Conditions: Diabetic Macular Edema Retina Vein Occlusion
Keywords: Macular Edema
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
Phase 2a multicenter, open-label, parallel-arm design study to evaluate the safety, tolerability and pharmacodynamics of a single intravitreal injection comparing 2 dose levels of GB-102 on subjects with Diabetic Macular Edema and Retinal Vein Occlusion

Detailed description:
Phase 2a multicenter, open-label, parallel-arm design study to evaluate the safety, tolerability and pharmacodynamics of a single intravitreal injection comparing 2 dose levels (1 mg and 2 mg) of GB-102 on subjects with Diabetic Macular Edema and Retinal Vein Occlusion who have received prior treatment with anti-vascular endothelial growth factor (VEGF)

Arms:
arm 1: Participants will receive intravitreal (IVT) GB-102 (1 mg) in the study eye at Baseline. arm 2: Participants will receive intravitreal (IVT) GB-102 (2 mg) in the study eye at Baseline.

Interventions: intervention 1: GB-102
Intervention descriptions: intervention 1: Intravitreal injection of GB-102

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
Graybug Vision Inc. 
 
CLINICAL STUDY PROTOCOL 
 
 
Official Title: A Phase 2a Multicenter Study Evaluating the Safety, Tolerability, and 
Pharmacodynamics of a Single Injection of a Long-acting Intravitreal 
Sunitinib Malate Depot Formulation (GB-102) in Subjects with Diabetic 
Macular Edema (DME) and Retinal Vein Occlusion (RVO) 
 
Protocol Number: GBV-102-003 
 
NCT Number: 04085341 
 
 


GB-102 (Sunitinib Malate) 
Protocol GBV-102-003 
 
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CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
A Phase 2a Multicenter Study Evaluating the Safety, 
Tolerability, and Pharmacodynamics of a Single Injection of 
a Long-acting Intravitreal Sunitinib Malate Depot 
Formulation (GB-102) in Subjects with Diabetic Macular 
Edema (DME) and Retinal Vein Occlusion (RVO) 
 
 
Sponsor: 
Graybug Vision, Inc. 
275 Shoreline Drive, Suite 450 
Redwood City, CA 94065 
 
 
IND Number: 
 
128451 
 
 
 
Indication: 
Macular edema secondary to diabetic retinopathy and retinal 
vein occlusion 
 
 
Protocol Number (Phase): 
GBV-102-003 (Phase 2a) 
 
 
Clinical Medical Officer: 
 
 
 
 
 
 
 
 
Medical Monitor: 
 
 
 
 
 
 
 
 
 
 
Protocol Version/Date: 
Version 2.0 / 13 November 2019 (Amendment 1) 
Version 1.0 / 18 July 2019 (Original) 
 
GRAYBUG 
VISION 


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CONFIDENTIALITY STATEMENT 
The information in this document is confidential and will not be disclosed to others without 
written authorization from Graybug Vision, Inc., except to the extent necessary to obtain 
informed consent from persons who are potential participants in the study or their legal 
guardians, persons participating in the conduct of the study, appropriate institutional review 
boards or independent ethics committees, or duly authorized representatives of the United 
States Food and Drug Administration or national regulatory authority. 
 
 


GB-102 (Sunitinib Malate) 
Protocol GBV-102-003 
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STUDY ACKNOWLEDGEMENT 
Amendment 1 
This protocol has been approved by Graybug Vision, Inc. and will be conducted as outlined 
herein in accordance with International Council for Harmonisation (ICH) guidelines, Good 
Clinical Practice (GCP), the Declaration of Helsinki, and will comply with the obligations and 
requirements of the Sponsor as listed in Title 21 of the United States Code of Federal 
Regulations. The following signature documents approval of the protocol. 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Graybug Vision, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Study Center Number 
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PROTOCOL SYNOPSIS 
 
Study GBV-102-003 
Graybug Vision, Inc. 
275 Shoreline Drive, Suite 450 
Redwood City, CA 94065 
 
Study Title: 
A Phase 2a Multicenter Study Evaluating the Safety, Tolerability, and 
Pharmacodynamics of a Single Injection of a Long-acting Intravitreal 
Sunitinib Malate Depot Formulation (GB-102) in Subjects with 
Diabetic Macular Edema (DME) and Retinal Vein Occlusion (RVO) 
Study Centers 
Planned: 
Approximately 4 to 6 study centers in the United States 
Objectives: 
Primary Objective 
To evaluate the safety and tolerability of a single intravitreal injection 
of two different dose strengths of GB-102 (1 mg, 2 mg) in subjects 
with macular edema secondary to diabetic retinopathy or retinal vein 
occlusion who have received prior treatment with anti-vascular 
endothelial growth factor (VEGF) 
Secondary Objectives 
To evaluate the pharmacodynamic response as measured by best 
corrected visual acuity (BCVA) and central subfield thickness (CST) 
and time to first rescue injection. 
Study Design: 
Multicenter, open-label, single injection, parallel arms, non-controlled 
safety, tolerability and pharmacodynamics study. 
Eligible subjects will be consecutively enrolled to 1 of 2 concurrently 
initiated open-label GB-102 treatment arms: 
Group 1: 1 mg (50-µL) (N=10) 
Group 2: 2 mg (50-µL) (N=10) 
GB-102 will be administered on Day 1 in both Groups (Table 3-1). 
Subjects will return to the study center on Days 14, 30, 60, 90, 120, 
150, and 180 for safety and clinical assessments. Subjects will exit 
the study following all study assessments on Day 180. 
The safety parameters to be collected include adverse events (AEs) 
and serious adverse events (SAEs), physical examination, vital signs, 
BCVA using the Early Treatment of Diabetic Retinopathy Study 
(ETDRS) protocol, slit-lamp biomicroscopy findings, intraocular 


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pressure (IOP) measurements, dilated ophthalmoscopy results, and 
date of administration of rescue treatment. 
Pharmacodynamic activity will be assessed by means of BCVA 
(using the ETDRS Protocol), retinal central subfield thickness (CST) 
using spectral-domain optical coherence tomography (SD-OCT), and 
color fundus photography (CFP) (including wide field fundus 
photography, if available). 
Safety Monitoring 
The medical monitor will evaluate the on-going open-label safety 
data. 
Masking 
This is an open-label study and the injecting investigator/physician 
may be the assessing investigator. The SD-OCT and CFP technicians 
and other site personnel, the Sponsor, and CRO are unmasked to 
treatment assignment.  
Rescue Treatment 
Rescue treatment (any anti-VEGF agent; aflibercept, bevacizumab, or 
ranibizumab) will be permitted in the study eye in any of the study 
arms if the qualifying criteria are met for rescue treatment. 
Study Eye 
Determination: 
The study eye is defined as the eye that meets all the inclusion 
criteria and none of the exclusion criteria. If both eyes meet the 
inclusion and none of the exclusion criteria, the eye with the worst 
visual acuity at baseline will be selected. If both eyes have the same 
baseline visual acuity, the right eye will be selected as the study eye. 
Rescue Treatment 
Criteria: 
Rescue treatment (any anti-VEGF agent; aflibercept, bevacizumab, or 
ranibizumab) for all subjects enrolled is allowed at any visit following 
the Day 30 study assessments in subjects who meet any of the 
following criteria regarding decrease in BCVA and/or increase in 
CST: 
Decrease in BCVA: 
o ≥ 10 ETDRS letter decrease compared with best on-study 
(i.e., post-treatment) BCVA ETDRS letter score 
Increase in CST (any of the following criteria): 
o ≥ 75 µm compared with the average of the last 2 on-study 
(i.e., post-treatment) visit CST measurements (µm), 
and/or, 


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o ≥ 100 µm compared with the lowest on-study (i.e., post-
treatment) CST measurement (µm) 
The investigator may elect to withhold rescue treatment if, in the 
opinion of the investigator, further clinical monitoring is warranted 
(e.g., subject has difficulty reading eye chart due to seasonal allergies 
and experiences a decline in BCVA but the OCT imaging shows no 
evidence of fluid). 
Rescued subjects will remain in the study for continued scheduled 
follow-up observation.  
Number of Subjects 
Planned: 
Approximately 20 subjects are planned: 10 subjects treated with 1 mg 
GB-102 and 10 subjects treated with 2 mg GB-102. There is no pre-
set limitation on the proportion of DME or RVO subjects per dose 
group.  
Target Population: 
Subjects eligible for screening must have a history of macular edema 
in the study eye secondary to DME or RVO that was diagnosed in the 
6 weeks to 24 months prior to screening, treated with at least 3 prior 
intravitreal (IVT) injections of anti-VEGF (aflibercept, bevacizumab, 
or ranibizumab), and demonstrated a response anti-VEGF treatment.  
The most recent anti-VEGF treatment must be administered within 42 
days of screening. 
The investigator will interpret SD-OCT used to determine subject 
eligibility; there is no third-party independent reading center 
confirmation of any images during screening or 
treatment/observation. 
Duration of Study 
Participation: 
Approximately 210 days (up to 30 days for screening and 180 days of 
treatment/observation) 
Inclusion Criteria: 
All Subjects (DME or RVO) 
1. Verbal and written informed consent obtained from the subject 
2. Males or females ≥ 21 years of age 
3. Willing and able to give informed consent, comply with all study 
procedures, and be likely to complete the study 
4. Subjects with known diagnosis of diabetic macular edema or 
macular edema due to retinal vein occlusion (central or branch) in 
the 6 weeks to 24 months prior to screening who have received at 
least 3 prior IVT injections of any anti-VEGF agent in the study 
eye and demonstrated a pharmacodynamic response in the study 
eye to IVT anti-VEGF treatment (aflibercept, bevacizumab, or 
ranibizumab) within 16 weeks of the first anti-VEGF treatment as 


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determined by the investigator and documented by at least 1 of 
the following: 
4a. Reduction of intraretinal/subretinal fluid by ≥ 10% from 
the initial diagnosis as determined using SD-OCT 
4b. Reduction of excess CST by ≥ 10% from the initial 
diagnosis as determined using SD-OCT (assuming 
nominal thickness is 300 microns) 
5. Demonstrate a maintained anti-VEGF response (as determined by 
the investigator) compared with the initial diagnosis (prior to any 
anti-VEGF treatment) as assessed by SD-OCT following the most 
recent anti-VEGF injection (defined as reduction in central 
subfield thickness, intraretinal/subretinal fluid, or maintenance of 
a dry retina) 
6. Subjects must have the most recent anti-VEGF agent administered 
within 42 days (6 weeks) of screening in the study eye. 
7. Screening and baseline BCVA letter score (by ETDRS protocol) 
of 31 to 88 (20/240 to 20/20 Snellen equivalent) 
8. If the screening and baseline BCVA letter score (by ETDRS 
protocol) in the nonstudy eye is worse than the study eye, the 
BCVA score in the nonstudy eye must be at least 53 letters 
(20/100 Snellen equivalent) or better 
9. Clear ocular media and adequate pupil dilation in both eyes to 
permit good quality photographic imaging 
10. Women of childbearing potential (ie, not postmenopausal for at 
least 12 months or not surgically sterile [bilateral tubal ligation, 
hysterectomy, or bilateral oophorectomy]) must have a negative 
urine pregnancy test at screening and baseline, and must use 
adequate birth control throughout the study if she has a 
nonsurgically sterile male sexual partner; adequate methods of 
birth control include hormonal contraceptives, intrauterine 
comtraceptive devices, condom with spermicide, diaphragm with 
spermicide, and cervical cap with spermicide. 
Exclusion Criteria: 
1. History, within 6 months prior to screening, of any of the 
following: myocardial infarction, any cardiac event requiring 
hospitalization, treatment for acute congestive heart failure, 
transient ischemic attack, or stroke 
2. Uncontrolled hypertension with systolic blood 
pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 95 mmHg 
at the Screening Visit 


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3. Uncontrolled diabetes mellitus, defined as hemoglobin 
A1c >12.0% at the Screening Visit 
4. Chronic renal disease requiring chronic hemodialysis or renal 
transplantation 
5. Participation in any investigational study within 30 days prior to 
screening, or planned use of an investigational product or device 
during the study; any exposure to a prior investigational drug 
product must be fully washed out (at least 5 half-lives) 
6. Previous participation in an investigational study of GB-102 
7. Spherical equivalent of the refractive error in the study eye 
demonstrating more than −6 diopters of myopia (prior to cataract 
or refractive surgery) at the Screening Visit 
8. Uncontrolled IOP, defined as an IOP > 25 mmHg, despite 
antiglaucoma medications in the study eye at the time of 
screening or controlled glaucoma that requires management 
with > 2 topical hypotensive medications 
9. Presence of any clinically significant epiretinal membrane or 
vitreomacular traction in the study eye 
10. History or evidence of any of the following in the study eye: 
a. Macular surgery or other surgical intervention for AMD 
b. Prior retinal detachment  
c. Vitrectomy 
d. Retinal laser treatment with the exception of prior laser 
photocoagulation for treatment of diabetic retinopathy 
e. Glaucoma filtering surgery (eg, trabeculectomy) or 
glaucoma drainage device (eg, Ahmed valve or Baerveldt 
valve) including minimally invasive glaucoma shunts (eg, 
minimally invasive glaucoma surgery) prior to the 
Screening Visit. Selective laser trabeculoplasty (SLT) >3 
months prior to Screening Visit is allowed. 
f. Cataract surgery within the 3 months prior to the 
Screening Visit 
g. Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser 
capsulotomy within the 30 days prior to the Screening 
Visit. Note: prior Nd:YAG laser posterior capsulotomy in 
association with a posterior intraocular lens implantation 
is allowed. 


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h. Corneal refractive procedures (laser-assisted in situ 
keratomileusis [LASIK] or photorefractive keratectomy) 
within the 6 months prior to the Screening Visit or planned 
during the study 
i. Corneal transplantation surgery 
j. History of advanced glaucoma with visual field loss 
encroaching on central fixation 
k. Intravitreal steroid injection (eg, triamcinolone 
suspension) within the past 3 months, bioabsorbable 
steroid implant (eg, Ozurdex®) within the past 12 months, 
and/or presence of any steroid implant in the study eye 
(eg, Iluvien® or Ozurdex®) at the time of the Screening 
Visit 
l. Active retinal or iris neovascularization in the study eye 
11. Anterior chamber intraocular lens, aphakia, or violation of the 
posterior capsule in the study eye 
12. History or clinical evidence of other concurrent conditions 
deemed by the investigator to likely impact the subject’s clinical 
safety or to interfere with the interpretation of the study results 
including, but not limited to: 
a. Proliferative diabetic retinopathy in the study eye 
b. Choroidal neovascular lesion secondary to wet AMD in 
the study eye 
c. Any retinal or choroidal vasculopathy, other than due to 
diabetes or retinal vein occlusion in the study eye 
d. Inflammatory conditions of the anterior or posterior 
segment (eg, chronic keratoconjunctivitis, uveitis, retinal 
vasculitis, neuritis, iritis, scleritis, or blepharitis) in the 
study eye 
e. Subfoveal involvement by any of the following: fibrosis, 
serous pigmented epithelial detachment, retinal pigmented 
epithelial tear, or geographic atrophy in the study eye 
f. Subfoveal hemorrhage that is ≥ 1 disc areas in size in the 
study eye 
g. Any media opacity that prevents proper visualization of 
the fundus and/or adversely alters visual acuity, in the 
opinion of the investigator in the study eye 
h. Prior radiation therapy in the region of the eyes 


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i. History of demyelinating disease (eg, multiple sclerosis, 
neuromyelitis optica), optic neuropathy, and/or optic 
neuritis. 
13. Any bacterial, viral, fungal, or parasitic infection in either eye 
within the 30 days prior to the Screening Visit 
14. Known allergy to constituents of the study drug formulation, 
ocular antimicrobicide solutions, or clinically relevant 
hypersensitivity to fluorescein 
15. Women who are pregnant or lactating 
16. Men who are unwilling to practice 2 measures of adequate 
contraception (if having sexual intercourse with a woman of 
child-bearing potential) or who desire to donate sperm during the 
time from first dose of study drug until exiting the study. If a male 
exits the study early and wants to donate sperm, a minimum wait 
period of 12 weeks following the last dose of study drug is 
required. 
17. Presence of any other concurrent medical or social condition 
deemed by the investigator to likely interfere with a subject’s 
ability to provide informed consent, comply with the study visits 
and assessments, or interfere with the interpretation of study 
results 
18. Prior exposure to oral sunitinib malate in the past 6 weeks 
Test Product, Dose, 
and Mode of 
Administration: 
GB-102 is a depot formulation of sunitinib malate (sunitinib) 
intended for IVT injection. Sunitinib is a small molecule receptor 
tyrosine kinase that inhibits multiple pathways associated with 
pathologic angiogenesis including VEGF receptors (VEGFR) -1, -2, 
and -3 known to be associated with macular edema. The formulation 
consists of microparticles made from poly(lactic-co-glycolic) acid 
(PLGA) and methoxy-polyethylene glycol (mPEG)-PLGA. The 
mPEG component provides a hydrophilic, biocompatible property. 
During production, the microparticles are surface-treated to facilitate 
their aggregation upon IVT injection to form a depot in the vitreous. 
After IVT injection, the microparticles degrade into lactic acid, 
glycolic acid, and mPEG. 
GB-102 is lyophilized and reconstituted with hyaluronic acid prior to 
intravitreal administration to produce an administered IVT dose of 
1 mg or 2 mg sunitinib in a 50 µL injection using a 27-gauge needle. 
Subjects will receive their assigned dose (1 mg or 2 mg GB-102) on 
Day 1 as a single IVT injection.  


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Reference Therapy, 
Dose, and Mode of 
Administration: 
No reference therapy is provided in this study (ie, there is no active 
control arm) 
Study Endpoints: 
Primary Safety Endpoint 
• Occurrence of ocular and non-ocular adverse events and serious 
adverse events at all study visits 
Secondary Pharmacodynamic Endpoints 
• BCVA (ETDRS protocol) at all study visits 
• CST (SD-OCT) at all study visits 
• Observed subjects rescue-free at each study visit 
Statistical Methods: 
Analysis Population 
• Safety analysis set (SS): Includes all subjects who receive a dose 
of study treatment. Subjects who receive rescue treatment during 
the study will be included in the SS. Subjects will be analyzed 
according to actual treatment received. 
• Full analysis set (FAS): Includes all subjects who receive a dose 
of study treatment, and complete the baseline and at least one 
post-baseline visit. All data collected from subjects who receive 
rescue treatment during the study will be included in the FAS. 
Subjects will be analyzed according to their assigned treatment 
regardless of actual treatment received. 
• Per protocol analysis set (PP): Consists of a subset of the FAS 
and includes subjects with no major protocol violations that 
would affect the assessment of the pharmacodynamics and rescue 
data. Data collected after the receipt of rescue therapy during the 
study will not be included in PP analyses. 
Safety Endpoint Analyses 
All reported adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent 
adverse events (TEAEs) will be summarized by system organ class 
(SOC) and preferred term (PT). Frequencies and percentages will be 
provided by treatment group for subjects with TEAEs, treatment 
related TEAEs, serious TEAEs, serious treatment related TEAEs, 
TEAEs leading to premature study discontinuation and TEAEs by 
maximum severity. Separate analyses will be performed for ocular 
AEs in the study eye, ocular AEs in the non-study eye, and nonocular 
AEs. 


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The SS will be the primary population used for analysis of the 
primary safety endpoint. 
Pharmacodynamic Endpoint Analyses  
Observed values at each visit and change from baseline values at each 
follow up visit for BCVA, CST will be summarized using descriptive 
statistics (eg, means, median, range). The FAS and PP will be used to 
analyze the pharmacodynamic endpoints. 
Sample Size Considerations 
The sample size of this study was not selected to support specific 
statistical hypothesis testing. A sample size of approximately 20 
evaluable subjects in the SS analysis set allows for detection of 
adverse events rates that exceed 15% overall and exceed 30% for 
each dose with approximately 95% confidence. 
Missing Data and Sensitivity Analyses 
A minimal amount of missing data is expected since most subjects 
will undergo the proposed study assessments as part of their standard 
of care. There will be no imputation for missing data. 
Sensitivity analyses will be conducted using the per protocol 
population.  
  
