Clinical trial NCT03953079
Conditions: Neovascular Age-Related Macular Degeneration
Keywords: Age-related macular degeneration (AMD) Choroidal neovascularization
Sponsor: Graybug Vision
Start date: 2019-09-26; Completion date: 2021-06-03
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 2b, multicenter, visual examiner-masked, randomized active-controlled, parallel-arm design study to evaluate the safety and duration of repeated IVT injections of 3 dose levels of GB-102 compared with aflibercept.

Detailed description:
Phase 2b, multicenter, visual examiner-masked, randomized active-controlled, parallel-arm design study to evaluate the safety and duration of the effect of GB-102, as measured by time to first rescue treatment across multiple dose levels of GB-102 administered every 6 months as compared to intravitreal (IVT) aflibercept administered every 2 months in subjects with neovascular (wet) age-related macular degeneration who have received prior induction with anti-vascular endothelial growth factor (VEGF)

Extension Study:

To monitor the safety and duration of effect of IVT GB-102 administered every 6 months compared to IVT aflibercept administered every 2 months in subjects in ALTISSIMO (Core Study) who complete all study visits through Month 12 (Day 360) and who do not require/receive rescue treatment at the Month 12 (Day 360) final study visit

Arms: arm 1: Participants will receive intravitreal (IVT) GB-102 1 mg in the study eye at Baseline and Month 6 and sham at Months 2, 4, 8 and 10. arm 2: Participants will receive intravitreal (IVT) GB-102 2 mg in the study eye at Baseline, intravitreal (IVT) GB-102 1 mg at Month 6 and sham at Months 2, 4, 8 and 10. arm 3: Participants will receive intravitreal (IVT) aflibercept 2 mg in the study eye at Baseline, Months 2, 4, 6, 8 and 10.
Interventions: intervention 1: Drug: GB-102 intervention 2: Aflibercept
Intervention descriptions: intervention 1: Intravitreal injection of GB-102 intervention 2: Intravitreal injection of aflibercept (2 mg dose)

Protocol documents:
Prot_000.pdf: 
Graybug Vision Inc. 
 
Clinical Study Protocol 
 
Official Title: A Phase 2b Multicenter Dose-Ranging Study Evaluating the Safety and Efficacy 
of a Long-acting Intravitreal Sunitinib Malate Depot Formulation (GB-102) Compared to 
Intravitreal Aflibercept in Subjects with Neovascular (Wet) Age-related Macular Degeneration 
(ALTISSIMO Study) 
 
Protocol Number: GBV-102-002 
 
Document Date: 08Sep2020 
 
NCT Number: NCT03953079 
 
 
 




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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. 


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STUDY ACKNOWLEDGEMENT 
 
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-102-002 
Graybug Vision, Inc. 
275 Shoreline Drive, Suite 450 
Redwood City, CA 94065 
Study Title: 
A Phase 2b Multicenter Dose-Ranging Study Evaluating the Safety 
and Efficacy of a Long-acting Intravitreal Sunitinib Malate Depot 
Formulation (GB-102) Compared to Intravitreal Aflibercept in 
Subjects with Neovascular (Wet) Age-related Macular Degeneration 
(ALTISSIMO Study) 
Study Centers 
Planned: 
Approximately 35 study centers in the United States 
Objectives: 
With this amendment, the ALTISSIMO Study is divided into the 
ALTISSIMO (Core Study) and the Extension Study. Unless 
otherwise specified, all segments of the protocol refer to ALTISSIMO 
(Core Study).  
Primary Objective 
To evaluate the safety and duration of the effect of GB-102, as 
measured by time to first rescue treatment across two different dosing 
schemes of GB-102 administered every 6 months (1 mg followed by 
1 mg or 2 mg followed by 1 mg) as compared to intravitreal (IVT) 
aflibercept administered every 2 months in subjects with neovascular 
(wet) age-related macular degeneration who have received prior 
induction with anti-vascular endothelial growth factor (VEGF) 
Secondary Objectives 
•
To evaluate the efficacy of two different dosing schemes of
IVT GB-102 administered every 6 months in maintenance of
best-correct visual acuity (BCVA, ETDRS letter score)
compared to subjects receiving IVT aflibercept every
2 months
•
To evaluate the efficacy of two different dosing schemes of
IVT GB-102 administered every 6 months in maintenance of
central subfield thickness (CST, µm) compared to subjects
receiving IVT aflibercept every 2 months


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EXTENSION STUDY 
Objective 
To monitor the safety and duration of effect of IVT GB-102 
administered every 6 months compared to IVT aflibercept 
administered every 2 months in subjects in ALTISSIMO (Core 
Study) who complete all study visits through Month 12 (Day 360) 
and who do not require/receive rescue treatment at the Month 12 
(Day 360) final study visit 
Study Design: 
Multicenter, visual examiner-masked, randomized, active controlled, 
parallel-arm design. 
Eligible subjects will be randomly assigned (3:3:2) to receive 50-µL 
IVT injections of 1 of 2 doses of study drug or aflibercept, 
respectively, in the study eye using a stratified, blocked 
randomization scheme. Stratification will include baseline BCVA 
(< 60 letters vs ≥ 60 letters). Approximately 15 to 20 subjects per 
group, 56 subjects total, will be randomized to one of the following 
treatment arms: 
Group 1:   1 mg GB-102 at baseline and Month 6 and sham at 
Months 2, 4, 8, and 10 (N=21) 
Group 2:   2 mg GB-102 at baseline and 1 mg GB-102 at 
Month 6 and sham at Months 2, 4, 8, and 10 (N=22) 
Group 3:   2 mg aflibercept q 2 months at baseline, Months 2, 
4, 6, 8 and 10 (N=13) 
Assigned study drug will be administered on Day 1 (Appendix 18.1). 
Subjects will return to the study center on Days 14, 30, 60, 90, 120, 
150, 180, 210, 240, 300, 330, and 360 for safety, clinical, and 
imaging assessments (Table 3-1). Subjects will exit the study 
following all study assessments on Day 360. 
An interim safety analysis was conducted when approximately 50% 
of subjects had 3-months of accrued data to determine if any changes 
to the protocol were needed prior to the Month 6 re-dosing schedule. 
Unmasking of the interim safety data was made available only to the 
Sponsor’s Chief Medical Officer and the Vice President of Global 
Clinical Operations. The interim analysis showed no serious ocular 
adverse events. Four subjects experienced medication in the anterior 
chamber (AC) in the GB-102, 2 mg dose arm as compared to 1 
subject in the GB-102, 1 mg dose arm. Based on this safety analysis, 
the sponsor decided to terminate the development of the GB-102 2 
mg dose, and amended the protocol to use GB-102 1 mg for re-dosing 
of all subjects on GB-102 at the Month 6 visit, regardless of their 
original dose assignment.  The enrollment was capped at 56 subjects 


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and the primary endpoint was shifted from Month 10 to Month 12 
based on suggested feedback from the Food and Drug Administration 
(FDA). 
An unmasked primary analysis for safety and efficacy is planned 
when all subjects complete the Day 360 visit. 
The safety parameters to be collected include adverse events (AEs), 
serious adverse events (SAEs), physical examination findings, 
clinical laboratory test results, vital sign measurements, best corrected 
visual acuity (BCVA) assessments using the Early Treatment 
Diabetic Retinopathy Study (ETDRS) protocol, slit-lamp 
biomicroscopy findings, Age-related Eye Disease Study (AREDS) 
lens assessments, intraocular pressure (IOP) measurements, dilated 
ophthalmoscopy results, and date of administration of rescue 
treatment. 
Efficacy parameters will be measured by means of rescue treatment, 
BCVA (using the ETDRS protocol), retinal central subfield thickness 
(CST) using spectral domain-optical coherence tomography (SD-
OCT), fluorescein angiography (FA), and color fundus photography 
(CFP). 
The systemic exposure will be based on subjects assigned to each 
sunitinib treatment group. An analysis of approximately 20% of the 
subjects assigned to each sunitinib group will be performed. 
Safety Monitoring 
A medical monitor (ophthalmologist) and the Sponsor’s medical 
officer will evaluate the on-going masked safety data.  
Masking 
The visual acuity examiners, the Sponsor (other than the Vice 
President of Global Clinical Operations), the masked contract 
research organization (CRO) personnel, the medical monitor, and 
other study personnel, including individuals at a central reading 
center, study coordinators, laboratory vendor, etc. will remain masked 
relative to the GB-102 treatment scheme. The visual acuity examiners 
are not allowed to perform any study related activities other than 
BCVA assessments to maintain masking including obtaining medical 
histories or attempting to elicit any information regarding treatment, 
adverse events, or clinical information from the subjects. The same 
BCVA examiner should be utilized for each subject throughout the 
study when possible. 
Each study center will have at least 2 investigators who are retina 
specialists; one will serve as the injecting investigator and the other 
will serve as the assessing investigator. To maintain study masking, 


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the roles of these investigators should not be switched during the 
conduct of the study. 
•
Injecting Investigator: An injecting investigator will perform the
study drug (GB-102 or aflibercept), sham, and/or rescue
injections, will supervise the preparation and tracking of study
drug, and will perform predose and postdose safety assessments
for the IVT injections.
•
Assessing Investigator: An assessing investigator will supervise
and assess the collection of AEs and efficacy parameters. The
assessing investigator will determine whether rescue treatment is
required.
The SD-OCT, FA, and CFP technicians are masked to treatment 
scheme; however, collected images may reveal to the assessing 
investigator or technician which subjects received the GB-102 depot. 
Study personnel performing reconstitution of the investigational drug 
product (GB-102) will be unmasked to treatment assignment but not 
the treatment scheme. Study drug will be boxed in numbered kits and 
identical in external appearance and weight. Kits containing GB-102 
are identical in physical appearance and drug vial/diluent (pre-filled 
syringe) configuration, and fully masked as to the dose strength (1 mg 
or 2 mg) of GB-102. 
Rescue Treatment 
Rescue treatment (using aflibercept) will be permitted in the study 
eye in any of the study arms if the eligibility criteria are met for 
rescue treatment. 
EXTENSION STUDY 
The Extension Study is a multicenter, visual examiner-masked study, 
designed to monitor the safety and duration of effect of IVT GB-102 
administered every 6 months compared to IVT aflibercept 
administered every 2 months in subjects in ALTISSIMO (Core 
Study) who complete all study visits through Month 12 (Day 360) 
and who do not require/receive rescue treatment at the Month 12 
(Day 360) final study visit. 
Enrolled subjects will be followed for monthly visits until they 
receive rescue treatment or for a maximum of 180 days (i.e, 
6 months). There will be no additional treatment with GB-102. 
The assessments to be collected include AEs, SAEs, concomitant 
medications, BCVA assessments using ETDRS protocol, slit-lamp 
biomicroscopy findings, AREDS lens assessments, IOP 
measurements, dilated ophthalmoscopy results, retinal CST using  


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SD-OCT, color fundus photography for depot imaging (ultra-
widefield imaging, where available) and date of administration of 
rescue treatment.  
Once a subject meets at least one rescue criteria and all study visit 
assessments are completed, they may receive an injection of 
aflibercept and exit the study. 
No formal statistical hypotheses testing will be performed. An 
exploratory analysis of safety and efficacy will be performed after all 
subjects have completed the study. 
Safety Monitoring 
A medical monitor (ophthalmologist) and the Sponsor’s medical 
officer will evaluate the on-going masked safety data.  
Masking 
The visual acuity examiners, the Sponsor (other than the Vice 
President of Global Clinical Operations), the masked contract 
research organization (CRO) personnel, the medical monitor, and 
other study personnel, including individuals at a central reading 
center, study coordinators, laboratory vendor, etc. will remain masked 
relative to the GB-102 treatment scheme. The visual acuity examiners 
are not allowed to perform any study related activities other than 
BCVA assessments to maintain masking including obtaining medical 
histories or attempting to elicit any information regarding treatment, 
adverse events, or clinical information from the subjects. The same 
BCVA examiner should be utilized for each subject throughout the 
study when possible. 
Each study center will have at least 2 investigators who are retina 
specialists; one will serve as the injecting investigator and the other 
will serve as the assessing investigator. To maintain study masking, 
the roles of these investigators should not be switched during the 
conduct of the study. 
•
Injecting Investigator: An injecting investigator will perform the
rescue injections, will supervise the preparation and tracking of
study drug, and will perform predose and postdose safety
assessments for the IVT injections.
•
Assessing Investigator: An assessing investigator will supervise
and assess the collection of AEs, SAEs, concomitant medications,
BCVA assessments using ETDRS protocol, slit-lamp
biomicroscopy findings, AREDS lens assessments, IOP
measurements, dilated ophthalmoscopy results, and retinal CST


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using SD-OCT. The assessing investigator will determine whether 
rescue treatment is required. 
The SD-OCT and color fundus photography imaging (ultra-widefield 
imaging, where available) technicians are masked to treatment 
scheme; however, collected images may reveal to the assessing 
investigator or technician which subjects received the GB-102 depot 
in ALTISSIMO (Core Study). 
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. 
EXTENSION STUDY 
The study eye is defined as the eye that was treated in ALTISSIMO 
(Core Study). 
Rescue Treatment 
Criteria: 
Rescue treatment (aflibercept) for all subjects enrolled is allowed at 
any visit following the Day 30 study assessments in ALTISSIMO 
(Core Study) or any visit following the Month 13 (Day 390) study 
assessments in the Extension Study in subjects who meet any of the 
following criteria regarding decrease in BCVA and/or increase in 
CST: 
• Decrease in BCVA (any of the following criteria): 
o ≥ 5 ETDRS letter decrease compared with the average of 
last 2 visit BCVA ETDRS letter scores, and/or, 
o ≥ 10 ETDRS letter decrease compared with best on-study 
BCVA ETDRS letter score 
• Increase in CST (any of the following criteria): 
o ≥ 75 µm compared with the average of the last 2 visit CST 
measurements (µm), and/or, 
o ≥ 100 µm compared with the lowest on-study CST 
measurement (µm) 
Before rescue treatment is administered, the assessing investigator 
must confirm that the criteria have been met using an interactive 
database system. 
Number of 
Subjects Planned: 
Approximately 15 to 20 subjects per treatment schemes will be 
randomized (approximately 56 subjects across all treatment schemes 
combined) 


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EXTENSION STUDY 
There will be no randomization in the Extension Study. 
Target Population: 
Subjects eligible for screening must have an active choroidal 
neovascularization (CNV) lesion in the study eye secondary to AMD 
that was diagnosed in the 12 weeks to 18 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 21 days of screening. 
Eligibility will be confirmed by a central reading center based upon 
SD-OCT, FA, and CFP evaluation of the CNV lesion. 
EXTENSION STUDY 
Subjects eligible for screening and enrollment must complete all 
study assessments at Month 12 (Day 360) including fluorescein 
angiography, and not require/receive a rescue treatment at the 
Month 12 (Day 360) final study visit in ALTISSIMO (Core Study). 
Duration of Study 
Participation: 
Approximately 390 days (up to 30 days for screening and 360 days of 
treatment/observation) 
EXTENSION STUDY 
Approximately 180 days of observation after exiting ALTISSIMO 
(Core Study). During the Extension Study, any subject who meets the 
rescue criteria at any visit will undergo end of the Extension Study 
assessments, receive a dose of aflibercept as the rescue medication, 
and exit the study. 
Inclusion Criteria: 
1. Verbal and written informed consent obtained from the subject 
2. Males or females ≥ 50 years of age
3. Willing and able to give informed consent, comply with all study
procedures, and be likely to complete the study
4. Presence of a subfoveal or juxtafoveal CNV lesion secondary to
AMD in the study eye that was diagnosed in the 12 weeks to
18 months prior to screening and has been treated with at least
3 prior IVT injections of an anti-VEGF agent (aflibercept,
bevacizumab, or ranibizumab). The study eye and CNV lesion
must demonstrate all of the following features at the Screening
Visit (as confirmed by the reading center):
a.
Total lesion size ≤ 12 disc areas (30.5 mm2)


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b. Absence of subfoveal fibrosis, serous pigmented epithelial
detachment, retinal pigmented epithelial tear, or subfoveal
geographic atrophy
c.
If fibrosis is present, it must be ≤ 25% of total lesion area
and not involve the center of the fovea
d. If subfoveal hemorrhage is present, it must be < 1 disc
area in size and not involve the center of the fovea
e.
If subretinal hemorrhage is present, it must be < 50% of
total CNV lesion and not involve the center of the fovea
5. Prior pharmacodynamic response of the CNV lesion 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:
a.
Reduction of intraretinal/subretinal fluid by ≥ 30% from
the initial diagnosis as determined using SD-OCT
b. Reduction of excess CST by ≥ 30% from the initial
diagnosis as determined using SD-OCT (assuming
nominal thickness is 300 microns)
6. Demonstrate a maintained anti-VEGF response (as determined by
the investigator) compared with the initial diagnosis (prior to any
anti-VEGF treatment) as assessed using SD-OCT following the
most recent anti-VEGF injection (defined as a reduction in central
subfield thickness, intraretinal/subretinal fluid, or maintenance of
dry retina)
7. Screening and baseline BCVA letter score (by ETDRS protocol)
of 35 to 88 (20/200 to 20/20 Snellen equivalent) in the study eye
8. Availability of prior central subfield thickness (CST)
measurements from SD-OCT imaging obtained from the time of
initial diagnosis (pre-anti-VEGF therapy) and/or maximal CST
thickness obtained any time following anti-VEGF induction
9. 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
10. Most recent dose of anti-VEGF agent administered within 21 days
of screening
11. Clear ocular media and adequate pupil dilation in both eyes to
permit good quality photographic imaging


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12. Women of childbearing potential (ie, not postmenopausal for at
least 12 months or not surgically sterile [defined as bilateral
tubal ligation performed at least 12 months previously,
hysterectomy, or bilateral oophorectomy]) must have a negative
urine pregnancy test at screening and baseline, and must use
adequate birth control throughout the study and until 12 weeks
following the last dose of study drug 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
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 > 8.0% at the Screening Visit
4. Chronic renal disease requiring chronic hemodialysis or renal
transplantation
5. Any screening laboratory result (hematology, chemistry, or
urinalysis) that, in the opinion of the investigator, is not suitable
for subject participation in the study
6. 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)
7. Previous participation in an investigational study of GB-102
8. 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
9. 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
10. Presence of any clinically significant epiretinal membrane or
vitreomacular traction in the study eye


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11. History or evidence of any of the following surgeries or
procedures in the study eye:
a.
Submacular surgery or other surgical intervention for
AMD
b. Prior retinal detachment or macular hole interventions
c.
Vitrectomy
d. Photodynamic therapy or thermal laser retinal treatment
e.
Intraocular laser treatments for glaucoma (eg, selective
laser trabeculoplasty or peripheral iridotomy)
f.
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
g. Cataract surgery within the 3 months prior to the
Screening Visit
h. 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.
i.
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
j.
Corneal transplantation surgery
k. History of advanced glaucoma with visual field loss
encroaching on central fixation
12. Anterior chamber intraocular lens, aphakia, or violation of the
posterior capsule in the study eye
13. 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.
Advanced pre-proliferative diabetic retinopathy (with
potential for development of macular edema or macular
hemorrhage) or proliferative diabetic retinopathy and/or
diabetic macular edema in either eye


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b. Any retinal or choroidal vasculopathy, other than AMD, in
either eye
c.
Inflammatory conditions of the anterior or posterior
segment (eg, chronic keratoconjunctivitis, uveitis, retinal
vasculitis, neuritis, iritis, scleritis, or blepharitis)
d. Subfoveal involvement by any of the following: fibrosis,
serous pigmented epithelial detachment, retinal pigmented
epithelial tear, or geographic atrophy
e.
Subfoveal hemorrhage that is ≥ 1 disc areas in size (if the
blood is under the fovea, the fovea must be surrounded
≥ 270° by visible CNV)
f.
Subretinal hemorrhage that is ≥ 50% of the total CNV
lesion area
g. Any vitreous opacity that prevents proper visualization of
the fundus and/or adversely alters visual acuity, in the
opinion of the investigator
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.
14. Any history of active bacterial, viral, fungal, or parasitic infection
in either eye within the 30 days prior to the Screening Visit
15. Known allergy to constituents of the study drug formulation,
ocular antimicrobicide solutions, or clinically relevant
hypersensitivity to fluorescein
16. Women who are pregnant or lactating
17. 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 12 weeks following the
last dose of study drug
18. 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 monthly study
visits and assessments, or interfere with the interpretation of study
results
19. Exposure to tetrahydrocannibol (THC) (eg, recreational or
medicinal marijuana containing THC) within the past 12 months


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20. Prior exposure to oral sunitinib malate in the past 6 weeks 
EXTENSION STUDY 
Inclusion Criteria: 
1. Verbal and written informed consent for the Extension Study 
obtained from the subject 
2. Completed all study assessments at Month 12 (Day 360) final 
study visit including fluorescein angiography, and did not 
require/receive a rescue treatment at the Month 12 (Day 360) final 
study visit in ALTISSIMO (Core Study) 
3. Willing and able to give informed consent, comply with all study 
procedures, and be likely to complete the Extension Study 
EXTENSION STUDY 
Exclusion Criteria: 
1. Subjects who terminated early from ALTISSIMO (Core Study) 
2. Subjects who did not complete all study assessments at Month 12 
(Day 360) final study visit including fluorescein angiography in 
ALTISSIMO (Core Study) 
3. Subjects who received rescue treatment at the Month 12 
(Day 360) final study visit in ALTISSIMO (Core Study) 


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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 nAMD. 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 is lyophilized and reconstituted with hyaluronic acid prior to 
intravitreal administration to produce an administered IVT dose of 
sunitinib of 1 mg or 2 mg in a 50 µL injection using a 
27 gauge needle. 
Subjects randomized to receive GB-102 will receive their assigned 
dose on Day 1 and Day 180. All subjects assigned to GB-102 will 
receive the 1 mg GB-102 dose at Month 6 (Day 180). To maintain 
masking to treatment scheme, sham injections will be performed in 
the study eye on Days 60, 120, 240, and 300 to correspond to the 
dosing schedule of aflibercept. 
EXTENSION STUDY 
GB-102 will not be administered during the Extension Study. 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Aflibercept is recombinant fusion protein consisting of portions of 
human VEGF receptors 1 and 2 extracellular domains fused to the Fc 
portion of human immunoglobulin (IgG)1 formulated as an 
iso-osmotic solution for intravitreal administration. The approved 
aflibercept dose is 2 mg in a 50 µL injection administered every 
2 months. 
Subjects randomized to receive aflibercept will receive active drug on 
Days 1, 60, 120, 180, 240, and 300. 
EXTENSION STUDY 
No doses for any treatment schemes (GB-102 1 mg dose or 
aflibercept) will be administered during the Extension Study. 
However, subjects may receive aflibercept for rescue treatment 
therapy provided they have met the rescue treatment criteria. Once 
any type of rescue treatment has been administered, the subject will 
exit the Extension Study after undergoing the end of the Extension 
Study assessments. 


