Clinical trial NCT03639675
Conditions: Glaucoma, Neovascular
Sponsor: Bayer
Start date: 2018-10-03; Completion date: 2019-03-14
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The researchers in this trial want to learn how the drug aflibercept works in in Japanese patients with increased eye pressure that is caused by new blood vessels growing in the eye (neovascular glaucoma or NVG). They also want to find out how patient tolerate the application of the drug that is injected in the vitreous humor of the eye and if this will cause any medical problems during the trial (vitreous humor, also called vitreous body is the clear gel that fills the space between the lens and the retina of the eyeball).

Detailed description:

Arms: arm 1: Japanese patients with neovascular glaucoma
Interventions: intervention 1: Aflibercept (EYLEA, BAY86-5321) intervention 2: Topical IOP-lowering drugs
Intervention descriptions: intervention 1: 2 mg (0.05 mL), Intravitreal injection (IVT), single dose. intervention 2: A combination of at least 3 topical IOP-lowering drugs will be administered during a run-in phase before treatment and should be kept unchanged until IOP evaluation at Week 1, after which they may be reduced according to the investigator's opinion

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
A single-arm, non-randomized and open-label phase 3 study 
evaluating the efficacy, safety and tolerability of intravitreal 
aflibercept in Japanese patients with neovascular glaucoma (NVG) 
NCT Number: 
NCT03639675 
Document Date: 
18-May-2018 
 


Clinical Study Protocol
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1.
Title page
A single-arm, non-randomized and open-label phase 3 study evaluating the efficacy, 
safety and tolerability of intravitreal aflibercept in Japanese patients with neovascular 
glaucoma (NVG) 
Japanese phase 3 study of aflibercept in NVG patients 
VENERA
Test drug:
BAY 86-5321  / Aflibercept 
Study purpose:
Efficacy and Safety 
Clinical study phase:
3 
Date:
18 May 2018   
Registration:
EudraCT:  N/A
Version no.:
Version 1.0   
Sponsor’s study no.:
19652 
Sponsor:
Bayer Yakuhin, Ltd.
4-9, Umeda 2-chome, Kita-ku, Osaka, 530-0001, Japan
Sponsor’s medical expert:
 
Bayer Yakuhin, Ltd.
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.  
Hence, the appearance of product names without these symbols does not imply that these names are 
not protected.
PPD
PPD


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Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
 
Role: 
Global Clinical Leader 
Date: 
Signature: 
PPD
PPD


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


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2.
Synopsis
Title
A single-arm, non-randomized and open-label phase 3 study evaluating the 
efficacy, safety and tolerability of intravitreal aflibercept in Japanese 
patients with neovascular glaucoma (NVG) 
Short title
Japanese phase 3 study of aflibercept in NVG patients 
Acronym
VENERA 
Clinical study phase
3 
Study objective(s)
Primary objective:

To assess the efficacy of intravitreal (IVT) administration of 
aflibercept on the change in intraocular pressure (IOP) in patients 
with neovascular glaucoma (NVG). 
Secondary objective:

To assess the safety and tolerability of IVT administration of 
aflibercept in patients with NVG. 
Test drug(s)
Name of active ingredient
Aflibercept 
Dose(s)
2 mg (0.05 mL) 
Route of administration
Intravitreal injection (IVT) 
Duration of treatment
1 day (single dose)
Reference drug(s)
Name of active ingredient
N/A 
Dose(s)
N/A 
Route of administration
N/A 
Duration of treatment
N/A 
Background treatment
Topical IOP-lowering drugs 
Indication
Neovascular glaucoma (NVG) 


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Diagnosis and main criteria for 
inclusion /exclusion
Key inclusion criteria:

Japanese men and women aged 20 years or older 

Patients diagnosed as having NVG with neovascularization in the 
anterior segment (both iris and anterior chamber angle) 

Patients with IOP higher than 25 mmHg in the study eye due to 
anterior segment (both iris and anterior chamber angle) 
neovascularization 
Key exclusion criteria:

Patients with angle-closure due to conditions other than NVG or 
complete angle-closure due to NVG 

Patients with a known or suspected ocular or peri-ocular infection 

Patients with severe intraocular inflammation in the study eye 

Women who are pregnant, suspected of being pregnant or lactating 

Patients with known allergy to aflibercept 
Study design
The study is a single-arm, non-randomized and open label trial to evaluate 
the efficacy, safety and tolerability of intravitreal aflibercept 
Methodology
Multicenter, single arm, non-randomized, and open label.
Efficacy
The efficacy of aflibercept 2 mg IVT will be assessed by the change in IOP 
from baseline (Day 1) to each visit.
Other measures as efficacy variables will include change in 
neovascularization grades of iris and anterior chamber angle (NVI and 
NVA) as assessed by gonioscopy in conjunction with slit-lamp microscopy 
and the proportion of subjects who achieve IOP equal or lower than 21 
mmHg.
Safety
Overall safety will be assessed by monitoring/evaluation of adverse events 
(AEs), physical examinations, vital signs (body temperature, blood 
pressure, and pulse rate), clinical safety laboratory tests (hematological test, 
blood biochemical examination and urine test),and ophthalmic 
examinations (indirect ophthalmoscopy, slit-lamp microscopy, gonioscopy, 
visual acuity test, and applanation tonometry) at pre-specified time points.
Type of control
N/A 
Data Monitoring Committee
N/A 
Number of subjects
The subjects' recruitment will be continued until 16 subjects are available 
as the per protocol set (PPS) 
Primary variable(s)
Change in IOP from baseline to Week 1 


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Time point/frame of 
measurement for primary 
variable(s)
Week 1 
Plan for statistical analysis
All variables will be analyzed with appropriate statistical methods: 
categorical variables by frequency tables and continuous variables by 
summary statistics (mean, standard deviation, minimum, median, and 
maximum).
Primary efficacy analysis
The change in IOP from baseline at Week 1 will be summarized 
descriptively.  The point estimate and its two-sided 95% confidence 
interval using one-sample t-statistics will be calculated.  The corresponding 
hypotheses for the efficacy analysis are the null hypothesis that μ equals to 
or greater than zero and the alternative hypothesis that μ is less than zero, 
where μ is the change in IOP from baseline at Week 1.  If the upper limit of 
the two-sided 95% confidence interval in PPS is less than the threshold 
(i.e., 0), the null hypothesis will be rejected and the study will be regarded 
as success.
Secondary efficacy analysis
The proportion of subjects who have improved NVI grade from baseline at 
Week 1 will be summarized descriptively.  The point estimate and its 
two-sided 95% confidence interval using Clopper-Pearson method will be 
calculated.  Improvement by at least one grade from baseline will be 
categorized to “Improved”.


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Table of contents
1.
Title page............................................................................................................................ 1
Signature of the sponsor’s medically responsible person..................................................... 2
Signature of principal investigator......................................................................................... 3
2.
Synopsis.............................................................................................................................. 4
Table of contents....................................................................................................................... 7
List of abbreviations................................................................................................................. 9
3.
Introduction..................................................................................................................... 10
4.
Study objectives............................................................................................................... 14
5.
Study design..................................................................................................................... 14
6.
Study population ............................................................................................................. 17
6.1
Inclusion criteria ............................................................................................................ 17
6.2
Exclusion criteria ........................................................................................................... 18
6.3
Justification of selection criteria.................................................................................... 19
6.4
Withdrawal of subjects from study................................................................................ 20
6.4.1
Withdrawal ................................................................................................................. 20
6.4.2
Replacement ............................................................................................................... 21
6.5
Subject identification ..................................................................................................... 21
7.
Treatments....................................................................................................................... 21
7.1
Treatments to be administered....................................................................................... 21
7.2
Identity of study treatment............................................................................................. 21
7.3
Treatment assignment.................................................................................................... 22
7.4
Dosage and administration............................................................................................. 22
7.5
Blinding (Masking)........................................................................................................ 22
7.6
Drug logistics and accountability................................................................................... 23
7.7
Treatment compliance.................................................................................................... 23
8.
Non-study therapy........................................................................................................... 23
8.1
Prior and concomitant therapy....................................................................................... 23
8.2
Post-study therapy.......................................................................................................... 24
9.
Procedures and variables ............................................................................................... 25
9.1
Tabular schedule of evaluations .................................................................................... 25
9.2
Visit description............................................................................................................. 26
9.2.1
Visit 1, Screening (Day -15 to 1)................................................................................ 26
9.2.2
Visit 2, Baseline (Day 1) ............................................................................................ 26
9.2.3
Visit 3, Week 1 (Day 8 + 3) ....................................................................................... 27
9.2.4
Visit 4, Week 2 (Day 15 ± 3)...................................................................................... 28
9.2.5
Visit 5, Week 5 (Day 36 ± 7): End of Study (also Early Termination) visit.............. 28
9.3
Population characteristics .............................................................................................. 28
9.3.1
Demographic .............................................................................................................. 28
9.3.2
Medical history........................................................................................................... 29
9.3.3
Other baseline characteristics..................................................................................... 29


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9.4
Efficacy.......................................................................................................................... 29
9.4.1
Intraocular pressure (IOP) .......................................................................................... 29
9.4.2
Neovascularization of iris and anterior chamber angle (NVI and NVA)................... 29
9.5
Pharmacokinetics / pharmacodynamics......................................................................... 30
9.6
Safety ............................................................................................................................. 30
9.6.1
Adverse events............................................................................................................ 30
9.6.2
Pregnancies................................................................................................................. 35
9.6.3
Further safety.............................................................................................................. 35
9.7
Other procedures and variables...................................................................................... 37
9.8
Appropriateness of procedures / measurements ............................................................ 37
10. Statistical methods and determination of sample size ................................................. 38
10.1
General considerations................................................................................................... 38
10.2
Analysis sets .................................................................................................................. 38
10.3
Variables and planned statistical analyses..................................................................... 39
10.3.1
Variables..................................................................................................................... 39
10.3.2
Statistical and analytical plan ..................................................................................... 39
10.3.3
Missing data / drop outs ............................................................................................. 41
10.4
Determination of sample size......................................................................................... 41
10.5
Planned interim analyses ............................................................................................... 42
11. Data handling and quality assurance............................................................................ 42
11.1
Data recording................................................................................................................ 42
11.2
Monitoring ..................................................................................................................... 43
11.3
Data processing.............................................................................................................. 44
11.4
Missing data................................................................................................................... 44
11.5
Audit and inspection ...................................................................................................... 44
11.6
Archiving ....................................................................................................................... 44
12. Premature termination of the study .............................................................................. 45
13. Ethical and legal aspects................................................................................................. 45
13.1
Investigator(s) and other study personnel...................................................................... 45
13.2
Funding and financial disclosure ................................................................................... 46
13.3
Ethical and legal conduct of the study........................................................................... 46
13.4
Subject information and consent.................................................................................... 47
13.5
Publication policy and use of data ................................................................................. 48
13.6
Compensation for health damage of subjects / insurance.............................................. 48
13.7
Confidentiality ............................................................................................................... 48
14. Reference list.................................................................................................................... 49
15. Protocol amendments...................................................................................................... 50
16. Appendices....................................................................................................................... 50


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List of abbreviations
AE
Adverse event
AMD
Age-related macular degeneration
APTC
Antiplatelet Trialists’ Collaboration
ATC
Anatomical Therapeutic Chemical
ATE
Arterial thrombotic event
BCVA
Best corrective visual acuity
CAI
Carbonic anhydrase inhibitor
CRO
Contract research organization
CRVO
Central retinal vein occlusion
DME
Diabetic macular edema
eCRF
Electronic case report form
EDC
Electronic data capture
FAS
Full analysis set
GCP
Good clinical practice
GMP
Good manufacturing practice
IB
Investigator’s Brochure
IgG1
Immune globulin G1
IOP
Intraocular pressure
IVT
Intravitreal
MedDRA
Medical Dictionary for Regulatory Activities
NVA
Neovascularization of the angle
NVG
Neovascular glaucoma
NVI
Neovascularization of the iris
OIS
Ocular ischemic syndrome
PAS
Peripheral anterior synechiae
PDR
Proliferative diabetic retinopathy
PG
Prostaglandin
PPS
Per protocol set 
PRP
Panretinal photocoagulation
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SUSAR
Suspected, unexpected, serious adverse reaction
TEAE
Treatment-emergent adverse event
UPCR
Urine protein-to-creatinine ratio
VEGF
Vascular endothelial growth factor
WHO-DD
World Health Organization Drug Dictionary