 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ................................................................................................................................ 1 
STUDY ACKNOWLEDGEMENT ............................................................................................................................... 3 
INVESTIGATOR STATEMENT ................................................................................................................................. 3 
PROTOCOL SYNOPSIS .............................................................................................................................................. 4 
GLOSSARY OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................. 16 
1 
INTRODUCTION .............................................................................................................................................. 19 
1.1 
Diabetic Macular Edema (DME) ........................................................................................................... 19 
1.2 
Macular Edema Following Retinal Vein Occlusion (RVO) ................................................................... 19 
1.3 
Unmet Need in DME and RVO: Less Frequent Injections .................................................................... 19 
1.4 
Investigational Product ........................................................................................................................... 20 
1.5 
General Information ............................................................................................................................... 21 
1.5.1 
Nonclinical Studies .............................................................................................................. 21 
1.6 
Clinical Studies ...................................................................................................................................... 28 
1.7 
Study Rationale for Protocol GBV-102-003 .......................................................................................... 28 
1.8 
Compliance ............................................................................................................................................ 28 
2 
OBJECTIVES ..................................................................................................................................................... 29 
2.1 
Primary Objective .................................................................................................................................. 29 
2.2 
Secondary Objectives ............................................................................................................................. 29 
3 
INVESTIGATIONAL PLAN ............................................................................................................................. 30 
3.1 
Overall Study Design Summary ............................................................................................................. 30 
3.2 
Study Design Rationale .......................................................................................................................... 30 
3.3 
Appropriateness of Measurements ......................................................................................................... 31 
4 
SUBJECT POPULATION .................................................................................................................................. 34 
4.1 
Number of Subjects and Subject Selection ............................................................................................ 34 
4.2 
Study Eye Determination ....................................................................................................................... 34 
4.3 
Inclusion Criteria .................................................................................................................................... 34 
4.4 
Exclusion Criteria................................................................................................................................... 35 
5 
INVESTIGATIONAL PRODUCTS ................................................................................................................... 38 
5.1 
Study Drug and Administration ............................................................................................................. 38 
5.1.1 
Investigational Product (GB-102) ........................................................................................ 38 
5.1.2 
Study Drug Administration .................................................................................................. 38 
5.2 
Treatment Assignment ........................................................................................................................... 39 
5.2.1 
Subject Identification Numbers ............................................................................................ 39 
5.2.2 
Enrollment and Method of Assigning Subjects to Treatment Groups .................................. 39 
5.3 
Study Drug Packaging, Labeling, and Storage ....................................................................................... 39 
5.4 
Study Drug Compliance ......................................................................................................................... 39 
5.5 
Study Drug Accountability..................................................................................................................... 40 
5.6 
Prior and Concomitant Therapy ............................................................................................................. 40 
5.6.1 
Rescue Treatment ................................................................................................................. 40 
5.6.2 
Other Permitted Medications ................................................................................................ 41 
5.6.3 
Prohibited Medications......................................................................................................... 41 
5.7 
Other Study Supplies .............................................................................................................................. 41 
6 
STUDY PROCEDURES .................................................................................................................................... 42 
6.1 
Subject Entry Procedures ....................................................................................................................... 42 


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6.2 
Study Visit Procedures ........................................................................................................................... 42 
6.2.1 
Screening (Day −30 through Day −3) .................................................................................. 42 
6.2.2 
Baseline (Day 1) ................................................................................................................... 43 
6.2.3 
Week 2 and Months 1, 2, 3, 4, and 5 .................................................................................... 44 
6.2.4 
Month 6 (Day 180 ± 7) / Early Termination ........................................................................ 45 
6.3 
Screen Failures ....................................................................................................................................... 46 
6.4 
Unscheduled Study Visits ...................................................................................................................... 46 
6.5 
Subject Discontinuation ......................................................................................................................... 46 
6.6 
Subject Replacement .............................................................................................................................. 47 
6.7 
Study Termination Criteria..................................................................................................................... 47 
7 
STUDY ASSESSMENTS ................................................................................................................................... 48 
7.1 
Demographic Data ................................................................................................................................. 48 
7.2 
Medical and Medication History/ Concomitant Medications ................................................................. 48 
7.3 
Physical Examination ............................................................................................................................. 48 
7.4 
Pregnancy Testing .................................................................................................................................. 48 
7.5 
Blood Chemistry .................................................................................................................................... 49 
7.6 
Vital Signs .............................................................................................................................................. 49 
7.7 
Best Corrected Visual Acuity ................................................................................................................. 49 
7.8 
Slit-lamp Biomicroscopy........................................................................................................................ 49 
7.9 
Intraocular Pressure ................................................................................................................................ 50 
7.10 
Dilated Ophthalmoscopy ........................................................................................................................ 50 
7.11 
Spectral Domain – Optical Coherence Tomography .............................................................................. 51 
7.12 
Intravitreal Depot Color Fundus Photography ....................................................................................... 51 
7.13 
Postinjection Assessments...................................................................................................................... 51 
8 
ADVERSE EVENTS .......................................................................................................................................... 52 
8.1 
Definition of an Adverse Event .............................................................................................................. 52 
8.1.1 
Severity ................................................................................................................................ 53 
8.1.2 
Expectedness ........................................................................................................................ 53 
8.2 
Serious Adverse Event ........................................................................................................................... 54 
8.3 
Study Drug Causality ............................................................................................................................. 54 
8.4 
Adverse Event Reporting Procedures..................................................................................................... 55 
8.5 
Reporting Serious Adverse Events to Regulatory Agencies .................................................................. 56 
8.6 
Pregnancy ............................................................................................................................................... 56 
8.7 
Overdose ................................................................................................................................................ 56 
8.8 
Follow-up of Adverse Events ................................................................................................................. 56 
9 
STATISTICAL CONSIDERATIONS ................................................................................................................ 57 
9.1 
General Methods of Analysis ................................................................................................................. 57 
9.2 
Study Endpoints ..................................................................................................................................... 57 
9.2.1 
Primary Endpoint ................................................................................................................. 57 
9.2.2 
Secondary Pharmacodynamic Endpoints ............................................................................. 57 
9.3 
Analysis Populations .............................................................................................................................. 57 
9.4 
Sample Size Considerations ................................................................................................................... 58 
9.5 
Analyses ................................................................................................................................................. 58 
9.5.1 
Safety Analyses .................................................................................................................... 58 
9.5.2 
Pharmacodynamic Analyses ................................................................................................. 58 
9.6 
Changes in the Conduct of the Study ..................................................................................................... 58 
10 
DATA QUALITY ASSURANCE ...................................................................................................................... 59 
11 
ELECTRONIC CASE REPORT FORMS AND SOURCE DOCUMENTS ...................................................... 60 
12 
STUDY MONITORING AND AUDITING ....................................................................................................... 62 


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13 
RETENTION OF RECORDS ............................................................................................................................. 63 
14 
USE OF INFORMATION AND PUBLICATION ............................................................................................. 64 
15 
ETHICS .............................................................................................................................................................. 65 
15.1 
Institutional Review Board..................................................................................................................... 65 
15.2 
Ethical Conduct of the Study ................................................................................................................. 65 
15.3 
Subject Information and Consent ........................................................................................................... 66 
16 
INVESTIGATOR RESPONSIBILITIES ........................................................................................................... 67 
17 
REFERENCES ................................................................................................................................................... 68 
18 
APPENDICES .................................................................................................................................................... 70 
18.1 
Study Schema Protocol GBV-102-003 .................................................................................................. 70 
18.2 
Nonocular and Systemic Adverse Event Severity Assessment .............................................................. 71 
18.3 
Ocular Adverse Event Severity Assessment .......................................................................................... 72 
18.4 
Ocular Grading Scales ............................................................................................................................ 73 
18.4.1 
Grading Scale for Ocular Inflammation ............................................................................... 73 
18.4.2 
Grading Scale of Retinal or Vitreous Hemorrhage............................................................... 73 
18.4.3 
Grading of Vitreous Haze ..................................................................................................... 74 
18.5 
Age-Related Eye Disease Study Lens Scale .......................................................................................... 75 
18.5.1 
Nuclear Sclerosis .................................................................................................................. 75 
18.5.2 
Cortical Opacities ................................................................................................................. 75 
18.5.3 
Posterior Subcapsular Opacities ........................................................................................... 75 
18.6 
Protocol Amendment Summary ............................................................................................................. 77 
 
LIST OF IN-TEXT TABLES 
Table 3-1. 
Study Plan and Schedule of Assessments ............................................................................... 32 
 
LIST OF IN-TEXT FIGURES 
Figure 1-1. 
Sunitinib Mechanism of Action .............................................................................................. 21 
Figure 1-2. 
Intravitreal Injection of GB-102 in rho/VEGF Mice Reduces Leukocytes and 
Improves Retinal Perfusion .................................................................................................... 22 
Figure 1-3. 
Oral Dosing of Sunitinib Reduces Laser-Induced Choroidal Neovascularization in a 
Murine Model ......................................................................................................................... 23 
Figure 1-4. 
Sustained Reduction in Laser-Induced CNV Following Single Injection of IVT GB-
102 Compared to IVT Aflibercept .......................................................................................... 24 
Figure 1-5. 
Single Injection of Intravitreal GB-102 Reduces Photoreceptor Death in Rho/VEGF 
Mice with Type 3 CNV .......................................................................................................... 25 
Figure 1-6. 
Ocular Tissue Drug Levels of Sunitinib Following a Single Intravitreal Injection of 
1.0 mg GB-102 in Pigmented New Zealand Rabbits .............................................................. 26 
 
 
 


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GLOSSARY OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADL 
activities of daily living 
AE 
adverse event 
AMD 
age-related macular degeneration 
BCVA 
BRVO 
best corrected visual acuity 
branch retinal vein occlusion 
CDM 
clinical data manager 
CFP 
color fundus photography 
CFR 
code of federal regulations 
CI 
confidence interval 
CNV 
choroidal neovascularization 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
CRVO 
clinical research organization 
central retinal vein occlusion 
CST 
central subfield thickness 
DLT 
DME 
DR 
ET 
dose limiting toxicity 
diabetic macular edema 
diabetic retinopathy 
early termination 
ETDRS 
early treatment diabetic retinopathy study 
EU 
endotoxin units 
FA 
fluorescein angiography 
FAS 
full analysis set 
FDA 
food and drug administration 
FITC 
fluorescein isothiocynate 
FOV 
field of view 
GCP 
good clinical practice 
GLP 
good laboratory practice 
HD 
high dose 
HIPAA 
health insurance portability and accountability act 
HSC 
I0 
human stem cell 
inferior pole 
IAG 
image acquisition guidelines 
IB 
investigator’s brochure 
ICH 
international council for harmonisation (of technical requirements for pharmaceuticals for 
human use) 
IgG 
immunoglobulin 
IOP 
intraocular pressure 
IRB 
institutional review board 


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IRT 
interactive response technology 
IVT 
intravitreal 
LASIK 
laser-assisted in situ keratomileusis 
LD 
low dose 
LLQ 
lower limit of quantitation 
LOCF 
last observation carried forward 
MCMC 
monte carlo markov chain 
MedDRA 
MP 
medical dictionary for regulatory activities 
microparticles 
mPEG 
methoxy-polyethylene glycol 
NCI-CTCAE 
national cancer institute – common terminology criteria for adverse events 
Nd:YAG 
neodymium:yttrium-aluminum-garnet 
NDA 
NOAEL 
ON 
ONL 
new drug application 
no observed adverse effect level 
optic nerve 
outer nuclear layer 
OU 
PBS 
both eyes 
phosphate buffered solution 
PDGF 
platelet-derived growth factor 
PK 
pharmacokinetic 
PLGA 
poly(lactic-co-glycolic) acid 
PP 
per protocol 
PT 
preferred term 
RET 
re-arranged during transcription tyrosine kinase receptor 
RGC 
retinal ganglion cell 
RPE 
RVO 
S0 
retinal pigment epithelium 
retinal vein occlusion 
superior pole 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD-OCT 
spectral domain – optical coherence tomography 
SOC 
system organ class 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
TKI 
tyrosine kinase inhibitor 
Tmax 
μg 
μl 
peak exposure 
microgram 
microliter 
US 
united states 
VEGF 
vascular endothelial growth factor 


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VEGFR 
vascular endothelial growth factor receptor 
 
 
 


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1 INTRODUCTION 
1.1 
Diabetic Macular Edema (DME) 
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and is a 
leading cause of vision loss and blindness in working aged adults in the United States and the 
industrialized world. Diabetic macular edema (DME) is swelling of the central retina that causes 
vision loss and is an advanced complication of DR. The prevalence of DME increases from < 5% 
in subjects with recent diagnoses to approximately 30% in those with diabetes for two decades or 
more. Because the population of people with diabetes is nearly 300 million worldwide and 
growing rapidly, vision loss from DR is a significant public health issue (Nguyen 2010). 
Currently approved treatments for DME/DR include intravitreal (IVT) administration of anti-
vascular endothelial growth factor (anti-VEGF) agents, such as aflibercept (EYLEA®) and 
ranibizumab (LUCENTIS®), or off-label use of bevacizumab (AVASTIN®). Monthly or every 
other month administration of these agents have demonstrated stabilization or improvements in 
visual acuity and corresponding reductions in VEGF-mediated retinal edema as observed on 
optical coherence tomography. 
1.2 
Macular Edema Following Retinal Vein Occlusion (RVO) 
Retinal vein occlusions (RVO) is a blockage of veins that drain the retina and are a common type 
of retinal vascular disease, second only to diabetic retinopathy. The retinal vascular bed is highly 
organized with little or no overlap in vascular distribution. RVO occurs most commonly due to 
atherosclerosis of the high-pressure retinal arteries that can compress and occlude the 
low-pressure draining veins. When retinal vessels are obstructed, there are few collaterals to 
compensate, and the retina becomes swollen and ischemic leading to the expression of VEGF 
which, in turn, leads to further vascular permeability and/or hemorrhage, and subsequent vision 
loss. RVO includes branch vein occlusions (BRVO) and central retinal vein occlusion (CRVO). 
The incidence of RVO is estimated at 180,000 eyes per year in the United States of which 
BRVOs account for nearly 80% (Campochiaro 2010).  
Currently approved treatments for RVO (BRVO and CRVO) include IVT administration of anti-
vascular endothelial growth factor (anti-VEGF) agents of aflibercept and ranibizumab, or off-
label use of bevacizumab. Monthly or every other month administration of these agents have 
demonstrated stabilization or improvements in visual acuity and corresponding reductions in 
VEGF-mediated retinal edema as observed on optical coherence tomography. 
1.3 
Unmet Need in DME and RVO: Less Frequent Injections 
Despite the effectiveness of IVT anti-VEGF agents to reduce the edema associated with 
DME/RVO, treatment requires frequent IVT injections to manage these often-chronic conditions 
– approximately every 4 to 8 weeks. An international survey of retinal specialists reported that
the most significant unmet need in managing retinal disease are long-acting sustained drug
delivery to reduce the treatment burden for both patients and physicians (ASRS 2016).


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To address the unmet medical need in patients with DME and RVO, Graybug Vision has 
developed a proprietary drug product (GB-102) intended to reduce the frequency of IVT 
injections (once every 6 to 12 months) and provide a mechanism of action involving blockade of 
multiple VEGF receptor targets associated with angiogenesis, vascular permeability, and cellular 
proliferation, which are key biologic processes associated with the progression of macular edema 
seen in DME and RVO. 
1.4 
Investigational Product 
GB-102 is a depot formulation of sunitinib malate intended for IVT injection. The formulation 
consists of microparticles made from poly(lactic-co-glycolic) acid (PLGA) and 
methoxy-polyethylene glycol (mPEG)-PLGA. The mPEG component provides a hydrophilic, 
biocompatible property. During production, the microparticles are surface treated to facilitate 
their aggregation upon IVT injection to form an implant-like depot in the vitreous. After IVT 
injection, the microparticles degrade into lactic acid, glycolic acid, and mPEG. GB-102 has been 
engineered to deliver therapeutic doses of sunitinib for at least 6 months with a single 50-μL IVT 
injection based upon clinical data, theoretically enabling dosing twice yearly as described in 
Section 1.5. 
SUTENT® (sunitinib malate) was approved by the Food and Drug Administration (FDA) and the 
European Medicines Agency in 2006 in oral capsule form for the treatment of gastrointestinal 
stromal tumor and renal cell carcinoma, and in 2011 for the treatment of pancreatic 
neuroendocrine tumor and represents a class of small molecules referred to as receptor tyrosine 
kinase inhibitors (TKIs). 
Sunitinib malate is a small molecule (532.6 g/mol) and is a multiple receptor TKI that prevents 
receptor phosphorylation and “turns off” the downstream effects of selected receptors, 
particularly all the vascular endothelial growth factor receptors (VEGFR-1, -2, and -3) (Figure 
1-1) which are known to influence macular edema. GB-102 offers the potential for more 
complete blockade of VEGF-mediated angiogenesis compared to blockade of VEGF-A ligand 
alone (eg, aflibercept, bevacizumab, or ranibizumab). A full description of sunitinib is provided 
in the Investigator’s Brochure. 


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Figure 1-1. 
Sunitinib Mechanism of Action 
 
1.5 
General Information 
1.5.1 Nonclinical Studies 
Sunitinib malate has been evaluated in nonclinical safety studies in compliance with 
International Council for Harmonisation (ICH) guidelines to support its approval for cancer 
indications (SUTENT®). Nonclinical IND-enabling studies describing SUTENT’s primary and 
secondary pharmacodynamics, safety pharmacology, pharmacokinetics (PK), 
toxicology/toxicokinetics (single and repeat dose), genotoxicity, reproductive toxicity, 
phototoxicity, and local tolerance (dermal and ocular) have been published in the literature and 
can be referenced in the Investigator’s Brochure for GB-102 (IB). 
A summary of the ocular pharmacology, tissue PK, and toxicology for GB-102 and sunitinib 
follows. 
1.5.1.1 Primary Pharmacology - Ocular 
Sunitinib has demonstrated evidence of inhibiting angiogenesis, vascular permeability, 
proliferation, and fibrosis – key findings associated with DME, RVO, and choroidal neovascular 
lesions in neovascular age-related macular degeneration (nAMD).  
Sunitinib has also demonstrated evidence in neuroprotection. 
Single Intravitreal Administration of GB-102 Reduces VEGF-induced Leukostasis and Retinal 
Nonperfusion 
VEGF plays a critical role in the pathogenesis of diabetic retinopathy as well as nAMD. 
Increased levels of VEGF in the retina cause leukocytic plugging and closure of retinal vessel 
exacerbating retinal hypoxia, the main driver of progression of DR. Adult rho/VEGF mice were 
given an intravitreous injection of 10 µg sunitinib (GB-102) or 40 µg of aflibercept in one eye 
and an equivalent mass of empty microparticles (MPs) or phosphate buffered saline (PBS) in the 
Aflibercept 
Bevacizumab 
Ranibizumab 


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fellow eye. After one week, mice were perfused with PBS through the left ventricle to remove all 
non-adherent erythrocytes and leukocytes, and then perfused with FITC-concanavalin A to stain 
remaining adherent leukocytes. Compared with eyes injected with empty MPs, those injected 
with sunitinib MPs had a significant reduction in the mean number of adherent intravascular 
leukocytes (Figure 1-2A). Similarly, aflibercept-injected eyes had a significant reduction in the 
mean number of adherent intravascular leukocytes compared with PBS-injected eyes. 
Rho/VEGF mice also had fluorescein angiography at baseline and then were given an 
intravitreous injection of 10 μg of sunitinib (GB-102) in one eye and 10 μg of empty MP in the 
other eye. Some areas of retinal nonperfusion at baseline showed improved perfusion 1 week 
after injection of GB-102, but this was not seen in empty MP-injected eyes (Figure 1-2B) 
(Data on file, 2019) 
Figure 1-2. 
Intravitreal Injection of GB-102 in rho/VEGF Mice Reduces 
Leukocytes and Improves Retinal Perfusion 
 
*p< 0.001 by Mann Whitney for difference from corresponding fellow eye control. 
Oral Sunitinib Malate Inhibits Choroidal Neovascularization (CNV) in a Murine Laser Injury 
Model 
The initial evidence to demonstrate the ability of sunitinib malate to inhibit choroidal 
neovascular permeability was in a laser-induced CNV mouse model (Takahashi 2006). Three 
groups of mice (N = 5 per group) were orally administered 40, 80, 150 mg/kg sunitinib malate or 
vehicle for 5 days following laser endophotocoagulation of the retina and Bruch’s membrane. 
Permeability leakage of the CNV lesions was assessed by fluorescein angiography (FA) in vivo. 
Volume of the CNV lesions was quantified histologically in ocular cross-sections. The authors 
reported a dose-response in both the FA scores and histologic CNV lesion volume compared 
with vehicle control (Figure 1-3). 
(A) 
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(B) 


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Figure 1-3. 
Oral Dosing of Sunitinib Reduces Laser-Induced Choroidal 
Neovascularization in a Murine Model 
 
 
CNV = choroidal neovascularization; FA = fluorescein angiogram 
(A) FA 
(B) FA scores  
(C) CNV histology scores 
Source: Takahashi, 2006  
Single Intravitreal Administration of GB-102 Demonstrates Sustained Inhibition of CNV in a 
Murine Laser Injury Model for Up to 6 Months 
The murine model of laser-induced rupture of Bruch’s membrane results in CNV that is similar 
to type 2 CNV in patients with nAMD, because the new vessels originate from the choroid and 
penetrate through Bruch’s membrane and the retinal pigmented epithelium (RPE) into the 
subretinal space (Data on file, 2019). Studies in this model helped to implicate VEGF as a 
critical stimulus for nAMD and predicted the clinical benefits seen with aflibercept, a 
recombinant VEGF-neutralizing protein commonly used to treat patients subjects with nAMD. In 
order to assess the efficacy of GB-102 microparticles (MPs) over time, C57BL/6 mice were 
given an IVT injection of microparticles (MPs) containing 10 µg sunitinib in one eye and empty 
MPs in the fellow eye and then had laser-induced rupture of Bruch’s membrane at 3 locations in 
each eye at time points ranging from 1 to 24 weeks after injection. Compared with empty MP 
fellow eye controls, the mean area of CNV at Bruch’s membrane rupture sites was significantly 
less in eyes injected with MPs containing 10 µg sunitinib at each time point through week 24 
(Figure 1-4). There was significant suppression of CNV 0.5 months after injection of 40 µg of 
aflibercept, but not 2 months or 3.5 months after injection. 
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GB-102 (Sunitinib Malate) 
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Figure 1-4. 
Sustained Reduction in Laser-Induced CNV Following Single 
Injection of IVT GB-102 Compared to IVT Aflibercept 
 
 
Sunitinib Exhibits In Vitro and In Vivo Neuroprotective Effects in Photoreceptors and Retinal 
Ganglion Cells 
Sunitinib malate was identified as one of the most potent small molecules in promoting retinal 
ganglion cell (RGC) survival and neurite outgrowth following high through-put screening of 
various small molecule libraries (Zack 2011). The neuroprotective effects of sunitinib appear to 
reduce stress-induced apoptosis of RGCs in models of ischemia and optic nerve crush injury 
(Sharma 2011). Sunitinib also promotes photoreceptor survival and function as demonstrated in a 
murine light damage model of retinal degeneration (Kim 2015). 
Intravitreal GB-102 has been shown to reduce photoreceptor death in preclinical murine models 
of Type 3 CNV (Figure 1-5) (Data on file, 2019) Rho/VEGF mice were given an intravitreous 
injection of 10 μg of sunitinib microparticles (GB-102) in one eye and 10 μg of empty MP in the 
other eye or 40 μg of aflibercept in one eye and PBS in the fellow eye. At P42, mice (n=7 for 
each group) were euthanized and serial frozen ocular sections were cut from the superior pole of 
the eye (S0) to the inferior pole (I0) and sections 25% (S1 and I1), 50% (S2 and I2), and 75% 
(S3 and I3) of the distance between each pole and the optic nerve (ON) were stained with 
hematoxylin and outer nuclear layer (ONL) thickness was measured by image analysis by a 
masked investigator. The ONL of sections from the S2 location of GB-102-injected eyes 
appeared thicker than those from empty MP-injected eyes, but those from aflibercept-injected 
eyes appeared similar to those from PBS-injected eyes (Figure 1-5A). The mean (±SEM) ONL 
thickness was significantly greater at 3 of 6 locations in GB-102-injected eyes compared with 
Mouse Laser CNV Model 
Aflibercept vs. GB-102 
0.03 
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(Tsujinaka 2018) 
• p<0.05 (GB-102 or aflibercept vs. fellow eye control) 


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empty MP-injected eyes, but there was no difference between aflibercept- and PBS-injected eyes 
(Figure 1-5B). At P49, mice (n=5 for each group) were euthanized and immunoblots of retinal 
homogenates from GB-102-injected eyes showed prominent bands for rhodopsin kinase 
(GRK-1) (Figure 1-5C). Densitometry showed that the mean (±SEM) GRK-1/Actin ratio was 
significantly greater in retinas from GB-102-injected eyes compared with empty MP-injected 
fellow eyes, but not aflibercept-injected eyes versus PBS-injected fellow eyes (Figure 1-5D).  
Figure 1-5. 
Single Injection of Intravitreal GB-102 Reduces Photoreceptor Death 
in Rho/VEGF Mice with Type 3 CNV 
 
**p< 0.01 by Mann Whitney for difference from fellow eye empty MP control. 
 
1.5.1.2 Pharmacokinetics of Intravitreal Administration of GB-102 – Preclinical Studies 
Single Intravitreal Injection of GB-102 Sustains Inhibitory Levels of Drug in the Retinal Pigment 
Epithelium-Choroid up to 6 Months in Pigmented Rabbits up to 6 Months 
Ocular tissue PK was conducted in male pigmented New Zealand rabbits receiving a single IVT 
administration of sunitinib malate GB-102 (1.0 mg/eye). Tissue levels of drug were determined 
in the posterior segment (retina, RPE-choroid, vitreous humor) and anterior segment (cornea, 
iris-ciliary body, and lens) as determined by liquid chromatography/tandem mass spectrometry at 
various time points (Peterson 2016). 
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Following injection, sunitinib drug levels are highest in tissues containing melanin pigment 
(Figure 1-6). Tissue drug levels, in descending order, are as follows: RPE-choroid > iris-ciliary 
body > retina/lens > cornea > vitreous. There were no toxicological concerns related to 
pigment-binding discovered during preclinical testing. Drug concentrations of sunitinib are 
present in RPE-choroid and retina at 2- to 3-log orders higher than the kinetic inhibition constant 
to suppress VEGFR through 6 months. The depot is fully resorbed by 12- to 14-weeks on 
ophthalmic examination. The sustained drug levels in the posterior segment tissue following 
resorption of the depot is attributed to the secondary reservoir effect of the RPE-choroid 
(melanin binding). 
Sunitinib was cleared from posterior segment ocular tissues with an average half-life of 
approximately 19 days with a range of 2-3.5 weeks. Peak exposure (Tmax) was typically within 
3 to 4 months for retina and RPE-choroid, whereas vitreous Tmax occurred at 1 month. Given a 
Tmax at 3 to 4 months and a half-life of 0.64 months, sunitinib would be cleared from the 
posterior segment ocular tissues within 6 to 8 months. 
Figure 1-6. 
Ocular Tissue Drug Levels of Sunitinib Following a Single 
Intravitreal Injection of 1.0 mg GB-102 in Pigmented New Zealand 
Rabbits 
 