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Study Endpoints: 
Primary Endpoint 
•
Time to first rescue treatment (GB-102 only). This would be
further validated through assessing time to fufillment of at least
one rescue criterion.
Secondary Endpoints 
•
Time to fulfillment of at least one rescue criterion starting at the
Month 6 visit through to the Month 12 visit (excluding any rescue
at the Month 12 visit).
•
Number of times that at least one rescue criterion is met
•
Number of treatments, including both rescue and scheduled study
treatments, during the study
•
Change from baseline in BCVA (ETDRS) at all visits
•
Categorical change from Baseline in BCVA (ETDRS) at all visits
•
Frequency of subjects with BCVA worse than 20/200 (Snellen
equivalent) at all visits
•
Change from baseline in CST (µm) at all visits
•
Frequency of subjects with absence of exudation
(intra-/sub-retinal fluid/cystoid edema) at all visits
Exploratory Endpoints 
•
Change from baseline in BCVA comparing all subjects receiving
GB-102 to subjects receiving aflibercept at all visits
•
Change from baseline in CST comparing all subjects receiving
GB-102 to subjects receiving aflibercept at all visits
•
Change from baseline in total lesion area (mm2) at Months 6 and
12 of treatment
•
Change from baseline in CNV lesion area (mm2) at Months 6 and
12 of treatment
•
Change from baseline in fluorescein leakage area (mm2) at
Months 6 and 12 of treatment
•
Change from thickest observed CST (µm) prior to enrollment
(pre-enrollment baseline) at all visits
•
Change from average of observed CST (μm) prior to enrollment
(pre-enrollment baseline) at all visits
•
ALTISSIMO (Core Study) Subject Exit Questionnaire


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o
The subject exit questionnaire (Appendix 18.6) is not a
validated patient reported outcome (PRO) measure and is
designed to explore a subject’s experience with the
medication. All subjects exiting the study on Month 12
(Day 360), regardless of whether or not the subject joins
the Extension Study, are required to complete the
questionnaire.
Safety Endpoints 
•
Occurrence of ocular and nonocular AEs and SAEs
•
Plasma levels of sunitinib (ng/mL)
EXTENSION STUDY
Exploratory Endpoints
All safety and efficacy data collected beyond Month 12 (Day 360) 
will be assessed in an exploratory manner. 
Statistical Methods: 
Analysis Population 
•
Safety analysis set (SS): Includes all randomized subjects who
receive at least one dose of study treatment. Subjects will be
analyzed according to actual treatment scheme received.
•
Full analysis set (FAS): Includes all randomized subjects who
receive at least one dose of study treatment, and complete a
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. All efficacy analyses will be conducted
on the FAS and these analyses will be considered primary.
•
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 primary efficacy endpoint of the
study. Analyses conducted on the PP set will be considered
secondary.
Primary Endpoint and Analysis 
The primary efficacy endpoint is the time to first rescue treatment 
(GB-102 only). This would be further validated throught assessing 
time to fulfillment of at least one rescue criterion. 


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Time to first rescue treatment/fulfillment of at least one rescue 
criterion will be analyzed using the Kaplan-Meier method. The 
probability of remaining rescue treatment free/not fulfilling at least 
one rescue criterion will be reported for the Month 6 and Month 12 
visits with associated 80% confidence intervals (CI) based on 
Greenwood’s standard error estimate. Kaplan-Meier curves will be 
produced. If calculable, estimates of the median time to fulfillment of 
at least on rescue criterion and the 25th and 75th percentiles will be 
calculated with corresponding 80% CIs. The FAS will be the primary 
population used for analysis of the primary efficacy endpoint. 
For this analysis, the interval censored nature of the time to first 
rescue treatment/fulfillment of at least one rescue criterion with 
regard to the scheduled study visits is considered: If a subject receives 
a rescue treatment/fulfills a rescue criterion during an unscheduled 
visit, then the subject will be considered to have met the event of 
interest in the visit interval which ends at the next scheduled study 
visit that occurs after the unscheduled visit. Subjects who do not 
receive rescue medication/fulfill a rescue criterion will be censored 
on last scheduled study visit recorded for the subject.  
Exploratory comparisons between each GB-102 scheme and 
aflibercept and between the combined GB-102 schemes versus 
aflibercept regarding time to first fulfillment of at least one rescue 
criterion will be conducted using a log-rank test stratified by baseline 
BCVA (< 60 letters vs ≥ 60 letters), as defined at the time of 
randomization. The Peto method will be used to estimate the hazard 
ratio and asymptotic 80% confidence interval based on the stratified 
log rank test statistic. 
A primary endpoint analysis will be conducted when all subjects 
complete the Month 12 (Day 360) visit. 
Secondary Endpoint Analyses 
The change from baseline in BCVA and CST will be presented by 
treatment scheme with associated 80% confidence intervals (CI) for 
all visits. A similar analysis will be done for absolute values and 
change in BCVA and CST relative to the time of first rescue 
treatment (response to rescue treatment). Time to fulfillment of at 
least one rescue criterion starting at the Month 6 visit through Month 
12 will be summarized using descriptive statistics including 80% CIs 
and will be presented for the number of rescue treatments, number of 
scheduled treatments, number of total of rescue and scheduled 
treatments, and number of times that at least one rescue criterion is 
met from baseline through Month 12. 


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Absence of exudation (intra-/sub-retinal fluid/cystoid edema),  
categories of change from Baseline in BCVA, and BCVA worse than 
20/200 (Snellen equivalent) will be summarized at each visit using 
discrete summary statistics, including 80% asymptotic normal CIs for 
each treatment scheme. 
Further details on the analysis of the secondary efficacy endpoints 
will be provided in the SAP. 
Exploratory Efficacy Endpoints 
Observed values at each visit and change from baseline values at each 
follow up visit for BCVA, CST, total lesion area, CNV lesion area, 
and fluorescein leakage area will be summarized using continuous 
summary statistics, including 80% CIs around the mean for each 
treatment scheme, as well as the combined GB-102 groups and the 
aflibercept control group. For CST, the change from the thickest pre-
enrollment value (µm) and change from average pre-enrollment value 
(µm) at each visit will be similarly summarized. 
For BCVA and CST, comparisons between each GB-102 group and 
the aflibercept control group and between the combined GB-102 
groups and the aflibercept control group will be made primarily for 
each visit using a linear model adjusting for the baseline value as a 
covariate/class variable and secondarily using 2 sample t-tests. 
Safety Analyses 
All reported adverse events will be coded using the current version of 
the Medical Dictionary for Regulatory Activities (MedDRA) at the 
time of database lock. Treatment-emergent adverse events will be 
summarized by system organ class (SOC) and preferred term (PT). 
Frequencies and percentages will be provided by treatment scheme 
for subjects with TEAEs, treatment related TEAEs, serious TEAEs, 
serious treatment related TEAEs, TEAEs leading to premature study 
discontinuation, TEAEs by maximum severity, TEAEs by day of 
onset, and arteriothromboembolic TEAEs using Antiplatelet Trialists’ 
Collaboration criteria (ATC 1994). Separate analyses will be 
performed for ocular AEs in the study eye, ocular AEs in the non-
study eye, and nonocular AEs. 
Sunitinib systemic exposure will be summarized by descriptive 
statistics by dose group and time points. An analysis of approximately 
20% of the subjects assigned to each sunitinib group will be 
performed. 
Sample Size Considerations 
The sample size of this study was not selected to support specific 
statistical hypothesis testing as all comparisons are exploratory.  


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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. However, if the amount of missing post-baseline values for a 
particular endpoint are substantial, multiple imputation methods will 
be considered for the imputation of missing values. 
Sensitivity analyses of primary and secondary efficacy endpoints will 
be conducted using the per protocol population. Additional sensitivity 
analyses will be specified in the statistical analysis plan. 
EXTENSION STUDY 
All safety and efficacy data collected beyond Month 12 (Day 360) 
will be presented in listings and summarized as appropriate using 
descriptive statistics. 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ................................................................................................................................ 1 
STUDY ACKNOWLEDGEMENT ............................................................................................................................... 3 
INVESTIGATOR STATEMENT ................................................................................................................................. 3 
PROTOCOL SYNOPSIS .............................................................................................................................................. 4 
TABLE OF CONTENTS ............................................................................................................................................ 22 
LIST OF IN-TEXT TABLES ...................................................................................................................................... 25 
LIST OF IN-TEXT FIGURES .................................................................................................................................... 25 
GLOSSARY OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................. 26 
1 
INTRODUCTION .............................................................................................................................................. 28 
1.1 
Background ............................................................................................................................................ 28 
1.2 
Investigational Product ........................................................................................................................... 28 
1.3 
General Information ............................................................................................................................... 29 
1.3.1 
Nonclinical Studies .............................................................................................................. 29 
1.4 
Clinical Studies ...................................................................................................................................... 34 
1.4.1 
Protocol GBV-102-001 (Part 1) ........................................................................................... 35 
1.4.2 
Protocol GBV-102-003 (Phase 2a) ....................................................................................... 43 
1.4.3 
Protocol GBV-102-002 (Phase 2b, ALTISSIMO Study) ..................................................... 44 
1.5 
Compliance ............................................................................................................................................ 45 
2 
OBJECTIVES ..................................................................................................................................................... 46 
2.1 
ALTISSIMO (Core Study): Objectives .................................................................................................. 46 
2.1.1 
Primary Objective ................................................................................................................ 46 
2.1.2 
Secondary Objectives ........................................................................................................... 46 
2.2 
Extension Study: Objective .................................................................................................................... 46 
3 
INVESTIGATIONAL PLAN ............................................................................................................................. 47 
3.1 
Overall Study Design Summary ............................................................................................................. 47 
3.1.1 
ALTISSIMO (Core Study): Overall Study Design Summary .............................................. 47 
3.1.2 
Extension Study: Overall Study Design Summary ............................................................... 48 
3.2 
Safety Monitoring .................................................................................................................................. 49 
3.3 
Masking .................................................................................................................................................. 49 
3.3.1 
ALTISSIMO (Core Study) and Extension Study: Masking ................................................. 49 
3.3.2 
ALTISSIMO (Core Study): Masking ................................................................................... 49 
3.3.3 
Extension Study: Masking .................................................................................................... 50 
3.4 
Rescue Treatment ................................................................................................................................... 50 
3.5 
Study Design Rationale .......................................................................................................................... 50 
3.5.1 
ALTISSIMO (Core Study): Study Design Rationale ........................................................... 50 
3.5.2 
Extension Study: Study Design Rationale ............................................................................ 51 
3.6 
Appropriateness of Measurements ......................................................................................................... 51 
3.6.1 
ALTISSIMO (Core Study): Appropriateness of Measurements .......................................... 51 
3.6.2 
Extension Study: Appropriateness of Measurements ........................................................... 52 
4 
SUBJECT POPULATION .................................................................................................................................. 57 
4.1 
Number of Subjects and Subject Selection ............................................................................................ 57 
4.1.1 
ALTISSIMO (Core Study): Number of Subjects and Subject Selection .............................. 57 
4.1.2 
Extension Study: Number of Subjects and Subject Selection .............................................. 57 


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4.2 
Study Eye Determination ....................................................................................................................... 57 
4.2.1 
ALTISSIMO (Core Study): Study Eye Determination ........................................................ 57 
4.2.2 
Extension Study: Study Eye Determination ......................................................................... 57 
4.3 
Inclusion Criteria: ALTISSIMO (Core Study) ....................................................................................... 57 
4.4 
Exclusion Criteria: ALTISSIMO (Core Study) ...................................................................................... 60 
4.5 
Inclusion Criteria: Extension Study ....................................................................................................... 62 
4.6 
Exclusion Criteria: Extension Study ...................................................................................................... 62 
5 
INVESTIGATIONAL PRODUCTS ................................................................................................................... 63 
5.1 
Study Drug and Administration ............................................................................................................. 63 
5.1.1 
Investigational Product (GB-102) ........................................................................................ 63 
5.1.2 
Study Drug Administration .................................................................................................. 63 
5.2 
Treatment Assignment ........................................................................................................................... 64 
5.2.1 
Subject Identification Numbers ............................................................................................ 64 
5.2.2 
Enrollment and Method of Assigning Subjects to Treatment Cohorts/Groups .................... 64 
5.3 
Study Drug Packaging, Labeling, and Storage ....................................................................................... 65 
5.4 
Study Drug Compliance ......................................................................................................................... 66 
5.5 
Study Drug Accountability..................................................................................................................... 66 
5.6 
Prior and Concomitant Therapy ............................................................................................................. 66 
5.6.1 
Rescue Treatment ................................................................................................................. 66 
5.6.2 
Other Permitted Medications ................................................................................................ 67 
5.6.3 
Prohibited Medications......................................................................................................... 67 
5.7 
Other Study Supplies .............................................................................................................................. 67 
6 
STUDY PROCEDURES .................................................................................................................................... 68 
6.1 
Subject Entry Procedures ....................................................................................................................... 68 
6.1.1 
ALTISSIMO (Core Study): Subject Entry Procedures ........................................................ 68 
6.1.2 
Extension Study: Subject Entry Procedures ......................................................................... 69 
6.2 
Study Visit Procedures ........................................................................................................................... 69 
6.2.1 
Screening (Day −30 through Day −3) .................................................................................. 69 
6.2.2 
Baseline (Day 1) ................................................................................................................... 70 
6.2.3 
Week 2 and Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 ........................................................ 71 
6.2.4 
Month 12 (Day 360 ± 7) / Early Termination....................................................................... 72 
6.3 
Months 13, 14, 15, 16, and 17 (Extension Study) .................................................................................. 73 
6.4 
Month 18 (Day 540 ± 7) / Early Termination (Extension Study) ........................................................... 74 
6.5 
Screen Failures ....................................................................................................................................... 74 
6.6 
Unscheduled Study Visits ...................................................................................................................... 74 
6.7 
Subject Discontinuation ......................................................................................................................... 75 
6.7.1 
ALTISSIMO (Core Study): Subject Discontinuation........................................................... 75 
6.7.2 
Extension Study: Subject Discontinuation ........................................................................... 75 
6.8 
Subject Replacement .............................................................................................................................. 76 
6.9 
Study Termination Criteria..................................................................................................................... 76 
7 
STUDY ASSESSMENTS ................................................................................................................................... 77 
7.1 
Demographic Data ................................................................................................................................. 77 
7.2 
Medical and Medication History/ Concomitant Medications ................................................................. 77 
7.3 
Physical Examination ............................................................................................................................. 77 
7.4 
Pregnancy Testing .................................................................................................................................. 77 
7.5 
Blood Chemistry, Hematology, and Urinalysis ...................................................................................... 78 
7.6 
Plasma Pharmacokinetics (Systemic Exposure) ..................................................................................... 78 
7.7 
Vital Signs .............................................................................................................................................. 78 
7.8 
Best Corrected Visual Acuity ................................................................................................................. 78 
7.9 
Slit-lamp Biomicroscopy........................................................................................................................ 79 
7.10 
Intraocular Pressure ................................................................................................................................ 79 


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7.11 
Dilated Ophthalmoscopy ........................................................................................................................ 80 
7.12 
Spectral Domain – Optical Coherence Tomography .............................................................................. 80 
7.13 
Fluorescein Angiography ....................................................................................................................... 80 
7.14 
Color Fundus Photography..................................................................................................................... 80 
7.15 
Intravitreal Depot Color Fundus Photography ....................................................................................... 81 
7.16 
Postinjection Assessments...................................................................................................................... 81 
8 
ADVERSE EVENTS .......................................................................................................................................... 82 
8.1 
Definition of an Adverse Event .............................................................................................................. 82 
8.1.1 
Severity ................................................................................................................................ 83 
8.1.2 
Expectedness ........................................................................................................................ 83 
8.2 
Serious Adverse Event ........................................................................................................................... 84 
8.3 
Study Drug Causality ............................................................................................................................. 84 
8.4 
Adverse Event Reporting Procedures..................................................................................................... 85 
8.5 
Reporting Serious Adverse Events to Regulatory Agencies .................................................................. 85 
8.6 
Pregnancy ............................................................................................................................................... 86 
8.7 
Overdose ................................................................................................................................................ 86 
8.8 
Follow-up of Adverse Events ................................................................................................................. 86 
9 
STATISTICAL CONSIDERATIONS ................................................................................................................ 87 
9.1 
General Methods of Analysis ................................................................................................................. 87 
9.1.1 
ALTISSIMO (Core Study): General Methods of Analysis .................................................. 87 
9.1.2 
Extension Study: General Methods of Analysis ................................................................... 87 
9.2 
Study Endpoints ..................................................................................................................................... 87 
9.2.1 
Primary Endpoint ................................................................................................................. 87 
9.2.2 
Secondary Endpoints ............................................................................................................ 87 
9.2.3 
Exploratory Endpoints .......................................................................................................... 88 
9.2.4 
Safety Endpoints .................................................................................................................. 88 
9.3 
Analysis Populations .............................................................................................................................. 89 
9.4 
Subject Demographics and Baseline Characteristics .............................................................................. 89 
9.5 
Analysis of Imaging Parameters............................................................................................................. 89 
9.6 
Efficacy Analyses................................................................................................................................... 89 
9.6.1 
Primary Efficacy Analysis .................................................................................................... 90 
9.6.2 
Secondary Efficacy Analysis ................................................................................................ 90 
9.6.3 
Exploratory Efficacy Analysis ............................................................................................. 91 
9.7 
Safety Analyses ...................................................................................................................................... 91 
Adverse Events....................................................................................................................................... 91 
Plasma Levels of Sunitinib ..................................................................................................................... 92 
Other Safety Endpoints .......................................................................................................................... 92 
9.8 
Sample Size Determination .................................................................................................................... 92 
9.9 
Missing Data and Sensitivity Analyses .................................................................................................. 92 
9.10 
Subjects Receiving Rescue Treatment ................................................................................................... 93 
9.11 
Units of Analysis .................................................................................................................................... 93 
9.12 
Changes in the Conduct of the Study or Planned Analyses.................................................................... 93 
10 
DATA QUALITY ASSURANCE ...................................................................................................................... 94 
11 
ELECTRONIC CASE REPORT FORMS AND SOURCE DOCUMENTS ...................................................... 95 
12 
STUDY MONITORING AND AUDITING ....................................................................................................... 97 
13 
RETENTION OF RECORDS ............................................................................................................................. 98 
14 
USE OF INFORMATION AND PUBLICATION ............................................................................................. 99 
15 
ETHICS ............................................................................................................................................................ 100 