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3.
Introduction
Background
Neovascular Glaucoma
Neovascular glaucoma (NVG) is a secondary glaucoma triggered by the formation of new 
blood vessels (neovascularization) on the iris and the anterior chamber angle. 
Neovascularization restricts aqueous outflow and consequently elevates intraocular pressure
(IOP). NVG is a serious condition that may lead to permanent loss of vision, a persistently 
painful eye and, especially in the advanced stages, is unlikely to respond to treatment. NVG 
is caused by eye diseases leading to retinal ischemia, the major ones being central retinal vein 
occlusion (CRVO), proliferative diabetic retinopathy (PDR) and ocular ischemic syndrome 
(OIS)1). Although there have been no epidemiological reports for NVG, papers reported by 
Japanese medical institutions2, 3, 4) indicated that PDR is the most common cause in Japan and 
estimated to be responsible for about 80% of NVG cases. The number of patients with 
diabetes mellitus in Japan is about 2,700,000 (summary of 2011 patient survey, Japanese 
Ministry of Health, Labour, and Welfare)5) and 1.0% of patients with type-2 diabetes mellitus, 
which accounts for about 95% of all diabetes mellitus6), are affected with NVG7). 
Approximately 27,000 Japanese diabetic patients are thus estimated to have NVG secondary 
to PDR. Given that PDR accounts for about 80% of the causes of NVG, the estimated 
number of NVG patients is therefore 30,000 to 40,000 in Japan.  
Treatment of Neovascular Glaucoma
The clinical manifestations of NVG include elevated IOP and neovascularization in the 
anterior segment of the eye (iris and/or anterior chamber angle). Therefore, a combined 
approach is used to both reduce IOP and promote regression of neovessels. Panretinal 
photocoagulation (PRP) is commonly used to treat ischemic retina, induce regression of 
neovascularization in the anterior segment, and reduce IOP. The effects of PRP are not 
produced immediately, and during this period, further neovascularization may be seen and the 
anterior chamber angle may become progressively occluded worsening the prognosis. 
Moreover, it is often difficult to perform PRP in eyes with NVG, due to corneal edema 
secondary to high IOP or to other opacities of the optic media such as cataract or vitreous 
hemorrhage.  If PRP is suboptimal, cryo-coagulation is conducted or endolaser coagulation 
may be combined with vitreous surgery.  Despite such invasive treatments, progression of the 
neovascularization may continue because of persistent ischemia. The role of intravitreal anti-
VEGF is to produce a fast regression of the anterior segment neovascularization, stabilizing 
disease progression and bridging the patient to a long-term solution after the effect of PRP is 
attained.  
Open- and closed-angle NVG are associated with significantly high IOP, which leads rapidly 
to optic nerve atrophy and permanent vision loss. Even if PRP is successfully applied, 
regression of neovascularization requires time8, 9), and IOP reduction is delayed. 
Additionally, in some cases neovascularization does not respond to PRP, or, in spite of 
responding (i.e. causing neovessel regression), an IOP decrease to the target level is not 
achieved. For this reason, PRP is routinely combined with conventional IOP-lowering agents.
Nevertheless, these agents provide limited control of IOP10, 11) and are thus considered 
adjunctive in the treatment of NVG. If the combination of PRP and medical treatment fails to 


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reduce IOP and there is a persistently high IOP, or if persistent neo-vascular membrane and 
synechiae lead to a closed-angle, the NVG becomes irreversible because of aqueous outflow.  
Invasive treatment is then necessary. The most frequently used surgical procedures are 
trabeculectomy (i.e. filtration surgery facilitating aqueous flow into the subconjunctival space 
through a fistula created under a scleral flap) and tube-shunt surgery (i.e. drainage-device 
surgery that promotes aqueous outflow to the subconjunctival space via an intraocular 
implant). Eyes with persistent neovascularization may have intra- and/or post-operative 
hemorrhage and often suboptimal control of IOP. As stated above, it was not uncommon for
conventional NVG therapies to have persistent neovascularization in the anterior segment and 
continuously high IOP causing advanced optic nerve damage and permanent vision loss.
NVG is therefore a disease of poor visual prognosis.
The potential of off-label administration of anti-VEGF drugs for the treatment of NVG was 
first reported in 200612, 13, 14). Since then, several reports have been published on the use of 
anti-VEGF drugs to treat NVG with high IOP in addition to the conventional therapies 
previously described. The onset of neovascularization requires complex interactions between 
various inhibitory and promoting factors. VEGF stimulates the formation of new blood 
vessels by promoting proliferation of vascular endothelial cells. Activation of pro-angiogenic 
pathways by VEGF results in proliferation and migration of vascular endothelial cells and the 
formation of ectopic fragile and highly permeable blood vessels. These mechanisms of 
aberrant increase in VEGF-mediated neovascularization are the key elements in the pathology 
of NVG.  
Intravitreally administered anti-VEGF drugs may be able to halt this process and even regress 
neovascularization by directly inhibiting VEGF. This process is also effective in causing 
regression of new blood vessels in the anterior segment of eyes with NVG. In eyes with 
open-angle NVG, anti-VEGF drugs may cause prompt regression of new vessels, IOP 
reduction, and prevention of the formation of a neo-vascular membrane and peripheral 
anterior synechiae (PAS).  Moreover, the anti-VEGF agent is considered to be a useful time-
buying treatment before the effect of PRP treatment for ischemic retina is exerted. In closed-
angle NVG, permanent PAS have developed, and although anti-VEGF drugs are able to 
induce regression of neovascularization, they are not expected much to lower IOP. However, 
they are potentially able to enable a safer performance of glaucoma surgery, reducing intra-
and/or post-operative hemorrhagic complications and improving post-operative outcomes2, 15). 
In recent years, intravitreal (IVT) administration of anti-VEGF drugs has been suggested to be 
an effective adjunctive treatment for NVG16, 17, 18). However, no anti-VEGF drugs have been
currently approved for the treatment of NVG. In the Clinical Guideline for Glaucoma 
(Version 4; January 2018) issued by Japanese Glaucoma Society, the following text was 
added: “The efficacy of IVT injection of anti-VEGF drugs for NVG has been reported. Also 
it has been reported that the intraoperative or postoperative complications can be suppressed 
by IVT injection of anti-VEGF drugs preoperatively when conducting surgeries for NVG.”19)  
As stated above, being unlikely to respond to conventional treatments and often resulting in 
permanent vision loss, NVG is a refractory disease. Nevertheless, there are no approved 
drugs that cause regression of neovascularization and reduction of IOP by directly targeting 
VEGF, which is the primary cause of neovascularization in the anterior segment of eyes with 
NVG. For these reasons, there is a significant unmet medical need for new and efficacious 
treatment option for NVG, which will be potentially provided with aflibercept.  


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About BAY 86-5321 (aflibercept)
BAY 86-5321 [JAN: aflibercept (genetically recombinant)] is a recombinant protein 
consisting of human VEGF receptor (VEGFR) extracellular domains fused to the constant 
region (Fc) portion of human immunoglobulin (Ig) G1. It contains portions of the 
extracellular domains of 2 different VEGFRs (Figure 3-1). VEGFR1 binds to VEGF with a 
high affinity (picomolar range), while VEGFR2 binds to VEGF much less tightly.  The 
recombinant protein is expressed in Chinese Hamster Ovary K1 cells. Recovery and
purification of the protein are accomplished via a combination of filtration and
chromatographic techniques. The protein is then formulated for intravitreal (IVT)
administration to produce aflibercept.  
Figure 3-1: Structure of aflibercept
The recombinant protein aflibercept exhibits very potent binding activity to human VEGF, 
with an equilibrium dissociation constant (Kd) of approximately 0.5 pM. This binding 
activity is more potent relative to the activity of anti-VEGF agent ranibizumab (with a Kd in 
the order of 100 pM) 20). The formulation, aflibercept, is developed for intraocular use.
Research using an animal ophthalmological disease model demonstrated that aflibercept 
adequately inhibits the incidence of retinal neovascularization, choroidal neovascularization 
(CNV), and retinal edema. Further details can be found in the most recent version of the 
Investigator’s Brochure (IB), which contains comprehensive information on the study drug.
Rationale for the study
NVG is a severe pathological condition with a risk for permanent vision loss, and anti-VEGF 
drugs have been suggested to have a positive influence on the outcome of patients with NVG. 
In expectation of aflibercept as an effective treatment for NVG, the sponsor have planned 
clinical development of aflibercept for this indication in Japan.  
Prior clinical reports of anti-VEGF drugs8, 12, 13, 16, 17, 18, 21) suggested drugs in this class were 
able to decrease high IOP caused by NVG with the same dose used to treat eyes with macular 
VEGFR1   VEGFR2    Aflibercept
IgG1 Fc


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edema secondary to CRVO, diabetic macular edema (DME), or wet age-related macular 
degeneration (AMD). 
The 2 mg dose was chosen based on the finding that, to date, 2 mg has been shown to be an 
effective and safe dose in all clinical trials of aflibercept in other ophthalmologic indications. 
Therefore, 2 mg, which is the currently-approved dose for the treatment of macular edema 
secondary to CRVO and DME in Japan, shall be recommended as a dose for testing the 
efficacy in Japanese patients with NVG.  Given the well-established safety profile of 
aflibercept in various indications and the reports of anti-VEGF therapies successfully given to 
patients with NVG, a Japanese phase 3 study 17584 [VEGA] in NVG patients was conducted 
to expand the aflibercept labeling to include NVG.  The results of all efficacy variables,
including the primary endpoint “change in IOP,” have consistently suggested the efficacy of 
aflibercept but did not show the statistical superiority of the aflibercept group to the control 
(sham) group in terms of the primary endpoint “change in IOP from baseline to pre-dose at 
Week 1” (two-sided 95%CI of treatment difference [aflibercept group minus sham group]: –
10.2 to 0.3 mmHg, p=0.0644).  It may have been mainly because systemic IOP-lowering 
drugs permitted to be used from baseline through Week 1 influenced efficacy assessment of 
aflibercept. Meanwhile, the proportion of subjects who have shown regression of NVI grade 
at Week 1 as a secondary endpoint was significantly higher in the aflibercept group when 
compared to the sham group (70.4% for the aflibercept group and 11.5% for the sham group
showed regression of NVI by end of Week 1), strongly indicating the NVI-regressing disease 
modifying effect of aflibercept. In the generation of NVI and NVA secondary to retinal 
ischemic change, VEGF is the major factor in the development of anterior segment 
neovascularization, which impedes the aqueous outflow through the trabecular meshwork 
resulting in the possible rise of IOP. Anti-VEGF action regresses this anterior segment 
neovascularization (NVI and NVA in this case) and re-establishes the aqueous outflow 
through this channel, thereby resulting in lowering of IOP. Thus, it can be said that 
aflibercept used in VEGA exerted anti-VEGF effects by regressing anterior segment 
neovascularization with consequent IOP-lowering effects, although it cannot be ruled out that
systemic medication may also have at least partly contributed to reduction of IOP among
subjects in the aflibercept group.  
The mean (± SD) IOP change from baseline to pre-dose at Week 1 in the subgroup 
comprising subjects without systemic IOP-lowering drugs in VEGA remained almost 
unchanged (–0.4 ± 7.7 mmHg) in the sham group versus markedly reduced
(–8.8 ± 8.4 mmHg) in the aflibercept group. The applicant considered that a study design in 
the absence of the influence of systemic IOP-lowering drugs would be able to revisit 
aflibercept’s IOP-lowering effect among NVG patients and consequently to complement 
efficacy evaluation in VEGA.  
Thus, the applicant has set up the current study, No. 19652, with the mean change in IOP as 
the primary endpoint for the purpose of evaluating IOP-lowering effect and at the same time 
NVI-regressing effect as the secondary endpoint.  
Benefit-risk assessment
Aflibercept has been administered to numerous patients, and the drug’s safety and tolerability 
profile has been well established.  Aflibercept IVT is not expected to have adverse effects 
other than those described in the IB.  An already described important identified risk is the 
transient IOP increase. This IOP increase usually normalizes within one hour after the IVT 


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injection.  Measures are implemented that ensure close monitoring of patients around 
injection procedure and emergency treatment.  Other risks associated with the IVT 
administration of aflibercept are expected to be similar to those of other anti-VEGF therapies 
requiring IVT administration.  Based on the efficacy of the drug in neovascular diseases other 
than NVG and existing reports on the use of anti-VEGF therapies in the NVG indication, it is
expected that aflibercept will have a beneficial effect on a disease with a high medical need 
for effective treatment.
Therefore, IVT injection of aflibercept is justified in use for treatment of NVG and supported 
by the favorable benefit risk assessment in the indication NVG.  
4.
Study objectives
Primary objective:

To assess the efficacy of IVT administration of aflibercept on the change in IOP in 
patients with NVG. 
Secondary objective:

To assess the safety and tolerability of IVT administration of aflibercept in patients 
with NVG. 
5.
Study design
Design overview
This study will enroll NVG patients. This is a multicenter, single-arm, non-randomized, and 
open-label phase 3 trial to evaluate the primary efficacy variable “change in IOP from 
baseline to Week 1” of IVT administration of aflibercept in NVG patients (Figure 5-1).  
Figure 5-1: Study outline
After eligibility is confirmed, subjects will initiate treatment with at least 3 of the 5 allowed 
classes of topical IOP-lowering drugs. With application of the first eyedrop, the run-in-phase 
will start and IOP is monitored to determine whether the subject qualifies for assignment.  If 
IOP is higher than 25 mmHg and all other criteria allow, the subject should be assigned
(according to Section 7.3) and given aflibercept.  Treatment with topical drug classes initiated
during Run-in phase should be continued unchanged until Week 1 (see below). 
If required, subjects can receive systemic IOP-lowering drugs, or undergo PRP or surgery 
intended to lower IOP, during study participation. Even if medically justifiable, any of these 
IOP-lowering interventions should not be performed before the primary endpoint visit. If 
IOP-lowering intervention is unavoidable or systemic IOP-lowering drugs are needed for the 
treatment of the study eye and/or fellow eye before the primary-endpoint visit, the evaluations 
of the Week-1 visit should be done before the intervention.  The data obtained before the 
Week 5
(Final follow-up)
Screening
Days -15 to 1
(Run-in)
Baseline
Day 1 / Assignment
(Aflibercept IVT)
Week 1
(Primary evaluation)
Week 2


