Cary, NC, USA).  
 
4.1 
General Principles 
All variables will be analyzed by descriptive statistical methods. The number of data available and 
missing data, mean, standard deviation (SD), minimum, quartiles, median, and maximum will be 
calculated for metric data. Mean and standard deviation will be reported to one decimal place greater 
than the data were collected. Quartiles, median, minimum and maximum values will be reported 
with the same precision as they were collected. 
Frequency tables will be generated for categorical data. These include the counts and percentages of 
each category including the category ‘missing’ as a separate category, if applicable. Percentages will 
be calculated using a denominator of all subjects in the specified population and treatment arm, and 
the percentage values will be reported to one decimal place. 
If not stated otherwise, ANCOVA tables will include the least squares (LS) means and the LS mean 
changes relative to Baseline for all treatment arms, and the difference in the LS means between 
2Q8fix and 2Q8ext or between 2Q8fix and 2PRN group as point estimate and as 95% confidence-
interval (CI). If comparisons between 2Q8ext and 2PRN are performed, they are considered as 
exploratory. 
 
4.2 
Handling of Dropouts 
Criteria for withdrawal of subjects from the study are specified in Section 6.3.1 of the protocol . 
Subjects who withdraw from the study will not be replaced. Premature permanent discontinuation 
from study medication implies premature discontinuation from study participation. 


 
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Depending on the time point of withdrawal, a withdrawn subject is referred to as either “Screening 
failure” or “Drop-out” as specified below: 
Screening failure (SF) 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “drop-out” (see below) is considered a “screening 
failure.” Re-screening is only allowed under special conditions, specified in Section 6.3.1 of the 
study protocol,. 
Drop-out 
A subject who discontinues study participation prematurely for any reason is defined as a “drop-out” 
if the subject has already been randomized. 
The number of SF will be summarized and the reasons will be listed. The number of subjects who 
withdrew, as well as the reasons for drop-out of study treatment will be summarized.  
4.3 
Handling of Missing Data 
Data from subjects who drop out of the study will be included in all summaries where possible. 
All missing or incomplete data will be presented in the subject data listings as they are recorded on 
the Case Report Form (CRF).  
When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data: 
 
4.3.1 
Adverse events 
In general, data will not be imputed for safety analysis. If dates of adverse experiences (clinical or 
laboratory untoward events) are missing so that the determination of whether or not the event is 
treatment emergent is questionable, the event will be presumed to be treatment emergent. If it is 
clearly stated that the adverse event occurred prior to first dose of study drug under this protocol or 
more than 30 days after the last dose of study drug, it will be treated as not treatment emergent. 
 
4.3.2 
Prior and concomitant medication 
Completely missing start and stop dates of medication are considered missing and no replacement is 
generated. A medication with a complete missing start date will be assumed to start before first 
application of the study drug. A complete missing stop date will be handled as “ongoing”.  
In addition, to flag the medications correctly, the worst-case scenario will be used:  
- 
for incomplete start dates:  if only day is missing - first of month, if day and month missing - 
first day (1st January) of year.  
- 
for incomplete stop dates:  if only day is missing - last of month, if day and month missing - 
last day (31st December) of year or “ongoing”, when last day of year is after last study-day of 
the subject. 


 
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4.3.3 
Efficacy analysis 
The primary method for replacing missing values for all efficacy analyses will be “last observation 
carried forward” (LOCF), see Section 4.3.3.1.  
The following other methods will be applied to account for missing data for the primary endpoint 
(assuming that the missing values are missing at random): 
 Multiple imputations (MI), see Section 4.3.3.2. 
 Repeated measurements model, see Section 4.3.3.3. 
Moreover, an observed case analysis (OC), see Section 4.3.3.4, will be provided. 
 
4.3.3.1 
Last observation carried forward 
Missing ETDRS BCVA letter scores will be replaced by LOCF using the last available scheduled 
post-baseline values. 
After the imputation the respective dataset will be filled and the data will be analyzed as if the 
missing values have been observed (as the last available value). For example, the primary efficacy 
variable will be analyzed as described in Section 6.2.1.  
 
4.3.3.2 
Multiple Imputation 
Multiple imputation methods involve three steps: 
I. 
Imputation  
i.e., the generation of multiple copies of the original dataset by replacing missing values 
using an appropriate stochastic model.  
a. First missing data will be imputed in order to achieve a monotone missing pattern 
using the Markov Chain Monte Carlo (MCMC) method, using SAS-procedure proc 
MI similarly as below. 
 
PROC MI DATA=<indata> SEED=24680 OUT=out1 NIMPUTE=20;  
MCMC impute=monotone; 
VAR base t1 t2 tx … ; 
RUN; 
 
b. Subsequently missing data will be imputed by a regression model. 
 
PROC MI DATA=out1 SEED=13579 OUT=full nimpute=1; 
BY _Imputation_; 
CLASS treatment; 
MONOTONE method=reg; 
VAR treatment base t1 t2 tx … ; 


 
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RUN; 
 
II. 
Analysis 
i.e., the analysis of the multiple imputed datasets as complete sets. The analysis step is 
performed for each of the multiply imputed datasets. Since all imputed datasets are complete 
there are no issues with missing data. On each imputed dataset the efficacy analysis will be 
performed as described. 
 
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. 
Please note, that this MI analysis assumes that the missing data is missing at random. 
After the imputation the respective efficacy dataset will be filled and analyzed as described in 
Section 6.2.1, with the exception of the use of Hochberg procedure to account for multiplicity, since 
MI is only supportive. For descriptive purposes the un-adjusted p-values will also be displayed. 
 
4.3.3.3 
Repeated measurements model 
The repeated measurements model (RMM) does not employ formal imputation. RMM has been 
extensively used in the analysis of longitudinal data especially when missing data is a concern and 
missing at random (MAR) is assumed (6) 
For RMM, if SAS mixed model is used, the sample SAS codes will be like the following:  
PROC MIXED DATA=<indata>;  
CLASS subject treatment(ref=2Q8) time-window stratum;  
MODEL chg = base treatment stratum time-window treatment*time-window 
/ddfm=kr;  
repeated time-window / sub = subject type = un;  
lsmeans treatment / cl diff at time-window = Week52; 
RUN; 
Where the treatment difference is obtained with the lsmeans statement for the treatment differences 
at time Week52. Actual classification2 of “10-letter gain from start of aflibercept treatment to 
baseline (yes/no)” will be used as stratum. Generally, the time-windows from Table 2 will be taken. 
To get robust results, the values from the mandatory visit “Week 52” will be used instead of the 
respective time-windows and the values from time-window “Week 49-51” will be dropped.  
Because the RMM is only supportive it is not necessary to account for multiplicity. 
 
