Clinical trial NCT02800642
Conditions: Central Retinal Vein Occlusion
Keywords: Bayer Aflibercept Eylea Intravitreal
Sponsor: Bayer
Start date: 2016-06-10; Completion date: 2019-07-31
Enrollment: 162 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Central retinal vein occlusion (CRVO) occurs when the main blood vessel that transports blood away from the retina (the very back portion of the eye) becomes blocked, causing the leakage of fluid into the retina and thereby causing a swelling of the macula (the portion of the retina responsible for fine vision). This swelling is called macular edema. When the macula swells with fluid, central vision becomes blurry. The study drug aflibercept has been shown to reduce the amount of fluid and blood leaked into the retina. It can help to stabilize, and in many cases, improve the vision loss related to CRVO. Aflibercept has been approved for the treatment of macular edema secondary to CRVO in the United States (US), European Union (EU), Japan, and other countries.

The study was considered research because, although the study drug was already on the market for macular edema secondary to CRVO, there were no studies available that addressed the questions of what were useful intervals for treating and assessing patients, how did they differ among patients, and how were criteria applied for retreatment. The purpose of this study was to evaluate the effectiveness, treatment interval, and safety of the treatment regimen (pattern for administering treatment) in subjects with macular edema secondary to CRVO. In addition, this study explored new imaging methods for assessing the affected eye.

Detailed description:

Arms: arm 1: Participants with macular edema secondary to CRVO were treated with the study drug intravitreal aflibercept
Interventions: intervention 1: Aflibercept (Eylea, BAY86-5321)
Intervention descriptions: intervention 1: The recommended dose for intravitreal aflibercept was 2 mg equivalent to 50 μL. Study treatment was administered at baseline and at monthly intervals until stabilization of disease. When stability was achieved, the treatment interval could be extended based on visual and anatomic outcomes as judged by the treating investigator.

Protocol documents:
Prot_000.pdf: 
Document Type: 
Study Protocol 
Official Title: 
A multi-center, single-arm, interventional Phase 4 study to 
evaluate a Treat and Extend regimen of intravitreal aflibercept 
for treatment of macular edema secondary to central retinal 
vein occlusion 
NCT Number: 
NCT02800642 
Document Date: 
20 Apr 2016 


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A multi-center, single-arm, interventional Phase 4 study to evaluate a Treat and Extend 
regimen of intravitreal aflibercept for treatment of macular edema secondary to central 
retinal vein occlusion
This protocol version is an integration of the following documents/sections:

Original protocol, Version 1.0, dated 02 Feb 2016

Amendment 01 (global amendment described in Section 15.1) forming integrated 
protocol Version 2.0, dated 20 Apr 2016
Amendments not included in the consecutive numbering of amendments are local 
amendments not forming part of this integrated global protocol.


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1.
Title page
A multi-center, single-arm, interventional Phase 4 study to evaluate a Treat and Extend 
regimen of intravitreal aflibercept for treatment of macular edema secondary to 
central retinal vein occlusion
CENTERA
Test drug:
BAY86-5321/IVT Aflibercept
Study purpose:
Interventional
Clinical study phase:
4
Date:
20 Apr 2016
Registration:
EudraCT: 2014-003193-17
Version no.:
2.0
Sponsor’s study no.:
BAY86-5321/17514
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
Bayer Pharma AG
Wuppertal, Germany
+
Email:
Please note that Bayer HealthCare AG merges with Bayer AG, an affiliated company within 
the Bayer Group, effective as of 1st July 2016. Thereby, Bayer HealthCare AG ceases to 
exist and Bayer AG becomes its legal successor and automatically takes over all of the 
Bayer HealthCare AG’s rights, obligations and liabilities by law. As a result of the above 
mentioned merger, Bayer AG assumes the role of the sponsor for these trials. Detailed 
information on the merger will be provided in due time.
The study will be conducted in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH-GCP) Guidelines, and any applicable regulatory 
requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation. Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical
investigation, or its use for any other purpose, without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (∀, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD
PPD


PPD
PPD


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


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2.
Synopsis – amended
Title
A multi-center, single-arm, interventional Phase 4 study to evaluate a Treat 
and Extend regimen of intravitreal aflibercept for treatment of macular edema 
secondary to central retinal vein occlusion
Acronym
CENTERA
Secondary ID
17514
Clinical study phase
4
Study objectives
Primary:

To determine the efficacy and durability (treatment interval) of 
2 mg intravitreal (IVT) aflibercept in a Treat and Extend (T&E) 
regimen over a treatment period of 76 weeks using protocol-defined 
visual and anatomic criteria in subjects with macular edema 
secondary to central retinal vein occlusion (CRVO)
Secondary:

To assess the efficacy of IVT aflibercept as measured by visual 
acuity and anatomic outcomes using spectral domain optical 
coherence tomography (SD-OCT), and perfusion status using 
fluorescein angiography (FA)/fundus photography (FP)

To assess T&E applied posology of IVT aflibercept (number of 
injections, length of injection interval)
Safety:

To assess the safety and tolerability of IVT aflibercept in this 
subject population
Test drug(s)
Name of active ingredient
Aflibercept
Dose(s)
2 mg (0.05 mL)
Route of administration
IVT
Duration of treatment
76 weeks
Reference drug
None
Background treatment
None
Indication
Macular edema secondary to CRVO
Diagnosis and main criteria 
for inclusion/exclusion
Treatment-naïve subjects ≥18 years of age with center-involved macular 
edema secondary to CRVO for no longer than 3 months before the first 
administration of study drug. Subjects must have documented best-corrected 
visual acuity (BCVA) of Early Treatment Diabetic Retinopathy Study 
(ETDRS) letter score of 73 to 24 letters (Snellen equivalent of 20/40 to 
20/320) in the study eye.


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Study design
International, multi-center, prospective, interventional, single-arm cohort, 
Phase 4 study in adult subjects with a diagnosis of macular edema secondary 
to CRVO who have previously not been treated with any systemic or IVT 
anti-vascular endothelial growth factor (VEGF) treatments. Intravitreal 
aflibercept will be administered to the study eye at specific intervals, with the 
possibility to extend the treatment interval based on visual and anatomic 
outcomes as judged by the treating investigator.
Methodology
The study comprises a screening phase (Visit 1: −21 days to baseline), a 
baseline (Visit 2, Day 1) visit, and a treatment phase (76 weeks).
Study treatment with IVT aflibercept will be administered at baseline and at 
monthly intervals until stabilization of disease. When stability is achieved, 
the treatment interval can be extended using a T&E approach based on visual 
and anatomic outcomes as judged by the treating investigator. The initiation 
phase of the treatment will extend from the first injection until the subject 
meets criteria for retreatment interval extension or until Week 20.
Monitoring will be performed at each injection visit and at Weeks 24, 52, and 
76. Starting at Week 8, the stability criteria will be evaluated and the 
frequency of injections may be adjusted1 (increased or decreased by 2-week 
intervals) to maintain stable visual and anatomic outcomes.
If the investigator considers the subject to have permanent resolution of 
macular edema, treatment may be discontinued, but monitoring should be 
continued with a follow-up visit at a minimum interval of 8 weeks and at all 
subsequent prescheduled visits (i.e. Weeks 24, 52, and 76). Treatment should 
be resumed if the retreatment criteria indicate worsening (i.e. at least 1 
criterion for deterioration is met).2
Type of control
None
Number of subjects
160 
Variables
Primary efficacy variables:

The proportion of subjects who gain ≥15 letters in BCVA on the 
ETDRS chart compared with baseline at Week 76

The proportion of subjects with a mean treatment interval between 
injections of ≥8 weeks from the last actual visit of the initiation 
phase to Week 76
Secondary efficacy variables:

The change in BCVA as measured by the ETDRS letter score from 
baseline to Weeks 24, 52, and 76

The change in central retinal thickness (CRT) from baseline to 
Weeks 24, 52, and 76
                                                
1 Wording changed to clarify that frequency of injections “may be adjusted” to maintain stable visual and anatomic 
outcomes per Amendment 1, Modification 1 (see Section 15.1.1.1).
2 Deleted text stating that subjects discontinued from treatment for not benefiting from continued treatment may 
resume treatment if retreatment criteria indicate worsening per Amendment 1, Modification 2 (Section 15.1.1.2).


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
The number of injections from baseline to Week 76

The mean treatment interval between injections from baseline to 
Week 76

The proportion of subjects who gain ≥15 letters in BCVA on the 
ETDRS chart compared with baseline at Weeks 24 and 52

The change in retinal perfusion (FA/FP) status from
screening/baseline3 to Weeks 24, 52 and 76

The proportion of subjects with absence of fluid at Weeks 24, 52, 
and 76
Safety variables:

Number and severity of ocular safety events detected by tonometry,
indirect ophthalmoscopy, slit lamp biomicroscopy, and gonioscopy

Number and severity of systemic adverse events (AEs)

Percentage of subjects requiring panretinal photocoagulation (PRP) 
in the course of the study
Plan for statistical analysis
The primary efficacy variable analysis will be conducted on the Full Analysis 
Set and Per-protocol Set as defined in Section 10.2.
The co-primary efficacy variables are as follows:

The proportion of subjects who gain ≥15 letters in BCVA on the 
ETDRS chart compared with baseline at Week 76

The proportion of subjects with a mean treatment interval between 
injections of ≥8 weeks from the last actual visit of the initiation 
phase to Week 76
Secondary and exploratory variables will be evaluated by means of 95% 
confidence intervals based on appropriate statistical methodology (either 
McNemar or t-distribution based).
For other efficacy variables, with regard to proportion of responder-based 
variables, subjects discontinued until the respective time point will be 
considered as non-responders (if no proof of permanent resolution of macular 
edema exists).
For change from baseline-based variables, missing data will be imputed by 
means of the last observation carried forward method. Sensitivity analyses 
for these variables will be provided, based on the multiple imputation method 
as outlined in the statistical analysis plan. In addition, observed case-based 
sensitivity analyses will be provided for secondary efficacy variables.
                                                
3 Clarified that assessment of secondary variable of change in retinal perfusion status will include 
screening/baseline combined visit per Amendment 1, Modification 3 (see Section 15.1.1.3).


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Table of contents
1.
Title page............................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis – amended .......................................................................................................... 5
Table of contents....................................................................................................................... 8
Table of tables......................................................................................................................... 15
List of abbreviations............................................................................................................... 16
3.
Introduction..................................................................................................................... 17
4.
Study objectives............................................................................................................... 20
5.
Study design – amended ................................................................................................. 21
6.
Study population – amended.......................................................................................... 25
6.1
Inclusion criteria ............................................................................................................ 25
6.2
Exclusion criteria – amended......................................................................................... 26
6.3
Withdrawal of subjects from the study.......................................................................... 28
6.3.1
Withdrawal – amended............................................................................................... 28
6.3.2
Replacement ............................................................................................................... 29
6.4
Subject identification ..................................................................................................... 29
7.
Treatments....................................................................................................................... 29
7.1
Treatments to be administered....................................................................................... 29
7.1.1
Treat and Extend treatment visits – amended............................................................. 29
7.1.2
Stability criteria – amended........................................................................................ 30
7.1.3
Determination of the next retreatment interval 
(extension/maintenance/reduction)............................................................................. 30
7.1.4
Deviation from the recommended retreatment interval.............................................. 31
7.1.5
Discontinuation of treatment ...................................................................................... 31
7.2
Identity of study treatment............................................................................................. 31
7.3
Treatment assignment.................................................................................................... 32
7.4
Dosage and administration – amended .......................................................................... 32
7.5
Drug logistics and accountability – amended................................................................ 32
7.5.1
Packaging ................................................................................................................... 33
7.5.2
Labeling...................................................................................................................... 34
7.5.3
Supply......................................................................................................................... 34
7.5.4
Return ......................................................................................................................... 34
7.6
Treatment compliance.................................................................................................... 34
8.
Non-study therapy........................................................................................................... 35
8.1
Prior and concomitant therapy – amended .................................................................... 35
8.2
Post-study therapy.......................................................................................................... 35
9.
Procedures and variables ............................................................................................... 35


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9.1
Tabular Schedule of Evaluations ................................................................................... 35
9.2
Visit descriptions – amended......................................................................................... 39
9.2.1
Screening visit (Visit 1, Day −21 to baseline) – amended ......................................... 39
9.2.2
Baseline visit (Visit 2, Day 1) – amended.................................................................. 40
9.2.3
Initiation phase (2Q4 treatment intervals ± 7 days) - amended.................................. 41
9.2.4
Treat and Extend phase............................................................................................... 42
9.2.4.1
Treat and Extend visits – amended ......................................................................... 42
9.2.4.2
Week 24 (± 7 days) interim visit – amended .......................................................... 42
9.2.4.3
Week 52 (± 7 days) interim visit – amended .......................................................... 44
9.2.4.4
Week 76 (± 7 days) final study visit – amended..................................................... 45
9.2.5
Early termination visit – amended.............................................................................. 46
9.3
Population characteristics .............................................................................................. 47
9.3.1
Demographic .............................................................................................................. 47
9.3.2
Medical history........................................................................................................... 47
9.3.3
Other baseline characteristics..................................................................................... 47
9.4
Efficacy.......................................................................................................................... 47
9.4.1
Primary efficacy variables.......................................................................................... 47
9.4.2
Secondary efficacy variables - amended .................................................................... 47
9.4.3
Exploratory efficacy variables - amended.................................................................. 48
9.4.4
Efficacy procedures .................................................................................................... 50
9.4.4.1
Best-corrected visual acuity .................................................................................... 50
9.4.4.2
Spectral domain optical coherence tomography ..................................................... 50
9.4.4.3
Fluorescein angiography and fundus photography – amended............................... 50
9.4.4.4
Wide-field fluorescein angiography – amended ..................................................... 51
9.4.4.5
Optical coherence tomography angiography – amended ........................................ 51
9.4.4.6
Full-field electroretinography – amended............................................................... 52
9.5
Pharmacokinetics/pharmacodynamics........................................................................... 52
9.6
Safety ............................................................................................................................. 53
9.6.1
Adverse events............................................................................................................ 53
9.6.1.1
Definitions............................................................................................................... 53
9.6.1.2
Classifications for adverse event assessment.......................................................... 54
9.6.1.2.1
Seriousness........................................................................................................... 54
9.6.1.2.2
Intensity................................................................................................................ 54
9.6.1.2.3
Causal relationship............................................................................................... 54
9.6.1.2.4
Action taken with study treatment ....................................................................... 56
9.6.1.2.5
Other specific treatment(s) of adverse events...................................................... 56
9.6.1.2.6
Outcome............................................................................................................... 57
9.6.1.3
Assessments and documentation of adverse events ................................................ 57
9.6.1.4
Reporting of serious adverse events........................................................................ 57
9.6.1.5
Expected adverse events.......................................................................................... 58
9.6.2
Pregnancies................................................................................................................. 58
9.6.3
Further safety.............................................................................................................. 59
9.6.3.1
Pregnancy test – amended....................................................................................... 59
9.6.3.2
Physical examination............................................................................................... 59
9.6.3.3
Vital signs (temperature, blood pressure, and heart rate)........................................ 59


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9.6.3.4
Ocular safety ........................................................................................................... 59
9.6.3.4.1
Intraocular pressure.............................................................................................. 59
9.6.3.4.2
Indirect ophthalmoscopy...................................................................................... 60
9.6.3.4.3
Slit lamp biomicroscopy ...................................................................................... 60
9.6.3.4.4
Gonioscopy .......................................................................................................... 60
9.6.3.4.5
Relative afferent pupillary defect assessment...................................................... 60
9.7
Appropriateness of procedures and measurements........................................................ 60
10. Statistical methods and determination of sample size ................................................. 61
10.1
General considerations................................................................................................... 61
10.2
Analysis sets .................................................................................................................. 61
10.3
Variables and planned statistical analyses..................................................................... 61
10.3.1
Variables – amended .................................................................................................. 61
10.3.2
Statistical and analytical plans.................................................................................... 62
10.3.2.1
Demography and baseline characteristics ............................................................... 62
10.3.2.2
Efficacy analyses..................................................................................................... 62
10.3.2.2.1
Primary efficacy analyses .................................................................................... 62
10.3.2.2.2
Secondary and exploratory efficacy variables ..................................................... 63
10.3.2.2.3
Statistical test ....................................................................................................... 64
10.3.2.3
Safety analysis......................................................................................................... 65
10.3.3
Missing data/dropouts ................................................................................................ 65
10.4
Determination of sample size......................................................................................... 65
10.5
Planned interim analyses ............................................................................................... 66
11. Data handling and quality assurance............................................................................ 66
11.1
Data recording................................................................................................................ 66
11.2
Monitoring ..................................................................................................................... 67
11.3
Data processing.............................................................................................................. 68
11.4
Missing data................................................................................................................... 68
11.5
Audit and inspection ...................................................................................................... 68
11.6
Archiving ....................................................................................................................... 69
12. Premature termination of the study .............................................................................. 69
13. Ethical and legal aspects................................................................................................. 70
13.1
Investigator(s) and other study personnel – amended.................................................... 70
13.2
Funding and financial disclosure ................................................................................... 71
13.3
Ethical and legal conduct of the study........................................................................... 71
13.4
Subject information and consent.................................................................................... 71
13.5
Publication policy and use of data ................................................................................. 73
13.6
Compensation for health damage of subjects/insurance................................................ 73
13.7
Confidentiality ............................................................................................................... 73
14. Reference list.................................................................................................................... 75
15. Protocol amendments...................................................................................................... 78
15.1
Amendment 1, dated 20 Apr 2016................................................................................. 78
15.1.1
Overview of changes to the study............................................................................... 78
15.1.1.1
Modification 1: Adjustments to Treat and Extend treatment interval..................... 78


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15.1.1.2
Modification 2: Subjects discontinued from treatment with indications of 
worsening ................................................................................................................ 78
15.1.1.3
Modification 3: Secondary variable change in retinal perfusion status .................. 79
15.1.1.4
Modification 4: Reference change .......................................................................... 79
15.1.1.5
Modification 5: Visits for screening and baseline................................................... 79
15.1.1.6
Modification 6: Time point for follow-up............................................................... 79
15.1.1.7
Modification 7: Window for post-baseline study visits .......................................... 79
15.1.1.8
Modification 8: Examinations based on investigator’s medical judgment and 
standard of care ....................................................................................................... 80
15.1.1.9
Modification 9: Exploratory variable perfusion status of retina ............................. 80
15.1.1.10 Modification 10: Study end..................................................................................... 80
15.1.1.11 Modification 11: Final study visit ........................................................................... 80
15.1.1.12 Modification 12: Assessment of eligibility............................................................. 81
15.1.1.13 Modification 13: Exclusion criterion 22 ................................................................. 81
15.1.1.14 Modification 14: Rescreening................................................................................. 81
15.1.1.15 Modification 15: Rescreening for inclusion/exclusion criteria............................... 81
15.1.1.16 Modification 16: Stability criteria........................................................................... 81
15.1.1.17 Modification 17: Dose preparation ......................................................................... 82
15.1.1.18 Modification 18: Disposal of study drug................................................................. 82
15.1.1.19 Modification 19: Rescue therapy ............................................................................ 82
15.1.1.20 Modification 20: Screening/baseline procedures .................................................... 82
15.1.1.21 Modification 21: Window for screening/baseline assessments............................... 82
15.1.1.22 Modification 22: Post-baseline visit procedures ..................................................... 83
15.1.1.23 Modification 23: Prescheduled visits at Weeks 24 and 52...................................... 83
15.1.1.24 Modification 24: Pregnancy testing ........................................................................ 83
15.1.1.25 Modification 25: Fluorescein angiography and fundus photography at 
baseline visit............................................................................................................ 84
15.1.1.26 Modification 26: Fluorescein angiography and fundus photography combined 
with wide-field examinations.................................................................................. 84
15.1.1.27 Modification 27: Telephone safety contact with investigator at 30 days post-
dose.......................................................................................................................... 84
15.1.1.28 Modification 28: Assessments at initial visit .......................................................... 84
15.1.1.29 Modification 29: Gonioscopy order of procedure................................................... 85
15.1.1.30 Modification 30: Post-treatment safety telephone calls.......................................... 85
15.1.1.31 Modification 31: Grammatical correction “pertain” ............................................... 85
15.1.1.32 Modification 32: Early termination visit................................................................. 86
15.1.1.33 Modification 33: Referrence removed .................................................................... 86
15.1.1.34 Modification 34: Central reading center for images ............................................... 86
15.1.1.35 Modification 35: Steering Committee..................................................................... 86
15.1.1.36 Modification 36: Adjudication committee.............................................................. 86
15.1.1.37 Modification 37: Study drug vials........................................................................... 86
15.1.2
Changes to the protocol text....................................................................................... 87
15.1.2.1
Adjustments to Treat and Extend treatment interval - Synopsis 
section Methodology............................................................................................... 87


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15.1.2.2
Subjects discontinued from treatment with indications of 
worsening - Synopsis section Methodology............................................................ 87
15.1.2.3
Secondary variable change in retinal perfusion status – Synopsis Section 
Variables.................................................................................................................. 88
15.1.2.4
Reference change – Section 3 Introduction............................................................. 88
15.1.2.5
Visits for screening and baseline – Section 5 Study design.................................... 88
15.1.2.6
Time point for follow-up – Section 5 Study design................................................ 88
15.1.2.7
Window for post-baseline study visits – Section 5 Study design ........................... 89
15.1.2.8
Examinations based on investigator’s medical judgment and standard of care 
– Section 5 Study design......................................................................................... 89
15.1.2.9
Study end – Section 5 Study design........................................................................ 89
15.1.2.10 Final study visit – Section 5 Study design .............................................................. 90
15.1.2.11 Secondary variable change in retinal perfusion status – Section 5 Study 
design ...................................................................................................................... 90
15.1.2.12 Exploratory variable perfusion status of retina – Section 5 Study design .............. 90
15.1.2.13 Assessment of eligibility – Section 6 Study population.......................................... 90
15.1.2.14 Exclusion criterion 22 – Section 6.2 Exclusion criteria.......................................... 91
15.1.2.15 Rescreening – Section 6.3.1 Withdrawal ................................................................ 91
15.1.2.16 Rescreening for inclusion/exclusion criteria – Section 6.3.1 Withdrawal.............. 92
15.1.2.17 Adjustments to Treat and Extend treatment interval – Section 7.1.1 Treat and 
Extend treatment visits............................................................................................ 92
15.1.2.18 Stability criteria for BCVA – Section 7.1.2 Stability criteria ................................. 92
15.1.2.19 Stability criteria for CRT – Section 7.1 Stability criteria........................................ 93
15.1.2.20 Dose preparation – Section 7.4 Dose age and administration................................. 93
15.1.2.21 Disposal of study drug – Section 7.5 Drug logistics and accountability................. 93
15.1.2.22 Rescue therapy – Section 8.1 Prior and concomitant therapy................................. 94
15.1.2.23 Schedule of Evaluations and Study Procedures – Table 9-1 Schedule of 
Evaluations and Study Procedures .......................................................................... 95
15.1.2.24 Screening/baseline procedures –Section 9.2 Visit descriptions............................ 102
15.1.2.25 Window for screening/baseline assessments – Section 9.2 Visit descriptions ..... 102
15.1.2.26 Assessments at initial visit – Section 9.2 Visit descriptions ................................. 102
15.1.2.27 Pregnancy testing – Section 9.2.2 Baseline visit (Visit 2, Day 1)......................... 103
15.1.2.28 Fluorescein angiography and fundus photography at baseline visit –
Section 9.2.2 Baseline visit (Visit 2, Day 1) ......................................................... 103
15.1.2.29 Fluorescein angiography and fundus photography combined with wide-field 
examinations – Section 9.2.2 Baseline visit (Visit 2, Day 1)................................ 104
15.1.2.30 Assessments at initial visit – Section 9.2.2 Baseline visit (Visit 2, Day 1)........... 104
15.1.2.31 Post-treatment safety telephone calls – Section 9.2.2 Baseline visit .................... 105
15.1.2.32 Post-treatment safety telephone calls – Section 9.2.3 Initiation phase (2Q4 
treatment intervals (± 7 days)................................................................................ 105
15.1.2.33 Pregnancy testing – Section 9.2.3 Initiation phase (2Q4 treatment intervals 
± 7 days)................................................................................................................ 105
15.1.2.34 Window for post-baseline study visits – Section 9.2.4.1 Treat and Extend 
visits ...................................................................................................................... 106
15.1.2.35 Pregnancy testing – Section 9.2.4.1 Treat and Extend visits ................................ 106


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15.1.2.36 Post-treatment safety telephone calls – Section 9.2.4.1 Treat and Extend 
visits ...................................................................................................................... 106
15.1.2.37 Pregnancy testing – Section 9.2.4.2 Week 24 (± 7 days) interim visit ................. 107
15.1.2.38 Grammatical correction “pertain” – Section 9.2.4.2 Week 24 (± 7 days)............. 107
15.1.2.39 Post-treatment safety telephone calls – Section 9.2.4.2 Week 24 (± 7 days)........ 107
15.1.2.40 Pregnancy testing – Section 9.2.4.3 Week 52 (± 7 days) interim visit ................. 108
15.1.2.41 Post-treatment safety telephone calls – Section 9.2.4.3 Week 52 (± 7 days) 
interim visit ........................................................................................................... 108
15.1.2.42 Telephone safety contact with investigator at 30 days post-dose –
Section 9.2.4.4 Week 76 (± 7 days) final study visit ............................................ 108
15.1.2.43 Telephone safety contact with investigator at 30 days post-dose –
Section 9.2.5 Early termination visit..................................................................... 109
15.1.2.44 Early termination visit – Section 9.2.5 Early termination visit............................. 109
15.1.2.45 Secondary variable change in retinal perfusion status – Section 9.4.2 
Secondary efficacy variables................................................................................. 109
15.1.2.46 Exploratory variable perfusion status of retina – Section 9.4.3 Exploratory 
efficacy variables................................................................................................... 110
15.1.2.47 Assessments at initial visit – Section 9.4.3 Exploratory efficacy variables.......... 110
15.1.2.48 Fluorescein angiography and fundus photography combined with wide-field 
examinations – Section 9.4.4.3 Fluorescein angiography and fundus 
photography........................................................................................................... 110
15.1.2.49 Assessments at initial visit – Section 9.4.4.4 Wide-field fluorescein 
angiography........................................................................................................... 110
15.1.2.50 Assessments at initial visit – Section 9.4.4.5 Optical coherence tomography 
angiography........................................................................................................... 111
15.1.2.51 Assessments at initial visit – Section 9.4.4.6 Full-field electroretinography........ 111
15.1.2.52 Pregnancy testing – Section 9.6.3.1 Pregnancy test.............................................. 111
15.1.2.53 Gonioscopy order of procedure – Section 9.6.3.4.4 Gonioscopy ......................... 112
15.1.2.54 Reference removed - Section 9.6.3.4.5 Relative afferent pupillary defect 
assessment ............................................................................................................. 112
15.1.2.55 Window for post-baseline study visits – Section 10.3.1 Variables....................... 112
15.1.2.56 Secondary variable change in retinal perfusion status – Section 10.3.2.2.2 
Secondary and exploratory efficacy variables ...................................................... 113
15.1.2.57 Exploratory variable perfusion status of retina – Section 10.3.2.2.2 Secondary 
and exploratory efficacy variables ........................................................................ 113
15.1.2.58 Central reading center for images – Section 13.1 Investigator(s) and other 
study personnel...................................................................................................... 113
15.1.2.59 Steering Committee – Section 13.1 Investigator(s) and other study personnel .... 114
15.1.2.60 Adjudication Committee – Section 13.1 Investigator(s) and other study 
personnel ............................................................................................................... 114
15.1.2.61 Reference change – Section 14 Referrence list..................................................... 114
15.1.2.62 Study drug vials – Section 16.1 Intravitreal aflibercept injection procedure........ 114
15.1.2.63 Dose preparation – Section 16.1 Intravitreal aflibercept injection procedure....... 115
15.1.2.64 Post-treatment safety telephone calls – Appendix 16.1 Intravitreal aflibercept 
injection procedure................................................................................................ 115


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16. Appendices – amended ................................................................................................. 116
16.1
Intravitreal aflibercept injection procedure - amended................................................ 116


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Table of tables
Table 7-1: Investigational Test Product.................................................................................. 32
Table 9-1: Schedule of Evaluations and Study Procedures – amended.................................. 36
Table 9-2: Schedule of Efficacy Variable Assessments ......................................................... 49


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List of abbreviations
2Q4
2 mg IVT injection every of 4 weeks
AE
Adverse event
AMD
Age-related macular degeneration
APTC
Antiplatelet Trialists' Collaboration
ATE
Arterial thrombotic events
BCVA
Best-corrected visual acuity
BRVO
Branch retinal vein occlusion
CRO
Clinical research organization
CRT
Central retinal thickness
CRVO
Central retinal vein occlusion
eCRF
Electronic case report form
EDC
Electronic data capture
e.g.
For example (exempli gratia)
ERG
Electroretinogram
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FA
Fluorescein angiography
FP
Fundus photography
GCP
Good Clinical Practice
ICF
Informed consent form
i.e.
That is (id est)
IEC
Independent Ethics Committee
IOP
Intraocular pressure
IRB
Institutional Review Board
ISCEV
The International Society for Clinical Electrophysiology of Vision
IVT
Intravitreal
IxRS
Interactive voice/web response system
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
OCT
Optical coherence tomography
PASS
Power Analysis and Sample Size
PRN
As needed (pro re nata)
PRP
Panretinal photocoagulation
RAPD
Relative afferent pupillary defect
RVO
Retinal vein occlusion
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SD-OCT
Spectral domain optical coherence tomography
SmPC
Summary of Product Characteristics
SUSAR
Suspected unexpected serious adverse reaction
T&E
Treat and Extend
US
United States
VEGF
Vascular endothelial growth factor


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3.
Introduction
Background
Retinal venous occlusive disease is an important cause of vision loss, particularly in patients 
with associated chronic macular edema (1). The 2 major categories are central retinal vein 
occlusion (CRVO) and branch retinal vein occlusion (BRVO).
Aflibercept is a potent, specific inhibitor of vascular endothelial growth factor (VEGF) with a 
high affinity for all isoforms of VEGF and placental growth factor. To date, intravitreal (IVT) 
aflibercept has been approved as a treatment for macular edema secondary to CRVO, 
neovascular age-related macular degeneration (AMD), diabetic macular edema, and macular 
edema secondary to BRVO and CRVO in the United States (US), European Union (EU), 
Japan, and other countries; for myopic choroidal neovascularization in Japan and other 
countries; and for diabetic retinopathy in patients with diabetic macular edema in the US.
Further details are provided in the applicable Summary of Product Characteristics (SmPC)
(2)4.
Central retinal vein occlusion
Central retinal vein occlusion results in impaired venous drainage from the eye, which may 
lead to increased venous pressure, reduced arterial perfusion, and retinal ischemia. One result 
of retinal non-perfusion is an increase in the production of VEGF, which can lead to vascular 
permeability, macular edema, retinal hemorrhage, and neovascularization. Patients with 
macular edema secondary to CRVO lose visual acuity, and the visual prognosis, if untreated, 
is frequently poor. As a result of the role that VEGF plays in the pathology of macular edema 
secondary to CRVO, VEGF has become an important drug target in treatment strategies.
Central retinal vein occlusion affects men and women equally and most often occurs in 
persons over the age of 65 years. Population-based studies report the prevalence of macular 
edema secondary to CRVO at 0.1% to 0.4%. While it is usually unilateral, it is estimated that 
up to 7% of persons may develop a similar macular edema secondary to CRVO in the fellow 
eye within 5 years from initial diagnosis (3, 4).
Development program of intravitreal aflibercept in macular edema secondary to CRVO
The Phase 3 program for IVT aflibercept in macular edema secondary to CRVO included 
2 pivotal studies, Study VGFT-OD-0819 (COPERNICUS) and Study 14130 (GALILEO) 
conducted in subjects with macular edema secondary to CRVO. Subjects in COPERNICUS 
were followed for a total of 2 years (i.e. 100 weeks), while subjects in GALILEO were 
followed for 18 months (i.e. 76 weeks). In both studies, subjects received either IVT 
aflibercept or sham injections every 4 weeks from baseline to Week 20. The primary efficacy 
variable for both studies was the proportion of subjects who gained ≥15 letters in 
best-corrected visual acuity (BCVA) at the Week 24 time point compared with baseline. In 
both studies, all assessments were made at Week 24 (the primary variable) before treatment 
was administered. Both Phase 3 studies fully met the stated primary variable and an integrated 
                                                
4 Reference to SmPC applied per Amendment 1, Modification 4 (see Section 15.1.1.4). 


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analysis confirmed the primary variable results of COPERNICUS and GALILEO. In both 
studies, the comparison of IVT aflibercept to sham treatment showed statistical significance in 
favor of IVT aflibercept and, thus, demonstrated the superiority of IVT aflibercept. In 
COPERNICUS, 56.1% of subjects treated with IVT aflibercept every 4 weeks gained 
≥15 letters in visual acuity at Week 24, versus 12.3% in the sham group. Similarly, in 
GALILEO, 60.2% of subjects treated with IVT aflibercept every 4 weeks gained ≥15 letters 
in visual acuity at Week 24, versus 22.1% in the sham group. The superiority of IVT 
aflibercept treatment every 4 weeks was confirmed in all supportive and sensitivity analyses. 
The superiority of IVT aflibercept was also supported by the results for the secondary 
variables of change in BCVA letter score (baseline to Week 24) and reduction in central 
retinal thickness (CRT) (baseline to Week 24).
A total of 317 subjects treated with at least 1 dose of IVT aflibercept constituted the safety 
population in the two Phase 3 studies with up to 100 weeks exposure. Intravitreal aflibercept 
was generally well tolerated in clinical trials, and there is little potential for systemic drug 
accumulation. Serious adverse reactions related to the injection procedure occurred in 3 out of 
2,728 injections with IVT aflibercept and included endophthalmitis, cataract, and vitreous 
detachment. The most common adverse reactions (in at least 5% of subjects treated with IVT 
aflibercept) were conjunctival hemorrhage (15.8%), increased intraocular pressure (IOP) 
(12.9%), eye pain (12.6%), vitreous detachment (6.9%), vitreous floaters (5.7%), increased 
lacrimation (5.0%), and ocular hyperemia (5.0%).
Additional information is provided in the applicable SmPC.
Overall, IVT aflibercept is an effective and generally well-tolerated agent that extends the 
options available for the treatment of macular edema secondary to CRVO.
Rationale of the study
Treat and Extend
The use of anti-VEGF agents for macular edema secondary to CRVO has become the 
standard of care.
To investigate the possibility of extending the treatment interval after the initial Q4 treatment 
phase, both pivotal Phase 3 studies (COPERNICUS and GALILEO) included an as needed 
(pro re nata) (PRN) dosing regimen that began after the first 6 months of treatment (i.e. began 
at the Week 24 visit after all assessments for the primary variable had been made).
Post-hoc analyses of the different dosing subgroup assessments (number of IVT aflibercept 
injections and interval between IVT aflibercept injections) in the two Phase 3 studies 
suggested some de-stabilization of the disease and return of signs and symptoms with PRN 
dosing. While the deterioration may be rather minor after only 6 months (i.e. the PRN phase 
in these studies), it is likely to become more significant over the expected long-term treatment 
duration needed by patients with macular edema secondary to CRVO. These data, therefore, 
support the recommendation that subjects be treated according to a more proactive dosing 
regimen rather than a reactive dosing regimen (e.g. PRN) based on deterioration in visual 
and/or morphology variables.