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intervention will be used for efficacy analysis according to the criteria established in Section 
10.  
Of note, since IOP may be transiently increased after aflibercept IVT injection, IOP will be 
carefully monitored.  
Run-in phase
After the inclusion criterion 3 (IOP > 25 mmHg) is confirmed at the screening visit, subjects
should initiate to receive topical IOP-lowering drug therapy as a run-in phase for a minimum 
of 1 to 2 hours.  Subjects will receive a combination of at least 3 topical IOP-lowering drugs 
from the classes in the following list:

Prostaglandin (PG) analog

Sympatholytic agent

Carbonic anhydrase inhibitor (CAI)

Sympathomimetic agent

Rho-kinase inhibitor
No more than 1 drug of each class should be used.  Subjects who are intolerant to more than 
2 drug classes should be treated with the highest number of drugs possible in light of their 
restrictions. The IOP will be re-evaluated 1 hour (± 10 minutes) after administration of the 
topical IOP-lowering drugs. If no decrease in IOP compared to screening is observed, this 
post-1-hour measurement can be considered the baseline measurement and the subject can 
immediately be assigned and treated with aflibercept. If a decrease in IOP compared to 
screening is detected, the subject will be kept under observation and re-evaluated 2 hours (±
10 minutes) after the start of the run-in phase. If the IOP is higher than 25 mmHg after 
2 hours, this measurement can be considered the baseline measurement and the subject can be 
assigned and treated with aflibercept. If treatment with aflibercept cannot be performed on 
the day of screening, the baseline evaluation and assignment can be performed a maximum of 
15 days after the diagnosis of NVG was made. If IOP drops to a value of 25 mmHg or lower 
between screening and planned assignment, the subject must not be assigned and will be 
excluded from the trial (see Sections 6 and 7.3). Intravitreal aflibercept injection should be 
administered as soon as the investigator considers either of them adequate after the baseline 
evaluation.  
The number of topical drugs in the run-in phase combination may be reduced to less than 3 
for subjects who have contraindications such as known allergies or potential suboptimal 
response to more than 2 of the drug classes. The topical drugs used during the run-in phase
should be kept unchanged until the IOP measurement is performed at Week 1, after which 
they may be reduced according to the investigator’s opinion.  
A flow diagram for run-in phase is shown in Figure 5-2.  


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Figure 5-2: Run-in phase
Primary variable

Change in IOP from baseline to Week 1 
Justification for the design
The objective of NVG treatment is to control the consequences of retinal ischemia: 
neovascularization and the secondary IOP increase. Patients with very high IOP require acute 
therapy to achieve IOP decrease, but since IOP increase is dependent on the presence of 
neovascularization, IOP-lowering drugs have limited effect in lowering IOP. Also, PRP has a 
delayed effect in producing regression of neovascularization, and IOP decrease is not 
expected in the acute stage by performing this treatment. Since anti-VEGF drugs have been 
reported to produce a rapid regression of neovascularization in the anterior segment, un-
blocking the angle and subsequently decreasing IOP, they present an ideal profile to treat 
patients in the acute stage, improving IOP control until full effect from PRP is obtained and 
long-term control is achieved. Therefore, the primary endpoint has been determined to be 
‘Change in IOP from baseline’.  
In patients with NVG, anti-VEGF drugs are expected to rapidly decrease IOP and 
subsequently produce an early relief of high IOP and symptoms. Previous data reporting 
practical experience with anti-VEGF agents in small case series as well as general 
considerations about the disease suggest that an early endpoint is appropriate to detect 
whether the treatment with anti-VEGF is able to provide earlier control of the disease 
manifestations than standard treatment options. The evaluation timing was therefore 
determined to be at Week 1. Study 17584 (VEGA) has shown the efficacy and safety of 
aflibercept up to 3 months after its first injection in the aflibercept group, and in the sham 
group which include the subjects who received aflibercept from Week 2 if necessary. Since 
the primary objective of the present study 19652 is to verify the IOP-lowering effect of 
aflibercept at Week 1 in NVG patients without systemic-IOP lowering drugs or PRP and since 
VEGA has already shown the efficacy and safety of aflibercept at 3 months, the present study 
19652 will focus on short-term efficacy at week 1 after a single dose of aflibercept and
patients will be followed up to Week 5 for safety assessment.
IOP > 25 mmHg
Topic IOP 
lowering drug
No Decrease in IOP 
from screening
+ 1 h ±10 m
Treatment
Decrease in IOP 
from screening
IOP > 25 mmHg
+ 1 h observation
(2 h ±10 m after start of run-in)
IOP ≤25 mmHg
IOP > 25 mmHg
Screen failure
+ 1 h ±10 m
IOP ≤25 mmHg
Screen failure
Treatment


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NVG patients have a high probability of permanent vision loss if IOP is not properly 
controlled. To provide benefit to the patients in the study, the concomitant use of topical IOP-
lowering drug therapy is required from screening, and only patients who do not achieve 
control of IOP before baseline with conventional therapy will be assigned. 
Safety variables are similar to those of aflibercept clinical trials for other diseases, i.e. adverse 
events (AEs), physical examination, vital signs (body temperature, blood pressure and pulse 
rate), clinical laboratory findings (hematological test, blood biochemical examination and 
urine test), and ophthalmic examinations (indirect ophthalmoscopy, slit-lamp microscopy and 
gonioscopy). Visual acuity testing, which is used to evaluate visual functions in patients with 
glaucoma, and applanation tonometry, which is used to evaluate IOP after IVT injection, are 
also to be performed as a safety evaluation.  
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject is 
completed in all centers.  
Primary completion
The primary completion event for this study is the visit of the final subject at Week 1 or Early 
Termination before Week 1.  This study will be continued up to Week 5.  
6.
Study population
Patients who meet all of the inclusion criteria and none of the exclusion criteria at both 
screening and baseline are eligible for assignment in the study.  
Inclusion criterion 2 must be met within 15 days before baseline. 
An individual subject may only be included in the study once and only one eye will be
designated as the study eye; however, safety of the fellow eye will be monitored, and all 
systemic AEs will be collected. For subjects who meet eligibility criteria in both eyes, the 
study eye will be selected at the discretion of the investigators considering the interests of the 
patients.
6.1
Inclusion criteria
1. Japanese men and women aged 20 years or older 
2. Patients diagnosed as having NVG with neovascularization in the anterior segment 
(both iris and anterior chamber angle) 
3. Patients with IOP higher than 25 mmHg in the study eye due to anterior segment (both 
iris and anterior chamber angle) neovascularization 
4. Patients who are willing and able to return for all planned visits and complete all study 
related procedures 
5. Patients who are able to read and understand informed consent documents (if difficult 
for a patient to read because of visual impairment, the study staff or the patient’s 
family member may read every word for the patient to help him/her understand the 
contents) 
6. Written informed consent 


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7. Women and men of reproductive potential must agree to use adequate contraception 
when sexually active. This applies for the time period between signing of the informed 
consent form and at least three 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 (i) condoms 
(male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap 
with spermicide; (iii) intrauterine device; (iv) hormone-based contraception. 
6.2
Exclusion criteria
1. Only one functional eye even if that eye is otherwise eligible for the study. 
Furthermore, subjects with only one eligible eye should not have other ocular 
conditions with poorer prognosis in the fellow eye 
2. Patients with angle-closure due to conditions other than NVG or complete angle-
closure due to NVG 
3. Patients with a known or suspected ocular or peri-ocular infection 
4. Patients with severe intraocular inflammation in the study eye 
5. Patients with any ocular disorder in the study eye that might contraindicate treatment 
with anti-VEGF drugs or confuse the interpretation of the results of the study 
6. Patients who have received intraocular administration of anti-VEGF drugs (pegaptanib 
sodium, bevacizumab, ranibizumab, aflibercept, etc.) within 60 days before Day 1 in 
the study eye 
7. Patients who have received intraocular or periocular injection of corticosteroids 
(solutions or suspensions) within 60 days before Day 1 in the study eye (topical 
corticosteroids are allowed) 
8. Patients who have received intraocular injection of corticosteroids (depot 
formulations) within 120 days before Day 1 in the study eye 
9. Patient who have received systemic anti-angiogenic agents within 180 days before 
Day 1 
10. Patients who have received topical ophthalmic atropine sulfate hydrate within 30 days 
before Day 1 in the study eye 
11. Patients who have received systemic IOP-lowering drugs in the past 3 days before 
Day 1 
12. Patients with prior filtrating surgery and/or surgery involving posterior vitrectomy or 
resulting in aphakia or rupture of the posterior capsule in the study eye, with the 
exception of posterior capsulotomy performed with yttrium aluminum garnet (YAG) 
laser or pseudophakia 
13. Patients who have received other intraocular surgeries including PRP in the study eye 
within 30 days before Day 1, and/or who are scheduled for surgery including PRP  in 
8 days following Day 1 
14. Patients whose blood pressure is poorly controlled on optimal medical treatment: 
patients with systolic blood pressure of >180 mmHg in a single measurement; patients 
with systolic blood pressure of >160 mmHg in two consecutive measurements; or 
patients with diastolic blood pressure of >100 mmHg 
15. Patients with a history of cerebrovascular disorder or myocardial infarction within 6 
months before Day 1 


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16. Patients who are prohibited from use of the study drug because they have prior 
medical history, metabolic dysfunction, physical findings, or laboratory test findings 
(i.e. patients suspected to have conditions that may have influence the evaluation of 
the study results, or diseases or conditions that may render them at higher risk of a 
concomitant disease after study treatment) 
17. Women who are pregnant, suspected of being pregnant or lactating 
18. Patients with renal failure requiring dialysis or renal transplant 
19. Previous assignment to treatment during this study 
20. Previous (within 30 days or 5 half-lives of the investigational drug, whichever is 
longer) or concomitant participation in another clinical study with investigational 
medicinal product(s) 
21. 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) 
22. Patients with known allergy to aflibercept 
6.3
Justification of selection criteria
Inclusion and exclusion criteria for this study have been referenced as the criteria used in 
clinical research reports of anti-VEGF drugs15, 16, 17) and the previous aflibercept trials for 
other diseases, and tailored for the indication. 
The present Study 19652 will include adult NVG patients who have high IOP. Although the 
upper limit of IOP in healthy adults is 21 mmHg, NVG is a disease condition usually 
associated with significantly higher IOP values. Therefore, the IOP for patient assignment
was determined to be higher than 25 mmHg in order to exclude patients with slight increases 
in IOP for the diseases other than NVG. The criteria include requirements for selecting 
patients who are willing to complete the required treatments and examinations for this study, 
complying with Good Clinical Practice (GCP). 
As exclusion criteria, patients whose underlying diseases can unreliably influence the efficacy 
and safety assessments, and from a view point of ensuring the safety of subjects, patients 
whose disease conditions may deteriorate because of participation in this study will be 
excluded.  
Additionally, VEGA has left the possibility of concomitant use of systemic IOP-lowering 
drugs, in large part, influencing primary efficacy evaluation (IOP). The same can be said of 
concomitant use of PRP. Therefore, for the purpose of removing the influence of these 
treatments, the present study 19652 will exclude patients who have received systemic IOP-
lowering drugs within 3 days and PRP within 30 days before baseline (Day 1) in the study 
eye. Additionally, in complete angle-closure NVG due to permanent PAS, IVT anti-VEGF 
drugs are not expected to lower IOP. Therefore, patients with complete angle-closure NVG
will be excluded.  


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6.4
Withdrawal of subjects from study
6.4.1
Withdrawal
Once a subject receive study treatment, every effort should be made so as not to terminate 
him/her from the study, and to keep him/her on the original visit schedule until the Week 5 / 
End of Study Visit. It is preferred that each subject be followed for the scheduled study 
duration.  
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. 

Systemic anti-angiogenic agents were taken by the subject during the study 

If the subject becomes pregnant 
Subjects may be withdrawn from the study if any of the following occurs:

If, in the investigator’s opinion, continuation of the study would be harmful to the
subject’s well-being. 

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns). 

Determination by the investigator that a subject requires alternate or additional 
treatment for NVG in the study eye. 
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 at screening or 
assignment), terminates the study before the time point used for the definition of “dropout” 
(see below) is regarded a “screening failure”. 
Re-starting the defined set of screening procedures to enable the “screening failure” subject’s 
participation at a later time point is allowed only once, and only if one of the following 
situations apply:  
The subject had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.  

The patient failed to meet inclusion criterion 3. A minimum of 24 hours must pass 
before the second screening can be performed.  
The patient met exclusion criteria 3, 6, 7, 8, 9, 10, 11, 13, 14, 15 or 20.  
Rescreening is not allowed in any other situations.  In any case, the investigator has to ensure 
that the repeated screening procedures do not expose the subject to an unjustifiable health 
risk.  Also, for re-screening, the subject has to re-sign the informed consent form, even if it 


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was not changed after the subject’s previous screening, and confirm that the patient meets all 
inclusion and no exclusion criteria.  
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been assigned.
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 of termination of the study).  
6.4.2
Replacement
Subjects who are withdrawn from the study after assignment, or who prematurely discontinue 
the study will not be replaced. For details for subject who deviated from PPS, see Section 
10.4 (Determination of sample size).  
6.5
Subject identification
The patient number is a 9 digit number consisting of:
Digits 1 to 5
=  Unique center number
Digits 6 to 9
=  Current patient number within the center
Subject registration 
The registration center will be used for subject registration in this study. Detailed instruction 
for registration can be found in the manual provided to study sites. The study sites register 
the subject according to the manual
7.
Treatments
7.1
Treatments to be administered
Subjects will receive one intravitreal injection of study drug (aflibercept) 2 mg.  
7.2
Identity of study treatment
Details of the study drug are given in Table 7-1. 
The study drug will be manufactured by Bayer AG, Berlin, Germany.  The study drug will be 
supplied by the Sponsor in sealed, single-use, sterile 2-mL vials, each with a final extractable 
volume of 0.10 mL.  