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15.1 
Institutional Review Board................................................................................................................... 100 
15.2 
Ethical Conduct of the Study ............................................................................................................... 100 
15.3 
Subject Information and Consent ......................................................................................................... 101 
16 
INVESTIGATOR RESPONSIBILITIES ......................................................................................................... 102 
17 
REFERENCES ................................................................................................................................................. 103 
18 
APPENDICES .................................................................................................................................................. 106 
18.1 
Study Schema Protocol GBV-102-002 ................................................................................................ 106 
18.1.1 
ALTISSIMO (Core Study) ................................................................................................. 106 
18.1.2 
Extension Study.................................................................................................................. 107 
18.2 
Nonocular and Systemic Adverse Event Severity Assessment ............................................................ 108 
18.3 
Ocular Adverse Event Severity Assessment ........................................................................................ 109 
18.4 
Ocular Grading Scales .......................................................................................................................... 110 
18.4.1 
Grading Scale for Ocular Inflammation ............................................................................. 110 
18.4.2 
Grading Scale of Retinal or Vitreous Hemorrhage............................................................. 110 
18.4.3 
Grading of Vitreous Haze ................................................................................................... 111 
18.5 
Age-Related Eye Disease Study Lens Scale ........................................................................................ 112 
18.5.1 
Nuclear Sclerosis ................................................................................................................ 112 
18.5.2 
Cortical Opacities ............................................................................................................... 112 
18.5.3 
Posterior Subcapsular Opacities ......................................................................................... 112 
18.6 
ALTISSIMO (Core Study) Subject Exit Questionnaire ....................................................................... 114 
18.7 
Protocol Amendment Summary ........................................................................................................... 116 
 
LIST OF IN-TEXT TABLES 
Table 1-1. 
Summary of Clinical Studies with GB-102 ............................................................................ 35 
Table 1-2. 
Disposition of Subjects by Cohort and Dose .......................................................................... 36 
Table 1-3. 
Protocol GBV-102-001 – Part 1: Subject Demographics at Baseline .................................... 37 
Table 1-4. 
Treatment Emergent Drug-Related Ocular Adverse Events > 1 Subject ................................ 38 
Table 1-5. 
Treatment Emergent Drug-Related Ocular AEs > 1 Subject Comparing AC 
Migration Subjects (N=9) versus No AC Migration Subjects (N=23) ................................... 39 
Table 3-1. 
Study Plan and Schedule of Assessments: ALTISSIMO (Core Study) .................................. 53 
Table 3-2.  
Study Plan and Schedule of Assessments: Extension Study .................................................. 56 
 
LIST OF IN-TEXT FIGURES 
Figure 1-1. 
Sunitinib Mechanism of Action .............................................................................................. 29 
Figure 1-2. 
Oral Dosing of Sunitinib Reduces Laser-Induced Choroidal Neovascularization in a 
Murine Model ......................................................................................................................... 30 
Figure 1-3. 
Sustained Reduction in Laser-Induced CNV Following Single Injection of IVT GB-
102 Compared to IVT Aflibercept .......................................................................................... 31 
Figure 1-4. 
Ocular Tissue Drug Levels of Sunitinib Following a Single Intravitreal Injection of 
1.0 mg GB-102 in Pigmented New Zealand Rabbits .............................................................. 33 
Figure 1-5. 
Mean BCVA (ETDRS) For Each Cohort at All Visits ........................................................... 41 
Figure 1-6. 
Mean CST (μm) For Each Cohort at All Visits ...................................................................... 41 
Figure 1-7. 
Pooled Results (All Cohorts) for BCVA and CST at All Visits ............................................. 42 
Figure 1-8. 
Rescue Free Survival (Pooled Data) ....................................................................................... 43 


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GLOSSARY OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AC 
anterior chamber 
ADL 
activities of daily living 
AE 
adverse event 
AMD 
age-related macular degeneration 
ANCOVA 
analysis of covariance 
AREDS 
age-related eye diseasesStudy 
ATC 
antiplatelet trialists’ collaboration 
BCVA 
best corrected visual acuity 
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 
clinical research organization 
CST 
central subfield thickness 
DLT 
dose limiting toxicity 
ETDRS 
early treatment diabetic retinopathy study 
EU 
endotoxin units 
FA 
fluorescein angiography 
FAS 
full analysis set 
FDA 
food and drug administration 
GCP 
good clinical practice 
GLP 
good laboratory practice 
HD 
high dose 
HIPAA 
health insurance portability and accountability act 
HSC 
human stem cell 
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 
IRT 
interactive response technology 
IVT 
intravitreal 
LASIK 
laser-assisted in situ keratomileusis 


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LD 
low dose 
LLQ 
lower limit of quantitation 
LOCF 
last observation carried forward 
MCMC 
monte carlo markov chain 
MedDRA 
medical dictionary for regulatory activities 
mPEG 
methoxy-polyethylene glycol 
NCI-CTCAE 
national cancer institute – common terminology criteria for adverse events 
Nd:YAG 
neodymium:yttrium-aluminum-garnet 
NDA 
new drug application 
OU 
both eyes 
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 
retinal pigment epithelium 
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 
THC 
tetrahydrocannibol 
TKI 
tyrosine kinase inhibitor 
Tmax 
peak exposure 
US 
united states 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
WOCF 
worst observation carried forward 
 
 


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1 INTRODUCTION 
1.1 
Background 
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among 
people who are 50 years of age or older in the industrialized world (Wong 2014). For more than 
a decade, intravitreally administered anti-vascular endothelial growth factor (VEGF) agents 
targeting VEGF-A have revolutionized the treatment of neovascular (wet) AMD with the use of 
aflibercept (EYLEA® Injection), ranibizumab (LUCENTIS® Intravitreal Injection), or off-label 
intravitreal (IVT) bevacizumab (AVASTIN® Solution, Collet 2013, Eandi 2016). Despite the 
dramatic clinical sight-saving success of these drugs, the need for frequent IVT injections has 
emerged as a burdensome consequence for both patients and retinal specialists. Intravitreal 
injections have become the most commonly performed ophthalmic procedure in the United 
States (US), surpassing cataract extraction, with an estimated 6 million injections performed in 
2016 alone and a projected annual growth rate of approximately 10% (Williams 2014). 
Randomized clinical studies have uniformly demonstrated that maximum gains in visual acuity 
can be achieved through regimented monthly IVT injections of anti-VEGF drugs (CATT 
Research Group 2011, Heier 2012, Rosenfeld 2006). However, mandated life-long monthly 
injections are impractical and unsustainable due to costs, disruption in quality-of-life 
(eg, appointments, travel, waiting times), and the clinical staffing required to manage an ever 
increasing number of patients with the disease (Prenner 2015). Furthermore, approximately 20% 
to 30% of treated patients exhibit persistent fluid in the retina despite maximal treatments, 
suggesting the need for newer pharmacologic approaches with broader mechanisms of action 
beyond VEGF-A suppression alone (Jaffe 2016). Given a decade of clinical experience in 
treating patients with wet AMD, retinal practitioners recently surveyed by the American Society 
of Retinal Specialists responded that the top 3 greatest unmet needs are: “long-acting sustained 
(drug) delivery” (74% of respondents); “reduced treatment burden” (72% of respondents); and 
“new treatment mechanisms of action” (45% of respondents) (ASRS 2016). 
To address the unmet medical need in patients with AMD, Graybug Vision has developed a 
proprietary drug product (GB-102) intended to reduce the frequency of IVT injections and 
provide a mechanism of action involving blockade of multiple VEGF receptor targets associated 
with angiogenesis, vascular permeability, cellular proliferation, which are key biologic processes 
associated with the progression of choroidal neovascularization (CNV), the hallmark lesion in 
neovascular AMD. 
1.2 
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 


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injection based upon preclinical studies, theoretically enabling dosing twice yearly as described 
in Section 1.3.1. 
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 (SUTENT® Capsules) and represents a class of small molecules referred 
to as receptor tyrosine kinase inhibitors (TKIs). 
Sunitinib 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 nAMD. 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. 
Figure 1-1. 
Sunitinib Mechanism of Action 
 
1.3 
General Information 
1.3.1 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. 
 
 
 


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1.3.1.1 Primary Pharmacology – Ocular 
Sunitinib has demonstrated evidence of inhibiting angiogenesis, vascular permeability, 
proliferation, and fibrosis – key findings associated with choroidal neovascular lesions in nAMD. 
Sunitinib has also demonstrated neuroprotective effects. 
Oral Sunitinib Malate Inhibits 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 1-2). 
Figure 1-2. 
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) 
 
 
 
 
 
 
   
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 (Tsujinaka 2018). 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 1-3). 
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. 
Figure 1-3. 
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 Retinal Ganglion Cells and 
Photoreceptors 
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 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
(Ruiz 2005, Sharma 2011). Sunitinib also promotes photoreceptor survival and function as 
demonstrated in a murine light damage model of retinal degeneration (Kim 2015). 
1.3.1.2 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). 
Following injection, sunitinib drug levels are highest in tissues containing melanin pigment 
(Figure 1-4). 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. 


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Figure 1-4. 
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.  
1.3.1.3 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 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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. 
1.4 
Clinical Studies 
Three clinical studies with GB-102 have been conducted or are ongoing as follows (Table 1-1). 


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Table 1-1. 
Summary of Clinical Studies with GB-102 
Protocol 
Title 
Design 
Subjects 
Status 
GBV-102-
001 
A Phase 1/2 multicenter study 
evaluating the safety, tolerability and 
efficacy of an intravitreal depot 
formulation of sunitinib male (GB-
102) in subjects with neovascular 
age-related macular degeneration 
Single injection, open-
label, sequentially-
enrolled, escalating dose 
cohorts followed for 8 
months 
GB-102: 
0.25 mg (N=8) 
0.5 mg (N=8) 
1 mg (N=8) 
2 mg (N=8) 
Completed 
GBV-102-
003 
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) ands retinal 
vein occlusion (RVO) 
Single injection, open-
label, concurrently-
enrolled parallel dose 
arms followed for 6 
months 
GB-102: 
1 mg (N=10) 
2 mg (N=11) 
Active. 
Enrollment 
completed. 
GBV-102-
002 
A Phase 2b multicenter dose-ranging 
study evaluating the safety and 
efficacy of a long-acting intravitreal 
sunitinib malate depot formulation 
(GB-102) compared to intravitreal 
aflibercept in subjects with 
neovascular (wet) age-related 
macular degeneration (ALTISSIMO 
study) 
Repeat injection, 
randomized, double-
masked, parallel arm 
study followed for 12 
months 
GB-102: 
1 mg (N=21) 
2 mg (N=22) 
Afllibercept:* 
2 mg (N=13) 
Active. 
Enrollment 
completed. 
*EYLEA®, aflibercept (2 mg) for intravitreal injection (Regeneron, Inc.) 
A summary of the clinical studies are provided below. 
1.4.1 Protocol GBV-102-001 (Part 1) 
Objectives. Part 1 of the Phase 1/2a protocol GBV-102-001 was the first-in-human evaluation 
study of GB-102. The primary study objective was to assess safety, tolerability, and 
pharmacodynamic parameters (BCVA, CST) following a single IVT injection of GB-102. 
[Note: Part 2 of Protocol GBV-102-001 was a planned randomized, controlled, 3-arm study 
comparing 2 doses levels of GB-102 administered every 6 months to aflibercept administered 
every 2 months.  This portion of the study was not be conducted but replaced with Phase 2b 
dose-ranging study (Protocol GBV-102-002)]. 
Study Population. Subjects with the diagnosis of nAMD within the past 18 months, had at 
least 3 prior IVT injections of any anti-VEGF agent (aflibercept, bevacizumab, or ranibizumab), 
showed a response to prior treatment, and had evidence of retinal fluid and/or leakage on 
fluorescein angiography at the time of screening. 
Methods. Following confirmation of lesion qualification by a third-party reading center, eligible 
subjects were assigned to receive a single IVT injection of GB-102 in 1 of 4 consecutively 
initiated, open-label, dose cohorts in the designated study eye (Table 1-2): 


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Table 1-2. 
Disposition of Subjects by Cohort and Dose 
Cohort 
Dose of GB-102 (mg) 
Number of Subjects 
A 
0.25 
8 
B 
0.5 
8 
C 
1 
8 
D 
2 
8 
GB-102 was administered on Day 1 in all cohorts. Subjects returned to the study center on 
targeted Days 3 (sentinel subjects only), 14, 30, 60, 90, 120, 150, 180, 210, and 240 for safety, 
clinical, and imaging assessments. Subjects exited the study following all study assessments on 
Day 240 (Month 8). Rescue treatment (aflibercept) was available to subject who met 
protocol-specified criteria. 
The safety parameters collected included adverse events (AEs), BCVA assessments (ETDRS 
protocol), and full ophthalmic examination (slit lamp biomicroscopy, intraocular pressure (IOP) 
measurements, and dilated ophthalmoscopy results). Plasma samples were obtained on all 
subjects to characterize systemic exposure to sunitinib. 
Functional and pharmacodynamic assessments included BCVA (ETDRS protocol), CST 
measurements (SD-OCT), fluorescein angiograms (FA), and color fundus photography (CFP). 
Imaging data was interpreted by an independent third-party reading center. 
The intent-to-treat (ITT) population is defined as all subjects who received any study treatment at 
baseline, have a baseline BCVA and CST measurement, and at least one post-baseline BCVA 
and CST measurement in the study eye, and includes subjects who have received rescue. The per 
protocol analysis set (PP) population in this report is defined the same as the ITT population but 
excludes subjects with major protocol violations that would affect the assessment of the primary 
efficacy endpoint of the study. The safety population are any subjects who have received study 
treatment.  
Results. Seventy-one (71) subjects were screened, and 32 subjects were enrolled from 8 study 
sites in the United States (Table 1-3). The first subject was enrolled on August 29, 2017 and the 
last subject completed the study on January 16, 2019. Four (4) subjects (Cohort A, N=1; 
Cohort B, N=3) were early terminations: 1 subject died secondary to metastatic gastric cancer 
(not previously diagnosed) and 3 subjects withdrew consent (hardships in complying with 
monthly visits from remote locations). The total cumulative subject-days exposed to GB-102 was 
approximately 7374 days. 
A summary of the study population at baseline is provided in Table 1-3. The mean age was 
74.2 years with a baseline BCVA of approximately 20/50 (estimated Snellen equivalent), central 
subfield thickness of 294 μm, mean number of prior anti-VEGF injections of 4.8, and 
approximately 60 days since the last anti-VEGF dose to first dose of GB-102. 


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Table 1-3. 
Protocol GBV-102-001 – Part 1: Subject Demographics at Baseline 
 
0.25 mg  
N=8 
0.5 mg  
N=8 
1 mg 
N=8 
2 mg 
N=8 
Total 
N=32 
Mean Age, years (SD) Range  
74.4 (11.6) 
59-89 
78.3 (9.4) 
60–90 
73.1 (7.6) 
60–83 
70.9 (9.9) 
59–84 
74.2 (9.7) 
59–90 
Sex, n (%)  
Female  
5 (62.5%) 
5 (62.5%) 
5 (62.5%) 
4 (50.0%) 
19 (59.4%) 
Mean BCVA [ETDRS letters] (SD) 
Estimated Snellen equivalent  
56.5 (11.1) 
20/80 
65.1 (9.9) 
20/50 
67.9 (7.5) 
20/50 
63.8 (14.3) 
20/50 
63.3 (11.3) 
20/50 
Mean CST, μm (SD) 
279 (84.3) 
310 (75.9) 
276 (57.4) 
308 (53.2) 
294 (68.7) 
Mean number of prior anti-VEGF 
injections (SD) Range  
3.5 (0.9) 
3–5 
4.5 (1.1)  
3–6 
5.0 (3.4) 
3–11 
6.3 (3.1) 
3–13 
4.8 (2.5) 
3–13 
Mean Days since last anti-VEGF injection 
(SD) Range  
45.3 (20.1) 
19–82 
74.9 (65.7) 
30–218 
62.4 (42.8) 
31–163 
54.6 (28.8) 
27–112 
59.3 (42.3) 
19–218 
1.4.1.1 Ocular Adverse Events 
There were no ocular serious adverse events (SAEs) or dose-limiting toxicity events including 
inflammatory events (eg, sterile endophthalmitis, vitritis, uveitis, or corneal decompensation). A 
summary of drug-related treatment emergent ocular AEs > 1 subject are presented in Table 1-4. 


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Table 1-4. 
Treatment Emergent Drug-Related Ocular Adverse 
Events > 1 Subject 
Reported Event 
0.25 mg 
N=8 
0.5 mg 
N=8 
1 mg 
N=8 
2 mg 
N=8 
Total 
N=32 
Ocular SAEs 
0 
0 
0 
0 
0 
Dose-limiting toxicity events 
0 
0 
0 
0 
0 
Medication in anterior 
chamber 
0 
2 (25%) 
3 (38%) 
4 (50%)a 
9 (28%) 
Vitreous floaters 
1 (12%) 
2 (25%) 
1 (12%) 
4 (50%) 
8 (25%) 
Medication residue present 
0 
3 (38%) 
1 (12%) 
4 (50%) 
8 (25%) 
Elevated IOPa 
0 
2 (25%) 
1 (12%) 
2 (25%) 
5 (16%) 
Visual impairment 
0 
1 (12%) 
2 (25%) 
2 (25%) 
4 (12%) 
Anterior chamber cellb 
0 
0 
1 (12%) 
2 (25%) 
3 (9%) 
Eye pain 
0 
0 
0 
2 (25%) 
2 (6%) 
Photophobia 
0 
0 
0 
2 (25%) 
2 (6%) 
Vision blurred 
0 
0 
0 
2 (25%) 
2 (6%) 
Vitreous hazeb 
0 
1 (12%) 
1 (12%) 
0 
2 (6%) 
aIncludes preferred term ocular hypertension. Subjects presented with IOP in the range of 25-38 mmHg 
bDiagnosis confounded by drug particle dispersion in the AC and/or vitreous 
The most frequently reported AE was the observation of microparticles migrating into the 
anterior chamber (AC). The cause was due to incomplete aggregation of the injected 
microparticles to form a solid depot allowing free-floating microparticles to move from the 
vitreous into the AC. Medication residue present were transient subjective reports from subjects 
whereby the investigator was able to identify floating microparticles in the visual axis that might 
possibly explain the subject’s symptoms. While migration of intravitreal drug-eluting implants 
into the anterior chamber can occur in aphakic or pseudophakic subjects (Collet 2013), the 
occurrence of microparticle AC migration in phakic subjects was unexpected and may be related 
to age-related changes in the zonules, similar to observations in patients receiving intravitreal 
steroid suspensions (Ruiz-Moreno 2005). 
Mildly elevated IOP was observed in 5 subjects that also had microparticles in the anterior 
chamber. AC migration presented generally 2 to 3 months following IVT GB-102; IOP elevation 
presented generally 1 to 2 months later. The cause for elevated IOP may be due, in part, to partial 
obstruction of the trabecular meshwork; however, the use of topical steroid eye drops to prevent 
corneal decompensation is a confounder. 
The management of particles in the AC was either AC lavage (N=3) or observation alone (N=6). 
With observation alone, the particles dissolved spontaneously approximately 1 to 2 months 
following the diagnosis. Thus, AC migration appears self-limited, reversible, with no long-term 
sequelae. IOP responded to topical IOP-lowering drops. 


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The vast majority of ocular drug-related AEs were from the subjects that experienced AC 
migration (N=9) compared to subjects that did not have this event (N=23) as shown in Table 1-5. 
In summary, the reported drug-related ocular adverse events were within expectations of an 
intravitreal delivery of a microparticle formulation with the exception of migration of drug 
product into the anterior chamber in phakic subjects and the presence of mildly elevated IOP. 
The event of AC migration is self-limited and reversible with conservative management and use 
of topical IOP-lowering eye drops as needed. 
Table 1-5. 
Treatment Emergent Drug-Related Ocular AEs > 1 Subject 
Comparing AC Migration Subjects (N=9) versus No AC Migration 
Subjects (N=23) 
Reported Event 
0.25 mg 
N=8 
0.5 mg 
N=8 
1 mg 
N=8 
2 mg 
N=8 
Total 
N=32 
AC Migration Subjects (N=9) 
Medication in anterior 
chamber 
0 
2 (25%) 
3 (38%) 
4 (50%) 
9 (28%) 
Medication residue present 
0 
2 (25%) 
1 (12%) 
4 (50%) 
7 (22%) 
Elevated IOPa 
0 
2 (25%) 
1 (12%) 
2 (25%) 
5 (16%) 
Visual impairment 
0 
1 (12%) 
2 (25%) 
2 (25%) 
5 (16%) 
Vitreous floaters 
0 
0 
1 (12%) 
2 (25%) 
3 (9%) 
Anterior chamber cellb 
0 
0 
1 (12%) 
2 (25%) 
3 (9%) 
Eye pain 
0 
0 
0 
2 (25%) 
2 (6%) 
Photophobia 
0 
0 
0 
2 (25%) 
2 (6%) 
Vision blurred 
0 
0 
0 
2 (25%) 
2 (6%) 
Vitreous hazeb 
0 
1 (12%) 
1 (12%) 
0 
2 (6%) 
No AC Migration Subjects (N=23) 
Medication in anterior 
chamber 
0 
0 
0 
0 
0 
Vitreous floaters 
1 (12%) 
2 (25%) 
0 
2 (25%) 
5 (16%) 
Medication residue present 
0 
1 (12%) 
0 
0 
1 (3%) 
aIncludes preferred term ocular hypertension. Subjects presented with IOP in range of 25-38 mmHg 
bDiagnosis confounded by drug particle dispersion in the AC and/or vitreous 
1.4.1.2 Non-ocular Adverse Events 
There were 4 non-ocular SAEs reported in 3 subjects: 1 subject (0.5 mg) was hospitalized for 
ascites and later died of metastatic gastric cancer (2 SAE events); 1 subject (0.5 mg) was 
hospitalized secondary to multiple injuries following a motor vehicle accident (subject was a 
passenger); 1 subject (0.5 mg) was hospitalized for colitis. None of these events were reported as 
drug-related. 