No Systemic Levels of Sunitinib Are Detected Following a Single Intravitreal Injection of 2 mg 
Dose/Eye of GB-102 in Pigmented Rabbits 
A Good Laboratory Practice (GLP) plasma toxicokinetics study was conducted in Dutch belted 
rabbits receiving a single IVT administration of a 2.0 mg/eye dose of GB-102 (50 µL) 
(CRL Report 5700643). Plasma samples were assayed for sunitinib (lower limit of quantitation 
[LLQ] > 0.3 ng/mL) predose and on Days 1, 2, 7, 16, 37, and 99 postdose. No measurable levels 
of sunitinib were detected systemically at any time point.  
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levels in GLP studies 
2 
3 
4 
5 
Months 
Sunitinib has high 
affinity for melanin 
binding 
6 
7 


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1.5.1.3 Toxicology 
Sunitinib malate was originally developed as an orally administered agent for the treatment of 
advanced malignancies at a daily dose of 37 to 50 mg (SUTENT® capsules) The steady state 
plasma levels of sunitinib at the oral recommended daily dose is approximately 60 to 100 ng/mL. 
Based on allometric scaling from nonclinical ocular PK studies (rabbits, rats) to humans, it is 
estimated that a single orally administered approved dose of 50 mg sunitinib in man results in 
uveal tissue concentration of drug that are 1-log to 2-log orders higher than a single IVT 
injection of GB-102 containing 1 mg sunitinib (Peterson 2016, Speed 2012). 
Three GLP ocular toxicology studies were conducted with GB-102: a single dose study in 
rabbits, a repeat dose study in rabbits, and a repeat dose study in minipigs. 
The ocular toxicity following a single IVT injection (50 µL) of GB-102 at doses of 0, 0.25, 0.5, 
1.0, and 2.0 mg/eye in pigmented rabbits was evaluated in a GLP study with up to 19 weeks 
observation. Assessments were conducted with in vivo ophthalmic examination, including ERGs, 
and postmortem histopathology of the enucleated eyes. The main findings included 1) time- and 
dose-dependent lens opacities, which were due to the high injection volume (50 µL), and 2) mild 
anterior and vitreous inflammation, which was due to endotoxin contamination of the test 
materials. 
In the repeat-dose rabbit study, animals received IVT injections of 0.125, 0.25 and 0.5 mg/eye 
GB-102 (in volumes up to 12 µL). Animals were injected on Day 1 and Day 141 over the course 
of 40 weeks. GB-102 was well tolerated compared to the GLP single dose ocular toxicology 
study in rabbits. The main findings in the repeat dose rabbit study included transient ocular 
inflammation at all dose levels regardless of dose volume, which was not test article related. 
Focal, peripheral and inferior lens opacities occurred in 3 out of 4 groups, which were test article 
related. 
In the repeat dose minipig study, animals received IVT injections of 0.25, 0.5, and 1 mg/eye 
GB-102 (in volumes up to 24 µL). Animals were injected on Day 1 and Day 141 over the course 
of 40 weeks. GB-102 was well tolerated based on all endpoint assessments including no findings 
on histology. There were no clinical observations of adverse events and no test article-related 
effects on hematology, coagulation or clinical chemistry parameters, which is consistent with a 
lack of detectable systemic exposure. The clinical ocular examination observations were limited 
to a transient, yellow discoloration of the vitreous humor and lens in some animals and there 
were no test article-related microscopic findings. Therefore, the no-observed-adverse-effect-level 
(NOAEL) is above the highest dose (1 mg/eye) tested in this study. 
Overall, toxicology results indicate that IVT injections of GB-102 twice with a 5-month interval 
and up to a 10-month observation period in rabbits or minipigs at a corresponding injection 
volume in the clinic, was well tolerated in the eyes and supports IVT administration of up to 
2 mg GB-102 every 6 months in the clinic. 


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1.6 
Clinical Studies 
There have been no prior studies of GB-102 in subjects with DME or RVO. 
A single IVT injection Phase 1/2a clinical study with GB-102 in subjects with nAMD has been 
completed and results are provided in the Investigator’s Brochure.  
1.7 
Study Rationale for Protocol GBV-102-003  
The purpose of this study is to assess the safety and pharmacodynamics of a single injection of 
2 dose levels of GB-102 (1 mg, 2 mg) in subjects with a known diagnosis of macular edema 
secondary to DME or RVO who have been treated with at least three prior injections of any anti-
VEGF agent (aflibercept, bevacizumab, or ranibizumab) and shown evidence of a prior response 
to anti-VEGF treatment. 
1.8 
Compliance 
This study will be conducted in compliance with this protocol, and in accordance with ICH 
guidelines, Good Clinical Practice (GCP), the Declaration of Helsinki, and will comply with the 
obligations and requirements of the Sponsor as listed in Title 21 of the US Code of Federal 
Regulations (CFR). 
 
 


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2 OBJECTIVES 
2.1 
Primary Objective 
To evaluate the safety and tolerability of a single intravitreal injection of two different dose 
strengths of GB-102 (1 mg, 2 mg) in subjects with macular edema secondary to diabetic 
retinopathy or retinal vein occlusion who have received prior treatment with anti-vascular 
endothelial growth factor (VEGF) 
2.2 
Secondary Objectives 
To evaluate the pharmacodynamic response as measured by best corrected visual acuity (BCVA) 
and central subfield thickness (CST) and time to first rescue injection. 


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3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design Summary 
This is a Phase 2a, multicenter, open-label, single injection, parallel arm, non-controlled safety, 
tolerability and pharmacodynamics study.  
Eligible subjects will be consecutively enrolled to 1 of 2 concurrently initiated open-label 
GB-102 treatment arms (Appendix 18.1): 
Group 1: 1 mg (50 µL) (N=10) 
Group 2: 2 mg (50 µL) (N=10) 
GB-102 will be administered on Day 1 in both Cohorts (Table 3-1). Subjects will return to the 
study center on Days 14, 30, 60, 90, 120, 150, and 180 for safety and clinical assessments. 
Subjects will exit the study following all study assessments on Day 180. 
The safety parameters to be collected include adverse events (AEs) and serious adverse events 
(SAEs), physical examination, vital signs, BCVA using the Early Treatment of Diabetic 
Retinopathy Study (ETDRS) protocol, slit-lamp biomicroscopy findings, intraocular pressure 
(IOP) measurements, dilated ophthalmoscopy results, and date of administration of rescue 
treatment. 
Pharmacodynamic activity will be assessed by means of BCVA (using the ETDRS Protocol), 
retinal central subfield thickness (CST) using spectral-domain optical coherence tomography 
(SD-OCT), and color fundus photography (CFP) (including wide field fundus photography, if 
available). 
Safety Monitoring 
The medical monitor will evaluate the on-going safety data in this open-label study. 
Masking 
This is an open-label study and the injecting investigator/physician may be the assessing 
investigator. The SD-OCT and CFP technicians and other site personnel, the Sponsor, and CRO 
are unmasked to treatment assignment.  
Rescue Treatment 
Rescue treatment (any anti-VEGF agent; aflibercept, bevacizumab, or ranibizumab) will be 
permitted in the study eye in any of the study arms if the qualifying criteria are met for rescue 
treatment. 
3.2 
Study Design Rationale 
The proposed study is designed to assess the safety and pharmacodynamics of a single injection 
of 2 dose levels of GB-102 (1 mg, or 2 mg) administered in subjects with DME/macular edema 


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due to RVO who have demonstrated a prior response to at least 3 prior injections of any IVT 
anti-VEGF agent. 
The medical monitor will evaluate masked safety data on an on-going basis. 
The planned study assessments (eg, AEs, abbreviated physical examinations, clinical laboratory 
tests, vital sign measurements, BCVA assessments, IOP, slit-lamp biomicroscopy examinations, 
SD-OCT, CFP (including wide field of view imaging, if available), dilated ophthalmoscopy 
evaluations) are conventional parameters used to evaluate the safety and pharmacodynamic 
activity of pharmacologic agents in retinal disease. 
The sample size of this study was not selected to support specific statistical hypothesis testing. A 
sample size of approximately 20 evaluable subjects in the SS analysis set allows for detection of 
adverse events rates that exceed 15% overall and exceed 30% for each dose with approximately 
95% confidence. 
Rescue treatment (any anti-VEGF agent; aflibercept, bevacizumab, or ranibizumab) for the study 
eye is within the standard-of-care for subjects with DME/macular edema due to RVO for the 
maintenance of visual acuity and/or the prevention of vision loss. 
3.3 
Appropriateness of Measurements 
The primary aim of the data analyses in this study is to assess the safety, tolerability and 
pharmacodynamics of a single IVT injections of GB-102 in subjects with DME/macular edema 
due to RVO who have shown prior response to IVT anti-VEGF agents. 
The safety, tolerability and pharmacodynamic parameters to be evaluated in this study are 
consistent with landmark, randomized, multicenter, registrational drug studies of IVT agents 
used to treat DME and RVO (Nguyen 2010, Campochiaro 2010). 
 
 


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Table 3-1. 
Study Plan and Schedule of Assessments 
Activity/Assessment 
Sa 
B 
W 2 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
(ET) 
Visit Day ± 
Windowb 
−30 to 
−3 
1 
14±2 
30±4 
60±7 
90±7 
120±7 
150±7 
180±7 
Informed 
Consent/HIPAA 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
Demographics Data 
X 
 
 
 
 
 
 
 
 
Medical/Medication 
History 
X 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
 
 
X 
Pregnancy Testingc 
X 
X 
 
 
 
X 
 
 
X 
Clinical Laboratory 
Testsd 
X 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X e  
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsf 
X 
X 
 
 
 
 
 
 
X 
BCVA (ETDRS)g 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Slit-lamp 
Biomicroscopy 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
IOPh 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Dilated 
Ophthalmoscopy 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
SD-OCTi 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Intravitreal Depot 
Photographyj 
 
SE 
SE 
SE 
SE 
SE 
SE 
SE 
SE 
GB-102 Injectionk 
 
SE 
 
 
 
 
 
 
 
Postinjection 
Assessmentl 
 
SE 
 
 
 
 
 
 
 
Follow-Up Call e 
 
+1 day 
 
 
 
 
 
 
 
B = Baseline Visit; BCVA = best corrected visual acuity; ET = Early Termination; ETDRS = Early Treatment Diabetic 
Retinopathy Study; HIPAA = Health Insurance Portability and Accountability Act; IOP = intraocular pressure; M = month; OU = 
both eyes; S = Screening Visit; SD-OCT = spectral domain-optical coherence tomography; SE = study eye; V = visit; W = week  
a 
Screening Visit to occur 3 to 30 days before study baseline (Day 1) to ensure that laboratory results are obtained. Imaging 
eligibility based on SD-OCT will be investigator determined; there is no reading center confirmation. 
b 
The protocol-specified procedures for a given study visit may be split across 2 days within the visit-specific window (if 
applicable); however, for each visit, all BCVA, ophthalmic examinations, and ophthalmic imaging must be performed on the 
same day and cannot be split across 2 or more days. Evaluations should be performed by the same evaluator for the same 
subject throughout the study whenever possible. If it is not possible to use the same evaluator to follow the subject, then 
evaluations should overlap (examine the subjects together and discuss findings) for at least 1 visit. 
c 
Urine pregnancy test in women of childbearing potential only; additional pregnancy tests may be performed at any time/day 
during the study. 
d 
Chemistry (non-fasting blood): hemoglobin A1c.  
e 
All subjects will receive a telephone call for the day after the intravitreal injection to assess for any significant complaints or 
adverse events.  


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f 
Heart rate, blood pressure; additional collection of height (without shoes) will be measured at Screening and body weight 
will be measured at Screening and Month 6/exit.  
g 
Visual acuity assessment using ETDRS protocol at 4 m with manifest refraction will be performed at all visits; 1 m may be 
performed if needed. 
h 
Goldmann applanation tonometry or Tono-Pen acceptable; however, technique used at baseline must be used at all 
subsequent visits. Intraocular pressure will be checked before dilation and the IVT injection of study drug at the dosing visit 
(Baseline [Day 1]). 
i 
Measurements for CST determined by the investigator (no central reading center confirmation) 
j 
Wide field color fundus photography (eg, Optos Ultra-widefield or Zeiss Clarus 500 or other ultra-widefield equipment) of 
the intravitreal GB-102 depot will be obtained following the dilated ophthalmic examination at all visits – if available at the 
study site. The initial images of the depot should be obtained at baseline (Day 1) after the IVT injection of GB-102 and 
conducted through (and include) the final study visit and any unscheduled visits. The photographs may be used to document 
the general appearance and rate of bioabsorbability of the depot. If no wide-FOV camera available, standard 30-degree field 
of view (FOV) imaging documenting the visual axis will be sufficient. For detailed instructions regarding collection of the 
intravitreal depot CFP imaging, refer to the separately provided guideline.  
k 
Following intravitreal injection of GB-102, the subject should remain seated for approximately 15 minutes post-injection 
with minimal to no movement of the head (e.g., bending over, shaking head, laying down) and avoid significant eye 
movement.  
l 
Postinjection assessment to consist of checking for count fingers or hand motion vision within 15 minutes after injection; if 
needed, subject can be examined (eg, additional IOP assessment or ophthalmoscopy, per discretion of the investigator) prior 
to going home. 
 
 


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4 SUBJECT POPULATION 
4.1 
Number of Subjects and Subject Selection 
Subjects eligible for screening must have the diagnosis of macular edema secondary to DME or 
RVO in the study eye that was diagnosed in the 6 weeks to 24 months prior to screening and 
treated with at least 3 prior IVT injections of an anti-VEGF agent (aflibercept, bevacizumab, or 
ranibizumab) and demonstrated a response to prior treatment within 16 weeks of initial diagnosis 
and treatment. Subjects must have the most recent anti-VEGF agent administered within 42 days 
of screening. Eligibility will be determined by the investigating physician based upon his/her 
interpretation of SD-OCT evaluation of the disease. There is no third-party reading center 
confirmation of any imaging parameters in this study. 
The complete inclusion and exclusion criteria are presented, respectively, in Sections 4.3 and 4.4. 
The study is planned to be conducted at approximately 4 to 6 study centers in the US.   
4.2 
Study Eye Determination 
The study eye is defined as the eye that meets all the inclusion criteria and none of the exclusion 
criteria. If both eyes meet the inclusion and exclusion criteria, the eye with the worst visual 
acuity at Baseline will be selected. If both eyes have the same baseline visual acuity, the right 
eye will be selected. 
4.3 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study. 
1. Verbal and written informed consent obtained from the subject 
2. Males or females ≥ 21 years of age 
3. Willing and able to give informed consent, comply with all study procedures, and be likely to 
complete the study 
4. Subjects with known diagnosis of diabetic macular edema or macular edema due to retinal 
vein occlusion (central or branch) in the 6 weeks to 24 months prior to screening who have 
received at least 3 prior IVT injections of any anti-VEGF agent in the study eye and 
demonstrated a pharmacodynamic response in the study eye to IVT anti-VEGF treatment 
(aflibercept, bevacizumab, or ranibizumab) within 16 weeks of the first anti-VEGF treatment 
as determined by the investigator and documented by at least 1 of the following: 
4a. Reduction of intraretinal/subretinal fluid by ≥ 10% from the initial diagnosis as 
determined using SD-OCT 
4b. Reduction of excess CST by ≥ 10% from the initial diagnosis as determined using 
SD-OCT (assuming nominal thickness is 300 microns) 


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5. Demonstrate a maintained anti-VEGF response (as determined by the investigator) compared 
with the initial diagnosis (prior to any anti-VEGF treatment) as assessed by SD-OCT 
following the most recent anti-VEGF injection (defined as reduction in central subfield 
thickness, intraretinal/subretinal fluid, or maintenance of a dry retina) 
6. Subjects must have the most recent anti-VEGF agent administered within 42 days (6 weeks) 
of screening in the study eye. 
7. Screening and baseline BCVA letter score (by ETDRS protocol) of 31 to 88 (20/240 to 20/20 
Snellen equivalent) 
8. If the screening and baseline BCVA letter score (by ETDRS protocol) in the nonstudy eye is 
worse than the study eye, the BCVA score in the nonstudy eye must be at least 53 letters 
(20/100 Snellen equivalent) or better 
9. Clear ocular media and adequate pupil dilation in both eyes to permit good quality 
photographic imaging 
10. Women of childbearing potential (ie, not postmenopausal for at least 12 months or not 
surgically sterile [bilateral tubal ligation, hysterectomy, or bilateral oophorectomy]) must 
have a negative urine pregnancy test at screening and baseline, and must use adequate birth 
control throughout the study if she has a nonsurgically sterile male sexual partner; adequate 
methods of birth control include hormonal contraceptives, intrauterine comtraceptive 
devices, condom with spermicide, diaphragm with spermicide, and cervical cap with 
spermicide. 
4.4 
Exclusion Criteria 
1. History, within 6 months prior to screening, of any of the following: myocardial infarction, 
any cardiac event requiring hospitalization, treatment for acute congestive heart failure, 
transient ischemic attack, or stroke 
2. Uncontrolled hypertension with systolic blood pressure ≥ 160 mmHg and/or diastolic blood 
pressure ≥ 95 mmHg at the Screening Visit 
3. Uncontrolled diabetes mellitus, defined as hemoglobin A1c >12.0% at the Screening Visit 
4. Chronic renal disease requiring chronic hemodialysis or renal transplantation 
5. Participation in any investigational study within 30 days prior to screening, or planned use of 
an investigational product or device during the study; any exposure to a prior investigational 
drug product must be fully washed out (at least 5 half-lives) 
6. Previous participation in an investigational study of GB-102 
7. Spherical equivalent of the refractive error in the study eye demonstrating more than −6 
diopters of myopia (prior to cataract or refractive surgery) at the Screening Visit 
8. Uncontrolled IOP, defined as an IOP > 25 mmHg, despite antiglaucoma medications in the 
study eye at the time of screening or controlled glaucoma that requires management with > 2 
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9. Presence of any clinically significant epiretinal membrane or vitreomacular traction in the 
study eye 
10. History or evidence of any of the following in the study eye: 
a. Macular surgery or other surgical intervention for AMD 
b. Prior retinal detachment  
c. Vitrectomy 
d. Retinal laser treatment with the exception of prior laser photocoagulation for 
treatment of diabetic retinopathy 
e. Glaucoma filtering surgery (eg, trabeculectomy) or glaucoma drainage device (eg, 
Ahmed valve or Baerveldt valve) including minimally invasive glaucoma shunts (eg, 
minimally invasive glaucoma surgery) prior to the Screening Visit. Selective laser 
trabeculoplasty (SLT) >3 months prior to Screening Visit is allowed. 
f. Cataract surgery within the 3 months prior to the Screening Visit 
g. Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy within the 30 
days prior to the Screening Visit. Note: prior Nd:YAG laser posterior capsulotomy in 
association with a posterior intraocular lens implantation is allowed. 
h. Corneal refractive procedures (laser-assisted in situ keratomileusis [LASIK] or 
photorefractive keratectomy) within the 6 months prior to the Screening Visit or 
planned during the study 
i. Corneal transplantation surgery 
j. History of advanced glaucoma with visual field loss encroaching on central fixation 
k. Intravitreal steroid injection (eg, triamcinolone suspension) within the past 3 months, 
bioabsorbable steroid implant (eg, Ozurdex®) within the past 12 months, and/or 
presence of any steroid implant in the study eye (eg, Iluvien® or Ozurdex®) at the 
time of the Screening Visit 
l. Active retinal or iris neovascularization in the study eye 
11. Anterior chamber intraocular lens, aphakia, or violation of the posterior capsule in the study 
eye 
12. History or clinical evidence of other concurrent conditions deemed by the investigator to 
likely impact the subject’s clinical safety or to interfere with the interpretation of the study 
results including, but not limited to: 
a. Proliferative diabetic retinopathy in the study eye 
b. Choroidal neovascular lesion secondary to wet AMD in the study eye 
c. Any retinal or choroidal vasculopathy, other than due to diabetes or retinal vein 
occlusion in the study eye 


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d. Inflammatory conditions of the anterior or posterior segment (eg, chronic 
keratoconjunctivitis, uveitis, retinal vasculitis, neuritis, iritis, scleritis, or blepharitis) 
in the study eye 
e. Subfoveal involvement by any of the following: fibrosis, serous pigmented epithelial 
detachment, retinal pigmented epithelial tear, or geographic atrophy in the study eye 
f. Subfoveal hemorrhage that is ≥ 1 disc areas in size in the study eye 
g. Any media opacity that prevents proper visualization of the fundus and/or adversely 
alters visual acuity, in the opinion of the investigator in the study eye 
h. Prior radiation therapy in the region of the eyes 
i. History of demyelinating disease (eg, multiple sclerosis, neuromyelitis optica), optic 
neuropathy, and/or optic neuritis. 
13. Any bacterial, viral, fungal, or parasitic infection in either eye within the 30 days prior to the 
Screening Visit 
14. Known allergy to constituents of the study drug formulation, ocular antimicrobicide 
solutions, or clinically relevant hypersensitivity to fluorescein 
15. Women who are pregnant or lactating 
16. Men who are unwilling to practice 2 measures of adequate contraception (if having sexual 
intercourse with a woman of child-bearing potential) or who desire to donate sperm during 
the time from first dose of study drug until exiting the study. If a male exits the study early 
and wants to donate sperm, a minimum wait period of 12 weeks following the last dose of 
study drug is required. 
17. Presence of any other concurrent medical or social condition deemed by the investigator to 
likely interfere with a subject’s ability to provide informed consent, comply with the study 
visits and assessments, or interfere with the interpretation of study results 
18. Prior exposure to oral sunitinib malate in the past 6 weeks 
 
 


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5 INVESTIGATIONAL PRODUCTS 
5.1 
Study Drug and Administration 
5.1.1 Investigational Product (GB-102) 
GB-102 is a depot formulation of sunitinib malate intended for IVT injection. 
The formulation consists of microparticles made from PLGA and mPEG-PLGA. The mPEG 
component provides a hydrophilic, biocompatible property. During production, the 
microparticles are surface treated to facilitate their aggregation upon IVT injection to form an 
implant-like depot in the vitreous. After IVT injection, the microparticles degrade into lactic 
acid, glycolic acid, and mPEG. GB-102 microparticles are approximately 25 μm in diameter, 
which allows IVT delivery in a 50-μL injection using a 27 G thin-walled needle in the inferior 
pars plana (6 o’clock region). The mPEG surface treatment of the microparticles facilitates 
aggregation into a single bioabsorbable, implant-like depot following IVT injection. This 
delivery method allows the microparticles to assume residence in the inferior portion of the 
posterior segment, away from the visual axis. The depot slowly biodegrades over 4 to 6 months. 
Because the released sunitinib avidly binds to ocular melanin, the RPE serves as a secondary 
drug reservoir to maintain therapeutic levels of sunitinib even though the depot is fully resorbed. 
5.1.2 Study Drug Administration 
Each study center will have a trained, technician who will prepare the study drug syringes for 
IVT injection. The Sponsor will provide the necessary training and all supplies required for the 
reconstitution of study drug, including vials containing lyophilized GB-102 dry powder, 
pre-filled syringe with hyaluronic acid, needles, and syringes.  
Rescue medication allowed is any anti-VEGF (aflibercept, bevacizumab, or ranibizumab) and 
should be used in accordance with the sites standard practice in administering these agents for 
the treatment of DME or RVO. The Sponsor will not supply rescue medication. 
Adequate anesthesia and eye preparation materials (eg, povidone iodine solution) will be given 
prior to the IVT injection per the injecting investigator’s standard-of-care. IOP measurement will 
be obtained before the injection at Baseline (Day 1). The investigational product, regardless of 
concentration, should be prepared and administered as follows in the study: 
GB-102: Reconstituted drug will be administered via IVT injection using a 1-cc tuberculin Luer 
Lock syringe with a 27 G thin-walled needle. 