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Table 7-1: Investigational test product
Name
Dose
Concentration
Volume
Formulation
Composition
BAY 86-5321 /  
aflibercept
2 mg
40 mg/mL
Injected: 
0.05 mL
For intravitreal 
injection
40 mg/mL aflibercept, 5% 
sucrose, 10 mM sodium 
phosphate, pH 6.2, 0.03% 
polysorbate 20, 40 mM 
sodium chloride, water for 
injection
Each aflibercept treatment kit will contain one vial of 40 mg/mL aflibercept, one 1-mL 
syringe, one 18-gauge filter needle, and one 30-gauge injection needle. 
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 (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk batch of the ingredients.  Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies QA group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.  
7.3
Treatment assignment
All eligible subjects will be assigned to aflibercept IVT injection.  
7.4
Dosage and administration
The volume of aflibercept IVT injection will be 50 μL (0.05 mL) for the 2 mg aflibercept
dose.  
The IVT administration of aflibercept is to be completed within 2 hours after the start of dose
preparation.  
When aflibercept vials are taken out of a refrigerator, the solution should be visually inspected 
for having no evidence of turbidity. If particulates, cloudiness, or discoloration is visible, the 
vial must not be used. Considering the stability of aflibercept and lack of bacteriostatic 
agents, aflibercept solution may only be kept at room temperature (25°C) for up to 2 hours.  
The study drug will be withdrawn using aseptic technique through an 18-gauge filter 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 in the syringe should be expelled until the
plunger is aligned with the line that marks 0.05 mL on the syringe.  
7.5
Blinding (Masking)
Not applicable for this open-label study.  


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7.6
Drug logistics and accountability
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate/CRO), and will be inaccessible to unauthorized personnel.  Special storage 
conditions and a complete record of batch numbers and expiry dates can be found in the 
sponsor’s study file; the site-relevant elements of this information will be available in the 
investigator site file.  On the day of receipt, the responsible site personnel will confirm receipt 
of study drug in writing.  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 study drugs are to be stored at 2°C to 8°C.  
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned drug will be provided.  
7.7
Treatment compliance
Study drug will be administered at the site; compliance with study treatments will be 
monitored by the monitor using the study site clinical records.  
8.
Non-study therapy
8.1
Prior and concomitant therapy
Prior therapy
See Section 6.2, exclusion criteria, for a description of prior therapies that exclude subjects 
from participation in this study. Treatment with systemic IOP-lowering drugs is prohibited 
for 3 days before Day 1.  
Concomitant therapy
Systemic use of anti-VEGF drugs, topical ophthalmic atropine sulfate hydrate will be 
prohibited during the period of the study.  Systemic IOP-lowering drugs, PRP or surgery 
intended to lower IOP are prohibited until IOP evaluation at Week 1 unless these treatments 
are inevitable at the discretion of the investigators.  
Systemic IOP-lowering drugs are followings:

Acetazolamide

Isosorbide

Glycerin

Mannitol
If the fellow eye also has NVG, it may receive any locally approved treatment except for 
systemic IOP-lowering drugs. If the fellow eye has conditions such as, but not limited to,
wAMD and CRVO for which anti-VEGF therapy is indicated, administrations should be 


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performed after the expected benefits and possible risks are carefully evaluated. Injecting both 
eyes in the same day is not recommended for safety reasons. The fellow eye will not be 
considered an additional study eye. Subjects who receive treatment for the fellow eye should 
remain in the study. Safety for the fellow eye will be monitored and AEs will be collected.  
Any previous and concomitant treatments given to the fellow eye for NVG will be recorded in 
the source documentation and then entered in the “Previous and Concomitant 
Medications/Therapies” eCRF using the brand names. Drugs used during the IVT injection 
procedure will not be recorded as concomitant medication/therapy.  
All previous and concomitant medications/therapies will be coded using an internationally
recognized and accepted coding dictionary.  
8.2
Post-study therapy
After the observation period (through Week 5), subjects will not be restricted in taking 
available treatments for NVG.


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9.
Procedures and variables
9.1
Tabular schedule of evaluations
Table 9-1: Tabular schedule of assessments
Procedure
Screening  a
Baseline
Observation
End of 
Study/Early 
Termination
Visit
1
2
3
4
5
Day/week
-
Day 1
Week 1
Week 2
Week 5
Day
-15 to 1
1
8+3
15±3
36±7
Informed consent
X
Inclusion/Exclusion criteria
X
X
Demographic data
X
Medical/ophthalmic history 
X
AEs
X
X
X
X
X
Concomitant medications
X
X
X
X
X
Physical exam
X
X
Vital signs (temperature, blood 
pressure and pulse rate)
X
X
X
X
X
Assignment (eligibility check) 
X
Study drug injection  b
X
Telephone safety check  c
X
Ophthalmological assessment
Visual acuity test
X
X
X
X
X
Slit-lamp microscopy
X
X
X
X
X
Gonioscopy
X
X
X
X
X
Evaluation of NVI and NVA 
grades
X
X
X
X
X
IOP  d
X
X
X
X
X
Indirect ophthalmoscopy
X
X  e
X
X
X
Topical IOP-lowering drug 
therapy  f
X
X
X
X
X
Laboratory test (central)
Hematology
X
X
Chemistry
X
X
Serum pregnancy test  g
X
Urinalysis (incl. UPCR) 
X
X
Footnotes:
AEs = adverse events, NVI = neovascularization of the iris, NVA = neovascularization of the angle,  IOP = 
Intraocular pressure, UPCR = Urine protein-to-creatinine ratio 
a
If screening eligibility is confirmed immediately and time permits, baseline procedures may be conducted 
at screening thus combining screening and Day 1 into one visit. 
b
Check of visual acuity (finger counting, hand movement and/or light perception) is to be performed in the 
study eye immediately after treatment, the presence or absence of the retinal perfusion should be 
verified by indirect ophthalmoscopy in the case the visual acuity is decreased, and an anterior chamber 
paracentesis should be performed in the case the IOP increases significantly after treatment. 
c
Telephone call to a subject to identify if there have been any signs or symptoms of retinal detachment, 
endophthalmitis, or other AEs at 3 ± 1 days post-treatment. Additionally, pay attention to the signs or 
symptoms of NVG and consider asking the patient to make an unscheduled visit if necessary. 
d
Assess pre-dose in both eyes, and again 15-60 minutes post-dose in the study eye at baseline.  After 
baseline (Visit 2), IOP will be measured within ± 2 hours of the measurement time at baseline. 
e
Assess pre-dose in both eyes, and again post-dose in the study eye. 


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f
A combination of at least 3 topical IOP-lowering drugs will be administered during a run-in phase before 
treatment and should be kept unchanged until IOP evaluation at Week 1, after which they may be 
reduced according to the investigator’s opinion. 
g
In women of childbearing potential, a urine pregnancy test can be done at a study site, if the result from 
the central laboratory cannot be waited for. 
9.2
Visit description
9.2.1 Visit 1, Screening (Day -15 to 1)

Signed informed consent

Inclusion / Exclusion criteria

Demographic data

Medical history (including smoking history) and ophthalmic history

Interval history (AEs and concomitant medications)

Physical examinations

Vital signs (temperature, blood pressure and pulse)

Visual acuity test

Slit-lamp microscopy and gonioscopy

Evaluation of NVI and NVA grades

IOP evaluation 

Indirect ophthalmoscopy 

Topical IOP-lowering drug therapy (run-in phase)

Hematology and chemistry

Serum pregnancy test (In women of childbearing potential, a urine pregnancy test can be 
done at a study site, if the result from the central laboratory cannot be waited for)

Urinalysis/urine protein-to-creatinine ratio (UPCR)
9.2.2 Visit 2, Baseline (Day 1)
If screening eligibility is confirmed immediately and time permits, baseline procedures may 
be conducted at screening thus combining screening and Day 1 into one visit.  
The injection in the vitreous cavity can cause IOP increase by the addition of the liquid 
volume. Before administering an intravitreal injection, therefore, the investigator must 
evaluate IOP to confirm that it has decreased to a level considered safe for performing the 
injection. Immediately after the injection, and while still in the injection room, the 
investigator must make a visual acuity check by asking the subject to count fingers, detect 
hand movement or light perception depending on the pre-dose visual acuity.  If a decrease in 
visual acuity is detected, indirect ophthalmoscopy should be performed to verify if the retinal 
perfusion has been compromised. If this is the case and this is considered to be caused by a 
significant increase in IOP due to the volume injection, an anterior chamber paracentesis 
should be performed to immediately reduce the IOP. If visual acuity is not decreased and 
retinal circulation not compromised, the subject may leave the injection room. The IOP will 
be reevaluated after a period ranging from 15 to 60 minutes, and the subject may be 


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discharged as soon as the IOP returns to the levels similar to or lower than those measured 
prior to the pre-injection IOP. If the IOP value is considered too high to discharge the 
subject, further therapy should be given within the choices available, and the subject should 
be kept under close observation until the IOP has decreased to the levels amenable to 
outpatient treatment.  

Inclusion / Exclusion criteria

Topical IOP-lowering drug therapy (run-in phase)

Interval history (AEs and concomitant medications)

Vital signs (temperature, blood pressure and pulse rate)

Visual acuity test

Slit-lamp microscopy and gonioscopy

Evaluation of NVI and NVA grades

IOP evaluation

Indirect ophthalmoscopy 

Assignment (eligibility check)

Study drug injection

Check of visual acuity (finger counting, hand movement and/or light perception; 
immediately after injection, only study eye)

If visual acuity is reduced: check retinal perfusion study eye by an indirect 
ophthalmoscopy

If necessary: anterior chamber paracentesis

Indirect ophthalmoscopy (post-treatment, only study eye)

IOP evaluation (15 to 60 minutes following injection, only study eye)

If necessary: further IOP-lowering measures

Topical IOP-lowering drug therapy (to be kept unchanged until IOP evaluation at Week 
1)

Telephone safety check (telephone call 3 ± 1 days post-treatment)
9.2.3 Visit 3, Week 1 (Day 8 + 3)

Interval history (AEs and concomitant medications)

Vital signs (temperature, blood pressure and pulse rate)

Visual acuity test

Slit-lamp microscopy and gonioscopy

Evaluation of NVI and NVA grades

IOP evaluation (± 2 hours of the measurement time at baseline)

Indirect ophthalmoscopy 


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
Topical IOP-lowering drug therapy (may be reduced according to the investigator’s 
opinion)
9.2.4 Visit 4, Week 2 (Day 15 ± 3)

Interval history (AEs and concomitant medications)

Vital signs (temperature, blood pressure and pulse rate)

Visual acuity test

Slit-lamp microscopy and gonioscopy

Evaluation of NVI and NVA grades

IOP evaluation (± 2 hours of the measurement time at baseline)

Indirect ophthalmoscopy 

Topical IOP-lowering drug therapy (may be reduced according to the investigator’s 
opinion)
9.2.5 Visit 5, Week 5 (Day 36 ± 7): End of Study (also Early Termination) visit

Interval history (AEs and concomitant medications)

Physical examinations

Vital signs (temperature, blood pressure and pulse rate)

Visual acuity test

Slit-lamp microscopy and gonioscopy

Evaluation of NVI and NVA grades

IOP evaluation (± 2 hours of the measurement time at baseline)

Indirect ophthalmoscopy 

Topical IOP-lowering drug therapy (may be reduced according to the investigator’s 
opinion)

Hematology and chemistry

Urinalysis/urine protein-to-creatinine ratio (UPCR)
9.3
Population characteristics
9.3.1
Demographic
The following demographic characteristics will be collected:

Year of birth

Age

Sex

Race/ethnicity

Weight

Height


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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:

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility.  
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 9.6.1.1.  
9.3.3
Other baseline characteristics
A complete ophthalmic history including NVG will be obtained at Screening.  
9.4
Efficacy
9.4.1 Intraocular pressure (IOP)
IOP will be measured in both eyes at each visit. IOP will be measured using applanation 
tonometry with Goldmann as standard technique for all screening, baseline and other visit
measurements.  Other measuring methods are not allowed.  After baseline, IOP will be 
measured within ± 2 hours of the measurement time at baseline.  See Section 9.6.3.7 for the 
evaluation of post-dose IOP.  
9.4.2 Neovascularization of iris and anterior chamber angle (NVI and NVA)
Subjects will be evaluated for the development of NVI and NVA by gonioscopy in 
conjunction with slit-lamp microscopy. NVI and NVA will be assessed in the study eye using 
the NVI and NVA grading systems22), as described in detail in Table 9-2, at each visit.  