4.3.3.4 
Observed cases 
                                                     
2 The wording “actual classification” refers to classification according to the BCVA-values given in the eCRF. It is used 
in opposite to the supportive analysis “stratified via IxRS”. 


 
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The primary analysis will be repeated on observed cases, without any imputation.  
 
4.4 
Interim Analyses and Data Monitoring 
No formal interim analysis in the sense of adaptive or group-sequential design will be conducted.  
The data will be analyzed at Week 52 and will serve as basis for the clinical study report to be 
written at this point, while the final analysis of the Week-100 data will be conducted at that 
point.The data collected up to Week 52 of this study (after at least two years of treatment with 
aflibercept) will be reported in a stand-alone clinical study report to make this important information 
available to the community as soon as possible. The data collected between Week 52 and Week 100 
will be reported in a separate clinical study report. 
 
4.5 
Data Rules 
Generally, pre-treatment values recorded at Visit 2 (Week 0/Day 1) will be used as baseline values. 
If no baseline values are available, then the last available screening values are used.  
Change from baseline is calculated as the value at the post-baseline time point minus the baseline 
value, i.e. value at time point – value at baseline. 
 
Handling of repeated measurements at the same visit/time-window 
If measurements were repeated at the same scheduled visit or in the same time window (see Table 2) 
the value actually flagged as scheduled will be the 
 Last non-missing repeated measurement, if measurement is before start of treatment for this 
protocol, and 
 First non-missing repeated measurement, if measurement is after start of treatment for this 
protocol. 
Generally, only scheduled measurements will be used for statistical summaries and analyses. 
Unscheduled measurements will not be used for analyses; however, they will be listed.  
 
Handling of time-windows 
Visit schedules may deviate by ±3 days. Scheduled visits should not be altered due to the deviation 
of the previous visit.  
 
Posology 
Treatment posology is detailed in Table 1.  


 
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Table 1: Treatment Posology 
 
2Q8fix 
2Q8ext 
2PRN 
 
Visit 
Treatment 
Visit 
Treatment 
Visit 
Treatment 
Screening mandatory Visit 1 no treatment mandatory Visit 1  
no treatment 
mandatory Visit 1  
no treatment 
Baseline 
mandatory Visit 2  
mandatory  
mandatory Visit 2  
mandatory  
mandatory Visit 2  
mandatory  
Week 4 
no visit 
no visit 
mandatory Visit 3 
throughout all 
visits between 
Week 4 and 
Week 96, 
treatment is 
optional according 
to the 
re-treatment 
criteria given in 
Protocol Section 5 
Table 1,  
Week 8 
mandatory visit with treatment 
between  
Week 8 and Week 52,  
visits (incl. treatment) can be 
scheduled at any time point  
(provided injection intervals 
are ≥ 8 weeks) 
mandatory Visit 4 
Week 12 
no visit 
mandatory Visit 5 
Week 16 
mandatory visit with treatment 
mandatory Visit 6 
Week 20 
no visit 
mandatory Visit 7 
Week 24 
mandatory visit with treatment 
mandatory Visit 8 
Week 28 
no visit 
mandatory Visit 9 
Week 32 
mandatory visit with treatment 
mandatory Visit 10 
Week 36 
no visit 
mandatory Visit 11 
Week 40 
mandatory visit with treatment 
mandatory Visit 12 
Week 44 
no visit 
mandatory Visit 13 
Week 48 
mandatory visit with treatment 
mandatory Visit 14 
Week 52 
mandatory  
no treatment 
mandatory  
optional 
mandatory Visit 15  
Week 56 
mandatory visit with treatment 
between  
Week 52 and Week 100,  
visits (incl. treatment) can be 
scheduled at any time point  
(provided injection intervals 
are ≥ 8 weeks) 
mandatory Visit 16 
Week 60 
no visit 
mandatory Visit 17 
Week 64 
mandatory visit with treatment 
mandatory Visit 18 
Week 68 
no visit 
mandatory Visit 19 
Week 72 
mandatory visit with treatment 
mandatory Visit 20 
Week 76 
no visit 
mandatory Visit 21 
Week 80 
mandatory visit with treatment 
mandatory Visit 22 
Week 84 
no visit 
mandatory Visit 23 
Week 88 
mandatory visit with treatment 
mandatory Visit 24 
Week 92 
no visit 
mandatory Visit 25 
Week 96 
mandatory visit with treatment 
mandatory Visit 26 
Week 100 
mandatory  
no treatment 
mandatory  
optional 
mandatory Visit 27 
no treatment 
The reasons for treatment cessation – and if applicable re-start – will be documented. The treatment 
schedule in the 2Q8fix and 2Q8ext groups may deviate from the schedule proposed if cessation and 
re-start become necessary. However, the visits at Week 52 and 100 are mandatory for all subjects 
regardless of any temporary cessation of treatment. 
 
Defining time-windows for the summaries 
Study days will be calculated relative to baseline. Study days prior to first injection date are 
calculated as (actual date – first injection date), after first injection date as (actual date – first 
injection date)+1. 