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The most frequently reported non-ocular AEs (> 5%) were abdominal pain, systolic pressure 
increased, and dehydration. None of these events were reported as drug-related. 
1.4.1.3 Systemic Exposure to Sunitinib 
In all subjects, plasma levels of sunitinib were evaluated on Day 1 (1 and 2 hours post-injection), 
Day 14, Months 1, 2, 3, 4, and 8. All samples were below the limit of quantitation on all subjects 
at all time points [LLQ > 0.3 ng/mL]. 
1.4.1.4 Functional and Pharmacodynamic Parameters 
Mean BCVA and CST at all visits for each dose cohort are presented in Figure 1-5 and 
Figure 1-6, respectively. Pooled results are presented in Figure 1-7. The CST values include 
historic (pre-study) worst observation measurements during the anti-VEGF induction period. 
GB-102 appears to maintain and stabilize visual acuity and retinal thickness in subjects who have 
received at least 3 prior doses of anti-VEGF. The pooled CST results demonstrate nominal 
statistical significance (P<0.05) at all visits relative to the historic pre-study CST values. 
Particle dispersion can interfere with visual acuity and was observed particularly in the 2 mg 
cohort as demonstrated by a U-shaped decline in BCVA at approximately month 3 to 4 when AC 
migration was reported (Figure 1-5). 


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Overall, the results are consistent with outcomes observed in masked randomized controlled 
studies evaluating sustained-release of anti-VEGF (Awh 2018 [LADDER]). 
Figure 1-5. 
Mean BCVA (ETDRS) For Each Cohort at All Visits 
 
Figure 1-6. 
Mean CST (μm) For Each Cohort at All Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1-7. 
Pooled Results (All Cohorts) for BCVA and CST at All Visits 
 
1.4.1.5 Rescue 
Protocol-specified criteria for rescue with aflibercept were: > 10 letter loss in BCVA with retinal 
fluid that, in the opinion of the investigator, was the cause of the BCVA loss, and/or > 75 µm 
increase in CST, and/or vision-threatening hemorrhage due to underlying nAMD. 
Kaplan-Meier survival curves were used to assess rescue-free survival rates. Overall, 88%, 68%, 
and 42% of the study population was rescue-free through Month 3, 6 and 8, respectively 
(Figure 1-8). 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1-8. 
Rescue Free Survival (Pooled Data) 
 
1.4.1.6 Conclusions 
Part 1 of the Phase 1/2a study met its primary endpoint of safety and tolerability. There were no 
ocular SAEs or dose-limiting toxicity events. The most commonly reported ocular AEs related to 
particle migration into the anterior chamber that may be associated with mild elevation in IOP; 
however, these events can be managed conservatively (biodegradation) and are self-limited, 
reversible, with no long-term sequelae. 
There is a clear and durable pharmacodynamic effect of GB-102 based on analyses of BCVA, 
CST, and rescue rates with ≥ 6-month dosing duration achieved in a majority of subjects. 
Overall, the results support continued development of GB-102. 
1.4.2 Protocol GBV-102-003 (Phase 2a) 
The purpose of this study is to assess the safety, tolerability, and pharmacodynamic response of 
two dose strengths (1 mg and 2 mg) of GB-102 administered as a single injection in subjects 
with refractory macular edema (ME) secondary to DME or RVO. This study is active and fully 
enrolled with a total of 21 subjects (N=10, 1 mg; N=11, 2 mg). Study completion is anticipated 
1H 2020. 
A single subject had a reported 2 drug-related ocular serious adverse events (SAEs).  
The subject with the ocular SAEs is a 61-year-old male with history of central retinal vein 
occlusion, bilateral cataract extraction with posterior intraocular lens placement, and glaucoma. 
No prior history of laser capsulotomy. On Day 1, the 2 mg GB-102 injection procedure was 
uncomplicated with a normal appearing drug depot. At the Month 2 visit, the subject experienced 
migration of drug material to the AC with partial blockage of the visual axis at the pupil, which 
resulted in the first SAE of decreased visual acuity. Associated findings included posterior 
uveitis with dispersed vitreous opacities from free-floating drug material. The investigator 
elected to remove the medication in the AC via AC lavage/washout followed by a pars plana 
vitrectomy to remove the dispersed drug in the vitreous. Per the investigator, the consistency 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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(firmness) of the study drug in the AC was unexpected resulting in difficulty in extracting the 
drug material. The vigorous and prolonged surgical lavage resulted in post-operative corneal 
edema (the second SAE) and reduction in vision to hand motion. The post-operative corneal 
edema is being managed with topical steroids and the SAE event is reported as 
resolving/recovering. 
There were also 3 non-ocular SAEs reported in 2 subjects: 1 subject was hospitalized twice for 
gastrointestinal hemorrhage twice, and 1 subject was hospitalized for non-ST elevated 
myocardial infaction. None of these events were reported as drug-related. 
1.4.3 Protocol GBV-102-002 (Phase 2b, ALTISSIMO Study) 
The purpose of this study is to assess the efficacy and safety of two different dosing schemes of 
GB-102 administered every 6 months (1 mg followed by 1 mg or 2 mg followed by 1 mg) 
compared with a fixed regimen of 2 mg aflibercept administered every 2 months. The study is 
active, and enrollment is complete. 
The first subject enrolled was September 2019 with a planned sample size of 160 subjects. Due 
to the reported SAE in Protocol GBV-102-003 on December 17, 2019, enrollment in the 
ALTISSIMO study was voluntarily suspended by the Sponsor on December 19, 2019 as a safety 
precaution after a total of 56 subjects had been enrolled. An unmasked limited interim safety 
review was conducted by the Sponsor (Chief Medical Officer and the Vice President of Global 
Clinical Operations) in February 2020. During this safety review, no SAEs had been reported in 
ALTISSIMO; however, 5 subjects had a report of drug material observed in the AC (N=4, 2 mg; 
N=1, 1 mg). All reported cases were mild-to-moderate in severity. One subject who received the 
2 mg dose developed a moderate pseudohypopyon and was managed with elective AC lavage 
and pars plana vitrectomy without complication. The subjects remain in the study and are under 
observation alone or undergoing treatment with a short course of prophylactic topical steroids.   
The Sponsor elected to stop further enrollment in ALTISSIMO and to re-dose (Month 6 visit) 
only the 1 mg dose of GB-102 for those subjects assigned to GB-102.  
EXTENSION STUDY 
The purpose of this portion of the ALTISSIMO study is to monitor the safety and duration of 
effect of IVT GB-102 administered every 6 months compared to IVT aflibercept administered 
every 2 months in subjects in ALTISSIMO (Core Study) who complete all study visits through 
Month 12 (Day 360) and who do not require/receive rescue treatment at the Month 12 (Day 360) 
final study visit. Enrolled subjects will be followed for monthly visits until they receive rescue 
treatment or for a maximum of 180 days (i.e, 6 months). There will be no additional treatment 
with GB-102. With this amendment, the ALTISSIMO study is divided into the ALTISSIMO 
(Core Study) and the Extension Study. Unless otherwise specified, all segments of the protocol 
refer to the ALTISSIMO (Core Study). 
 


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1.5 
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 
ALTISSIMO (Core Study): Objectives 
With this amendment, the ALTISSIMO Study is divided into the ALTISSIMO (Core Study) and 
the Extension Study. Unless otherwise specified, all segments of the protocol refer to 
ALTISSIMO (Core Study).  
2.1.1 Primary Objective 
To evaluate the safety and duration of the effect of GB-102, as measured by time to first rescue 
treatment across two different dosing schemes of GB-102 administered every 6 months (1 mg 
followed by 1 mg or 2 mg followed by 1 mg) as compared to intravitreal (IVT) aflibercept 
administered every 2 months in subjects with neovascular (wet) age-related macular 
degeneration who have received prior induction with IVT anti-VEGF. 
2.1.2 Secondary Objectives 
• To evaluate the efficacy of two different dosing schemes of IVT GB-102 administered every 
6 months in maintenance of best-correct visual acuity (BCVA, ETDRS letter score) compared 
to subjects receiving IVT aflibercept every 2 months 
• To evaluate the efficacy of two different dosing schemes of IVT GB-102 administered every 
6 months in maintenance of central subfield thickness (CST, µm) compared to subjects 
receiving IVT aflibercept every 2 months 
2.2 
Extension Study: Objective 
To monitor the safety and duration of effect of IVT GB-102 administered every 6 months 
compared to IVT aflibercept administered every 2 months in subjects in ALTISSIMO (Core 
Study) who complete all study visits through Month 12 (Day 360) and who do not 
require/receive rescue treatment at the Month 12 (Day 360) final study visit. 


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3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design Summary 
3.1.1 ALTISSIMO (Core Study): Overall Study Design Summary 
This is a Phase 2b, multicenter, visual examiner-masked, randomized active-controlled, 
parallel-arm design. 
Subjects eligible for screening must have an active CNV lesion in the study eye secondary to 
AMD that was diagnosed in the 12 weeks to 18 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 21 days of 
screening. Eligibility will be confirmed by a central reading center based upon SD-OCT, FA, and 
color fundus photography (CFP) evaluation of the CNV lesion. 
Eligible subjects will be randomly assigned (3:3:2) to receive 50-µL IVT injections of 1 of 
2 doses of study drug or aflibercept, respectively, in the study eye using a stratified, blocked 
randomization scheme. Stratification will include baseline BCVA (< 60 letters vs ≥ 60 letters). 
Approximately 15 to 20 subjects per group, 56 subjects total, will be randomized to one of the 
following treatment arms: 
Group 1:   1 mg GB-102 at baseline and Month 6 and sham at Months 2, 4, 8, and 10 
(N=21) 
Group 2:   2 mg GB-102 at baseline and 1 mg GB-102 at Month 6 and sham at 
Months 2, 4, 8, and 10 (N=22) 
Group 3:   2 mg aflibercept q 2 months at baseline, Months 2, 4, 6, 8 and 10 (N=13) 
Assigned study drug will be administered on Day 1 (Appendix 18.1). Subjects will return to the 
study center on Days 14, 30, 60, 90, 120, 150, 180, 210, 240, 300, 330, and 360 for safety, 
clinical, and imaging assessments (Table 3-1). Subjects will exit the study following all study 
assessments on Day 360. 
An interim safety analysis was conducted when approximately 50% of subjects had 3-months of 
accrued data to determine if any changes to the protocol were needed prior to the Month 6  
re-dosing schedule. Unmasking of the interim safety data was made available only to the 
Sponsor’s Chief Medical Officer and the Vice President of Global Clinical Operations. The 
interim analysis showed no serious ocular adverse events. Four subjects experienced medication 
in the anterior chamber (AC) in the GB-102, 2 mg dose arm as compared to 1 subject in the GB-
102, 1 mg dose arm. Based on this safety analysis, the sponsor decided to terminate the 
development of the GB-102 2 mg dose, and amended the protocol to use GB-102 1 mg for re-
dosing of all subjects on GB-102 at the Month 6 visit, regardless of their original dose 
assignment.  The enrollment was capped at 56 subjects and the primary endpoint was shifted 


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from Month 10 to Month 12 based on suggested feedback from the Food and Drug 
Administration (FDA). 
An unmasked primary analysis for safety and efficacy is planned when all subjects complete the 
Day 360 visit. 
The safety parameters to be collected include adverse events (AEs), serious adverse events 
(SAEs), physical examination findings, clinical laboratory test results, vital sign measurements, 
best corrected visual acuity (BCVA) assessments using the Early Treatment Diabetic 
Retinopathy Study (ETDRS) protocol, slit-lamp biomicroscopy findings, Age-related Eye 
Disease Study (AREDS) lens assessments, intraocular pressure (IOP) measurements, dilated 
ophthalmoscopy results, and date of administration of rescue treatment. 
Efficacy parameters will be measured by means of rescue treatment, BCVA (using the ETDRS 
protocol), retinal central subfield thickness (CST) using spectral domain-optical coherence 
tomography (SD-OCT), fluorescein angiography (FA), and color fundus photography (CFP). 
The systemic exposure will be based on subjects assigned to each sunitinib treatment group. An 
analysis of approximately 20% of the subjects assigned to each sunitinib group will be 
performed. 
3.1.2 Extension Study: Overall Study Design Summary 
The Extension Study is a multicenter, visual examiner-masked study, designed to monitor the 
safety and duration of effect of IVT GB-102 administered every 6 months compared to IVT 
aflibercept administered every 2 months in subjects in ALTISSIMO (Core Study) who complete 
all study visits through Month 12 (Day 360) and who do not require/receive rescue treatment at 
the Month 12 (Day 360) final study visit. 
Enrolled subjects will be followed for monthly visits until they receive rescue treatment or for a 
maximum of 180 days (i.e, 6 months). There will be no additional treatment with GB-102. 
The assessments to be collected include AEs, SAEs, concomitant medications, BCVA 
assessments using ETDRS protocol, slit-lamp biomicroscopy findings, AREDS lens assessments, 
IOP measurements, dilated ophthalmoscopy results, retinal CST using SD-OCT, color fundus 
photography for depot imaging (ultra-widefield imaging, where available) and date of 
administration of rescue treatment.  
Once a subject meets at least one rescue criteria and all study visit assessments are completed, 
they may receive an injection of aflibercept and exit the study. 
No formal statistical hypotheses testing will be performed. An exploratory analysis of safety and 
efficacy will be performed after all subjects have completed the study. 


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3.2 
Safety Monitoring 
A medical monitor (ophthalmologist) and the Sponsor’s medical officer will evaluate the 
on-going masked safety data.  
3.3 
Masking 
3.3.1 ALTISSIMO (Core Study) and Extension Study: Masking 
The visual acuity examiners, the Sponsor (other than the Vice President of Global Clinical 
Operations), the masked CRO personnel, the medical monitor, and other study personnel, 
including individuals at a central reading center, study coordinators, laboratory vendor, etc. will 
remain masked relative to GB-102 scheme. The visual acuity examiners are not allowed to 
perform any study related activities other than BCVA assessments to maintain masking including 
obtaining medical histories or attempting to elicit any information regarding treatment, adverse 
events, or clinical information from the subjects. The same BCVA examiner should be utilized 
for each subject throughout the study when possible. 
Each study center will have at least 2 investigators who are retina specialists; one will serve as 
the injecting investigator and the other will serve as the assessing investigator. To maintain study 
masking, the roles of these investigators should not be switched during the conduct of the study. 
3.3.2 ALTISSIMO (Core Study): Masking 
• Injecting Investigator: An injecting investigator will perform the study drug (GB-102 or 
aflibercept), sham, and/or rescue injections, will supervise the preparation and tracking of 
study drug, and will perform predose and postdose safety assessments for the IVT injections. 
• Assessing Investigator: An assessing investigator will supervise and assess the collection of 
AEs and efficacy parameters. The assessing investigator will determine whether rescue 
treatment is required. 
The SD-OCT, FA, and CFP technicians are masked to treatment scheme; however, collected 
images may reveal to the assessing investigator or technician which subjects received the 
GB-102 depot. 
Study personnel performing reconstitution of the investigational drug product (GB-102) will be 
unmasked to treatment assignment but not the treatment scheme. Study drug will be boxed in 
numbered kits and identical in external appearance and weight. Kits containing GB-102 are 
identical in physical appearance and drug vial/diluent (pre-filled syringe) configuration, and fully 
masked as to the dose strength (1 or 2 mg) of GB-102. 


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3.3.3 Extension Study: Masking 
• Injecting Investigator: An injecting investigator will perform the rescue injections, will 
supervise the preparation and tracking of study drug, and will perform predose and postdose 
safety assessments for the IVT injections.  
• Assessing Investigator: An assessing investigator will supervise and assess the collection of 
AEs, SAEs, concomitant medications, BCVA assessments using ETDRS protocol, slit-lamp 
biomicroscopy findings, AREDS lens assessments, IOP measurements, dilated 
ophthalmoscopy results, and retinal CST using SD-OCT. The assessing investigator will 
determine whether rescue treatment is required. 
The SD-OCT and color fundus photography imaging (ultra-widefield imaging, where available) 
technicians are masked to treatment scheme; however, collected images may reveal to the 
assessing investigator or technician which subjects received the GB-102 depot in ALTISSIMO 
Core Study. 
3.4 
Rescue Treatment 
Rescue treatment (using aflibercept) will be permitted in the study eye in any of the study arms if 
the eligibility criteria are met for rescue treatment. Subjects receiving rescue treatment will 
continue to be evaluated at scheduled study visits. 
The nonstudy eye may receive IVT anti-VEGF treatment (aflibercept, bevacizumab, or 
ranibizumab) for the treatment of wet AMD at the discretion of the investigator. 
3.5 
Study Design Rationale 
3.5.1 ALTISSIMO (Core Study): Study Design Rationale 
The proposed study is designed to assess the efficacy and safety of two different dosing schemes 
of GB-102 (1 mg followed by 1 mg or 2 mg followed by 1 mg) administered every 6 months 
compared with a fixed regimen of aflibercept every 2 months. 
The medical monitor (ophthalmologist) and the Sponsor’s medical officer will evaluate masked 
safety data on an on-going basis.  
An interim safety analysis was conducted when approximately 50% of subjects had 3-months of 
accrued data to determine if any changes to the protocol were needed prior to the Month 6 re-
dosing schedule. Unmasking of the interim safety data was made available only to the Sponsor’s 
Chief Medical Officer and the Vice President of Global Clinical Operations.  
Use of at least 2 retinal physician investigators at each study center, including an assessing 
investigator and an injecting investigator, is a well-established method for conducting 
registrational drug studies in subjects with wet AMD (CATT Research Group 2011, Heier 2012, 
Rosenfeld 2006). 


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The subjects, visual acuity examiners, the Sponsor (other than the Vice President of Global 
Clinical Operations), the medical monitor, and other study personnel, including individuals at a 
central reading center, study coordinators, laboratory vendor, etc. will remain masked relative to 
GB-102 scheme. Though the GB-102 depot may be visible initially upon ocular examination, the 
observer will be masked as to the treatment scheme. The depot is expected to fully bioabsorb 
after approximately 4 to 6 months. Sham injections are incorporated in the study plan to maintain 
subject masking. 
The planned study assessments (eg, AEs, abbreviated physical examinations, clinical laboratory 
tests, vital sign measurements, BCVA assessments, slit-lamp biomicroscopy examinations, 
AREDS lens assessments, SD-OCT, FA, CFP, dilated ophthalmoscopy evaluations, and systemic 
exposure) are conventional parameters used to evaluate the safety and pharmacodynamic activity 
of pharmacologic agents in retinal disease. 
The sample size of this study (56 subjects randomized 3:3:2 to two GB-102 dosing schemes and 
the aflibercept group, respectively) was not selected to support specific statistical hypothesis 
testing; however, approximately 12 evaluable subjects in the full analysis set are planned for the 
aflibercept group, and 20 evaluable subjects in the full analysis set per GB-102 group will be 
sufficient to establish estimates of serious ocular event rates related to GB-102. Details regarding 
the determination of sample size are described in Section 9.8. 
Rescue treatment with aflibercept for the study eye and the frequency of monthly injections is 
within the standard-of-care for subjects with wet AMD for the maintenance of visual acuity 
and/or the prevention of vision loss. 
3.5.2 Extension Study: Study Design Rationale 
The Extension Study is designed to monitor the safety and duration of effect of IVT GB-102 
administered every 6 months compared to IVT aflibercept administered every 2 months in 
subjects in ALTISSIMO (Core Study) who complete all study visits through Month 12 
(Day 360) and who do not require/receive rescue treatment at the Month 12 (Day 360) final 
study visit. 
In order to maintain masking of the treatment schemes for ALTISSIMO (Core Study), all 
subjects from all treatment schemes on ALTISSIMO (Core Study) will be allowed to enroll in 
the Extension Study provided all entry criteria are met prior to study entry. 
3.6 
Appropriateness of Measurements 
3.6.1 ALTISSIMO (Core Study): Appropriateness of Measurements 
The primary aim of the data analyses in this study is to assess the safety and exploratory efficacy 
of two different GB-102 treatment schemes in subjects with wet AMD. 