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Table 9-2: Grading systems for NVI and NVA
Grade
Neovascularization of Iris
Neovascularization of Angle
0
No iris neovascularization
No angle neovascularization
1
Fine surface neovascularization of the 
pupillary zone of the iris involving less than 
two quadrants.
Fine neovascular twigs crossing the scleral 
spur and ramifying on the trabecular 
meshwork involving less than two quadrants.
2
Surface neovascularization of the pupillary 
zone of the iris involving more than two 
quadrants.
Neovascular twigs crossing the scleral spur 
and ramifying on the trabecular meshwork 
involving more than two quadrants.
3
In addition to neovascularization of the 
pupillary zone, neovascularization of the 
ciliary zone of the iris and/or ectropion uveae 
involving one to three quadrants.
In addition to neovascularization of the 
trabecular meshwork, peripheral anterior 
synechiae (PAS) involving one to three 
quadrants.
4
In addition to neovascularization of the 
pupillary zone, neovascularization of the 
ciliary zone of the iris and/or ectropion uveae 
involving more than three quadrants.
In addition to neovascularization of the 
trabecular meshwork, PAS involving more 
than three quadrants.
9.5
Pharmacokinetics / pharmacodynamics
Not applicable.  
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of 
a medicinal (investigational) product.  
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).  
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, and laboratory.  
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).  


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Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  This includes intercurrent illnesses.  
Definition of serious adverse event (SAE)
A SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a
Results in death
b
Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.  
c
Requires inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
The admission results in a hospital stay of less than 12 hours
The admission is pre-planned 
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2)
The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).  
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.  
d
Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.  
e
Is a congenital anomaly / birth defect
f
Is another serious or important medical event as judged by the investigator
9.6.1.2 Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.  
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.  
9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:
Mild


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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.  
Causality should be assessed separately for each study treatment as detailed in the eCRF. If 
the investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment.  
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.  
Possible answers are “yes” or “no”
An assessment of “no” would include:
1.
The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.  
or
2.
Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.  
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment.  
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


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The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered.  
The assessment is not possible.  
Causal relationship to protocol-required procedures
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).  
Possible answers are “yes” or “no”
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.  
The study treatment action should be recorded separately for each study treatment as detailed 
in the eCRF.  
Drug withdrawn
Drug interrupted
Dose not changed
Not applicable
Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events
None
Remedial drug therapy
Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 
Recovered/resolved
Recovering/resolving
Recovered/resolved with sequelae
Not recovered/not resolved
Fatal
Unknown
9.6.1.3
Assessments and documentation of adverse events
The investigator has to record on the respective eCRF pages all AEs occurring in the period 
between the signing of the informed consent and the end of the follow-up phase; after the end 


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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 SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness 
and causal relationship to study drug.  
9.6.1.4
Reporting of serious adverse events
The definition of serious adverse events (SAEs) is given in Section 9.6.1.1. Each SAE must 
be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.  
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as 
needed.  
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File.  For this, an 
AE page in the eCRF as well as the complementary pages provided in the Investigator File 
must be completed for each SAE. 
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.  
Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.  
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.  
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.  
9.6.1.5 Expected adverse events
For this study, the applicable reference document is the most current version of the IB / 
summary of product characteristics.  
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB.  If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.  


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The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.  
9.6.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study.  The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.  
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.  
For all reports, the forms provided are to be used.  The investigator should submit them within 
the same timelines as an SAE. 
9.6.3
Further safety
Safety assessments, in addition to AEs, will include ophthalmic examinations and laboratory 
measures. Instructions for phlebotomy and sample handling can be found in each manual.  
Reporting of medical device failures
The investigator must report immediately all non-approved medical device failures which 
could cause health damage, as well as any health damage that may be causally associated with 
a non-approved medical device failure.  For this reporting, the forms provided are to be used 
and sent to the designated recipient.  
9.6.3.1
Physical Examination
Abnormal physical examination findings are recorded as medical history or adverse event (see 
Section 9.6.1.1).  
9.6.3.2
Vital Signs
Body temperature, blood pressure and pulse rate will be measured. Vital signs should be 
assessed in a consistent, standardized way at each assessment.  
9.6.3.3
Visual acuity test
Best corrective visual acuity (BCVA) (decimal visual acuity) will be measured by using 
Landolt ring in both eyes. Check of visual acuity (finger counting, hand movement and/or
light perception) will be performed in the study eye immediately after.  
9.6.3.4
Slit-lamp microscopy
The condition of the anterior segment of the eye and annexes (lids, conjunctiva, cornea, 
anterior chamber, iris, pupil and lens) is assessed in both eyes.  
9.6.3.5
Gonioscopy
The condition of the iris root and anterior chamber angle is assessed in both eyes.  
9.6.3.6
Indirect ophthalmoscopy
The intraocular condition of the posterior segment of the eye (vitreous body, vitreous cells, 
optic nerve head, macula, peripheral retina) is assessed pre-dose in both eyes, and again post-


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dose in the study eye.  If a decrease in visual acuity is detected after treatment, additional 
indirect ophthalmoscopy should be performed immediately after treatment to verify if the 
retinal perfusion has been compromised.  Mydriasis is usually needed to allow a 
comprehensive retinal exam. However, in patients with poor control of the IOP, the risk of 
additional IOP increase after mydriasis should be carefully considered before performing it. 
9.6.3.7
Applanation tonometry
IOP will be measured 15 to 60 minutes post-dose in the study eye at baseline. IOP will be 
measured using applanation tonometry (e.g. Goldmann as the standard technique or Tonopen). 
In case of discrepancy, the final result will be evaluated by Goldman.  Non-contact tonometry 
is not allowed.  Since IOP is increased transiently after aflibercept injection, pre- and post-
dose IOP will be monitored.  If medically necessary, further IOP will be monitored. 
9.6.3.8
Laboratory values
The laboratory tests will be performed at the Central Laboratory and results will be 
electronically transferred to the Sponsor.  In addition, a copy of the results will be provided to 
the study site for the investigator’s assessment.  These results are to be filed in the subject’s 
source documentation.  All abnormal laboratory values will require a comment in a timely 
manner from the investigator in terms of their significance, if any. Clinically significant 
changes in laboratory values should be designated as AEs and so reported. When necessary, 
appropriate ancillary investigations should be initiated. If the abnormality fails to resolve or 
cannot be explained by events or conditions unrelated to the study medication or its 
administration, the investigator should consult with the sponsor.  
Samples for laboratory testing will be collected at the screening and Week 5/ End of Study or 
Early Termination visit.  Laboratory test parameters are presented in Table 9-3, Table 9-4, and 
Table 9-5.  
Table 9-3: Laboratory test Chemistry panel
Sodium
Potassium
Chloride
Carbon dioxide
Calcium
Amylase
Glucose
Albumin
Total protein, serum
Creatinine
Blood urea nitrogen (BUN)
Creatine phosphokinase
Creatine kinase MB 
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase (AP)
Lactate dehydrogenase (LDH)
Total bilirubin
Total cholesterol
Uric acid


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Table 9-4: Laboratory test Hematology panel
Hemoglobin
Hematocrit
White blood cells (WBCs)
Red blood cells (RBCs)
Red cell Indices
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration (MCHC)
Differential count
Neutrophils, Lymphocytes, Monocytes, Basophils, Eosinophils
Platelet count
Hemoglobin A1c (HbA1c)
Table 9-5: Laboratory test Urinalysis
Glucose 
Blood 
Hyaline and other casts
Crystals
Creatinine
Protein
Ketones
Bacteria
Yeast
Protein/creatinine ratio (UPCR)
Specific gravity
RBC
Epithelial cells
WBC
Cells
9.6.3.9
Other laboratory tests
In women of childbearing potential, serum pregnancy test (beta HCG) will be performed at 
screening.  A urine pregnancy test can be done at a study site, if the result from the central 
laboratory cannot be waited for.  
9.7
Other procedures and variables
Not applicable.  
9.8
Appropriateness of procedures / measurements
All efficacy and safety variables and the methods to measure them are standard variables and 
methods in clinical studies, and in ophthalmic practice. They are widely used and generally 
recognized as reliable, accurate, and relevant.


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10.
Statistical methods and determination of sample size
10.1
General considerations
All variables will be analyzed descriptively with appropriate statistical methods: categorical 
variables by frequency tables and continuous variables by summary statistics (mean, standard 
deviation, minimum, median, and maximum).  
Statistical analysis will be performed using SAS; the version used will be specified in the 
statistical analysis plan (SAP).  
Medical history findings and AEs will be coded by Medical Dictionary for Regulatory 
Activities (MedDRA) codes and medications by Anatomical Therapeutic Chemical (ATC) 
codes (World Health Organization Drug Dictionary [WHO-DD]).  
The analyses and data conventions are as follows:

Definition of baseline: The baseline assessment will be the latest valid pre-injection
assessment.  

Unscheduled assessments: Unless otherwise specified, extra assessments (e.g. vital 
signs associated with non-protocol clinical visits or obtained in the course of 
investigating or managing AEs) will be included in data listings, but not in data 
summaries. If more than one measurement is available for a given visit, the first 
observation will be used in the data summaries and all observations will be presented 
in the data listings.  
The details of the statistical analyses will be specified in the SAP.  
10.2
Analysis sets
Full Analysis Set (FAS)
The FAS will include all subjects who;

are assigned,

received at least one IVT administration of study drug on Day 1,

have baseline valid IOP measurement, and

have at least one post-baseline IOP measurement before or at Week 1. 
The FAS will be used for supplemental analyses in efficacy.  
Per Protocol Set (PPS)
The PPS will include the all subjects who;

are assigned, 

received at least one IVT administration of study drug on Day 1,

have baseline valid IOP measurement,

have at least one valid (e.g. before prohibit treatment) post-baseline IOP measurement 
before or at Week 1, and

show no validity findings that may affect efficacy.  


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The efficacy variables, which measured within four days from the dose (the day included),
will be excluded from analyses in PPS.  The PPS will be the primary analysis set for efficacy 
analyses.  
Safety Analysis Set (SAF)
The SAF will include all subjects who are assigned and received at least one IVT 
administration of study drug.  
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.  
10.3
Variables and planned statistical analyses
10.3.1 Variables
10.3.1.1
Primary efficacy variable
Primary efficacy variable is

Change in IOP from baseline to Week 1 
10.3.1.2
Secondary efficacy variable
Secondary efficacy variable is

Proportion of subjects who have improved NVI grade from baseline to Week 1. 
10.3.1.3
Exploratory efficacy variables
Exploratory efficacy variables include, but not limited to, the followings:

IOP and change from baseline to each visit, 

NVI and NVA and change from baseline to each visit, and 

Proportion of subjects who could control IOP (≤ 21 mmHg) at each visit. 
10.3.1.4
Safety variables
The following are summarized descriptively for safety evaluations:

AEs, 

Vital signs, 

Visual acuity, and 

Laboratory values. 
10.3.2 Statistical and analytical plan
10.3.2.1
Demographic and other baseline characteristics
Study sample size and subject validity reasons for exclusion from analysis will be 
summarized using frequency tables.  Subject disposition: end of treatment i.e., Week 1 and 
end of follow-up i.e., Week 5 will be summarized. Demographic and other baseline 
characteristics will be summarized descriptively.


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10.3.2.2
Efficacy
The PPS is the primary analysis set for efficacy. The FAS is a set for supplemental analysis 
of the PPS analysis.  No alpha adjustment for multiple comparisons is considered, therefore 
confidence interval of other analyses except the primary analysis in PPS will be interpreted in
consideration of false positives due to multiple testing.
Primary efficacy analysis
Primary efficacy variable is

Change in IOP from baseline to Week 1.  
The imputation rule will be described in Sec 10.3.3.  
The change in IOP from baseline at Week 1 will be summarized descriptively.  The point 
estimate and its two-sided 95% confidence interval using one-sample t-statistics will be 
calculated.  The corresponding hypotheses for the efficacy analysis are
:  ≥0,
:  < 0,
where  is the change in IOP from baseline at Week 1.  If the upper limit of the two-sided 
95% confidence interval in PPS is less than the threshold (i.e., 0), the null hypothesis will be
rejected and the study will be regarded as success.  
Secondary efficacy analysis
Secondary efficacy variable is

Proportion of subjects who have improved NVI grade from baseline to Week 1.  
The proportion of subjects who have improved NVI grade from baseline at Week 1 will be 
summarized descriptively. The point estimate and its two-sided 95% confidence interval 
using Clopper-Pearson method will be calculated.  Improvement by at least one grade from 
baseline will be categorized to “Improved”.  
Exploratory efficacy analysis
All exploratory efficacy variables will be summarized descriptively with appropriate 
statistical methods.  
In addition, for the proportion of subjects who have improved NVA grade from baseline at 
Week 1, the point estimates and its two-sided 95% confidence interval using Clopper-Pearson 
method will be calculated.  
The change in NVI and NVA grades categorized to “Improved” (improvement by at least one 
grade from baseline), “Worsened” (worsened by at least one grade from baseline) or “Stable” 
(no change in grade from baseline) will be also summarized by frequency tables.  
In addition, the subgroup analyses will be performed in primary variable and secondary 
efficacy variables.  The subgroups will include:

Age (years): < 65, ≥ 65;

Sex: Male, Female;


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
Primary Diagnosis: CRVO, PDR, OIS, other;

IOP at Baseline group (mmHg): ≤ median, > median;

NVI grade at Baseline group: Grade 1 or 2, Grade 3 or 4;