 
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For the 2Q8fix- and the 2PRN-groups, the mandatory visits (see Table 1) will be used for the 
summaries of the efficacy (Section 6.2) and the safety variables (Section 0), with the exception of 
Adverse Events.  
The following time-windows (mostly 8-weeks- intervals) will be used for summarizing the 
respective results in the 2Q8ext-group:  
Table 2: Time-windows for the 2Qext-group. 
Screening: 
before first Study drug 
administration 
Baseline: 
study day 1 
Week 1-8:  
study days 2 to 59  
Week 9-16:  
study days 60 to 116  
Week 17-24:  
study days 117 to 172  
Week 25-32:  
study days 173 to 228  
Week 33-40:  
study days 229 to 284 
Week 41-48:  
study days 285 to 340 
Week 49-51:  
study days 341 to 361  
Week 52: 
study days 362 to 368 
Week 53-60:  
study days 369 to 424  
Week 61-68:  
study days 425 to 480  
Week 69-76:  
study days 481 to 536  
Week 77-84:  
study days 537 to 592  
Week 85-92:  
study days 593 to 648  
Week 93-99:  
study days 649 to 697  
Week 100: 
study days 698 to 704 
> Week 100: 
study days > 704  
In case of multiple scheduled visits in a specific time-window, the following procedures will be 
performed to get only one value per subject in a window: 
 Efficacy variables: the measurement of the last scheduled visit before or at the upper bound 
of the time interval will be displayed in each time interval. 
 Safety variables:  
o Intra-ocular pressure (IOP): The highest values will be used. 
o Indirect ophthalmoscopy: “Abnormal” values and their descriptions will be used, if 
available, and the highest stage/numbers of vitreous cells. 
o Slit lamp biomicroscopy: “Abnormal” values and their descriptions will be used, if 
available, and the highest stage/numbers of anterior chamber flare or cells. 
For repeated measurement analysis (Section 4.3.3.3), time-windows are also applied to the 2Q8fix 
and 2PRN treatment groups. 
 


 
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Early termination (ET) 
If a subject is terminated early, data from the early termination visit will be mapped to the next 
scheduled visit where collection of this data was mandatory (LOCF-approach), if he/she was 
randomized to the 2Q8fix- or the 2PRN-group. For the 2Q8ext-group the time-windows from Table 
2 apply. Only variables that were mandatory at the visit will be shown in descriptive tables. All 
variables mandatory at the ET will be used for LOCF analyses. 
Pooling centers 
All centers will be combined for the purposes of the analyses. 
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. 
Coding 
The following panels will be coded verbatim by the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA) available before database lock: 
 Medical history  
 Adverse events  
 Surgeries after start of study 
Prior and concomitant medications will be coded by the latest version of World Health Organization 
Drug classification Dictionary (WHO-DD) available before database lock. 
Presentation 
Listings will be sorted by treatment group, unique subject identifier, and date time 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 down numbers ending in 0-4 and rounding up numbers ending 5-9 
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 Standard Operating 
Procedures (SOP) and will be led by Lead Data Manager (LDM) of Syneos Health. Details are 
available in the Data Management Plan (DMP). 


 
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The results of the VRM will be documented in the Validity Review Report and may comprise 
decisions and details relevant for statistical evaluation. Any changes to the statistical analysis 
prompted by the results of the VRM will be documented in an amendment or, if applicable, in a 
supplement to this SAP. 
 
5 
Analysis Sets and Subgroups 
5.1 
Analysis Sets 
Populations for analysis are defined as follows: 
Full Analysis Set (FAS) 
The FAS will include all randomized subjects who received any study drug and have a baseline 
BCVA assessment and at least one post-baseline BCVA assessment. The FAS will be analyzed as 
randomized. 
Per-Protocol Set (PPS) 
The PPS will include all FAS subjects who have at least one BCVA assessment at Week 36 or later 
and do not have a major protocol deviation until Week 52. The PPS will be analyzed as randomized. 
Major protocol deviations are described in the Study protocol deviation document, version 1.0, dated 
26 April 2016. 
Safety Analysis Set (SAF) 
The SAF will include all subjects who receive any study drug under this protocol. The safety 
analysis set will be analyzed as randomized. 
5.2 
Definition of subgroups 
5.2.1 
Subgroups for efficacy and safety analyses 
 Sex 
 Baseline age: <55years; ≥55 to <65years; ≥65 to <75years; ≥75years 
 Race: White vs. Other3 
 Ethnicity: Hispanic or Latino (no/yes) 
 Geographic region:  North America vs. Europe 
 Baseline HbA1c: above/below 8% (> 8% and ≤ 8%) 
 Prior participation in AQUA study: yes  / no 
 10-letter gain from start of aflibercept treatment: yes / no (according Interactive Voice / Web 
(either/both) Response System (IxRS)) 
 10-letter gain from start of aflibercept treatment: yes / no (actual values) 
                                                     
3 Race = „Not reported“ is not included here 


 
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5.2.2 
Subgroups for efficacy analyses only 
 Baseline visual acuity (VA) category: 
o < 40 letters 
o ≥ 40 letters to < 55 letters 
o ≥ 55 letters to < 65 letters 
o ≥ 65 letter 
5.2.3 
Subgroups for safety analyses only 
These subgroups will be identified using standardised MedDRA queries (SMQs) of the Maintenance 
and Support Services Orgainisation (MSSO): 
 Medical history of hypertension (HT): yes / no 
o MSSO-SMQ (20000147) ‘Hypertension (SMQ)’  
 Medical history of cerebrovascular disease e.g. cerebrovascular accident (CVA)/stroke: yes / 
no 
o MSSO-SMQ 20000060 ‘Cerebrovascular disorders’  
including sub-SMQs 20000061, 20000063 and 20000064, i.e ‘Central nervous 
system haemorrhages (SMQ)’, ‘Cerebrovascular conditions (SMQ)’ and 
‘Haemorrhagic cerebrovascular conditions (SMQ)’ 
 Medical history of ischemic heart disease e.g. myocardial infarction: yes / no  
o MSSO-SMQ (20000043 and 20000047) ‘Ischaemic heart disease (SMQ)’ 
or ‘Myocardial Infarction (SMQ)’ 
 Medical history of renal impairment (normal/mild/moderate/severe) will be classified with 
Creatinine Clearance (CLCR) and dialysis. 
o Normal: CLCR >80 ml/min 
o Mild: CLCR >50-80 ml/min 
o Moderate: CLCR >30-50 ml/min 
o Severe: CLCR <=30 ml/min or requiring dialysis 
‘Requiring dialysis’: Preferred term from product-specific Bayer MedDRA query 
(SMQ_1274) ‘Medical history of renal impairment requiring dialysis’. 
CLCR will be calculated using baseline values (creatinine, age, weight, sex) for the 
Cockcroft-Gault equation: 
Males: CLCR = (140-age)*body weight / (72*creatinine) 
Females: CLCR = (140-age)*body weight*0.85 / (72*creatinine). 
 Medical history of hepatic impairment: yes / no 
o MSSO-SMQ 20000005 ‘Hepatic disorders’ including all sub-SMQs except sub-SMQ 
20000018 ‘Pregnancy-related hepatic disorders’ 
 
 


 
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6 
Statistical Methodology 
If not specified otherwise, all tables will be summarized overall and by treatment arms. 
 