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The safety and pharmacodynamic parameters to be evaluated in this study are consistent with 
landmark, randomized, multicenter, registrational drug studies of IVT agents used to treat wet 
AMD (CATT Research Group 2011, Heier 2012, Rosenfeld 2006). 
Additional safety parameters intended to assess systemic AEs related to sunitinib exposure 
include clinical laboratory tests (eg, chemistry, hematology, and urinalysis). 
Systemic PK will be evaluated to characterize systemic exposure from IVT sunitinib 
administration. 
3.6.2 Extension Study: Appropriateness of Measurements 
The aim of the Extension Study is to monitor the safety and duration of effect of two different 
GB-102 treatment schemes in subjects with wet AMD.  
No additional safety parameters intended to assess systemic AEs related to sunitinib exposure or 
systemic PK will be evaluated in the Extension Study. 






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j 
Fluorescein angiography and color fundus photography will be conducted prior to intravitreal injection at Month 6. 
k Additional color fundus photography of the intravitreal GB-102 depot will be obtained following the dilated ophthalmic examination at all visits. 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 where 
rescue treatment is administered. The photographs may be used to document the general appearance and rate of bioabsorbability of the depot. For detailed instructions 
regarding collection of the intravitreal depot CFP imaging, refer to the separately provided guideline. Select sites will collect additional intravitreal depot color fundus 
photography using the Zeiss Clarus 500 or Optos California Ultra-widefield Fundus Imaging system at all visits after initial dosing at Baseline and at any unscheduled visits 
where rescue treatment is administered. 
l 
For all dosing procedures (intravitreal or sham), subject should remain seated for approximately 15 minutes post-injection with minimal to no movement of the head. 
Aflibercept dosing to be conducted per instructions in prescribing information by the injecting physician. All subjects receiving GB-102 at baseline will receive 1 mg GB-102 
at Month 6. 
m 
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. 
n 
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. 
o 
Along with the vital signs, height (without shoes) will be measured at Screening and body weight will be measured at Screening and Month 12. The same arm and method of 
obtaining blood pressure and heart rate should be used throughout the study. 
p 
Each subject that completes a Month 12 (Day 360) visit must complete the subject exit questionnaire before exiting the ALTISSIMO (Core Study). 
 
 
 


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Table 3-2.  
Study Plan and Schedule of Assessments: Extension Study 
Activity/Assessment 
M12 (S/B)a 
 M 13 
M 14  
M 15  
M 16  
M 17  
M 18/ET  
Visit Day ± Windowf 
360 
390±7 
420±7 
450±7 
480±7 
510±7 
540±7 
Informed Consent/HIPAA 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
BCVA (ETDRS)b 
 
OU 
OU 
OU 
OU 
OU 
OU 
Slit-lamp Biomicroscopyc 
 
OU 
OU 
OU 
OU 
OU 
OU 
IOPd 
 
OU 
OU 
OU 
OU 
OU 
OU 
Dilated Ophthalmoscopy 
 
OU 
OU 
OU 
OU 
OU 
OU 
SD-OCT 
 
OU 
OU 
OU 
OU 
OU 
OU 
Intravitreal Depot Color Fundus Photographye 
 
SE 
SE 
SE 
SE 
SE 
SE 
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  
a 
Screening/Baseline Visit of the Extension Study to occur on the same day as Month 12 (Day 360) in ALTISSIMO (Core Study). 
b 
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. 
c 
The Age-Related Disease Study lens assessment will be conducted and graded by the investigator as part of the biomicroscopy examination. 
d 
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 rescue treatment. 
e 
Additional color fundus photography of the intravitreal GB-102 depot will be obtained following the dilated ophthalmic examination at all visits and conducted through (and 
include) the final study visit and any unscheduled visits where rescue treatment is administered. The photographs may be used to document the general appearance and rate of 
bioabsorbability of the depot. For detailed instructions regarding collection of the intravitreal depot CFP imaging, refer to the separately provided guideline. Select sites will 
collect additional intravitreal depot color fundus photography using the Zeiss Clarus 500 or Optos California Ultra-widefield Fundus Imaging system at all visits and at any 
unscheduled visits where rescue treatment is administered. 
f 
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. 


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4 SUBJECT POPULATION 
4.1 
Number of Subjects and Subject Selection 
4.1.1 ALTISSIMO (Core Study): Number of Subjects and Subject Selection 
Subjects eligible for screening must have an active CNV lesion in the study eye secondary to 
AMD that was diagnosed in the 12 weeks to 18 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 21 days of 
screening. Eligibility will be confirmed by a central reading center based upon SD-OCT, FA, and 
color fundus photography (CFP) evaluation of the CNV lesion. The complete inclusion and 
exclusion criteria are presented, respectively, in Section 4.3 and Section 4.4. 
The study is planned to be conducted at approximately 35 study centers in the US and will 
include approximately 15 to 20 subjects per treatment scheme (approximately 56 subjects across 
all treatment schemes combined). 
4.1.2 Extension Study: Number of Subjects and Subject Selection 
Subjects eligible for screening and enrollment must complete all study assessments at the Month 
12 (Day 360) including fluorescein angiography, and not require/receive a rescue treatment at the 
Month 12 (Day 360) final study visit in ALTISSIMO (Core Study). The complete inclusion and 
exclusion criteria are presented, respectively, in Section 4.5 and Section 4.6. 
There will be no randomization in the Extension Study. 
4.2 
Study Eye Determination 
4.2.1 ALTISSIMO (Core Study): 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. 
4.2.2 Extension Study: Study Eye Determination 
The study eye is defined as the eye that was treated in the ALTISSIMO (Core Study). 
4.3 
Inclusion Criteria: ALTISSIMO (Core Study) 
Subjects must meet all the following inclusion criteria to be eligible for participation in this 
study. 


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1. Verbal and written informed consent obtained from the subject 
2. Males or females ≥ 50 years of age 
3. Willing and able to give informed consent, comply with all study procedures, and be likely to 
complete the study 
4. Presence of a subfoveal or juxtafoveal CNV lesion secondary to AMD in the study eye that 
was diagnosed in the 12 weeks to 18 months prior to screening and has been treated with at 
least 3 prior IVT injections of an anti-VEGF agent (aflibercept, bevacizumab, or 
ranibizumab). The study eye and CNV lesion must demonstrate all of the following features 
at the Screening Visit (as confirmed by the reading center): 
a. Total lesion size ≤ 12 disc areas (30.5 mm2) 
b. Absence of subfoveal fibrosis, serous pigmented epithelial detachment, retinal 
pigmented epithelial tear, or subfoveal geographic atrophy 
c. If fibrosis is present, it must be ≤ 25% of total lesion area and not involve the center 
of the fovea 
d. If subfoveal hemorrhage is present, it must be < 1 disc area in size and not involve the 
center of the fovea 
e. If subretinal hemorrhage is present, it must be < 50% of total CNV lesion and not 
involve the center of the fovea 
5. Prior pharmacodynamic response of the CNV lesion 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: 
a. Reduction of intraretinal/subretinal fluid by ≥ 30% from the initial diagnosis as 
determined using SD-OCT 
b. Reduction of excess CST by ≥ 30% from the initial diagnosis as determined using 
SD-OCT (assuming nominal thickness is 300 microns) 
6. Demonstrate a maintained anti-VEGF response (as determined by the investigator) compared 
with the initial diagnosis (prior to any anti-VEGF treatment) as assessed using SD-OCT 
following the most recent anti-VEGF injection (defined as a reduction in central subfield 
thickness, intraretinal/subretinal fluid, or maintenance of dry retina) 
7. Screening and baseline BCVA letter score (by ETDRS protocol) of 35 to 88 (20/200 to 
20/20 Snellen equivalent) in the study eye 
8. Availability of central subfield thickness (CST) measurements from SD-OCT imaging 
obtained from the time of initial diagnosis (pre-anti-VEGF therapy) and/or maximal CST 
thickness obtained any time following anti-VEGF induction 
9. 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 
10. Most recent dose of anti-VEGF agent administered within 21 days of screening 


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11. Clear ocular media and adequate pupil dilation in both eyes to permit good quality 
photographic imaging 
12. Women of childbearing potential (ie, not postmenopausal for at least 12 months or not 
surgically sterile [defined as bilateral tubal ligation performed at least 12 months previously, 
hysterectomy, or bilateral oophorectomy]) must have a negative urine pregnancy test at 
screening and baseline, and must use adequate birth control throughout the study and until 
12 weeks following the last dose of study drug 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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4.4 
Exclusion Criteria: ALTISSIMO (Core Study) 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 
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 > 8.0% at the Screening Visit 
4. Chronic renal disease requiring chronic hemodialysis or renal transplantation 
5. Any screening laboratory result (hematology, chemistry, or urinalysis) that, in the opinion 
of the investigator, is not suitable for subject participation in the study 
6. 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) 
7. Previous participation in an investigational study of GB-102 
8. 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 
9. 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 
10. Presence of any clinically significant epiretinal membrane or vitreomacular traction in the 
study eye 
11. History or evidence of any of the following surgeries or procedures in the study eye: 
a. Submacular surgery or other surgical intervention for AMD 
b. Prior retinal detachment or macular hole interventions 
c. Vitrectomy 
d. Photodynamic therapy or thermal laser retinal treatment 
e. Intraocular laser treatments for glaucoma (eg, selective laser trabeculoplasty or 
peripheral iridotomy) 
f. 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 
g. Cataract surgery within the 3 months prior to the Screening Visit 
h. Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy within the 
30 days prior to the Screening Visit. Note: prior Nd:YAG laser posterior 


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capsulotomy in association with a posterior intraocular lens implantation is 
allowed 
i. 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 
j. Corneal transplantation surgery 
k. History of advanced glaucoma with visual field loss encroaching on central 
fixation 
12. Anterior chamber intraocular lens, aphakia, or violation of the posterior capsule in the 
study eye 
13. 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. Advanced pre-proliferative diabetic retinopathy (with potential for development 
of macular edema or macular hemorrhage) or proliferative diabetic retinopathy 
and/or diabetic macular edema in either eye 
b. Any retinal or choroidal vasculopathy, other than AMD, in either eye 
c. Inflammatory conditions of the anterior or posterior segment (eg, chronic 
keratoconjunctivitis, uveitis, retinal vasculitis, neuritis, iritis, scleritis, or 
blepharitis) 
d. Subfoveal involvement by any of the following: fibrosis, serous pigmented 
epithelial detachment, retinal pigmented epithelial tear, or geographic atrophy 
e. Subfoveal hemorrhage that is ≥ 1 disc areas in size (if the blood is under the 
fovea, the fovea must be surrounded ≥ 270° by visible CNV) 
f. Subretinal hemorrhage that is ≥ 50% of the total CNV lesion area 
g. Any vitreous opacity that prevents proper visualization of the fundus and/or 
adversely alters visual acuity, in the opinion of the investigator 
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. 
14. Any history of active bacterial, viral, fungal, or parasitic infection in either eye within the 
30 days prior to the Screening Visit 
15. Known allergy to constituents of the study drug formulation, ocular antimicrobicide 
solutions, or clinically relevant hypersensitivity to fluorescein 
16. Women who are pregnant or lactating 
17. 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 


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sperm during the time from first dose of study drug until 12 weeks following the last dose 
of study drug 
18. 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 
monthly study visits and assessments, or interfere with the interpretation of study results 
19. Exposure to tetrahydrocannibol (THC) (eg, recreational or medicinal marijuana 
containing THC) within the past 12 months 
20. Prior exposure to oral sunitinib malate in the past 6 weeks 
4.5 
Inclusion Criteria: Extension Study 
1. Verbal and written informed consent for the Extension Study obtained from the subject 
2. Completed all study assessments at Month 12 (Day 360) final study visit including 
fluorescein angiography, and did not require/receive a rescue treatment at the Month 12 
(Day 360) final study visit in ALTISSIMO (Core Study). 
3. Willing and able to give informed consent, comply with all study procedures, and be 
likely to complete the study for the Extension Study 
4.6 
Exclusion Criteria: Extension Study 
1. Subjects who terminated early from ALTISSIMO (Core Study). 
2. Subject who did not complete all study assessments at Month 12 (Day 360) final study 
visit including fluorescein angiography in ALTISSIMO (Core Study).  
3. Subjects who received rescue treatment at the Month 12 (Day 360) final study visit in 
ALTISSIMO (Core Study). 
 


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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. This technician will be unmasked to treatment assignment but not the treatment 
scheme of GB-102. 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. Aflibercept (EYLEA®, 2.0 mg) 
and associated administration supplies will be provided by the Sponsor for subjects randomized 
to receive aflibercept. 
Each study center will have at least 2 retinal physician investigators, and to maintain masking, 
their roles should not be switched for an individual subject during the conduct of the study. 
Information regarding the 2 physician investigators is presented in Section 3.1. 
Adequate topical anesthesia and eye preparation materials (eg, povidone iodine solution) will be 
given prior to the IVT or sham injection per the injecting investigator’s standard-of-care. All IOP 
measurements will be obtained before each injection. 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. 
The comparator product (aflibercept) and the sham injection should be prepared and 
administered as follows: 


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Aflibercept (2 mg): The comparator product will be prepared and administered in a 
manner consistent with the approved package insert for EYLEA®. 
Sham injections: To maintain masking for subjects, the injecting investigator will conduct 
the standard preparations for IVT injection of the eye (topical anesthesia and eye 
preparation). The injecting investigator will press the tip of a sterile 1-cc Luer Lock 
syringe, without a needle, against the globe in a manner similar to an IVT injection. 
5.2 
Treatment Assignment 
5.2.1 Subject Identification Numbers 
5.2.1.1 ALTISSIMO (Core Study): Subject Identification Numbers 
After signing the informed consent form, each subject will be assigned a unique screening 
number via interactive response technology (IRT). 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 via IRT and assigned a randomization number. The screening numbers 
will be used to identify all enrolled subjects throughout the study. 
5.2.1.2 Extension Study: Subject Identification Numbers 
The subject identification number assigned in the ALTISSIMO (Core Study) for each subject 
will be the same number used to identify the subject in the Extension Study. 
5.2.2 Enrollment and Method of Assigning Subjects to Treatment Cohorts/Groups 
5.2.2.1 ALTISSIMO (Core Study): Enrollment and Method of Assigning Subjects to Treatment 
Cohorts/Groups 
The visual acuity examiners, the Sponsor (other than the Vice President of Global Clinical 
Operations), the masked CRO personnel, the medical monitor, and other study personnel, 
including individuals at a central reading center, study coordinators, laboratory vendor, etc. will 
remain masked relative to treatment assignment during the randomization process and to the  
GB-102 treatment scheme post-randomization throughout the study. 
Eligible subjects will be randomly assigned (3:3:2) to receive 50-µL IVT injections of 1 of 
2 doses of study drug or aflibercept, respectively, in the study eye using a stratified, blocked 
randomization scheme. Stratification will include baseline BCVA (< 60 letters vs ≥ 60 letters). 
The study eye will be selected based upon the study qualification criteria and will be used for 
stratification into the IRT at randomization. 
An independent, unmasked designee who is not otherwise involved in the study will generate the 
randomization code used by the IRT, which subsequently will be used to assign masked study kit 


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numbers for dispensing to each enrolled subject at Baseline and Months 2, 4, 6, 8 and 10. A new 
kit will be dispensed at each study visit based on the subject’s randomization. 
5.2.2.2 Extension Study: Enrollment and Method of Assigning Subjects to Treatment 
Cohorts/Groups 
The visual acuity examiners, the Sponsor (other than the Vice President of Global Clinical 
Operations), the masked CRO personnel, the medical monitor, and other study personnel, 
including individuals at a central reading center, study coordinators, laboratory vendor, etc. will 
remain masked relative to treatment assignment during randomization process for the 
ALTISSIMO (Core Study) and to the GB-102 treatment scheme post-randomization throughout 
the Extension Study. 
The study eye selected in the ALTISSIMO (Core Study) will remain the same for the Extension 
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. 
Sham and sham ancillary supply kits will be provided in identical medication kits and medication 
ancillary supply kits, respectively, to maintain masking to the subject. 
The control treatment, aflibercept (EYLEA®) will be supplied in commercial packaging 
(including filter needle, syringe, and needle for injection) and provided in identical medication 
kits for masking purposes. 
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. Aflibercept must be stored per the EYLEA® 
label. 
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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. 
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 (aflibercept) is allowed as rescue treatment at any visit following the Day 30 
study assessments in ALTISSIMO (Core Study) or any visit following the Month 13 (Day 390) 
study assessments in the Extension Study in subjects who meet any of the following criteria 
regarding disease in BCVA and/or increase in CST: 
• Decrease in BCVA (any of the following criteria): 
o ≥ 5 ETDRS letter decrease compared with the average of last 2 visit BCVA ETDRS 
letter scores, and/or, 
o ≥ 10 ETDRS letter decrease compared with best on-study BCVA ETDRS letter score 
• Increase in CST (any of the following criteria): 


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o ≥ 75 µm compared with the average of the last 2 visit CST measurements (µm), 
and/or, 
o ≥ 100 µm compared with the lowest on-study CST measurement (µm) 
Before rescue treatment is administered, the assessing investigator must confirm that the criteria 
have been met using an interactive database system. 
Use of rescue treatment will be recorded on the case report forms (CRFs) and source documents. 
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 (aflibercept, bevacizumab, or ranibizumab) 
• Any exposure to a prior investigational drug product that is fully washed out (at least 
5 half-lives) 
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 
• Use of THC (eg, recreational or medicinal marijuana containing THC) 
5.7 
Other Study Supplies 
Graybug Vision or its designee will make provisions (directly or indirectly) to supply the study 
centers with standard photographs for AREDS lens grading, 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. 
A bulk supply of urine pregnancy tests and lab kits for collection of clinical laboratory analyses 
will be provided by a central laboratory. 
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. 
 
 


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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 for the ALTISSIMO (Core Study) and Table 3-2 for the Extension 
Study; 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. 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. 
6.1 
Subject Entry Procedures 
6.1.1 ALTISSIMO (Core Study): Subject Entry Procedures 
Prospective subjects who meet the entry criteria (inclusion/exclusion criteria) defined in 
Section 4.3 and Section 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 have entered 
the study at the time of administration of the first dose on Day 1. 
Subject eligibility based on lesion characteristics must be confirmed by the central reading center 
prior to subject randomization/treatment assignment. In addition, all screening laboratory tests 
must be performed, and the results must be evaluated and determined to be acceptable to the 
investigator prior to subject randomization into the study. Screening laboratory tests may be 
repeated once at the discretion of the investigator or the Sponsor. 
A urine pregnancy test administered to women of childbearing potential at the Baseline visit 
must be negative for the subject to receive study drug. 