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5.2 
Treatment Assignment  
5.2.1 Subject Identification Numbers 
After signing the informed consent form, each subject will be assigned a unique screening 
number by the site staff. All screening numbers will be assigned in strict numerical sequence at a 
study center and no numbers will be skipped or omitted. Subjects who meet all entry criteria (ie, 
all the inclusion and none of the exclusion criteria) will be confirmed for enrollment. The 
screening numbers will be used to identify all enrolled subjects throughout the study. 
5.2.2 Enrollment and Method of Assigning Subjects to Treatment Groups 
This study is open-label with consecutive enrollment. When a potential subject is identified, the 
investigator must contact Graybug Vision’s designated project manager or assigned team 
member managing enrollment to confirm availability for enrollment/dosing group in the study. 
5.3 
Study Drug Packaging, Labeling, and Storage 
The study drug will be packaged, labeled, and supplied by Graybug Vision’s designated supplier. 
GB-102 will be supplied in sterile, single use, glass vials. One single dose vial, one pre-filled 
syringe with hyaluronic acid and required materials for reconstitution and syringe preparation for 
IVT injection will be included in the kits. The designated medication kits should be stored 
at 2-8°C (36-46°F) and prevented from freezing. A second kit will be provided to include 
ancillary supplies such as needles, syringes, a drape cloth, alcohol spray, etc. to use during the 
reconstitution process. The ancillary supplies kits may be stored at room temperature. Additional 
details are provided in the pharmacy manual. 
Rescue medication allowed is any anti-VEGF (aflibercept, bevacizumab, or ranibizumab).  The 
Sponsor will not supply rescue medication nor ancillary supplies used to administer these agents.  
These anti-VEGF agents should be stored in accordance to the standard practices of the site. 
All medication and ancillary supplies kits will be labeled with numbers. The label will also 
specify the storage conditions and state that the study medication is limited to investigational 
use. 
The study drug must be stored in a secure area and administered only to subjects who entered the 
clinical study, at no cost to the subject, in accordance with the conditions specified on the study 
medication kit label and the pharmacy manual.  
Only assigned individuals authorized by the investigator may have access to the study drug. 
5.4 
Study Drug Compliance 
All notifications for assignment of medication kits are to be maintained with the study source 
documents. Additionally, the date, time of study treatment, and the name of the injecting 
investigator must be documented for each subject in the source record. 


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5.5 
Study Drug Accountability 
The investigator must keep accurate accounting of the number of medication kits received from 
Graybug Vision’s designated vendor, the number dispensed to the subjects, and the number 
returned to the vendor during and at the completion of the study. A detailed dispensing record 
must also be completed. Only an appropriately qualified person must dispense the study 
medication to subjects in the study. The medication is to be used in accordance with the protocol 
by subjects who are under the direct supervision of an investigator. 
All clinical study medications/treatments and/or supplies should be stored, inventoried, 
reconciled and destroyed (on site) per site destruction standard operating procedure according to 
applicable state and federal regulations or returned to Graybug Vision’s designee for destruction. 
5.6 
Prior and Concomitant Therapy 
All past and current use of therapies (eg, aflibercept, bevacizumab, ranibizumab, pegaptanib, 
and/or verteporfin) to treat CNV prior to screening will be recorded. The subject’s source record 
should include start and stop dates or dates of administration, doses, routes, frequencies, and 
indications for all therapies. 
All other medications (prescription, over-the-counter, and herbal) and nutritional supplements 
taken by the subjects from 30 days prior to screening through the completion of the study will be 
recorded. Changes in the dosing and/or frequency of concomitant medications must be captured 
with new start and stop dates indicating the previous and current doses/frequencies. 
5.6.1 Rescue Treatment 
Rescue treatment (any anti-VEGF agent; aflibercept, bevacizumab, or ranibizumab) for all 
subjects enrolled is allowed at any visit following the Day 30 study assessments in subjects who 
meet any of the following criteria regarding decrease in BCVA and/or increase in CST: 
• Decrease in BCVA: 
o ≥ 10 ETDRS letter decrease compared with best on-study (i.e., post-treatment) BCVA 
ETDRS letter score 
• Increase in CST (any of the following criteria): 
o ≥ 75 µm compared with the average of the last 2 visit on-study (i.e., post-treatment) 
CST measurements (µm), and/or, 
o ≥ 100 µm compared with the lowest on-study (i.e., post-treatment) CST measurement 
(µm) 
Before rescue treatment is administered, the assessing investigator should confirm, if possible, 
with the medical monitor. 
Use of rescue treatment will be recorded on the case report forms (CRFs) and source documents. 


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5.6.2 Other Permitted Medications 
Medications that are permitted during the study include the following: 
• Direct thrombin inhibitor class of drugs such as warfarin, dabigatran, or rivaroxaban 
• Aspirin (acetylsalicylic acid) 
• Any intravitreally administered anti-VEGF therapy in the nonstudy eye for the treatment of 
wet AMD, DME, and/or RVO (aflibercept, bevacizumab, or ranibizumab) 
• Any exposure to a prior investigational drug product that is fully washed out (at least 
5 half-lives) and/or or does not meet any of the exclusion criteria  
5.6.3 Prohibited Medications 
Medications that are not permitted during the study include the following: 
• Use of more than 2 topical hypotensive medications for the treatment of glaucoma in the 
study eye 
• Intravitreal steroid injection (eg, triamcinolone suspension)  
• Any steroid implant in the study eye (eg, Iluvien® or Ozurdex®) 
• Oral sunitinib malate 
• Any intravitreally administered anti-VEGF therapy in the study eye for the treatment of wet 
AMD, DME, and/or RVO (aflibercept, bevacizumab, or ranibizumab) unless the subject 
qualifies for rescue treatment per the rescue treatment criteria 
5.7 
Other Study Supplies 
Graybug Vision or its designee will make provisions (directly or indirectly) to supply the study 
centers with supplies for study drug preparation (syringes, needles, vortex mixers, vial adapters, 
drape towels, alcohol spray, alcohol prep pads and vial stand), and blood sampling and shipment 
kits for sunitinib exposure assessment. 
Study centers will be allowed to use their own ETDRS supplies, once verified through the 
BCVA certification process. Study centers will use their own medications/supplies 
(anti-infective ophthalmic solution, local anesthetic eye drop, dilating eye drop, povidone iodine, 
cotton tip swabs, sterile fields, and cellulose sponges) to prep the eye for ocular assessments 
and/or study drug administrations. CLIA-approved urine pregnancy test kits and lab kits for 
collection of Hemoglobin A1c assessment should be supplied by the site’s local laboratory. 
 


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6 STUDY PROCEDURES  
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Table 3-1. The procedures to be conducted are summarized by visit within 
Section 6.2. The investigator must document any deviation from the prespecified protocol 
procedures and notify the Sponsor or contract research organization if/when deviations occur. 
The protocol-specified procedures for a given study visit may be split across 2 days within the 
visit-specific window (if applicable); however, for each visit, all BCVA, ophthalmic 
examinations, and ophthalmic imaging must be performed on the same day and cannot be split 
across 2 or more days.  
6.1 
Subject Entry Procedures 
Prospective subjects who meet the entry criteria (inclusion/exclusion criteria) defined in 
Sections 4.3 and 4.4 will be considered for inclusion in this study. 
The study will be discussed with each subject and a subject wishing to participate must give 
informed consent prior to the study center performing any study related procedures or changes in 
concomitant treatment. All subjects must also give authorization and other written 
documentation in accordance with relevant country and local privacy requirements (where 
applicable) prior to the study center performing any study related procedures or changes in 
concomitant treatment. 
Each subject who provides informed consent will be assigned a screening number that will be 
used on all source documentation throughout the study. A subject is considered to enrolled into 
the study at the time of administration of the first dose on Day 1. 
Subject eligibility based on lesion characteristics must be determined by the investigating prior 
to subject treatment; there is no third-party confirmation of images obtained at screening or 
during the conduct of the study. In addition, screening laboratory test (i.e., hemoglobin A1c) 
must be performed, and the results must be evaluated and determined to be acceptable to the 
investigator prior to subject enrollment into the study.  
A urine pregnancy test administered to women of childbearing potential at the Screening and 
Baseline visit must be negative for the subject to receive study drug at the Baseline visit. 
6.2 
Study Visit Procedures 
6.2.1 Screening (Day −30 through Day −3) 
The Screening Visit should occur 3 to 30 days before study Baseline (Day 1) to ensure that 
laboratory results are obtained and the investigator has confirmed eligibility. The following 
procedures are to be performed at this visit: 


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• Obtain informed consent and authorization 
• Collect demographic information and medical and ophthalmic history 
• Collect information about concomitant medications and procedures 
• Conduct a physical examination 
• Draw blood samples for hemoglobin A1c  
• Conduct a urine pregnancy test on women of childbearing potential (note that additional 
pregnancy tests may be performed at any time/day during the study) 
• Obtain vital signs (blood pressure, heart rate, height [without shoes] and weight) 
• Assess BCVA (using the ETDRS protocol with manifest refraction) in both eyes 
• Perform the slit-lamp biomicroscopy of both eyes  
• Measure IOP (via Goldmann applanation tonometry or Tono-Pen) in both eyes (the same 
measurement method should be used throughout the study) 
• Perform dilated ophthalmoscopy of both eyes 
• Obtain SD-OCT imaging of both eyes 
• Assess the subject regarding the inclusion/exclusion criteria 
• Query for AEs 
• If the subject meets the entry criteria, schedule the subject to return for the Baseline visit, 
otherwise, exit the subject from the study as a screen failure 
6.2.2 Baseline (Day 1) 
The following procedures are to be performed: 
• Review concomitant medications and procedures 
• Query for AEs 
• Conduct a urine pregnancy test on women of childbearing potential (note that additional 
pregnancy tests may be performed at any time/day during the study) 
• Obtain vital signs (blood pressure and heart rate) 


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• Assess BCVA (using the ETDRS protocol with manifest refraction) in both eyes 
• Perform the slit-lamp biomicroscopy of both eyes 
• Measure IOP (via Goldmann applanation tonometry or Tono-Pen) in both eyes (must be 
performed prior to the IVT injection of study drug) 
• Perform dilated ophthalmoscopy of both eyes 
• Obtain SD-OCT imaging of both eyes 
After completion of these procedures, if the subject still meets entry criteria, and the investigator 
has confirmed subject eligibility based on ocular inclusion/exclusion criteria, the results from the 
screening blood chemistry (i.e., hemoglobin A1c) and urine pregnancy tests, as well as BCVA 
assessments, and obtained sponsor confirmation to enroll, the subject can be prepared for 
treatment.  
• When medically appropriate, dispense pre-injection and postinjection anti-infectives 
according to standard clinic procedure at the study center 
• Perform the IVT injection of the allocated dose of study drug into the study eye 
• Perform the postinjection assessment of the study eye checking for count fingers or hand 
motion vision within 15 minutes after injection while ensuring that the subject has minimal to 
no movement of the head and avoids significant eye movement during the 15 minutes after 
injection. If needed, the subject can be examined (eg, additional IOP or ophthalmoscopy) per 
the discretion of the injecting investigator prior to going home. 
• Perform CFP in the study eye to document the position of the depot and the status of the 
visual axis 
• Schedule the subject to return for the Week 2 visit 
• All subjects will receive a telephone call from qualified study center personnel as a safety 
follow-up the day after the IVT injection procedure 
6.2.3 Week 2 and Months 1, 2, 3, 4, and 5 
The visits windows are as follows: Week 2 (Day 14 ± 2) and Months 1, 2, 3, 4, and 5 (Day 30 ± 
4, Day 60 ± 7, Day 90 ± 7, Day 120 ± 7, Day 150 ± 7). 
The following procedures are to be performed at each of the visits unless otherwise specified: 
• Review concomitant medications and procedures 
• Query for AEs 


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• Conduct a urine pregnancy test on women of childbearing potential at Month 3 only (note 
that additional pregnancy tests may be performed at any time/day during the study)  
• Assess BCVA (using the ETDRS protocol with manifest refraction) in both eyes 
• Perform the slit-lamp biomicroscopy of both eyes  
• Measure IOP (via Goldmann applanation tonometry or Tono-Pen) in both eyes 
• Perform dilated ophthalmoscopy of both eyes 
• Obtain SD-OCT imaging of both eyes 
• Perform CFP in the study eye to document the position of the depot and the status of the 
visual axis 
• Schedule the subject to return for the next study visit 
6.2.4 Month 6 (Day 180 ± 7) / Early Termination 
The following procedures are to be performed: 
• Review concomitant medications and procedures 
• Query for AEs 
• Conduct a physical examination 
• Conduct a urine pregnancy test on women of childbearing potential 
• Obtain vital signs (blood pressure, heart rate and weight) 
• Assess BCVA (using the ETDRS protocol with manifest refraction) in both eyes 
• Perform the slit-lamp biomicroscopy of both eyes  
• Measure IOP (via Goldmann applanation tonometry or Tono-Pen) in both eyes 
• Perform dilated ophthalmoscopy of both eyes 
• Obtain SD-OCT imaging of both eyes 
• Perform CFP in the study eye to document the position of the depot and the status of the 
visual axis 
• Exit the subject from the study 


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If follow-up is needed after the early termination visit, it should occur as a poststudy, 
unscheduled visit at the discretion of the investigator.  
Subjects with an ongoing SAE at this visit should be followed until the event resolves or 
stabilizes as described in Section 8.8. 
6.3 
Screen Failures 
Subjects who miss a scheduled visit prior to the baseline (Day 1) visit or do not qualify for 
enrollment in the study will be considered screen failures. 
6.4 
Unscheduled Study Visits 
Unscheduled visits may be necessary due to AEs or other reasons. The investigator may examine 
a subject as often as is medically necessary while the subject is enrolled in the study. Any 
follow-up that is performed to monitor subject safety should be recorded as an unscheduled visit. 
The following procedures may also be conducted at an unscheduled visit as well as any 
procedures deemed necessary by the investigator to assess safety: 
• Monitor and query AEs 
• Record changes in concomitant medications 
6.5 
Subject Discontinuation 
Subjects should not be withdrawn due to an AE (unless related to subject death), pregnancy, lack 
of efficacy, protocol deviations, or other reason except for the subject withdrawing consent, or 
being lost to follow-up. If a subject is enrolled in the study and discontinues from treatment, 
he/she should be encouraged to remain in the study through study completion to allow continued 
safety assessment and monitoring, unless the subject withdraws consent. 
In the event of subject withdrawal prior to the end of the study, study assessments for the early 
termination visit should be conducted whenever possible. If a subject withdraws from the study, 
he or she may not re-enter the study. At the time of withdrawal, the investigator should advise 
the subject of other available treatment options. When a subject withdraws from the study, the 
reason(s) for withdrawal will be recorded on the CRF. 
In the event of a subject death during the study, the date of death (as listed on the death 
certificate) will be used as the date of study withdrawal. 
If a subject fails to return for a scheduled visit, it is the responsibility of the investigator or 
designee to document all efforts made to contact the subject and to determine the reason the 
subject did not return. If a subject cannot be contacted with 3 documented telephone call 
attempts, followed by a certified letter, and does not have a known reason for discontinuation 
(eg, withdrawal of consent), the reason for discontinuation will be recorded as “lost to 


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follow-up.” The date that the certified letter was mailed will be considered the date of study 
withdrawal. 
6.6 
Subject Replacement 
One rescreening of a nontreated screen failure subject may be allowed. 
If an enrolled (i.e., treated) subject withdraws prior to Month 3, for any reason, the subject may 
be replaced following discussion with the medical monitor.  
6.7 
Study Termination Criteria 
The Sponsor may terminate this study at any time for any reason. The Sponsor also may 
discontinue participation by an individual investigator or study center for poor enrollment or 
noncompliance. At the time of study termination, any active subjects should complete the early 
termination visit. All ongoing AEs should be followed as appropriate and all ongoing SAEs 
should be followed until the resolution or stabilization. 
 
 


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7 STUDY ASSESSMENTS  
This section describes the study assessment procedures. Refer to Appendix 18.1 and Table 3-1 
for information regarding the timing of each assessment. 
7.1 
Demographic Data 
Demographic data will be recorded including date of birth, sex, eye color, race, and ethnicity. 
7.2 
Medical and Medication History/ Concomitant Medications 
Medical history will be recorded and should elicit all major illnesses, diagnoses, and surgeries 
for the subject within the past two years prior to screening. All ocular history will also be 
recorded and should be specific to eye involvement, as appropriate. 
All past and current use of therapies (eg, aflibercept, bevacizumab, and ranibizumab) to treat 
DME/RVO prior to screening will be recorded. The subject’s source record and CRF should 
include start and stop dates, dose, route, frequency, and indication. 
Other prior and concomitant medications taken from 30 days prior to screening through the last 
study visit will be recorded and will include any prescription and over-the-counter medications, 
as well as herbal or nutritional supplements; the subject’s source record should include start and 
stop dates, dose, route, frequency, and indication. 
Prior SD-OCT assessments and visual acuity values must also be recorded for the past 24 months 
if available. 
7.3 
Physical Examination 
The physical examination will consist of, at a minimum, a routine evaluation of the organ 
systems including general appearance, neck, head, ears, nose, throat, cardiovascular, respiratory, 
abdomen, and skin/extremities. At the final study visit, the physical examination will include a 
query of the subject to determine if changes in his/her physical condition have occurred since the 
screening examination. 
7.4 
Pregnancy Testing 
Urine pregnancy testing will be conducted on women of childbearing potential as appropriate. 
Women of childbearing potential (ie, not postmenopausal for at least 12 months or not surgically 
sterile [bilateral tubal ligation, hysterectomy, or bilateral oophorectomy]) must have a negative 
urine pregnancy test at Screening and Baseline, and must use adequate birth control throughout 
the study if she has a nonsurgically sterile male sexual partner. Adequate methods of birth 
control include hormonal contraceptives, intrauterine contraceptive device, condom with 
spermicide, diaphragm with spermicide, and cervical cap with spermicide. 


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7.5 
Blood Chemistry 
Blood samples for Hemoglobin A1c will be collected using the site’s local laboratory. Samples 
and results should be obtained prior to administration of study drug. The minimum tests to be 
performed include the following: 
• Nonfasting chemistry (blood): Hemoglobin A1c 
7.6 
Vital Signs  
Vitals signs will consist of blood pressure and heart rate measurements. Systolic and diastolic 
pressure and heart rate (bpm) will be measured after subjects have been at rest (seated) for at 
least 5 minutes. The same arm and method of obtaining blood pressure and heart rate should be 
used throughout the study. Measurements may be repeated once at the discretion of the 
investigator. Along with the vital signs, height (without shoes) will be measured at Screening and 
body weight will be measured at Screening and Month 6. 
7.7 
Best Corrected Visual Acuity 
Manifest refraction will be conducted prior to BCVA. The BCVA assessment will be conducted 
for each eye, prior to dilating pupils, using the standard ETDRS protocol with back-illuminated 
eye charts. A study-specific manifest refraction and BCVA testing protocol is described in a 
separately provided BCVA Manual. 
Visual acuity testing will be performed by a certified visual acuity examiner and should occur 
before any examination requiring contact with the eye. The same BCVA examiner should be 
utilized for each subject throughout the study when possible. 
7.8 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy will be performed for each eye by a qualified assessing investigator at 
each study visit. Slit-lamp biomicroscopy, including magnification, will be performed without 
dilation of the pupil and consistent with standard practice. The subject will be seated during the 
examination. This procedure should be conducted in the same manner for all subjects and will 
include an assessment of each of the following as normal or abnormal: 
• Eyelids 
• Conjunctiva 
• Cornea 
• Anterior chamber 
• Iris 


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• Pupil 
• Lens 
If any findings are abnormal, exact findings should be specified and noted as either clinically or 
not clinically significant. 
7.9 
Intraocular Pressure 
IOP will be measured according to routine clinical practice using Goldmann applanation 
tonometry or Tono-Pen in both eyes at all study visits. At the Baseline (Day 1) dosing visit, IOP 
must be performed prior to dilation and the IVT injection of study drug. A single measurement 
will be made to obtain a determination of the IOP at each study visit. Whether Goldmann 
applanation tonometry or Tono-Pen is used during the study, the Investigator’s standard 
technique will be used throughout the study. In addition, all reasonable efforts will be made to 
have the same examiner obtain all IOP measurements for a given subject using the same 
instrument for screening and the subject follow-up assessments for each subject. 
The Goldmann applanation tonometer or Tono-Pen instrument must be calibrated for accuracy 
before the first subject in the study at a given study center undergoes the first examination, and 
continue to be performed in accordance with the manufacturer’s specifications until the last 
subject at the study center has exited the study. For detailed instructions regarding instrument 
calibration, refer to the calibration instructions supplied with the instrument.  
7.10 Dilated Ophthalmoscopy 
Dilated fundus examination of both eyes will be performed in all subjects by designated qualified 
study center personnel (i.e., an ophthalmologist). The following will be observed for the 
presence of abnormalities: 
• Vitreous body 
• Macula 
• Peripheral retina 
• Choroid 
• Optic nerve 
If any findings are abnormal, exact description of the findings should be specified and noted as 
either clinically or not clinically significant. All abnormal findings that are clinically significant 
and were not present at baseline, will be described and reported as AEs. 