6.1 
Population characteristics 
If not specified otherwise, these variables will be summarized for all 3 analysis populations (overall 
and stratified by 10-letter gain from start of aflibercept treatment), depending on the type of data as 
described in Section 4.1.  
 
6.1.1 
Screening failures 
All available data from Screening Failures (SF) will be listed. At minimum, the following data from 
SF should be displayed:   
 demographic information 
 date of informed consent 
 reason for premature discontinuation 
 date of last visit 
For SF with an SAE, the following data will be listed in addition to the data specified above: 
 All information related to the SAE such as: 
o Concomitant medication 
o Medical history 
 Other information needed for SAE complementary page 
 
6.1.2 
Disposition 
Disposition will be summarized for all screened subjects.  
An overview table for all randomized subjects will be given, displaying the number and percentages 
of subjects in each treatment arm and overall:  
 Completed 
 Not completed  
o withdrawn after randomization / including to Week 52  
o withdrawn after Week 52 
o withdrawn during study 
Primary reason: 
 Adverse Event 


 
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 Lost to follow-up 
 Withdrawal by subject 
 Physician decision 
 Pregnancy 
 Study terminated by sponsor 
 Death 
 Protocol violation 
 Other 
Another overview table for all screened subjects will be given, displaying the number and 
percentages of subjects in each treatment arm and overall:  
 Enrolled4  
 Screening failures 
 Safety Analysis Set (SAF) 
 Randomized 
 Full Analysis Set (FAS) 
 Randomized, but not FAS 
Reason for exclusion from FAS  
 Per-Protocol Set (PPS) 
 FAS, but not PPS 
Reason for exclusion from PPS 
The screened but not randomized subjects (screening failures, SF) will be summarized together with 
the reason(s) for non-treatment. Possible reasons are: 
 Adverse event 
 Death 
 Withdrawal by subject 
 Lost to follow-up 
 Not met inclusion criteria / met exclusion criteria 
 Other 
 
6.1.3 
Demography 
                                                     
4 defined as subjects with approved informed consent. 


 
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The following demographic variables are recorded at screening. In case of repeated measures the 
last available value before baseline will be used for summary tables. 
 Age (years) 
 Sex 
 Childbearing potential 
 Ethnicity 
 Race 
 Height 
 Weight 
 Body Mass Index (BMI) 
 Study eye - left or right 
 Smoking status (yes/no) 
 
6.1.4 
Baseline characteristics 
The following baseline characteristics are observed at screening and/or baseline. In case of repeated 
measures the last available value before the first application of the study drug will be used for 
summary tables. 
 BCVA letter scores (study eye) 
 Central retinal thickness (CRT) (study eye) 
 Diabetic retinopathy severity scale (DRSS) (study eye)  
 
Additionally, the categorized BCVA (5-letter intervals) for the study eye will be presented for 
baseline values for each of the analysis populations (FAS, PPS, SAF). 
 
6.1.5 
Medical/ophthalmic history 
Medical history findings (i.e. previous diagnoses, diseases, or surgeries) meeting all criteria listed 
below will be collected for SAF and FAS: 
 Start date before signing of the informed consent 
 Considered relevant for the subject’s study eligibility 
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 finding 
 System Organ Classes (SOCs) 


 
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 Preferred Terms (PT) 
The SOCs will be sorted by descending frequency of subjects, within each SOC the PTs will be 
sorted by descending frequency of subjects affected. 
The tables will be repeated for ocular medical history (i.e. ocular medical history ticked as Yes) by 
eye (study eye, fellow eye and both eyes). Ocular medical history findings in both eyes will be 
assigned to the study eye as well as to the fellow eye. 
 
6.1.6 
Medical history of diabetes and DME 
Medical history of diabetes and DME will be summarized for SAF and FAS, and listed for all 
subjects, with screening failures on a separate page. 
The following variables will be summarized by number of subjects and percentages. 
 Diabetes mellitus type 1 
 Diabetes mellitus type 2 
 DR – study eye 
 DR – fellow eye 
 DME – study eye 
 DME – fellow eye 
 Baseline HbA1c classified (> 8%, ≤8%) 
The following variables will be summarized as described in Section 4.1. 
 Duration of diabetes until baseline 
 Duration of DR until baseline 
 Duration of DME until baseline 
 Baseline HbA1c  
 
6.1.7 
Prior and concomitant medications 
Summaries of all prior and concomitant medications recorded will be presented in tabular form for 
SAF using 3-digit Anatomical Therapeutic Chemical (ATC) classification codes and preferred drug 
name via the WHO-DD (latest version available before database lock). 
The medications will be classified as 
 Concomitant: Medications that are ongoing at, began after the start of study drug under this 
protocol, or medications that were started after end of study drug. 
 New Concomitant: Medications that began after the start of study drug under this protocol, 
and those that were started after end of study drug. 


 
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 Prior: Medications that started and stopped before the start of study drug under this protocol. 
For each of these categories, a table consisting of medication class and preferred name will be 
created, sorted by descending frequencies and stratified by  
 ocular medication (yes/no) and  
 eye (study eye vs. fellow eye)  
 
6.1.8 
Exposure 
The following parameters will be summarized for all 3 populations (SAF, FAS, PPS): 
 The number of study drug injections into the study eye under this protocol. 
 The total amount of aflibercept injected into the study eye under this protocol. 
 The number of injections into the study eye under this protocol per subject-year: defined as 
52*(Number of iv injections until Week 52) / (Number of weeks participating).  
 Study drug exposure into the study eye under this protocol (weeks): calculated as (date of 
last injection - date of first injection at/after randomization +28)/7.  
 Study drug exposure into the study eye in total (weeks): defined as (date of last injection - 
date of first injection of aflibercept +28)/7 and will be tabulated the same way. The date of 
first injection of aflibercept shall be recorded as concomitant medication. 
For subjects with a treatment cessation, the reasons for cessation as well as the reason for a restart (if 
applicable) will be summarized in a listing. 
 