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Furthermore, frequent dosing for anti-VEGFs has introduced a burden of illness on patients 
and caregivers as well as capability constraints on physicians in practice. Physicians have 
developed a practicing trend toward individualizing treatment to reduce the burden and 
minimize reimbursement issues and healthcare costs. The current proactive individualized 
treatment gaining momentum with practicing physicians is referred to as Treat and Extend 
(T&E).
In the T&E dosing paradigm, the subject is injected every visit and intervals for follow-up 
treatments are typically adapted in incremental intervals according to the response to 
treatment.
The T&E regimen for neovascular AMD was initially described by Spaide in 2007 (5) and 
applied in several studies since then (6, 7, 8, 9, 10, 11, 12); however, no large-scale studies 
have examined the use of IVT aflibercept in a T&E regimen for macular edema secondary to 
CRVO or other indications.
In February 2015, the macular edema secondary to CRVO indication in the EU SmPC for 
IVT aflibercept was expanded to retinal vein occlusion (RVO), based on data from the 
VIBRANT study (Phase 3 study in patients with macular edema secondary to BRVO), and 
was updated to reflect a T&E approach to extend treatment intervals:
“After the initial injection, treatment is given monthly. The interval between two doses 
should not be shorter than 1 month. If visual and anatomic outcomes indicate that the 
patient is not benefiting from continued treatment, Eylea should be discontinued. 
Monthly treatment continues until maximum visual acuity is achieved and/or there are 
no signs of disease activity. Three or more consecutive, monthly injections may be 
needed. Treatment may then be continued with a T&E regimen with gradually 
increased treatment intervals to maintain stable visual and/or anatomic outcomes, 
however there are insufficient data to conclude on the length of these intervals. If 
visual and/or anatomic outcomes deteriorate, the treatment interval should be 
shortened accordingly. The monitoring and treatment schedule should be determined 
by the treating physician based on the individual patient’s response. Monitoring for 
disease activity may include clinical examination, functional testing or imaging 
techniques (e.g. optical coherence tomography [OCT] or fluorescein angiography
[FA])” (2).
Treat and Extend has emerged as a preferred regimen for many treating physicians as it is a 
proactive approach to individualized treatment, monitoring frequency, and intervals. This 
concept aims to maintain maximized visual and anatomic outcomes gained in the initiation 
phase of treatment by proactively treating the subject at each visit and minimizing the burden 
of intervention by extending the treatment interval (if extension criteria are met) and thus 
limiting visits, monitoring, and injections.
However, there are no studies available that address the question of what are useful intervals 
for treating and monitoring, how do they differ among subjects, and how are retreatment 
criteria applied to achieve long-term desirable outcomes in real world practice.


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Furthermore, previous studies identified the importance of perfusion status (e.g. as a 
prognostic variable) in CRVO but assessment of perfusion status was often limited to 
standard angiography of the central sections of the retina (GALILEO) (13,14).
This study aims to evaluate the efficacy, durability, posology, and safety of the T&E regimen 
with IVT aflibercept in subjects with macular edema secondary to CRVO.
In addition, this study will explore emerging imaging methods, including non-invasive and 
wide-angle assessment of perfusion status of the affected eye.
Benefit-risk assessment
Injection of IVT aflibercept in this study of subjects with macular edema secondary to CRVO 
is justified and supported by the drug’s safety and tolerability profile known from previous 
registration studies investigating IVT aflibercept in macular edema secondary to CRVO and 
other indications. The beneficial effect on visual acuity in patients with macular edema 
secondary to CRVO has previously been demonstrated, both with IVT aflibercept treatment 
and with other anti-VEGF therapy.
Due to the low systemic level of aflibercept after IVT injection, the likelihood of adverse 
events (AEs) other than ocular is very low and systemic pharmacodynamic effects such as 
blood pressure changes are unlikely. Proteinuria and hypertension are potential systemic 
effects from intravenous or subcutaneous administration of this class of drug; however, the 
low systemic blood levels observed in previous IVT studies suggest that direct IVT injection, 
at the dose levels proposed for this study, are not expected to have clinically significant 
systemic effects (15,16). In addition, arterial thromboembolic events (ATEs) are AEs 
potentially related to systemic VEGF inhibition. The risks associated with IVT aflibercept 
observed in the Phase 3 studies are thought to be similar to those of IVT administration of 
pegaptanib sodium and ranibizumab.
Given its higher affinity for VEGF compared with ranibizumab and its ability to be 
administered at higher doses, IVT aflibercept may provide a clinical benefit with the potential 
for a longer dosing interval that is equivalent to and potentially greater than that of 
ranibizumab (17,18,19). Given that the subjects to be enrolled in this study generally have 
advanced blinding disease with a poor prognosis, and given the potential for IVT aflibercept 
to provide as good or potentially better therapy than ranibizumab without known increased 
risk, it is reasonable to assume that the potential benefit of IVT aflibercept, a highly potent 
therapeutic agent, outweighs any attendant short-term risks for subjects participating in this 
study.
4.
Study objectives
Primary objective

To determine the efficacy and durability (treatment interval) of 2 mg IVT aflibercept 
in a T&E regimen over a treatment period of 76 weeks using protocol-defined visual 
and anatomic criteria in subjects with macular edema secondary to CRVO


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Secondary objectives

To assess the efficacy of IVT aflibercept as measured by visual acuity and anatomic 
outcomes using spectral domain optical coherence tomography (SD-OCT), and 
perfusion status using FA/fundus photography (FP)

To assess T&E applied posology of IVT aflibercept (number of injections, length of 
injection interval)
Safety objective

To assess the safety and tolerability of IVT aflibercept in this subject population
Exploratory objectives (only at those sites with equipment available)

To evaluate wide-field (angle) FA for utility in assessing perfusion status in the 
periphery of the retina, which is currently not evaluable using traditional FA, and 
examination of morphological changes related to disease progression in CRVO

To evaluate OCT angiography for dynamic assessment of retinal capillary perfusion 
status

To evaluate full-field electroretinography (ERG) for functional assessment of retinal 
ischemia

To evaluate relative afferent pupillary defect (RAPD) appearance or changes related to 
disease progression in CRVO
5.
Study design – amended
Design overview
This is an international, multi-center, prospective, interventional, single-arm cohort, Phase 4 
study in adult subjects with a diagnosis of macular edema secondary to CRVO who have 
previously not been treated with any systemic or IVT anti-VEGF treatments.
The diagnosis and treatment decision is made at the discretion of the attending investigator. 
The investigator will have made the choice of treatment (IVT aflibercept) as well as the 
decision to use IVT aflibercept according the core SmPC principles (or other applicable 
product information) prior to enrolling the subject in this study.
One-hundred sixty subjects will be enrolled in this international study.
The initial screening visit must be within the enrollment period in the respective country (i.e. 
no retrospective inclusion). Subjects must give written informed consent prior to any data 
documentation. Subjects will receive the first study treatment at the baseline visit on Day 1.5
The treatment phase comprises an initiation phase followed by a T&E phase. During the T&E 
phase, all subjects will be treated with the study drug IVT aflibercept using a T&E approach. 
                                                
5 “Screening and baseline need to be separate visits in order to confirm the inclusion/exclusion criteria” removed 
for consistency with rest of protocol that screening and baseline visits can be combined per Amendment 1, 
Modification 5 (see Section 15.1.1.5).


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Subjects will be followed for a time period of 76 weeks or until follow-up is no longer 
possible.6 The treatment period for each subject is scheduled to be 76 weeks. Subjects may 
receive treatment of their underlying disease at their physician’s discretion at Week 76 after 
the end-of-study visit and the assessments for all variables are completed. For patients that 
have received a study drug injection less than 30 days before the end-of-study visit, an 
additional AE follow-up phone call will be scheduled 30 days after the last study drug 
injection. Therefore, the study duration will be 76 weeks plus the screening period and 
potential AE follow-up.
This study comprises a screening period of up to 21 days and a treatment period of 76 weeks. 
There will be prescheduled visits at baseline, Weeks 24, 52, and 76 (end-of-study visit).7
Other visits between baseline and Week 76 will depend on the applied posology of IVT 
aflibercept and the monitoring schedule for each subject. A ± 7-day window will be allowed 
for all post-baseline visits.8
Subjects treated with a deviation from the proposed regimen will continue to be assessed
according to the posology interval of the subject.
Under this protocol, FA/FP evaluations will be conducted in both eyes at screening/baseline, 
and in the study eye only at Weeks 24, 52, and 76, and the early termination visit (and in the 
fellow eye if there are signs of vein occlusion). Best-corrected visual acuity and SD-OCT will 
be conducted in both eyes at every visit. Wide-field FA, OCT angiography, and full-field 
ERG may be conducted, at selected study sites, in both eyes at baseline and in the study eye 
only at Weeks 24, 52, and 76, and the early termination visit (and in the fellow eye if there are 
signs of vein occlusion). However, the treating investigator may perform FA/FP, wide-field 
FA, OCT angiography, or full-field ERG at other times during the 76 weeks of study 
treatment based on his/her medical judgment and standard of care.9
Primary, secondary, safety, and exploratory variables
Co-primary efficacy variables:

The proportion of subjects who gain ≥15 letters in BCVA on the Early Treatment 
Diabetic Retinopathy Study (ETDRS) chart compared with baseline at Week 76

The proportion of subjects with a mean treatment interval between injections of 
≥8 weeks from the last actual visit of the initiation phase to Week 76
                                                
6 Subjects will continue to be followed to Week 76 or until follow-up is no longer possible per Amendment 1, 
Modification 6 (see Section 15.1.1.6).
7 Removed sentence that visit schedules at Weeks s 24, 52, and 76 may deviate by ± 7 days sentence to clarify 
that a ± 7-day window will be allowed for all post-baseline visits per Amendment 1, Modification 7 (see 
Section 15.1.1.7).
8 Added sentence to clarify that a ± 7-day window will be allowed for all post-baseline visits per Amendment 1, 
Modification 7 (see Section 15.1.1.7).
9 Added wide-field FA and OCT angiography to the examinations that may be performed at other times during the 
study based on the investigator’s medical judgment and standard of care per Amendment 1, Modification 8 (see 
Section 15.1.1.8).


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Secondary efficacy variables:

The change in BCVA as measured by the ETDRS letter score from baseline to 
Weeks 24, 52, and 76

The change in CRT from baseline to Weeks 24, 52, and 76

The number of injections from baseline to Week 76

The mean treatment interval between injections from baseline to Week 76

The proportion of subjects who gain ≥15 letters in BCVA on the ETDRS chart 
compared with baseline at Weeks 24 and 52

The change in retinal perfusion (FA/FP) status from screening/baseline10 to Weeks 24, 
52, and 76

The proportion of subjects with absence of fluid at Weeks 24, 52, and 76
Safety variables:

Number and severity of ocular safety events detected by tonometry, indirect 
ophthalmoscopy, slit lamp biomicroscopy, and gonioscopy

Number and severity of systemic AEs

Percentage of subjects requiring panretinal photocoagulation (PRP) in the course of 
the study
Exploratory variables:

Perfusion status of the retina assessed by wide-field FA at screening/baseline,11
Weeks 24, 52, and 76

OCT angiography measures for assessing perfusion status of the retina and 
examination of morphological changes related to disease progression in CRVO at 
baseline, Weeks 24, 52, and 76

Full-field ERG assessments at baseline, Weeks 24, 52, and 76

Status of RAPD at baseline, Weeks 24, 52, and 76
Justification of the design
The primary objective of this single-arm unmasked study is to determine the efficacy and 
durability (treatment interval) of 2 mg IVT aflibercept in a T&E regimen over a treatment 
period of 76 weeks using protocol-defined visual and anatomic criteria in subjects with 
macular edema secondary to CRVO.
                                                
10 Clarified that assessment of secondary variable of change in retinal perfusion status will include 
screening/baseline combined visit per Amendment 1, Modification 3 (see Section 15.1.1.3).
11 Clarified that exploratory variable of perfusion status of the retina will be assessed by wide-field FA at 
screening/baseline per Amendment 1, Modification 9 (see Section 15.1.1.9).


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Single-arm design
The single-arm design using T&E for all patients was chosen since substantial data is 
available for comparison from previous macular edema secondary to CRVO studies that used 
fixed dosing followed by PRN dosing. The Phase 3 program for IVT aflibercept in macular 
edema secondary to CRVO included 2 pivotal studies (COPERNICUS and GALILEO) 
combining fixed dosing and PRN dosing. Subjects in the COPERNICUS study were followed 
for a total of 2 years (i.e. 100 weeks), while subjects in the GALILEO study were followed 
for 18 months (i.e. 76 weeks). The prespecified time points in both studies were the same as 
in CENTERA (baseline, Weeks 24, 52, and 76), and the variables and study populations were 
similar to that of CENTERA.
Treat and Extend
CENTERA is the first Phase 4 study to investigate a proactive T&E regimen with IVT 
aflibercept for the treatment of macular edema secondary to CRVO. Efficacy observations in 
the 2 previous studies (COPERNICUS and GALILEO) suggest some destabilization or 
reactivation of disease with the switch to PRN dosing. A more proactive regimen of treating 
patients (T&E) at each visit and individualizing the treatment interval to maintain visual and 
anatomic stability may provide additional benefit. Based on advice received in expert 
meetings and based on the two Phase 3 studies, a set of visual and anatomic (OCT based) 
retreatment criteria were defined. Therefore, CENTERA will explore treatment with IVT 
aflibercept according to a proactive T&E dosing regimen with adjustment of treatment 
intervals based on the monitoring of stability by protocol-defined visual and/or anatomical 
outcomes.
Variables
The primary and secondary variables in CENTERA were studied in previous Phase 3 RVO 
trials. CENTERA will also incorporate several exploratory variables to add to the 
understanding of pathology and treatment-related changes of macular edema secondary to 
CRVO. Ischemic CRVO is defined by the appearance of neovascularization on the surface of 
the iris (rubeosis iridis) or by FA-confirmed areas of retinal ischemia larger than 10 disc 
areas. The latter has been assessed in clinical Phase 3 trials, but this dichotomized variable is 
not fully satisfactory to characterize perfusion status in the affected eye. In this study, in 
addition to the standard FA assessment, the following 2 imaging and 1 functional assessment 
will be applied at selected sites where instrumentation and technical competence are 
available:

Wide-field (angle) FA will allow for the assessment of perfusion status in the 
periphery of the retina, which is currently not evaluable using traditional FA but seems 
to be affected in CRVO

OCT angiography for dynamic assessment of retinal capillary perfusion status at 
baseline, which does not require a contrast agent to evaluate dynamic changes

Full-field ERG will allow for functional assessment of retinal ischemia


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The combination of these methods will enable a comprehensive assessment of perfusion 
status, including within the periphery and functional changes. The comparison of 
methodology and results may yield important insights for future clinical studies.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject,
including safety follow-up12 is reached in all centers in all participating countries (EU and 
non-EU).
Primary completion of study
The primary completion event for this study is the final study visit at Week 76, including the 
mandatory safety follow-up contact.13
6.
Study population – amended
Eligibility for participation in this study will be based on the inclusion/exclusion criteria.
All inclusion/exclusion criteria will be assessed during the screening phase, and the subject 
must sign the informed consent form (ICF) before any of the inclusion/exclusion criteria are 
assessed.
In order to be enrolled into this study, a subject must meet ALL of the eligibility criteria.14
Only 1 eye will be designated as the study eye. For subjects who meet eligibility criteria in 
both eyes, the eye with the worse visual acuity will be selected as the study eye. If both eyes 
have equal visual acuity, the eye with the clearest lens and ocular media, as determined by the 
investigator, will be selected. If there is no objective basis for selecting the study eye, factors 
such as ocular dominance, other ocular pathology, and subject preference should be 
considered in making the selection. The fellow eye will be assessed as outlined in Section 9.
6.1
Inclusion criteria
1. Signed informed consent.
2. Center-involved macular edema secondary to CRVO for no longer than 3 months (at 
the screening visit it should be ensured that the subjects will comply with the criterion 
of ≤3 months since onset of macular edema at their scheduled baseline visit).
3. Adult subjects diagnosed with macular edema secondary to CRVO who are scheduled 
to be treated with IVT aflibercept as per investigator’s routine treatment practice with 
the intent to use a T&E regimen after initial dosing.
                                                
12 Clarified that the safety follow-up period is included in the definition of the end of the study per Amendment 1, 
Modification 10 (see Section 15.1.1.10).
13 Clarified that the mandatory safety follow-up contact is included in the definition of completion of the final study 
visit per Amendment 1, Modification 11 (see Section 15.1.1.11).
14 Removed sentence that assessment based on OCT assessment, BCVA, and FA and FP will be repeated at 
the baseline visit per Amendment 1, Modification 12 (see Section 15.1.1.12).


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4. Treatment-naïve subjects for macular edema secondary to CRVO.
5. Men and women ≥18 years of age.
6. Documented BCVA of ETDRS letter score of 73 to 24 letters (Snellen equivalent of 
20/40 to 20/320) in the study eye.
7. Subject is willing, committed, and able to return for all clinic visits and complete all 
study-related procedures.
8. Women and men of reproductive potential15 must agree to use adequate contraception 
when sexually active. This applies for the time period between signing of the ICF and 
3 months after the last administration of study drug. The definition of adequate 
contraception will be based on the judgment of the investigator and on local 
requirements. Acceptable methods of contraception include, but are not limited to, 
(i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or 
cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based 
contraception. Subjects must agree to utilize two reliable and acceptable methods of 
contraception simultaneously.
9. Negative pregnancy test (women of childbearing potential only15).
6.2
Exclusion criteria – amended
1. Previous (within 12 months) or concomitant participation in another clinical study 
with investigational medicinal product(s).
2. 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).
3. Previous PRP or macular laser photocoagulation in the study eye.
4. Any prior or concomitant ocular treatment (e.g. anti-VEGF therapy, corticosteroids) in 
the study eye for macular edema secondary to RVO, except dietary supplements or 
vitamins prior to inclusion in the study. Intraocular anti-VEGF treatment is permitted 
for the treatment of diseases of fellow eye except for those that are specifically 
excluded.
5. Prior systemic anti-VEGF or corticosteroid therapy, investigational or approved, 
within the last 3 months before the first dose in the study.
6. Previous use of intraocular corticosteroids in the study eye at any time or use of 
periocular corticosteroids in the study eye within 12 months prior to Day 1.
7. Any active intraocular, extraocular, and periocular inflammation or infection in either 
eye within 4 weeks of screening.
8. Any history of allergy to povidone iodine.
9. Known serious allergy to the fluorescein sodium for injection in angiography.
                                                
15 Women of reproductive or childbearing potential: Postmenopausal women must be amenorrheic for at least 12 
months in order not to be considered of childbearing potential. (footnote to text; not a modification)


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10. Presence of any contraindications indicated in the EU commission/locally approved 
label for IVT aflibercept: hypersensitivity to the active substance IVT aflibercept or to 
any of the excipients; active or suspected ocular or periocular infection; active severe 
intraocular inflammation.
11. A history of vitreoretinal surgery in the study eye prior to Day 1 (Visit 2) or 
anticipated within the 18 months following Day 1.
12. Iris neovascularization, neovascularization or fibrosis of the iridocorneal angle, or 
vitreous hemorrhage in the study eye.
13. History of vitreomacular traction in either the study eye or the fellow eye evident by 
biomicroscopic or OCT assessment that is considered by the investigator to affect 
central vision significantly.
14. History of retinal detachment or treatment or surgery for retinal detachment in the 
study eye.
15. Any history of macular hole of stage 2 and above in the study eye.
16. Prior trabeculectomy or other filtration surgery in the study eye.
17. Uncontrolled glaucoma (defined as IOP more than 25 mm Hg despite treatment with 
antiglaucoma medication) in the study eye.
18. Aphakia or pseudophakia with absence of posterior capsule (unless it occurred as a 
result of an yttrium aluminum garnet posterior capsulotomy) in the study eye.
19. Previous therapeutic radiation in the region of the study eye.
20. History of corneal transplant or corneal dystrophy in the study eye.
21. Significant media opacities, including cataract, in the study eye that interfere with 
visual acuity or FP.
22. History or clinical evidence of diabetic macular edema, AMD (neovascular AMD or 
geographic atrophy), BRVO, or any retinal vascular disease other than macular edema 
secondary to CRVO in either eye.16
23. Any history of uveitis in either eye.
24. Presence of scleromalacia in either eye.
25. Pregnancy or breastfeeding.
                                                
16 Types of AMD defined per Amendment 1, Modification 13 (see Section 15.1.1.13).


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6.3
Withdrawal of subjects from the study
6.3.1
Withdrawal – amended
Withdrawal criteria
Subjects must be withdrawn from the study if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further. The subject will not suffer any disadvantage as a result.
Subjects may be withdrawn from the study if any of the following occurs:

If, in the investigator’s opinion, the subject is not benefiting from continued treatment 
or 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.”
Restarting the defined set of screening procedures to enable the “screening failure” subject’s 
participation at a later time point is not allowed, with the following exceptions:

The subject had successfully passed the screening procedures but could not start 
subsequent treatment on schedule.

Initial screening occurred too early to complete the required washout period after prior 
therapy.

The inclusion/exclusion criteria preventing the subject’s initial attempt to participate 
have been changed (via protocol amendment).

The reason for the screening failure was subsequently resolved (e.g. elevated IOP 
decreases, inflammation or infection resolves) within 30 days.17
However, if a subject fails screening (i.e. does not meet all inclusion criteria or meets 1 or 
more of the exclusion criteria),18 the subject can be re-screened 1 time, if the reason(s) for the 
screening failure is(are) resolved.
                                                
17 Added that subjects may be rescreened if reason for initial screening failure was resolved within 30 days of 
initial screening per Amendment 1, Modification 14 (see Section 15.1.1.14).
18 Removed examples of exclusion criteria per Amendment 1, Modification 15 (see Section 15.1.1.15).


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In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk. In addition, for re-screening, the subject has 
to re-sign the ICF, even if it was not changed after the subject’s previous screening.
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already received IVT aflibercept.
General procedures
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) 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.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (premature termination of the study).
6.3.2
Replacement
Withdrawn subjects will not be replaced.
6.4
Subject identification
The subject number is a 9-digit number consisting of a 2-digit country code, a 3-digit center 
number, and a 4-digit subject number (within the center).
Once assigned to a subject, the subject identification number will not be re-used.
7.
Treatments
7.1
Treatments to be administered
This study is an open-label single-arm study. The recommended dose for IVT aflibercept is 
2 mg equivalent to 50 μL. All subjects will be treated with the study drug IVT aflibercept 
using a T&E approach. The sponsor will provide study drug.
7.1.1
Treat and Extend treatment visits – amended
Study treatment with IVT aflibercept will be administered at baseline and at monthly intervals 
until stabilization of disease. When stability is achieved, the treatment interval can be 
extended based on visual and anatomic outcomes as judged by the treating investigator.
Criteria for determination of retreatment intervals are summarized in Section 7.1.3 below. If 
visual and anatomic outcomes indicate that the subject is not benefiting from continued 
treatment, IVT aflibercept should be discontinued.
The initiation phase of the treatment will extend from the first injection until the subject meets 
retreatment interval extension criteria as summarized in Section 7.1.3.


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Monitoring will be performed at each injection visit and at Weeks 24, 52, and 76. Starting at 
Week 8, the retreatment interval will be determined as described in Section 7.1.3 and the 
frequency of injections may be adjusted19 (increased or decreased by 2-week intervals) to 
maintain stable visual and anatomic outcomes.
7.1.2
Stability criteria – amended
At every injection visit, the stability of the patient’s condition will be evaluated. To be 
considered stable, the condition must fulfill the following criteria:

No new cysts on OCT

BCVA within a ± 5 letter “stability corridor” defined by:
-
No more than 5 letters gain since the last or second to last visit20
-
No more than 5 letters loss from best previous BCVA at any visit

CRT within a ± 20% “stability corridor” defined by:
-
No more than 20% thickness reduction since the last or second to last visit21
-
No more than 20% thickening from best previous CRT at any visit
Values of BCVA and CRT outside these “stability corridors” will be considered as 
“improvements” for higher BCVAs and lower CRTs and “deteriorations” for lower BCVAs 
and higher CRTs.
7.1.3
Determination of the next retreatment interval 
(extension/maintenance/reduction)
The initiation phase of the treatment will extend from the first injection until the subject meets 
all stability criteria as summarized in Section 7.1.2 or until Week 20 (whichever occurs first).
At every injection visit, the investigator will enter into the eCRF the measured BCVA and 
CRT. The eCRF will then suggest a stability status of the patient’s condition (stable / 
improving / deteriorating) for each of the 3 stability criteria and propose a recommended 
retreatment interval (based on the below algorithm) which the investigator must confirm.
Algorithm for determination of the retreatment interval
-
If the condition is stable (all stability criteria met):
o
Treatment interval extended by 2 weeks
-
If the condition is improving (No new cysts and improvement in at least one of the 
disease activity criteria [BCVA or CRT] while the other is improving or stable):
                                                
19 Wording changed to clarify that frequency of injections “may be adjusted” to maintain stable visual and 
anatomic outcomes per Amendment 1, Modification 1 (see Section 15.1.1.1).
20 Text reworded from “previous last visit” to “second to last visit” per Amendment 1, Modification 16 (see 
Section 15.1.1.16).
21 Text reworded from “previous last visit” to “second to last visit” per Amendment 1, Modification 16 (see 
Section 15.1.1.16).


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o
Treatment interval maintained
-
If the condition is deteriorating (New cysts and/or deterioration in at least one of 
the other disease activity criteria [BCVA or CRT]):
o
Treatment interval reduced by 2 weeks
Injections will not be administered more frequently than every 4 weeks (minimum retreatment 
interval).
7.1.4
Deviation from the recommended retreatment interval
Deviation from the recommended treatment regimen or retreatment interval, if required for 
the well-being of the subject, will be recorded in the eCRF with a detailed clinical explanation 
of the reasons for deviation from protocol-defined dosing.
7.1.5
Discontinuation of treatment
If it is determined by the investigator (in the investigator’s best judgment) that the subject is 
not benefiting from continued treatment, the subject may be withdrawn from the study (see 
Section 6.3.1).
If the investigator considers permanent resolution of macular edema, treatment may be 
withheld, but monitoring should be continued with a follow-up visit at a minimum interval of 
8 weeks and at all subsequent prescheduled visits (i.e. Weeks 24, 52, and 76). Treatment 
should be resumed if the retreatment criteria indicate worsening (i.e. at least 1 criterion for 
deterioration is met).
7.2
Identity of study treatment
All study drugs will be labeled according to the requirements of local law and legislation. 
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice will be used, ensuring that each dose of study drug can be traced back 
to the respective bulk batch of the ingredients. Lists linking all numbering levels will be 
maintained by the sponsor’s clinical supplies Quality Assurance group.
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.
The study drug, IVT aflibercept, will be manufactured by Bayer Pharma AG, Berlin, 
Germany and supplied by the sponsor in sealed, single-use, sterile 2-mL vials, each with a 
final extractable volume of 0.10 mL. Details of the study drug are provided in Table 7-1.