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7.11 Spectral Domain – Optical Coherence Tomography 
The SD-OCT imaging will be performed for both eyes to measure and assess cross-sectional 
images of the anatomic layers of the retina and to detect the presence of retinal fluid. Images will 
be obtained using a SD-OCT device by designated certified study center personnel. Preferably 
the same device will be used for screening and the subsequent follow-up assessments for each 
subject. For detailed instructions regarding collection of SD-OCT imaging, refer to the separately 
provided Image Acquisition Guidelines (IAG). 
7.12 Intravitreal Depot Color Fundus Photography 
CFP images will be taken on each subject’s study eye to help identify the IVT 
GB-102 depot and the status of the visual axis. The initial images of the depot in the study eye, 
as well as the status of the visual axis should be obtained at baseline (Day 1) after the IVT 
injection and conducted through study completion at each visit for all subjects. Where available, 
Zeiss Clarus 500, Optos California Ultra-widefield or other specified Fundus Imaging systems 
should be used to collect these images. 
The photographs may be used to document the general appearance and rate of bioabsorbability of 
the depot and to confirm that the depot is not interfering with the visual axis. For detailed 
instructions regarding collection of the IVT depot CFP imaging, refer to the separately provided 
guideline. 
7.13 Postinjection Assessments 
Following intravitreal injection of GB-102 at the Baseline (Day 1) visit, the subject should 
remain seated for approximately 15 minutes post-injection with minimal to no movement of the 
head (e.g., bending over, shaking head, laying down) and avoid significant eye movement. 
During this 15 minute-time period, the injecting investigator/physician will assess postinjection 
safety using count fingers or hand motion vision. The injecting investigator/physician can 
conduct additional safety assessments (eg, additional IOP measurement and/or ophthalmoscopy), 
if needed, prior to the subject leaving the clinic. All subjects will receive a telephone call from 
the study center the following day to ensure there are no significant complaints or AEs. 
 
 


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8 ADVERSE EVENTS 
Adverse events will be monitored continuously during the study from the time that the subject 
has provided written informed consent through the subject’s last day of study participation. The 
following information will be collected for all AEs and recorded on the subject’s source 
document and AE CRF: 
• Event description (diagnosis preferred, if unknown, record the signs/symptoms) 
• Onset and resolution dates 
• Severity (intensity) 
• Relationship to study drug or study procedure (causality) as determined by the assessing 
investigator 
• Seriousness 
• Expectedness 
• Action taken with study drug 
• Action taken with nondrug therapy 
• Outcome 
8.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug-related. 
An AE can therefore be: 
• Any unfavorable and unintended medical diagnosis, sign, or symptom 
• Any new undesirable medical occurrence or unfavorable or unintended change in a 
pre-existing condition that occurs during or after study treatment 
• Vital sign or ophthalmic assessment that is assessed as clinically significant and different 
from baseline (eg, requiring discontinuation of study treatment, specific treatment, or a 
change in subject management); if possible, changes in laboratory results or changes in vital 
signs that meet the definition of an AE should be reported as a medical diagnosis rather than 
as the abnormal value (eg, “hypertension” rather than “blood pressure increased”) 


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The following are special considerations when determining and reporting AEs: 
• Whenever possible, the investigator should group signs or symptoms that constitute a single 
diagnosis under a single AE term (eg, “cough, rhinitis, and sneezing” might be grouped 
together as “upper respiratory tract infection”). 
• Progression of neovascular AMD, including worsening of anticipated clinical signs or 
symptoms, which are collected as clinical efficacy variable and assessed as unequivocally 
associated with the disease progression and/or lack of efficacy, should NOT be reported as 
AEs unless disease progression is greater than anticipated in the natural course of the disease. 
• A pre-existing condition is not considered an AE unless the condition worsens (increases in 
frequency, severity, or specificity) during or following study drug administration. 
Fluctuations in a pre-existing condition should be assessed by the investigator, and those that 
fall within the limits of expected fluctuations for the disease state (and are not assessed as 
worsening of the disease) should not be considered AEs. Any change assessed as clinically 
significant worsening of the disease from baseline must be documented as an AE. 
• Elective surgery or routine diagnostic procedures are not considered AEs. However, an 
untoward medical event occurring during the prescheduled elective surgery or diagnostic 
procedure should be recorded as an AE. 
• Death itself is not considered an AE; it is instead the outcome of an AE. 
A treatment emergent adverse event (TEAE) is an AE with an onset anytime from when the 
subject has received study drug through 30 days after the study ends whether or not it is 
considered causally related to the study drug. 
Note: AEs must be collected once informed consent has been obtained, regardless of whether or 
not the subject has been administered study drug. 
8.1.1 Severity  
Refer to Appendix 18.2 and Appendix 18.3 for definitions and assessment scales for ocular and 
nonocular/systemic AEs. 
8.1.2 Expectedness 
The expectedness of an AE should be determined based upon existing safety information about 
the investigational product using these explanations: 
• 
Unexpected: an AE that is not listed in the IB or is not listed at the specificity or severity that 
has been observed. 
• 
Expected: an AE that is listed in the IB at the specificity and severity that has been observed. 


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• 
Not applicable: an AE unrelated to the investigational product. 
Adverse events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/ mechanical (or other) properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation are to be 
considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final classification is 
subject to the Medical Monitor’s and Sponsor’s determination. 
8.2 
Serious Adverse Event 
All AEs will be assessed as either serious or nonserious. An SAE is any event that involves or 
results in any of the following outcomes: 
• Death 
• Life-threatening occurrence (ie, if in the view of the investigator or Sponsor, the event’s 
occurrence placed the subject 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) 
• Requires in-patient hospitalization or prolongation of existing hospitalization (hospitalization 
for elective surgery for a pre-existing condition or for surgery planned before study entry is 
not considered an SAE) 
• A persistent or significant disability/incapacity (permanent or substantial disruption of the 
subject’s ability to perform normal life functions); this definition is not intended to include 
experiences of relatively minor or temporary medical significance 
• Congenital anomaly/birth defect (an AE that occurs in the child or fetus of a subject exposed 
to study drug prior to conception or during pregnancy) 
An important medical event or serious medical condition that does not meet any of the above 
criteria may be considered an SAE if, based upon appropriate medical judgment, it jeopardizes 
the subject or requires medical or surgical intervention to prevent one of the outcomes listed 
above. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias, or convulsions that do not result 
in in-patient hospitalization, or the development of drug dependency or drug abuse. 
8.3 
Study Drug Causality 
The assessing investigator will assess the relationship of the AE to the study drug or study 
procedure as either related or not related. The following should be taken into consideration when 
assessing AE causality: 


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• Positive temporal relationship to study drug, such as if the study drug was withdrawn and the 
AE resolved or the event recurred after re-introduction 
• If there is a reasonable possibility that the AE is associated with an underlying or 
concomitant illness 
• Possible association with previous or concomitant therapy 
• No temporal relationship to the study drug and/or a more likely alternative etiology exists 
• If the AE is directly related to study procedures 
8.4 
Adverse Event Reporting Procedures 
The occurrence of AEs should be sought by nonleading questioning of the subject at each 
scheduled or unscheduled study visit. At each visit, study personnel should ask the following 
question: “Have you had any problems since your last visit?” An AE may also be detected when 
volunteered by the subject during and between visits, or through physical examination or other 
assessments. All AEs (serious and nonserious) reported by the subject will be reviewed by a 
qualified physician participating in the study and must be recorded on the subject’s source 
documents and AE CRF. 
All SAEs, whether or not related to study drug, must be reported to the Sponsor or Sponsor’s 
designated Pharmacovigilance contact immediately and must be submitted on an SAE report 
form within 24 hours after the investigator becomes aware of the event. 
If an SAE occurs, the study center should immediately notify Graybug Vision email notification: 
GB102@oraclinical.com. The project manager will notify the medical monitor and/or the 
Sponsor immediately (within 24 hours).  
Alternatively, the investigator may contact the medical monitor directly: 
 
 
 
  
Note that any SAEs that occur after the subject has provided written informed consent, but 
before administration of study drug and are considered related to a protocol procedure must also 
be reported to the Sponsor or Sponsor’s designated project manager within 24 hours after the 
investigator’s awareness of the event. 
Investigators should not wait to receive additional information to fully document an SAE before 
reporting the event to the Sponsor or Sponsor’s designated project manager. If only limited 
information is initially available, follow-up reports are required. Additional relevant information 


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such as hospital records, laboratory test results, or autopsy reports should be provided as soon as 
these are available. 
8.5 
Reporting Serious Adverse Events to Regulatory Agencies 
An AE, whether serious or nonserious, is considered “unexpected” if the event is not reported in 
the clinical safety section of the reference document (eg, an IB or package insert) or if the event 
is of greater severity or frequency than is reported in the reference document. 
Expedited reporting of SAEs is required for serious events that are both unexpected based on the 
reference document and considered related to the study drug (ie, the relationship cannot be ruled 
out). The Sponsor will determine which SAEs qualify for expedited reporting. 
Reports of those SAEs that qualify for expedited reporting submitted to regulatory agencies in 
accordance with applicable local regulation (eg, 21 CFR 312.32). 
Expedited reports will also be distributed to investigators. Upon receiving such notices, the 
investigator must immediately submit a copy of this information to the governing institutional 
review board (IRB) in accordance with the board’s guidelines and any applicable local 
regulations. 
8.6 
Pregnancy 
Pregnancy alone is not an AE. However, any report of pregnancy in a female subject at any time 
during the study and that becomes known to the investigator, must be reported to the Sponsor 
even if the subject is withdrawn from the study. The pregnancy should be followed to term, 
reporting the outcome after delivery. 
8.7 
Overdose 
Overdose is defined as any dose higher than the protocol-prescribed dose of study drug. 
Occurrences of overdose leading to an AE will be reported on the AE CRF. Overdoses leading to 
an SAE will be handled in accordance with SAE reporting procedures. 
8.8 
Follow-up of Adverse Events 
Subjects with an ongoing SAE will be followed until the event is resolved, the significant 
changes return to baseline, the condition stabilizes, the event is no longer considered clinically 
significant by the investigator, the subject withdraws consent, or the subject is lost to follow-up. 
This may imply that follow-up will continue after the subject has left the study and that 
additional investigation may be requested by the Sponsor. If the severity or relationship to study 
drug worsens for an ongoing SAE, a follow-up report should be sent to the Sponsor within 
24 hours after the investigator becomes aware of the change in status. 
All nonserious AEs will be followed through the last study visit. If a nonserious AE is first 
identified at the last scheduled study visit, the event will be recorded on the AE CRF with the 
current status noted, but no further follow-up is required. 
 


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9 STATISTICAL CONSIDERATIONS 
9.1 
General Methods of Analysis 
No formal hypothesis testing will be conducted 
General descriptive statistics will be used to evaluate the data (eg, means, median, ranges, 
standard deviations). All summaries will be presented by treatment group and, where 
appropriate, by visit. 
9.2 
Study Endpoints 
9.2.1 Primary Endpoint 
• Occurrence of ocular and nonocular AEs and SAEs 
9.2.2 Secondary Pharmacodynamic Endpoints 
• BCVA at all study visits 
• CST at all study visits 
• Observed subjects who are rescue-free at each study visit 
9.3 
Analysis Populations 
Three analysis sets will be defined as follows: 
• Safety analysis set (SS): Includes all subjects who receive a dose of study treatment. 
Subjects who receive rescue treatment during the study will be included in the SS. Analyses 
will group subjects according to the treatment actually received. 
• Full analysis set (FAS): Includes all subjects who receive a dose of study treatment, and 
complete the baseline and at least one post-baseline visit. All data collected from subjects 
who receive rescue treatment during the study will be included in the FAS. Subjects will be 
analyzed according to their assigned treatment regardless of actual treatment received. The 
analyses conducted on the FAS will be considered primary for all efficacy analyses. 
• Per protocol analysis set (PP): Consists of a subset of the FAS and includes subjects with 
no major protocol violations that would affect the assessment of the pharmacodynamics and 
rescue data. Data collected after the receipt of rescue therapy during the study will not be 
included in PP analyses. The PP analyses will be considered secondary for all efficacy 
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9.4 
Sample Size Considerations 
The sample size of this study was not selected to support specific statistical hypothesis testing. A 
sample size of approximately 20 evaluable subjects in the SS analysis set allows for detection of 
adverse events rates that exceed 15% overall and exceed 30% for each dose with approximately 
95% confidence. 
9.5 
Analyses 
9.5.1 Safety Analyses 
All reported adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent adverse events (TEAEs) will be summarized by system organ 
class (SOC) and preferred term (PT). Frequencies and percentages will be provided by treatment 
group for subjects with TEAEs, treatment related TEAEs, serious TEAEs, serious treatment 
related TEAEs, TEAEs leading to premature study discontinuation, and TEAEs by maximum 
severity. Separate analyses will be performed for ocular AEs in the study eye, ocular AEs in the 
non-study eye, and nonocular AEs. 
The SS will be the primary population used for analysis of the primary safety endpoint. 
9.5.2 Pharmacodynamic Analyses 
Observed values at each visit and change from baseline values at each follow up visit for BCVA, 
CST will be summarized using descriptive statistics (eg, means, median, range). The FAS and PP 
will be used to analyze the pharmacodynamic endpoints. 
9.6 
Changes in the Conduct of the Study 
Only Graybug Vision may modify the protocol. Any change in study conduct considered 
necessary by the investigator will be made only after consultation with Graybug Vision, who will 
then issue a formal protocol amendment to implement the change. The only exception is when an 
investigator considers that a subject’s safety could be compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB must be sought, and the 
investigator should inform Graybug Vision and the full IRB within 2 working days after the 
emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB must review and 
approve all protocol amendments. Protocol amendments that have an impact on subject risk or 
the study objectives, or require revision of the informed consent document, must receive 
approval from the IRB prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to subjects, the informed consent document will be amended and approved by Graybug Vision 
and approved by the IRB; all active subjects must provide written informed consent using the 
revised consent form once available. 
 


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10 DATA QUALITY ASSURANCE 
Graybug Vision personnel (or designee) will visit the study center prior to initiation of the study 
to review with the study center personnel information about the study drug, protocol and other 
regulatory document requirements, any applicable enrollment procedures, source document 
requirements, CRF completion, monitoring requirements, and procedures for reporting AEs, 
including SAEs. 
At visits during and after the study, the Sponsor and/or designee will monitor the study center for 
compliance with regulatory documentation, with a focus on accurate and complete recording of 
data on CRFs from source documents, adherence to protocol, randomization (if applicable), SAE 
reporting, and drug accountability records. 
A Sponsor-designated clinical data management group will design and program a study database 
and corresponding CRFs, and will provide training for study centers and clinical research 
associates (CRA) on data entry and cleaning procedures. The data quality control and analysis 
will be performed by Graybug Vision (or designee), including study monitoring and clinical data 
management, based on a predefined data management plan and a SAP. 
 
 


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11 ELECTRONIC CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic data capture will be used. Therefore, subject data from source documents will be 
entered directly into the clinical database at the study centers using electronic CRFs. Designated 
study center personnel must complete the applicable CRFs as soon as possible after a subject 
visit, and the CRFs must be available for review at the next scheduled monitoring visit. Prior to 
locking the clinical database, the investigator must review and approve the completed CRFs to 
verify their accuracy. 
Electronic CRF completion guidelines that are approved by Graybug Vision, or designee, will 
designate how to appropriately enter data into CRFs from the source documents. Typically, 
blank fields are not acceptable. If a field is blank because the item was not done, the field will be 
marked “ND.” If the item is unknown, the field will be marked “UNK.” If the item is not 
applicable, the field will be marked “NA.” 
Discrepancies (ie, queries) will be generated for suspect data (eg, vital signs that are out of 
expected range, potential protocol compliance concerns, and date discrepancies) and missing 
data in the clinical database. Some discrepancies will be automatically generated during data 
entry into the CRFs as potential data quality issues arise. Other discrepancies will be 
automatically generated after batch validation is executed on the clinical database during which 
more advanced, cross-panel edit checks are executed. Finally, manual discrepancies may be 
generated by investigators, CRAs, the clinical data manager (CDM), or clinical data analysts as 
the study data is further analyzed during monitoring visits or data listing reviews. All 
discrepancies will be routed within the clinical database system to the appropriate clinical study 
staff, typically beginning with the study center coordinator and ending with either the CRA or 
the CDM for resolution. When these discrepancies are opened within the system on CRF pages 
that have already been verified by the CRA or approved by the investigator, the database system 
will automatically require the CRA to reverify and the investigator to reapprove the applicable 
pages. 
Graybug Vision policy is that CRF study data must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and subject records. In addition, 
all source data should be attributable (signed and dated). The investigator must therefore agree to 
allow direct access to all source data. Subjects must also allow access to their medical records 
(ie, records at the study center that have previous medical history/information), and subjects will 
be informed of this and will confirm their agreement when giving written informed consent. If an 
investigator or institution refuses to allow access to subject records because of confidentiality, 
arrangements must be made to allow an “interview” style of data verification. 
A CRA designated by Graybug Vision will compare the CRFs with the original source 
documents at the study center and evaluate the CRFs for completeness and accuracy. If 
necessary, the study center’s personnel will be contacted for corrections and/or clarifications. 
Data that are modified in the clinical database to resolve related discrepancies must be supported 
in the source documents. 


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After the clinical database is locked, compact disks with copies of all applicable subjects’ CRFs 
will be provided to each study center to be maintained on file by the investigator. 
 
 


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12 STUDY MONITORING AND AUDITING 
Qualified individuals designated by Graybug Vision will monitor all aspects of the study 
according to ICH and GCP and standard operating procedures for compliance with applicable 
government regulations. The investigator agrees to allow these monitors direct access to the 
clinical supplies, dispensing, and storage areas and to the clinical files, including original 
medical records, of the study subjects, and, if requested, agrees to assist the monitors. The 
investigator and staff are responsible for being present or available for consultation during 
routinely scheduled study center visits conducted by Graybug Vision, the contract research 
organization, or its designees. A review of the subjects’ medical records will be performed in a 
manner to ensure that subject confidentiality is adequately maintained. Further details of the 
study monitoring will be outlined in a monitoring plan. 
Members of Graybug Vision GCP Compliance Department or designees may conduct an audit of 
a study center at any time during or after completion of the study. The investigator will be 
informed if an audit is to take place and advised as to the scope of the audit. Representatives of 
the FDA or other regulatory agencies may also conduct an audit of the study. If informed of such 
an inspection, the investigator should notify Graybug Vision immediately. The investigator will 
ensure that the auditors have access to the clinical supplies, study center facilities, original source 
documentation, and all study files. All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that local, state, 
and federal laws apply. 


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13 RETENTION OF RECORDS 
The investigator must retain all study records required by Graybug Vision and by the applicable 
regulations in a secure and safe facility. The investigator must consult a Graybug Vision 
representative before disposal of any study records, and must notify Graybug Vision of any 
change in the location, disposition, or custody of the study files. The investigator/institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and the 
quality of the data produced, including paper copies of study records (eg, subject charts), as well 
as any original source documents that are electronic as required by applicable regulatory 
requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the US or an ICH region or (2) at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug. The investigator/institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation of 
the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution, or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a Graybug Vision agreement. Graybug Vision must be notified 
and will assist with retention should the investigator/institution be unable to continue 
maintenance of subject files for the full 15 years. It is the responsibility of Graybug Vision to 
inform the investigator/institution as to when these documents no longer need to be retained. 


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14 USE OF INFORMATION AND PUBLICATION 
Graybug Vision recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences. The 
details of the processes of producing and reviewing reports, manuscripts, and presentations based 
on the data from this study will be described in the Clinical Study Agreement between Graybug 
Vision, the contract research organization, and the investigator. 
Due to the confidential nature of this development program, the results of the study may not be 
published or publicly presented without the prior approval of Graybug Vision. Any investigator 
wishing to publish or present any study finding must present a manuscript or abstract to Graybug 
Vision 120 days prior to submission for publication or presentation to provide Graybug Vision 
an opportunity for review and comment. 


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15 ETHICS 
15.1 Institutional Review Board 
The protocol, IB, informed consent form, advertisements to be used for subject recruitment, and 
any other written information provided to subjects for this study, including all consent forms 
translated to a language other than the native language of the study center must be approved by 
the investigator’s IRB before the study is initiated at the study center. Documentation of this 
approval must be maintained by the study center and provided to the Sponsor (or designee) and 
must be made available during an inspection by the US FDA or other regulatory agency 
inspectors. Prior to initiating the study, the investigator will obtain written confirmation that the 
IRB is properly constituted and compliant with ICH and GCP requirements, and all applicable 
laws and local regulations. 
The study will not be initiated at the study center until documentation confirming approval of the 
protocol, informed consent form, and any written materials supplied to the subject are received 
by the Sponsor or its designee. Approval documentation from the IRB should be signed by the 
IRB chairperson or designee, identify the IRB by name and address, refer to the study protocol 
by title and/or protocol number and version or date, identify documents reviewed, and include 
the date of the review and approval or favorable opinion was granted. 
Appropriate reports on the progress of the study will be made to the IRB and to the Sponsor (or 
designee) by the investigator in accordance with applicable governmental regulations and local 
regulations, and in agreement with policies of the IRB. The investigator must provide written 
documentation of the following to the Sponsor (or designee): 
• IRB periodic (eg, semi-annually, annually) re-approval of the protocol as required by the 
study center’s IRB 
• IRB approvals of any amendments to the protocol or revisions to the informed consent form 
• IRB receipt of safety and SAE reports, as appropriate 
• Any additional submissions (including an end of study report) required by the study center’s 
IRB 
15.2 Ethical Conduct of the Study 
This study will be conducted in compliance with GCP as described in FDA regulations 
(21 CFR Parts 50, 54, 56, and 312), the ICH document “Guidance for Good Clinical Practice, 
E6 (R1),” and the principles of the World Medical Association Declaration of Helsinki – Ethical 
Principles for Medical Research Involving Human Subjects, including all amendments and Notes 
of Clarification. The investigator is expected to comply with the requirements of the protocol, 
and will conduct all aspects of this study in accordance with all national, state, and local laws or 
regulations. 


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15.3 Subject Information and Consent 
Written informed consent in compliance with FDA regulations (21 CFR 50.25), the ICH 
document “Guideline for Good Clinical Practice, E6 (R1),” and other applicable local regulations 
shall be obtained from each subject prior to entering the study or performing any study related 
procedure. An informed consent template will be provided by the Sponsor (or designee) to the 
study centers. The informed consent will be submitted by the investigator or IRB for review and 
approval prior to the start of the study. If any modifications to the content are proposed or made 
by the study center, the informed consent should be reviewed by the Sponsor (or designee) prior 
to IRB submission. 
The investigator is responsible for obtaining written informed consent from each subject 
participating in the study. If there are any revisions to the informed consent during the course of 
the study, all active participating subjects must be reconsented using the revised informed 
consent in a timely fashion. 
Written informed consent must be obtained from the subject before any study related screening 
activity or treatment is undertaken that is not part of routine care. This includes, but is not limited 
to, the performance of diagnostic or therapeutic procedures and the administration of the first 
dose of the study treatment. All pertinent aspects of the study must be explained to the 
prospective subject before signing the informed consent. The subject will be informed that 
participation is voluntary and he/she can withdraw from the study at any time. The subject will 
be allowed to read the IRB approved informed consent. If a subject is unable to read the consent, 
an impartial witness should be present during the entire informed consent discussion. Once the 
investigator or designee is assured the subject agrees to participate in the study, the subject will 
be asked to give consent by signing the informed consent. The informed consent must be signed 
and dated by the subject, and by the person who conducted the informed consent discussion, and 
impartial witness (if required). The investigator shall provide a copy of the signed and dated 
informed consent to the subject. The original shall be maintained in the subject’s medical records 
at the study center. This document should not be displayed or made accessible to any third party 
except the Sponsor, its designee or regulatory agency representatives. 
If a subject permanently revokes informed consent and declines further observation and/or 
contact, then this must be clearly documented in the subject’s chart and recording of further data 
will be discontinued. 