 
 


 
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6.2 
Efficacy 
The efficacy variables and the ranking of their statistical analyses at the different time points 
(primary, secondary, exploratory) are specified in Table 3. 
Table 3: Efficacy variables 
Variable 
Ranking 
 
Week 52 
Week 100 
Change from baseline in ETDRS BCVA letter score for the study eye  
Primary 
Secondary 
Change from baseline in CRT in the study eye 
Secondary 
Secondary 
Proportion of subjects who gained ≥ 10, ≥ 15 letters 
Secondary 
Secondary 
Proportion of subjects who lost ≥ 30 letters 
Secondary 
Secondary 
Total number of intravitreal injections required in the study eye 
Exploratory 
Exploratory 
Total number of visits 
Exploratory 
Exploratory 
Proportion of subjects who lost ≥ 0, ≥ 5, ≥ 10, ≥ 15 letters  
Exploratory 
Exploratory 
Proportion of subjects who gained ≥ 0, ≥ 5 letters 
Exploratory 
Exploratory 
Total number of OCT / FA / FP procedures 
Exploratory 
Exploratory 
Mean change from baseline in NEI VFQ-25 total score 
Exploratory 
Exploratory 
BCVA: best corrected visual acuity; CNV: choroidal neovascularization; CRT: central retinal thickness;  
ETDRS: Early Treatment Diabetic Retinopathy Study 
Efficacy analyses will use LOCF-imputed datasets as the datasets of first choice.  
 
6.2.1 
Primary efficacy variable 
The primary efficacy variable is the change from baseline in ETDRS BCVA letter score for the 
study eye at Week 52. 
It will be assessed at the end of the first year of treatment under this protocol. As the protocol is 
designed, subjects completing one year in the study will have also completed the end of their second 
year of treatment given that subjects entering this study will have received a first year of treatment 
outside of this study.  
The primary analysis of the primary efficacy variable will be conducted on the full analysis set 
(FAS). The analyses will be repeated on the PPS to provide supportive evidence (sensitivity 
analysis). Additionally, MI, RMM and OC will be performed on the primary efficacy variable for 
the FAS. 
Statistical testing will be conducted to prove the non-inferiority of each of the two extended-dosing 
regimens (2Q8ext, 2PRN) to the 2Q8 fixed-dosing regimen. The corresponding hypotheses are 


 
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1. P2Q8ext: 
Null hypothesis  
H01: μ2Q8ext ≤ μ2Q8fix– D 
versus 
Alternative hypothesis  H11: μ2Q8ext > μ2Q8fix – D,  
2. P2PRN: 
Null hypothesis  
H02: μ2PRN ≤ μ2Q8fix – D 
versus 
Alternative hypothesis  H12: μ2PRN > μ2Q8fix – D,  
where  
D 
= non-inferiority margin chosen as 4 letters (see below for a justification) 
μ2Q8ext = true mean change in BCVA letter score for the study eye from baseline to Week 52 in 
the 2Q8ext treatment regimen 
μ2Q8fix = true mean change in BCVA letter score for the study eye from baseline to Week 52 in 
the 2Q8fix dosing treatment regimen 
μ2PRN = true mean change in BCVA letter score for the study eye from baseline to Week 52 in 
the 2PRN treatment regimen 
The two hypotheses stated above will be tested based on an analysis of covariance (ANCOVA) 
model with the baseline measure as a covariate and treatment group and stratum = “10-letter gain 
from start of aflibercept treatment to baseline (yes/no)” as a fixed factor: 
The observation (BCVA-change from baseline to Week 52) Yit of subject i receiving treatment t can 
be written as follows: 
Yit = µt + γj + xiit 
with 
t 
denoting the treatment effect for treatment t (2Q8ext, 2Q8fix, 2PRN), 
γj 
denoting the effect of the stratification variable “10-letter gain from start of 
aflibercept treatment (yes/no)” (actual classification) 
ix  
denoting the baseline BCVA of subject i,  
β 
denoting the coefficient associated with baseline BCVA and 
)
,0
(
~
2
t
it
N


 denoting the residual error.  
In the data analysis, ANCOVA can be performed using SAS PROC MIXED procedure with the 
following key SAS statements: 
PROC MIXED data=<input dataset>; 
 
CLASS treatment stratum;  
 
MODEL chg = base treatment stratum / DDFM=KenwardRoger; 
      REPEATED / group = treatment 
 
LSMEANS treatment / PDIFF=CONTROL(‘2Q8fix’) CL ALPHA=0.05; 
RUN; 
To control the overall type-I error rate for multiple comparisons, Hochberg procedure (4) as 
implemented in PROC MULTTEST in SAS will be used to adjust for multiplicity. 
data a; 
   input Test$ Raw_P @@; 
   datalines; 
test01  <p2Q8ext>    
test02  <p2PRN>; 


 
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run; 
PROC MULTTEST inpvalues=a hoc;run; 
 
with p2Q8ex and p2PRN as the p-values of the respective treatment-effects. Non-inferiority of the 
respective treatment-group versus 2Q8fix is indicated if the lower bound of the 95% CI is above the 
non-inferiority margin of -4 letters. 
Because of possible unequal variances, the Kenward-Roger approximation will be used to the 
degrees of freedom for the reference distribution. 
 
6.2.2 
Secondary efficacy variables 
The secondary variables will be analyzed descriptively on the FAS using LOCF, if applicable. They 
will be summarized overall and by treatment group, including 95% CI. 
Though no confirmatory hypothesis testing will be performed, the same model as outlined for the 
primary efficacy variable will be applied for the following secondary efficacy variables to calculate 
95% CI using normal approximation for the differences between the 2Q8ext or 2PRN, respectively 
and the 2Q8fix group. 
 Change from baseline in ETDRS BCVA letter score for the study eye to Week 100 
 Change from baseline in CRT in the study eye to Week 52 
 Change from baseline in CRT in the study eye to Week 100 
 
The proportions derived from ETDRS BCVA letter scores are summarized per treatment group and 
overall, including Cochran-Mantel-Haenszel 95% CI for the differences between the flexible 
regimen and the 2Q8fix group, adjusting for the stratification variable “10-letter gain from start of 
aflibercept treatment (yes/no)” (actual stratification).  
 Proportion of subjects who gained ≥ 10 at Week 52 
 Proportion of subjects who gained ≥ 10 at Week 100 
 Proportion of subjects who gained ≥ 15 at Week 52 
 Proportion of subjects who gained ≥ 15 at Week 100 
 Proportion of subjects who lost ≥ 30 letters at Week 52 
 Proportion of subjects who lost ≥ 30 letters at Week 100 
 
6.2.3 
Exploratory efficacy variables  
The exploratory variables will be analyzed descriptively on the FAS using LOCF, if applicable. 
They will be summarized overall and by treatment group, including descriptive 95% CI. No analysis 
for the differences between the 2Q8ext or 2PRN, respectively and the 2Q8fix will be performed. 