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Table 7-1:
Investigational Test Product
Name
Dose
Concentration
Volume
Formulation
Composition
BAY 86-5321/ IVT 
aflibercept
2 mg
40 mg/mL
Injected: 
0.05 mL
Solution for 
intravitreal 
injection
- 40 mg aflibercept/mL
- 5% sucrose
- 10 mM sodium phosphate
- 0.03% polysorbate 20
- 40 mM sodium chloride 
(NaCl)
- Water for injection
7.3
Treatment assignment
Subjects enrolled in this single-arm study will receive treatment at the discretion of the 
investigator. However, as this study has the aim to investigate the T&E regimen with IVT 
aflibercept, the expectation is that the investigator and subject will apply the T&E regimen as 
described in this study protocol if no medical or other reasons indicate otherwise.
7.4
Dosage and administration – amended
The volume of injection will be 50 μL (0.05 mL) for the 2 mg dose of IVT aflibercept. The 
study drug will be withdrawn using aseptic technique through an 18-gauge filter needle 
attached to a 1-mL syringe. The filter needle will be discarded after withdrawal of the vial 
contents and should not be used for IVT injection. The filter needle should be replaced with a 
sterile 30-gauge needle for the IVT injection. The contents in the syringe should be expelled 
until the plunger is aligned with the line that marks 0.05 mL on the syringe.
Prior to administration, visually inspect the solution for injection. Do not use the vial if 
particulates, cloudiness, or discoloration are visible.
Vials of IVT aflibercept are to be stored at 2°C to 8°C. Do not freeze. Keep the vial in the 
outer carton to protect it from light. Prior to usage, the unopened vial of IVT aflibercept may 
be stored at room temperature (below 25°C/77°F) for up to 24 hours. After opening the vial, 
procedures must take place under aseptic conditions.22
Intravitreal aflibercept will be administered to the study eye. For the dosing schedule and 
planned duration, see Section 7. The study drug injection procedure is detailed in 
Appendix 16.1.
7.5
Drug logistics and accountability – amended
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practice requirements and the instructions given by 
the clinical supplies department of the sponsor (or its affiliate/clinical research organization 
[CRO]), and will be inaccessible to unauthorized personnel. Special storage conditions and a 
                                                
22 Removed text stating that dose must be administered within 2 hours of start of dose preparation per 
Amendment 1, Modification 17 (see Section 15.1.1.17).


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complete record of batch numbers and expiry dates can be found in the sponsor study file; the 
site-relevant elements of this information will be available in the investigator site file.
Vials of IVT aflibercept are to be stored at 2°C to 8°C. The drug must not be frozen. Before 
usage, the unopened IVT aflibercept vial may be stored at room temperature (below 
25°C/77°F) for up to 24 hours. Keep the vial in the outer carton to protect it from light. The 
temperature in the storage refrigerator has to be measured daily on working days with a 
minimum/maximum thermometer (continuous temperature monitoring is also allowed). 
Records of actual storage conditions (i.e. temperature log) at the study site must be 
maintained. These must include a record of the dates on which the storage refrigerator was 
checked, the initials of the person checking the temperature, and the temperature at that time.
The responsible site personnel will confirm receipt of study drug via interactive voice/web 
response system (IxRS) on the day of receipt or the earliest possible time point. The personnel 
will use the study drug only within the framework of this clinical study and in accordance 
with this protocol. Receipt, distribution, return, and destruction (if any) of the study drug must 
be properly documented according to the sponsor’s agreed and specified procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
The physician or designated medical or pharmacy personnel handling the drug product are 
responsible for the accountability of all used, partially used, and unused study drug. Drug 
accountability records must be kept current and should contain the dates, quantities, kit 
numbers, and batch numbers (or lot numbers) of study drug received by the investigator, 
dispensed or administered to specified subjects, disposed of at the site (disposal at the site 
may occur only with a sponsor or designee approval or by a specified designee).23 Drug
accountability will be overseen by study site personnel. All inventories, along with shipment 
receipts, shipment temperature recordings (if applicable), storage temperature logs, pharmacy 
dose preparation logs, and IxRS confirmation reports must be made available for inspection 
by study site personnel. At the conclusion of the study, photocopies of all drug accountability 
records will be provided by each site to the sponsor.
7.5.1
Packaging
All IVT aflibercept study medication will be packaged with a kit number. Each IVT 
aflibercept treatment kit will contain 40 mg/mL IVT aflibercept in a sealed, single use, sterile 
2-mL vial with a final extractable volume of 0.10 mL. In accordance with local regulations, 
each kit will contain one 18-gauge filter needle.
                                                
23 Added that sponsor designee may approve disposal of drug and removed that study drug may be returned to 
the sponsor for disposal per Amendment 1, Modification 18 (see Section 15.1.1.18).


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7.5.2
Labeling
The study-drug label will generally contain the following information according to regulations 
applicable to the study countries. Additional information, as required, may be added to the 
study-drug label. In certain cases, local regulations may also require some of the following 
information to be removed.

Name and address of sponsor

Protocol number

Kit number

Lot number

Dosage form

Quantity

Storage conditions

Expiration date

Route of administration

“To be Used as Instructed by the Clinical Study Documentation. For Clinical Trial 
Use Only.”
Each vial of IVT aflibercept will be labeled. The subject identification number will be 
recorded on each vial and the subject identification number and investigator name (if locally 
required) will be recorded on the kit boxes for all the treatment kits. The kit number will be 
recorded in the subject’s source documentation and entered into the eCRF.
7.5.3
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.
7.5.4
Return
At the end of the study and following reconciliation and documentation by the site monitor, 
all used, partially used, and unused vials of IVT aflibercept will either be destroyed at the site 
or returned to a specified designee for disposal.
7.6
Treatment compliance
All injections will be given at the clinical site. Study personnel will monitor and document 
treatment compliance.


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8.
Non-study therapy
8.1
Prior and concomitant therapy – amended
For prohibited drugs and procedures prior to the study, see Section 6.
Subjects may not receive any treatment (approved or investigational) for macular edema 
secondary to CRVO in the study eye other than the assigned study treatment of IVT 
aflibercept until the Week 76 or early termination visit assessments are completed. This 
includes medications administered locally (e.g. by IVT, topical, juxtascleral, subconjunctival, 
or periorbital routes) in the study eye or medications administered systemically with the intent 
of treating the study and/or the fellow eye, including systemic anti-VEGF therapy. In 
addition, macular laser photocoagulation is prohibited during the study (in the study eye). 
Intravitreal injections as well as other medications administered via other routes of 
administration (e.g. topical, juxtascleral, subconjunctival, or periorbital routes) in the fellow 
eye are permitted.
All subjects may receive PRP rescue at any time during the study if deemed necessary by the 
investigator24 and will continue to be assessed in this study.
Any other medications that are considered necessary for the subject’s welfare, and that are not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of 
the investigator, with the exceptions noted above. Subjects are permitted to continue with 
ongoing medications needed to maintain stable disease management (e.g. hypertension, 
hyperlipidemia, and so forth) except for any medications specifically named in the exclusion 
criteria.
8.2
Post-study therapy
After the end of the study, subjects will be treated with either IVT aflibercept or other 
treatment according to their physician’s decision. No additional therapy will be provided once 
subjects complete the trial.
9.
Procedures and variables
9.1
Tabular Schedule of Evaluations
A tabular schedule of study evaluations and procedures is provided in Table 9-1, Schedule of 
Evaluations and Study Procedures.
                                                
24 Removed conditions when subjects may receive PRP rescue, and added that subjects may receive PRP 
rescue per investigator discretion per Amendment 1, Modification 19 (see Section 15.1.1.19).


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Table 9-1:
Schedule of Evaluations and Study Procedures – amended
Initiation Phase
T&E Phase
Visit Description 
Screeninga
Baselinea
Treatment Every 
4 Weeks (2Q4)b
T&E Treatment Visits
b
Interimb,c
Interimb,c
End of 
Studyb
Early 
Termination
Time Point
Visit 1
Day −21
to Baseline
Visit 2 
(Day 1)
Visit 3 and following 
until stability achieved 
or Week 20 (± 7 days)
According to 
Individual T&E 
Schedule (± 7 days)d
Week 24
(± 7 days)
Week 52
(± 7 days)
Week 76
(± 7 days)
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographic data
X
Medical/ophthalmic history
X
Physical examination
X
Pregnancy teste
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Refraction and BCVA (ETDRS chart 
starting at 4 m)f
X
X
X
X
X
X
X
X
SD-OCT 
X
X
X
X
X
X
X
X
FA/FPg,h,i
X
X
X
X
X
X
AEsj
X
X
X
X
X
X
X
X
Indirect ophthalmoscopyk
X
X
X
X
X
X
X
X
RAPDl
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
X
X
X
Gonioscopym
X
X
X
IOPk
X
X
X
X
X
X
X
X
Full-field ERGh,i,n
(X)
X
X
X
X
X
Wide-field (angle) FAg,h,i,n
(X)
X
X
X
X
X
OCT angiographyh,i,n
(X)
X
X
X
X
X


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Initiation Phase
T&E Phase
Visit Description 
Screeninga
Baselinea
Treatment Every 
4 Weeks (2Q4)b
T&E Treatment Visits
b
Interimb,c
Interimb,c
End of 
Studyb
Early 
Termination
Time Point
Visit 1
Day −21
to Baseline
Visit 2 
(Day 1)
Visit 3 and following 
until stability achieved 
or Week 20 (± 7 days)
According to 
Individual T&E 
Schedule (± 7 days)d
Week 24
(± 7 days)
Week 52
(± 7 days)
Week 76
(± 7 days)
Vital signso
X
X
X
X
X
X
X
X
Administration of study treatmentp
X
X
X
(X)
(X)
q
Telephone safety checkr
X
X
X
(X)
(X)
X
Evaluation of posology, how disease 
activity is monitored, including monitoring 
frequency
X
X
X
X
X
X
X
Prior/concomitant medications
X
X
X
X
X
X
X
X
Abbreviations: AE, adverse event; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; FA, fluorescein angiography; FP, fundus 
photography; IOP, intraocular pressure; OCT, optical coherence tomography; RAPD, relative afferent pupillary defect; SD-OCT; spectral domain optical coherence 
tomography T&E, Treat and Extend.
Note: Ocular assessments are to be conducted in both eyes unless otherwise indicated.
a:
The screening and baseline visits can be combined if eligibility criteria are met, all inclusion criteria are fulfilled, and none of the exclusion criteria apply. If screening and 
baseline occur on the same visit, pregnancy test results and reading center evaluations need to be available prior to treatment with study drug. The necessary procedures can 
be performed on separate days. However, slit lamp (anterior segment), IOP measurement, and indirect ophthalmoscopy are recommended to take place/be repeated on the 
same day as the IVT injection. There will be a 7-day window allowed for all procedures to be completed for the combined screening/baseline and the baseline visit.
b:
A ± 7-day window will be allowed for all post-baseline visits. The procedures required at each visit have to be completed within 7 days (i.e. split visits are allowed); 
however, all procedures have to be completed within the ± 7-day window. Slit lamp (anterior segment), IOP measurement, and indirect ophthalmoscopy are recommended to 
take place on the same day as the IVT injection.
c:
The visits at Weeks 24 and 52 do not pertain to the T&E posology; however, based on the subject’s T&E schedule, the subject may receive IVT injection of study drug.
d:
Monitoring will be performed at each injection visit and at Weeks 24, 52, and 76. Starting at Week 8, the stability criteria will be evaluated as described in Section 7.1.2 and 
the frequency of injections may be adjusted (increased or decreased by 2-week intervals) to maintain stable visual and anatomic outcomes.
e:
Urine pregnancy test for women of child-bearing potential only. If positive, a serum pregnancy test for confirmation should be performed. Postmenopausal women must be 
amenorrheic for at least 12 months in order not to be considered of childbearing potential. After screening, a urine pregnancy test is mandatory for women of childbearing 
potential at every treatment visit (prior to injection) in all countries where it is required by local regulations. If required by local regulations, a pregnancy test should be 
performed for women of childbearing potential at the End of Study visit.
f:
Refraction and BCVA using the ETDRS chart are to be performed at each visit.
g:
If the investigator considers no significant change in indirect ophthalmoscopy, an additional FA/FP is not mandatory at the baseline visit. Traditional FA/FP examinations 
can be combined with wide-field examinations if possible. A separate fluorescein injection, especially, should be avoided.
h:
The treating investigator may perform these examinations at other times during the 76 weeks of the study based on his/her medical judgment and standard of care.
i:
Conduct in both eyes at screening/baseline and in the study eye only at the other visits indicated unless there are signs of vein occlusion in the fellow eye.


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j:
Any AE occurring up to 30 days after the last injection of IVT aflibercept is to be documented regardless of the relationship to the study drug or the seriousness of the event, 
and reported in accordance with this protocol (see Section 9.6.1.3). A mandatory telephone safety contact with the investigator 30 days after the last administration of study 
medication is scheduled to ensure that the patient has not experienced any AEs.
k:
Conduct pre- and post-dose as applicable. If a subject receives a study injection, indirect ophthalmoscopy should be conducted post-dose and IOP should be assessed in the 
study eye 30 to 60 minutes after dosing.
l:
Conducted in both eyes (procedure for conducting RAPD testing is provided in the study manual). If the screening and baseline visits are combined, these assessments
should be performed at the initial visit.
m:
Performed in the study eye only. Conducted at screening and at Week 76 and the early termination visit. May be repeated if needed as determined by the investigator.
n:
Conducted where feasible and available at selected sites. If the screening and baseline visits are combined, these assessments should be performed at the initial visit.
o:
Temperature, blood pressure, and heart rate.
p:
See Appendix 16.1 for an example study drug injection procedure. Note: Study drug will be administered according to the criteria and timing described in Section 7. If the 
investigator considers permanent resolution of macular edema, treatment may be discontinued, but monitoring should be continued with a follow-up visit at a minimum 
interval of 8 weeks and at all subsequent prescheduled visits (i.e. Weeks 24, 52, and 76).
q:
Subjects may receive treatment of their underlying disease at their physician`s discretion at Week 76 after the end-of-study visit and the assessments for all variables are 
completed.
r:
A mandatory safety telephone call will be made within 3 days after treatment to ensure no signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred.25
                                                
25 Details of changes to the Schedule of Evaluations and Study Procedures are displayed in Section 15.1.2 for modifications per Amendment 1, Modification 1 
(see Section 15.1.1.1), Modification 2 (see Section 15.1.1.2), Modification 3 (Section 15.1.1.3), Modification 7 (see Section 15.1.1.7), Modification 8 (see 
Section 15.1.1.8), Modification 20 (see Section 15.1.1.20), Modification 21 (see Section 15.1.1.21), Modification 22 (see Section 15.1.1.22), Modification 23 
(see Section 15.1.1.23), Modification 24 (see Section 15.1.1.24), Modification 25 (see Section 15.1.1.25), Modification 26 (see Section 15.1.1.26), Modification 
27 (see Section 15.1.1.27), Modification 28 (see Section 15.1.1.28), Modification 29 (see Section 15.1.1.29), Modification 30 (see Section 15.1.1.30), and 
Modification 31 (see Section 15.1.1.31).


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9.2
Visit descriptions – amended
The screening and baseline visits can be combined if eligibility criteria are met, all inclusion 
criteria are fulfilled, and none of the exclusion criteria apply. The necessary procedures can be 
performed on separate days.26 There will be a 7-day window allowed for all procedures to be 
completed in such a combined visit.27 If screening and baseline occur on the same visit, 
pregnancy test results and reading center evaluations need to be available prior to treatment 
with study drug. Furthermore, the additional examinations at baseline should be performed at 
the initial visit prior to treatment with study drug if the investigator intends to combine 
screening and baseline visit.28
9.2.1
Screening visit (Visit 1, Day −21 to baseline) – amended

Obtain signed ICF

Assess inclusion and exclusion criteria

Obtain demographic data

Prior and concomitant medications

Obtain medical and ophthalmic history

Physical examination

Vital signs (temperature, blood pressure, and heart rate)

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy
o
Gonioscopy (study eye only)
o
FA/FP (the study manual will further specify the standards for FA/FP during 
the study)

Pregnancy test (urine) for women of childbearing potential. If the result is positive, a 
serum pregnancy test will be done for confirmation. Postmenopausal women must be 
                                                
26 Clarified that procedures may be performed on separate days if screening and baseline visits are combined 
per Amendment 1, Modification 20 (see Section 15.1.1.20).
27 Added that for baseline and screening visits to be considered a combined visit, the assessments must take 
place within a 7-day window per Amendment 1, Modification 21 (see Section 15.1.1.21).
28 Examinations required at baseline should be performed at the initial visit, prior to treatment with study drug, if 
the investigator intends to combine the screening and baseline visits per Amendment 1, Modification 28 (see 
Section 15.1.1.28).


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amenorrheic for at least 12 months in order not to be considered of childbearing 
potential.
9.2.2
Baseline visit (Visit 2, Day 1) – amended

Confirm inclusion criteria and exclusion criteria. This includes a negative pregnancy 
test for women of childbearing potential. Postmenopausal women must be 
amenorrheic for at least 12 months in order not to be considered of childbearing 
potential.

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations.29

Confirm medical history of macular edema secondary to CRVO

Prior and concomitant medications

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy
o
RAPD test
o
FA/FP (the study manual will further specify the standards for FA/FP during 
the study). If the investigator considers no significant change in indirect 
ophthalmoscopy, an additional FA/FP is not mandatory at the baseline visit.30
Traditional FA/FP examinations can be combined with wide-field examination 
if possible. A separate fluorescein injection, especially, should be avoided.31
o
Wide-field FA, at selected study sites (if screening and baseline visits are 
combined, assessment should be performed at the initial visit)32
o
OCT angiography, at selected study sites (if screening and baseline visits are 
combined, assessment should be performed at the initial visit)33
                                                
29 Added that pregnancy testing is mandatory for women of childbearing potential at every treatment visit prior to 
injection and at End of Study visit if required by local regulations per Amendment 1, Modification 24 (see 
Section 15.1.1.24).
30 If there is no significant change in indirect ophthalmoscopy, an additional FA/FP at baseline is not required per 
Amendment 1, Modification 25 (see Section 15.1.1.25).
31 When possible, FA/FP examinations can be combined with wide-field examination and separate fluorescein 
injection should be avoided per Amendment 1, Modification 26 (see Section 15.1.1.26).
32 Added that assessment should be performed at the initial visit if screening and baseline visits are combined 
per Amendment 1, Modification 28 (see Section 15.1.1.28).


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o
Full-field ERG, at selected study sites (if screening and baseline visits are 
combined, assessment should be performed at the initial visit)34

IVT injection of study drug (see Appendix 16.1 for an example study drug injection 
procedure), followed by a 30- to 60-minute observation period
o
Measure IOP again in the study eye 30 to 60 minutes following IVT injection
o
Indirect ophthalmoscopy (post-dose)
o
Mandatory safety telephone call within 3 days35 after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
9.2.3
Initiation phase (2Q4 treatment intervals ± 7 days) - amended

Prior and concomitant medications

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations36

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
Slit lamp biomicroscopy
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
IVT injection of study drug (see Appendix 16.1 for an example study drug 
injection procedure), followed by a 30- to 60-minute observation period
o
Measure IOP again in the study eye 30 to 60 minutes following IVT injection
o
Indirect ophthalmoscopy (post-dose)
o
Mandatory safety telephone call within 3 days37 after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
                                                                                                                                                        
33 Added that assessment should be performed at the initial visit if screening and baseline visits are combined 
per Amendment 1, Modification 28 (see Section 15.1.1.28).
34 Added that assessment should be performed at the initial visit if screening and baseline visits are combined 
per Amendment 1, Modification 28 (see Section 15.1.1.28).
35 Schedule for safety follow-up telephone calls changed from 3 days after treatment to within 3 days per 
Amendment 1, Modification 30 (see Section 15.1.1.30).
36 Added mandatory pregnancy testing for women of childbearing potential at every treatment visit prior to 
injection and at End of Study visit if required by local regulations per Amendment 1, Modification 24 (see 
Section 15.1.1.24).


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
IVT injection of study drug (see Appendix 16.1 for an example study drug injection 
procedure), followed by a 30- to 60-minute observation period
9.2.4
Treat and Extend phase
9.2.4.1
Treat and Extend visits – amended
Treat and Extend visits are scheduled according to an individual subject’s T&E schedule
(± 7 days).38

Prior and concomitant medications

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations39

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy

IVT injection of study drug (see Appendix 16.1 for an example study drug injection 
procedure), followed by a 30- to 60-minute observation period
o
Measure IOP again in the study eye 30 to 60 minutes following IVT injection
o
Indirect ophthalmoscopy (post-dose)
o
Mandatory safety telephone call within 3 days40 after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
9.2.4.2
Week 24 (± 7 days) interim visit – amended

Prior and concomitant medications

Vital signs (temperature, blood pressure, and heart rate)
                                                                                                                                                        
37 Schedule for safety follow-up telephone calls changed from 3 days after treatment to within 3 days per 
Amendment 1, Modification 30 (see Section 15.1.1.30).
38 Added a ± 7-day window to Treat and Extend visits to clarify window for all post-baseline visits per 
Amendment 1, Modification 7 (see Section 15.1.1.7).
39 Added mandatory pregnancy testing for women of childbearing potential at every treatment visit prior to 
injection and at End of Study visit if required by local regulations Amendment 1, Modification 24 (see 
Section 15.1.1.24).
40 Schedule for safety follow-up telephone calls changed from 3 days after treatment to within 3 days per 
Amendment 1, Modification 30 (see Section 15.1.1.30).


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
AEs (pre- and post-dose)

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations41

Ocular assessments (to be conducted in both eyes unless otherwise indicated)
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy
o
RAPD test
o
FA/FP (study eye only unless there are signs of vein occlusion in the fellow 
eye; the study manual will further specify the standards for FA/FP during the 
study)
o
Wide-field FA (study eye only unless there are signs of vein occlusion in the 
fellow eye) at selected study sites
o
OCT angiography (study eye only unless there are signs of vein occlusion in 
the fellow eye) at selected study sites
o
Full-field ERG (study eye only unless there are signs of vein occlusion in the 
fellow eye) at selected study sites

The Week 24 visit does not pertain42 to the T&E posology. The posology should 
follow the retreatment criteria and not be adjusted to coincide with the Week 24 
monitoring visit. However, if the subject meets the criteria outlined in Section 7.1.3
(T&E phase treatment criteria), the subject may receive IVT injection of study drug 
(see Appendix 16.1 for an example study drug injection procedure), followed by a 
30- to 60-minute observation period.
o
Measure IOP again in the study eye 30 to 60 minutes following IVT injection
o
Indirect ophthalmoscopy (post-dose)
o
Mandatory safety telephone call within 3 days43 after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
                                                
41 Added mandatory pregnancy testing for women of childbearing potential at every treatment visit prior to 
injection and at End of Study visit if required by local regulations Amendment 1, Modification 24 (see 
Section 15.1.1.24).
42 Wording changed from “is not a visit pertaining” to “does not pertain” in reference to T&E posology per 
Amendment 1, Modification 31 (see Section 15.1.1.31).
43 Revised schedule for safety follow-up telephone calls from 3 days after treatment to within 3 days per 
Amendment 1, Modification 30 (see Section 15.1.1.30).


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9.2.4.3
Week 52 (± 7 days) interim visit – amended

Prior and concomitant medications

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations44

Ocular assessments (to be conducted in both eyes unless otherwise indicated)
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy
o
RAPD test
o
FA/FP (study eye only unless there are signs of vein occlusion in the fellow 
eye, the study manual will further specify the standards for FA/FP during the 
study)
o
Wide-field FA (study eye only unless there are signs of vein occlusion in the 
fellow eye) at selected study sites
o
OCT angiography (study eye only unless there are signs of vein occlusion in 
the fellow eye) at selected study sites, evaluation of posology, how disease 
activity is monitored, including monitoring frequency
o
Full-field ERG (study eye only unless there are signs of vein occlusion in the 
fellow eye) at selected study sites

The Week 52 visit does not pertain to the T&E posology. The posology should follow 
the retreatment criteria and not be adjusted to coincide with the Week 52 monitoring 
visit. However, if the subject meets the criteria outlined in Section 7.1.3 (T&E phase 
treatment criteria), the subject may receive IVT injection of study drug (see 
Appendix 16.1 for an example study drug injection procedure), followed by a 30- to 
60-minute observation period.
o
Measure IOP again in the study eye 30 to 60 minutes following IVT injection
o
Indirect ophthalmoscopy (post-dose)
                                                
44 Added pregnancy testing is mandatory for women of childbearing potential at every treatment visit prior to 
injection and at End of Study visit if required by local regulations per Amendment 1, Modification 24 (see 
Section 15.1.1.24).


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o
Mandatory safety telephone call within 3 days45 after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
9.2.4.4
Week 76 (± 7 days) final study visit – amended

Prior and concomitant medications

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy
o
Gonioscopy (study eye only)
o
RAPD test
o
FA/FP (study eye only unless there are signs of vein occlusion in the fellow 
eye, the study manual will further specify the standards for FA/FP during the 
study)
o
Wide-field FA (study eye only unless there are signs of vein occlusion in the 
fellow eye) at selected study sites
o
OCT angiography (study eye only unless there are signs of vein occlusion in 
the fellow eye) at selected study sites
o
Full-field ERG (study eye only unless there are signs of vein occlusion in the 
fellow eye) at selected study sites

The Week 76 visit does not pertain to the T&E posology.46 However, if treatment of 
the patient`s underlying disease is needed on that day, it will not be part of the study 
and no study drug can be injected. Treatment is up to the discretion/decision of the 
patient`s physician. Such treatment should only occur after all study relevant 
assessments have been performed.

Any AE occurring up to 30 days after the last injection of study drug is to be 
documented regardless of the relationship to the study drug or the seriousness of the 
event, and reported in accordance with this protocol. (see Section 9.6.1.3). A 
mandatory telephone safety contact with the investigator 30 days after the last 
                                                
45Revised schedule for safety follow-up telephone calls from 3 days after treatment to within 3 days per 
Amendment 1, Modification 30 (see Section 15.1.1.30).
46 Wording changed from “is not a visit pertaining” to “does not pertain” in reference to T&E posology per 
Amendment 1, Modification 31 (see Section 15.1.1.31).


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administration of study medication is scheduled to ensure that the patient has not 
experienced any AEs.47
9.2.5
Early termination visit – amended

48Prior and concomitant medications

Vital signs (temperature, blood pressure, and heart rate)

AEs

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy
o
Gonioscopy (study eye only)
o
RAPD test
o
FA/FP (study eye only unless there are signs of vein occlusion in the fellow 
eye, the study manual will further specify the standards for FA/FP during the 
study)
o
Wide-field FA (study eye only unless there are signs of vein occlusion in the 
fellow eye) at selected study sites.
o
OCT angiography (study eye only unless there are signs of vein occlusion in 
the fellow eye) at selected study sites
o
Full-field ERG (study eye only unless there are signs of vein occlusion in the 
fellow eye) at selected study sites

Any AE occurring up to 30 days after the last injection of IVT aflibercept is to be 
documented regardless of the relationship to the study drug or the seriousness of the 
event, and reported in accordance with this protocol (see Section 9.6.1.3). A 
mandatory telephone safety contact with the investigator 30 days after the last 
administration of study medication is scheduled to ensure that the patient has not 
experienced any AEs.49
                                                
47 Reworded for clarity that telephone contact is a safety telephone contact with the investigator 30 days after last 
dose of study drug to ensure patient has not experienced any AEs per Amendment 1, Modification 27 (see 
Section 15.1.1.27).
48 Removed sentence describing monitoring interval if subject is withdrawn from the study per Amendment 1, 
Modification 32 (see Section 15.1.1.32).
49 Reworded for clarity that telephone contact is a safety telephone contact with the investigator 30 days after last 
dose of study drug to ensure patient has not experienced any AEs per Amendment 1, Modification 27 (see 
Section 15.1.1.27).


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9.3
Population characteristics
9.3.1
Demographic
Subjects will be recruited from men and women ≥18 years of age. The following 
demographic parameters will be recorded:

Sex

Year of birth

Weight

Height

Race/ethnicity
9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases, or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

A complete medical and ophthalmic history will be obtained

Start date before signing of the informed consent

Considered relevant for the subject’s study eligibility
Detailed instructions on the differentiation between medical history and AEs can be found in 
Section 9.6.1.1.
9.3.3
Other baseline characteristics
Subjects participating in this study will have a diagnosis of macular edema secondary to 
CRVO. Visual function of the study eye at the initiation of IVT aflibercept treatment must be 
an ETDRS letter score of 73 to 24 letters (Snellen equivalent of 20/40 to 20/320).
9.4
Efficacy
9.4.1
Primary efficacy variables

The proportion of subjects who gain ≥15 letters in BCVA on the ETDRS chart 
compared with baseline at Week 76

The proportion of subjects with a mean treatment interval between injections of 
≥8 weeks from the last actual visit of the initiation phase to Week 76
9.4.2
Secondary efficacy variables - amended

The change in BCVA as measured by the ETDRS letter score from baseline to 
Weeks 24, 52, and 76

The change in CRT from baseline to Weeks 24, 52, and 76

The number of injections from baseline to Week 76

The mean treatment interval between injections from baseline to Week 76


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
The proportion of subjects who gain ≥15 letters in BCVA on the ETDRS chart 
compared with baseline at Weeks 24 and 52

The change in retinal perfusion (FA/FP) status from screening/baseline50 to Weeks 24, 
52, and 76

The proportion of subjects with absence of fluid at Weeks 24, 52, and 76
9.4.3
Exploratory efficacy variables - amended

Perfusion status of the retina assessed by wide-field FA at screening/baseline,51
Weeks 24, 52, and 76

OCT angiography measures for assessing perfusion status of the retina and 
examination of morphological changes related to disease progression in CRVO at 
baseline, Weeks 24, 52, and 76

Full-field ERG assessments at baseline, Weeks 24, 52, and 76

Status of RAPD at baseline, Weeks 24, 52, and 76
Table 9-2 shows the schedule of efficacy variable assessments.
                                                
50 Clarified that assessment of secondary variable of change in retinal perfusion status will include 
screening/baseline combined visit per Amendment 1, Modification 3 (see Section 15.1.1.3).
51 Clarified that assessment of exploratory variable of perfusion status of the retina by wide-field FA will include 
screening/baseline combined visit. per Amendment 1, Modification 9 (see Section 15.1.1.9).