NVA grade at Baseline group: Grade 1 or 2, Grade 3 or 4.  
Further details will be described in the SAP.  
10.3.2.3
Safety
The safety analyses will be conducted in the SAF.  
AEs that occurred or worsened after the first dose of study drug and no later than 30 days
after the last dose of study drug will be considered as treatment-emergent AEs (TEAEs).  
Treatment-emergent ocular AEs will be presented by MedDRA preferred term within the
primary system organ class and summarized for the study eye and the fellow eye, separately.
Treatment-emergent non-ocular AEs will be also summarized.  
Intensity and causal relationship to the study drug / intravitreal injection will be analyzed
descriptively.  
Other safety variables will be analyzed descriptively including changes from baseline.  
10.3.3 Missing data / drop outs
All missing or partial data will be presented in the subject data listing as recorded in the eCRF.  
If no valid IOP is available at the Week 1, the last post-baseline before Week 1 will be 
utilized for imputation.  If the prohibited treatment is received, the IOP after prohibited 
treatment will not be utilized for imputation in PPS analysis. On the other hand, the IOP after 
prohibited treatment will be utilized in FAS analysis.  The same imputation rule will be 
conducted for NVI and NVA.  
10.4
Determination of sample size
The target number of subjects to be treated with aflibercept was set at 16 as the PPS. 
If left untreated, anterior segment neovascularization in NVG persists or becomes worse, 
which progresses chamber angle obstruction, leading eventually to elevated IOP. In the study 
design excluding influence of PRP on IOP to the extent possible, true change in IOP from 
baseline to at Week 1 is assumed not to fall below 0 mmHg in NVG patients who will receive 
neither anti-VEGF agents nor systemic IOP-lowering drugs, based on which the threshold for 
positive IOP-lowering effect was determined to be 0 mmHg. 
A retrospective study8) compared mean change in IOP from baseline between bevacizumab 
IVT plus conventional treatment (e.g., IOP-lowering drugs, PRP) (11 eyes) and conventional 
treatment alone (12 eyes) in NVG patients. The combination therapy group had a mean 
change of –11.1 mmHg (at 9.2 [mean] days) while IOP remained unchanged without 
reduction (0 mmHg) in the monotherapy group (at 18.8 [mean] days). In VEGA, change 
(mean ± SD) in IOP from baseline to pre-dose at Week 1 in the sham group of the subgroup 
comprising subjects without systemic IOP-lowering drugs until pre-dose at Week 1 was -0.4
± 7.7 (confidence interval –5.6 to 4.8).  


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Meanwhile, change (mean ± SD) in IOP from baseline to pre-dose at Week 1 in the 
aflibercept group of the subgroup comprising subjects without systemic IOP-lowering drugs 
until pre-dose at Week 1 in VEGA was –8.8 ± 8.4 mmHg.  Therefore, change (mean ± SD) in 
IOP from baseline to pre-dose at Week 1 was assumed to be –8.0 ± 9.0 mmHg in the present 
study 19652 designed to prohibit the concomitant use of systemic IOP-lowering drugs until 
pre-dose at Week 1. 
Based on the above assumption, 16 patients are required to achieve >90% power to detect “an 
upper limit of 2-sided 95% confidence interval (by 1-sample t-statistics) of mean change in 
IOP from baseline to pre-dose at Week 1 is less than the predetermined threshold of 0 mmHg 
(assumed change in IOP if untreated).”  
The subjects' recruitment will be continued until 16 subjects as the PPS is assured.  Finally,
approximately 20 subjects will be assigned in case deviations of PPS (See Section 10.2) 
occurred during ongoing data review and cleaning.
10.5
Planned interim analyses
No formal 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 EDC system called RAVE.  Subject 
data necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system (TOSCA; SAS). 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 
from Medidata Solutions Worldwide.  RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies.  RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel.  Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study.  Data queries 
resulting from the application of the software logic are resolved by the site personnel.  The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer’s internal computer system via a secure Virtual 
Private Network.  
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software.  All internal Bayer and external investigator site personnel seeking 
access must go through a thorough RAVE training process before they are granted access to 
RAVE for use in Bayer’s clinical studies.  Training records are maintained.  
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.  
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made.  This information is available both at the investigator’s site and at Bayer.  Data 


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


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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, adjudication committees).  
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.  
11.4
Missing data 
In principle, in order to achieve the goal of a well conducted clinical trial according to Good 
Clinical Practice (GCP), all efforts will be made to collect complete data for all subjects who 
receive study treatment in this study, and all subjects will be followed to the study end and 
will complete all required data collection. 
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.  
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.  
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study.  
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.  
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.  


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The investigator/institution notifies the sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership).  
The investigator site file is not to be destroyed without the sponsor’s approval.  
The contract with the investigator/institution will contain all regulations relevant for the study 
center.  
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to the 
following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,
Safety findings from this study (e.g. SAEs)
Results of any interim analysis
Results of parallel clinical studies
Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity)  

If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.  
The investigator has the right to close his/her center at any time.  
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing.  

All affected institutions [e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center] must be informed as applicable according to local law.  

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification is given by the sponsor for destruction.  

In the event of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner.  
Details for individual subject’s withdrawal can be found in Section 6.4.1.  
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.  


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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.  
External data evaluation bodies
An Adjudication Committee will perform an additional analysis on possible arterial
thrombotic events (ATEs) using criteria as proposed by the Antiplatelet Trialists’ 
Collaboration (APTC). The members of the committee, the functional roles, and 
responsibilities are specified in its charter.  
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.  
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file.  
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).  
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor.  The responsible unit (e.g. 
IEC/IRB, head of the study center/medical institution) must supply to the sponsor, upon 
request, a list of the IEC/IRB members involved in the vote and a statement to confirm that 
the IEC/IRB is organized and operates according to GCP and applicable laws and regulations.  
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. 


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Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.  
Details on discontinuation of the entire study or parts thereof can be found in Section 12.  
13.4
Subject information and consent
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center.  A sample 
subject information and informed consent form is provided as a document separate to this 
protocol.  
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject prior to his/her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).  
The investigator will also mention that written approval of the IRB/IEC has been obtained.  
Each subject will be informed about the following aspects of premature withdrawal:

Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 

The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2 to be conducted after withdrawal of consent.

The subject’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan. 

Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such 
as blood, urine or tissues); these data would also be retained and statistically analyzed 
in accordance with the statistical analysis plan.  The subject has the right to object to 
the generation and processing of this post-withdrawal data.  The subject’s oral 
objection may be documented in the subject’s source data.  
Each subject / legal representative or proxy consenter will have ample time and opportunity to 
ask questions.  
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study.  Additionally, the 
investigator will personally sign and date the form.  The subject / legal representative or proxy 
consenter will receive a copy of the signed and dated form.  
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.  


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In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.  
The informed consent form and any other written information provided to subjects / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the subject information and / or the 
written informed consent form.  The investigator will inform the subject / legal representative 
or proxy consenter of changes in a timely manner and will ask the subject to confirm his/her 
participation in the study by signing the revised informed consent form.  Any revised written 
informed consent form and written information must receive the IEC/IRB’s approval / 
favorable opinion in advance of use.  
13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.  
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs. 
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript. 
13.6
Compensation for health damage of subjects / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.  
13.7
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.  
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the eCRF, and if the subject name appears on any other document (e.g. pathologist report), 
it must be obliterated before a copy of the document is supplied to the sponsor.  Study 
findings stored on a computer will be stored in accordance with local data protection laws.  As 
part of the informed consent process, the subjects will be informed in writing that 
representatives of the sponsor, IEC/IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available 


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for inspection will be handled in strictest confidence and in accordance with local data 
protection laws.  
If the results of the study are published, the subject’s identity will remain confidential.  
The investigator will maintain a list to enable subjects to be identified.  
14.
Reference list 
1.
Brown GC, Magargal LE, Schachat A, Shah H. Neovascular glaucoma. Etiologic 
considerations. Ophthalmology. 1984:91:315-20.
2.
Takihara Y, Inatani M, Kawaji T, Fukushima M, Iwao K, Iwao M, et al. Combined 
intravitreal bevacizumab and trabeculectomy with mitomycin C versus trabeculectomy 
with mitomycin C alone for neovascular glaucoma. J Glaucoma. 2011:20:196-201.
3.
Tatsumi T, Yamamoto S, Uehara J, Sugawara T, Baba T, Inoue M, et al. Panretinal 
photocoagulation with simultaneous cryoretinopexy or intravitreal bevacizumab for 
neovascular glaucoma. Graefes Arch Clin Exp Ophthalmol. 2013:251:1355-60.
4.
Saito Y, Higashide T, Takeda H, Murotani E, Ohkubo S, Sugiyama K. Clinical factors 
related to recurrence of anterior segment neovascularization after treatment including 
intravitreal bevacizumab. Am J Ophthalmol. 2010:149:964-72.
5.
Ministry of Health, Labour and Welfare. Summary of Patient Survey,2011. 
Available from: http://www.mhlw.go.jp/english/database/db-hss/ps.html
6.
Takaku F, Ogata E, Kurokawa K, Yazaki Y. Modern internal medicine (Shin Rinsho 
Naikagaku, in Japanese). 9th ed. Tokyo: Igaku-Shoin; 2009:674-6.
7.
Funatsu H, Suto C, Hori S, Kitamura Y, Iwakiri T, Iwasaki M, et al. Prevalence of 
diabetic ocular complications and systemic factors (in Japanese). Nihon Ganka Gakkai 
Zasshi. 1993:97:947-54.
8.
Ehlers JP, Spirn MJ, Lam A, Sivalingam A, Samuel MA, Tasman W. Combination 
intravitreal bevacizumab/panretinal photocoagulation versus panretinal photocoagulation 
alone in the treatment of neovascular glaucoma. Retina. 2008:28:696-702.
9.
Saito Y. Glaucoma treatment, neovascular glaucoma and ant-VEGF agents (Rhokunai-
sho chirho kekkan shinsei rhokunaisho to kou VEGF koutai, in Japanese). Japanese 
Journal of Clinical Ophthalmology. 2011:65:233-7.
10. Higashide T. Effective treatment for neovascular glaucoma (kekkan shinsei rhokunaisho 
ha kou naosu, in Japanese). Journal of the eye. 2009:26:323-9.
11. Morita H, Hirose N, Nasu T, Kubota T, Tawara A. Therapeutic results in neovascular 
glaucoma (Sangho-ikadaigaku niokeru kekkan shinsei rhokunaisho no chirho seiseki, in 
Japanese). Journal of the eye. 2007:24:947-51
12. Iliev ME, Domig D, Wolf-Schnurrbursch U, Wolf S, Sarra GM. Intravitreal bevacizumab 
(Avastin) in the treatment of neovascular glaucoma. Am J Ophthalmol. 2006:142:1054-6.
13. Avery RL. Regression of retinal and iris neovascularization after intravitreal 
bevacizumab (Avastin) treatment. Retina. 2006:26:352-4.


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14. Oshima Y, Sakaguchi H, Gomi F, Tano Y. Regression of iris neovascularization after 
intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy.
Am J Ophthalmol. 2006:142:155-7.
15. Saito Y, Higashide T, Takeda H, Ohkubo S, Sugiyama K. Beneficial effects of 
preoperative intravitreal bevacizumab on trabeculectomy outcomes in neovascular 
glaucoma. Acta Ophthalmol. 2010:88:96-102.
16. Lüke J, Nassar K, Lüke M, Grisanti S. Ranibizumab as adjuvant in the treatment of 
rubeosis iridis and neovascular glaucoma−results from a prospective interventional case 
series. Graefes Arch Clin Exp Ophthalmol. 2013:251:2403-13.
17. Kotecha A, Spratt A, Ogunbowale L, dell’Omo R, Kulkarni A, Bunce C, et al.
Intravitreal bevacizumab in refractory neovascular glaucoma: a prospective, 
observational case series. Arch Ophthalmol 2011:129:145-50.
18. Costagliola C, Cipollone U, Rinaldi M, della Corte M, Semeraro F, Romano MR.
Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma: a survey on 23 
cases throughout 12-month follow-up. Br J Clin Pharmacol. 2008:66:667-73.
19. Tanihara H. Aihara M, Inatani M, Inoue T, Kiuchi Y, Sugiyama K, et al. The Japan 
Glaucoma Society Guidelines for Glaucoma (4th Edition). Nippon ganka gakkai zasshi. 
2018:122:5-53.
20. Pharmacology/ toxicology review and evaluation. BLA Application number 125156 
(Drug name Lucentis TM, ranibizumab), 2.6.2.2 Primary pharmacodynamics:8-10
21. Yamamoto A, Nakashizuka H, Shimada H. Intravitreal bevacizumab injection to treat 
neovascular glaucoma (Kekkan shinsei rhokunaisho ni taisuru bevacizumab shoshitainai 
chusha, in Japanese). Ganka. 2010:52:1853-60.
22. Teich SA, Walsh JB. A grading system for iris neovascularization. Prognostic 
implications for treatment. Ophthalmology. 1981:88:1102-6.
15.
Protocol amendments
Not applicable.  
16.
Appendices
Not applicable.  