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16 INVESTIGATOR RESPONSIBILITIES 
Conduct of Study and Protection of Human Subjects 
In accordance with FDA Form 1572, the investigator will ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and will 
only make changes in a protocol after notifying the Sponsor, except when necessary to 
protect the safety, rights, or welfare of subjects. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential subjects, or any persons used as controls, that the drugs 
are being used for investigational purposes and he or she will ensure that the requirements 
relating to obtaining informed consent in 21 CFR Part 50 and IRB review and approval in 
21 CFR Part 56 are met. 
• He or she will report to the Sponsor adverse experiences that occur in the course of the 
investigation in accordance with 21 CFR 312.64. 
• He or she has read and understands the information in the IB, including potential risks and 
side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed about their 
obligations in meeting the above commitments. 
• He or she will ensure that adequate and accurate records in accordance with 21 CFR 312.62 
and to make those records available for inspection in accordance with 21 CFR 312.68. 
• He or she will ensure that the IRB complies with the requirements of 21 CFR Part 56, and 
other applicable regulations, and conducts initial and ongoing reviews and approvals of the 
study. He or she will also ensure that any change in research activity and all problems 
involving risks to human subjects or others are reported to the IRB. Additionally, he or she 
will not make any changes in the research without IRB approval, except where necessary to 
eliminate apparent immediate hazards to human subjects. 
• He or she agrees to comply with all other requirements regarding the obligations of clinical 
investigators and all other pertinent requirements in 21 CFR Part 312. 
 
 


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17 REFERENCES 
American Society of Retina Specialists, 2016 Annual Membership Survey (Poster). Presented at 
the Retina Subspecialty Day Meeting during the American Academy of 
Ophthalmology annual meeting, Chicago, IL, USA: 14-15 Oct 2016. 
AVASTIN® (bevacizumab) Solution for Intravenous Infusion. [US Prescribing Information]. 
South San Francisco, CA: Genentech, Inc; 2014. 
EYLEA® (aflibercept) Injection. [US Prescribing Information]. Tarrytown, NY: Regeneron 
Pharmaceuticals, Inc; 2014. 
Campochiaro A, Heier J, Feiner L, Gray S, Saroj N, et al. Ranibizumab for macular edema 
following branched retinal vein occlusion. Six-month primary end point results of 
a Phase III study. Ophthalmology 2010; 117:1102-1112.  
Chew EY, Kim J, Sperduto RD, Datiles MB, 3rd, Coleman HR, Thompson DJ, et al. Evaluation 
of the age-related eye disease study clinical lens grading system AREDS report 
No. 31. Ophthalmology. 2010;117(11):2112-9 e3. 
Kim B, Masuda T, Shaw GC, Berlincke CA, Zack DJ. Sunitinib promotes the survival and 
function of photoreceptors in murine light damage model. Poster A0103. 
Presented at the Association for Vision and Research in Ophthalmology (ARVO) 
annual meeting, Denver, CO, USA. 05 May 2015. 
Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature Working 
Group. Standardization of uveitis nomenclature for reporting clinical data. Results 
of the first international workshop. Am J Ophthalmol. 2005;140(3):509-16. 
Krzystolik MG, Afshari MA, Adamis AP, Gaudreault J, Gragoudas ES, Michaud NA, et al. 
Prevention of experimental choroidal neovascularization with intravitreal anti-
vascular endothelial growth factor antibody fragment. Arch Ophthalmol. 
2002;120(3):338-46. 
LUCENTIS® (ranibizumab injection) Intravitreal Injection. [US Prescribing Information]. San 
Francisco, CA: Genentech, Inc; 2014. 
Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, et al. Ranibizumab for diabetic 
macular edema. Results from 2 Phase III randomized trials: RISE and RIDE. 
Ophthalmology 2010; 119:789-801.  
Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology. 1985;92(4):467-71. 


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Peterson W, Yang M, Yu Y, Kays J, Cardona D. Preclinical efficacy and safety of GB-102 for 
the treatment of wet-AMD: an injectable depot formulation of sunitinib malate for 
twice per year dosing. Poster PO268 16 Oct 2016. 
Sharma SM, Wu-chen W-Y, Yang Z, Vilson FL, Guo Y, Miller NR, et al. Sunitinib malate 
preserves retinal ganglion cells in rodent NAION. Invest Ophthalmol Vis Sci. 
2011;52(14):6614. 
Speed B, Bu HZ, Pool WF, Peng GW, Wu EY, Patyna S, et al. Pharmacokinetics, distribution, 
and metabolism of [14C]sunitinib in rats, monkeys, and humans. Drug Metab 
Dispos. 2012;40(3):539-55. 
SUTENT® (sunitinib malate) capsules. [US Prescribing Information]. New York, NY: Pfizer; 
2015. 
Takahashi H, Obata R, Tamaki Y. A novel vascular endothelial growth factor receptor 2 
inhibitor, SU11248, suppresses choroidal neovascularization in vivo. J Ocul 
Pharmacol Ther. 2006;22(4):213-8. 
Zack DJ, Yang Z, Vojkovsky T, Ge Y, Welsbie D, Berlinicke C, et al. Identification of the 
receptor tyrosine kinase inibitor sunitinib, and related analogues, as candidate 
molecules for glaucoma neuroprotection. Invest Ophthalmol Vis Sci. 
2011;52(14):3086. 
 
 
 
 


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18 APPENDICES 
18.1 Study Schema Protocol GBV-102-003 
(Green box = administration of GB-102) 
 
 
 
Cohort A 
N=lO 
Cohort B 
N=lO 
GB-102 
1 mg 
GB-102 
2 mg 
DD D DD D D 
DD D DD D D 
D1 D14 Ml 
M2 
M3 
M4 
MS 
M6 


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18.2 Nonocular and Systemic Adverse Event Severity Assessment 
The NCI-CTCAE (version 4.03) is a descriptive terminology that will be used to grade the 
severity of nonocular and systemic AEs reported in this study. 
The NCI-CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for 
each AE based on this general guideline: 
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observation 
only; intervention not indicated 
Grade 2:  Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)* 
Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limited 
self-care ADL** 
Grade 4:  Life-threatening consequences; urgent intervention indicated 
Grade 5:  Death related to an AE 
A semicolon indicates “or” within the above descriptions. A single dash (-) can be used to 
indicate that a grade is not available. Not all grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than 5 options for grade selection. 
* Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc 
** Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not being bedridden. 


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18.3 Ocular Adverse Event Severity Assessment 
The severity of an ocular AE will be defined as a qualitative assessment of the degree of 
intensity of an ocular AE as determined by the investigator or reported to him/her by the subject. 
The assessment of severity will be made irrespective of relationship to investigational product or 
seriousness of the event and should be evaluated according to the following scale: 
• Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere with the 
subject’s daily activities 
• Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with 
the subject’s daily activities 
• Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities 
 
 


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18.4 
Ocular Grading Scales 
Ocular inflammation, fundus hemorrhage, and vitreous haze will be assessed during slit-lamp 
biomicroscopy and indirect ophthalmoscopy. The standard practice for the slit-lamp 
biomicroscopy and indirect ophthalmoscopy assessments should be used. 
18.4.1 
Grading Scale for Ocular Inflammation 
Anterior Chamber Cells 
Grade 
Cells in Field (1 mm × 1 mm slit beam)  
0 
None 
+0.5 
1 - 5 
+1 
6 - 15 
+2 
16 - 25 
+3 
26 - 50 
+4 
> 50 
Source: (Jabs 2005) 
Anterior Chamber Flare 
Grade 
Description  
0 
None 
+1 
Trace 
+2 
Moderate (iris and lens detail clear) 
+3 
Marked (iris and lens detail hazy) 
+4 
Intense (fibrin or plastic aqueous) 
Source: (Jabs 2005) 
18.4.2 
Grading Scale of Retinal or Vitreous Hemorrhage 
Grade 
Hemorrhage Size (Disc Areas) 
0 
None present 
+1 
< 3  
+2 
3 to 6 (inclusive) 
+3 
> 6 
Source: (Krzystolik 2002) 


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18.4.3 
Grading of Vitreous Haze 
Grade 
Amount of Vitreal Haze  
0 
None 
+0.5 
Trace 
+1 
Clear optic disc and vessels; hazy nerve fiber layer 
+2 
Hazy optic disc and vessels 
+3 
Optic disc visible 
+4 
Optic disc not visible 
Source: (Nussenblatt 1985) 
 
Source: (Nussenblatt 1985) 
 
 
 


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18.5 
Age-Related Eye Disease Study Lens Scale 
Presence and severity of nuclear sclerosis, cortical opacities, and posterior subcapsular opacities 
will be evaluated according to the Age-Related Eye Disease Study (AREDS) Clinical Lens 
Grading Protocol (Chew 2010). Biomicroscopic findings will be compared with standard 
photographs. The Sponsor or its delegate will supply the investigational centers with a copy of 
the standard photographs. 
18.5.1 
Nuclear Sclerosis 
Grade 
Description 
+1 
Opacity is absent 
+2 
Opacity is present, but less than Nuclear Standard Photograph #2 
+3 
Opacity is present, and as severe or worse than Nuclear Standard Photograph #2 
Source: (Chew 2010) 
18.5.2 
Cortical Opacities 
Grade 
Description 
+1 
Opacity is absent 
+2 
Opacity is present, but less than Cortical Standard Photograph #2 
+3 
Opacity is present, and as severe or worse than Cortical Standard Photograph #2 
Source: (Chew 2010) 
18.5.3 
Posterior Subcapsular Opacities 
Grade 
Description 
+1 
Opacity is absent 
+2 
Opacity is present, but less than PSC Standard Photograph #2 
+3 
Opacity is present, and as severe or worse than PSC Standard Photograph #2 
PSC = posterior subcapsular opacity 
Source: (Chew 2010) 
 
 
 
 
 
 
 
 
 
 


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Source: (Chew 2010) 
 
 
 
Nuclear Standard 1 
Nuclear Standard 2 
Nuclear Standard 3 
PSC Standard 1 
PSC Standard 2 
PSC Standard 3 
Cortical Standard 1 
Cortical Standard 2 
Cortical Standard 3 


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18.6 
Protocol Amendment Summary 
This summary includes changes made to Protocol Amendment 1 GBV-102-003 (Version 2.0) 
dated 13 November 2019. 
Graybug Vision, Inc. has added Appendix 18.5, Age-Related Eye Disease Study Lens Scale as a 
reference for sites to utilize to document biomicroscopic findings. 

SAP_001.pdf: 
 
 
 
 
 
 
 
Graybug Vision Inc. 
 
STATISTICAL ANALYSIS PLAN 
 
 
Official Title: A Phase 2a Multicenter Study Evaluating the Safety, Tolerability, and 
Pharmacodynamics of a Single Injection of a Long-acting Intravitreal 
Sunitinib Malate Depot Formulation (GB-102) in Subjects with Diabetic 
Macular Edema (DME) and Retinal Vein Occlusion (RVO) 
 
Protocol Number: GBV-102-003 
 
NCT Number: 04085341 
 


STATISTICAL ANALYSIS PLAN 
A Phase 2a Multicenter Study Evaluating the Safety, Tolerability, and 
Pharmacodynamics of a Single Injection of a Long-acting Intravitreal 
Sunitinib Malate Depot Formulation (GB-102) in Subjects with Diabetic 
Macular Edema (DME) and Retinal Vein Occlusion (RVO)
Sponsor: 
Graybug Vision, Inc.
Protocol Number:
GBV-102-003
Author: 
Date: 
18 SEP 2020
Version: 
2.0
Page 1 of 30


Page 2 of 30
A Phase 2a Multicenter Study Evaluating the Safety, Tolerability, and 
Pharmacodynamics of a Single Injection of a Long-acting Intravitreal 
Sunitinib Malate Depot Formulation (GB-102) in Subjects with Diabetic 
Macular Edema (DME) and Retinal Vein Occlusion (RVO)
Protocol Number:
GBV-102-003
SAP Version: 
2.0
SAP Date:  
18 SEP 2020
Statistical Analysis Plan Approval
Prepared by:
 Date
Reviewed by:
Date
Approved by:
Date
Approved by:
 Date


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Table of Contents
1.
Introduction ..............................................................................................................................6
2. 
Study Objectives ......................................................................................................................6
3. 
Study Variables ........................................................................................................................6
4. 
Study Design and Procedures .................................................................................................7
4.1
General Study Design..............................................................................................................7
4.2
Schedule of Visits and Assessments .......................................................................................7
4.3
Masking....................................................................................................................................9
5. 
Sample Size .............................................................................................................................9
6. 
Data Preparation......................................................................................................................9
7. 
Analysis Sets..........................................................................................................................10
7.1
Safety Analysis Set ................................................................................................................10
7.2
Full Analysis Set.....................................................................................................................10
7.3
Per Protocol............................................................................................................................10
8. 
General Statistical Considerations.........................................................................................10
8.1
Unit of Analysis ......................................................................................................................10
8.2
Missing or Inconclusive Data Handling..................................................................................10
8.3
Definition of Baseline .............................................................................................................11
8.4
Data Analysis Conventions ....................................................................................................11
8.5
Adjustments for Multiplicity.....................................................................................................12
9. 
Disposition of Subjects...........................................................................................................12
10. 
Demographic Variables and Pretreatment Variables.............................................................12
10.1 Demographic Variables..........................................................................................................12
10.2 Pretreatment Variables and Anti-VEGF History.....................................................................13
11. 
Medical History and Concomitant Medications......................................................................13
11.1 Medical History.......................................................................................................................13
11.2 Prior and Concomitant Medications .......................................................................................13
11.3 Study Drug Administration .....................................................................................................14
12. 
Pharmacodynamic Analysis...................................................................................................14
12.1 BCVA......................................................................................................................................15
12.1.1 
LOCF and Observed data approach..........................................................................15
12.1.2 
Response to first rescue treatment analysis ..............................................................15
12.2 CST (spectral-domain optical coherence tomography [SD-OCT]).........................................15
12.2.1 
Last Observation Carried Forward and Observed Data approach ............................15
12.2.2 
Response to first rescue treatment analysis..............................................................16
12.3 Rescue-free treatment ...........................................................................................................16
13. 
Safety Analyses .....................................................................................................................17


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13.1 Adverse Events ......................................................................................................................17
13.2 BCVA (ETDRS)......................................................................................................................20
13.3 Slit-Lamp Biomicroscopy Examination...................................................................................20
13.4 Dilated Ophthalmoscopy........................................................................................................21
13.5 Intraocular Pressure (IOP) .....................................................................................................21
13.6 Physical Examination.............................................................................................................21
13.7 Vital Signs ..............................................................................................................................21
13.8 Blood Chemistry.....................................................................................................................22
13.9 Pregnancy Testing .................................................................................................................22
14. 
Interim Analyses.....................................................................................................................22
15. 
Tables.....................................................................................................................................23
16. 
Listings ...................................................................................................................................29
17. 
Figures ...................................................................................................................................30


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List of Abbreviations
ADL
Activities of Daily Living
AE
Adverse Event
AREDS
Age-Related Eye Disease Study
ATC
Anatomical Therapeutic Chemical
BCVA
Best Corrected Visual Acuity
CFP
Color Fundus Photography
CS
Clinically Significant
CST
Central Subfield Thickness
DME
Diabetic Macular Edema
DR
Diabetic Retinopathy
eCRF
Electronic Case Report Form
ETDRS
Early Treatment Diabetic Retinopathy Study
FAS
Full Analysis Set
ICH
International Council for Harmonisation
IOP
Intraocular Pressure
IVT
Intravitreal
MedDRA
Medical Dictionary for Regulatory Activities
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria For Adverse Events
NCS
Not Clinically Significant
PP
Per Protocol
PT
Preferred Term
RVO
Retinal Vein Occlusion
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDC
Statistics & Data Corporation
SD-OCT
Spectral Domain – Optical Coherence Tomography
SOC
System Organ Class
SS
Safety Analysis Set
TEAE
Treatment-Emergent Adverse Event
VEGF
Vascular Endothelial Growth Factor
WHODrug
World Health Organization Drug Dictionary


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1.
Introduction
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol GBV-102-003, version 2.0 dated 13 November 2019.
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports.
This SAP describes the data that will be analyzed and the subject characteristics, pharmacodynamics, and 
safety assessments that will be evaluated. This SAP provides details of the specific statistical methods that 
will be used. The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol. If additional analyses are required to supplement the 
planned analyses described in this SAP they may be completed and identified in the clinical study report.
2.
Study Objectives
Primary Objective:
To evaluate the safety and tolerability of a single intravitreal (IVT) injection of two different dose strengths 
of GB-102 (1 mg, 2 mg) in subjects with macular edema secondary to diabetic retinopathy (DR) or retinal 
vein occlusion (RVO) who have received prior induction with anti-vascular endothelial growth factor (VEGF).
Secondary Objective:
To evaluate the pharmacodynamic response as measured by best corrected visual acuity (BCVA) and 
central subfield thickness (CST) and time to first rescue injection.
3.
Study Variables
Primary Endpoint
Safety
Occurrence of ocular and non-ocular adverse events (AE) and serious adverse events (SAE) at all 
study visits
Secondary Endpoints
Pharmacodynamic Activity –
BCVA (Early Treatment Diabetic Retinopathy Study [ETDRS] protocol) at all study visits
CST (spectral-domain optical coherence tomography [SD-OCT]) at all study visits
Observed subjects rescue-free at each study visit
Time to first rescue injection
Response to rescue treatment
Other Variables
Slit-lamp biomicroscopy


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Dilated ophthalmoscopy
Intraocular pressure (IOP)
Physical examination
Vital signs
Color fundus photography (CFP)
4.
Study Design and Procedures
4.1
General Study Design
This is a Phase 2a, multicenter, open-label, single injection, parallel arm, non-controlled safety, tolerability,
and pharmacodynamics study. Eligible subjects will be enrolled to 1 of 2 concurrently initiated open-label 
GB-102 treatment arms: Group 1: 1 mg (50 µL) and Group 2: 2 mg (50 µL). Subjects will receive the IVT 
injection of the study drug in the study eye on Day 1.
The planned study assessments (AEs including SAEs, physical examinations, vital signs, BCVA using the 
ETDRS protocol, slit-lamp biomicroscopy findings, IOP measurements, dilated ophthalmoscopy results, 
and date of administration of rescue treatment) are conventional parameters used to evaluate the safety of 
pharmacologic agents in retinal disease. Approximately 20 subjects are planned: 10 subjects treated with 
1 mg GB-102 and 10 subjects treated with 2 mg GB-102. There is no pre-set limitation on the proportion of 
diabetic macular edema (DME) or RVO subjects per dose group. Rescue treatment allowed is any anti-
VEGF (aflibercept, bevacizumab, or ranibizumab) and should be used in accordance with the sites standard 
practice in administering these agents for the treatment of DME or RVO.
Pharmacodynamic activity will be assessed by means of BCVA (using the ETDRS Protocol), retinal CST 
using SD-OCT, and CFP (including wide field fundus photography, if available).
The null and alternative hypotheses, based on the primary variables, are as follows:
4.2
Schedule of Visits and Assessments 
GB-102 will be administered on Day 1 in both Cohorts. Subjects will return to the study center on Days 14, 
30, 60, 90, 120, 150, and 180 for safety and clinical assessments. Subjects will exit the study following all 
study assessments on Day 180.
The schedule of visits and assessments is provided in Table 1 below.


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Table 1.
Study Plan and Schedule of Assessments
Activity/Assessment
Sa
B
W 2
M 1
M 2
M 3
M 4
M 5
M 6
(ET)
Visit Day ± Windowb
30 to 
1
14 2
30 4
60 7
90 7
120 7
150 7
180 7
Informed 
Consent/HIPAA
X
Inclusion/Exclusion
Criteria
X
Demographics Data
X
Medical/Medication 
History
X
Physical Examination
X
X
Pregnancy Testingc
X
X
X
X
Clinical Laboratory 
Testsd
X
Adverse Events
X
X e
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
Vital Signsf
X
X
X
BCVA (ETDRS)g
OU
OU
OU
OU
OU
OU
OU
OU
OU
Slit-lamp Biomicroscopy
OU
OU
OU
OU
OU
OU
OU
OU
OU
IOPh
OU
OU
OU
OU
OU
OU
OU
OU
OU
Dilated 
Ophthalmoscopy
OU
OU
OU
OU
OU
OU
OU
OU
OU
SD-OCTi
OU
OU
OU
OU
OU
OU
OU
OU
OU
Intravitreal Depot 
Photographyj
SE
SE
SE
SE
SE
SE
SE
SE
GB-102 Injectionk
SE
Post-injection 
Assessmentl
SE
Follow-Up Call e
+1 day
B = Baseline Visit; BCVA = Best Corrected Visual Acuity; ET = Early Termination; ETDRS = Early Treatment Diabetic 
Retinopathy Study; HIPAA = Health Insurance Portability and Accountability Act; IOP = Intraocular Pressure; M = 
Month; OU = Both Eyes; S = Screening Visit; SD-OCT = Spectral Domain-Optical Coherence Tomography; SE = 
Study Eye; V = Visit; W = Week
a
Screening Visit to occur 3 to 30 days before study baseline (Day 1) to ensure that laboratory results are 
obtained. Imaging eligibility based on SD-OCT will be Investigator determined; there is no reading center 
confirmation.
b
The protocol-specified procedures for a given study visit may be split across 2 days within the visit-specific 
window (if applicable); however, for each visit, all BCVA, ophthalmic examinations, and ophthalmic imaging must 
be performed on the same day and cannot be split across 2 or more days. Evaluations should be performed by 
the same evaluator for the same subject throughout the study whenever possible. If it is not possible to use the 
same evaluator to follow the subject, then evaluations should overlap (examine the subjects together and 
discuss findings) for at least 1 visit.
c
Urine pregnancy test in women of childbearing potential only; additional pregnancy tests may be performed at 
any time/day during the study.
d
Chemistry (non-fasting blood): hemoglobin A1c. 
e
All subjects will receive a telephone call for the day after the intravitreal injection to assess for any significant 
complaints or adverse events.