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Table 9-2:
Schedule of Efficacy Variable Assessments
WEEK 24
WEEK 52
WEEK 76
PRIMARY EFFICACY VARIABLES
The proportion of subjects who gain ≥15 letters in BCVA on 
the ETDRS chart compared with baseline at Week 76
X
The proportion of subjects with a mean treatment interval 
between injections of ≥8 weeks from the last actual visit of the 
initiation phase to Week 76
X
SECONDARY EFFICACY VARIABLES
The change in BCVA as measured by the ETDRS letter score 
from baseline to Weeks 24, 52, and 76
X
X
X
The change in CRT from baseline to Weeks 24, 52, and 76
X
X
X
The number of injections from baseline to Week 76
X
The mean treatment interval between injections from baseline 
to Week 76
X
The proportion of subjects who gain ≥15 letters in BCVA on 
the ETDRS chart compared with baseline at Weeks 24 and 52
X
X
The change in retinal perfusion (FA/FP) status from 
screening/baseline52 to Weeks 24, 52, and 76
X
X
X
The proportion of subjects with absence of fluid at Weeks 24, 
52, and 76
X
X
X
EXPLORATORY EFFICACY VARIABLESa
Perfusion status of the retina assessed by wide-field FA at 
screening/baseline53 Weeks 24, 52, and 76
X
X
X
OCT angiography measures for assessing perfusion status of 
the retina and examination of morphological changes related to 
disease progression in CRVO at baseline, Weeks 24, 52, and 
76
X
X
X
Full-field ERG assessments at baseline, Weeks 24, 52, and 76
X
X
X
Status of RAPD at baseline, Weeks 24, 52, and 76
X
X
X
Abbreviations: BCVA, best-corrected visual acuity; CRT, central retinal thickness; CRVO, central retinal vein occlusion; 
ERG, electroretinogram; ETDRS, Early Treatment Diabetic Retinopathy Study; FA, fluorescein angiography; FP, 
fundus photography; OCT, optical coherence tomography; RAPD, relative afferent pupillary defect.
a:
At selected sites where instrumentation and technical competence are available. If screening and baseline visits are 
combined, these assessments should be performed at the initial visit.54
                                                
52 Clarified that assessment of secondary variable of change in retinal perfusion status will include 
screening/baseline combined visit per Amendment 1, Modification 3 (see Section 15.1.1.3).
53 Clarified that exploratory variable of perfusion status will be assessed by wide-field FA including at 
screening/baseline combined visit per Amendment 1, Modification 9 (see Section 15.1.1.9).
54 Added that assessments should be performed at the initial visit if screening and baseline visits are combined 
per Amendment 1, Modification 28 (see Section 15.1.1.28).


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9.4.4
Efficacy procedures
Assessments of efficacy will include BCVA, SD-OCT, and FA/FP. At selected sites where 
instrumentation and technical competence is available, assessments will also include 
wide-field FA, OCT angiography, and full-field ERG.
Study manual refers to all manuals used in the study including central reading evaluation and 
BCVA assessment.
9.4.4.1
Best-corrected visual acuity
Visual function of the study eye and the fellow eye will be assessed at each study visit using 
the ETDRS visual acuity chart starting at 4 meters. Visual acuity examiners must be certified 
to ensure consistent measurement of BCVA. A detailed protocol for conducting visual acuity 
testing and refraction is provided in the study manual.
9.4.4.2
Spectral domain optical coherence tomography
Retinal characteristics such as CRT will be evaluated by SD-OCT in both eyes at every study 
visit. Images of the study eye will be captured and assessed by study-site personnel.
Initially, the SD-OCT images taken at the study site of up to 2 volunteers per site may be 
assessed by the central reading site to certify the site for central reading. During the study, all 
SD-OCT images will be reviewed and assessed by readers at the central reading center.
Additional details regarding the SD-OCT procedure will be provided in the study manual.
All SD-OCT assessments will be archived as part of the subject’s source documentation.
9.4.4.3
Fluorescein angiography and fundus photography – amended
The anatomical state of the retinal vasculature of the study eye will be evaluated by 
funduscopic examination, FP and FA. Fundus photography and FA obtained at the screening 
visit will be reviewed by the central reading center to confirm eligibility. During the study, all 
additional scheduled FA and FP images will be reviewed and assessed by readers at the 
central reading center.
To evaluate perfusion status, FA and FP will be performed on subjects according to the 
schedule as described in Section 9.2. The area of posterior retinal capillary non-perfusion will 
be measured on FAs by certified graders at the central reading center.
In addition to the required FA/FP evaluations at screening/baseline, Weeks 24, 52, and 76, 
and the early termination visit, the investigator may perform additional FA/FP evaluations at 
other times during the study based on his/her medical judgment and standard of care. At 
screening/baseline, FA/FP will be assessed in both eyes. Unless there are signs of vein 
occlusion in the fellow eye, FA and FP will not be assessed in the fellow eye at Weeks 24, 52, 
76, or at the early termination visit. As such images would be obtained outside the framework 
of this protocol, they should not be routinely forwarded by the investigator/study site to the 
central reading center. Traditional FA/FP examinations can be combined with wide-field 
examination if possible. A separate fluorescein injection, especially, should be 


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avoided.55Additional details regarding the FA and FP procedure will be provided in the study 
manual.
All FA and FP images will be archived as part of the subject’s source documentation.
9.4.4.4
Wide-field fluorescein angiography – amended
Angiographic images will be captured for a subpopulation at selected sites using 
instrumentation with so-called “wide-field” or “ultra-wide-field” capture systems, which can 
increase the viewable retinal surface from 30° up to 50° to 200° for visualization of the 
perifoveal area. A shortcoming of most existing studies is the lack of visualization of the 
retinal periphery, which is limited by the standard 30° or 60° images of traditional FA. Even 
with composite images, which can provide a 75° view of the retina, the majority of the retinal 
periphery is still not visualized. Thus, limited information is available about the role that this 
region may play in retinal ischemia, macular edema, and vision loss in eyes with RVO. 
Wide-field FA provides a new method to visualize more than 100° of the retina using a 
non-contact lens–based system to assess peripheral perfusion status in RVO.
Wide-field FA of both eyes will be performed at baseline (or initial visit at combined 
screening/baseline),56 and of only the study eye at Weeks 24, 52, and 76, and the early 
termination visit (and in the fellow eye if there are signs of vein occlusion). Specific 
registration procedures will be employed to reproduce the location for imaging longitudinally. 
The protocol for imaging and analysis procedures will be described in the study manual. 
Peripheral perfusion status will be reported in terms of clock position (e.g. 12 o’clock).
All images will be assessed at the central reading center. All wide-field FA images will be 
archived as part of the subject’s source documentation.
9.4.4.5
Optical coherence tomography angiography – amended
Optical coherence tomography angiography will be assessed for a subpopulation at selected 
sites using OCT angiography.
Optical coherence tomography angiography assists in the visualization of the ocular 
vasculature and quantification of blood flow at the posterior pole of the eye. The OCT 
angiography technique offers 2 major advantages over standard techniques such as FA: no 
dye is required and depth resolution is provided for visualization of retinal capillaries. Optical 
coherence tomography angiography has the potential to improve our abilities to diagnose and 
monitor ocular vascular diseases.
Optical coherence tomography angiography images of both eyes will be captured at baseline 
(or initial visit at combined screening/baseline)57 and of only the study eye at Weeks 24, 52, 
and 76, and the early termination visit (and in the fellow eye if there are signs of vein 
                                                
55 When possible, FA/FP examinations can be combined with wide-field examination and separate fluorescein 
injection should be avoided per Amendment 1, Modification 26 (see Section 15.1.1.26).
56 Added that assessment should be performed at initial visit if screening and baseline visits are combined per 
Amendment 1, Modification 28 (see Section 15.1.1.28).
57 Added that assessment should be performed at initial visit if screening and baseline visits are combined per 
Amendment 1, Modification 28 (see Section 15.1.1.28).


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occlusion). Additional details regarding the imaging measures will be provided in the study 
manual.
All OCT angiography images will be assessed at the central reading center.
All OCT angiography images will be archived as part of the subject’s source documentation.
9.4.4.6
Full-field electroretinography – amended
Electroretinograms will be taken for a subpopulation at selected sites using full-field ERG.
Electroretinography is a non-invasive examination that was introduced in 1945 by Karpe (20) 
as a possible prognostic marker in patients with macular edema secondary to CRVO. Since 
then, others have demonstrated that different parameters of the ERG can be helpful in 
distinguishing between ischemic and non-ischemic forms of CRVO. Hayreh confirmed that 
full-field ERG specifically decreased B-wave amplitude coupled with the so-called RAPD 
test, differentiated ischemic from non-ischemic CRVO in subjects with a 97% sensitivity, and 
that this combined testing constituted the most reliable method for identifying ischemic 
subjects (21).
Full-field ERG is a widely used electrophysiologic test of retinal function. The International 
Society for Clinical Electrophysiology of Vision (ISCEV) established standardized basic 
clinical ERG protocols so that comparable ERGs could be recorded across different sites. The 
ISCEV standard for full-field clinical ERG (2015 update) will serve as a methodological basis 
for this study (22). Electroretinography may be more sensitive to detect ischemia than 
angiography, especially in the early stages when retinal hemorrhages may limit angiographic 
interpretation.
Full-field ERGs will be performed in both eyes at baseline (or initial visit at combined 
screening/baseline)58 and only in the study eye at Weeks 24, 52, and 76, and the early 
termination visit (and in the fellow eye if there are signs of vein occlusion). Additional details 
regarding the full-field ERG procedure will be provided in the study manual.
Electroretinogram images will be assessed at the site by the investigator.
All full-field ERG images will be archived as part of the subject’s source documentation.
9.5
Pharmacokinetics/pharmacodynamics
Not applicable.
                                                
58 Added that assessment should be performed at initial visit if screening and baseline visits are combined per 
Amendment 1, Modification 28 (see Section 15.1.1.28).


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9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom, or disease) in a subject 
or clinical investigation subject after providing written informed consent for participation in 
the study. Therefore, an AE may or may not be temporally or causally associated with the use 
of a medicinal (investigational) product.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory findings, or 
other abnormal findings.

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs. This includes intercurrent illnesses.
Definition of serious adverse event
A serious AE (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 that hypothetically 
might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least 1 of the following exceptions is met:

The admission results in a hospital stay of less than 12 hours


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
The admission is pre-planned (i.e. 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.
9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:

Mild

Moderate

Severe
9.6.1.2.3
Causal relationship
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the eCRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”


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An assessment of “no” would include:

The existence of a highly likely alternative explanation (e.g. mechanical bleeding at 
surgical site),
or

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.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:

The temporal sequence from drug administration: the event should occur after the drug 
is given. The length of time from drug exposure to event should be evaluated in the 
clinical context of the event.

Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Subject’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question.

Underlying, concomitant, intercurrent diseases: Each event should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have.

Concomitant medication or treatment: The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them 
might have caused the event in question.

Known response pattern for this class of drug: Clinical/preclinical.

Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.

The pharmacology and pharmacokinetics of the study treatment: the pharmacokinetic 
properties (absorption, distribution, metabolism, and excretion) of the study treatment, 
coupled with the individual subject’s pharmacodynamics should be considered.

The assessment is not possible.
In this study, AEs will be assessed as related/not related to the study drug, IVT injection, and 
other protocol-specified procedures. The causal relationship will be recorded using the 
following terms:
Evaluation of relationship to the study drug

Not related: AEs that were clearly and incontrovertibly due to causes other than the 
study drug (e.g. disease, environment), or were felt with a reasonable degree of 
certainty to be unrelated to the study drug.


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


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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 AEs at all stages of the examination. Thus, the 
subject should be closely observed by the investigator. In case of ongoing drug- or 
injection-related AEs and medically relevant AEs at the end of the study, the investigator 
should monitor the subject and document the outcome on the subject’s source documents.
The investigator must record on the respective eCRF pages all AEs occurring in the period 
between the signing of the informed consent and the end of the follow-up phase; after the end 
of the follow-up phase, there is no requirement to actively collect AEs, including deaths. The 
type of information that should be assessed and recorded by the investigator for each AE is 
listed in Section 9.6.1.2.
“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
underlying AE(s).
For all AEs and SAEs, the sponsor has to carry out a separate assessment for expectedness, 
seriousness, and causal relationship to study drug.
Any AE occurring up to 30 days after the last injection of IVT aflibercept is to be documented 
regardless of the relationship to the study drug or the seriousness of the event, and reported in 
accordance with this protocol (i.e. not as a spontaneous report). For any drug-related AE 
occurring after 30 days after the last application of IVT aflibercept, the standard procedures 
that are in place for spontaneous reporting will be followed. If a subject prematurely 
withdraws from the study, AEs should be recorded until withdrawal or 30 days after the last
dose of study drug, whichever is later.
9.6.1.4
Reporting of serious adverse events
The definition of an SAE 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.


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All SAEs occurring during the observation period defined in Section 9.6.1.3 must 
immediately (within 24 hours of the investigator’s awareness) be reported to the recipient 
detailed in the manual. An SAE form must also be completed within 24 hours of the 
investigator awareness and forwarded to the designated recipient. Each SAE must be followed 
up until resolution or stabilization by submission of updated reports to the designated 
recipient. For this, an AE page in the eCRF as well as the complementary pages provided in 
the Investigator File must be completed for each SAE.
Serious AEs will be collected up until 30 days after the last dose of study drug or the early 
termination visit, whichever is later.
Serious AEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the Independent Ethics Committees/Institutional Review Boards
Notification of the Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs) about all relevant events (e.g. SAEs, suspected unexpected serious adverse reactions 
[SUSARs]) will be performed by the sponsor and/or by the investigator according to all 
applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.
9.6.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the Company 
Core Data Sheet.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document (Company Core Data Sheet) and according to all local regulations.
9.6.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a study subject during 
her participation in this study, although a pregnancy per se is not considered an SAE. The 
outcome of the pregnancy should be followed up carefully, and any outcome of the mother 
and the child at delivery should be reported.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
The child’s health should be followed up for a post-natal period of not less than 3 months.


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9.6.3
Further safety
9.6.3.1
Pregnancy test – amended
All women of child-bearing potential will have a urine pregnancy test at screening. If the 
result of a urine pregnancy test is positive, a serum pregnancy test to confirm results will be 
done at a local laboratory. After screening, a urine pregnancy test for women of childbearing 
potential is mandatory at every treatment visit (prior to injection) in all countries where it is 
required by local regulations. If required by local regulations, a pregnancy test should be 
performed for women of childbearing potential at the End of Study visit.59
Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.
9.6.3.2
Physical examination
At screening (Visit 1), a complete physical examination will be performed. Abnormal 
physical examination findings are recorded either as medical history or as AEs (see 
Section 9.6.1.1).
9.6.3.3
Vital signs (temperature, blood pressure, and heart rate)
Temperature, blood pressure, and heart rate will be measured at all study visits (and early 
termination if applicable). Temperature and blood pressure should be taken in a consistent 
manner.
9.6.3.4
Ocular safety
Assessments of ocular safety will include IOP, indirect ophthalmoscopy, and slit lamp 
biomicroscopy. Relative afferent pupillary defect will also be assessed.
9.6.3.4.1
Intraocular pressure
Intraocular pressure will be measured in both eyes at all visits. At visits where the study drug 
is administered, IOP will be measured pre-dose in both eyes and again 30 to 60 minutes 
post-dose in the study eye. Any case of new-onset clinically significant increase in IOP that 
does not respond to treatment (not including the transient pressure rise observed immediately 
after IVT injection) must be recorded by the investigator as an AE.
Intraocular pressure is to be measured using applanation tonometry (Goldmann or Tono-Pen). 
The same method of IOP measurement must be used in each subject throughout the study. 
Non-contact tonometry may be used, but re-examination with applanation tonometry is 
recommended in cases where pathological IOP (> 22 mm Hg) is detected.
For the measurement of IOP, a local anesthetic combined with fluorescein must be topically 
applied to the eye being tested (e.g. 1 drop of oxybuprocain plus fluorescein).
                                                
59 Added that pregnancy testing is mandatory for women of childbearing potential at every treatment visit prior to 
injection and at End of Study visit if required by local regulations per Amendment 1, Modification 24 (see 
Section 15.1.1.24).


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9.6.3.4.2
Indirect ophthalmoscopy
Indirect ophthalmoscopy is to be obtained in a standard manner (i.e. usually using a 
head-mounted light source and a 20-diopter lens).
9.6.3.4.3
Slit lamp biomicroscopy
The slit lamp examination is to be performed in both the study eye and the fellow eye 
irrespective of whether the fellow eye has macular edema secondary to CRVO. If the fellow 
eye is not diagnosed with macular edema secondary to CRVO, it will be followed to 
determine whether macular edema secondary to CRVO develops.

Anterior segment assessment: The examination of the anterior segment is to be 
performed only with the slit lamp without any additive drugs or lenses.

Posterior segment assessment: The posterior segment should be examined with the slit 
lamp and the appropriate lens. For this examination, the pupil of the eye must be 
dilated (mydriasis) with 2 to 3 drops of phenylephrin-tropicamide (or any other 
mydriatic) applied topically to the eye.
9.6.3.4.4
Gonioscopy
Subjects will be evaluated for the development of neovascularization and/or scarring of the 
iridocorneal angle by gonioscopy in conjunction with slit lamp biomicroscopy. Subjects with 
neovascularization of the iris or neovascularization of the anterior chamber angle at screening 
should be excluded from the study.
The evaluation will be conducted at screening and at Week 76 and the early termination visit, 
and may be repeated if needed as determined by the investigator. Gonioscopy will be 
performed in the study eye only.60
9.6.3.4.5
Relative afferent pupillary defect assessment
Testing for RAPD will be conducted at baseline, Weeks 24, 52, and 76, and the early 
termination visit. Testing will be conducted in both eyes.61 A detailed protocol for conducting 
RAPD testing is provided in the study manual.
9.7
Appropriateness of procedures and measurements
All efficacy and safety variables and the methods by which they are assessed are standard 
variables and methods in clinical studies and in ophthalmic practice. They are widely used 
and generally recognized as reliable, accurate, and relevant.
                                                
60 Removed wording that gonioscopy is performed after OCT and before FA/FP per Amendment 1, 
Modification 29 (see Section 15.1.1.29).
61 Removed citation to reference Thompson HS,et al per Amendment 1, Modification 33 (see Section 15.1.1.33).


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10.
Statistical methods and determination of sample size
10.1
General considerations
Further details on statistical evaluation, including format and content of tables, will be 
detailed in the statistical analysis plan (SAP). The SAP will be finalized before study database 
lock.
All variables will be analyzed descriptively with appropriate statistical methods: continuous 
variables by sample statistics (i.e. mean, standard deviation, median, quartiles, minimum, and 
maximum) and categorical variables by frequency tables (absolute and relative frequencies). 
Statistical analyses will be performed using Statistical Analysis System (SAS) version 9.2 or 
higher.
Sample size and disposition information by analysis time point will be displayed in a 
frequency table.
10.2
Analysis sets
Populations for analysis will be defined as follows:
The Full Analysis Set will include all enrolled subjects who received any study drug, have a 
baseline BCVA assessment, and have at least 1 post-baseline BCVA assessment. With regard 
to the efficacy evaluation of this study, the Full Analysis Set is considered the primary 
analysis.
The Per-protocol Set will include all enrolled subjects who receive any study drug, have a 
BCVA assessment at study baseline, have at least 1 BCVA assessment at Week 24 or later, 
and do not have a major protocol deviation.
The Safety Analysis Set will include all subjects who receive any study drug under this 
protocol.
A subgroup analysis of the primary endpoint will be performed for each country contributing 
at least 5 patients to the Full Analysis Set.
10.3
Variables and planned statistical analyses
10.3.1
Variables – amended
A complete list of efficacy variables is provided in Section 9.4. Safety variables are detailed 
in Section 9.6.
A ± 7-day window will be allowed for all post-baseline visits.62
                                                
62 Revised wording to clarify that a ± 7-day window will be allowed for all post-baseline visits per Amendment 1, 
Modification 7 (see Section 15.1.1.7).


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10.3.2
Statistical and analytical plans
10.3.2.1
Demography and baseline characteristics
Demographic variables and baseline characteristics will be summarized for all 3 analysis 
populations, depending on the type of data as described in Section 10.1. Medical history will 
be coded by Medical Dictionary for Regulatory Activities (MedDRA) codes and prior and 
concomitant medications by Anatomical Therapeutic Chemical codes (World Health 
Organization Drug Dictionary).
10.3.2.2
Efficacy analyses
10.3.2.2.1 Primary efficacy analyses
The primary efficacy variable analysis will be conducted on the Full Analysis Set and 
Per-protocol Set as defined in Section 10.2.
The co-primary efficacy variables are as follows:

The proportion of subjects who gain ≥15 letters in BCVA on the ETDRS chart 
compared with baseline at Week 76

The proportion of subjects with a mean treatment interval between injections of 
≥8 weeks from the last actual visit of the initiation phase to Week 76
Definition: Gain ≥15 letters in BCVA at Week 76 compared with baseline
Subjects will be considered to be fulfilling this criterion if they show a change from baseline 
to Week 76 in BCVA of greater than or equal to 15 letters.
All subjects who drop out of the study will be deemed to have not met the co-primary efficacy 
variable, except for the following:

If the investigator assesses in a subject who drops out after Week 24 resolution of 
macular edema secondary to CRVO with no need for further treatment with IVT 
aflibercept, the change from baseline to the last measurement of BCVA for this 
subject will be categorized using the last observation carried forward (LOCF)
methodology. As proof of permanent resolution of macular edema, at least 
1 additional, confirmatory monitoring visit is required (after a minimum of 8 weeks 
and no later than the Week 76 visit). Any additional CRT and BCVA measurements at 
subsequent visits need to be consistent with the permanent resolution of macular 
edema as well. In case these conditions are not fulfilled, the respective subject is 
considered to have not met the variable.
Definition: Proportion of subjects with a mean treatment interval between injections of 
≥8 weeks from the last actual visit of the initiation phase to Week 76
The co-primary efficacy variable of the proportion of subjects with a mean treatment interval 
between injections of ≥8 weeks from the last actual visit of the initiation phase to Week 76 
will be assessed as follows:

For subjects completing the study to Week 76, the mean treatment interval between 
injections from the last actual visit of the initiation phase to Week 76 will be 
calculated as follows:


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(date of last injection up to and including Week 76 visit – date of last 
actual visit of initiation phase)/(number of injections taken from last visit 
of initiation phase until immediately prior to the Week 76 visit – 1)

Should the mean treatment interval for a subject between injections from the last 
actual visit of the initiation phase to Week 76 be ≥56 days, then the mean treatment 
interval is deemed to be ≥8 weeks and the co-primary efficacy variable has been met, 
if the mean is < 56 days, then the co-primary efficacy variable has not been met for 
this subject.

All subjects who drop out of the study will be deemed to have not met the co-primary 
efficacy variable, except for the following:
Subjects who drop out after Week 24 and who are defined by the investigator 
as having a permanent resolution of macular edema are considered to have met 
the co-primary efficacy variable. For subjects considered by the investigator to 
have a permanent resolution of macular edema, at least 1 additional 
confirmatory visit is required (after a minimum interval of 8 weeks from the 
visit when resolution was determined and up to the regular Week 76 visit).
The approach to handle discontinued subjects is considered sufficiently conservative with 
regard to assessing mean treatment interval. The number and percentage of subjects who gain 
≥15 letters in BCVA on the ETDRS chart compared with baseline at the Week 76 variable 
and the subjects with a mean treatment interval between injections of ≥8 weeks from the last 
actual visit of initiation phase to Week 76 will be presented, and, in addition, the mean and 
median treatment interval and frequency from baseline to Week 76, and during the T&E 
phase, will be described based on 95% confidence intervals.
10.3.2.2.2 Secondary and exploratory efficacy variables
Analyses of secondary, other, and exploratory efficacy variables will be conducted on the Full 
Analysis Set as defined in Section 10.2.
The secondary efficacy variables are as follows:

The change in BCVA as measured by the ETDRS letter score from baseline to 
Weeks 24, 52, and 76

The change in CRT from baseline to Weeks 24, 52, and 76

The number of injections from baseline to Week 76

The mean treatment interval between injections from baseline to Week 76

The proportion of subjects who gain ≥15 letters in BCVA on the ETDRS chart 
compared with baseline at Weeks 24 and 52

The change in retinal perfusion (FA/FP) status from screening/baseline63 to Weeks 24, 
52, and 76
                                                
63Clarified that assessment of secondary variable of change in retinal perfusion status will include 
screening/baseline combined visit per Amendment 1, Modification 3 (see Section 15.1.1.3).


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
The proportion of subjects with absence of fluid at Weeks 24, 52, and 76
The exploratory variables are as follows:

Perfusion status of the retina assessed by wide-field at screening/baseline,64 Weeks 24, 
52, and 76

OCT angiography measures for assessing perfusion status of the retina and 
examination of morphological changes related to disease progression in CRVO at 
baseline, Weeks 24, 52, and 76

Full-field ERG assessments at baseline, Weeks 24, 52, and 76

Status of RAPD at baseline, Weeks 24, 52, and 76
For other efficacy variables, with regard to proportion of responder-based variables, subjects 
discontinued until the respective time point will be considered as non-responders (if no proof 
of permanently resolved macular edema exists). For change from baseline-based variables, 
missing data will be imputed by means of LOCF method. Sensitivity analyses for these 
variables will be provided based on the multiple imputation method as outlined in the SAP. In 
addition, observed case-based analyses will be provided for secondary efficacy variables.
For those variables for which change will be evaluated, 95% confidence intervals based on 
t-distribution–based methodology will be provided.
For the change in retinal perfusion status, the number of subjects perfused at baseline will be 
compared with the number of subjects perfused at Weeks 24, 52, and 76, by means of 95% 
confidence intervals using exact McNemar methodology. Similar approaches will be used for 
variables regarding proportions of subjects, if applicable.
More details on tests with regard to statistical analysis (going beyond what is described in 
Section 10.3.2.2.3) of the co-primary, secondary, and exploratory efficacy variables, including 
sensitivity analyses, will be provided in the SAP.
10.3.2.2.3 Statistical test
By means of evaluating both co-primary variables, the exact 1-sample binomial test will be 
used for both co-primary variables.
Study success requires to prove that both a gain of ≥15 letters in BCVA at Week 76 is 
reached by at least 40% of subjects, and, additionally, at least 50% of subjects have a mean 
treatment interval of ≥8 weeks in the T&E phase.
In further explanations, the null hypothesis for evaluation of the co-primary variable 1 
(proportion of subjects with gain of ≥15 letters in BCVA at Week 76) will be labeled as H01, 
the alternative hypothesis as H11.
Similarly, for evaluation of the co-primary variable 2 (proportion of subjects with a mean 
treatment interval of ≥8 weeks), the null-hypothesis will be labeled as H02, while the 
alternative hypothesis will be labeled as H12.
                                                
64 Exploratory variable assessment clarified to include screening/baseline combined visit per Amendment 1, 
Modification 9 (see Section 15.1.1.9).


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Then, the primary hypothesis H0 will be tested statistically, as:

H0: H01: p1 < 40%
or 
H02: p2 < 50% versus

H1: H11: p1 ≥ 40%
and
H12: p2 ≥ 50%
Where p1 is the proportion of subjects with a ≥15-letter gain in BCVA at Week 76, while p2 is 
the proportion of subjects with a mean treatment interval of ≥8 weeks. The significance level 
α for this 2-sided test will be 5%.
Given the statistical paradigm of the intersection-union test, the test on H0 can be performed 
as independent statistical tests on H01 and H02.
The subgroup of subjects having a mean treatment interval of ≥8 weeks will be analyzed with 
regard to gain of ≥15 letters in BCVA at Week 76 as a sensitivity analysis.
The primary study result will be from the evaluation of the co-primary efficacy variables, 
based on the Full Analysis Set.
10.3.2.3
Safety analysis
The safety analysis will be conducted in the Safety Analysis Set. Treatment-emergent AEs 
will be presented by MedDRA preferred term within primary system organ class and 
summarized. Intensity and causal relationship to the investigational product will be analyzed 
descriptively. Serious AEs, including narratives, will be documented separately.
Other safety variables (e.g. IOP measurements and vital signs) will be analyzed descriptively 
including changes from baseline.
10.3.3
Missing data/dropouts
Data from subjects who drop out of the study will be included in all summaries where 
possible.
Further details are provided in the SAP.
10.4
Determination of sample size
Sample size estimation was performed with PASS (Power Analysis and Sample Size) 
software, version 11.
For the overall power of the study to reach ≥90%, the required power for each of the 
2 co-primary efficacy tests has to be ≥94.9%, resulting from the intersection-union test 
strategy.
For the co-primary efficacy variable related to the proportion of subjects with a ≥15-letter 
gain in BCVA at Week 76, to detect a proportion of at least 40% (null hypothesis 
H0: p [≥15 letters] < 40%), 150 fully evaluable subjects result in a power to reject this 
co-primary null-hypothesis of 94.9% (under assumption of true proportion in population of 
55%).65
                                                
65 In the GALILEO trial, the percentage of subjects with ≥15 letter gain until Week 76 (in the aflibercept-treated 
arm) was 57.3%. (footnote to text; not a modification)


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For the co-primary efficacy variable related to proportion of subjects with a mean treatment 
interval of ≥8 weeks in the T&E phase at Week 76, to detect a proportion of at least 50% 
(null hypothesis H0: p [≥8 weeks]) < 50%), 150 fully evaluable subjects result in a power to 
reject this co-primary null-hypothesis of 95.5% (under assumption of true proportion in 
population of 65%).66
The study power to have a significant primary result (i.e. significant result in both co-primary 
variables) is therefore 94.93%*95.52% = 90.68%.
The dropout rate before Week 24 is considered to be about 6.5%,67 resulting in a recruitment 
of 160 subjects to have 150 fully evaluable subjects in the T&E phase.
No additional subjects to account for dropouts are required.
A sufficient number of subjects will be screened to enroll 160 subjects plus 60 volunteers for 
SD-OCT/FA/FP certification.
10.5
Planned interim analyses
No interim analysis is planned.
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be a validated electronic data capture (EDC) 
system called RAVE. Subject data necessary for analysis and reporting will be 
entered/transmitted into a validated database or data system.
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE that Bayer has licensed from 
Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions Worldwide 
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. The CRO extensively applies the logic to ensure data are complete and 
reflect the clinical data requirements of the study. Data queries resulting from the application 
of the software logic are resolved by the site personnel. The data are stored at a secure host 
facility maintained by Medidata Solutions Worldwide and transferred on a periodic basis to 
Bayer's internal computer system via a secure Virtual Private Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer, CRO, and external investigator site personnel seeking 
access must go through a thorough RAVE training process before they are granted access to 
RAVE for use in Bayer's clinical studies. Training records are to be maintained.
                                                
66 Post-hoc evaluations on the GALILEO trial data had shown that about 65% of subjects had a treatment interval 
of ≥8 weeks (in the PRN phase of GALILEO). (footnote to text; not a modification)
67 Expected dropout rate, taking into account dropout behavior in the GALILEO trial until Weeks 24 (for 
aflibercept-treated arm). (footnote to text; not a modification)


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All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made, and the date and time
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.
Source documentation
It is the expectation of the sponsor that data entered into the eCRF has source documentation 
available at the site. All data must be available in source documents before entry into eCRFs. 
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the site 
to identify the source data for key data points collected and the monitor will work with the site 
to complete this.
Data recorded from screening failures
Data of “only screened subjects” will be recorded at least as source data, as far as the reason 
for the premature discontinuation is identifiable. At minimum, the following data should be 
recorded in the eCRF:

Demographic information (subject number; year of birth/age; 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 eCRF in 
addition to the data specified above:

All information related to the SAE such as:
o
Concomitant medication
o
Medical history
o
Other information needed for SAE complementary page
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 


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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 eCRF as well as for data from other 
sources (e.g. laboratory, electrocardiogram, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
11.4
Missing data
Most important is to avoid missing data by monitoring in time for completeness 
(Section 10.3.2.2.1) and investigators’ training, especially to motivate subjects to be 
compliant with the study protocol.
Moreover, the risk of bias to the efficacy results due to missing data may be decreased in this 
study, since all subjects will receive IVT aflibercept during the course of this study. With 
regard to primary efficacy, discontinued subjects will be handled as defined in 
Section 10.3.2.2.1.
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 IECs/IRBs 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.