 
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6.2.3.1 
Total number of IVT injections required in the study eye 
The total number of IVT injections is defined as the number of administered injections per subject 
at/after randomization until Week 52 and Week 100, respectively, without using LOCF.  
In this context, compliance will be summarized similarly (no LOCF, no treatment-differences). 
Compliance (%) is calculated as the number of intravitreal injections in the study eye at the 
scheduled injection visits (+/- 3 days) at or after randomization divided by number of scheduled 
injection visits (multiplied by 100). Scheduled injection visits in the 2Q8ext group are those visits 
for which the subject was scheduled by the investigator.  
 
6.2.3.2 
Total number of visits 
The total number of visits as the number of scheduled and un-scheduled visits including Week 52 
and Week 100, without using LOCF.  
 
6.2.3.3 
Categorized changes of ETDRS BCVA letter score for the study eye 
The following proportions will be summarized descriptively using LOCF. 
 Proportion of subjects who lost ≥ 0, ≥ 5, ≥ 10, ≥ 15 letters  
 Proportion of subjects who gained ≥ 0, ≥ 5 letters 
 
6.2.3.4 
Total number of OCT / FA / FP procedures 
OCT, FA and FP procedures are mandatory at screening, Week 52 and Week 100. Additionally, 
OCT is mandatory in the 2PRN group only throughout the study. Otherwise OCT, FA and FP 
procedures will be done if deemed necessary by the investigator or required by local medical 
practice. 
 The number of these procedures will be summarized on the FAS without using LOCF, 
overall and by treatment group, including descriptive 95% CI. 
 
6.2.3.5 
Mean change from baseline in NEI VFQ-25 total score 
NEI VFQ-25 total scores at Week 52 and Week 100 will be calculated without LOCF. For details 
see Appendix 9.1. The summary will be done on FAS and PPS without any CI. 
In addition, the near and distance activities scale will be presented in the same way as the total score. 
 
6.2.4 
Further exploratory efficacy analyses 
6.2.4.1 
Diabetic retinopathy severity scale as assessed by FP 


 
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The 7-Field-FP for both eyes will be transmitted to the central reading center for ETDRS diabetic 
retinopathy severity scale (DRSS) grading according to the following scale for both eyes. 
- 
10 – DR absent  
- 
14 – DR questionable  
- 
15 – DR questionable  
- 
20 – Micro-aneurysms only  
- 
35 – Mild Non-Proliferative Diabetic Retinopathy (NPDR)  
- 
43 – Moderate NPDR  
- 
47 – Moderately severe NPDR  
- 
53 – Severe NPDR  
- 
61 – Mild Proliferative Diabetic Retinopathy (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   
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”.  
The following summaries will be performed by treatment arm for the study eye: 
 Shift tables will be created, displaying the number and percentages of subjects in each class 
at baseline and at Week 52. 
 A “≥ 2 step improver” 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. 
The proportion of subjects progressing to ≥ 61 in ETDRS DRSS will be displayed together with 
exact binomial 95% CI, restricted to subjects < 61 in ETDRS DRSS at baseline (LOCF, FAS).  
 
6.2.4.2 
Change in BCVA from start of aflibercept treatment 
Descriptive statistics for the change in BCVA from start of aflibercept treatment will be provided by 
visit and treatment group. 
 
6.2.4.3 
Average change (AUC) from baseline to Week 52 (Week 100) in BCVA 
For each subject the average change from baseline to Week 52 (Week 100)  will be calculated using 
the following formula. 
Let 𝑥𝑖1, … , 𝑥𝑖𝑛𝑖 be the changes from Baseline in BCVA for subject i measured at the (ordered) 
planned time points (weeks) 𝑡𝑖1, … , 𝑡𝑖𝑛𝑖, and let 𝑥𝑖0 = 0 and 𝑡𝑖0 = 0. Then the average change is 
calculated as 


 
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𝑎𝑣𝑔𝑖= (∑(𝑡𝑖𝑗−𝑡𝑖𝑗−1) 𝑥𝑖𝑗−𝑥𝑖𝑗−1
2
𝑛𝑖−1
𝑗=0
)
𝑡𝑖𝑛𝑖
⁄
 
This corresponds to the area under the individual ‘change from Baseline in BCVA’ curve, if the 
points are connected with straight lines. 
Only observed values (no LOCF) are used for this calculation. 
The individual averages will be summarized by descriptive statistics. Furtheremore, the averages 
will be analyzed by an ANCOVA model using treatment and stratification factor (actual 
classification) as fixed factor and baseline BCVA as covariate. 
 
6.2.5 
Subgroup analyses 
Descriptive statistics will be displayed for subgroups defined in Section 5.2 for the primary and all 
secondary efficacy endpoints in Year 1, Year 2 and split by treatment and visit, based on the FAS, 
and on PPS for the primary endpoint.  
For the primary endpoint ANCOVAs will be conducted on the FAS following key SAS statements: 
PROC MIXED data=<input dataset>; 
 
CLASS treatment stratum;  
 
By subgroup; 
 
MODEL chg = base treatment stratum / DDFM=KenwardRoger; 
      REPEATED / group = treatment 
 
LSMEANS treatment / PDIFF=CONTROL(‘2Q8fix’) CL ALPHA=0.05; 
RUN; 
 
6.3 
Pharmacokinetics/pharmacodynamics 
Not applicable. 
 
 
 


 
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6.4 
Safety 
The safety analysis will be conducted on the SAF (as defined in Section 5). The following safety 
variables will be assessed: 
 Adverse events 
 Clinical laboratory parameters 
 Further safety analyses (vital signs, Surgeries, indirect ophthalmoscopy, slit lamp 
biomicroscopy) 
 