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f
Heart rate, blood pressure; additional collection of height (without shoes) will be measured at Screening and 
body weight will be measured at Screening and Month 6/exit. 
g
Visual acuity assessment using ETDRS protocol at 4 m with manifest refraction will be performed at all visits; 1 
m may be performed if needed.
h
Goldmann applanation tonometry or Tono-Pen acceptable; however, technique used at baseline must be used at 
all subsequent visits. Intraocular pressure will be checked before dilation and the IVT injection of study drug at 
dosing visits.
i
Measurements for CST determined by the Investigator (no central reading center confirmation).
j
Wide field color fundus photography (eg, Optos Ultra-widefield or Zeiss Clarus 500 or other ultra-widefield 
equipment) of the intravitreal GB-102 depot will be obtained following the dilated ophthalmic examination at all 
visits – if available at the study site. The initial images of the depot should be obtained at baseline (Day 1) after 
the IVT injection of GB-102 and conducted through (and include) the final study visit and any unscheduled visits. 
The photographs may be used to document the general appearance and rate of bioabsorbability of the depot. If 
no wide-FOV camera available, standard 30-degree field of view (FOV) imaging documenting the visual axis will 
be sufficient. For detailed instructions regarding collection of the intravitreal depot CFP imaging, refer to the 
separately provided guideline. 
k
Following intravitreal injection of GB-102, the subject should remain seated for approximately 15 minutes post-
injection with minimal to no movement of the head (e.g., bending over, shaking head, laying down) and avoid 
significant eye movement. 
l
Postinjection assessment to consist of checking for count fingers or hand motion vision within 15 minutes after 
injection; if needed, subject can be examined (eg, additional IOP or ophthalmoscopy, per discretion of the 
Investigator) prior to going home.
4.3
Masking
This is an open-label study and the injecting investigator/physician may be the assessing investigator. The 
SD-OCT and CFP technicians and other site personnel, the Sponsor, and CRO are unmasked to treatment 
assignment.  
5.
Sample Size 
The sample size is within clinical standards for the establishment of preliminary safety of GB-102. The 
sample size of this study was not selected to support specific statistical hypothesis testing. A sample size 
of approximately 20 evaluable subjects in the FAS analysis set allows for detection of adverse events with 
rates that exceed 15% overall and exceed 30% for each dose with approximately 95% confidence.
6.
Data Preparation
All reported study data will be recorded on the electronic case report forms (eCRF) supplied by Statistics &
Data Corporation (SDC) using iMedNet™. Only the Principal Investigator and authorized study staff 
according to the Delegation of Responsibilities log are entitled to make entries in the eCRF. After data is 
entered into the clinical study database, electronic edit checks, and data review will be performed. All data 
validation specifications and procedures are detailed in the Data Validation Manual as a separate 
document. When the database has been declared to be complete and accurate, the database will be locked. 
Any changes to the database after data have been locked can only be made with the approval of the 
Sponsor and Ora in consultation with SDC.
All analyses outlined in this document will be carried out after the following have occurred:
All data management requirements are met according to SDC standard operating procedures, 
including data entry, performance of edit and validation checks, documentation, and resolution of 


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data queries and database lock with written authorization provided by appropriate SDC and 
Sponsor personnel.
Protocol deviations have been identified and status defined (major/minor deviations).
Analysis sets have been determined.
7.
Analysis Sets
7.1
Safety Analysis Set
The safety analysis set (SS) includes all subjects who received a dose of study treatment. Subjects who
receive rescue treatment during the study will be included in the SS. Subjects will be analyzed according 
to actual treatment received.
7.2
Full Analysis Set
The full analysis set (FAS) includes all subjects who received a dose of study treatment and complete a 
baseline and a post-baseline visit. Subjects will be analyzed according to the actual treatment they received.
7.3
Per Protocol
The per protocol (PP) analysis set consists of a subset of the FAS and includes subjects with no major 
protocol violations that would affect the assessment of the pharmacodynamics, and rescue data. 
8.
General Statistical Considerations
8.1
Unit of Analysis
The unit of analysis in this study will be the study eye for all safety and pharmacodynamic summaries. The 
study eye was selected as the eye that meets all the inclusion criteria and none of the exclusion criteria. If 
both eyes meet the inclusion and none of the exclusion criteria, the eye with the worst visual acuity at 
baseline will be selected. If both eyes have the same baseline visual acuity, the right eye will be selected 
as the study eye. Additionally, non-ocular AEs and medical history will be presented at the subject level. 
Non-study eye safety summaries will also be presented as appropriate.
8.2
Missing or Inconclusive Data Handling
In general, there will be no imputation of missing data other than for partial or missing dates where complete 
dates are required to flag data as treatment-emergent or concomitant with treatment. Partial/missing start 
and end dates for AEs and concomitant medications will be imputed as follows:
Partial/missing start date:
· Dates with missing day only will be imputed as the 1st of the month unless the month and year are same 
as the month and year of first dose of study medication, in which case missing day will be imputed as the 
first dose day of study medication.


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· Dates with both day and month missing will be imputed as 1 Jan unless the year is same as the year of 
first dose of study medication, in which case missing day and month will be imputed as the first dose day 
and month of study medication.
· Completely missing dates will not be imputed.
Partial/missing end date:
· Dates with missing day only will be imputed as the last day of the month unless the month and year are 
the same as the month and year of the last dose of study medication, in which case missing day will be 
imputed as the last dose day of study medication.
· Dates with both day and month missing will be imputed as 31 Dec unless the year is same as the year of 
the last dose of study medication, in which case missing day and month will be imputed as the last dose 
day and month of study medication.
· If the ongoing flag is missing or “Yes” then the date will not be imputed unless death date is available, in 
which case the missing date will be imputed as the death date. If ongoing is “No” then the missing end date 
will be imputed as the last dose date.
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc).
8.3
Definition of Baseline
Baseline is defined as the last measurement prior to the administration of study medication. Change from 
baseline will be calculated as post-baseline visit minus baseline visit.
8.4
Data Analysis Conventions
The final data analysis will be performed by SDC after the study is completed and the database has been 
locked. Statistical programming and analyses will be performed using SAS® Version 9.4 or higher. Output 
will be provided in rich text format (RTF) for tables and portable document format (PDF) for tables, listings, 
and figures using landscape orientation. All study data will be listed by subject, treatment, and visit (as 
applicable).
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum. Minima and maxima will be reported with 
the same precision as the raw values; means and medians will be presented to one additional decimal 
place than reported in the raw values. Standard deviations will be presented to two additional decimal 
places than reported in the raw values. Summaries for discrete variables will include number of 
observations, and percentages. All percentages will be rounded to one decimal place (i.e., XX.X%). Unless 
otherwise specified, summaries will be presented by cohort and, where appropriate, visit.


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8.5
Adjustments for Multiplicity
No statistical adjustments for multiplicity are planned due to the exploratory nature of this study.
9.
Disposition of Subjects
Subject disposition will be presented in terms of the numbers and percentages of subjects who completed 
the study and discontinued from the study. Subjects who are not discontinued from the study will be 
considered study completers. Disposition will be summarized by cohort and for total subjects. The number 
of subjects in each of the analysis sets (FAS, PP, and SS) will be displayed by cohort total subjects.
Percentages will be calculated using enrolled subjects as the denominator.
The number and percentage of subjects enrolled, and failed screening will be presented using total number 
of subjects screened as denominator. Reasons for screen failures would include number and percentage 
of subjects who either failed to meet inclusion criteria or met exclusion criteria.
The number and percentage of subjects prematurely discontinued from the study and the reasons for study 
discontinuation will be summarized by cohort for all enrolled subjects. The reasons for study discontinuation 
that will be summarized include withdrawal of consent, lost to follow-up, adverse event, sponsor termination 
of study, and other. A subject listing will be provided that includes the date of and reason for premature 
study discontinuation.
The number and percentage of subjects with major protocol deviations will be summarized by cohort and
total enrolled subjects. The protocol deviations that will be summarized include: informed consent, 
inclusion/exclusion or treatment assignment, test article/study drug administration at site, improper protocol 
procedures at site, site’s failure to report SAE, visit out of window, subject’s use of prohibited concomitant 
medication, subject’s failure to follow instructions, and other. A subject listing will be provided that includes 
the start and end date of the deviation, the deviation code, the deviation description, and the classification 
of whether the deviation was judged to be major or minor.
In addition, subject listings will be provided that include informed consent date, inclusion and exclusion 
criteria violations, and exclusions from the Per Protocol Analysis Set.
10. Demographic Variables and Pretreatment Variables
10.1
Demographic Variables
The demographic variables collected in this study include age, sex, race, ethnicity, and iris color of study 
eye. Demographic variables will be summarized for the FAS, PP and Safety analysis sets, separately. 
Subjects who report more than one race will be summarized in the Multiple Race category. Age will also be 
categorized as follows: < 65 and 65 years. Age will be reported in years and calculated using the following 
formula:
Age = (Informed Consent Date - Date of Birth) / 365.25, truncated as an integer


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The number and percentage of subjects will be presented, overall and by cohort, for age, sex, race, 
ethnicity, and iris color for the study eye.  
A subject listing that includes all demographic variables will be provided.
10.2
Pretreatment Variables and Anti-VEGF History
Pretreatment variables will include baseline BCVA and CST in the study eye. Baseline BCVA, and baseline 
CST will be summarized, total and by cohort, using continuous descriptive statistics. Additionally, all two 
pretreatment variables will be categorized as follows: SD-OCT ( 350 and >350 micrometers), and BCVA 
( 68 versus >68 letters).
Anti-VEGF history will include previous number of Anti-VEGF injections, time (in months) since first anti-
VEGF and last anti-VEGF. Number of injections will be summarized as categorical variable (<5 versus 5) 
and time since first and last injections will be summarized as continuous variables. All the summaries will 
be presented, total and by cohort.  
Subject listings including all pretreatment variables and Anti-VEGF history will be provided.
11. Medical History and Concomitant Medications
11.1
Medical History
Medical history will be coded using the medical dictionary for regulatory activities (MedDRA) version 22.0.
Non-ocular medical history will be summarized using discrete summary statistics and presented by cohort 
at the subject and event level by System Organ Class (SOC) and Preferred Term (PT) using the SS. Ocular 
medical history will be similarly summarized at the subject level by study and non-study eye. If a subject 
reports the same PT multiple times within the same SOC, that PT will only be reported once within that 
SOC. As with the PT, if a subject reports multiple conditions within the same SOC, that SOC will only be 
reported once. SOCs and PTs will be listed in alphabetical order.
Listings of medical history will be generated separately for ocular and non-ocular data.
11.2
Prior and Concomitant Medications
Prior and concomitant medications will be coded using the World Health Organization Drug Dictionary
(WHODrug) Global (B3, March 2019) and summarized to the therapeutic drug class (Anatomical 
Therapeutic Chemical [ATC] 4 classification) and preferred name. If the ATC 4 classification is not provided, 
the next lowest classification that is provided in the coding dictionary will be used. The preferred name will 
be defined as the active ingredient; if the active ingredient is not provided or includes more than two 
ingredients (e.g., multivitamins), then the drug name will be summarized as the preferred name. Any 
uncoded terms will be summarized under the ATC classification and preferred name of “Uncoded.” Prior 
medications are defined as those medications listed as having stopped prior to initiation of study drug. 
Concomitant medications are defined as those medications listed as having been taken: (1) prior to initiation 
of study drug and continuing for any period of time following the first administration of study drug, or (2) at 


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any time following the first administration of study drug. Prior medications are defined as medications 
initiated prior to study drug Administration including both those stopped before baseline and those 
continued after baseline.
Prior and Concomitant medications will be summarized for ocular and non-ocular medications separately 
using the SS. All the ocular events will also be further summarized by study and non-study eye. Medications 
will be tabulated for each cohort using frequencies and percentages. Subjects may have more than 1 
medication per ATC text. At each level of subject summarization, a subject will be counted once if 1 or more 
medications is reported. Percentages will be based on the number of subjects in each cohort. ATC classes 
and preferred names within an ATC class are listed in alphabetical order.
Listings of prior and concomitant medications and procedures will be generated separately for ocular and 
non-ocular data.
11.3
Study Drug Administration
Descriptive summary statistics of study drug administration will be tabulated by each cohort. Variables like 
study eye (OD/OS), drug administration performed as per pharmacy manual (Yes/No), completion of post-
injection assessment (Yes/no) will be included in the analysis.  
A subject listing of study drug administration will be generated.  
12. Pharmacodynamic Analysis
BCVA, CST (using SD-OCT), and rescue treatment (time to first rescue treatment, number of rescue 
treatments) will be included as pharmacodynamic endpoints. No formal hypothesis testing will be 
conducted. Descriptive summaries will include the arithmetic mean, SD, median, minimum, and maximum 
values for continuous variable, and the number of subjects and percentages for categorical variable. 
Observed data will contain assessments performed during protocol defined and unscheduled visits 
including ones performed after the first rescue treatment. To allow for an efficacy assessment of GB-102 
while excluding potential effects from rescue injections data collected after first rescue treatment will be 
censored and replaced with the last value collected prior to the first rescue treatment. The LOCF approach 
is used for the analysis of BCVA and CST.  
Sensitivity analysis will also be conducted using observed data without any censoring and imputation as 
mentioned in the previous paragraph. 
The response to anti-VEGF rescue treatment is assessed for BCVA and CST based on the data collected 
prior and after the first rescue treatment. This response analysis will include all subjects receiving at least 
one rescue treatment. The last assessment performed before receiving the first rescue treatment will be 
used as the rescue treatment related baseline value. Data from one month and two months prior to the 
rescue treatment - baseline as well as one and two months post rescue treatment will be used to assess 


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the response to rescue treatment. These five timepoints will represent the time-scale for these analyses. 
No imputation for missing data will be done.
Summaries will be produced for the overall as well as by diagnosis (DME or RVO) within FAS and PP
analysis set.
All observed pharmacodynamic variables will also be presented by visit in subject listings.
12.1
BCVA
Visual acuity assessment (BCVA) using ETDRS protocol with manifest refraction will be performed in both 
eyes at all visits. The number of letters read correctly in the study eye will be the BCVA endpoint.  
12.1.1
LOCF AND OBSERVED DATA APPROACH
Values and change from baseline in number of letters read correctly will be summarized using LOCF 
approach for study eye by visit and cohort using continuous descriptive statistics. Categorical change from 
baseline will also be summarized for study eye by visit, total and by cohort.  
Observed values and change from baseline in number of letters read correctly will be summarized for study 
eye by visit and cohort using continuous descriptive statistics. Categorical changes from baseline will also 
be summarized for study eye by visit, total and by cohort.
12.1.2
RESPONSE TO FIRST RESCUE TREATMENT ANALYSIS
For the subset of subjects with at least one rescue treatment the observed and change from rescue 
treatment baseline in number of letters read correctly will be summarized for study eye by time-point and 
cohort using continuous descriptive statistics.   
12.2
CST (spectral-domain optical coherence tomography [SD-OCT])
The SD-OCT imaging will be performed for both eyes to measure and assess cross-sectional images of 
the anatomic layers of the retina and to detect the presence of retinal fluid. Images will be obtained using a 
SD-OCT device by designated certified study center personnel. Preferably the same device will be used for 
screening and the subsequent follow-up assessments for each subject. Images will be read centrally, and 
CST measurement data provided to SDC.
12.2.1
LAST OBSERVATION CARRIED FORWARD AND OBSERVED DATA APPROACH
Values and change from baseline in CST measurements will be summarized using LOCF approach for 
study eye by visit and cohort using continuous descriptive statistics. Categorical change from baseline will 
also be summarized for study eye by visit, total and by cohort.  
Observed values and change from baseline in CST measurements will be summarized for study eye by 
visit and cohort using continuous. Categorical changes from baseline will also be summarized for study eye 
by visit, total and by cohort.


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12.2.2
RESPONSE TO FIRST RESCUE TREATMENT ANALYSIS
For the subset of subjects with at least one rescue treatment the observed and change from rescue 
treatment baseline in number of letters read correctly will be summarized for study eye by time-point and 
cohort using continuous descriptive statistics.   
12.3
Rescue-free treatment
Rescue treatment (any anti-VEGF agent; aflibercept, bevacizumab, or ranibizumab) for all subjects enrolled
is allowed at any visit following the Day 30 study assessments in subjects who meet any of the following 
criteria regarding decrease in BCVA and/or increase in CST: 
Decrease in BCVA:
-study (i.e., post-treatment) BCVA ETDRS 
letter score
Increase in CST (any of the following criteria)
-study (i.e., post-treatment) visit CST 
measurements (µm), and/or,
-study (i.e., post-treatment) CST measurement (µm)
Subjects may receive rescue treatment during a scheduled or unscheduled visit. Rescue treatment received 
during an unscheduled visit will be counted towards next scheduled visit.
Time to first rescue treatment including median time to first rescue treatment will be assessed using Kaplan-
Meier product-limit approach by cohort. Subjects will be considered to have an event at the date where 
rescue treatment for study eye was first initiated. Since rescue treatment may be initiated at any time – at 
a scheduled visit or between scheduled visits – the timing of rescue treatment usage will be based on the 
date in at which rescue treatment was started. Subjects who do not have any usage of rescue treatment in 
the study eye will be censored at the date of the last visit. Subjects who discontinue prior to completing all 
treatment period visits will be evaluated based on the visits which are available. Kaplan-Meier plots will be 
generated.  
For the subgroup of subjects with rescue treatment the time to first rescue treatment will be summarized by 
cohort using continuous descriptive statistics.  
Proportion of subjects receiving rescue treatment during any protocol defined visit will be tabulated by 
cohort. As subjects will be eligible to receive rescue treatment on or after Day 30, Month 1 will be the first 
visit to be included in this table.   
A contingency table will be generated to represent a cross-classification between whether rescue criteria 
were met (yes or no) versus received rescue treatment (yes or no). Contingency will be checked across all 
visits as well as at every visit starting from Month 1.  
The total number of rescue treatments received by each subject will be tabulated.  


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Rescue treatment will be listed by subject and medication.
13. Safety Analyses
All safety analyses will be conducted using the SS.
13.1
Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether it is considered drug related. An AE can therefore be any unfavorable and unintended 
medical diagnosis, sign, or symptom; any new undesirable medical occurrence or unfavorable or 
unintended change in a pre-existing condition that occurs during or after study treatment; or laboratory 
abnormality, vital sign, or ophthalmic assessment that is assessed as clinically significant and different from 
baseline (e.g., requiring discontinuation of study treatment, specific treatment, or a change in subject 
management). If possible, changes in laboratory results or changes in vital signs that meet the definition of 
an AE should be reported as a medical diagnosis rather than as the abnormal value. All AEs will be coded 
using MedDRA Version 22.0.
A treatment-emergent adverse event (TEAE) is an AE with an onset anytime from when the subject has 
received study drug through 30 days after the study ends whether it is considered causally related to the 
study drug. Adverse events recorded in the eCRF which began prior to treatment will not be included in the 
summary tables but will be included in the AE data listings. An SAE is any event that involves or results in 
any of the following outcomes:
Death
Life-threatening occurrence (i.e., if in the view of the investigator or Sponsor, the event’s occurrence 
placed the subject 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)
Requires in-patient hospitalization or prolongation of existing hospitalization (hospitalization for 
elective surgery for a pre-existing condition or for surgery planned before study entry is not 
considered an SAE)
A persistent or significant disability/incapacity (permanent or substantial disruption of the subject’s 
ability to perform normal life functions); this definition is not intended to include experiences of 
relatively minor or temporary medical significance
Congenital anomaly/birth defect (an AE that occurs in the child or fetus of a subject exposed to 
study drug prior to conception or during pregnancy)
An important medical event or serious medical condition that does not meet any of the above criteria 
may be considered an SAE if, based upon appropriate medical judgment, it jeopardizes the subject 
or requires medical or surgical intervention to prevent one of the outcomes listed above. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not result in in-patient 
hospitalization, or the development of drug dependency or drug abuse.


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An overall summary will be presented that includes the number of TEAEs and the number and percentage 
of subjects who experienced at least one TEAE, total and by cohort. This summary will also include 
breakdowns of TEAEs further categorized as ocular (study eye and non-study eye, separately), non-ocular, 
serious TEAEs, TEAEs by maximum severity, treatment-related TEAEs, and TEAEs leading to subject 
withdrawal.
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE and total number of events. These summaries will be presented by SOC 
and PT. Non-ocular TEAEs will be summarized using discrete summary statistics and presented by cohort 
and total subjects at the subject and event level by SOC and PT. Ocular TEAEs will be similarly summarized 
at the subject level for study and non-study eyes separately. If a subject has multiple TEAEs coded to the
same PT within same SOC, that PT will only be reported once. As with the PT, if a subject reports multiple 
conditions within the same SOC, that SOC will only be reported once at the subject level. In the summary,
SOCs are listed in order of decreasing frequency for total subjects.  PTs are listed in order of decreasing 
frequency within each SOC for total subjects. The occurrence of non-ocular and ocular TEAEs will also be
tabulated by SOC and PT for the following: maximal severity and suspected relationship to study drug.
Separate summaries will be provided for the following categories of AEs:
Ocular TEAEs in the study eye
Ocular TEAEs in the non-study eye
Non-ocular TEAEs
Treatment-related ocular TEAEs in the study eye
Treatment-related ocular TEAEs in the non-study eye
Treatment-related non-ocular TEAEs
Ocular serious TEAEs in the study eye
Ocular Serious TEAEs in the non-study eye
Non-ocular serious TEAEs
Treatment-related ocular serious TEAEs in the study eye
Treatment-related ocular serious TEAEs in the non-study eye
Treatment-related non-ocular TEAEs
Ocular TEAEs by maximal severity in the study eye
Ocular TEAEs by maximal severity in the non-study eye
Non-ocular TEAEs by maximal severity
TEAEs leading to premature study discontinuation (if applicable)
The NCI-CTCAE (National Cancer Institute – Common Terminology Criteria for Adverse Events) (version 
4.03) is a descriptive terminology that will be used to grade the severity of non-ocular AEs reported in this 


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study. The NCI-CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each 
AE based on this general guideline:
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observation only; intervention 
not indicated
Grade 2: 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)*
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limited self-care ADL**
Grade 4: 
Life-threatening consequences; urgent intervention indicated
Grade 5: 
Death related to an AE
A semicolon indicates “or” within the above descriptions. A single dash (-) can be used to indicate that 
a grade is not available. Not all grades are appropriate for all AEs. Therefore, some AEs are listed with 
fewer than 5 options for grade selection.
*
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not being bedridden.
The severity grading of ocular AEs reported in this study will not employ the NCI-CTCAE criteria defined 
above but will be graded as described here. Severity of an ocular AE is defined as a qualitative assessment 
of the degree of intensity of an AE as determined by the Investigator or reported to him/her by the subject. 
The assessment of severity is made irrespective of relationship to the study drug or seriousness of the 
event and should be evaluated according to the following scale:
Mild: Event is noticeable to the subject but is easily tolerated and does not interfere with the subject’s 
daily activities.
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with the 
subject’s daily activities.
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and interferes 
with the subject’s daily activities.
Summaries of TEAEs by maximal severity will be provided showing the number and percentage of subjects 
who experienced at least one TEAE and total number of events. These summaries will be presented by SOC 
and PT. Non-ocular TEAEs will be summarized using discrete summary statistics and presented by cohort 
and total subjects at the subject and event level by SOC and PT. Ocular TEAEs will be similarly summarized 
at the subject level for study and non-study eyes separately. 
The relationship of each AE to the study drug should be determined by the Investigator using these 
explanations:


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Related: A reasonable possibility exists that the study drug caused the AE.
Not Related: A reasonable possibility does not exist that the study drug caused the AE.
Summaries of all ocular and non-ocular TEAEs, TEAEs by maximal severity, TEAES related to the study 
drug, and serious TEAEs will also be tabulated by study site for each cohort and total subjects. All ocular 
AEs occurred in study eye and non-study eye will be summarized separately.
All TEAEs will be presented in a subject listing. The TEAEs leading to study treatment discontinuation will 
be listed separately. In addition, all serious AEs will be presented in a separate listing.
13.2
BCVA (ETDRS)
The observed and change from baseline BCVA letter score will be summarized for the study eye and non-
study eye using continuous descriptive statistics by visit for each cohort and for all subjects combined. A 
subject listing of visual acuity will also be produced. This listing will include a variable that indicates if a 
13.3
Slit-Lamp Biomicroscopy Examination
A slit-lamp biomicroscopy examination of the eyelid, cornea, conjunctiva, anterior chamber, iris, pupil, lens,
lens status, and Age-Related Eye Disease Study (AREDS) scores for Nuclear, Cortical, and PCS opacity
will be performed at each visit. The results will be graded as normal, abnormal not clinically significant 
(NCS), or abnormal clinically significant (CS) for all but the lens status and AREDS scores. Lens status will 
be denoted phakic, pseudophakic, or aphakic. AREDS opacity scores are <1, 1, 1.5, 2, 2.5, 3, or >3. Anterior 
chamber cells and flare will also be assessed using categorical responses that range from 0 to 4+, as 
described below.
Anterior Chamber Cells:
Grade
Number of cells
0
None
+0.5 
1 – 5
+1 
6 - 15
+2 
16 – 25
+3 
26 – 50
+4 
> 50
Anterior Chamber Flare:
Grade
Description
0
None
+1 
Trace
+2 
Moderate (iris and lens detail clear)


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+3 
Marked (iris and lens detail hazy)
+4 
Intense (fibrin or plastic aqueous)
The results will be summarized using counts and percentages for each cohort and for all GB-102 treated 
subjects combined at each visit for each eye (study eye and non-study eye). Percentages will be based on 
the number of subjects in each cohort with responses. Shift tables for each biomicroscopy parameter will 
also be provided comparing each follow-up visit to baseline. A subject listing of the slit-lamp biomicroscopy 
parameters will also be produced.
13.4
Dilated Ophthalmoscopy
A dilated fundus examination of the vitreous, macula, peripheral retina, choroid, and optic nerve will be 
performed at each visit. The results will be graded as normal, abnormal NCS, or abnormal CS. The results 
will be summarized using counts and percentages for each cohort and for all subjects at each visit for each 
eye (study eye and non-study eye). Percentages will be based on the number of subjects in each cohort 
with responses. A shift table for the dilated ophthalmoscopy parameters will also be provided comparing 
each follow-up visit to baseline. A subject listing of the dilated ophthalmoscopy parameters will also be 
produced.
13.5
Intraocular Pressure (IOP)
Intraocular pressure (IOP) will be assessed using Goldmann applanation tonometry or Tono-Pen at each 
visit. Results will be taken from a single measurement and will be recorded in mmHg. Clinically relevant 
change in IOP indicates increase from baseline is at least 10 mmHg and absolute value is at least 25 mmHg 
at a visit. The IOP values, changes from baseline, and clinically relevant change for each eye (study eye 
and non-study eye) will be summarized using continuous descriptive statistics by visit and eye for each 
cohort and for all subjects combined. A subject listing of IOP will also be produced.
13.6
Physical Examination
The physical examination will consist of, at a minimum, a routine evaluation of the organ systems including 
general appearance, neck, head, ears, nose, throat, cardiovascular, respiratory, abdomen, and 
skin/extremities. At the final study visit, the physical examination will include a query of the subject to 
determine if changes in his/her physical condition have occurred since the screening examination. A subject 
listing of the physical examination results will be produced.
13.7
Vital Signs
Vital signs, including height, heart rate (HR) and systolic and diastolic blood pressure will be measured at 
Screening, Day 1, and Month 6. Body weight will be measured at Screening and Month 6. Height will be 
measured only at Screening. Changes from baseline will be summarized at Month 6 for applicable 
parameters. A subject listing of the vital signs results will also be produced.