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11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
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.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due to, but not limited 
to, the following reasons:

If risk-benefit ratio becomes unacceptable owing to, for example,
o
Safety findings from this study (e.g. SAEs)
o
Results of parallel clinical studies
o
Results of parallel animal studies 
(e.g. on toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g. recruitment rate; dropout 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. IECs/IRBs; 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.


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Details for an individual subject's withdrawal can be found in Section 6.3.1.
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel – amended
All other study personnel are identified in a separate personnel list (not part of this clinical 
study protocol) as appropriate. This list will be updated as needed; an abbreviated version 
with personnel relevant for the centers will be available in each center’s investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained, and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before subject recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study 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 the ophthalmic images defined in 
Section 9.68
External data evaluation bodies
The sponsor may decide to institute a Steering Committee to guide the trial in all aspects of 
safety and efficacy and must ensure that all relevant information is provided by investigators. 
The composition of the team, the functional roles, and responsibilities will be specified in the 
Charter.69
Finally, an adjudication committee will perform an additional analysis of arterial thrombotic 
events (ATEs) based on the Antiplatelet Trialists' Collaboration (APTC) endpoint of non-fatal 
myocardial infarction, non-fatal stroke, and fatal vascular events, including fatal hemorrhages 
and sudden unexplained death. Details will be described in the Adjudication Committee 
Charter.70
                                                
68 Added that ophthalmic images will be evaluated by an independent central reading center per Amendment 1, 
Modification 34 (see Section 15.1.1.34).
69 Steering Committee may be used to guide the study; responsibilities will be outlined in the Charter per 
Amendment 1, Modification 35 (see Section 15.1.1.35).
70 An Adjudication Committee will perform additional analysis of arterial thrombotic events based on the listed 
APTC endpoints per Amendment 1, Modification 36 (see Section 15.1.1.36).


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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 
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 IECs/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 forwarded to the sponsor. The responsible unit (e.g. IEC/IRB, 
head of the study center/medical institution) must supply to the sponsor, upon request, a list of 
the EC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
All relevant information on the study will be summarized in integrated subject information 
sheets and ICFs provided by the sponsor. A sample subject information and ICF is provided 
as a document separate to this protocol.


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Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject/legal representative or proxy consenter (if the subject is 
under legal protection) 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/legal representative or proxy consenter 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 in Section 9.2.5 to be conducted after withdrawal of consent.

The subject’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the SAP.

Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such 
as blood, urine, or tissues); these data would also be retained and statistically analyzed 
in accordance with the SAP. The subject has the right to object to the generation and 
processing of this post-withdrawal data. For this, he/she needs to sign a corresponding 
declaration of objection; alternatively, the subject’s oral objection may be documented 
in the subject’s source data.
Each subject/legal representative or proxy consenter will have ample time and opportunity to 
ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision.
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the ICF 
and has done so, may he/she enter the study. Additionally, the investigator and other 
information provider (if any) 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 screening study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
If the subject is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the sponsor and the 
investigator). This is to be documented by a signature from the informing physician as well as 
by a signature from the witness.
For adults under legal protection, consent shall be given by the legal guardian(s). The consent 
of an adult under legal protection shall also be requested where such a person is able to 


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express his/her own will. His/her refusal or the withdrawal of his/her consent may not be 
disregarded.
The ICF 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 ICF. 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 
ICF. Any revised written ICF and written information must receive the IEC/IRB`s 
approval/favorable opinion in advance of use.
13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations. The sponsor is interested in the publication of the 
results of every study it performs.
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study. However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission. To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract. 
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.
13.6
Compensation for health damage of subjects/insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor. Only the subject number will be recorded 
in the eCRF, and if the subject name appears on any other document (e.g. pathologist report), 
it must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the subjects will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 


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information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.


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14.
Reference list
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2392/human_med_001598.jsp&mid=WC0b01ac058001d124  71
3. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein 
occlusion: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc. 
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4. Ryan SJ, Hinton DR, Schachat AP, Wilkinson P, editors. Retina. St. Louis 
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5. Spaide R. Ranibizumab according to need: a treatment for age-related macular 
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therapy. Retina. 2010 Oct;30(9):1368-75.
7. Gupta OP, Shienbaum G, Patel AH, Fecarotta C, Kaiser RS, Regillo CD. A treat 
and extend regimen using ranibizumab for neovascular age-related macular 
degeneration clinical and economic impact. Ophthalmology. 2010 
Nov;117(11):2134-40.
8. Oubraham H, Cohen SY, Samimi S, Marotte D, Bouzaher I, Bonicel P, et al. 
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study of ranibizumab in exudative age-related macular degeneration. Retina. 
2011 Jan;31(1):26-30.
9. Shienbaum G, Gupta OP, Fecarotta C, Patel AH, Kaiser RS, Regillo CD. 
Bevacizumab for neovascular age-related macular degeneration using a 
treat-and-extend regimen: clinical and economic impact. Am J Ophthalmol. 
2012 Mar;153(3):468-73.
10. Toalster N, Russell M, Ng P. A 12-month prospective trial of inject and extend 
regimen for ranibizumab treatment of age-related macular degeneration. Retina. 
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11. Pruente C. Efficacy and Safety of Ranibizumab in "Treat and Extend" Treatment 
Algorithms Versus Ranibizumab As Needed in Patients With Macular Edema 
                                                
71 Reference list change, SmPC replaced Investigator’s Brochure and moved from reference list 13 to 2 per 
Amendment 1, Modification 15.1.1.4 (see Section 15.1.1.4).


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and Visual Impairment Secondary to Diabetes Mellitus (RETAIN). Presented at 
AAO 2013.
12. Mrejen S, Jung J, Gallego-Pinazo R, et al. Long-Term Visual Outcomes for a 
Treat and Extend Anti-VEGF Regimen in Eyes with Neovascular Age-Related 
Macular Degeneration. Poster presented at ARVO 2013.
13. Shroff D, Mehta DK, Arora R, Narula R, Chauhan D. Natural history of macular 
status in recent-onset branch retinal vein occlusion: an optical coherence 
tomography study. Int Ophthalmol. 2008 Aug;28(4):261-8.
14. Finkelstein D. Ischemic macular edema. Recognition and favorable natural 
history in branch vein occlusion. Arch Ophthalmol. 1992 Oct;110(10):1427-34.
15. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, et al. 
Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular 
degeneration. Ophthalmology. 2012 Dec;119(12):2537-48.
16. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen 
QD, et al. Intravitreal aflibercept injection for neovascular age-related macular 
degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 
2014 Jan;121(1):193-201.
17. Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, et al. 
Binding and neutralization of vascular endothelial growth factor (VEGF) and 
related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 
2012 Jun;15(2):171-85.
18. Stewart MW, Rosenfeld PJ, Penha FM, Wang F, Yehoshua Z, Bueno-Lopez E, 
et al. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with 
intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial 
growth factor Trap-eye). Retina. 2012 Mar;32(3):434-57.
19. Fauser S, Schwabecker V, Muether PS. Suppression of intraocular vascular 
endothelial growth factor during aflibercept treatment of age-related macular 
degeneration. Am J Ophthalmol. 2014 Sep;158(3):532-6.
20. Karpe G. The basis of clinical electroretinography. Acta Ophthalmol. 1945; 
24(suppl):1–118.
21. Haeyreh SS, Zimmerman MB. Fundus changes in central retinal vein occlusion. 
Retina. 2015 Jan;35(1):29-42.
22. McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, et 
al. ISCEV Standard for full-field clinical electroretinography (2015 update). Doc 
Ophthalmol. 2015 Feb;130(1):1-12.


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23. Aiello LP, Brucker AJ, Chang S, Cunningham ET Jr, D'Amico DJ, Flynn HW Jr, 
et al. Evolving guidelines for intravitreous injections. Retina. 2004 
Oct;24(5 Suppl):S3–19.72
                                                
72 Reference removed for Thompson HS, et al per Amendment 1, Modification 15.1.1.33 (see Section 15.1.1.33).


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15.
Protocol amendments
Editorial note
In the Section 15.1.2 on changes to the protocol text, all protocol sections affected by the 
respective amendment are detailed; the sequence of the sections follows the structure of the 
most recent previous protocol version. As applicable, changes to the protocol text are 
indicated as follows:

Addition of a whole new portion: Brief identification of the new portion

Removal of a whole portion: Complete display of the removed portion, formatted as 
crossed out

Editing of an existing portion: Comparative presentation of “Old text” versus “New 
text”, with “Old text” referring to the most recent previous protocol version. Deletions 
are crossed out in the “Old text”. Additions are underlined in the “New text”.

Tables/figures: The term “amended” is added to the caption.

Terminological changes: Brief specification of the terminological change
Corrections of typos or omissions are not highlighted.
15.1
Amendment 1, dated 20 Apr 2016
15.1.1
Overview of changes to the study
15.1.1.1
Modification 1: Adjustments to Treat and Extend treatment interval
Wording change from “will be adjusted” to “may be adjusted”.
Rationale: To clarify that frequency of injections may be adjusted to maintain stable visual 
and anatomic outcomes.
The following protocol sections are affected by this modification:
Synopsis Section Methodology
Section 7.1.1 Treat and Extend treatment visits
Table 9-1 Schedule of Evaluations and Study Procedures
15.1.1.2
Modification 2: Subjects discontinued from treatment with indications 
of worsening
Deleted text stating that subjects discontinued from treatment for not benefiting from 
continued treatment may resume treatment if retreatment criteria indicate worsening.
Rationale: To clarify that subjects who are withdrawn do not need to be followed-up.
The following protocol sections are affected by this modification:
Synopsis Section Methodology
Table 9-1 Schedule of Evaluations and Study Procedures


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15.1.1.3
Modification 3: Secondary variable change in retinal perfusion status
Secondary efficacy variable of change in retinal perfusion (FA/FP) status will be assessed 
from screening/baseline to Weeks 24, 52, and 76.
Rationale: Clarified that secondary variable of change in retinal perfusion status will include 
data from screening/baseline combined visit.
The following protocol sections are affected by this modification:
Synopsis Section Variables
Section 5 Study design
Section 9.4.2 Secondary efficacy variables
Table 9-2 Schedule of Efficacy Variable Assessments
Section 10.3.2.2.2 Secondary and exploratory efficacy variables
15.1.1.4
Modification 4: Reference change
Referrence list change, SmPC replaced Investigator’s Brochure and moved from reference list 
13 to 2.
Rationale: SmPC relevant (replaced Investigator’s Brochure)
The following protocol sections are affected by this modification:
Section 3 Introduction
Section 14 Reference list
15.1.1.5
Modification 5: Visits for screening and baseline
Screening and baseline visits can be combined.
Rationale: Clarification and correction of text to align with other sections of the protocol.
The following protocol section is affected by this modification:
Section 5 Study design
15.1.1.6
Modification 6: Time point for follow-up
Subjects will continue to be followed to Week 76 or until follow-up is no longer possible.
Rationale: Correction of text to clarify that follow-up to Week 76 is necessary, regardless of 
whether subject requires further injections, providing that follow-up is possible (i.e. subject is 
not lost to follow-up or prematurely discontinued).
The following protocol section is affected by this modification:
Section 5 Study design
15.1.1.7
Modification 7: Window for post-baseline study visits
A ± 7-day window will be allowed for all post-baseline visits.
Rationale: For consistency among all post-baseline visits.


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The following protocol sections are affected by this modification:
Section 5 Study design
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.2.4.1 Treat and Extend visits
Section 10.3.1 Variables
15.1.1.8
Modification 8: Examinations based on investigator’s medical 
judgment and standard of care
Examinations that may be performed at other times during the 76 weeks of the study based on 
the investigator’s medical judgment and standard of care include FA/FP, wide-field FA,OCT 
angiography, and full-field ERG.
Rationale: Specified ERG is full-field and added wide-field FA and OCT angiography 
examinations that may be performed at other times during the study based on the 
investigator’s medical judgment and standard of care.
The following protocol sections are affected by this modification:
Section 5 Study design
Table 9-1 Schedule of Evaluations and Study Procedures
15.1.1.9
Modification 9: Exploratory variable perfusion status of retina
Exploratory variable of perfusion status of the retina will be assessed by wide-field FA at 
screening/baseline, Weeks 24, 52, and 76.
Rationale: Clarified that assessment of exploratory variable of perfusion status of the retina by 
wide-field FA will include screening/baseline combined visit.
The following protocol sections are affected by this modification:
Section 5 Study design
Section 9.4.3 Exploratory efficacy variables
Table 9-2 Schedule of Efficacy Variable Assessments
Section 10.3.2.2.2 Secondary and exploratory efficacy variables
15.1.1.10 Modification 10: Study end
The last visit of the last subject (end of the study) includes the safety follow-up period.
Rationale: To clarify the time point for the end of the study.
The following protocol section is affected by this modification:
Section 5 Study design
15.1.1.11 Modification 11: Final study visit
Completion of the final study visit at Week 76 includes the mandatory safety follow-up 
contact.


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Rationale: To clarify the time point for completion of the final study visit.
The following protocol section is affected by this modification:
Section 5 Study design
15.1.1.12 Modification 12: Assessment of eligibility
Eligibility criteria based on OCT assessment, BCVA, and FA and FP do not need to be 
repeated at the baseline visit.
Rationale: To clarify that assessment of eligibility criteria based on OCT assessment, BCVA 
and FA and FP is not required at the baseline visit if these assessments are performed at the 
initial/screening.
The following protocol section is affected by this modification:
Section 6 Study population
15.1.1.13 Modification 13: Exclusion criterion 22
Exclusion criteria AMD types are neovascular AMD or geographic atrophy.
Rationale: Types of AMD defined.
The following protocol section is affected by this modification:
Section 6.2 Exclusion criteria
15.1.1.14 Modification 14: Rescreening
Added that subjects may be rescreened if reason for initial screening failure was resolved 
within 30 days of initial screening.
Rationale: To clarify rescreening criteria.
The following protocol section is affected by this modification:
Section 6.3.1 Withdrawal
15.1.1.15 Modification 15: Rescreening for inclusion/exclusion criteria
Removed examples of exclusion criteria.
Rationale: For clarity, examples are mentioned above.
The following protocol section is affected by this modification:
Section 6.3.1 Withdrawal
15.1.1.16 Modification 16: Stability criteria
The time period for stability criteria is reworded from “previous last visit” to “second to last 
visit.”
Rationale: For clarity.
The following protocol sections are affected by this modification:
Section 7.1.2 Stability criteria


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15.1.1.17 Modification 17: Dose preparation
Removed text stating that dose must be administered within 2 hours of start of dose 
preparation.
Rationale: In accordance with updated drug information.
The following protocol sections are affected by this modification:
Section 7.4 Dosage and administration
Appendix 16.1 Intravitreal aflibercept injection procedure
15.1.1.18 Modification 18: Disposal of study drug
Added that a sponsor designee may approve disposal of drug at the site and removed that 
study drug may be returned to the sponsor for disposal.
Rationale: Correction of process for disposal of study drug.
The following protocol section is affected by this modification:
Section 7.5 Drug logistics and accountability
15.1.1.19 Modification 19: Rescue therapy
Removed conditions when subjects may receive PRP rescue, and added that subjects may 
receive PRP rescue per investigator discretion.
Rationale: Clarified that PRP rescue may be used per investigator discretion.
The following protocol section is affected by this modification:
Section 8.1 Prior and concomitant therapy
15.1.1.20 Modification 20: Screening/baseline procedures
Procedures may be performed on separate days if screening and baseline visits are combined; 
however, procedures for slit lamp (anterior segment), IOP measurement, and indirect 
ophthalmoscopy are recommended to take place/be repeated on the same day as the IVT 
injection.
Rationale: Clarified that subjects do not need to undergo all procedures on same day if 
screening and baseline are combined and specified procedures recommended to take place on 
same day as IVT injection.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.2 Visit descriptions
15.1.1.21 Modification 21: Window for screening/baseline assessments
For the baseline and screening visits to be considered a combined visit, the assessments must 
take place within a 7-day window.


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Rationale: To clarify that assessments for screening/baseline combined visit must be 
completed within a 7-day period.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.2 Visit descriptions
15.1.1.22 Modification 22: Post-baseline visit procedures
Post-baseline visits may be split, but procedures required at each visit but must be completed 
within 7 days; however, procedures for slit lamp (anterior segment), IOP measurement, and 
indirect ophthalmoscopy are recommended to take place on the same day as the IVT injection.
Rationale: Procedures for each post-baseline visit may be completed on separate days but 
must be completed within a 7-day period.
The following protocol section is affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
15.1.1.23 Modification 23: Prescheduled visits at Weeks 24 and 52 
Prescheduled visits at Weeks 24 and 52 do not pertain to T&E posology; however, subject 
may receive IVT injection based on subject’s T&E schedule.
Rationale: Clarified that visits at Weeks 24 and 52 are not considered part of the T&E 
posology.
The following protocol section is affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
15.1.1.24 Modification 24: Pregnancy testing
Pregnancy testing is mandatory for women of childbearing potential at every treatment visit 
prior to injection and at End of Study visit if required by local regulations.
Rationale: Added visits at which pregnancy testing is mandatory if required to accommodate 
local regulatory requirements.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.2.2 Baseline visit (Visit 2, Day 1)
Section 9.2.3 Initiation phase (2Q4 treatment intervals ± 7 days)
Section 9.2.4.1 Treat and Extend visits
Section 9.2.4.2 Week 24 (± 7 days) interim visit
Section 9.2.4.3 Week 52 (± 7 days) interim visit
Section 9.6.3.1 Pregnancy test


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15.1.1.25 Modification 25: Fluorescein angiography and fundus photography at
baseline visit
If there is no significant change in indirect ophthalmoscopy, an additional FA/FP at baseline 
is not required.
Rationale: Clarified that FA/FP examination at baseline is not necessary if indirect 
ophthalmoscopy does not indicate change.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.2.2 Baseline visit (Visit 2, Day 1)
15.1.1.26 Modification 26: Fluorescein angiography and fundus photography 
combined with wide-field examinations
When possible, FA/FP examinations can be combined with wide-field examination and 
separate fluorescein injection should be avoided.
Rationale: For clarification that FA/FP examinations combined with wide-field examinations 
to avoid separate fluorescein injection.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.2.2 Baseline visit (Visit 2, Day 1)
Section 9.4.4.3 Fluorescein angiography and fundus photography
15.1.1.27 Modification 27: Telephone safety contact with investigator at 30 days 
post-dose
Mandatory telephone safety contact with the investigator 30 days after last dose of study drug.
Rationale: Reworded for clarity.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.2.4.4 Week 76 (± 7 days) final study visit
Section 9.2.5 Early termination visit
15.1.1.28 Modification 28: Assessments at initial visit
Specified assessments that should be performed at the initial visit when screening/baseline 
visits are combined.
Rationale: Clarified testing that should take place when subject is first seen if screening and 
baseline visits are combined.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures


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Section 9.2 Visit descriptions
Section 9.2.2 Baseline visit (Visit 2, Day 1)
Table 9-2 Schedule of Efficacy Variable Assessments
Section 9.4.4.4 Wide-field fluorescein angiography
Section 9.4.4.5 Optical coherence tomography angiography
Section 9.4.4.6 Full-field electroretinography
15.1.1.29 Modification 29: Gonioscopy order of procedure
Removed wording that gonioscopy is performed after OCT and before FA/FP.
Rationale: Not necessary to specify order in which gonioscopy is performed.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.6.3.4.4 Gonioscopy
15.1.1.30 Modification 30: Post-treatment safety telephone calls
Schedule for safety follow-up telephone calls changed from 3 days after treatment to within 
3 days.
Rationale: Addition made to allow flexibility for time of post-treatment safety follow-up calls.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.2.2 Baseline visit (Visit 2, Day 1)
Section 9.2.3 Initiation phase (2Q4 treatment intervals (± 7 days)
Section 9.2.4.1 Treat and Extend visits
Section 9.2.4.2 Week 24 (± 7 days)
Section 9.2.4.3 Week 52 (± 7 days) interim visit
Appendix 16.1 Intravitreal aflibercept injection procedure
15.1.1.31 Modification 31: Grammatical correction “pertain”
Wording changed from “is not a visit pertaining” to “does not pertain” in reference to T&E 
posology.
Rationale: Grammatical correction.
The following protocol sections are affected by this modification:
Table 9-1 Schedule of Evaluations and Study Procedures
Section 9.2.4.2 Week 24 (± 7 days)
Section 9.2.4.3 Week 52 (± 7 days) interim visit


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Section 9.2.4.4 Week 76 (± 7 days) final study visit
15.1.1.32 Modification 32: Early termination visit
Removed sentence describing monitoring interval if subject is withdrawn from the study.
Rationale: Did not pertain to early termination visit.
The following protocol section is affected by this modification:
Section 9.2.5 Early termination visit
15.1.1.33 Modification 33: Referrence removed
Removed reference to Thompson HS, et al.
Rationale: Not relevant.
The following protocol sections are affected by this modification:
Section 9.6.3.5 Investigator(s) and other study personnel
Section 14 Reference List
15.1.1.34 Modification 34: Central reading center for images
Added that ophthalmic images will be evaluated by an independent central reading center.
Rationale: To clarify that an independent central reading center will evaluate images.
The following protocol section is affected by this modification:
Section 13.1 Investigator(s) and other study personnel
15.1.1.35 Modification 35: Steering Committee
Steering Committee may be used to guide the study; responsibilities will be outlined in the 
Charter.
Rationale: Identified that study may be overseen by a Steering Committee.
The following protocol section is affected by this modification:
Section 13.1 Investigator(s) and other study personnel
15.1.1.36 Modification 36: Adjudication committee
An Adjudication Committee will perform additional analysis of arterial thrombotic events 
based on the listed APTC endpoints.
Rationale: Added that an Adjudication Committee will be used for additional analysis.
The following protocol section is affected by this modification:
Section 13.1 Investigator(s) and other study personnel
15.1.1.37 Modification 37: Study drug vials
Study drug will be supplied in 2-mL vials.
Rationale: Correction of text in accordance with study drug vials to be supplied.


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The following protocol section is affected by this modification:
Section 16.1 Intravitreal aflibercept injection procedure
15.1.2
Changes to the protocol text
Changes to the protocol text are indicated as specified at the beginning of Section 14.
15.1.2.1
Adjustments to Treat and Extend treatment interval - Synopsis 
section Methodology
Wording change from “will be adjusted” to “may be adjusted” to clarify that frequency of 
injections may be adjusted to maintain stable visual and anatomic outcomes per 
Modification 1 (Section 15.1.1.1).
Old text
Starting at Week 8, the stability criteria will be evaluated and the frequency of injections will 
be adjusted (increased or decreased by 2-week intervals) to maintain stable visual and 
anatomic outcomes.
New text
Starting at Week 8, the stability criteria will be evaluated and the frequency of injections may
be adjusted (increased or decreased by 2-week intervals) to maintain stable visual and 
anatomic outcomes.
15.1.2.2
Subjects discontinued from treatment with indications of 
worsening - Synopsis section Methodology
Deleted text stating that subjects discontinued from treatment for not benefiting from 
continued treatment may resume treatment if retreatment criteria indicate worsening
Old text
If it is determined by the investigator (in the investigator’s best judgment) that the subject is 
not benefiting from continued treatment or if the investigator considers the subject to have 
permanent resolution of macular edema, treatment may be discontinued, but monitoring 
should be continued with a follow-up visit at a minimum interval of 8 weeks and at all 
subsequent prescheduled visits (i.e. Weeks 24, 52, and 76). Treatment should be resumed if 
the retreatment criteria indicate worsening (i.e. at least 1 criterion for deterioration is met).
New text
If the investigator considers the subject to have permanent resolution of macular edema, 
treatment may be discontinued, but monitoring should be continued with a follow-up visit at a 
minimum interval of 8 weeks and at all subsequent prescheduled visits (i.e. Weeks 24, 52, and 
76). Treatment should be resumed if the retreatment criteria indicate worsening (i.e. at least 1 
criterion for deterioration is met).


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15.1.2.3
Secondary variable change in retinal perfusion status – Synopsis 
Section Variables
Clarified that assessment of secondary variable of change in retinal perfusion status will 
include screening/baseline combined visit per Modification 2 (Section 15.1.1.2).
Old text

The change in retinal perfusion (FA/FP) status from baseline to Weeks 24, 52 and 76
New text

The change in retinal perfusion (FA/FP) status from screening/baseline to Weeks 24, 
52 and 76
15.1.2.4
Reference change – Section 3 Introduction
Citation for reference to SmPC applied per Modification 3 (Section 15.1.1.4).
Old text
Further details are provided in the applicable SmPC.
New text
Further details are provided in the applicable Summary of Product Characteristics (SmPC) (2)
15.1.2.5
Visits for screening and baseline – Section 5 Study design
Clarified that screening and baseline visits can be combined per Modification 4
(Section 15.1.1.5).
Old text
The initial screening visit must be within the enrollment period in the respective country (i.e. 
no retrospective inclusion). Subjects must give written informed consent prior to any data 
documentation. Subjects will receive the first study treatment at the baseline visit on Day 1. 
Screening and baseline need to be separate visits in order to confirm the inclusion/exclusion 
criteria.
New text
The initial screening visit must be within the enrollment period in the respective country (i.e. 
no retrospective inclusion). Subjects must give written informed consent prior to any data 
documentation. Subjects will receive the first study treatment at the baseline visit on Day 1.
15.1.2.6
Time point for follow-up – Section 5 Study design
Clarified that follow-up to Week 76 is necessary, regardless of whether subject requires 
further injections, providing that follow-up is possible per Modification 6 (Section 15.1.1.6).
Old text
Subjects will be followed for a time period of 76 weeks or until follow-up is no longer 
necessary or possible.


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New text
Subjects will be followed for a time period of 76 weeks or until follow-up is no longer
possible.
15.1.2.7
Window for post-baseline study visits – Section 5 Study design
Clarified that a ± 7-day window will be allowed for all post-baseline visits per Modification 7
(Section 15.1.1.7).
Old text
This study comprises a screening period of up to 21 days and a treatment period of 76 weeks. 
There will be prescheduled visits at baseline, Weeks 24, 52, and 76 (end-of-study visit). The 
visit schedules at Weeks 24, 52, and 76 may deviate by ± 7 days. Other visits between 
baseline and Week 76 will depend on the applied posology of IVT aflibercept and the 
monitoring schedule for each subject.
New text
This study comprises a screening period of up to 21 days and a treatment period of 76 weeks. 
There will be prescheduled visits at baseline, Weeks 24, 52, and 76 (end-of-study visit). Other 
visits between baseline and Week 76 will depend on the applied posology of IVT aflibercept 
and the monitoring schedule for each subject. A ± 7-day window will be allowed for all 
post-baseline visits.
15.1.2.8
Examinations based on investigator’s medical judgment and standard 
of care – Section 5 Study design
Specified ERG is full-field and added wide-field FA and OCT angiography examinations that 
may be performed at other times during the study based on the investigator’s medical 
judgment and standard of care per Modification 8 (Section 15.1.1.8).
Old text
However, the treating investigator may perform FA/FPs or ERGs at other times during the 
76 weeks of study treatment based on his/her medical judgment and standard of care.
New text
However, the treating investigator may perform FA/FP, wide-field FA, OCT angiography, or 
full-field ERG at other times during the 76 weeks of study treatment based on his/her medical 
judgment and standard of care.
15.1.2.9
Study end – Section 5 Study design
Clarified that the last visit of the last subject (end of the study) includes the safety follow-up 
period per Modification 10 (Section 15.1.1.10).
Old text
The end of the study as a whole will be reached as soon as the last visit of the last subject is 
reached in all centers in all participating countries (EU and non-EU). 


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New text
The end of the study as a whole will be reached as soon as the last visit of the last subject,
including safety follow-up, is reached in all centers in all participating countries (EU and 
non-EU).
15.1.2.10 Final study visit – Section 5 Study design
Clarified that completion of the final study visit at Week 76 includes the mandatory safety 
follow-up contact per Modification 11 (Section 15.1.1.11).
Old text
The primary completion event for this study is the final study visit at Week 76.
New text
The primary completion event for this study is the final study visit at Week 76, including the 
mandatory safety follow-up contact.
15.1.2.11 Secondary variable change in retinal perfusion status – Section 5 Study 
design
Clarified that assessment of secondary variable of change in retinal perfusion status will 
include screening/baseline combined visit per Modification 3 (Section 15.1.1.2).
Old text

The change in retinal perfusion (FA/FP) status from baseline to Weeks 24, 52, and 76
New text

The change in retinal perfusion (FA/FP) status from screening/baseline to Weeks 24, 
52, and 76
15.1.2.12 Exploratory variable perfusion status of retina – Section 5 Study design
Exploratory variable assessment clarified to include screening/baseline combined visit per 
Modification 9 (Section 15.1.1.9).
Old text

Perfusion status of the retina assessed by wide-field FA at baseline, Weeks 24, 52, and 
76
New text

Perfusion status of the retina assessed by wide-field FA at screening/baseline, 
Weeks 24, 52, and 76
15.1.2.13 Assessment of eligibility – Section 6 Study population
Clarified that assessment of eligibility criteria based on OCT assessment, BCVA and FA and 
FP is not required at the baseline visit if these assessments are performed at the 
initial/screening per Modification 12 (Section 15.1.1.12).


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Old text
In order to be enrolled into this study, a subject must meet ALL of the eligibility criteria. 
Assessment of eligibility criteria based on OCT assessment, BCVA, and FA and FP will be 
repeated at the baseline visit.
New text
In order to be enrolled into this study, a subject must meet ALL of the eligibility criteria.
15.1.2.14 Exclusion criterion 22 – Section 6.2 Exclusion criteria
Defined types of AMD per Modification 13 (Section 15.1.1.13).
Old text
22. History or clinical evidence of diabetic macular edema, age-related macular degeneration 
(AMD), BRVO, or any retinal vascular disease other than macular edema secondary to 
CRVO in either eye.
New text
22. History or clinical evidence of diabetic macular edema, AMD (neovascular AMD or 
geographic atrophy), BRVO, or any retinal vascular disease other than macular edema 
secondary to CRVO in either eye.
15.1.2.15 Rescreening – Section 6.3.1 Withdrawal
Added that subjects may be rescreened if reason for initial screening failure was resolved 
within 30 days of initial screening per Modification 14 (Section 15.1.1.14).
Old text
Restarting the defined set of screening procedures to enable the “screening failure” subject’s 
participation at a later time point is not allowed, with the following exceptions:

The subject had successfully passed the screening procedures but could not start 
subsequent treatment on schedule.