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A single-arm, non-randomized and open-label phase 3 study 
evaluating the efficacy, safety and tolerability of intravitreal 
aflibercept in Japanese patients with neovascular glaucoma (NVG) 
NCT Number: 
NCT03639675 
Document Date: 
7-Sep-2018 
 


Statistical Analysis Plan
BAY 86-5321/19652
Page: 1 of 14:
Reference Number: RD-OI-0119
Supplement Version: 9.0
Title page
A single-arm, non-randomized and open-label phase 3 study evaluating 
the efficacy, safety and tolerability of intravitreal aflibercept in Japanese 
patients with neovascular glaucoma (NVG)
Japanese phase 3 study of aflibercept in NVG patients [VENERA]
Bayer study drug
BAY86-5321/Aflibercept/Eylea
Study purpose:
Efficacy and Safety
Clinical study 
phase:
III
Date:
7 Sep 2018
Study No.:
19652
Version:
1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
Protocol No.: BAY 86-5321/19652
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Reference Number: RD-OI-0119
Supplement Version: 9.0
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 4
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 5
4.
General Statistical Considerations .................................................................................. 5
4.1
General Principles............................................................................................................ 5
4.2
Handling of Dropouts ...................................................................................................... 5
4.3
Handling of Missing Data................................................................................................ 6
4.4
Interim Analyses and Data Monitoring ........................................................................... 6
4.5
Data Rules........................................................................................................................ 6
4.6
Blind Review ................................................................................................................... 6
5.
Analysis Sets ...................................................................................................................... 7
5.1
Assignment of analysis sets ............................................................................................. 7
6.
Statistical Methodology .................................................................................................... 7
6.1
Population characteristics ................................................................................................ 7
6.1.1
Subject validity and disposition.................................................................................... 7
6.1.2
Demography ................................................................................................................. 8
6.1.3
Medical history............................................................................................................. 8
6.1.4
Prior and concomitant therapy...................................................................................... 8
6.1.5
Study Drug Exposure ................................................................................................... 9
6.2
Efficacy............................................................................................................................ 9
6.2.1
Primary efficacy analysis.............................................................................................. 9
6.2.2
Secondary efficacy analysis ......................................................................................... 9
6.2.3
Exploratory efficacy analysis ..................................................................................... 10
6.3
Pharmacokinetics/pharmacodynamics........................................................................... 11
6.4
Safety ............................................................................................................................. 11
6.4.1
Adverse events............................................................................................................ 11
6.4.2
Listings of deaths, other serious and significant adverse events ................................ 13
6.4.3
Pregnancies................................................................................................................. 13
6.4.4
Laboratory values ....................................................................................................... 13
6.4.5
Vital signs................................................................................................................... 13
6.4.6
Ophthalmic examinations........................................................................................... 13
7.
Document history and changes in the planned statistical analysis............................. 14
8.
References ........................................................................................................................ 14


Statistical Analysis Plan
Protocol No.: BAY 86-5321/19652
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Reference Number: RD-OI-0119
Supplement Version: 9.0
Abbreviations
AE
Adverse event
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
CRVO
Central retinal vein occlusion
FAS
Full Analysis Set 
IOP
Intraocular pressure
IVT
Intravitreal
MedDRA
Medical Dictionary for Regulatory Activities
NVA
Neovascularization of the angle
NVG
Neovascular glaucoma
NVI
Neovascularization of the iris
OIS
Ocular ischemic syndrome
PDR
Proliferative diabetic retinopathy
PPS
Per Protocol Set
PRP
Photocoagulation 
PT
Preferred Term  
SAF
Safety Analysis Set
SOC
System Organ Class
VEGF
Vascular endothelial growth factor
WHO-DD
World Health Organization Drug Dictionary
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
CRVO
Central retinal vein occlusion
FAS
Full Analysis Set 
IOP
Intraocular pressure
IVT
Intravitreal
MedDRA
Medical Dictionary for Regulatory Activities
NVA
Neovascularization of the angle


Statistical Analysis Plan
Protocol No.: BAY 86-5321/19652
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Reference Number: RD-OI-0119
Supplement Version: 9.0
1.
Introduction
Treatment of Neovascular Glaucoma
The clinical manifestations of NVG include elevated intraocular pressure (IOP) and 
neovascularization in the anterior segment of the eye (iris and/or anterior chamber angle). 
Therefore, a combined approach is used to both reduce IOP and promote regression of 
neovessels. Panretinal photocoagulation (PRP) is commonly used to treat ischemic retina, 
induce regression of neovascularization in the anterior segment, and reduce IOP. The effects 
of PRP are not produced immediately, and during this period, further neovascularization may 
be seen and the anterior chamber angle may become progressively occluded worsening the 
prognosis. Moreover, it is often difficult to perform PRP in eyes with NVG, due to corneal 
edema secondary to high IOP or to other opacities of the optic media such as cataract or 
vitreous hemorrhage.  If PRP is suboptimal, cryo-coagulation is conducted or endolaser 
coagulation may be combined with vitreous surgery.  Despite such invasive treatments,
progression of the neovascularization may continue because of persistent ischemia. The role 
of intravitreal anti-VEGF is to produce a fast regression of the anterior segment 
neovascularization, stabilizing disease progression and bridging the patient to a long-term 
solution after the effect of PRP is attained.
About BAY 86-5321 (aflibercept)
The recombinant protein aflibercept exhibits very potent binding activity to human VEGF, 
with an equilibrium dissociation constant (Kd) of approximately 0.5 pM.  This binding 
activity is more potent relative to the activity of anti-VEGF agent ranibizumab (with a Kd in 
the order of 100 pM).  The formulation, aflibercept, is developed for intraocular use.  
Research using an animal ophthalmological disease model demonstrated that aflibercept 
adequately inhibits the incidence of retinal neovascularization, choroidal neovascularization 
(CNV), and retinal edema.
Intravitreal administered anti VEGF drugs may be able to halt this process and even regress 
neovascularization by directly inhibiting VEGF.  Therefore, anti VEGF drugs, Aflibercept, 
shall be recommended for testing the efficacy in patients with NVG.  Given the well 
established safety profile of aflibercept in various indications and the reports of anti VEGF 
therapies successfully given to patients with NVG, the applicant plans an additional study, 
No. 19652, with the mean change in IOP as the primary endpoint for the purpose of 
evaluating IOP lowering effect and at the same time neovascularization of the iris (NVI)  
regressing effect as the secondary endpoint.  
This statistical analysis plan (SAP) is based on the following protocol:
-
Clinical Study Protocol, Version 1.0, dated 18 May 2018
2.
Study Objectives
Primary objective:
-
To assess the efficacy of intravitreal (IVT) administration of aflibercept on the 
change in IOP in patients with NVG. 
Secondary objective:
-
To assess the safety and tolerability of IVT administration of aflibercept in patients 
with NVG.


Statistical Analysis Plan
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3.
Study Design
Design overview
This study will enroll NVG patients.  This is a multicenter, single-arm, non-randomized, and 
open-label phase 3 trial to evaluate the primary efficacy variable “change in IOP from 
baseline to Week 1” of IVT administration of aflibercept in NVG patients (Figure 3-1).
Figure 3-1 Study outline
After eligibility is confirmed, subjects will initiate treatment with at least 3 of the 5 allowed 
classes of topical IOP-lowering drugs.  With application of the first eyedrop, the run-in-phase 
will start and IOP is monitored to determine whether the subject qualifies for assignment.  If 
IOP is higher than 25 mmHg and all other criteria allow, the subject should be assigned and 
given aflibercept.  Treatment with topical drug classes initiated during Run-in phase should be 
continued unchanged until Week 1.  
If required, subjects can receive systemic IOP-lowering drugs, or undergo PRP or surgery 
intended to lower IOP, during study participation. Even if medically justifiable, any of these 
IOP-lowering interventions should not be performed before the primary endpoint visit. If 
IOP-lowering intervention is unavoidable or systemic IOP-lowering drugs are needed for the 
treatment of the study eye and/or fellow eye before the primary-endpoint visit, the evaluations 
of the Week-1 visit should be done before the intervention.
4.
General Statistical Considerations
4.1
General Principles
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, 
minimum, median, and maximum will be calculated for metric data.  Frequency tables will be 
generated for categorical data.  Graphical displays may also be used to summarize the data.
Applicable standards are as follows:
-
Global Standards for Data Displays Version 3.0, dated 16 Jan 2017,
-
Global Standard Tables Version 3.0, dated 16 Jan 2017, and
-
Global Standard Listings Version 3.1, dated 16 Jan 2017.
The statistical analysis plan can be updated based on the result of the validity review meeting 
before database lock.  
A detailed overview of the tables, figures, and listings that will be created can be found in the
corresponding Table, Listing, and Figure (TLF) Specification document.
4.2
Handling of Dropouts
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been assigned.  Subjects who are withdrawn from the 
study after assignment, or who prematurely discontinue the study will not be replaced.
Week 2
Week 5
(Final evaluation)
Screening
Days -15 to 1
(Run-in)
Baseline
Day 1 / Assignment
(Aflibercept IVT)
Week 1
(Primary evaluation)


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The number of subjects who discontinue prematurely (i.e., screening failure and dropout, 
respectively) will be summarized by reason for premature discontinuation.
4.3
Handling of Missing Data
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form (CRF). 
In principle, last observation carried forward (LOCF) will be used to impute missing data for 
efficacy analysis.  Baseline values will not be carried forward, but unscheduled assessments 
after baseline will be utilized if available.  The further detail is described in Sec 6.2 Efficacy.
Efficacy Variables 
If no valid IOP is available at the Week 1, the last post baseline before Week 1 will be utilized 
for imputation.  If the prohibited treatment will be received, the IOP after prohibited treatment 
will not be utilized for imputation in PPS analysis.  On the other hand, the IOP after 
prohibited treatment will be utilized in FAS analysis.  The same imputation rule will be 
conducted for NVI and Neovascularization of the angle (NVA).  
Safety Variables
No imputation for safety analyses is planned.
4.4
Interim Analyses and Data Monitoring
No formal interim analysis is planned.  
4.5
Data Rules
Baseline value
In principal, baseline values are defined as the latest valid pre injection assessments.
Unscheduled assessments
Unless otherwise specified, extra assessments (e.g. vital signs associated with non protocol 
clinical visits or obtained in the course of investigating or managing adverse events[AEs]) 
will be included in data listings, but not in data summaries.  If more than one measurement is 
available for a given visit, the first observation will be used in the data summaries and all 
observations will be presented in the data listings.
Coding
Medical history findings and AEs will be coded by Medical Dictionary for Regulatory 
Activities (MedDRA) codes and medications including surgery by Anatomical Therapeutic 
Chemical (ATC) codes (World Health Organization Drug Dictionary [WHO-DD]).  
4.6
Blind Review
The results of the final data assessment will be documented in the final list of important 
deviations, validity findings, and assignment to analysis set(s).  Any changes to the statistical 
analyses prompted by the results of the review of study data will be documented in an 
amendment and any change after the final validity review meeting will be documented in a 
supplement to this SAP.


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5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
review of study data and documented in the final list of important deviations, validity findings 
and assignment to analysis set(s) (see section 4.6).
Full Analysis Set (FAS)
The FAS will include all subjects who; 
-
are assigned, 
-
received at least one IVT administration of study drug on Day 1, 
-
have baseline valid IOP measurement, and 
-
have at least one post-baseline IOP measurement before or at Week 1.  
The FAS will be used for supplemental analyses in efficacy.  
Per Protocol Set (PPS)
The PPS will include the all subjects who; 
-
are assigned, 
-
received at least one IVT administration of study drug on Day 1, 
-
have baseline valid IOP measurement, 
-
have at least one valid (e.g., measured during valid time window and before 
prohibit treatment) post-baseline IOP measurement before or at Week 1, and
-
show no validity findings that may affect efficacy.
e.g., meet all of inclusion criteria, do not meet any exlusion critriea
The efficacy variables, which measured within four days from the dose (the day included), 
will be excluded from analyses in PPS because the effect occurring of drug may assumed to 
need a few days according to mechanism of action of aflibercept.  The post baseline IOP, 
which measured two hours before or after the measurement clock time at baseline, will be 
excluded from analyses in PPS in order to exclude diurnal variation of IOP(1).  The PPS will 
be the primary analysis set for efficacy analyses.  
Safety Analysis Set (SAF)
The SAF will include all subjects who are assigned and received at least one IVT 
administration of study drug.  
6.
Statistical Methodology
6.1
Population characteristics
6.1.1
Subject validity and disposition
Study sample size and subject validity reasons for exclusion from analysis will be 
summarized using frequency tables.  Subject disposition: end of treatment i.e., Week 1 and 
end of follow-up i.e., Week 5 will be summarized.