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6.1.2 Extension Study: Subject Entry Procedures 
Prospective subjects who meet the entry criteria (inclusion/exclusion criteria) defined in 
Section 4.5 and Section 4.6 will be considered for inclusion in this study. 
The study will be discussed with each subject and a subject willing 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 for the Extension Study will be assigned the same 
subject identification number assigned in ALTISSIMO (Core Study) that will be used on all 
source documentation throughout the study.  
A subject is considered enrolled into the Extension Study once all study entry criteria for the 
study have been met and determined to be acceptable by the investigator. 
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 reading center has confirmed eligibility. The following 
procedures are to be performed at this visit: 
• 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 blood chemistry and hematology 
• Collect urine samples for urinalysis and urine drug screen 
• 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 with AREDS lens assessment of both eyes (to be 
conducted and graded by the investigator as part of the biomicroscopy examination) 
• Measure IOP (via Goldmann applanation tonometry or Tono-Pen) in both eyes 


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• Perform dilated ophthalmoscopy of both eyes 
• Obtain SD-OCT imaging of both eyes 
• Perform FA and CFP for 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 
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) 
• Assess BCVA (using the ETDRS protocol with manifest refraction) in both eyes 
• Perform the slit-lamp biomicroscopy with AREDS lens assessment of both eyes (to be 
conducted and graded by the investigator as part of the biomicroscopy examination) 
• 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, the Medical 
Monitor has confirmed eligibility based on ocular inclusion criteria, and the investigator has 
confirmed subject eligibility based on the results from the screening blood chemistry, 
hematology, urinalysis, and urine pregnancy tests, as well as BCVA assessments, use the IRT for 
randomization/assignment of treatment. For subjects assigned to receive aflibercept, dosing will 
be conducted per the prescribing information for EYLEA by the injecting investigator. 
• Perform the IVT injection 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; if needed, the subject can be examined 
(eg, additional IOP or ophthalmoscopy) per the discretion of the injecting investigator prior 
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• Perform CFP in the study eye to document the position of the depot and the status of the 
visual axis 
• Draw blood samples for plasma PK (systemic exposure) analyses 1.0 hour ± 15 minutes 
post-IVT injection 
• When medically appropriate, dispense pre-injection and postinjection anti-infectives 
according to standard clinic procedure at the study center 
• 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, 5, 6, 7, 8, 9, 10, and 11 
The visits windows are as follows: Week 2 (Day 14 ± 2) and Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 
and 11 (Day 30 ± 4, Day 60 ± 7, Day 90 ± 7, Day 120 ± 7, Day 150 ± 7, Day 180 ± 7, 
Day 210 ± 7, Day 240 ± 7, Day 270 ± 7, Day 300 ± 7, and Day 330 ± 7, respectively). 
The following procedures are to be performed at each of the visits unless otherwise specified: 
• Review concomitant medications and procedures 
• Query for AEs 
• Assess BCVA (using the ETDRS protocol with manifest refraction) in both eyes 
• Perform the slit-lamp biomicroscopy with AREDS lens assessment of both eyes (to be 
conducted and graded by the investigator as part of the biomicroscopy examination) 
• Measure IOP (via Goldmann applanation tonometry or Tono-Pen) in both eyes (must be 
performed prior to the IVT injection of study drug at relevant study visit) 
• 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 
Additional procedures to be performed at specific visits are as follows: 
• At Month 4 only: obtain blood and urine samples for clinical laboratory tests 
• At the Week 2, and Months 1, 2, 4, 6, 8, and 10 study visits only: obtain vital signs (blood 
pressure and pulse rate) 
• At the Month 6 study visit only: perform FA and CFP for both eyes (this procedure must be 
completed prior to study drug administration) 


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• At the Week 2, and Months 1, 2, 3, 4, 6, 7, 8, and 9 study visits only: draw blood samples for 
plasma PK (systemic exposure). (The Month 6 blood sample must be obtained 
1.0 hour ± 15 minutes post-IVT injection) 
• At Months 2, 4, 6, 8, and 10 only: 
o Perform the IVT injection of study drug into the study eye 
o Perform the postinjection assessment of the study eye (checking for count fingers or hand 
motion vision within 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) 
o When medically appropriate, dispense pre-injection and postinjection anti-infectives 
according to standard clinic procedure at the study center 
o All subjects will receive a telephone call from qualified study center personnel as a safety 
follow-up the day after the IVT injection procedure 
6.2.4 Month 12 (Day 360 ± 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 
• Draw blood samples for blood chemistry and hematology 
• Draw blood samples for plasma PK (systemic exposure) 
• Collect urine samples for urinalysis 
• 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 with AREDS lens assessment of both eyes (to be 
conducted and graded by the investigator as part of the biomicroscopy examination) 
• 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 FA and CFP of both eyes; document the position of the depot and the status of the 
visual axis in the study eye 
• Have the subject complete the subject exit questionnaire (Appendix 18.6) 
• Exit the subject from ALTISSIMO (Core Study) 


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• Determine if the subject is willing to participate in the Extension Study and if so, perform the 
procedures noted in Section 6.2.4.1 
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 visibly detectable GB-102 depot on ophthalmic examination at this visit should be 
followed until the depot is no longer observed. 
Subjects with an ongoing SAE at this visit should be followed until the event resolves or 
stabilizes as described in Section 8.8. 
6.2.4.1 Month 12 (Day 360 ± 7 – Screening/Baseline) – Extension Study  
The Screening/Baseline visit for the Extension Study is the same day as the Month 12 (Day 360) 
visit for ALTISSIMO (Core Study). If the subject is willing to participate in the Extension Study 
the following procedures are to be performed at this visit after the subject has exited 
ALTISSIMO (Core Study): 
• Obtain informed consent and authorization 
• Assess the subject regarding the inclusion/exclusion criteria 
• If the subject meets the entry criteria, schedule the subject to return for the Month 13 
(Day 390) visit, otherwise, exit the subject from the Screening portion of the Extension Study 
6.3 
Months 13, 14, 15, 16, and 17 (Extension Study) 
The visits windows are as follows: Months 13, 14, 15, 16, and 17 (Day 390 ± 7, Day 420 ± 7, 
Day 450 ± 7, Day 480 ± 7, and Day 510 ± 7, respectively). 
The following procedures are to be performed at each of the visits unless otherwise specified: 
• Review concomitant medications and procedures 
• Query for AEs 
• Assess BCVA (using the ETDRS protocol with manifest refraction) in both eyes 
• Perform the slit-lamp biomicroscopy with AREDS lens assessment of both eyes (to be 
conducted and graded by the investigator as part of the biomicroscopy examination) 
• Measure IOP (via Goldmann applanation tonometry or Tono-Pen) in both eyes (must be 
performed prior to the IVT injection of study drug at relevant study visit) 
• 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 
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• Schedule the subject to return for the next study visit 
6.4 
Month 18 (Day 540 ± 7) / Early Termination (Extension Study) 
The following procedures are to be performed: 
• Review concomitant medications and procedures 
• Query for AEs 
• Assess BCVA (using the ETDRS protocol with manifest refraction) in both eyes 
• Perform the slit-lamp biomicroscopy with AREDS lens assessment of both eyes (to be 
conducted and graded by the investigator as part of the biomicroscopy examination) 
• Measure IOP (via Goldmann applanation tonometry or Tono-Pen) in both eyes (must be 
performed prior to the IVT injection of study drug at relevant study visit) 
• 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 
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 visibly detectable GB-102 depot on ophthalmic examination at this visit should be 
followed until the depot is no longer observed. 
Subjects with an ongoing SAE at this visit should be followed until the event resolves or 
stabilizes as described in Section 8.8. 
6.5 
Screen Failures 
Subjects who miss a scheduled visit prior to randomization or do not qualify for enrollment in 
the study will be considered screen failures. 
6.6 
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 


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• Record changes in concomitant medications 
6.7 
Subject Discontinuation 
6.7.1 ALTISSIMO (Core Study): 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 
follow-up.” The date that the certified letter was mailed will be considered the date of study 
withdrawal. 
6.7.2 Extension Study: 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, 
receiving a rescue treatment (aflibercept or any other type of rescue treatment [i.e., anti-VEGF 
therapy]) or being lost to follow-up.  
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. 


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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/s 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 
follow-up.” The date that the certified letter was mailed will be considered the date of study 
withdrawal. 
6.8 
Subject Replacement 
One rescreening of a nontreated screen failure subject may be allowed. However, rescreening is 
not allowed in the Extension Study. 
Subjects will not be replaced for any reason. 
6.9 
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 
and Table 3-2 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 
CNV 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 18 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, Hematology, and Urinalysis 
Blood and urine samples for routine clinical laboratory tests will be collected. Samples should be 
obtained prior to administration of study drug. Screening laboratory tests may be repeated once 
at the discretion of the investigator. The minimum tests to be performed include the following: 
• Nonfasting chemistry (blood): sodium, potassium, chloride, bicarbonate, albumin, alkaline 
phosphatase, aspartate amino transferase, alanine amino transferase, bilirubin direct, bilirubin 
indirect, total bilirubin, creatinine, blood urea nitrogen, total protein, calcium, phosphorus, 
and hemoglobin A1c 
• Hematology (complete blood count with differential): white blood cell count, red blood cell 
count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, red cell distribution width, platelet count, and 
mean platelet volume 
• Urinalysis (dipstick): glucose, protein, and pH 
• Urine drug screen (Screening visit only) 
For detailed instructions regarding the collection of laboratory tests, refer to the separately 
provided Laboratory Manual. 
7.6 
Plasma Pharmacokinetics (Systemic Exposure) 
A descriptive statistical summary of plasma concentration of sunitinib and concentration time 
plots will be generated. Blood samples for plasma analysis will be collected from all subjects and 
an analysis of approximately 20% of subjects assigned to each sunitinib group will be performed. 
For detailed instructions regarding the collection of plasma samples, refer to the separately 
provided Laboratory Manual. 
7.7 
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 12. 
7.8 
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. 


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Visual acuity testing will be performed by a certified visual acuity examiner and should occur 
before any examination requiring contact with the eye. The visual acuity examiners are not 
allowed to perform any study related activities other than BCVA assessments to maintain 
masking including obtaining medical histories or attempting to elicit any information regarding 
treatment, adverse events, or clinical information from the subjects. The same BCVA examiner 
should be utilized for each subject throughout the study when possible. 
7.9 
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 
• Pupil 
• Lens 
If any findings are abnormal, exact findings should be specified and noted as either clinically or 
not clinically significant. 
In addition, the lens will be graded by the assessing investigator for the presence and severity of 
nuclear, cortical, and posterior subcapsular lens opacities using the AREDS photographic 
reference scale. For detailed instructions regarding AREDS lens scoring, refer to the separately 
provided AREDS lens grading scale (Chew 2010). 
7.10 Intraocular Pressure 
At each study visit, IOP will be measured according to routine clinical practice using Goldmann 
applanation tonometry or Tono-Pen in both eyes at all study visits (must be performed prior to 
dilation and the IVT injection of study drug at dosing visits). 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. 


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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.  
7.11 Dilated Ophthalmoscopy 
Dilated fundus examination of both eyes will be performed in all subjects by designated qualified 
study center personnel. The following will be observed for the presence of abnormalities: 
• Vitreous body 
• Macula 
• Peripheral retina 
• Choroid 
• Optic nerve 
If any findings are abnormal, exact findings should be specified and noted as either clinically or 
not clinically significant. All abnormal findings that are clinically significant will be described 
and noted as AEs. 
7.12 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). 
7.13 Fluorescein Angiography 
The FA imaging (after IVT administration of fluorescein dye) of both eyes will be performed to 
examine the circulation of the retina and characteristics of the CNV lesion in the study eye 
according to standard FA image capture protocol. The FA images will be obtained using a digital 
camera by designated certified study center personnel. For detailed instructions regarding 
collection of FA imaging, refer to the separately provided IAG. 
7.14 Color Fundus Photography 
The CFP of both eyes will be performed to assess characteristics of the retina. The photographs 
will be obtained using a digital fundus camera and will be performed by certified study center 
personnel. For detailed instructions regarding collection of CFP imaging, refer to the separately 
provided Image Acquisition Guidelines (IAG). 


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7.15 Intravitreal Depot Color Fundus Photography 
Supplemental 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 or Optos California Ultra-widefield 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 to confirm that the depot is not interfering with the visul axis. For detailed instructions 
regarding collection of the IVT depot CFP imaging, refer to the separately provided guideline. 
7.16 Postinjection Assessments 
Following the IVT injection procedure or sham injection procedure, the injecting investigator 
will assess postinjection safety using count fingers or hand motion vision within 15 minutes after 
injection. The injecting investigator can conduct additional safety assessments (eg, additional 
IOP and ophthalmoscopy), prior to the subject leaving the clinic if needed. 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 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 
• Laboratory abnormality, 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”) 
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”). 


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• 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 the end of study and at least 30 days after the last dose 
of study drug, 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. 
• 
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. 


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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: 
• 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 


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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 the Pharmacovigilance at Syneos 
Health using email notification: safetyreporting@syneoshealth.com or 
fax number: 1 (877) 464-7787. Pharmacovigilance will notify the medical monitor and the 
Sponsor immediately (within 24 hours).  
Alternatively, the investigator may contact the medical monitor directly: 
Steven Gross, MD 
Medical Monitor 
Phone: 813-695-9151 
Email: steven.gross@syneoshealth.com 
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 
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. 


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Reports of those SAEs that qualify for expedited reporting submitted to regulatory agencies in 
accordance with applicable local regulation (eg, 21 CFR 312.32 and, as applicable, European 
Union Directives 2001/83/EC and 2001/20/EC). 
Expedited reports will also be distributed to investigators. Upon receiving such notices, the 
investigator must review the IB and 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 within 
30 days after the subject’s last administration of study drug, and that becomes known to the 
investigator, must be reported to the Sponsor even if the subject is withdrawn from the study. 
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. 
A visibly detectable GB-102 depot on ophthalmic examination at the final study visit is not 
considered an AE. Nevertheless, the investigator should follow the subject until the depot is no 
longer observed. 
All nonserious AEs will be followed through the last study visit. If a nonserious AE is first 
identified at the last scheduled study contact, 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 
A separate statistical analysis plan (SAP) will provide a detailed description of the planned 
statistical analyses. 
9.1 
General Methods of Analysis 
9.1.1 ALTISSIMO (Core Study): General Methods of Analysis 
Summaries for continuous variables will include the number of observations (n), arithmetic 
mean, standard deviation, median, minimum, and maximum. Minima and maxima will be 
reported with the same precision as the raw values; means, standard deviations, and medians will 
be presented to 1 additional decimal place than reported in the raw values. 
Summaries for discrete variables will include frequencies and percentages. Differences between 
treatment schemes will be calculated as GB-102 minus aflibercept and change from baseline will 
be calculated as the value at follow-up study visit minus the value at Baseline (Day 1). The 
baseline visit will be defined as the last nonmissing measure prior to initiation of study drug. 
All summaries will be presented by treatment scheme and, where appropriate, by visit. When 
presenting by treatment scheme, a combined GB-102 group will be presented (all subjects dosed 
to 1 mg GB-102 followed by 1 mg dosing and all subjects dosed to 2 mg GB-102 followed by 
1 mg dosing) along with each individual treatment scheme (aflibercept, 1 mg GB-102 followed 
by 1 mg and 2 mg GB-102 followed by 1 mg dosing). 
9.1.2 Extension Study: General Methods of Analysis 
All safety and efficacy data collected beyond Month 12 (Day 360) will be presented in listings 
and summarized as appropriate using descriptive statistics. 
9.2 
Study Endpoints 
9.2.1 Primary Endpoint 
• Time to first rescue treatment (GB-102 only). This would be further validated through 
assessing time to fufillment of at least one rescue criterion.   
9.2.2 Secondary Endpoints 
• Time to fulfillment of at least one rescue criterion starting at the Month 6 visit through to 
the Month 12 visit (excluding any rescue at the Month 12 visit). 
• Number of times that at least one rescue criterion is met 
• Number of treatments, including both rescue and scheduled study treatments, during the 
study 


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• Change from baseline in BCVA (ETDRS) at all visits 
• Categorical change from Baseline in BCVA (ETDRS) at all visits 
• Frequency of subjects with BCVA worse than 20/200 (Snellen equivalent) at all visits 
• Change from baseline in CST (μm) at all visits 
• Frequency of subjects with absence of exudation (intra-/sub-retinal fluid/cystoid edema) 
at all visits 
9.2.3 Exploratory Endpoints 
• Change from baseline in BCVA comparing all subjects receiving GB-102 to subjects 
receiving aflibercept at all visits 
• Change from baseline in CST comparing all subjects receiving GB-102 to subjects 
receiving aflibercept at all visits 
• Change from baseline in total lesion area (mm2) at Months 6 and 12 of treatment 
• Change from baseline in CNV lesion area (mm2) at Months 6 and 12 of treatment 
• Change from baseline in fluorescein leakage area (mm2) at Months 6 and 12 of treatment 
• Change from thickest observed CST (µm) prior to enrollment (pre-enrollment baseline) at 
all visits 
• Change from average of observed CST (μm) prior to enrollment (pre-enrollment 
baseline) at all visits 
ALTISSIMO (Core Study) Subject Exit Questionnaire  
• The subject exit questionnaire (Appendix 18.6) is not a validated patient reported 
outcome (PRO) measure and is designed to explore a subject’s experience with the 
medication. All subjects exiting the study on Month 12 (Day 360), regardless of whether 
or not the subject joins the Extension Study, are required to complete the questionnaire. 
9.2.3.1 Exploratory Endpoints: Extension Study 
• All safety and efficacy data collected beyond Month 12 (Day 360) will be assessed in an 
exploratory manner. 
9.2.4 Safety Endpoints 
• Occurrence of ocular and nonocular AEs and SAEs 
• Plasma levels of sunitinib (ng/mL) 


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9.3 
Analysis Populations 
Three analysis sets will be defined as follows: 
• Safety analysis set (SS): Includes all randomized subjects who receive at least one dose of 
study treatment. Analyses will group subjects according to the treatment scheme actually 
received. 
• Full analysis set (FAS): Includes all randomized subjects who receive at least one dose of 
study treatment, and complete a 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. All efficacy analyses 
will be conducted on the FAS and these analyses will be considered primary. 
• 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 primary efficacy endpoint 
of the study. Analyses conducted on the PP set will be considered secondary. 
9.4 
Subject Demographics and Baseline Characteristics 
Continuous summary statistics will be generated for the quantitative demographic variable 
(age, in years), tabulated by treatment scheme for the SS and FAS. Discrete summary statistics 
will be generated for qualitative demographic variables (age category, sex, ethnicity, race, and 
iris color for the study eye), tabulated by treatment scheme for the SS and FAS. 
Baseline clinical characteristics and disease history, such as baseline BCVA, CST, and SD-OCT 
measurements, fluorescein angiography values, and color fundus photography values, will also 
be summarized descriptively by treatment group for the SS and FAS. 
Medical history will be coded using the current version of MedDRA at the time of database lock. 
Medical history will be summarized using discrete summary statistics for each MedDRA SOC 
and preferred term (PT) by treatment scheme for the SS and FAS. Medical history will be 
presented separately for ocular and nonocular conditions. Subjects with multiple medical 
histories in the same SOC or PT will be counted only once for that respective SOC or PT. 
9.5 
Analysis of Imaging Parameters 
Data from a central reading center will be used for descriptive summaries of imaging parameters 
based upon SD-OCT, FA, and CFP. Descriptive summary statistics will be provided and 
exploratory inference testing will be described in the SAP. 
9.6 
Efficacy Analyses 
A separate SAP will provide a detailed description of the planned statistical analyses. Efficacy 
parameters will be summarized and analyzed for the FAS (primary population for analysis) and 
PP (secondary/sensitivity population for analysis). 


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9.6.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the time to first rescue treatment (GB-102 only). This would be 
further validated through assessing time to fulfillment of at least one rescue criterion.  
Time to first rescue treatment/fulfillment of at least one rescue criterion will be analyzed using 
the Kaplan-Meier method. The probability of remaining rescue treatment free/not fulfilling at 
least one rescue criterion will be reported for the Month 6 and Month 12 visits with associated 
80% confidence intervals (CI) based on Greenwood’s standard error estimate. Kaplan-Meier 
curves will be produced. If calculable, estimates of the median time to fulfillment of at least on 
rescue criterion and the 25th and 75th percentiles will be calculated with corresponding 80% CIs. 
The FAS will be the primary population used for analysis of the primary efficacy endpoint. 
For this analysis, the interval censored nature of the time to first rescue treatment/fulfillment of 
at least one rescue criterion with regard to the scheduled study visits is considered: If a subject 
receives a rescue treatment/fulfills a rescue criterion during an unscheduled visit, then the subject 
will be considered to have met the event of interest in the visit interval which ends at the next 
scheduled study visit that occurs after the unscheduled visit. Subjects who do not receive rescue 
medication/fulfill a rescue criterion will be censored on last scheduled study visit recorded for 
the subject.  
Exploratory comparisons between each GB-102 scheme and aflibercept and between the 
combined GB-102 schemes versus aflibercept regarding time to first fulfillment of at least one 
rescue criterion will be conducted using a log-rank test stratified by baseline BCVA (< 60 letters 
vs ≥ 60 letters), as defined at the time of randomization. The Peto method will be used to 
estimate the hazard ratio and asymptotic 80% confidence interval based on the stratified log rank 
test statistic. 
A primary endpoint analysis will be conducted when all subjects complete the Month 12 
(Day 360) visit. 
9.6.2 Secondary Efficacy Analysis 
The change from baseline in BCVA and CST will be presented by treatment scheme with 
associated 80% confidence intervals (CI) for all visits. A similar analysis will be done for 
absolute values and change in BCVA and CST relative to the time of first rescue treatment 
(response to rescue treatment). Time to fulfillment of at least one rescue criterion starting at the 
Month 6 visit through Month 12 will be summarized using descriptive statistics including 80% 
CIs and will be presented for the number of rescue treatments, number of scheduled treatments, 
number of total of rescue and scheduled treatments, and number of times that at least one rescue 
criterion is met from baseline through Month 12. 
Absence of exudation (intra-/sub-retinal fluid/cystoid edema),  categories of change from 
Baseline in BCVA, and BCVA worse than 20/200 (Snellen equivalent) will be summarized at 
each visit using discrete summary statistics, including 80% asymptotic normal CIs for each 
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Further details on the analysis of the secondary efficacy endpoints will be provided in the SAP. 
9.6.3 Exploratory Efficacy Analysis 
Observed values at each visit and change from baseline values at each follow up visit for BCVA, 
CST, total lesion area, CNV lesion area, and fluorescein leakage area will be summarized using 
continuous summary statistics, including 80% CIs around the mean for each treatment scheme, 
as well as the combined GB-102 groups and the aflibercept control group. For CST, the change 
from the thickest pre-enrollment value (µm) and change from average pre-enrollment value (µm) 
at each visit will be similarly summarized. 
For BCVA and CST, comparisons between each GB-102 group and the aflibercept control group 
and between the combined GB-102 groups and the aflibercept control group will be made 
primarily for each visit using a linear model adjusting for the baseline value as a covariate/class 
variable and secondarily using 2-sample t-tests. 
9.6.3.1 Exploratory Efficacy Analysis: Extension Study 
All safety and efficacy data collected beyond Month 12 (Day 360) will be presented in listings 
and summarized as appropriate using descriptive statistics. 
9.7 
Safety Analyses 
All safety analyses will be performed on the safety analysis set. 
Adverse Events 
The safety of GB-102 will primarily be assessed by the incidence of treatment emergent AEs 
(TEAE). An AE will be considered a TEAE if it occurs or worsens on or after initiation of study 
drug. An overall summary of TEAEs will be presented including the number of events and the 
number of subjects with events (along with percentages) by treatment scheme for TEAEs in 
several categories based on location, seriousness, relationship to study drug, and severity. 
All AEs will be coded to system organ class (SOC) and preferred term (PT) using the current 
version of MedDRA at the time of database lock. The number of TEAEs and the number and 
percentage of subjects with any TEAEs will be tabulated overall and by SOC and PT within each 
SOC by treatment scheme and over all treatment schemes. 
The following categories of adverse events will be summarized separately for ocular TEAEs in 
the study eye, ocular TEAEs in the non-study eye, non-ocular TEAEs, and all TEAEs combined, 
with full detail provided in the SAP: 
• TEAEs 
• Treatment related TEAEs 
• Serious TEAEs 