6.4.1 
Adverse events (AEs) 
The definitions of AEs and serious AEs (SAEs) are provided in Section 9.6.1.1 of the study 
protocol,. The classifications according to seriousness, intensity, causality, action taken, other 
specific treatment and outcome are provided in Section 9.6.1.2 of the study protocol,. 
Treatment-emergent adverse events (TEAEs) are AEs that start after the first application of 
aflibercept under this protocol.  
Potential arterial thrombotic events (ATEs) will be evaluated by a masked adjudication committee 
according to criteria formerly applied and published by the Anti-Platelet Trialists’Collaboration  
(APTC). Further details are described in the adjudication committee charter.  
A summary table by treatment and overall will be produced for the following categories for all 
TEAEs: 
 Subjects with at least one TEAE 
 Subjects with at least one ocular TEAE  
 Subjects with at least one ocular TEAE in the study eye 
 Subjects with at least one ocular TEAE in the fellow eye 
 Subjects with at least one non-ocular TEAE  
 Subjects with at least one serious TEAE 
 Maximum intensity for TEAEs Maximum intensity for study drug-related AEs  
 Subjects with at least one (treatment emergent) ATPC event 
 Subjects with at least one TEAE causally related to study drug 
 Subjects with at least one TEAE causally related to injection procedure      
 Subjects with at least one TEAE causally related to other procedures required by the protocol 
 Deaths      
 Study-drug related SAEs 
 SAEs related to procedures required by the protocol 


 
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 Discontinuation of study-drug due to AEs  
 Discontinuation of study-drug due to SAEs 
The following tables will present the respective TEAEs by MedDRA preferred term (PT) within 
primary system organ class (SOC) and summarized by treatment arms. Subjects may be counted 
under multiple system organ classes and preferred terms, but for each system organ class and 
preferred term, subjects are only counted once.  
 TEAEs 
 Ocular TEAEs  
 Ocular TEAEs in the study eye 
 Ocular TEAEs in the fellow eye 
 Serious TEAEs 
 TEAEs by maximum severity 
 Serious ocular TEAEs in the study eye 
 Serious non-ocular TEAEs in the study eye 
 TEAEs by maximum severity 
 Treatment-emergent APTC events 
 TEAEs in the study eye causally related to study drug  
 TEAEs in the study eye causally related to injection procedure     
 TEAEs in the study eye causally related to other procedures required by the protocol  
 Serious TEAEs in the study eye causally related to study drug  
 Serious TEAEs by maximum severity 
 TEAEs causally related to study drug by maximum severity 
 Serious TEAEs causally related to study drug by maximum severity 
 TEAEs by worst outcome 
 Serious TEAEs by worst outcome 
 TEAEs resulting in discontinuation of aflibercept     
 Non-Serious TEAEs 
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 PT will be sorted by 
descending frequency of subjects affected. 
 
Subgroup analyses 


 
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Subgroup analyses for TEAEs will be performed for the subgroups described in Section 5.2 Error! 
Reference source not found., for each of the following types of TEAE: 
Number of subjects with  
 ocular TEAEs study eye 
 non-ocular TEAEs 
 Serious ocular TEAEs study eye 
 Serious non-ocular TEAEs 
Tables will be displayed by treatment, MedDRA SOC and PT. 
 
6.4.2 
Laboratory evaluations and pregnancy tests 
Hematology, chemistry and urinalysis will be conducted by local laboratories at screening, Week 52 
and Week 100. Safety laboratory parameters to be evaluated are summarized in Table 4. 
Table 4: 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  
Total cholesterol 
HDL cholesterol 
Urinalysis  
Glucose  
Protein 
Specific Gravity 
Blood 
Ketones  
Protein:Creatinine Ratio (UPCR) 
 
Pregnancy test for women of 
childbearing potential  
(either urine or serum test) 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular hemoglobin (MCH) 
Leukocyte 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 listings. 
Treatment-emergent laboratory abnormalities, defined as laboratory abnormalities after 
randomization under this study protocol, will be summarized by laboratory category and 
treatment group. 


 
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Summary statistics for the laboratory values will only be provided, when they are converted in 
comparable SI values. Values below “Normal Range Lower Limit” (LL) will be set to 0.5*LL for 
the calculation of summary statistics. Values above “Normal Range Higher Limit” (HL) will be set 
to HL. 
Pregnancy tests will be performed for women of childbearing potential; a serum pregnancy test will 
be performed at screening and urine tests will be performed at baseline, Week 52 and Week 100. 
Beyond that schedule, pregnancy tests are to be done in women of childbearing potential as 
frequently as requested. 
Results of the pregnancy tests for women of childbearing potential will be listed only. 
 
6.4.3 
Further Safety  
6.4.3.1 
Vital signs 
Vital signs (body temperature, systolic and diastolic blood pressure, heart rate) will be analyzed 
descriptively including changes from baseline. 
 
6.4.3.2 
Surgeries after start of study 
Separate tables for treatment-emergent surgeries will be presented, overall and split by study eye 
and fellow eye. 
 
6.4.3.3 
Intra-ocular pressure (IOP) 
At visits with study drug administration, pre-injection and 30 to 60-min post-injection IOP will be 
assessed for the study eye. All IOP measurements will be classified as follows: 
 25 mmHg  
 ≥ 30 mmHg 
 ≥ 35 mmHg  
 ≥ 40 mmHg  
Any increase from pre-injection/baseline of ≥ 10 mmHg will be flagged.  
The IOP analysis will include 
 original measurements 
 changes from pre-injection  
 changes from baseline 
 classified measurements 
 flagged measurements  
This analysis will be performed descriptively at all visits depending on the type of data as described 
in Section 4.1. 
Additionally, the changes of the measurements between pre- and post-injection will be analyzed 
descriptively depending on the type of data as described in Section 4.1.  


 
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6.4.3.4 
Slit lamp biomicroscopy 
The slit lamp examination will be performed according to local medical practice and applicable 
medical standards at the site. 
Frequency tables for normal/abnormal slit lamp biomicroscopy findings as well as for the grading of  
‘anterior chamber flare’, ‘anterior chamber cells’ and ‘anterior vitreous cells’ will be provided.  
 