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6.1.2
Demography
Demographic and other baseline characteristics will be summarized for the SAF.  If the other 
analysis sets (i.e., FAS, and PPS) differs from the SAF, the same analyses will be also 
conducted in the each analysis set.
Demography includes:
-
Age (years),
-
Sex,
-
Ethnicity,
-
Race,
-
Body height (cm),
-
Body weight (kg),
-
Body mass index (kg m
⁄
),
-
Vital signs (temperature, blood pressure, and pulse), and
-
Smoking history.
Baseline characteristics include:
-
Primary underlying disease leading to development of NVG,
-
Stage of NVG,
-
Duration of disease (days),
Duration of disease = first study drug administration date - NVG diagnosis start 
date
-
IOP (mmHg),
-
NVI grade, and
-
NVA grade.
6.1.3
Medical history
These analyses will be conducted in the SAF.  If the other analysis sets (i.e., FAS, and PPS) 
differs from the SAF, the same analyses will be also conducted in the each analysis set.
Medical history findings will be summarized using frequency tables presented by MedDRA 
term.  This summary will be also provided for ocular (study eye and fellow eye, respectively) 
and non-ocular findings.
6.1.4
Prior and concomitant therapy
Medications
These analyses will be conducted in the SAF.  If the other analysis sets (i.e., FAS, and PPS) 
differs from the SAF, the same analyses will be also conducted in the each analysis set.
The number of subjects who took the following medication will be summarized using 
frequency tables presented by WHO-DD ATC subclass within ATC class.
-
medications that started and ended before the start of study drug


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medications that are ongoing at or began after the start of study drug
-
medications that are ongoing at the start of study drug
-
medications that began after the start of study drug
The number of subjects who took systemic IOP-lowering drugs will be also summarized.
6.1.5
Study Drug Exposure
These analyses will be conducted in the SAF.
Total number of study drug administered during the study period will be summarized using 
frequency tables.
6.2
Efficacy
The PPS is the primary analysis set for efficacy.  The FAS is a set for supplemental analysis 
of the PPS analysis.  No alpha adjustment for multiple comparisons was considered, because 
confidence interval of other analyses except the primary analysis in PPS will be interpreted in 
consideration of false positives due to multiple testing.  
6.2.1
Primary efficacy analysis
Primary efficacy variable is 
-
Change in IOP from baseline to Week 1.  
If no valid IOP is available at the Week 1, the last post-baseline before Week 1 will be 
utilized for imputation.  If the prohibited treatment will be received, the IOP after prohibited 
treatment will not be utilized for imputation in PPS analysis.  On the other hand, the IOP after 
prohibited treatment will be utilized in FAS analysis. 
The change in IOP from baseline at Week 1 will be summarized descriptively.  The point 
estimate and its two-sided 95% confidence interval using one-sample t-statistics will be 
calculated.  The corresponding hypotheses for the efficacy analysis are
:  ≥0,
:  < 0,
where  is the change in IOP from baseline at Week 1.  If the upper limit of the two-sided 
95% confidence interval in PPS is less than the threshold (i.e., 0), the null hypothesis will be 
rejected and the study will be regarded as success.  
Supplemental analysis
The same analysis will be conducted in the FAS.  In addition, the same analys is of PPS will 
be conducted using observed case i.e., not apply imputation rule.
6.2.2
Secondary efficacy analysis
Secondary efficacy variable is 
-
Proportion of subjects who have improved NVI grade from baseline to Week 1.  
Improvement by at least one grade from baseline will be categorized to “Improved”.  The 
same imputation rule as IOP will be conducted.  
The proportion of subjects who have improved NVI grade from baseline at Week 1 will be 
summarized descriptively.  The point estimate and its two-sided 95% confidence interval 
using Clopper-Pearson method will be calculated.  If the valid NVI is not available at Week 1 


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in spite of applying imputation rule, the subject will be regarded as not improve but included 
in denominator.  The subject who do not have valid NVI at baseline will be excluded from 
this analysis, i.e. excluded from denominator even if the subject has valid/invalid NVI at 
Week 1.
Supplemental analysis
The same analysis will be conducted in the FAS.  In addition, the same analysis of PPS will 
be conducted using observed case i.e., not apply imputation rule.
6.2.3
Exploratory efficacy analysis
Exploratory efficacy variables include, but not limited to, the followings: 
-
IOP and change from baseline to each visit, 
-
NVI and NVA and change from baseline to each visit, and 
-
Proportion of subjects who could control IOP (≤21 mmHg) at each visit.
Exploratory efficacy analyses will be conducted in the PPS.  If FAS differs from the PPS, the 
same analyses will be also conducted in FAS.
6.2.3.1
IOP and change from baseline to each visit
The IOP and change from baseline to each visit will be summarized using summary statistics.  
Graphical displays of individual data as well as mean values with SD will be included.  
Graphical displays of the change from baseline will be presented.
6.2.3.2
NVI and NVA and change from baseline to each visit
The same imputation rule as IOP (see Sec. 6.2.1) will be conducted.  The change in NVI and 
NVA grades will be categorized to “Improved” (improvement by at least one grade from 
baseline), “Worsened” (worsened by at least one grade from baseline) or “Stable” (no change 
in grade from baseline).
The NVI and NVA grades and their change from baseline at each visit will be summarized 
descriptively using frequency tables.  Graphical displays of the change from baseline will be 
presented.
In addition, for the proportion of subjects who have improved NVA grade from baseline at 
Week 1, the point estimates and its two-sided 95% confidence interval using Clopper-Pearson 
method will be calculated.  If the valid NVI/NVA is not available at each visit even if the 
subjects continue the study, the subject will be regarded as “Missing” and included in the 
denominator.  If the subjects discontinue the study before the visit, the subjects will not be 
included as denominator.
6.2.3.3
Proportion of subjects who could control IOP (≤21 mmHg) at each 
visit
The Proportion of subjects who could control IOP (≤21 mmHg) at each visit will be 
summarized descriptively using frequency tables.  Graphical displays of the change from 
baseline will be presented.
In addition, for the Proportion of subjects who could control IOP (≤21 mmHg) at Week 1, the 
point estimates and its two-sided 95% confidence interval using Clopper-Pearson method will 
be calculated.  If the valid IOP is not available at each visit even if the subjects continue the 
study, the subject will be regarded as “Missing” and included in the denominator.  If the 


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subjects discontinue the study before the visit, the subjects will not be included as 
denominator.
6.2.3.4
Subgroup analyses
The subgroup analyses will be performed in primary variable and secondary efficacy variable.  
The subgroups will include: 
-
Age (years): < 65, ≥65; 
-
Sex: Male, Female; 
-
Primary Diagnosis: CRVO, PDR, OIS, other; 
-
IOP at Baseline group (mmHg): ≤ median, > median; 
-
NVI grade at baseline group: Grade 1 or 2, Grade 3 or 4; 
-
NVA grade at baseline group: Grade 1 or 2, Grade 3 or 4.  
Graphical displays using forest plot will be included.
6.3
Pharmacokinetics/pharmacodynamics
Not applicable.
6.4
Safety
The safety analyses will be conducted in the SAF.
6.4.1
Adverse events
AEs that occurred or worsened after the first dose of study drug and no later than 30 days 
after the last dose of study drug (i.e., not later than 30 days after the last injection) will be 
considered as treatment-emergent AE (TEAE).
Evaluations of AEs will be done for four sets of AEs, which will be identified from the 
information in the CRF:
-
Ocular AE in the study eye,
-
Ocular AE in the fellow eye,
-
Non-ocular AE, and
-
All AE (i.e., all AEs mentioned above combined).
Overall summary
Overall summary for AEs, pre-treatment AE, and TEAEs will be provided using frequency 
tables.
Incidence
The number of subjects with the following kinds of AE will be summarized using frequency 
tables presented by MedDRA Preferred Term (PT) within primary System Organ Class 
(SOC):
-
Treatment-emergent AE,
-
Treatment-emergent serious AE,
-
Treatment-emergent study drug or intravitreal procedure-related AE,


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Treatment-emergent study drug-related AE,
-
Treatment-emergent intravitreal procedure-related AE,
-
Treatment-emergent protocol required procedures-related AE,
-
Treatment-emergent serious study drug or intravitreal procedure-related AE,
-
Treatment-emergent serious study drug-related AE,
-
Treatment-emergent serious intravitreal procedure-related AE,
-
Treatment-emergent serious protocol required procedures-related AE, and
-
Treatment-emergent non-serious AE.  
Incidence by Maximum intensity
The number of subjects with the following kinds of AE will be summarized using frequency 
tables presented by MedDRA PT within primary SOC by maximum intensity:
-
Treatment-emergent AE and
-
Treatment-emergent study drug-related AE.
Results of Antiplatelet Trialists’ Collaboration (APTC) adjudication
An adjudication of AEs according to the APTC criteria will be performed.  A frequency table 
of adjudication terms, cross-tabulated with related MedDRA PT terms, will be displayed.
Subgroup analysis
Treatment-emergent AEs and treatment-emergent study drug related AEs will be also 
summarized for the subgroups described in section 6.2.3.4. 
The following subgroups will be considered only for safety evaluation.

Renal impairment: Yes (CrCl ≤ 80 mL/min), No (CrCl > 80 mL/min) classified by 
creatinine clearance (CrCl) at baseline.  
CrCl is calculated according to the Cockcroft-Gault formula as below (Renal 
impairment guideline of FDA, 1998).
                          







female
if
male
if
dl
mg
creatinine
serum
kg
weight
years
age
CrCl
,
85
.0
,0.1
*
)
/
(
72
)
(
)]
(
140
[

Medical history of hepatic impairment: Yes, No
o
Subjects with the medical history of MedDRA PBMQ MedDRA SMQ 
“Hepatic disorders (SMQ)” (code=20000005) are considered “Yes”

Medical history of hypertension: Yes, No
o
Subjects with the medical history of MedDRA PBMQ “Medical history of 
hypertension (VEGF Trap-Eye)” (code=SMQ_1275) are considered “Yes”

Medical history of cerebrovascular accident (CVA) / Stroke: Yes, No
o
Subjects with one of the following medical history are considered “Yes”

MedDRA SMQ “Central nervous system vascular disorders (SMQ)” 
(code=20000060)


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
MedDRA SMQ “Central nervous system haemorrhages and 
cerebrovascular conditions (SMQ)” (code=20000061)

MedDRA SMQ “Ischaemic central nervous system vascular conditions 
(SMQ)” (code=20000063)

MedDRA SMQ “Haemorrhagic central nervous system vascular 
conditions (SMQ)” (code=20000064)

Medical history of myocardial infarction (MI): Yes, No
o
Subjects with the medical history of MedDRA PBMQ “Medical history of 
myocardial infarction (VEGF Trap-Eye)” (code=SMQ_1278) are considered 
“Yes”
6.4.2
Listings of deaths, other serious and significant adverse events
Deaths, serious AEs will be listed by subject.
6.4.3
Pregnancies
The number of female subjects taking a pregnancy test will be summarized with the results.
6.4.4
Laboratory values
The absolute values and the change from baseline at each visit will be summarized for all 
quantitative parameters.
All laboratory values will be categorized according to the normal range:
-
Laboratory results below the lower limit of the normal range will be “Low”,
-
Laboratory results within the normal range will be “Normal”, and
-
Laboratory results above the upper limit of the normal range will be “High”.
The incidence of laboratory values outside normal range will be presented.
6.4.5
Vital signs
The absolute values and the change from baseline at each visit will be summarized for body 
temperature, blood pressure, and pulse rate.
6.4.6
Ophthalmic examinations
Unless otherwise specified, results for the study eye will be tabulated, and results for the 
fellow eye will be listed only.
Visual acuity
The number of subjects who meet the followings will be summarized, respectively using 
frequency tables:
-
Visual acuity in decimal score was ≥0.01 at baseline but deteriorated to be not 
assessable or < 0.01 at post-baseline visit,
-
Visual acuity in decimal score was > 0.1 at baseline but ≤0.1 at post-baseline visit, 
and
-
Lost half of visual acuity in decimal score at post-baseline visit compared to 
baseline.


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The absolute values and the change from baseline at each visit will be summarized using 
logMAR BCVA scores.  The logMAR scores will be derived from the decimal scores as 
follows:
−1 × log(Decimal score).
For this purpose, BCVA categories lower to the minimum value assessable with the BCVA 
chart will be converted to decimal score as follows(2):
Table 6-1 Conversion table for low visual acuity
Table Category
Visual acuity in decimal score
Count Fingers
0.005
Hand Motion
0.0025
Light Perception
0.00125
No Light Perception
0.0001
(Takihara Y et al, 2009)
Applanation tonometry
The absolute values and change from pre-dose IOP will be summarized for post-dose IOP.
Slit-lamp microscopy
A frequency table for each parameter of slit lamp microscopy, including lids, conjunctiva, 
cornea, anterior chamber, iris, pupil, lens, and other, will be displayed by visit.  In addition, a 
separate frequency table for those subjects with ‘abnormal’ in any parameter measured will be 
given.
Frequency tables by visit will be provided for grading of anterior chamber flare and cells 
(categories: 0 / Trace / 1+ / 2+ / 3+ / 4+).  Additionally, shift tables will be presented by visit.
Gonioscopy
A frequency table for gonioscopy will be displayed by visit.  In addition, a separate frequency 
table for those subjects with ‘abnormal’ will be given.
Indirect ophthalmoscopy
A frequency table for each parameter of indirect ophthalmoscopy, including vitreous body, 
optic nerve head, macula, peripheral retina, and the number of quadrants affected by 
pathologic findings, will be displayed by visit.  In addition, a separate frequency table for 
those subjects with ‘abnormal’ in any parameter measured will be given.
7.
Document history and changes in the planned statistical analysis
Not applicable.
8.
References
1.
Hara T, Nakayama Shoten: Ophthalmologic diagnosis qualification for medical 
specialists 3 2011_1(1): p233
2.
Takihara Y, Inatani M, Fukushima M, et al. Trabeculectomy with Mitomycin C for 
Neovascular Glaucoma: Prognostic Factors for Surgical Failure.  American Journal of 
Ophthalmology. 2009; 147 (5): 912-8.