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• Serious treatment related TEAEs 
• TEAEs leading to premature study discontinuation 
• TEAEs by maximum severity 
• TEAEs by day of onset 
• Arteriothromboembolic TEAEs using ATC criteria 
Descriptive summaries will be provided for SAEs, SUSARs, and AEs leading to study 
discontinuation. 
Plasma Levels of Sunitinib 
Plasma concentrations will be summarized at each visit using continuous descriptive statistics. 
Other Safety Endpoints 
Study drug exposure, concomitant medication use, physical examination results, vital signs, and 
laboratory results will be summarized by treatment scheme. 
IOP measurements will be summarized by treatment scheme separately for the study eye and for 
the nonstudy eye. The IOP data will be summarized by visit using both continuous and discrete 
summaries. Changes from baseline will also be summarized continuously and discretely. 
Discrete categories for IOP measurements will include (in mmHg) ≤ 5, 6 to 14, 15 to 21, 22 to 
29, and ≥ 30. These categories will be used to summarize results by visit and to summarize shifts 
from baseline IOP for each treatment scheme by visit. Discrete categories for changes from 
baseline in IOP will include ≤ −5, −4 to 0, 1 to 4, 5 to 9, 10 to 14, and ≥ 15. The numbers and 
percentages of eyes with an IOP measurement ≥ 30 mmHg and the numbers and percentages of 
eyes with an increase from baseline in IOP measurement ≥ 10 mmHg will also be summarized. 
Slit-lamp biomicroscopy and dilated ophthalmoscopy results will be summarized for each 
treatment scheme for the study eye and nonstudy eye by visit using discrete summary statistics.  
Presence and severity of nuclear sclerosis, cortical opacities, and posterior subcapsular opacities 
evaluated according to the AREDS protocol will be summarized by treatment scheme. 
9.8 
Sample Size Determination 
The sample size of this study was not selected to support specific statistical hypothesis testing as 
all comparisons are exploratory.  
9.9 
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. However, if the amount of missing post-
baseline values for a particular endpoint are substantial, multiple imputation methods will be 


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considered for the impution of missing values and details will be included in the statistical 
analysis plan. 
Sensitivity analyses of primary and secondary efficacy endpoints will be conducted using the per 
protocol population. Additional sensitivity analyses will be specified in the statistical analysis 
plan. 
9.10 Subjects Receiving Rescue Treatment 
Subjects receiving rescue treatment will continue to be evaluated at scheduled visits. Rescued 
subjects will be included in all analyses sets. Descriptive analyses will be conducted including 
time to first rescue treatment (GB-102 only), time to fulfillment of at least one rescue criterion 
from Baseline to Month 6 and Month 12, and number of rescue injections. 
9.11 Units of Analysis 
The unit of analysis will be the individual study eye for assessments performed by eye, or the 
subject for assessments performed at the subject level. 
9.12 Changes in the Conduct of the Study or Planned Analyses 
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. 
Note: If discrepancies exist between minor features of the statistical analysis as planned in the 
protocol and as described in the final SAP, a protocol amendment will not be issued and the SAP 
will prevail. 


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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 randomization 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; June 2019. 
Awh C, Campochiaro P, Regillo C, Marcus D, Tang F, Erickson S, Singh N, Gune S, Barteselli 
G, Ladder Trial of the Port Delivery System With Ranibizumab: Initial Study 
Results Presented at the 36th Annual Scientific Meeting of the American Society 
of Retina Specialists, Jul 2018. 
CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, et al. 
Ranibizumab and bevacizumab for neovascular age-related macular degeneration. 
N Engl J Med. 2011;364(20):1897-908. 
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. 
Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, 
myocardial infarction, and stroke by prolonged antiplatelet therapy in various 
categories of patients. Antiplatelet Trialists’ Collaboration. BMJ. 
1994;308(6921):81-106. 
Collet B. Management of Ozurdex in the anterior chamber. JAMA Ophthalmol 2013; 131: 1651-
1652. 
Eandi CM, Alovisi C, De Sanctis U, Grignolo FM. Treatment for neovascular age related 
macular degeneration: the state of the art. Eur J Pharmacol. 2016;787:78-83. 
EYLEA® (aflibercept) Injection. [US Prescribing Information]. Tarrytown, NY: Regeneron 
Pharmaceuticals, Inc; August 2019. 
Heier JS, Boyer D, Nguyen QD, Marcus D, Roth DB, et al. The 1-year results of CLEAR-IT 2, a 
Phase 2 study of the vascular endothelial growth factor trap-eye dosed as-needed 
after 12-week fixed dosing. Ophthalmology. 2011; 118(6):1098-1106. 
Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, et al. Intravitreal 
aflibercept (VEGF trap-eye) in wet age-related macular degeneration. 
Ophthalmology. 2012;119(12):2537-48. 


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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. 
Jaffe GJ, Ciulla TA, Ciardella AP, Devin F, Dugel PU, Eandi CM, et al. Dual antagonism of 
PDGF and VEGF in neovascular age-related macular degeneration: A Phase IIb, 
multicenter, randomized controlled trial. Ophthalmology. 2016; (ePub ahead of 
print, 20 Oct 2016). 
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. 
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; Mar 2018. 
Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology. 1985;92(4):467-71. 
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. 
Prenner JL, Halperin LS, Rycroft C, Hogue S, Williams Liu Z, Seibert R. Disease burden in the 
treatment of age-related macular degeneration: findings from a time-and-motion 
study. Am J Ophthalmol. 2015;160(4):725-31 e1. 
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for 
neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-
31. 
Ruiz-Moreno JM, Montero JA, Artola A. Anterior chamber transit of triamcinolone after 
intravitreal injection. JAMA Ophthalmol 2005; 123:129-130. 
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. 


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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; 
May 2019. 
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. 
Tsujinaka H, Fu J, Shen J, Yang M, Lu L, et al. Sustained treatment of choroidal and retinal 
vascular diseases by intravitreous injection of sunitinib microparticles. 
(Manuscript submitted for publication, 2018) 
Williams GA. Intravitreal injections: health policy implications. Rev Ophthalmol [Internet]. 
2014 (Accessed: 10 October 2016). Available from: 
https://www.reviewofophthalmology.com/article/ivt-injections-health-policy-
implications. 
Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, et al. Global prevalence of age-related 
macular degeneration and disease burden projection for 2020 and 2040: a 
systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-16. 
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-102-002 
18.1.1 ALTISSIMO (Core Study) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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18.1.2 Extension Study 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 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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18.6 
ALTISSIMO (Core Study) Subject Exit Questionnaire 
Each subject will be asked to complete a study subject exit questionnaire about their experience 
in the Phase 2b GBV-102-002 ALTISSIMO (Core Study). This questionnaire must be completed 
by each subject who completes the Month 12 (Day 360) visit before exiting the study. This 
questionnaire is not a validated patient reported outcome (PRO) assessment and is designed to 
explore the subject’s experience with the study drug treatment.  
Questions 
1. What was your experience with the assigned study drug treatment you received in the 
ALTISSIMO Study? Please circle one answer that best describes your experience and 
provide comments: 
1. Dissatisfied 
2. Slightly dissatisfied 
3. Satisfied  
4. Moderately satisfied 
5. Very satisfied  
Please also provide comments on your experience: 
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________ 
2. How did the assigned study drug treatment you received in the ALTISSIMO Study compare 
with the treatment(s) you received before entering the study? Please circle one answer that 
best describes your experience and provide comments: 
1. Much worse 
2. Slightly worse 
3. About the same 
4. Slightly better 
5. Much better 
 
Please also provide comments on your experience: 
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________ 


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3. Did you notice any difference in your experience with the study drug treatment between the 
first 6 months of the ALTISSIMO Study versus the last 6 months of the ALTISSIMO Study? 
Please circle one answer that best describes your experience and provide comments: 
1. First 6 months were better than the last 6 months 
2. Last 6 months were better than the first 6 months 
3. Last 6 months were the same as the first 6 months 
Please also provide comments on your experience: 
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________ 
4. Based on your experience in this study, how likely are you to request from your physician to 
receive a long-acting treatment for wet AMD (approximately 4-6 months between treatment 
injections) if it means less frequent injections? Please circle one answer that best describes 
your experience and provide comments: 
1. Extremely unlikely 
2. Unlikely 
3. Neutral 
4. Likely 
5. Extremely likely 
Please also provide comments on your experience: 
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________ 
 
 


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18.7 
Protocol Amendment Summary 
This summary includes changes made to Protocol Amendment 3 GBV-102-002 (Version 4.0 
dated 08 September 2020. 
Graybug Vision, Inc. has decided to include an option for subjects completing the GBV-102-002 
Phase 2b ALTISSIMO (Core Study) to enter an Extension Study. The Extension Study is 
designed to follow subjects who complete all study visits through Month 12 (Day 360), complete 
all study assessments at Month 12 (Day 360) including fluorescein angiography, and do not 
receive a rescue treatment at the Month 12 (Day 360) final study visit on ALTISSIMO (Core 
Study). Subjects who enter the Extension Study will be followed for safety until administered 
rescue treatment as per the rescue treatment criteria or until study completion at Month 18 (Day 
540). 
Additionally, the definition of the primary and secondary endpoints and statistical plans were 
further clarified. In particular, the primary endpoint was updated from probability of receiving 
rescue treatment through Month 12 to time to first rescue treatment (GB-102 only) in order to 
avoid potential bias in the assessment of the duration of effect. 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial changes and document 
formatting revisions have not been summarized. 
Section 
Revision 
Rationale 
Title Page  
Updated the name and 
contact information on the 
title page to reflect the 
change in Chief Medical 
Officer for Graybug Vision, 
Inc. 
Sponsor decision 
Synopsis, Sections 2, 3, 4, 
5.2, 6, and 9 
Updated the objectives, 
study design, masking, 
number of subjects, study 
endpoints and statistical 
methods & considerations, 
enrollment and method for 
assigning subjects to 
treatment cohorts/groups, 
study assessments to 
describe the activities 
planned in the Extension 
Study. 
Sponsor decision 


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Synopsis and Section 9 
Updated the Study Endpoints 
and Statistical Methods for 
ALTISSIMO (Core Study) 
Sponsor decision 
Section 1.4 
Provided updated 
information regarding the 
status of ongoing studies and 
added in the purpose of and 
plan for the extension study.  
Updated information 
Table 3.1, Section 6.2.4 and 
18.6 
Added a subject exit 
questionnaire to explore the 
subject’s experience with the 
study medication in 
ALTISSIMO (Core Study). 
Sponsor decision 
Appendix 18.1.2 
Added Study Schema for the 
Extension Study 
Sponsor decision 
 

SAP_001.pdf: 
Graybug Vision Inc. 
 
Statistical Analysis Plan 
 
Official Title: A Phase 2b Multicenter Dose-Ranging Study Evaluating the Safety and Efficacy 
of a Long-acting Intravitreal Sunitinib Malate Depot Formulation (GB-102) Compared to 
Intravitreal Aflibercept in Subjects with Neovascular (Wet) Age-related Macular Degeneration 
(ALTISSIMO Study) 
 
Protocol Number: GBV-102-002 
 
Document Date: 08Jan2021 
 
NCT Number: NCT03953079 
 
 
 




 
 
 
 
 
This document is confidential. 
SAP Version: 3.0 08JAN2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 1 of 47 
 Statistical Analysis Plan for Interventional Studies 
 
Sponsor Name: Graybug Vision, Inc. 
 
Protocol Number: GBV-102-002 (Phase 2b) 
Protocol Title: A Phase 2b Multicenter Dose-Ranging Study Evaluating the Safety and Efficacy of a 
Long-acting Intravitreal Sunitinib Malate Depot Formulation (GB-102) Compared to Intravitreal Aflibercept 
in Subjects with Neovascular (Wet) Age-related Macular Degeneration (ALTISSIMO Study) 
 
Protocol Version and Date: Version 4.0 / 08 September 2020 (Amendment 3) 
 
Syneos Health Project Code: 1011627 
 
Authors: 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Graybug Vision, Inc.  Acceptance 
of this document constitutes agreement by the recipient that no information contained herein will be 
published or disclosed without prior written authorization from an official of Graybug Vision, Inc.  
However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential.  In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 




Statistical Analysis Plan for Interventional Studies
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) 
This document is confidential. 
SAP Version: 3.0 08JAN2021 
Controlled Document ID: 3903A.01, Effec ive Date 29-Oct-2018 
Filing requirements: TMF 
Page 3 of 47 
I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) 
 
 
This document is confidential. 
SAP Version: 3.0 08JAN2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 4 of 47 
Table of Contents 
Revision History ............................................................................................................................ 2 
Approvals .................................................................................................................................... 3 
 
Glossary of Abbreviations .................................................................................................... 7 
 
Purpose ................................................................................................................................ 9 
 
Study Objectives ................................................................................................................ 10 
 
Endpoints ........................................................................................................................... 20 
 
Analysis Sets ...................................................................................................................... 22 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) 
 
 
This document is confidential. 
SAP Version: 3.0 08JAN2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 5 of 47 
 
General Aspects for Statistical Analysis ............................................................................. 25 
 
Demographic, Other Baseline Characteristics and Medication .......................................... 29 
 
Efficacy ............................................................................................................................... 31 
 
Safety ................................................................................................................................. 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) 
 
 
This document is confidential. 
SAP Version: 3.0 08JAN2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 6 of 47 
 
Changes from Analysis Planned in Protocol ...................................................................... 40 
 
Reference List .................................................................................................................... 41 
 
Programming Considerations ............................................................................................. 42 
 
Quality Control ................................................................................................................... 47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) 
 
 
This document is confidential. 
SAP Version: 3.0 08JAN2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 9 of 47 
 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables, and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives stated in Protocol GBV-102-002 
(Phase 2b), Version 4.0, dated 08 September 2020 (Amendment 3). This document addresses only the 
analyses associated with the core study. The analyses for the extension study will be addressed in a later 
document. 
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. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality 
control of all tables, figures, and listings. 
 
Timings of Analyses 
An unmasked primary analysis for safety and efficacy is planned at the end of the study after database 
lock when all subjects complete the Day 360 visit or discontinue prematurely from the study.  All data up 
to Day 360 visit and all data that were to be performed at Day 360 visit but were performed late are also 
included.  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) 
 
 
This document is confidential. 
SAP Version: 3.0 08JAN2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 10 of 47 
 
Study Objectives 
 
Primary Objective 
The primary objective of the study is to evaluate the safety and duration of the effect of GB-102, as 
measured by time to first rescue treatment/first fulfillment of rescue treatment criteria across two different 
dosing schemes of GB-102 administered every 6 months (1 mg followed by 1 mg or 2 mg followed by 1 
mg) as compared to intravitreal (IVT) aflibercept administered every 2 months in subjects with 
neovascular (wet) age-related macular degeneration (AMD) who have received prior induction with IVT 
anti-vascular endothelial growth factor (VEGF). 
If the need for rescue treatment was identified at a given study visit, a rescue treatment was only given in 
case no study treatment was scheduled. Due to the imbalance in treatment visits between GB-102 and 
aflibercept, corresponding comparisons for the time to first rescue treatment may be biased. Therefore 
analyses of the time to first rescue treatment are limited to the GB-102 treatment arms. Based on a 
comparison of time to first rescue treatment and time to first fulfillment of a least one rescue criterion (as 
derived from the recorded BCVA and CST measurements) for the GB-102 treatment arms the 
consistency between these two endpoints will be assessed, with the objective to establish time to 
fulfillment of at least one rescue criterion as an alternative endpoint for the assessment of duration of 
effect versus aflibercept. If the two endpoints are consistent for GB-102, the alternative endpoint can be 
used to make an unbiased comparison to aflibercept.  
 
Secondary Objective(s) 
The secondary objectives of the study are: 
• 
To evaluate the efficacy of two different dosing schemes of IVT GB-102 administered every 6 
months in maintenance of best-correct visual acuity (BCVA, Early Treatment Diabetic 
Retinopathy [ETDRS] letter score) compared to subjects receiving IVT aflibercept every 2 months 
• 
To evaluate the efficacy of two different dosing schemes of IVT GB-102 administered every 6 
months in maintenance of central subfield thickness (CST, µm) compared to subjects receiving 
IVT aflibercept every 2 months 
 
Brief Description 
The study was planned as a Phase 2b, multicenter, visual examiner-masked, randomized active-
controlled, parallel-arm design, conducted at approximately 35 study centers in the United States. Eligible 
subjects will be randomly assigned (3:3:2) to receive 50-µL IVT injections of 1 of 2 doses of study drug or 
aflibercept, respectively, in the study eye using a stratified, blocked randomization scheme. Stratification 
will include baseline BCVA (< 60 letters vs ≥ 60 letters). 
The first subject enrolled was September 2019 with a planned sample size of 160 subjects. Due to the 
reported SAE in Protocol GBV-102-003 on December 17, 2019, enrollment in the ALTISSIMO study was 
voluntarily suspended by the Sponsor on December 19, 2019 as a safety precaution after a total of 56 
subjects had been enrolled. An unmasked limited interim safety review was conducted by the Sponsor 
(Chief Medical Officer and the Vice President of Global Clinical Development Operations) in February 
2020. Subsequently, the only unmasked person at the sponsor is the Vice President of Global Clinical 
Development Operations.  The current Chief Medical Officer remains masked to data subsequent to 
February 2020 analysis. No SAEs have been reported in ALTISSIMO; however, 5 subjects have reported 


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drug material observed in the AC (N=4, 2 mg; N=1, 1 mg). All reported cases have been mild-to-moderate 
in severity. One subject who received the 2 mg dose developed a moderate pseudohypopyon and was 
managed with elective AC lavage and pars plana vitrectomy without complication. The subjects remain in 
the study and are under observation alone or undergoing treatment with a short course of prophylactic 
topical steroids.   The Sponsor elected to stop further enrollment in ALTISSIMO and to re-dose only the 1 
mg dose of GB-102 for those subjects assigned to GB-102.  
As further enrollment was suspended (see above), the resulting number of patients per treatment arm are 
as follows: : 
Group 1:   1 mg GB-102 at baseline and Month 6 and sham at Months 2, 4, 8, and 10 (N=21) 
Group 2:   2 mg GB-102 at baseline and 1 mg GB-102 at Month 6 and sham at Months 2, 4, 8, 
and 10 (N=22) 
Group 3:   2 mg aflibercept q 2 months at baseline, Months 2, 4, 6, 8 and 10 (N=13) 
After baseline (Day 1) subjects will return to the study center on Days 14, 30, 60, 90, 120, 150, 180, 210, 
240, 300, 330, and 360 for safety, clinical, and imaging assessments. Subjects will exit the study following 
all study assessments on Day 360. 
Rescue treatment (using aflibercept) will be permitted in the study eye in any of the study arms if the 
eligibility criteria are met for rescue treatment. Subjects receiving rescue treatment will continue to be 
evaluated at scheduled study visits and to follow the scheduled dosing regimen at subsequent visits. In 
the event that a subject meets the criteria for rescue treatment at a scheduled dosing visit, no rescue 
treatment was to be administered; the subject would just receive the scheduled study treatment. 
The nonstudy eye may receive IVT anti-VEGF treatment (aflibercept, bevacizumab, or ranibizumab) for 
the treatment of wet AMD at the discretion of the investigator. 
Subjects should not be withdrawn from the study due to an adverse event (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. 
 
Subject Selection 
Subjects eligible for screening must have an active choroidal neovascularization (CNV) lesion in the study 
eye secondary to AMD that was diagnosed in the 12 weeks to 18 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 21 days of screening.  Eligibility will be 
confirmed by a central reading center based upon spectra domain optical coherence tomography 
(SD-OCT), fluorescein angiography (FA), and color fundus photography (CFP) evaluation of the CNV 
lesion. 


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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. 
 