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13.8
Blood Chemistry
Blood samples for Hemoglobin A1c (nonfasting) will be collected prior to administration of study drug. 
Screening laboratory tests may be repeated once at the discretion of the Investigator. A subject listing of 
the blood chemistry results will be produced.
13.9
Pregnancy Testing
Urine pregnancy test will be conducted on women of childbearing potential as appropriate. Women of 
childbearing potential (i.e., not postmenopausal for at least 12 months or not surgically sterile [bilateral tubal 
ligation, hysterectomy, or bilateral oophorectomy]) must have a negative urine pregnancy test at Screening
and must use adequate birth control throughout the study if she has a nonsurgically sterile male sexual 
partner. A subject listing of urine pregnancy test results will be produced. 
14. Interim Analyses
Once all subjects complete the 3-month visit, an interim analysis (IA) will be performed on safety data. No 
statistical adjustments will be made for this exploratory study and due to the analysis being limited to 
safety endpoints and due to the absence of any hypothesis testing.


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15. Tables
Tables that will be included in the topline delivery are shown in boldface italics font.
Table Number
Title
POPULATION
Table 14.1.1.1
Subject Disposition
All Enrolled Subjects
Table 14.1.1.2
Subject Enrollment Status
All Subjects Including Screen 
Failures
Table 14.1.2.1
Demographic and Pretreatment Variables in Study Eye
Full Analysis Set
Table 14.1.2.2
Demographic and Pretreatment Variables in Study Eye
Safety Analysis Set
Table 14.1.2.3
Demographic and Pretreatment Variables in Study Eye
Per Protocol Analysis Set
Table 14.1.4.1
Ocular Medical History
Safety Analysis Set
Table 14.1.4.2
Non-Ocular Medical History
Safety Analysis Set
Table 14.1.5.1
Ocular Prior Medications
Safety Analysis Set
Table 14.1.5.2
Ocular Concomitant Medications
Safety Analysis Set
Table 14.1.5.3
Non-Ocular Prior Medications
Safety Analysis Set
Table 14.1.5.4
Non-Ocular Concomitant Medications
Safety Analysis Set
Table 14.1.6
Study Drug Administration
Safety Analysis Set
Table 14.2.1.1
Change from Baseline in Number of Letters Read 
Correctly (using BCVA) in the Study Eye at Scheduled 
Visits
Full Analysis Set – As 
Observed (Including Rescue 
Treatment)
Table 14.2.1.2
Change from Baseline in Number of Letters Read Correctly 
(using BCVA) in the Study Eye at Scheduled Visits
Per Protocol Analysis Set – As 
Observed (Including Rescue 
Treatment)
Table 14.2.1.3
Change from Baseline in Number of Letters Read Correctly 
(using BCVA) in the Study Eye at Scheduled Visits by 
Diagnosis 
Full Analysis Set – As 
Observed (Including Rescue 
Treatment)
Table 14.2.1.4
Change from Baseline in Number of Letters Read Correctly 
(using BCVA) in the Study Eye at Scheduled Visits by 
Diagnosis 
Per Protocol Analysis Set – As 
Observed (Including Rescue 
Treatment)
Table 14.2.1.5
Change from Baseline in Number of Letters Read 
Correctly (using BCVA) in the Study Eye at Scheduled 
Visits 
Full Analysis Set – LOCF 
With Censoring For Rescue1


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Table 14.2.1.6
Change from Baseline in Number of Letters Read Correctly 
(using BCVA) in the Study Eye at Scheduled Visits
Per Protocol Analysis Set –
LOCF With Censoring For 
Rescue1
Table 14.2.1.7
Change from Baseline in Number of Letters Read Correctly 
(using BCVA) in the Study Eye at Scheduled Visits by 
Diagnosis 
Full Analysis Set – LOCF With 
Censoring For Rescue1
Table 14.2.1.8
Change from Baseline in Number of Letters Read Correctly 
(using BCVA) in the Study Eye at Scheduled Visits by 
Diagnosis 
Per Protocol Analysis Set –
LOCF With Censoring For 
Rescue1
Table 14.2.2.1
Change from Baseline in Retinal CST (Using SD-OCT in 
µm) in the Study Eye at Scheduled Visits 
Full Analysis Set – As 
Observed (Including Rescue 
Treatment)
Table 14.2.2.2
Change from Baseline in Retinal CST (Using SD-OCT in µm)
in the Study Eye at Scheduled Visits
Per Protocol Analysis Set – As 
Observed (Including Rescue 
Treatment)
Table 14.2.2.3
Change from Baseline in Retinal CST (Using SD-OCT in µm)
in the Study Eye at Scheduled Visits by Diagnosis 
Full Analysis Set – As 
Observed (Including Rescue 
Treatment)
Table 14.2.2.4
Change from Baseline in Retinal CST (Using SD-OCT in µm)
in the Study Eye at Scheduled Visits by Diagnosis 
Per Protocol Analysis Set – As 
Observed (Including Rescue 
Treatment)
Table 14.2.2.5
Change from Baseline in Retinal CST (Using SD-OCT in 
µm) in the Study Eye at Scheduled Visits 
Full Analysis Set – LOCF 
With Censoring For Rescue1
Table 14.2.2.6
Change from Baseline in Retinal CST (Using SD-OCT in µm)
in the Study Eye at Scheduled Visits
Per Protocol Analysis Set –
LOCF With Censoring For 
Rescue1
Table 14.2.2.7
Change from Baseline in Retinal CST (Using SD-OCT in µm)
in the Study Eye at Scheduled Visits by Diagnosis 
Full Analysis Set – LOCF With 
Censoring For Rescue1
Table 14.2.2.8
Change from Baseline in Retinal CST (Using SD-OCT in µm)
in the Study Eye at Scheduled Visits by Diagnosis 
Per Protocol Analysis Set –
LOCF With Censoring For 
Rescue1
Table 14.2.3.1
Time to Receipt of Rescue Treatment Using Kaplan-Meier 
Approach
Full Analysis Set
Table 14.2.3.2
Time to Receipt of Rescue Treatment Using Kaplan-Meier 
Approach 
Per Protocol Analysis Set
Table 14.2.3.3
Time to Receipt of Rescue Treatment Using Kaplan-Meier 
Approach by Diagnosis
Full Analysis Set
Table 14.2.3.4
Time to Receipt of Rescue Treatment Using Kaplan-Meier 
Approach by Diagnosis
Per Protocol Analysis Set


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Table 14.2.3.5
Mean Time to Receipt of First Rescue Treatment Among 
Rescued Subjects 
Full Analysis Set
Table 14.2.3.6
Mean Time to Receipt of First Rescue Treatment Among 
Rescued Subjects 
Per Protocol Analysis Set
Table 14.2.3.7
Mean Time to Receipt of First Rescue Treatment Among 
Rescued Subjects by Diagnosis 
Full Analysis Set
Table 14.2.3.8
Mean Time to Receipt of First Rescue Treatment Among 
Rescued Subjects by Diagnosis 
Per Protocol Analysis Set
Table 14.2.4.1
Proportion of Subjects Receiving Rescue Treatment by 
Visit 
Full Analysis Set
Table 14.2.4.2
Proportion of Subjects Receiving Rescue Treatment by Visit 
Per Protocol Analysis Set
Table 14.2.4.3
Proportion of Subjects Receiving Rescue Treatment by Visit,
and Diagnosis 
Full Analysis Set
Table 14.2.4.4
Proportion of Subjects Receiving Rescue Treatment by Visit, 
and Diagnosis 
Per Protocol Analysis Set
Table 14.2.4.5
Contingency 
Table 
Showing 
Proportion 
of 
Subjects 
Receiving Rescue Treatment and Meeting Treatment Criteria 
by Visit 
Full Analysis Set
Table 14.2.4.6
Contingency 
Table 
Showing 
Proportion 
of 
Subjects 
Receiving Rescue Treatment and Meeting Treatment Criteria
by Visit 
Per Protocol Analysis Set
Table 14.2.4.7
Contingency 
Table 
Showing 
Proportion 
of 
Subjects 
Receiving Rescue Treatment and Meeting Treatment Criteria 
by Visit, and Diagnosis 
Full Analysis Set
Table 14.2.4.8
Contingency 
Table 
Showing 
Proportion 
of 
Subjects 
Receiving Rescue Treatment and Meeting Treatment Criteria 
by Visit, and Diagnosis 
Per Protocol Analysis Set
Table 14.2.5.1
Total Number of Rescue Treatments Received by Each 
Subject 
Full Analysis Set
Table 14.2.5.2
Total Number of Rescue Treatments Received by Each 
Subject 
Per Protocol Analysis Set
Table 14.2.5.3
Total Number of Rescue Treatments Received by Each 
Subject, and Diagnosis 
Full Analysis Set
Table 14.2.5.4
Total Number of Rescue Treatments Received by Each 
Subject, and Diagnosis 
Per Protocol Analysis Set
Table 14.2.6.1
Time in the Study From First Rescue Treatment Received 
by Each Subject 
Full Analysis Set


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Table 14.2.6.2
Time in the Study From First Rescue Treatment Received by 
Each Subject
Per Protocol Analysis Set
Table 14.2.6.3
Time in the Study From First Rescue Treatment Received by 
Each Subject, and Diagnosis 
Full Analysis Set
Table 14.2.6.4
Time in the Study From First Rescue Treatment Received by 
Each Subject, and Diagnosis
Per Protocol Analysis Set
Table 14.2.8.1
Change in Number of Letters Read Correctly (Using BCVA) 
in Response to Anti-VEGF Rescue Treatment at Scheduled 
Visits in the Study Eye
Full Analysis Set with a 
Rescue Treatment – As 
Observed
Table 14.2.8.2
Change in Number of Letters Read Correctly (Using BCVA) 
in Response to Anti-VEGF Rescue Treatment at Scheduled 
Visits in the Study Eye
Per Protocol Analysis Set with 
a Rescue Treatment – As 
Observed
Table 14.2.8.3
Change in Number of Letters Read Correctly (Using BCVA) 
in Response to Anti-VEGF Rescue Treatment at Scheduled 
Visits in the Study Eye, by Diagnosis 
Full Analysis Set with a 
Rescue Treatment – As 
Observed
Table 14.2.8.4
Change in Number of Letters Read Correctly (Using BCVA) 
in Response to Anti-VEGF Rescue Treatment at Scheduled 
Visits in the Study Eye by Diagnosis 
Per Protocol Analysis Set with 
a Rescue Treatment – As 
Observed
Table 14.2.9.1
Change in Retinal CST (Using SD-OCT in µm) in Response 
to Anti-VEGF Rescue Treatment at Scheduled Visits in the 
Study Eye
Full Analysis Set with a 
Rescue Treatment – As 
Observed
Table 14.2.9.2
Change in Retinal CST (Using SD-OCT in µm) in Response 
to Anti-VEGF Rescue Treatment at Scheduled Visits in the 
Study Eye
Per Protocol Analysis Set with 
a Rescue Treatment – As 
Observed
Table 14.2.9.3
Change in Retinal CST (Using SD-OCT in µm) in Response 
to Anti-VEGF Rescue Treatment at Scheduled Visits in the 
Study Eye by Diagnosis 
Full Analysis Set with a 
Rescue Treatment – As 
Observed
Table 14.2.9.4
Change in Retinal CST (Using SD-OCT in µm) in Response 
to Anti-VEGF Rescue Treatment at Scheduled Visits in the 
Study Eye by Diagnosis 
Per Protocol Analysis Set with 
a Rescue Treatment – As 
Observed
Table 14.3.1.1
Overall Summary of Adverse Event
Safety Analysis Set
Table 14.3.2.1
All Ocular Treatment-Emergent Adverse Events in the 
Study Eye
Safety Analysis Set
Table 14.3.2.2
All Ocular Treatment-Emergent Adverse Events in the Non-
Study Eye
Safety Analysis Set
Table 14.3.2.3
All Non-Ocular Treatment-Emergent Adverse Events
Safety Analysis Set
Table 14.3.3.1
All Ocular Treatment-Emergent Adverse Events Suspected to
be Related to Investigational Product in the Study Eye
Safety Analysis Set


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Table 14.3.3.2
All Ocular Treatment-Emergent Adverse Events Suspected to
be Related to Investigational Product in the Non-Study Eye
Safety Analysis Set
Table 14.3.3.3
All 
Non-Ocular 
Treatment-Emergent 
Adverse 
Events 
Suspected to be Related to Investigational Product
Safety Analysis Set
Table 14.3.4.1
All Ocular Treatment-Emergent Serious Adverse Events
in the Study Eye
Safety Analysis Set
Table 14.3.4.2
All Ocular Treatment-Emergent Serious Adverse Events in 
the Non-Study Eye
Safety Analysis Set
Table 14.3.4.3
All Non-Ocular Treatment-Emergent Serious Adverse 
Events
Safety Analysis Set
Table 14.3.5.1
All Serious Ocular Treatment-Emergent Adverse Events 
Suspected to be Related to Investigational Product in the 
Study Eye
Safety Analysis Set
Table 14.3.5.2
All Serious Ocular Treatment-Emergent Adverse Events 
Suspected to be Related to Investigational Product in the 
Non-Study Eye
Safety Analysis Set
Table 14.3.5.3
All Serious Non-Ocular Treatment-Emergent Adverse Events 
Suspected to be Related to Investigational Product
Safety Analysis Set
Table 14.3.6.1
Incidence of Ocular Treatment-Emergent Adverse Events in 
the Study Eye by Maximum Severity, System Organ Class 
and Preferred Term
Safety Analysis Set
Table 14.3.6.2
Incidence of Ocular Treatment-Emergent Adverse Events in 
the Non-Study Eye by Maximum Severity, System Organ 
Class and Preferred Term
Safety Analysis Set
Table 14.3.6.3
Incidence of Non-Ocular Treatment-Emergent Adverse 
Events by Maximum Severity, System Organ Class and 
Preferred Term
Safety Analysis Set
Table 14.3.7
All Treatment-Emergent Adverse Events
Leading to 
Premature Study Discontinuation
Safety Analysis Set
Table 14.3.8
Best Corrected Visual Acuity (BCVA) In Letters (ETDRS)
Safety Analysis Set
Table 14.3.9.1
Slit-Lamp Biomicroscopy
Safety Analysis Set
Table 14.3.9.2
Shifts in Slit-Lamp Biomicroscopy from Baseline to Each 
Post-Baseline Visit: Normal/Abnormal Responses
Safety Analysis Set
Table 14.3.9.3
Shifts in Slit-Lamp Biomicroscopy from Baseline to Each 
Post-Baseline Visit: AREDS Scores and Anterior Chamber 
Cells and Flare
Safety Analysis Set
Table 14.3.10.1
Dilated Ophthalmoscopy
Safety Analysis Set


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Table 14.3.10.2
Shifts in Dilated Ophthalmoscopy from Baseline to Each 
Post-Baseline Visit
Safety Analysis Set
Table 14.3.11
Intraocular Pressure
Safety Analysis Set
Table 14.3.12
Vital Signs
Safety Analysis Set
Table 14.3.13.1
All Ocular Treatment-Emergent Adverse Events in the Study 
Eye by Site
Safety Analysis Set
Table 14.3.13.2
All Ocular Treatment-Emergent Adverse Events in the Non-
Study Eye by Site
Safety Analysis Set
Table 14.3.13.3
All Non-Ocular Treatment-Emergent Adverse Events by Site
Safety Analysis Set
Table 14.3.14.1
Incidence of Ocular Treatment-Emergent Adverse Events in 
the Study Eye by Maximum Severity, System Organ 
Class,Preferred Term, and Site
Safety Analysis Set
Table 14.3.14.2
Incidence of Ocular Treatment-Emergent Adverse Events in 
the Non-Study Eye by Maximum Severity, System Organ 
Class,Preferred Term, and Site
Safety Analysis Set
Table 14.3.14.3
Incidence of Non-Ocular Treatment-Emergent Adverse 
Events by Maximum Severity, System Organ Class, 
Preferred Term, and Site
Safety Analysis Set
Table 14.3.15.1
All Ocular Treatment-Emergent Adverse Events Suspected 
to be Related to Investigational Product in the Study Eye by 
Site
Safety Analysis Set
Table 14.3.15.2
All Ocular Treatment-Emergent Adverse Events Suspected 
to be Related to Investigational Product in the Non-Study 
Eye by Site
Safety Analysis Set
Table 14.3.15.3
All Non-Ocular Treatment-Emergent Adverse Events 
Suspected to be Related to Investigational Product by Site
Safety Analysis Set
Table 14.3.16.1
All Ocular Treatment-Emergent Serious Adverse Events in 
the Study Eye by Site
Safety Analysis Set
Table 14.3.16.2
All Ocular Treatment-Emergent Serious Adverse Events in 
the Non-Study Eye by Site
Safety Analysis Set
Table 14.3.16.3
All Non-Ocular Treatment-Emergent Serious Adverse 
Events by Site
Safety Analysis Set


Protocol GBV-102-003 SAP, Version 2.0
18 SEP 2020
Confidential & Proprietary
Page 29 of 30
16. Listings
Listing Number
Title
Population
Listing 16.2.1
Subject Disposition
All Enrolled and Screen 
Failed Subjects 
Listing 16.2.2.1
Major Protocol Deviations 
All Enrolled Subjects
Listing 16.2.2.2
Inclusion/Exclusion Criteria Assessed by Investigator 
All Enrolled and Screen 
Failed Subjects
Listing 16.2.3
Subjects Excluded from the Analysis Sets Per Protocol 
Population
All Enrolled Subjects
Listing 16.2.4.1
Demographics Variables
All Enrolled Subjects
Listing 16.2.4.2
Anti-VEGF History 
All Enrolled Subjects
Listing 16.2.4.3
Baseline Disease Characteristics
All Enrolled Subjects
Listing 16.2.4.4
Ocular Medical History
All Enrolled Subjects
Listing 16.2.4.5
Non-Ocular Medical History
All Enrolled Subjects
Listing 16.2.4.6
Ocular Prior and Concomitant Medications
All Enrolled Subjects
Listing 16.2.4.7
Non-Ocular Prior and Concomitant Medications
All Enrolled Subjects
Listing 16.2.4.8
Prior Anti-VEGF Medications
All Enrolled Subjects
Listing 16.2.4.9
Concomitant Anti-VEGF Medications
All Enrolled Subjects
Listing 16.2.4.10
Ocular and Non-Ocular Prior and Concomitant Procedures
All Enrolled Subjects
Listing 16.2.4.11
Study Drug Administration
Safety Analysis Set
Listing 16.2.6.1
Retinal Central Subfield Thickness (CST) Using Spectral 
Domain Optical Coherence Tomography (SD-OCT in µm)
All Enrolled Subjects
Listing 16.2.7.1
All Adverse Events
Safety Analysis Set
Listing 16.2.7.2
Treatment Emergent Serious Adverse Events
Safety Analysis Set
Listing 16.2.7.3
Treatment-Emergent Adverse Events Leading to Premature 
Study Discontinuation
Safety Analysis Set
Listing 16.2.8.1
Best Corrected Visual Acuity (BCVA) Scores
All Enrolled Subjects
Listing 16.2.8.2
Slit Lamp Biomicroscopy
All Enrolled Subjects
Listing 16.2.8.3
Dilated Ophthalmoscopy
All Enrolled Subjects


Protocol GBV-102-003 SAP, Version 2.0
18 SEP 2020
Confidential & Proprietary
Page 30 of 30
Listing Number
Title
Population
Listing 16.2.8.4
Intraocular Pressure (IOP)
All Enrolled Subjects
Listing 16.2.8.5
Physical Examination
All Enrolled Subjects
Listing 16.2.8.6
Vital Signs
All Enrolled Subjects
Listing 16.2.8.7
Blood Chemistry
All Enrolled Subjects
Listing 16.2.8.8
Urine Pregnancy Test Results
All Enrolled Female 
Subjects
17. Figures
Figure Number
Title
Population
Figure 14.2.2.1
Kaplan Meier Curves of Time to Receipt of Rescue treatment Full Analysis Set
Figure 14.2.2.2
Kaplan Meier Curves of Time to Receipt of Rescue treatment, 
Diagnosis = DME
Full Analysis Set
Figure 14.2.2.3
Kaplan Meier Curves of Time to Receipt of Rescue treatment, 
Diagnosis = RVO
Full Analysis Set