6.4.3.5 
Indirect ophthalmoscopy 
At visits with study drug administration, pre-injection indirect ophthalmoscopy will be assessed for 
the study eye. Post-injection assessments will be carried out 30-60 minutes following the IVT 
injection. 
Frequency tables for normal/abnormal findings in the pre-injection assessment will be provided. The 
cup-to-disc ratio will presented by summary statistics. All other data will be listed. 
 
 
 


 
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7 
Document history and changes in the planned statistical analysis 
Statistical Analysis Plan, version 1.0, 31st May 2016 was not approved.  
The main changes to Statistical Analysis Plan, version 2.0, 1st June 2016 are as follows: 
a) Section 4.3.3.3: (SAS-Code of) Repeated Mesurement Model has been clarified 
b) Section 4.5: Table 2: Time-windows for the 2Qext-group. Eight-week (instead of ten-week) 
windows have been implemented. 
c) Section 5.2.2: Subgroups for “10-letter gain from start of aflibercept treatment” added 
d) Section 6.17: Prior and concomitant medications: Analysis for FAS has been dropped. 
e) Section 6.1.8: Exposure: Clarifications 
f) Section 6.2.4: Other ophthalmic examinations has been shifted:  
 “Diabetic retinopathy severity scale as assessed by FP” now in “Further exploratory 
efficacy analyses” 
 “Indirect ophthalmoscopy”, “Slit lamp biomicroscopy” and “Intra-ocular pressure 
(IOP)” in “Other Safety Analysis”.   
g) The parameters from “Indirect ophthalmoscopy” and “Slit lamp biomicroscopy to be 
summarized in tables have been clarified. 
h) Section 6.2.5: Subgroup-Analysis: ANCOVAs implemented. 
i) Section 9.2: Process to derive cut-off data for the Week 52 analysis from the global study 
database has been updated. Now a reference document from Bayer was available. 
 
The main changes to Statistical Analysis Plan, version 3.0, 26 Jan 2018 are as follows: 
j) Section 4.3.2: The worst-case scenario for incomplete dates has been explained in detail. 
k) Section 4.3.3.3: The RMM has been clarified, derivations are needed to get converging 
results. 
l) Section 5.2.3: The derivations of the subgroups have been described. 
m) Section 6.4.2: The analysis of laboratory values below LL has been described. 
n) Appendix 9.2:  The process to derive cut-off data for the Week 52 analysis has been 
clarified. 
 
 
 


 
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8 
References 
1) Clinical Study Protocol No. BAY86-5321/17613, version 1.0, 07 December 2015 
2) Study Protocol Deviation Document (PDD) version 1.0, 26 April 2016  
3) COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP), EMA: 
GUIDELINE ON MISSING DATA IN CONFIRMATORY CLINICAL TRIALS, 2009. 
4) Hochberg Y: A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 1988; 75: 800-802. 
5) Mangione CM: NEI VFQ-25 Scoring Algorithm – August 2000, Version 2000: The 
National Eye Institute 25-Item, Visual Function Questionnaire (VFQ-25) Drug 
Information Journal dij.sagepub.com, August 2000.  
6) Mallinckrodt CH, Lane PW, Schnell D, Peng Y, Mancuso JP: Recommendations for the 
Primary Analysis of Continuous Endpoints in Longitudinal Clinical Trials. Therapeutic 
Innovation & Regulatory Science, July 2008, vol. 42 no. 4 303-319. 
 


 
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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“ (5). 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. 
Additionally, the NEI 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 NEI 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 5. 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 6 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. 
Table 5: 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 
100 
75 
50 


 
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4 
5 
6 
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 NEI VFQ-25, simply average the vision-targeted 
subscale scores, excluding the general health rating question. By averaging the sub-scale scores 
rather than the individual items we have given equal weight to each sub-scale, whereas averaging 
the items would give more weight to scales with more items. 
Table 6: Averaging of Items to Generate NEI VFQ-25 Sub-Scales 
Scale 
Number of items 
Items to be averaged   
(after recoding per Table 5) 
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 
 


 
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Scoring example 
Items 5, 6, and 7 are used to generate the near activities sub-scale score  (Table 6). 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  to “0” points 
before taking an average of all three items.  
 To score all items in the same direction,  
 In step 2, items within each sub-scale are averaged together to create the 12 sub-scale scores. 
Table 6 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. 
 Table 5 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. 
 
9.2 
Process to derive cut-off data for the Week 52 analysis from the global study database 
General rules from the guidelines “Database Cutoff Specification v1.0, 15Sept2017” will be 
followed: 
 All variables which are set by the timing concept, e. g., relative days,  as well as the 
treatment emergent flag will be re-calculated after the cutoff is done.  
 If there is a domain, which depends on another, the parent domain is always cut first, the 
dependent domain will then be cut accordingly5.  
                                                     
5 For example, after removal of an AE after cut-off, the respective concomitant medication for this AE shall also be 
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 If an observation has a partial date, the observation will be cut only if the partial date is 
without any doubt after the cutoff date. 
There are some exceptions with regard to the guideline mentioned above.: 
Section 5.1: Cutoff Visit: The visit which indicates any data collected by this visit will be used for 
analysis 
As described in Section 6, the interim data release will be based on a planned observation 
time for each subject, i.e., a visit-based cut-off will be used. In addition to the definitions 
given above,  study drug injections given at the cut-off visit as well as data of any 
assessments scheduled post-injection at this visit will not be included. 
Section 7.1: Date based cutoff: Specification for different Operational Acquisition Data (OAD ) 
Domains  
Usually authorities request a special listing of all subjects who died after cutoff date. For 
this purpose the information related to “death” (primary cause of death, death date, etc.) 
should not be removed even if after the cutoff date.   
This rule is applicable in oncological studies and will not be used here. Therefore, in this 
study fatal AEs are not treated differently to other serious AEs.  
In addition, some algorithms for specific domains have been created: 
a. In case of an injection at Week 52, this exposure and the IOP after injection will not be 
included in the cut data. Last injection will be the respective previous injection of this 
subject. 
b. In case of missing Week 52 date, study-day 365+7=372 will be used as the cutoff date in 
general 
c. AE-dataset (to account for the AEs starting in the time-window 30 days after last injection) 
o if Week 52 is available, the maximum of last injection-date + 30 days and Week 52-
date will be used as the cutoff date 
o if Week 52 is not available, the maximum of last injection-date + 30 days and  study-
day 365+7=372 will be used as the cutoff date.