Initial screening occurred too early to complete the required washout period after prior 
therapy.

The inclusion/exclusion criteria preventing the subject’s initial attempt to participate 
have been changed (via protocol amendment).
New text
Restarting the defined set of screening procedures to enable the “screening failure” subject’s 
participation at a later time point is not allowed, with the following exceptions:

The subject had successfully passed the screening procedures but could not start 
subsequent treatment on schedule.

Initial screening occurred too early to complete the required washout period after prior 
therapy.


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
The inclusion/exclusion criteria preventing the subject’s initial attempt to participate 
have been changed (via protocol amendment).

The reason for the screening failure was subsequently resolved (e.g. elevated IOP 
decreases, inflammation or infection resolves) within 30 days.
15.1.2.16 Rescreening for inclusion/exclusion criteria – Section 6.3.1 Withdrawal
Removed examples of exclusion criteria per Modification 15 (Section 15.1.1.15).
Old text
However, if a subject fails screening, i.e. does not meet all inclusion criteria or meets 1 or 
more of the exclusion criteria (e.g. increased IOP or BP), the subject can be re-screened 
1 time, if the reason(s) for the screening failure is(are) resolved.
New text
However, if a subject fails screening (i.e. does not meet all inclusion criteria or meets 1 or 
more of the exclusion criteria), the subject can be re-screened 1 time, if the reason(s) for the 
screening failure is(are) resolved.
15.1.2.17 Adjustments to Treat and Extend treatment interval – Section 7.1.1 
Treat and Extend treatment visits
Wording change to clarify that frequency of injections may be adjusted to maintain stable 
visual and anatomic outcomes per Modification 1 (Section 15.1.1.1).
Old text
Starting at Week 8, the retreatment interval will be determined as described in Section 7.1.3 
and the frequency of injections will be adjusted (increased or decreased by 2-week intervals) 
to maintain stable visual and anatomic outcomes.
New text
Starting at Week 8, the retreatment interval will be determined as described in Section 7.1.3
and the frequency of injections may be adjusted (increased or decreased by 2-week intervals) 
to maintain stable visual and anatomic outcomes.
15.1.2.18 Stability criteria for BCVA – Section 7.1.2 Stability criteria
The time period for the stability criteria of BCVA was reworded for clarity per 
Modification 16 (Section 15.1.1.16).
Old text

BCVA within a ±5 letter “stability corridor” defined by:
-
No more than 5 letters gain since the last or previous last visit
-
No more than 5 letters loss from best previous BCVA at any visit
New text

BCVA within a ± 5 letter “stability corridor” defined by:


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-
No more than 5 letters gain since the last or second to last visit
-
No more than 5 letters loss from best previous BCVA at any visit
15.1.2.19 Stability criteria for CRT – Section 7.1 Stability criteria
The time period for the stability criteria of CRT was reworded for clarity per Modification 16
(Section 15.1.1.16).
Old text

CRT within a ± 20% “stability corridor” defined by:
-
No more than 20% thickness reduction since the last or previous last visit
-
No more than 0% thickening from best previous CRT at any visit
New text

CRT within a ± 20% “stability corridor” defined by:
-
No more than 20% thickness reduction since the last or second to last visit
-
No more than 20% thickening from best previous CRT at any visit
15.1.2.20 Dose preparation – Section 7.4 Dose age and administration
Removed text stating that dose must be administered within 2 hours of start of dose 
preparation per Modification 17 (Section 15.1.1.17).
Old text
Vials of IVT aflibercept are to be stored at 2°C to 8°C. Do not freeze. Keep the vial in the 
outer carton to protect it from light. Prior to usage, the unopened vial of IVT aflibercept may 
be stored at room temperature (below 25°C/77°F) for up to 24 hours. After opening the vial, 
procedures must take place under aseptic conditions and the dose must be administered within 
2 hours of the start of dose preparation.
New text
Vials of IVT aflibercept are to be stored at 2°C to 8°C. Do not freeze. Keep the vial in the 
outer carton to protect it from light. Prior to usage, the unopened vial of IVT aflibercept may 
be stored at room temperature (below 25°C/77°F) for up to 24 hours. After opening the vial, 
procedures must take place under aseptic conditions.
15.1.2.21 Disposal of study drug – Section 7.5 Drug logistics and accountability
Added that a sponsor designee may approve disposal of drug at the site and removed that 
study drug may be returned to the sponsor for disposal per Modification 18
(Section 15.1.1.18).
Old text
Drug accountability records must be kept current and should contain the dates, quantities, kit 
numbers, and batch numbers (or lot numbers) of study drug received by the investigator, 
dispensed or administered to specified subjects, disposed of at the site (disposal at the site 


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may occur only with a sponsor approval), or returned to the sponsor or a specified designee 
for disposal.
New text
Drug accountability records must be kept current and should contain the dates, quantities, kit 
numbers, and batch numbers (or lot numbers) of study drug received by the investigator, 
dispensed or administered to specified subjects, disposed of at the site (disposal at the site 
may occur only with a sponsor or designee approval or by a specified designee).
15.1.2.22 Rescue therapy – Section 8.1 Prior and concomitant therapy
Removed conditions when subjects may receive PRP rescue, and added that subjects may 
receive PRP rescue per investigator discretion per Modification 19 (Section 15.1.1.19).
Old text
All subjects may receive PRP rescue at any time during the study if they progress to anterior 
segment neovascularization, neovascularization on optic disc, or clinically relevant 
neovascularization elsewhere in fundus and will continue to be assessed in this study.
New text
All subjects may receive PRP rescue at any time during the study if deemed necessary by the 
investigator and will continue to be assessed in this study.


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15.1.2.23 Schedule of Evaluations and Study Procedures – Table 9-1 Schedule of 
Evaluations and Study Procedures
Due to the complexity of changes made to the table per Modification 1 (Section 15.1.1.1),
Modification 2 (Section 15.1.1.2), Modification 3 (Section 15.1.1.3), Modification 7 
(Section 15.1.1.7), Modification 8 (Section 15.1.1.8), Modification 20 (Section 15.1.1.20), 
Modification 21 (Section 15.1.1.21), Modification 22 (Section 15.1.1.22), Modification 23
(Section 15.1.1.23), Modification 24 (Section 15.1.1.24), Modification 25 (Section 15.1.1.25), 
Modification 26 (Section 15.1.1.26), Modification 27 (Section 15.1.1.27), Modification 28
(Section 15.1.1.28), Modification 29 (Section 15.1.1.29), Modification 30 (Section 15.1.1.30), 
and Modification 31 (Section 15.1.1.31), no footnotes to these changes are added for the new 
table. Changes to the table are indicated as specified at the beginning of Section 14. Deletions 
are crossed out in the “Old text”. Additions are underlined in the “New text”.


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Old Text
Table 9-1 Schedule of Evaluations and Procedures
Initiation Phase
T&E Phase
Visit Description 
Screeninga
Baselinea
Treatment Every 4 
Weeks (2Q4)
T&E Treatment 
Visits
Interimb
Interimb
End of 
Studyb
Early 
Termination
Time Point
Visit 1
Day −21
to Baseline
Visit 2 
(Day 1)
Visit 3 and following 
until stability achieved 
or Week 20 (± 7 days)
According to 
Individual T&E 
Schedulec
Week 24
(± 7 days)
Week 52
(± 7 days)
Week 76
(± 7 days)
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographic data
X
Medical/ophthalmic history
X
Physical examination
X
Pregnancy testd
X
X
Refraction and BCVA (ETDRS chart starting at 
4 m)e
X
X
X
X
X
X
X
X
SD-OCT 
X
X
X
X
X
X
X
X
FA/FPf,g
X
X
X
X
X
X
AEsh,i
X
X
X
X
X
X
X
X
Indirect ophthalmoscopyh
X
X
X
X
X
X
X
X
RAPDj
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
X
X
X
Gonioscopyk
X
X
X
IOPj
X
X
X
X
X
X
X
X


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Initiation Phase
T&E Phase
Visit Description 
Screeninga
Baselinea
Treatment Every 4 
Weeks (2Q4)
T&E Treatment 
Visits
Interimb
Interimb
End of 
Studyb
Early 
Termination
Time Point
Visit 1
Day −21
to Baseline
Visit 2 
(Day 1)
Visit 3 and following 
until stability achieved 
or Week 20 (± 7 days)
According to 
Individual T&E 
Schedulec
Week 24
(± 7 days)
Week 52
(± 7 days)
Week 76
(± 7 days)
Full-field ERGf,g,l
X
X
X
X
X
Wide-field (angle) FAg,l
X
X
X
X
X
OCT angiographyg,l
X
X
X
X
X
Vital signsm
X
X
X
X
X
X
X
X
Administration of study treatmentn
X
X
X
X
X
o
Telephone safety checkp
X
X
X
X
X
X
Evaluation of posology, how disease activity is 
monitored, including monitoring frequency
X
X
X
X
X
X
X
Prior/concomitant medications
X
X
X
X
X
X
X
X
Abbreviations: AE, adverse event; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; FA, fluorescein angiography; FP, fundus 
photography; IOP, intraocular pressure; OCT, optical coherence tomography; RAPD, relative afferent pupillary defect; SD-OCT; spectral domain optical coherence 
tomography T&E, Treat and Extend.
Note: Ocular assessments are to be conducted in both eyes unless otherwise indicated.
a:
The screening and baseline visits can be combined if eligibility criteria are met, all inclusion criteria are fulfilled, and none of the exclusion criteria apply. If screening and 
baseline occur on the same visit, pregnancy test results and reading center evaluations need to be available prior to treatment with study drug at baseline.
b:
Visit schedules at Weeks 24, 52, and 76 may deviate by ± 7 days. These visits are not pertaining to the T&E posology; however, based on the subject’s T&E schedule, the 
subject may receive IVT injection of study drug.
c:
Monitoring will be performed at each injection visit and at Weeks 24, 52, and 76. Starting at Week 8, the stability criteria will be evaluated as described in Section 7.1.2 and 
the frequency of injections will be adjusted (increased or decreased by 2-week intervals) to maintain stable visual and anatomic outcomes.
d:
Urine pregnancy test for women of child-bearing potential only. If positive, a serum pregnancy test for confirmation should be performed. Postmenopausal women must be 
amenorrheic for at least 12 months in order not to be considered of childbearing potential.
e:
Refraction and BCVA using the ETDRS chart is to be performed at each visit.
f:
The treating investigator may perform these examinations at other times during the 76 weeks of the study based on his/her medical judgment and standard of care.
g:
Conduct in both eyes at baseline (FA/FP additionally in both eyes at screening) and in the study eye only at the other visits indicated unless there are signs of vein occlusion 
in the fellow eye.
h:
Conduct pre- and post-dose as applicable. If a subject receives a study injection, indirect ophthalmoscopy should be conducted post-dose and IOP should be assessed in the 


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study eye 30 to 60 minutes after dosing.
i:
Any AE occurring up to 30 days after the last injection of IVT aflibercept is to be documented regardless of the relationship to the study drug or the seriousness of the event, 
and reported in accordance with this protocol (see Section 9.6.1.3). A mandatory safety patient contact by telephone 30 days after the last administration of study medication 
by the investigator is scheduled to ensure no AEs have occurred.
j:
Conducted in both eyes (procedure for conducting RAPD testing is provided in the study manual).
k:
Performed in the study eye only, after OCT and before FA/FP. Conducted at screening and at Week 76 and the early termination visit. May be repeated if needed as 
determined by the investigator.
l:
Conducted where feasible and available at selected sites; exploratory measures.
m:
Temperature, blood pressure, and heart rate.
n:
See Appendix 16.1 for an example study drug injection procedure. Note: Study drug will be administered according to the criteria and timing described in Section 7. If it is 
determined by the investigator (in the investigator’s best judgement) that the subject is not benefiting from continued treatment or the investigator considers permanent 
resolution of macular edema, treatment may be discontinued, but monitoring should be continued with a follow-up visit at a minimum interval of 8 weeks and at all 
subsequent prescheduled visits (i.e. Weeks 24, 52, and 76).
o:
Subjects may receive treatment of their underlying disease at their physician`s discretion at Week 76 after the end-of-study visit and the assessments for all variables are 
completed.
p:
A mandatory safety telephone call will be made 3 days after treatment to ensure no signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred.


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New text
Table 9-1 Schedule of Evaluations and Procedures
Initiation Phase
T&E Phase
Visit Description 
Screeninga
Baselinea
Treatment Every 
4 Weeks (2Q4)b
T&E Treatment 
Visits b
Interimb,c
Interimb,c
End of 
Studyb
Early 
Termination
Time Point
Visit 1
Day −21
to Baseline
Visit 2 
(Day 1)
Visit 3 and following 
until stability achieved 
or Week 20 (± 7 days)
According to 
Individual T&E 
Schedule (± 7 days)d
Week 24
(± 7 days)
Week 52
(± 7 days)
Week 76
(± 7 days)
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographic data
X
Medical/ophthalmic history
X
Physical examination
X
Pregnancy teste
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Refraction and BCVA (ETDRS chart starting 
at 4 m)f
X
X
X
X
X
X
X
X
SD-OCT 
X
X
X
X
X
X
X
X
FA/FPg,h,i
X
X
X
X
X
X
AEsj
X
X
X
X
X
X
X
X
Indirect ophthalmoscopyk
X
X
X
X
X
X
X
X
RAPDl
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
X
X
X
Gonioscopym
X
X
X
IOPk
X
X
X
X
X
X
X
X
Full-field ERGh,i,n
(X)
X
X
X
X
X


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Initiation Phase
T&E Phase
Visit Description 
Screeninga
Baselinea
Treatment Every 
4 Weeks (2Q4)b
T&E Treatment 
Visits b
Interimb,c
Interimb,c
End of 
Studyb
Early 
Termination
Time Point
Visit 1
Day −21
to Baseline
Visit 2 
(Day 1)
Visit 3 and following 
until stability achieved 
or Week 20 (± 7 days)
According to 
Individual T&E 
Schedule (± 7 days)d
Week 24
(± 7 days)
Week 52
(± 7 days)
Week 76
(± 7 days)
Wide-field (angle) FAg,h,i,n
(X)
X
X
X
X
X
OCT angiographyh,i,n
(X)
X
X
X
X
X
Vital signso
X
X
X
X
X
X
X
X
Administration of study treatmentp
X
X
X
(X)
(X)
q
Telephone safety checkr
X
X
X
(X)
(X)
X
Evaluation of posology, how disease activity 
is monitored, including monitoring frequency
X
X
X
X
X
X
X
Prior/concomitant medications
X
X
X
X
X
X
X
X
Abbreviations: AE, adverse event; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; FA, fluorescein angiography; FP, fundus 
photography; IOP, intraocular pressure; OCT, optical coherence tomography; RAPD, relative afferent pupillary defect; SD-OCT; spectral domain optical coherence 
tomography; T&E, Treat and Extend.
Note: Ocular assessments are to be conducted in both eyes unless otherwise indicated.
a:
The screening and baseline visits can be combined if eligibility criteria are met, all inclusion criteria are fulfilled, and none of the exclusion criteria apply. If screening and 
baseline occur on the same visit, pregnancy test results and reading center evaluations need to be available prior to treatment with study drug. The necessary procedures can 
be performed on separate days. However, slit lamp (anterior segment), IOP measurement, and indirect ophthalmoscopy are recommended to take place/be repeated on the 
same day as the IVT injection. There will be a 7-day window allowed for all procedures to be completed for the combined screening/baseline and the baseline visit.
b:
A ± 7-day window will be allowed for all post-baseline visits. The procedures required at each visit have to be completed within 7 days (i.e. split visits are allowed); 
however, all procedures have to be completed within the ± 7-day window. Slit lamp (anterior segment), IOP measurement, and indirect ophthalmoscopy are recommended to 
take place on the same day as the IVT injection.
c:
The visits at Weeks 24 and 52 do not pertain to the T&E posology; however, based on the subject’s T&E schedule, the subject may receive IVT injection of study drug.
d:
Monitoring will be performed at each injection visit and at Weeks 24, 52, and 76. Starting at Week 8, the stability criteria will be evaluated as described in Section 7.1.2 and 
the frequency of injections may be adjusted (increased or decreased by 2-week intervals) to maintain stable visual and anatomic outcomes.
e:
Urine pregnancy test for women of child-bearing potential only. If positive, a serum pregnancy test for confirmation should be performed. Postmenopausal women must be 
amenorrheic for at least 12 months in order not to be considered of childbearing potential. After screening, a urine pregnancy test is mandatory for women of childbearing 
potential at every treatment visit (prior to injection) in all countries where it is required by local regulations. If required by local regulations, a pregnancy test should be 
performed for women of childbearing potential at the End of Study visit.
f:
Refraction and BCVA using the ETDRS chart are to be performed at each visit.
g:
If the investigator considers no significant change in indirect ophthalmoscopy, an additional FA/FP is not mandatory at the baseline visit. Traditional FA/FP examinations 


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can be combined with wide-field examinations if possible. A separate fluorescein injection, especially, should be avoided.
h:
The treating investigator may perform these examinations at other times during the 76 weeks of the study based on his/her medical judgment and standard of care.
i:
Conduct in both eyes at screening/baseline and in the study eye only at the other visits indicated unless there are signs of vein occlusion in the fellow eye.
j:
Any AE occurring up to 30 days after the last injection of IVT aflibercept is to be documented regardless of the relationship to the study drug or the seriousness of the event, 
and reported in accordance with this protocol (see Section 9.6.1.3). A mandatory telephone safety contact with the investigator 30 days after the last administration of study 
medication is scheduled to ensure that the patient has not experienced any AEs.
k:
Conduct pre- and post-dose as applicable. If a subject receives a study injection, indirect ophthalmoscopy should be conducted post-dose and IOP should be assessed in the 
study eye 30 to 60 minutes after dosing.
l:
Conducted in both eyes (procedure for conducting RAPD testing is provided in the study manual). If the screening and baseline visits are combined, these assessments
should be performed at the initial visit.
m:
Performed in the study eye only. Conducted at screening and at Week 76 and the early termination visit. May be repeated if needed as determined by the investigator.
n:
Conducted where feasible and available at selected sites. If the screening and baseline visits are combined, these assessments should be performed at the initial visit.
o:
Temperature, blood pressure, and heart rate.
p:
See Appendix 16.1 for an example study drug injection procedure. Note: Study drug will be administered according to the criteria and timing described in Section 7. If the 
investigator considers permanent resolution of macular edema, treatment may be discontinued, but monitoring should be continued with a follow-up visit at a minimum 
interval of 8 weeks and at all subsequent prescheduled visits (i.e. Weeks 24, 52, and 76).
q:
Subjects may receive treatment of their underlying disease at their physician`s discretion at Week 76 after the end-of-study visit and the assessments for all variables are 
completed.
r:
A mandatory safety telephone call will be made within 3 days after treatment to ensure no signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred.


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15.1.2.24 Screening/baseline procedures –Section 9.2 Visit descriptions
Procedures may be performed on separate days if screening and baseline visits are combined 
per Modification 20 (Section 15.1.1.20).
Old text
The screening and baseline visits can be combined if eligibility criteria are met, all inclusion 
criteria are fulfilled, and none of the exclusion criteria apply.
New text
The screening and baseline visits can be combined if eligibility criteria are met, all inclusion 
criteria are fulfilled, and none of the exclusion criteria apply. The necessary procedures can be 
performed on separate days.
15.1.2.25 Window for screening/baseline assessments – Section 9.2 Visit 
descriptions
Clarified that assessments for screening/baseline combined visit must be completed within a 
7-day period per Modification 21 (Section 15.1.1.21).
Old text
The screening and baseline visits can be combined if eligibility criteria are met, all inclusion 
criteria are fulfilled, and none of the exclusion criteria apply. If screening and baseline occur 
on the same visit, pregnancy test results and reading center evaluations need to be available 
prior to treatment with study drug at baseline.
New text
The screening and baseline visits can be combined if eligibility criteria are met, all inclusion 
criteria are fulfilled, and none of the exclusion criteria apply. The necessary procedures can be 
performed on separate days. There will be a 7-day window allowed for all procedures to be 
completed in such a combined visit. If screening and baseline occur on the same visit, 
pregnancy test results and reading center evaluations need to be available prior to treatment 
with study drug.
15.1.2.26 Assessments at initial visit – Section 9.2 Visit descriptions
Clarified when procedures should be performed if screening and baseline visits are combined 
per Modification 28 (Section 15.1.1.28).
Old text
If screening and baseline occur on the same visit, pregnancy test results and reading center 
evaluations need to be available prior to treatment with study drug at baseline.
New text
If screening and baseline occur on the same visit, pregnancy test results and reading center 
evaluations need to be available prior to treatment with study drug. Furthermore, the 
additional examinations at baseline should be performed at the initial visit prior to treatment 
with study drug if the investigator intends to combine screening and baseline visit.


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15.1.2.27 Pregnancy testing – Section 9.2.2 Baseline visit (Visit 2, Day 1)
Added that pregnancy testing is mandatory to accommodate local regulatory or institutional 
requirements per Modification 24 (Section 15.1.1.24).
Old text

Confirm inclusion criteria and exclusion criteria. This includes a negative pregnancy 
test for women of childbearing potential. Postmenopausal women must be 
amenorrheic for at least 12 months in order not to be considered of childbearing 
potential.
New text

Confirm inclusion criteria and exclusion criteria. This includes a negative pregnancy 
test for women of childbearing potential. Postmenopausal women must be 
amenorrheic for at least 12 months in order not to be considered of childbearing 
potential. 

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations.
15.1.2.28 Fluorescein angiography and fundus photography at baseline visit –
Section 9.2.2 Baseline visit (Visit 2, Day 1)
Added that an additional FA/FP at baseline is not required if there is no significant change in 
indirect ophthalmoscopy per Modification 25 (Section 15.1.1.25).
Old text

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy 
o
RAPD test
o
FA/FP (the study manual will further specify the standards for FA/FP during 
the study)
New text

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy


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o
Slit lamp biomicroscopy
o
RAPD test
o
FA/FP (the study manual will further specify the standards for FA/FP during 
the study). If the investigator considers no significant change in indirect 
ophthalmoscopy, an additional FA/FP is not mandatory at the baseline visit.
15.1.2.29 Fluorescein angiography and fundus photography combined with 
wide-field examinations – Section 9.2.2 Baseline visit (Visit 2, Day 1)
When possible, FA/FP examinations can be combined with wide-field examination and 
separate fluorescein injection should be avoided per Modification 26 (Section 15.1.1.26).
Old text

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy 
o
RAPD test
o
FA/FP (the study manual will further specify the standards for FA/FP during 
the study)
New text

Ocular assessments (to be conducted in both eyes unless otherwise indicated):
o
Refraction and BCVA using the ETDRS chart (to be performed at each visit)
o
SD-OCT
o
IOP
o
Indirect ophthalmoscopy
o
Slit lamp biomicroscopy
o
RAPD test
o
FA/FP (the study manual will further specify the standards for FA/FP during 
the study). If the investigator considers no significant change in indirect 
ophthalmoscopy, an additional FA/FP is not mandatory at the baseline visit. 
Traditional FA/FP examinations can be combined with wide-field examination 
if possible. A separate fluorescein injection, especially, should be avoided.
15.1.2.30 Assessments at initial visit – Section 9.2.2 Baseline visit (Visit 2, Day 1)
Specified assessments that should be performed at the initial visit when screening/baseline 
visits are combined per Modification 28 (Section 15.1.1.28).


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Old text
o
Wide-field FA, at selected study sites
o
OCT angiography, at selected study sites
o
Full-field ERG, at selected study sites
New text
o
Wide-field FA, at selected study sites (if screening and baseline visits are 
combined, assessment should be performed at the initial visit)
o
OCT angiography, at selected study sites (if screening and baseline visits are 
combined, assessment should be performed at the initial visit)
o
Full-field ERG, at selected study sites (if screening and baseline visits are 
combined, assessment should be performed at the initial visit)
15.1.2.31 Post-treatment safety telephone calls – Section 9.2.2 Baseline visit
Revised schedule for safety follow-up telephone calls from 3 days after treatment to within 
3 days per Modification 30 (Section 15.1.1.30).
Old text
o
Mandatory safety telephone call 3 days after treatment to ensure no signs or 
symptoms of retinal detachment, endophthalmitis, or other AEs have occurred
New text
o
Mandatory safety telephone call within 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
15.1.2.32 Post-treatment safety telephone calls – Section 9.2.3 Initiation phase 
(2Q4 treatment intervals (± 7 days)
Revised schedule for safety follow-up telephone calls from 3 days after treatment to within 
3 days per Modification 30 (Section 15.1.1.30).
Old text
o
Mandatory safety telephone call 3 days after treatment to ensure no signs or 
symptoms of retinal detachment, endophthalmitis, or other AEs have occurred
New text
o
Mandatory safety telephone call within 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
15.1.2.33 Pregnancy testing – Section 9.2.3 Initiation phase (2Q4 treatment 
intervals ± 7 days)
Added that pregnancy testing is mandatory to accommodate local regulatory or institutional 
requirements per Modification 24 (Section 15.1.1.24).


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Old text

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)
New text

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations
15.1.2.34 Window for post-baseline study visits – Section 9.2.4.1 Treat and 
Extend visits
Clarified that a ± 7-day window will be allowed for all post-baseline visits per Modification 7
(Section 15.1.1.7). 
Old text
Treat and Extend visits are scheduled according to an individual subject’s T&E schedule.
New text
Treat and Extend visits are scheduled according to an individual subject’s T&E schedule 
(± 7 days)
15.1.2.35 Pregnancy testing – Section 9.2.4.1 Treat and Extend visits
Added that pregnancy testing is mandatory to accommodate local regulatory or institutional 
requirements per Modification 24 (Section 15.1.1.24).
Old text

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)
New text

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations
15.1.2.36 Post-treatment safety telephone calls – Section 9.2.4.1 Treat and 
Extend visits
Revised schedule for safety follow-up telephone calls from 3 days after treatment to within 
3 days per Modification 30 (Section 15.1.1.30).


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Old text
o
Mandatory safety telephone call 3 days after treatment to ensure no signs or 
symptoms of retinal detachment, endophthalmitis, or other AEs have occurred
New text
o
Mandatory safety telephone call within 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
15.1.2.37 Pregnancy testing – Section 9.2.4.2 Week 24 (± 7 days) interim visit
Added that pregnancy testing is mandatory to accommodate local regulatory or institutional 
requirements per Modification 24 (Section 15.1.1.24)
Old text

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)
New text

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations
15.1.2.38 Grammatical correction “pertain” – Section 9.2.4.2 Week 24 (± 7 days)
Wording changed from “is not a visit pertaining” to “does not pertain” in reference to T&E 
posology per Modification 31 (Section 15.1.1.31). 
Old text
The Week 24 visit is not a visit pertaining to the T&E posology.
New text
The Week 24 visit does not pertain to the T&E posology 
Note: This change also occurs in Section 9.2.4.3 Week 52 (± 7 days) interim visit and 
Section 9.2.4.4 Week 76 (± 7 days) final study visit. Per template, a terminological change is 
defined only once, without displaying “Old text” versus “New text” for each appearance.
15.1.2.39 Post-treatment safety telephone calls – Section 9.2.4.2 Week 24 
(± 7 days)
Revised schedule for safety follow-up telephone calls from 3 days after treatment to within 
3 days per Modification 30 (Section 15.1.1.30).
Old text
o
Mandatory safety telephone call 3 days after treatment to ensure no signs or 
symptoms of retinal detachment, endophthalmitis, or other AEs have occurred


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New text
o
Mandatory safety telephone call within 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
15.1.2.40 Pregnancy testing – Section 9.2.4.3 Week 52 (± 7 days) interim visit
Added that pregnancy testing is mandatory for women of childbearing potential at every 
treatment visit prior to injection if required by local regulations per Modification 24
(Section 15.1.1.24).
Old text

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)
New text

Vital signs (temperature, blood pressure, and heart rate)

AEs (pre- and post-dose)

A urine pregnancy test is mandatory prior to injection for women of childbearing 
potential in all countries where it is required by local regulations
15.1.2.41 Post-treatment safety telephone calls – Section 9.2.4.3 Week 52 
(± 7 days) interim visit
Revised schedule for safety follow-up telephone calls from 3 days after treatment to within 
3 days per Modification 30 (Section 15.1.1.30).
Old text
o
Mandatory safety telephone call 3 days after treatment to ensure no signs or 
symptoms of retinal detachment, endophthalmitis, or other AEs have occurred
New text
o
Mandatory safety telephone call within 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred
15.1.2.42 Telephone safety contact with investigator at 30 days post-dose –
Section 9.2.4.4 Week 76 (± 7 days) final study visit
Reworded for clarity that telephone contact is a safety telephone contact with the investigator 
per Modification 27 (Section 15.1.1.27).
Old text
o
A mandatory safety patient contact by telephone 30 days after the last 
administration of study medication is scheduled to ensure no AEs have 
occurred if the 30-day follow-up period ends after the scheduled Week 76 visit.


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New text
o
A mandatory telephone safety contact with the investigator 30 days after the 
last administration of study medication is scheduled to ensure that the patient 
has not experienced any AEs.
15.1.2.43 Telephone safety contact with investigator at 30 days post-dose –
Section 9.2.5 Early termination visit
Reworded for clarity that telephone contact is a safety telephone contact with the investigator 
per Modification 27 (Section 15.1.1.27).
Old text
o
A mandatory safety patient contact by telephone 30 days after the last 
administration of study medication is scheduled to ensure no AEs have 
occurred if the 30-day follow-up period ends after the scheduled Week 76 visit.
New text
o
A mandatory telephone safety contact with the investigator 30 days after the 
last administration of study medication is scheduled to ensure that the patient 
has not experienced any AEs.
15.1.2.44 Early termination visit – Section 9.2.5 Early termination visit
Removed sentence describing monitoring interval if subject is withdrawn from the study per 
Modification 32 (Section 15.1.1.32).
Old text
In the event that a subject is withdrawn from the study before completing the Week 76 visit, 
monitoring should be continued with a follow-up visit at a minimum interval of 8 weeks and 
at all subsequent prescheduled visits (i.e. Weeks 24, 52, and 76). The following assessments 
should be performed:

Prior and concomitant medications
New text

Prior and concomitant medications
15.1.2.45 Secondary variable change in retinal perfusion status – Section 9.4.2 
Secondary efficacy variables
Clarified that assessment of secondary variable of change in retinal perfusion status will 
include screening/baseline combined visit per Modification 3 (Section 15.1.1.3).
Old text

The change in retinal perfusion (FA/FP) status from baseline to Weeks 24, 52, and 76
New text

The change in retinal perfusion (FA/FP) status from screening/baseline to Weeks 24, 
52, and 76


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15.1.2.46 Exploratory variable perfusion status of retina – Section 9.4.3 
Exploratory efficacy variables
Exploratory variable assessment clarified to include screening/baseline combined visit per 
Modification 9 (Section 15.1.1.9).
Old text
Perfusion status of the retina assessed by wide-field at baseline, Week 24, Week 52, and 
Week 76
New text
Perfusion status of the retina assessed by wide-field FA at screening/baseline, Weeks 24, 52, 
and 76
15.1.2.47 Assessments at initial visit – Section 9.4.3 Exploratory efficacy 
variables
Table 9-2: Specified assessments that should be performed at the initial visit when 
screening/baseline visits are combined per Modification 28 (Section 15.1.1.28).
Old text
EXPLORATORY EFFICACY VARIABLESa
a At selected sites where instrumentation and technical competence are available.
New text
EXPLORATORY EFFICACY VARIABLESa
a At selected sites where instrumentation and technical competence are available. If screening 
and baseline visits are combined, these assessments should be performed at the initial visit.
15.1.2.48 Fluorescein angiography and fundus photography combined with 
wide-field examinations – Section 9.4.4.3 Fluorescein angiography and 
fundus photography
Clarified that FA/FP examinations can be combined with wide-field examinations to avoid 
separate fluorescein injection per Modification 26 (Section 15.1.1.26).
Old text
No related text
New text
Traditional FA/FP examinations can be combined with wide-field examination if possible. A 
separate fluorescein injection, especially, should be avoided.
15.1.2.49 Assessments at initial visit – Section 9.4.4.4 Wide-field fluorescein 
angiography
Added that assessment should be performed at initial visit if screening and baseline visits are 
combined per Modification 28 (Section 15.1.1.28).


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Old text
Wide-field FA of both eyes will be performed at baseline, and of only the study eye at 
Week 24, Week 52, Week 76, and the early termination visit (and in the fellow eye if there are 
signs of vein occlusion).
New text
Wide-field FA of both eyes will be performed at baseline (or initial visit at combined 
screening/baseline), and of only the study eye at Weeks 24, 52, and 76, and the early 
termination visit (and in the fellow eye if there are signs of vein occlusion).
15.1.2.50 Assessments at initial visit – Section 9.4.4.5 Optical coherence 
tomography angiography
Added that assessment should be performed at initial visit if screening and baseline visits are 
combined per Modification 28 (Section 15.1.1.28).
Old text
Optical coherence tomography angiography images of both eyes will be captured at baseline 
and of only the study eye at Week 24, Week 52, Week 76, and the early termination visit (and 
in the fellow eye if there are signs of vein occlusion).
New text
Optical coherence tomography angiography images of both eyes will be captured at baseline 
(or initial visit at combined screening/baseline) and of only the study eye at Weeks 24, 52, 
and 76, and the early termination visit (and in the fellow eye if there are signs of vein 
occlusion).
15.1.2.51 Assessments at initial visit – Section 9.4.4.6 Full-field 
electroretinography
Added that assessment should be performed at initial visit if screening and baseline visits are 
combined per Modification 28 (Section 15.1.1.28).
Old text
Full-field ERGs will be performed in both eyes at baseline, and only in the study eye at 
Week 24, Week 52, Week 76, and the early termination visit (and in the fellow eye if there are 
signs of vein occlusion).
New text
Full-field ERGs will be performed in both eyes at baseline (or initial visit at combined 
screening/baseline) and only in the study eye at Weeks 24, 52, and 76, and the early 
termination visit (and in the fellow eye if there are signs of vein occlusion).
15.1.2.52 Pregnancy testing – Section 9.6.3.1 Pregnancy test
Added that pregnancy testing is mandatory for women of childbearing potential at every 
treatment visit prior to injection if required by local regulations per Modification 24
(Section 15.1.1.24).


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Old text
All women of child-bearing potential will have a urine pregnancy test at screening and 
baseline. If the result of a urine pregnancy test is positive, a serum pregnancy test to confirm 
results will be done at a local laboratory.
New text
All women of child-bearing potential will have a urine pregnancy test at screening. If the 
result of a urine pregnancy test is positive, a serum pregnancy test to confirm results will be 
done at a local laboratory. After screening, a urine pregnancy test for women of childbearing 
potential is mandatory at every treatment visit (prior to injection) in all countries where it is 
required by local regulations. If required by local regulations, a pregnancy test should be 
performed for women of childbearing potential at the End of Study visit.
15.1.2.53 Gonioscopy order of procedure – Section 9.6.3.4.4 Gonioscopy 
Removed wording that gonioscopy is performed after OCT and before FA/FP per 
Modification 29 (Section 15.1.1.29).
Old text
The evaluation will be conducted at screening and at Week 76 and the early termination visit, 
and may be repeated if needed as determined by the investigator. Gonioscopy will be 
performed.in the study eye only. The examination should be performed after OCT and before 
FP and FA.
New text
The evaluation will be conducted at screening and at Week 76 and the early termination visit, 
and may be repeated if needed as determined by the investigator. Gonioscopy will be 
performed in the study eye only.
15.1.2.54 Reference removed - Section 9.6.3.4.5 Relative afferent pupillary defect 
assessment
Removed reference to Thompson HS, et al per Modification 33 (Section 15.1.1.33).
Old text
Testing for RAPD will be conducted at baseline, Week 24, Week 52, Week 76, and the early 
termination visit. Testing will be conducted in both eyes as described by Thompson et al). A 
detailed protocol for conducting RAPD testing is provided in the study manual.
New text
Testing for RAPD will be conducted at baseline, Weeks 24, 52, and 76, and the early 
termination visit. Testing will be conducted in both eyes. A detailed protocol for conducting 
RAPD testing is provided in the study manual.
15.1.2.55 Window for post-baseline study visits – Section 10.3.1 Variables
Clarified that a ± 7-day window will be allowed for all post-baseline visits per Modification 7
(Section 15.1.1.7).


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Old text
The visit schedules at Weeks 24, 52, and 76 may deviate by ± 7 days.
New text
A ± 7-day window will be allowed for all post-baseline visits.
15.1.2.56 Secondary variable change in retinal perfusion status –
Section 10.3.2.2.2 Secondary and exploratory efficacy variables
Clarified that assessment of secondary variable of change in retinal perfusion status will 
include screening/baseline combined visit per Modification 3 (Section 15.1.1.3).
Old text

The change in retinal perfusion (FA/FP) status from baseline to Weeks 24, 52, and 76
New text

The change in retinal perfusion (FA/FP) status from screening/baseline to Weeks 24, 
52, and 76
15.1.2.57 Exploratory variable perfusion status of retina – Section 10.3.2.2.2 
Secondary and exploratory efficacy variables
Exploratory variable assessment clarified to include screening/baseline combined visit per 
Modification 9 (Section 15.1.1.9).
Old text
Perfusion status of the retina assessed by wide-field at baseline, Week 24, Week 52, and 
Week 76
New text
Perfusion status of the retina assessed by wide-field FA at screening/baseline, Weeks 24, 52, 
and 76
15.1.2.58 Central reading center for images – Section 13.1 Investigator(s) and 
other study personnel
Identified that study may be overseen by a Steering Committee per Modification 34
(Section 15.1.1.34).
Old text
No related text
New text
Central reading center for images
An independent central reading center will evaluate the ophthalmic images defined in 
Section 9.


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15.1.2.59 Steering Committee – Section 13.1 Investigator(s) and other study 
personnel
Added that the study may be overseen by a Steering Committee per Modification 35
(Section 15.1.1.35).
Old text
No related text
New text
External data evaluation bodies
The sponsor may decide to institute a Steering Committee to guide the trial in all aspects of 
safety and efficacy and must ensure that all relevant information is provided by investigators. 
The composition of the team, the functional roles, and responsibilities will be specified in the 
Charter.
15.1.2.60 Adjudication Committee – Section 13.1 Investigator(s) and other study 
personnel
Added that an Adjudication Committee will perform additional analysis per Modification 36
(Section 15.1.1.36).
Old text
No related text
New text
Finally, an adjudication committee will perform an additional analysis of arterial thrombotic 
events (ATEs) based on the Antiplatelet Trialists' Collaboration (APTC) endpoint of non-fatal 
myocardial infarction, non-fatal stroke, and fatal vascular events, including fatal hemorrhages 
and sudden unexplained death. Details will be described in the Adjudication Committee 
Charter.
15.1.2.61 Reference change – Section 14 Referrence list
Reference list change for SmPC from 24 to 2 per Modification 4 (Section 15.1.1.4).
Old text
24. European Medicines Agency. Eylea (Aflibercept) solution for intravitreal injection: 
summary of product characteristics
New text
2. European Medicines Agency. Eylea (Aflibercept) solution for intravitreal injection: 
summary of product characteristics 
15.1.2.62 Study drug vials – Section 16.1 Intravitreal aflibercept injection 
procedure
Correction of text in accordance with study drug vials to be supplied per Modification 37
(Section 15.1.1.37).


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Old text
Intravitreal aflibercept is formulated as a sterile liquid to a final concentration of 40 mg/mL 
IVT Aflibercept in 5% sucrose, 10 mM sodium phosphate pH 6.2, 0.03% polysorbate 20, and 
40 mM NaCl. Intravitreal aflibercept study drug will be supplied by the sponsor in sealed, 
sterile 3mL-vials, each with a “withdrawable” volume of approximately 0.1 mL.
New text
Intravitreal aflibercept is formulated as a sterile liquid to a final concentration of 40 mg/mL 
IVT Aflibercept in 5% sucrose, 10 mM sodium phosphate pH 6.2, 0.03% polysorbate 20, and 
40 mM NaCl. Intravitreal aflibercept study drug will be supplied by the sponsor in sealed, 
sterile 2-mL vials, each with a “withdrawable” volume of approximately 0.1 mL.
15.1.2.63 Dose preparation – Section 16.1 Intravitreal aflibercept injection 
procedure
Removed text stating that dose must be administered within 2 hours of start of dose 
preparation per Modification 17 (Section 15.1.1.17).
Old text
Based on present stability data and the fact that the dosing solution contains no bacteriostatic 
agents, IVT aflibercept dosing solutions may be kept at room temperature (25°C/77°F) for up 
to 24 hours. The injection of IVT aflibercept must be completed within 2 hours of the start of 
dose preparation.
New text
Based on present stability data and the fact that the dosing solution contains no bacteriostatic 
agents, IVT aflibercept dosing solutions may be kept at room temperature (25°C/77°F) for up 
to 24 hours.
15.1.2.64 Post-treatment safety telephone calls – Appendix 16.1 Intravitreal 
aflibercept injection procedure
Revised schedule for safety follow-up telephone calls from 3 days after treatment to within 
3 days per Modification 30 (Section 15.1.1.30).
Old text
3. A mandatory safety telephone call should be made 3 days after treatment to ensure no 
signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred.
New text
3. A mandatory safety telephone call should be made within 3 days after treatment to 
ensure no signs or symptoms of retinal detachment, endophthalmitis, or other AEs have 
occurred.


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16.
Appendices – amended
16.1
Intravitreal aflibercept injection procedure - amended
Study drug dose and volume for administration
Intravitreal aflibercept is formulated as a sterile liquid to a final concentration of 40 mg/mL 
IVT Aflibercept in 5% sucrose, 10 mM sodium phosphate pH 6.2, 0.03% polysorbate 20, and 
40 mM NaCl. Intravitreal aflibercept study drug will be supplied by the sponsor in sealed, 
sterile 2-mL vials,73 each with a “withdrawable” volume of approximately 0.1 mL. The 
volume of injection will be 50 μL (0.05 mL) for the 2 mg dose of IVT aflibercept. The study 
drug will be withdrawn using aseptic technique through an 18-gauge filtered needle attached 
to a 1-mL syringe. The needle will be discarded after withdrawal of the vial contents and 
should not be used for IVT injection. The needle should be replaced with a sterile 30-gauge 
needle for the IVT injection. The contents should be expelled until the plunger is aligned with 
the line that marks 0.05 mL on the syringe.
When IVT 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. Exposure of the material to temperatures 
outside these limits, except for warming to room temperature prior to administration, is not 
recommended and may result in loss of activity. Records of actual storage conditions (i.e. 
temperature log) at the study site must be maintained and must include a record of the dates 
when the refrigerator was checked, the initials of person checking, and the temperature.
Based on present stability data and the fact that the dosing solution contains no bacteriostatic 
agents, IVT aflibercept dosing solutions may be kept at room temperature (25°C/77°F) for up 
to 24 hours.74
Subject preparation for injection
The physician or designee will prepare the subject for injection.
Use of topical antibiotic agents
At the time of this study, the use of topical antibiotics as prophylaxis in IVT injections, both 
in the preparation and post injection, varies considerably between different practices. There is 
no consensus on the use of topical antibiotics, the agent to be used, and the dose administered. 
In this protocol, it is recommended that a broad-spectrum topical antibiotic be used as part of 
the preparation for the IVT injection procedure, and as prophylaxis in the days immediately 
following the injection.
The use of a topical antibiotic is recommended but is at the discretion of the investigator.
Suggested use:
                                                
73 Corrected size of vials from 3 mL to 2 mL in accordance with study drug vials to be supplied per Amendment 1, 
Modification 37 (see Section 15.1.1.37).
74 Removed text stating that dose must be administered within 2 hours of start of dose preparation per 
Amendment 1, Modification 17 (see Section 15.1.1.17).


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
Instruct the subject to self-administer 1 to 2 drops of the antibiotic to the study eye, 
3 times a day, for 3 days before the injection day

On the injection day, as part of the preparation for injection, instill 1 drop to the eye 
1 hour before the injection, and another drop 15 minutes before the injection

After the injection, instruct the subject to self-administer 1 to 2 drops of the topical 
antibiotic to the injected eye, 3 times a day, for additional 3 days
Study drug preparation
The mandatory sequence of steps required for preparation must be followed for 
administration of the dose in this clinical trial, as described below. This drug administration 
protocol is based upon the recent guideline published in Retina (23) and current standard of 
practice.
Preparatory steps:
1. Preparation
a.
Apply topical anesthetic.
b. Apply povidone-iodine to eyelid margins, eyelashes, and conjunctival surface.
c.
Place 1 or 2 drops of 5% povidone-iodine on the ocular surface at the intended 
injection site.
d. Use sterilized forceps and calipers (speculum) to stabilize the globe and 
measure the injection site.
e.
Optional: Inject 0.5 mL of 2% xylocaine without epinephrine
subjconjunctivally at the intended injection site (the entry site of the needle for 
the intravitreous injection should be in the inferotemporal quadrant, 3.0 to 
3.5 mm from the limbus in aphakic/pseudophakic subjects, and 3.5 to 4.0 mm 
in the phakic subjects).
f.
Use sterile fluorescein strips and single use proparacaine bottles for all 
subjects. Fluoracaine or other combination fluorescein sodium and 
proparacaine HCl mixtures should NOT be used.
g. Drape.
h. Apply additional drop of povidone iodine to site of injection.
2. Study drug (VEGF Trap-Eye) administration
a.
Insert needle at marked injection point.
b. Gently inject study drug.
c.
As the needle is withdrawn, a sterile cotton tip applicator should be rolled over 
the entry site to minimize the risk of drug reflux. This should be held in place 
for a full 10 seconds.
Further guidance can be found in The Royal College of Ophthalmologists Intravitreal 
Injections Procedure Guideline 


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(http://www.rcophth.ac.uk/docs/publications/publishedguidelines/IntravitrealInjectionsJuly20
06.pdf).
Post-injection procedures
1. Indirect ophthalmoscopy in the study eye only.
2. Measure IOP approximately 30 minutes after injection in the study eye only.
3. A mandatory safety telephone call should be made within 3 days75 after treatment to 
ensure no signs or symptoms of retinal detachment, endophthalmitis, or other AEs 
have occurred.
Additional post-injection management procedures as recommended by the guidelines are as 
follows:
1. After the injection, instruct the subject to self-administer 1 to 2 drops of a topical 
antibiotic to the injected eye, 3 times a day, for an additional 3 days.
2. Post-injection reperfusion of the optic nerve:
a.
Visualize the optic nerve to verify reperfusion of the central retinal artery in 
the immediate post-injection period.
b. Verify IVT location of therapeutic agent when possible.
c.
Verify that the retina is attached and that there is no new intraocular 
hemorrhage.
3. Intraocular pressure
Intraocular pressure may be lowered by pharmaceutical or surgical intervention, if 
required. If a Tono-Pen is used to check pressure, a clean Tono-Pen condom should be 
placed on the tip before taking each measurement. If applanation tonometry is used, the 
applanator tip should be swabbed with alcohol and allowed to dry before using it to 
measure IOP.
a.
Monitor IOP approximately 30 minutes after each injection.
b. Check IOP while maintaining a clean field.
c.
Monitor IOP closely until it is below 25 mm Hg.
d. Treatment should be initiated whenever IOP is increased to the extent that the 
central retinal artery remains closed and the subject has no light perception for 
more than 1 to 2 minutes.
e.
Transient graying or obscuration of vision following injection is expected and 
should not be treated.
f.
Paracentesis should be used only in extreme circumstances when the degree of 
pressure elevation poses an imminent and irreversible threat to vision. In the 
                                                
75 Revised schedule for safety follow-up telephone calls from 3 days after treatment to within 3 days per 
Amendment 1, Modification 30 (see Section 15.1.1.30).


Integrated Clinical Study Protocol
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Version 2.0
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rare situation when a paracentesis is warranted, IOP should be recorded both 
before and after the procedure. A 0.1- to 0.2-mL paracentesis may be 
performed at the temporal limbus using a 27- or 30-gauge needle or surgical 
knife, if judged to be necessary by the investigator.
g. Record all IOP measurements and related treatments in the source document 
and on the appropriate eCRF page.
Discharge
No special precautions are required before discharge of a subject who has had an uneventful 
recovery from IVT injection, but subjects and/or caregivers should be educated to avoid 
rubbing the eye and to recognize the signs and symptoms of endophthalmitis, retinal 
detachment, or intraocular hemorrhage. These signs and symptoms include eye pain or 
increased discomfort, increased redness of the eye (compared with immediately after 
injection), blurred or decreased vision, and increased ocular sensitivity to light.

Subjects should be informed that some blurring of vision is common after an injection, 
which is often described as seeing spots floating in the eye. Floaters usually resolve 
after a few days or weeks.

Subjects who experience AEs after injection that require additional monitoring should 
remain in the clinic until the condition is resolved, and should be treated according to 
the investigator’s medical judgment.

SAP_001.pdf: 
Document Type: 
Study Analysis Plan 
Official Title: 
A multi-center, single-arm, interventional Phase 4 study to 
evaluate a Treat and Extend regimen of intravitreal 
aflibercept for treatment of macular edema secondary to 
central retinal vein occlusion
NCT Number: 
NCT02800642 
Document Date: 
14 Nov 2019 


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PPD


 
Statistical Analysis Plan 
 
 
 
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Reference Number: BHC-RD-OI-119 
Supplement Version: 7 
 
Table of Contents 
1 
Introduction .................................................................................................................................................. 5 
1.1 
Objective ............................................................................................................................................. 5 
1.2 
Background ......................................................................................................................................... 5 
1.3 
Treat and Extend ................................................................................................................................ 5 
2 
Study Objectives .......................................................................................................................................... 6 
3 
Study Design ............................................................................................................................................... 7 
3.1 
Design Overview ................................................................................................................................. 7 
3.2 
Inclusion/Exclusion ............................................................................................................................. 7 
3.3 
Visit Overview ..................................................................................................................................... 7 
3.4 
Efficacy and Safety variables.............................................................................................................. 7 
4 
General Statistical Considerations .............................................................................................................. 8 
4.1 
General Principles .............................................................................................................................. 8 
4.2 
Handling of Dropouts .......................................................................................................................... 8 
4.3 
Handling of Missing Data .................................................................................................................... 9 
4.4 
Interim Analyses and Data Monitoring ................................................................................................ 9 
4.5 
Data Rules .......................................................................................................................................... 9 
4.6 
Validity Review ................................................................................................................................. 12 
5 
Analysis Sets and Subgroups ................................................................................................................... 13 
5.1 
Assignment of analysis sets ............................................................................................................. 13 
5.2 
Definition of subgroups ..................................................................................................................... 13 
6 
Statistical Methodology ............................................................................................................................. 14 
6.1 
Population characteristics ................................................................................................................. 14 
6.1.1 
Study periods and sample sizes ................................................................................................... 14 
6.1.2 
Subject validity status ................................................................................................................... 14 
6.1.3 
Subject Disposition ....................................................................................................................... 14 
6.1.4 
Demography ................................................................................................................................. 15 
6.1.5 
Baseline Characteristics ............................................................................................................... 15 
6.1.6 
Medical history .............................................................................................................................. 15 
6.1.7 
Prior and concomitant medication ................................................................................................ 16 
6.1.8 
Exposure ....................................................................................................................................... 16 
6.2 
Efficacy ............................................................................................................................................. 16 
6.2.1 
Co-Primary Efficacy Variables ...................................................................................................... 17 
6.2.2 
Secondary  and Exploratory Efficacy Variables ............................................................................ 21 
6.3 
Pharmacokinetics/pharmacodynamics ............................................................................................. 22 
6.4 
Safety ................................................................................................................................................ 22 
6.4.1 
Adverse Events (AEs) ................................................................................................................... 22 
6.4.2 
Indirect Ophthalmoscopy .............................................................................................................. 25 
6.4.3 
Gonioscopy ................................................................................................................................... 25 
6.4.4 
Intraocular Pressure / Tonometry ................................................................................................. 25 
6.4.5 
Subjects requiring panretinal photocoagulation in the course of the study .................................. 26 
6.4.6 
Pregnancy test .............................................................................................................................. 26 
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6.4.7 
Vital Signs and BMI ...................................................................................................................... 26 
7 
Document history and changes in the planned statistical analysis ........................................................... 27 
8 
References ................................................................................................................................................ 28 
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Reference Number: BHC-RD-OI-119 
Supplement Version: 7 
Abbreviations 
AE 
Adverse Event  
APTC 
Antiplatelet Trialists' Collaboration  
ATC 
Anatomical Therapeutic Chemical  
ATE 
Arterial Thrombotic Events 
AUC 
Area Under the Curve 
BCVA 
Best Corrected Visual Acuity  
BMI 
Body Mass Index 
BRVO 
Branch Retinal Vein Occlusion 
CI 
Confidence Interval 
CRF 
Case Report Form  
CRT 
Central Retinal Thickness 
CRVO 
Central Retinal Vein Occlusion 
ERG 
Electroretinogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study  
FA 
Fluorescein Angiography 
FAS 
Full Analysis Set  
FP 
Fundus Photography  
FPFV 
First patient first visit 
IOP 
Intraocular Pressure 
IVT 
Intravitreal 
LOCF 
Last Observation Carried Forward 
LR 
Likelihood Ratio 
MedDRA  
Medical Dictionary For Regulatory Activities 
MI 
Multiple Imputation 
OCT 
Optical Coherence Tomography 
PPS  
Per-Protocol Set 
PRP 
Panretinal Photocoagulation 
PT 
Preferred Term 
RAPD 
Relative Afferent Pupillary Defect 
SAE  
Serious Adverse Event 
SAF  
Safety Analysis Set 
SAP  
Statistical Analysis Plan 
SD 
Standard Deviation 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SOC  
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Events 
T&E 
Treat and Extend 
VEGF  
Vascular Endothelial Growth Factor 
WHO-DD 
World Health Organization Drug Dictionary 
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1 
Introduction 
1.1 
Objective 
This statistical analysis plan (SAP) describes the statistical methods and data presentations to be 
used in the summary and analyses of data from a multi-center, single-arm interventional Phase 4 
study, to assess efficacy and durability of 2 mg aflibercept administered by intravitreal (IVT) 
injections in a Treat and Extend (T&E) regimen to subjects with macular edema secondary to central 
retinal vein occlusion.  
SAP version 1.0 based on the Integrated Clinical Study Protocol No. BAY 86-5321 /17514, version 
2.0 dated 20 April 2016, and was finalised before first patient first visit (FPFV). 
SAP version 2.0, will be finalized before database-lock and contains some clarifications and 
updates. For details see section 7.  
 
1.2 
Background 
Retinal venous occlusive disease is an important cause of vision loss, particularly in patients with 
associated chronic macular edema. The 2 major categories are central retinal vein occlusion (CRVO) 
and branch retinal vein occlusion (BRVO). 
Central retinal vein occlusion results in impaired venous drainage from the eye, which may lead to 
increased venous pressure, reduced arterial perfusion, and retinal ischemia.  
Aflibercept is a potent, specific inhibitor of vascular endothelial growth factor (VEGF) with a high 
affinity for all isoforms of VEGF and placental growth factor.  
Further details are provided in the applicable Summary of Product Characteristics and the Clinical 
Study Protocol. 
Further details are provided in the Clinical Study Protocol. 
 
1.3 
Treat and Extend 
CENTERA is a Phase 4 study to investigate a proactive T&E regimen with IVT aflibercept for the 
treatment of macular edema secondary to CRVO.  
Further details are provided in the Clinical Study Protocol. 
 
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2 
Study Objectives 
Primary objective 
• To determine the efficacy and durability (treatment interval) of 2 mg IVT aflibercept in a 
T&E regimen over a treatment period of 76 weeks using protocol-defined visual and 
anatomic criteria in subjects with macular edema secondary to CRVO 
Secondary objectives 
• To assess the efficacy of IVT aflibercept as measured by visual acuity and anatomic 
outcomes using spectral domain optical coherence tomography (SD-OCT), and perfusion 
status using fluorescein angiography (FA) / fundus photography (FP). 
• To assess T&E applied posology of IVT aflibercept (number of injections, length of injection 
interval) 
Safety objective 
• To assess the safety and tolerability of IVT aflibercept in this subject population 
Exploratory objectives (only at those sites with equipment available) 
• To evaluate wide-field (angle) FA for utility in assessing perfusion status in the periphery of 
the retina, which is currently not evaluable using traditional FA, and examination of 
morphological changes related to disease progression in CRVO 
• To evaluate optical coherence tomography (OCT) angiography for dynamic assessment of 
retinal capillary perfusion status 
• To evaluate full-field electroretinography (ERG) for functional assessment of retinal 
ischemia 
• To evaluate relative afferent pupillary defect (RAPD) appearance or changes related to 
disease progression in CRVO 
The number of available data for the exploratory endpoints from patients were much lower than 
expected as well as collected with different machines for which the pooling of the data is not ot not 
easily possible. Based on this and thus the very limited representativeness of the data it was decided 
to not statistically evaluate them but only provide the assessed parameters in the listings in the 
appendix of the CSR 
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3 
Study Design 
3.1 
Design Overview 
This is an international, multi-center, prospective, interventional, single-arm, cohort Phase 4 study in 
adult subjects with a diagnosis of macular edemea secondary to CRVO who have previously not 
been treated with any systemic or IVT anti-VEGF treatments. 
 
3.2 
Inclusion/Exclusion 
Main inclusion/exclusion criteria are as follows:  
Treatment-naïve subjects ≥ 18 years of age with center-involved macular edema secondary to 
CRVO for no longer than 3 months before the first administration of study drug. Subjects must have 
documented best-corrected visual acuity (BCVA) of Early Treatment Diabetic Retinopathy Study 
(ETDRS) letter score of 73 to 24 letters (Snellen equivalent of 20/40 to 20/320) in the study eye. 
The inclusion and exclusion criteria will be assessed during the screening phase. Details are 
available in the Clinical Study Protocol, Sections 6.1 and 6.2.  
 
3.3 
Visit Overview 
This study comprises a screening period of up to 21 days and a treatment period of 76 weeks, which 
begins with an initiation  phase followed by the T&E phase. The treatment period is up to the last 
T&E visit before the final study visit at Week 76. There will be prescheduled visits at baseline, 
Weeks 24, 52, and 76 (end-of-study visit).  Other visits between baseline and Week 76 will depend 
on the applied posology of IVT aflibercept and the monitoring schedule for each subject. A ± 7-day 
window will be allowed for all post-baseline visits. 
Table 9-1 of the Clinical Study Protocol gives a description of the planned assessments and study 
procedures. 
 
3.4 
Efficacy and Safety variables 
The co-primary efficacy variables will be as follows: 
• The proportion of subjects who gain ≥ 15 letters in BCVA on the ETDRS chart compared 
with baseline at Week 76 
• The proportion of subjects with a mean treatment interval between injections of ≥ 8 weeks 
from the last actual visit of the initiation phase to Week 76 
A complete list of all efficacy variables is provided in Section 6.2.  
The primary and secondary efficacy variables assessed at Weeks 24, 52, and 76 will use last 
observation carried forward (LOCF) method. The primary efficacy variable analysis will be 
conducted on the Full Analysis Set and Per-protocol Set as defined in Section 5.1. 
Assessments of ocular safety will include tonometry, indirect ophthalmoscopy, slit lamp 
biomicroscopy, and gonioscopy.  
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Overall safety of the subjects will be assessed throughout the study by recording vital signs as well 
as by monitoring adverse events (AEs) and ophthalmological parameters. 
Safety variables are provided in Section 6.4.  
 
4 
General Statistical Considerations 
4.1 
General Principles 
The first version of the SAP of this open-label study was finalized before FPFV to avoid additional 
reporting bias. The current version takes recent changes in eCRF into account, clarifies  and is 
finalized before database-lock.  
The statistical evaluation will be performed by using the software package SAS release 9.2 or higher 
(SAS Institute Inc., Cary, NC, USA).  
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.  
Frequency tables will be generated for categorical data.  For categorical variables, the number and 
percentage of patients with a specific level of the variable will be presented. 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. 
 
4.2 
Handling of Dropouts 
Subjects must or might be withdrawn from the study for different reasons, which are specified in the 
protocol in Section 6.3.1.  
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“. 
Drop-out 
A subject who discontinues study participation prematurely for any reason is defined as a “drop-out“ 
if the subject has already received IVT aflibercept. 
The number of screening failures and drop-outs as well as the respective reasons will be 
summarized. Data from subjects who drop-out of the study will be included in all summaries where 
possible. 
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4.3 
Handling of Missing Data 
All missing or incomplete data will be presented in the subject data listings as they are recorded on 
the Case Report Form (CRF). In general missing or incomplete data will not be substituted or 
replaced, except for the parameters described below and in Section 6.2 for efficacy analysis. 
When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data: 
• Safety variables 
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.  
• 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. 
• Efficacy variables 
Efficacy analysis imputations will use LOCF for subjects in analysis populations. Multiple 
imputations (MIs) for missing values will additionally be performed on the primary and key 
secondary efficacy variables (see Section 6.2.1.4). 
 
4.4 
Interim Analyses and Data Monitoring 
No interim analysis and no data safety monitoring are planned. 
 
4.5 
Data Rules 
Determination of baseline values 
Generally, pre-treatment values recorded at Visit 2 (Day 1) will be used as baseline values. This visit 
should take place within 3 weeks of the screening visit. However, according to the Clinical Study 
Protocol Section 9.2, screening and baseline visits can be combined. In case screening and baseline 
are combined or no baseline value is available, then last available screening values are used. Change 
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from baseline is calculated as the value at the post-baseline time point minus the baseline value, i.e. 
value at time point – value at baseline. 
Handling of repeated measurements at the same visit 
If measurements are repeated at the same scheduled visit, the value actually flagged as scheduled 
will be the 
• Last non-missing repeated measurement, if visit is before start of treatment, and 
• First non-missing repeated measurement, if visit is after start of treatment. 
Generally, only scheduled measurements will be used for statistical summaries and analysis. 
Unscheduled measurements will not be used for analysis, but only listed.  
Handling time-windows 
The screening visit must occur within 3 weeks of the baseline visit (Day 1). Screening values 
collected more than 3 weeks before baseline will be flagged in the patient listings, however they will 
still be used for summary tables and analysis.. 
There will be prescheduled visits at baseline, Weeks 4, 24, 52, and 76 (end-of-study visit). Other 
visits between baseline and Week 76 will depend on the applied posology of IVT aflibercept and the 
monitoring schedule for each subject. A ± 7-day window will be allowed for all post-baseline visits. 
The initiation phase of the treatment will extend from the first injection until the subject meets 
retreatment interval extension criteria as summarized in Section 7.1.3 in the Clinical Study Protocol. 
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Table 2: Time Windows 
Analysis time point 
Study days range 
Screening 
–21 to 1 
Baseline (prescheduled) 
1 
Week 4 (prescheduled) 
22 to 36 
Week 5-8 
37 to 59 
Week 9-16 
60 to 116 
Week 17-23 
117 to165 
Week 24 (prescheduled) 
166 to 172 
Week 25-32 
173 to 228 
Week 33-40 
229 to 284 
Week 41-48 
285 to 340 
Week 49-51  
341 to 361 
Week 52 (prescheduled) 
362 to 368 
Week 53-60  
369 to 424 
Week 61-68 
425 to 480 
Week 69-75 
481 to 529 
Week 76 (prescheduled) 
530 to 536 
> Week 76 
> 536 
The screening and baseline visits can be combined. The necessary procedures can be performed on 
separate days. There will be a 7-day window allowed for all procedures to be completed in such a 
combined visit. If screening and baseline occur on the same visit, pregnancy test results and reading 
center evaluations need to be available prior to treatment with study drug. 
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 grading/numbers of vitreous cells.  
o Slit lamp biomicroscopy: “Abnormal” values and their descriptions will be used, if 
available, and the highest grading/numbers of anterior chamber flare or cells.  
o Vital signs: The highest values will be used. 
 
Early termination 
Visit-based information of the early termination visit will be mapped to the next (not unscheduled) 
visit if the visit was performed 2 weeks (± 1 week) after the last scheduled visit. This can result in 
data for visits at which this variable was not scheduled to be collected. This data will nevertheless be 
included into the (LOCF) analyses and be reported as observed value for the respective visit. 
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Early termination visits outside this window will not be used for analyses and will be handled in the 
same way as unscheduled assessments (see above) and the data will only be shown in the patient 
listings.  
Pooling centers 
Not applicable as no analysis by study center will be conducted. All centers will be combined for the 
purposes of the analysis. 
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 days, weeks, months, or years.  
The integer value of the durations will be listed and summarized, if not specified otherwise. 
Coding 
The verbatim of the following panels will be coded by the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA) available before database lock 
• Medical history  
• Adverse events  
• Surgeries after start of study 
Prior and concomitant medications will be coded by the latest version of World Health Organization 
Drug classification Dictionary (WHO-DD) available before database lock. 
Presentation 
Listings will be sorted by unique subject identifier and analysis time point and/or date if applicable.  
Dates will be formatted as DDMMMYYYY. Partial dates will be presented on data listings as 
recorded on CRFs. 
Rounding for all variables will occur only as the last step, immediately prior to presentation in 
listings and tables. No intermediate rounding will be performed on derived variables. The standard 
rounding practice of rounding numbers ending in 0-4 down and numbers ending 5-9 up will be 
employed. 
Every table, listing, and figure will be produced with an electronic date stamp to document when it 
was produced. 
4.6 
Validity Review 
Validity Review Meetings are performed according to Bayer Standard Operating Procedures (SOP) 
and will be led by the Syneos Health Lead Data Manager. Details are available in the Data 
Management Plan. 
The results of the validity review meeting will be documented in the Validity Review Report and 
may comprise decisions and details relevant for statistical evaluation. Any changes to the statistical 
analysis prompted by the results of the validity review meeting will be documented in an 
amendment and, if applicable, in a supplement to this SAP. 
 
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5 
Analysis Sets and Subgroups 
5.1 
Assignment of analysis sets 
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
Validity Review Meeting and documented in the Validity Review Report (see Section 4.6). 
Populations for analysis will be defined as follows: 
Full Analysis Set (FAS) 
The FAS will include all enrolled subjects who receive any study drug, have a baseline BCVA 
assessment, and have at least 1 post-baseline BCVA assessment. With regard to the efficacy 
evaluation of this study, the FAS is considered the primary analysis. 
Per-protocol Set (PPS) 
The PPS will include all enrolled subjects who receive any study drug, have a BCVA assessment at 
study baseline, have at least 1 BCVA assessment at Week 24 or later, and do not have a major 
protocol deviation. The detailed definitions and the assignment of subjects to this analysis set will be 
based on the validity review meeting and the protocol deviations document. 
Safety Analysis Set (SAF) 
The SAF will include all subjects who receive any study drug. 
5.2 
Definition of subgroups 
A subgroup analysis will be performed for each country contributing at least 5 patients to the FAS 
on both co-primary variables (see Section 6.2.1.1). 
A subgroup analysis for subjects classified by mean treatment intervals (< 8 weeks, ≥ 8 weeks) 
between injections from the last actual visit of the initiation phase to Week 76 will be conducted in 
the FAS on the first co-primary variable (see Section 6.2.1.1). 
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6 
Statistical Methodology 
6.1 
Population characteristics 
Population characteristics will be summarized depending on the type of data as described in Section 
4.1, if not specified otherwise. 
For the Screening failures, the reason for the exclusion from study will be summarized and listed. 
Demographic and disposition data will be displayed in patient listings.  
For screening failures with a serious AE (SAE), all information related to any AE or SAE will be 
listed.  
Efficacy data from Screening failures will neither be summarized nor listed. 
6.1.1 
Study periods and sample sizes 
Number of subjects enrolled and valid for the different analysis populations will be displayed in 
total and per trial unit.  
Major protocol deviations will be summarized per category given in the latest available Protocol 
Deviation Document. 
6.1.2 
Subject validity status 
An overview table will be given, displaying the number and percentages of subjects:  
• Screening (failure/pass) 
• Safety analysis set (SAF) 
• SAF, but not FAS (by reason) 
• Full analysis set (FAS) 
• FAS, but not PPS (by reason) 
• Per protocol set (PPS) 
 
6.1.3 
Subject Disposition 
Subject disposition at the end of  screening will be presented for all enrolled subjects, including 
number of subjects who completed screening period and entered treatment period or did not 
enter treatment period. The primary reason for withdrawal from treatment period will be 
summarized. 
Another table will describe the subject disposition at end of treatment for SAF, including the 
number and percentages of subjects:  
• Completed treatment 
• Not completed treatment 
• Reason for Withdrawal  
o Reason 1 
o Reason 2 
o … 
• Time until Withdrawal  
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o Withdrawal until Week 24 
o Withdrawal after Week 24 but before Week 52 
o Withdrawal after Week 52  
Similarily, a table with respect to the end of study will be created for SAF.  
6.1.4 
Demography 
Demographic variables will be summarized for SAF, FAS and PPS and listed for all subjects, with 
screening failures on a separate page. 
The following demographic parameters will be summarized: 
• Sex 
• Age 
• Race 
• Ethnicity 
• Weight 
• Height  
• Body mass index (BMI) 
• Study eye - left or right 
6.1.5 
Baseline Characteristics  
The following baseline characteristics of the study eye are observed at screening and/or baseline. In 
case of repeated measures the last available value before first application of the study drug will be 
used for summary tables for SAF, FAS and PPS. 
• BCVA letter scores 
• BCVA letter scores - categorized (5 letters ranges) 
• Central retinal thickness (CRT) 
• Refraction sphere (dpt) 
• Capillary nonperfusion from fluorescein angiography 
• Gonioscopy 
 
The number and percentages of the subgroups defined in Section 5.2 will be presented in a separate 
table for FAS. 
6.1.6 
Medical history 
Medical history will be summarized for SAF and listed for all subjects, with screening failures on a 
separate page. 
Overall medical history will be summarized based on the MedDRA version available before 
database lock. The number and percentages of subjects affected will be displayed. The following 
variables are of interest: 
• Any medical history 
• System Organ Classes (SOCs) 
• Preferred Terms (PT) 
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The SOCs will be sorted by descending frequency of subjects, within each SOC the PT will be 
sorted by descending frequency of subjects affected. 
The table will be presented overall, by ocular medical history (yes/no), by eye (study eye, fellow 
eye).  
6.1.7 
Prior and concomitant medication 
Prior and concomitant medication will be summarized for SAF and listed for all subjects, with 
screening failures on a separate page. 
Summaries of all prior and concomitant medications recorded will be presented in tabular form 
using 3-digit Anatomical Therapeutic Chemical Classification (ATC) classification codes and 
preferred drug name via the WHO-DD, latest version available before database lock. 
The medications will be classified as. 
• Concomitant: Medications that are ongoing at, began after the start of study drug, or 
medications that were started up to 30 days after end of study drug. 
• New Concomitant: Medications that began after the start of study drug, and those that were 
started up to 30 days after end of study drug. 
• Prior: Medications that started and stopped before the start of study drug. 
Medication that is started more than 30 days after end of study will be listed as post-treatment 
medication. 
Each of these categories will be summarized by medication class and preferred name and sorted by 
descending frequencies. The tables will be displayed overall, by ocular medication (yes/no) and eye 
(study eye/fellow eye). 
6.1.8 
Exposure 
The number of injections per subject will be tabulated, classified (1-5, 6-10, >10), and presented as a 
metric variable, see Section 4.1. In addition, the total amount of study drug injected (mg), the 
number of injections per subject year and the duration of study drug exposure will be summarized.  
The number of injections per subject year is calculated as 52*(Number of IVT injections) / (Number 
of weeks participating in the study). Study drug exposure in weeks is defined as (date of last 
injection – date of first injection + 28) / 7.  
This table will be performed on SAF, FAS and PPS. 
6.2 
Efficacy 
Assessments of efficacy will include BCVA, SD-OCT, and FA/FP procedures. At selected sites 
where instrumentation and technical competence is available, assessments will also include 
wide-field FA, OCT angiography, and full-field ERG.  
The following co-primary, secondary and exploratory variables will be assessed:  
Co-primary efficacy variables: 
• The proportion of subjects who gain ≥ 15 letters in BCVA on the ETDRS chart compared 
with baseline at Week 76 
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• The proportion of subjects with a mean treatment interval between injections of ≥ 8 weeks 
from the last actual visit of the initiation phase to Week 76  
Secondary efficacy variables: 
• The change in BCVA as measured by the ETDRS letter score from baseline to Weeks 24, 52, 
and 76 
• The change in CRT from baseline to Weeks 24, 52, and 76 
• The number of injections from baseline to Week 76 
• The mean treatment interval between injections from baseline to Week 76 
• The proportion of subjects who gain ≥ 15 letters in BCVA on the ETDRS chart compared 
with baseline at Weeks 24 and 52 
• The change in retinal perfusion (FA/FP) status from screening / baseline to Weeks 24, 52 and 
76 
• The proportion of subjects with absence of fluid at Weeks 24, 52, and 76 
Exploratory efficacy variables as defined in the protocol: 
• Perfusion status of the retina assessed by wide-field FA at screening/baseline, Weeks 24, 52, 
and 76  
• OCT angiography measures for assessing perfusion status of the retina and examination of 
morphological changes related to disease progression in CRVO at baseline, Weeks 24, 52, 
and 76 
• Full-field ERG assessments at baseline, Week 24, Week 52, and Week 76 
• Status of RAPD at baseline, Weeks 24, 52, and 76 
 
6.2.1 
Co-Primary Efficacy Variables 
6.2.1.1 The proportion of subjects who gain ≥ 15 letters in BCVA on the ETDRS chart compared with 
baseline at Week 76 
The BCVA values range from 0 to 100.  
Subjects will be considered to be fulfilling this criterion if they show a change from baseline to 
Week 76 in BCVA of greater than or equal to 15 letters.  
All subjects who drop out of the study will be deemed to have not met the co-primary efficacy 
variable, except for the following: 
If the investigator assesses in a subject who drops out after Week 24 resolution of macular edema 
secondary to CRVO with no need for further treatment with IVT aflibercept, the change from 
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baseline to the last measurement of BCVA for this subject will be categorized using the LOCF 
methodology1.  
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).  
LOCF is considered to be conservative because subjects dropping out due to lack of efficacy might 
be stable and only a responder if having gained 15 letters before dropping out. 
 
6.2.1.2 The proportion of subjects with a mean treatment interval between injections of ≥ 8 weeks 
from the last actual visit of the initiation phase to Week 76 
The co-primary efficacy variable of the proportion of subjects with a mean treatment interval 
between injections of ≥ 8 weeks from the last actual visit of the initiation phase to Week 76 will be 
assessed as follows: 
• For subjects completing the study to Week 76, the mean treatment interval between 
injections from the last actual visit of the initiation phase to Week 76 will be calculated as 
follows: 
(date of last injection up to and including Week 76 visit – date of last actual visit 
of initiation phase)/(number of injections taken from last visit of initiation phase 
until immediately prior to the Week 76 visit – 1) 
• Should the mean treatment interval for a subject between injections from the last actual visit 
of the initiation phase to Week 76 be ≥ 56 days, then the mean treatment interval is deemed 
to be ≥ 8 weeks and the co-primary efficacy variable has been met, if the mean is < 56 days, 
then the co-primary efficacy variable has not been met for this subject. 
• All subjects who drop out of the study will be deemed to have not met the co-primary 
efficacy variable, except for the following: 
o Subjects who drop out after Week 24 and who are defined by the investigator as 
having a permanent resolution of macular edema are considered to have met the 
co-primary efficacy variable. For subjects considered by the investigator to have a 
permanent resolution of macular edema, at least 1 additional confirmatory visit is 
required (after a minimum interval of 8 weeks from the visit when resolution was 
determined and up to the regular Week 76 visit). 
The approach to handle discontinued subjects is considered sufficiently conservative with regard to 
assessing mean treatment interval. The number and percentage of subjects who gain ≥ 15 letters in 
BCVA on the ETDRS chart compared with baseline at the Week 76 variable and the subjects with a 
                                                     
1 As proof of permanent resolution of macular edema, at least 1 additional, confirmatory monitoring visit is required 
(after a minimum of 8 weeks and no later than the Week 76 visit). Any additional CRT and BCVA measurements at 
subsequent visits need to be consistent with the permanent resolution of macular edema as well. In case these conditions 
are not fulfilled, the respective subject is considered to have not met the variable. 
 
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mean treatment interval between injections of ≥ 8 weeks from the last actual visit of initiation phase 
to Week 76 will be presented, and, in addition, the mean and median treatment interval and 
frequency from baseline to Week 76, and during the T&E phase, will be described based on 95% 
confidence intervals (CIs).  
6.2.1.3 Primary analysis for the co-primary efficacy variables 
By means of evaluating both co-primary variables, the exact 1-sample binomial test will be used for 
both co-primary variables using FAS. 
Study success requires proof that both a gain of ≥ 15 letters in BCVA at Week 76 is reached by more 
than 40% of subjects and, additionally, 50% of subjects have a mean treatment interval of ≥ 8 weeks 
in the T&E phase. 
In further explanations, the null hypothesis for evaluation of the co-primary variable 1 (proportion of 
subjects with gain of ≥ 15 letters in BCVA at Week 76) will be labeled as H01, the alternative 
hypothesis as H11. 
Similarly, for evaluation of the co-primary variable 2 (proportion of subjects with a mean treatment 
interval of ≥ 8 weeks), the null hypothesis will be labeled as H02, while the alternative hypothesis 
will be labeled as H12. 
Then, the primary hypothesis H0 will be tested statistically2, as: 
• H0: H01: p1 ≤ 40% 
 
or  
H02: p2 ≤ 50% versus 
• H1: H11: p1 > 40% 
 
and 
H12: p2 > 50% 
Where p1 is the proportion of subjects with a ≥ 15-letter gain in BCVA at Week 76, p2 is the 
proportion of subjects with a mean treatment interval of ≥ 8 weeks. The significance level α for this 
2-sided test will be 5%. 
Given the statistical paradigm of the intersection-union test, the test on H0 can be performed as 
independent statistical tests on H01 and H02. 
For descriptive purposes, the co-primary efficacy variables will be summarized, including 
supportive 2-sided 95% CIs. 
 
6.2.1.4 Sensitivity analysis for the co-primary efficacy variables 
The primary efficacy variable analysis as described in Section 6.2.1.3 will be conducted based on 
the PPS, using LOCF for the first co-primary variable.  
Additionally, the following sensitivity analyses will be performed on the FAS to support results of 
the primary analysis. 
 
                                                     
2 In the study protocol the hypothesis was given by mistake as follows: 
H0: H01: p1 < 40% 
 
or  
H02: p2 < 50% versus 
H1: H11: p1 ≥ 40% 
 
and 
H12: p2 ≥ 50% 
In the correct mathematical notation the equality is part of the Null-hopthesis. This correction has no impact on the 
analysis-strategy, results and interpretation. 
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Subgroup analysis by length of treatment interval  
The subgroup of subjects having a mean treatment interval of ≥ 8 weeks vs < 8 weeks will be 
analyzed with regard to gain of  ≥ 15 letters in BCVA at Week 76 as a sensitivity analysis in FAS. 
Subgroup analysis by country 
A subgroup analysis of the primary variables will be performed for each country contributing at 
least 5 patients to the FAS. 
Observed Cases (OC) 
The primary method (LOCF) is considered to be conservative because subjects dropping out due to 
lack of efficacy are considered as stable. 
Therefore, the primary analysis will be repeated on the observed values, i.e., only  including patients 
that have a BCVA score result at Week 76 (+/- 7 days), i.e. without LOCF-imputation. 
Multiple imputation (MI) 
Multiple imputations (MI) for missing BCVA-values will be performed and used on the respective 
co-primary efficacy variable (see Section 6.2.1.1), as described below, seed1=8357, 
seed2=99721:  
Multiple imputation methods involve three steps: 
Imputation, 
i.e., the generation of multiple copies of the original dataset by replacing missing values 
using an appropriate stochastic model.  
First missing data will be imputed in order to achieve a monotone missing pattern using the 
Markov-Chain-Monte-Carlo method, using SAS-procedure proc MI similarly as below. 
PROC MI DATA=<indata> SEED=<seed1> OUT=out1 NIMPUTE=20;  
MCMC impute=monotone; 
VAR base Week1 Week4 Week8 … ; RUN; 
Subsequently missing data will be imputed by a regression model. 
PROC MI DATA=out1 SEED=<seed2> OUT=full nimpute=1; 
BY _Imputation_; 
CLASS treatment; 
MONOTONE method=reg; 
VAR treatment base Week1 Week4 Week8 … ; 
Analysis,  
i.e., the analysis of the multiple imputed datasets as complete sets. The analysis step is 
performed for each of the multiply imputed datasets. Since all imputed datasets are complete 
there is no need to bother with any missing data. On each imputed dataset the primary and 
key secondary analysis will be performed. It should be clarified that classifications (gain of 
< 15 letters) will be performed after the imputation of the missing BCVA values. 
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. 
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6.2.2 
Secondary  and Exploratory Efficacy Variables 
The secondary and exploratory efficacy variable analysis will be conducted on the FAS.  
6.2.2.1 Secondary efficacy variables 
For the following change from baseline-based secondary efficacy variables, missing data will be 
imputed by means of the LOCF method. Sensitivity analyses for these variables will be provided 
based on MI as described for the primary variable. The respective seed numbers are pre-selected in 
brackets. 
1. The change in BCVA as measured by the ETDRS letter score from baseline to  
a. Week 24,  
b. Week 52,  
c. Week 76 (MI: seed1=61932, seed2=20056). 
2. The change in CRT from baseline to  
a. Week 24,  
b. Week 52,  
c. Week 76 (MI: seed1=1000, seed2=30864). 
3. The proportion of subjects who gain ≥ 15 letters in BCVA on the ETDRS chart compared 
with baseline at Weeks 24 and 52. These will be calculated from using the values from 1. 
These variables will be summarized descriptively as described in Section 4.1. The following two 
secondary efficacy variables will be summarized as described in Section 4.1 on the observed cases 
only: 
4. The number of injections from baseline to Week 76 
5. The mean treatment interval between injections from baseline to Week 76 
For the following variables the exact 95%CI will be calculated: 
6. The change in retinal perfusion (FA/FP) status, defined as a change from perfused (ischemia 
< 10 disc areas) to non-perfused (ischemia ≥ 10 disc area) or vice versa, from 
screening/baseline to Weeks 24, 52, and 76  
7. The proportion of subjects with absence of fluid at Weeks 24, 52, and 76 
For the change in retinal perfusion status, the number of subjects non-perfused at baseline will be 
compared with the number of subjects non-perfused at Week 24, Week 52, and Week 76 with shift 
tables. McNemar’s test will be used, to describe the changes in the course of time. 
 
6.2.2.2 Exploratory efficacy variables 
Fluorescein Angiography (FA)/ Fundus Photography (FP) evaluations will be conducted in both 
eyes at screening/baseline, and in the study eye only at Weeks 24, 52, and 76, and the early 
termination visit (and in the fellow eye if there are signs of vein occlusion).  
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Wide-field FA, OCT angiography, and full-field ERG may be conducted, at selected study sites, in 
both eyes at baseline and in the study eye only at Weeks 24, 52, and 76, and the early termination 
visit (and in the fellow eye if there are signs of vein occlusion). The respective data will be collected 
for post-hoc analysis and will only be listed in the appendix of the CSR.  
6.3 
Pharmacokinetics/pharmacodynamics 
Not applicable.  
6.4 
Safety 
Safety parameters will be summarized as described in Section 4.1. The SAF will be used for the 
summary and listings of safety parameters. 
The following safety variables are of special interest: 
• Number and severity of systemic adverse events (AEs) 
• Number and severity of ocular adverse events, which might all be detected by 
o tonometry,  
o indirect ophthalmoscopy,  
o slit lamp biomicroscopy, or  
o gonioscopy 
• Percentage of subjects requiring panretinal photocoagulation (PRP) in the course of the study 
 
6.4.1 
Adverse Events (AEs) 
The definitions of AEs and serious AEs (SAEs) are provided in the Clinical Study Protocol, Section 
9.6.1.1. The classifications according to seriousness, intensity, causality, action taken, other specific 
treatment and outcome are provided in the Clinical Study Protocol, Section 9.6.1.2. 
Treatment emergent adverse events (TEAEs) are AEs that start after the first application of 
aflibercept in the study. In addition, if it is clearly documented that the adverse event occurred more 
than 30 days after the last dose of study drug, it will be treated as not treatment emergent. The same 
rules apply due the surgeries. 
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A summary table will display the number and percentages of subjects with at least one 
Any AE  
Any AE causally related to study drug     
Any AE causally related to intravitreal injection procedures  
Any AE causally related to other protocol-required procedures 
Maximun intensity for any AE 
Maximum intensity for study drug-related AE 
AE with outcome death      
Any serious AE 
Any serious AE causally related to study drug 
Any serious AE causally related to intravitreal injection procedures 
Any serious AE causally related to protocol-required procedures 
Any APTC event 
Discontinuation of study drug due to AE 
Discontinuation of study drug due to serious TEAE 
 
This overall summary will be repeated for  
o Ocular AE in the study eye 
o Ocular AE in the fellow eye 
o Non-ocular AE  
o TEAE 
o Ocular TEAE in the study eye 
o Ocular TEAE in the fellow eye 
o Non-ocular TEAE  
 
Number of subjects with TEAE will be presented by MedDRA PT within primary SOC for the 
following: 
o All TEAE  
o Ocular TEAE in the study eye 
o Ocular TEAE in the fellow eye 
o Non-ocular TEAE  
o All study drug-related TEAE  
o Ocular study drug-related TEAE in the study eye 
o Ocular study drug-related TEAE in the fellow eye 
o Non-ocular study drug-related TEAE 
o All intravitreal procedure-related TEAE  
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o All serious TEAE  
o Ocular serious TEAE in the study eye 
o Ocular serious TEAE in the fellow eye 
o Non-ocular serious TEAE 
o All serious study drug-related TEAE  
o Ocular serious study drug-related TEAE in the study eye 
o Ocular serious study drug-related TEAE in the fellow eye 
o Non-ocular serious study drug-related TEAE 
o All serious intravitreal procedure-related TEAE  
o All TEAE leading to discontinuation of study-drug 
o Ocular TEAE in the study eye leading to discontinuation of study-drug 
o Ocular TEAE in the fellow eye leading to discontinuation of study-drug 
o Non-ocular TEAE leading to discontinuation of study-drug 
o All TEAE by maximum intensity 
o Ocular TEAE in the study eye by maximum intensity 
o Ocular TEAE in the fellow eye by maximum intensity 
o Non-ocular TEAE by maximum intensity 
o All study-drug related TEAE by maximum intensity 
o Ocular study-drug related TEAE in the study eye by maximum intensity 
o Ocular study-drug related TEAE in the fellow eye by maximum intensity 
o Non-ocular study-drug related TEAE by maximum intensity 
o All non-serious TEAE 
o Ocular non-serious TEAE in the study eye 
o Ocular non-serious TEAE in the fellow eye  
o Non-ocular non-serious TEAE 
o All non-treatment emergent AE 
o Ocular non-treatment emergent AE in the study eye 
o Ocular non-treatment emergent AE in the fellow eye  
o Non-ocular non-treatment emergent AE  
o All TEAE by worst outcome 
o Ocular TEAE in the study eye by worst outcome 
o Ocular TEAE in the fellow eye by worst outcome 
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o Non-ocular TEAE by worst outcome 
Subjects may be counted under multiple SOCs and PTs, but for each SOC and PT, subjects are only 
counted once. SOCs will be sorted by descending frequency of subjects, within each SOC the PT 
will be sorted by descending frequency of subjects affected. 
Potential arterial thrombotic events (ATEs) will be evaluated by an adjudication committee 
according to criteria formerly applied and published by the Anti-Platelet Trialists‘ Collaboration 
(APTC). The definition of ATEs as well as further details are described in the adjudication 
committee charter. They will be presented separately. 
6.4.2 
Indirect Ophthalmoscopy 
At visits with study drug administration, pre-injection indirect ophthalmoscopy will be assessed for 
both the study eye and fellow eye. Post-injection assessments will be carried out in the study eye 
only. 
Frequency tables for normal/abnormal findings for the study will be provided. The cup-to-disc ratio 
will presented by summary statistics.  
6.4.3 Slit Lamp Biomicroscopy 
The slit lamp examination is to be performed at all visits in both the study eye and the fellow eye 
irrespective of whether the fellow eye has signs of vein occlusion.  
Frequency tables for normal/abnormal slit lamp biomicroscopy findings as well as for the grading of  
‘anterior chamber flare’ and ‘anterior chamber cells’ will be provided for the study eye only.  
6.4.3 
Gonioscopy 
The evaluation will be conducted at screening and at Week 76 and the early termination visit, and 
may be repeated if needed as determined by the investigator. Gonioscopy will be performed in the 
study eye only. 
Frequency tables for normal/abnormal findings for the study will be provided.  
6.4.4 
Intraocular Pressure / Tonometry 
Intraoculare pressure will be assessed for both the study eye and fellow eye at all scheduled visits.  
At visits with study drug administration, pre-injection IOP will be assessed for both the study eye 
and fellow eye. Assessment of IOP 30-60 minutes following IVT injection will be carried out in the 
study eye only. 
All IOP measurements will be classified as follows: 
• > 25 mm Hg  
• ≥ 30 mm Hg 
• ≥ 35 mm Hg  
• ≥ 40 mm Hg  
Any increase from baseline of ≥ 10 mm Hg will be flagged.  
The IOP summaries will include 
• original measurements 
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• 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 for the study eye, the changes of the measurements between pre- and post-injection 
will be analysed descriptively depending on the type of data as described in Section 4.1.  
 
6.4.5 
Subjects requiring panretinal photocoagulation in the course of the study 
Panretinal photocoagulation (PRP) during the study will be captured in “Surgery after the study” 
page in CRF. 
Number and percentages of subjects requiring PRP during the study will be presented in frequency 
tables.  
6.4.6 
Pregnancy test 
Results of the pregnancy tests will be listed only. 
6.4.7 
Vital Signs and BMI 
Vital signs (body temperature, blood pressure [diastolic and systolic] and heart rate),will be 
summarized as described in Section 4.1 during the course of the study. 
 
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Statistical Analysis Plan 
 
 
 
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Reference Number: BHC-RD-OI-119 
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Document history and changes in the planned statistical analysis 
The main changes to Statistical Analysis Plan, version 1.0, 20th June 2016 are as follows: 
a) Section  4.1: clarifications for displaying TFLs according to Bayer standards 
b) Section 4.3: clarification of handling missing start- and stop-dates 
c) Section 4.5: correction of time-windows and clarification of handling repeated measurements 
d) Section 5.2: already defined subgroups in a separate section 
e) Section 6.1: clarification of presentation of population characteristics, especially 
• Section 6.1.5: drop of some baseline characteristics which are not applicable anymore 
• Section 6.1.8: including “injections per subject year” 
f) Section 6.2.1.1: clarification of LOCF main analysis. 
g) Section 6.2.2.: exploratory variables will only be listed 
h) Section 6.4.1:  
• adaption of “treatment-emergent” to apply for a 30-day window 
• adaption and calrification of presentation the Adverse Events summaries 
i) Section 6.4.2: adaption and clarification of presentation 
j) Section 6.4.3: adaption and clarification of presentation 
k) Section 6.4.4: adaption and clarification of presentation 
l) Section 6.4.6: adaption and clarification of presentation 
 
The main changes to Statistical Analysis Plan, version 2.0, 31st January 2019 are as follows: 
m) Section 6.1.6: number of events will not be displayed. 
n) Section 6.2.1.3: Primary hypothesis corrected – typo in study protocol has been copied over in 
previous SAP versions. 
o) Section 6.2.2.1:  
• No separate seeds needed for the multiple imputations of Week 24 and Week 52 analysis. 
• McNemar’s methodology, relative risk and CI are not applicable here and will be 
dropped.  
• McNemar’s test can only be provided for the change in retinal perfusion status, to 
describe the changes in the course of time. 
 
Clinical Study Report
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Statistical Analysis Plan 
 
 
 
Protocol No.: BAY86 5321/17514 
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28 of 
28
 
Reference Number: BHC-RD-OI-119 
Supplement Version: 7 
8 
References 
1. Integrated Clinical Study Protocol No. BAY86  5321/17514: A multi center, single 
arm, interventional Phase 4 study to evaluate a Treat and Extend regimen of intravitreal 
aflibercept for treatment of macular edema secondary to central retinal vein occlusion. 
Version 2.0, 20 Apr 2016, Bayer HealthCare AG, D 51368 Leverkusen, Germany. 
 
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