Inclusion Criteria 
1. Verbal and written informed consent obtained from the subject 
2. Males or females ≥ 50 years of age 
3. Willing and able to give informed consent, comply with all study procedures, and be likely to complete 
the study 
4. Presence of a subfoveal or juxtafoveal CNV lesion secondary to AMD in the study eye that was 
diagnosed in the 12 weeks to 18 months prior to screening and has been treated with at least 3 prior 
IVT injections of an anti-VEGF agent (aflibercept, bevacizumab, or ranibizumab). The study eye and 
CNV lesion must demonstrate all of the following features at the Screening Visit (as confirmed by the 
reading center): 
a. Total lesion size ≤ 12 disc areas (30.5 mm2) 
b. Absence of subfoveal fibrosis, serous pigmented epithelial detachment, retinal pigmented 
epithelial tear, or subfoveal geographic atrophy 
c. If fibrosis is present, it must be ≤ 25% of total lesion area and not involve the center of the 
fovea 
d. If subfoveal hemorrhage is present, it must be < 1 disc area in size and not involve the center 
of the fovea 
e. If subretinal hemorrhage is present, it must be < 50% of total CNV lesion and not involve the 
center of the fovea 
5. Prior pharmacodynamic response of the CNV lesion 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: 
a. Reduction of intraretinal/subretinal fluid by ≥ 30% from the initial diagnosis as determined 
using SD-OCT 
b. Reduction of excess CST by ≥ 30% from the initial diagnosis as determined using SD-OCT 
(assuming nominal thickness is 300 µm) 
6. Demonstrate a maintained anti-VEGF response (as determined by the investigator) compared with 
the initial diagnosis (prior to any anti-VEGF treatment) as assessed using SD-OCT following the most 
recent anti-VEGF injection (defined as a reduction in central subfield thickness, intraretinal/subretinal 
fluid, or maintenance of dry retina) 
7. Screening and baseline BCVA letter score (by ETDRS protocol) of 35 to 88 (20/200 to 20/20 Snellen 
equivalent) in the study eye 
8. Availability of CST measurements from SD-OCT imaging obtained from the time of initial diagnosis 
(pre-anti-VEGF therapy) and/or maximal CST thickness obtained any time following anti-VEGF 
induction 
9. If the screening and baseline BCVA letter score (by ETDRS protocol) in the nonstudy eye is worse 


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than the study eye, the BCVA score in the nonstudy eye must be at least 53 letters (20/100 Snellen 
equivalent) or better 
10. Most recent dose of anti-VEGF agent administered within 21 days of screening. 
11. Clear ocular media and adequate pupil dilation in both eyes to permit good quality photographic 
imaging 
12. Women of childbearing potential (ie, not postmenopausal for at least 12 months or not surgically 
sterile [defined as bilateral tubal ligation performed at least 12 months previously, hysterectomy, or 
bilateral oophorectomy]) must have a negative urine pregnancy test at screening and baseline, and 
must use adequate birth control throughout the study and until 12 weeks following the last dose of 
study drug 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 
 
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 > 8.0% at the Screening Visit 
4. Chronic renal disease requiring chronic hemodialysis or renal transplantation 
5. Any screening laboratory result (hematology, chemistry, or urinalysis) that, in the opinion of the 
investigator, is not suitable for subject participation in the study 
6. 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) 
7. Previous participation in an investigational study of GB-102 
8. 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 
9. Uncontrolled IOP (IOP > 25 mm) despite antiglaucoma medications in the study eye at the time of 
screening or controlled glaucoma that requires management with > 2 topical hypotensive medications 
10. Presence of any clinically significant epiretinal membrane or vitreomacular traction in the study eye 
11. History or evidence of any of the following surgeries or procedures in the study eye: 
a. Submacular surgery or other surgical intervention for AMD 
b. Prior retinal detachment or macular hole interventions 
c. Vitrectomy 
d. Photodynamic therapy or thermal laser retinal treatment 
e. Intraocular laser treatments for glaucoma (eg, selective laser trabeculoplasty or peripheral 
iridotomy) 


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f. 
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 
g. Cataract surgery within the 3 months prior to the Screening Visit 
h. 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. 
i. 
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 
j. 
Corneal transplantation surgery 
k. History of advanced glaucoma with visual field loss encroaching on central fixation 
12. Anterior chamber intraocular lens, aphakia, or violation of the posterior capsule in the study eye 
13. 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. Advanced pre-proliferative diabetic retinopathy (with potential for development of macular 
edema or macular hemorrhage) or proliferative diabetic retinopathy and/or diabetic macular 
edema in either eye 
b. Any retinal or choroidal vasculopathy, other than AMD, in either eye 
c. Inflammatory conditions of the anterior or posterior segment (eg, chronic keratoconjunctivitis, 
uveitis, retinal vasculitis, neuritis, iritis, scleritis, or blepharitis) 
d. Subfoveal involvement by any of the following: fibrosis, serous pigmented epithelial 
detachment, retinal pigmented epithelial tear, or geographic atrophy 
e. Subfoveal hemorrhage that is ≥ 1 disc areas in size (if the blood is under the fovea, the fovea 
must be surrounded ≥ 270° by visible CNV) 
f. 
Subretinal hemorrhage that is ≥ 50% of the total CNV lesion area 
g. Any vitreous opacity that prevents proper visualization of the fundus and/or adversely alters 
visual acuity, in the opinion of the investigator 
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. 
14. Any history of active bacterial, viral, fungal, or parasitic infection in either eye within the 30 days prior 
to the Screening Visit 
15. Known allergy to constituents of the study drug formulation, ocular antimicrobicide solutions, or 
clinically relevant hypersensitivity to fluorescein 
16. Women who are pregnant or lactating 
17. 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 12 weeks following the last dose of study drug 


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18. 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 monthly study visits and 
assessments, or interfere with the interpretation of study results 
19. Exposure to tetrahydrocannibol (THC) (eg, recreational or medicinal marijuana containing THC) 
within the past 12 months 
20. Prior exposure to oral sunitinib malate in the past 6 weeks 
 
Determination of Sample Size 
Due to early termination of enrollment, the sample size of this study is not sufficient to support specific 
statistical hypothesis testing; all analyses and comparisons are descriptive only. 
 
Treatment Assignment and Masking 
After signing the informed consent form, each subject will be assigned a unique screening number via 
interactive response technology (IRT). 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 via IRT and 
assigned a randomization number. The screening numbers will be used to identify all enrolled subjects 
throughout the study. 
Eligible subjects will be randomly assigned (3:3:2) to receive 50-µL IVT injections of 1 of 2 doses of study 
drug or aflibercept, respectively, in the study eye using a stratified, blocked randomization scheme. 
Stratification will include baseline BCVA (< 60 letters vs ≥ 60 letters). Originally, the 2 doses of study drug 
were 1 mg at Baseline and Month 6 and 2 mg at Baseline and Month 6.  However, due to emerging 
uncertainty regarding the safety profile of 2 mg GB-102 (see above), there was a decision to re-dose all 
patients on GB-102 with the 1 mg dose at Month 6 regardless of the original dose.  
Enrolled subjects will be masked to treatment assignment.  The visual acuity examiners, the Sponsor 
(other than the Vice President of Global Clinical Development Operations), the masked contract research 
organization personnel, the medical monitor, and other study personnel, including individuals at a central 
reading center, study coordinators, laboratory vendor, etc. will remain masked relative to the GB-102 
treatment scheme. The visual acuity examiners are not allowed to perform any study related activities 
other than BCVA assessments to maintain masking including obtaining medical histories or attempting to 
elicit any information regarding treatment, adverse events, or clinical information from the subjects. The 
same BCVA examiner should be utilized for each subject throughout the study when possible. 
Each study center will have at least 2 investigators who are retina specialists; one will serve as the 
injecting investigator and the other will serve as the assessing investigator. To maintain study masking, 
the roles of these investigators should not be switched during the conduct of the study. 
• 
Injecting Investigator: An injecting investigator will perform the study drug (GB-102 or aflibercept), 
sham, and/or rescue injections, will supervise the preparation and tracking of study drug, and will 
perform predose and postdose safety assessments for the IVT injections. 
• 
Assessing Investigator: An assessing investigator will supervise and assess the collection of AEs and 
efficacy parameters. The assessing investigator will determine whether rescue treatment is required. 


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The SD-OCT, FA, and CFP technicians are masked to treatment scheme; however, collected images 
may reveal to the assessing investigator or technician which subjects received the 
GB-102 depot (but not the treatment scheme). 
Study personnel performing reconstitution of the investigational drug product (GB-102) will be unmasked 
to treatment assignment but not the treatment scheme. Study drug will be boxed in numbered kits and 
identical in external appearance and weight. Kits containing GB-102 are identical in physical appearance 
and drug vial/diluent (pre-filled syringe) configuration, and fully masked as to the dose strength (1 or 2 
mg) of GB-102. 
An unmasked primary analysis for safety and efficacy is planned at the end of study after database lock 
when all subjects complete the Day 360 visit or discontinue prematurely. 
As it pertains to any analysis to be performed, pharmacokinetic (PK) concentration data will be made 
available only to unmasked Syneos Health statistical personnel. 
 
Administration of Study Medication 
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. 
The comparator product (aflibercept) and the sham injection should be prepared and administered as 
follows: 
Aflibercept (2 mg): The comparator product will be prepared and administered in a manner 
consistent with the approved package insert for EYLEA®. 
Sham injections: To maintain masking for subjects, the injecting investigator will conduct the 
standard preparations for IVT injection of the eye (topical anesthesia and eye preparation). The 
injecting investigator will press the tip of a sterile 1-cc Luer Lock syringe, without a needle, 
against the globe in a manner similar to an IVT injection. 
 
Study Procedures 
The schedule of assessments is provided in Table 2, and includes the expected study day relative to the 
date of first dose, acceptable ranges of study days for each visit, and visit nomenclature. 
 
 
 






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rescue treatment is administered. The photographs may be used to document the general appearance and rate of bioabsorbability of the depot. For detailed instructions 
regarding collection of the intravitreal depot CFP imaging, refer to the separately provided guideline. Select sites will collect additional intravitreal depot color fundus 
photography using the Zeiss Clarus 500 or Optos California Ultra-widefield Fundus Imaging system at all visits after initial dosing at Baseline and at any unscheduled visits 
where rescue treatment is administered. 
l 
For all dosing procedures (intravitreal or sham), subject should remain seated for approximately 15 minutes post-injection with minimal to no movement of the head. 
Aflibercept dosing to be conducted per instructions in prescribing information by the injecting physician. All subjects receiving GB-102 at baseline will receive 1 mg GB-102 
at Month 6. 
m 
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. 
n 
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. 
o 
Along with the vital signs, height (without shoes) will be measured at Screening and body weight will be measured at Screening and Month 12. The same arm and method of 
obtaining blood pressure and heart rate should be used throughout the study. 
p 
Each subject that completes a Month 12 (Day 360) visit must complete the subject exit questionnaire before exiting the ALTISSIMO (Core Study). 
 


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Endpoints 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to first rescue treatment/first fulfillment of at least one rescue 
criterion from Baseline through Month 12.  
If the need for rescue treatment was identified at a given study visit, a rescue treatment was only given in 
case no study treatment was scheduled. Due to the imbalance in treatment visits between GB-102 and 
aflibercept, corresponding comparisons for the time to first rescue treatment may be biased. Therefore 
analyses of the time to first rescue treatment are limited to the GB-102 treatment arms. Based on a 
comparison of time to first rescue treatment and time to first fulfillment of a least one rescue criterion (as 
derived from the recorded BCVA and CST measurements) for the GB-102 treatment arms the 
consistency between these two endpoints will be assessed, with the objective to establish time to 
fulfillment of at least one rescue criterion as an alternative endpoint for the assessment of duration of 
effect versus aflibercept.  
 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• 
Time to first rescue treatment/first fulfillment of at least one rescue criterion starting at the Month 
6 visit through Month 12  
• 
Change from baseline in BCVA (ETDRS) at all visits 
• 
Categorical change from baseline in BCVA (ETDRS) at all visits 
• 
Frequency of subjects with BCVA worse than 20/200 (Snellen equivalent) at all visits 
• 
Change from baseline in CST (µm) at all visits 
• 
Number of treatments, including both rescue and scheduled treatments (combined and separate) 
during the study 
• 
Number and percentage of subjects receiving treatment at each visit, including both rescue and 
scheduled treatments (combined and separate) 
• 
Number of visit intervals during which at least one rescue criterion is met 
• 
Number and percentage of subjects meeting at least one rescue criterion at each visit 
• 
Frequency of subjects with absence of exudation (intra-/sub-retinal fluid/cystoid edema) at each 
visit 
 
Exploratory Endpoints 
The exploratory endpoints include: 
• 
Change from baseline in BCVA comparing subjects receiving GB-102 to subjects receiving 
aflibercept at all visits 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 9 and 10 


Statistical Analysis Plan for Interventional Studies 
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• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 10 and 11 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 11 and 12 
• 
Change from baseline in CST comparing subjects receiving GB-102 to subjects receiving 
aflibercept at all visits 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 9 and 10 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 10 and 11 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 11 and 12 
• 
Change in CST from thickest observed CST (µm) prior to enrollment (pre-enrollment baseline) at 
all visits 
• 
Change in CST from mean observed CST (µm) prior to enrollment (pre-enrollment baseline) at all 
visits 
• 
Change from baseline in total lesion area (mm2) at Months 6 and 12 
• 
Change from baseline in CNV lesion area (mm2) at Months 6 and 12 
• 
Change from baseline in fluorescein leakage area (mm2) at Months 6 and 12 
• 
Absolute values and change in BCVA and CST compared to values at the time of first rescue 
treatment (response to first rescue treatment) 
• 
ALTISSIMO (Core Study) Subject Exit Questionnaire 
 
Safety Endpoints 
The main safety endpoint is the occurrence of ocular and nonocular AEs and serious AEs. Other safety 
endpoints include physical examination results, vital signs, laboratory results, intraocular pressure, slit-
lamp biomicroscopy, dilated ophthalmoscopy, and the presence and severity of nuclear sclerosis, cortical 
opacities, and posterior subcapsular opacities. 
 
Other Endpoints 
Other endpoints include study drug exposure, concomitant medication use, the subject exit questionnaire, 
and plasma levels of sunitinib (ng/mL). 


Statistical Analysis Plan for Interventional Studies 
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Analysis Sets 
Protocol deviation management at Syneos Health is detailed in “Processing and Management of Protocol 
Deviations” (3101.W02). For details on the process for defining analysis datasets refer to “(Blind) Data 
Review and Definition of Analysis Sets” (SOP 3911). 
Analysis sets are defined in the following sections.  Subjects to be included within and excluded from 
each analysis set will be determined at a Blind Data Review Meeting (BDRM) before unmasking.  A 
separate BDRM Preparation Plan will include, as a minimum, (1) the criteria which will be used to 
determine the subjects to be excluded from the analysis sets, (2) the listings which will be prepared for 
sponsor review in order to determine the subjects to exclude, and (3) the sponsor review forum (i.e., 
BDRM). 
 
Screened Set 
The Screened Set will include all subjects screened. Subjects can be re-screened; in such a case, one 
screening number will be entered into the database with the details of the screening failure, and a second 
screening number will be used when the subject re-screens. This set will be used only for subject 
disposition data. 
 
Randomized Set 
The Randomized Set will include all subjects that were randomized. This set will be used for listings of 
protocol deviations, inclusion/exclusion criteria deviations, exclusions from analysis sets, demographics, 
and baseline characteristics. 
 
Safety Set  
The Safety Set (SS) will include all randomized subjects who receive at least one 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 scheme actually received. The SS will be used for all 
analyses of safety endpoints and for all non-disposition subject listings. 
 
Full Analysis Set  
The Full Analysis Set (FAS) will include all randomized subjects who receive at least one dose of study 
treatment, and complete a 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 scheme. All efficacy analyses will be conducted on the FAS and 
these analyses will be considred primary.  
 
Per Protocol Set 
The Per Protocol Set (PPS) will consist of a subset of the FAS and will include subjects with no major 
protocol violations that would affect the assessment of the primary objective of the study. The PP 
analyses will be conducted according to assigned treatment scheme.  Only analyses of the time to first 
rescue treatment/first fulfillment of rescue criteria (excluding the Month 6 to Month 12 analyses) and the 
change from baseline on BCVA and CST will be conducted on the PPS.  


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Criteria for exclusion from the PPS may include the following important protocol deviations if they are 
determined to potentially bias the assessment of the duration of treatment effect: 
• 
Inclusion/exclusion violations that could impact efficacy endpoints 
• 
Treatment assignment errors 
• 
Study drug administration errors 
• 
Out of window/missed visits 
• 
Subject’s use of prohibited concomitant medication 
• 
Any other deviations determined to potentially bias the efficacy endpoints 
Potential protocol deviations will be reviewed during BDRMs during the study. Criteria used to determine 
subjects to be excluded from specific analysis sets will be defined and documented prior to database 
lock. 
 
Month 6 to Month 12 Per Protocol Set 
The Month 6 to Month 12 Per Protocol Set (PPS2) will include subjects that received the Month 6 dose 
with no major protocol violations that would affect the assessment of the primary endpoint of the study 
after the Month 6 dose. The PP analyses will be conducted according to assigned treatment scheme.  
Only analyses of the time to first rescue treatment/first fulfillment of rescue criteria from Month 6 to Month 
12 will be conducted on the PPS2.  
Criteria for exclusion from the PPS2 may include the following important protocol deviations if they are 
determined to potentially bias the assessment of the duration of treatment effect: 
• 
Inclusion/exclusion violations that could impact efficacy endpoints 
• 
Treatment assignment errors 
• 
Study drug administration errors 
• 
Out of window/missed visits 
• 
Subject’s use of prohibited concomitant medication 
• 
Any other deviations determined to potentially bias the efficacy endpoints 
Potential protocol deviations will be reviewed during BDRMs during the study. Criteria used to determine 
subjects to be excluded from specific analysis sets will be defined and documented prior to database 
lock. 
 
Non-COVID-19 Full Analysis Set 
The Non-COVID-19 Full Analysis Set (NCFAS) will consist of a subset of the FAS and will include 
subjects with no major protocol violations due to COVID-19 that would affect the assessment of the 
primary efficacy endpoint of the study. Only analyses of the time to first rescue treatment/first fulfillment of 
rescue criteria and the change from baseline on BCVA and CST will be conducted on the NCFAS.  


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Criteria for exclusion from the NCFAS are the same as for the PPS, except that the deviations leading to 
exclusion should be associated with COVID-19. 
 
Pharmacokinetic Set  
The Pharmacokinetic Set (PKS) will include all subjects in the SS that have at least one quantifiable 
sunitinib PK concentration measured.  


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General Aspects for Statistical Analysis 
 
General Methods 
Statistical programming and analyses will be performed using SAS® Version 9.4 or higher. 
Summaries for continuous variables will include the number of observations (n), arithmetic mean, 
standard deviation, 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 1 additional decimal place than 
reported in the raw values. Standard deviations will be presented to 2 additional decimal places than 
reported in the raw values. Summaries for discrete variables will include the number of observations (n), 
frequencies and percentages by categories. All percentages will be rounded to one decimal place (i.e., 
XX.X%).  
Differences between treatment schemes will be calculated as GB-102 minus aflibercept and change from 
baseline will be calculated as the value at follow-up study visit minus the value at baseline. 
The unit of analysis in this study will be the study eye for all efficacy, safety, and pharmacodynamic 
summaries. According to protocol the study eye is 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. Nonstudy eye safety summaries will also be presented as 
appropriate. 
All summaries will be presented by treatment scheme and, where appropriate, by visit. When presenting 
by treatment scheme, each individual treatment scheme (aflibercept, 1 mg GB-102 followed by 1 mg and 
2 mg GB-102 followed by 1 mg dosing) will be presented. 
All relevant subject data will be included in listings. 
 
Key Definitions 
Study day, for a particular date, relative to the date of first injection of study medication will be computed 
as (particular date – date of first injection of study medication) + 1 day if the particular date is on or after 
the date of first injection of study medication.  As a result of this definition, the date of first injection of 
study medication will by Study Day 1, and the date immediately preceding the date of first injection of 
study medication will be Study Day -1, thus there will be no Study Day 0. 
Baseline is defined as the last nonmissing measurement prior to the first injection of study medication. 
Change from baseline will be computed as follow-up value minus baseline value. 
 
Missing Data 
The details regarding the handling of missing data (imputations or calculations for specific endpoints) for 
efficacy data will be included in the sections specific to each endpoint (Section 8 and associated 
subsections). 


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The handling of missing or partial dates related to adverse events is detailed in Section 9.3. 
 
Visit Windows and Allocation 
For parameters which will be summarized by visit, parameters that are associated with a scheduled visit 
in the CRF will remain allocated to that study visit. If data is missing at a scheduled visit and there is an 
unscheduled visit or end of study visit (conducted when a subject has early terminated the study) that 
occurred in the analysis range of study days (Tables 3 through 7) for the missed visit, then the data from 
the unscheduled visit will be assigned to the missing visit.  
A listing of all such imputed visits will be presented, including the study day of the unscheduled or end of 
study visit used in place of the missing visit. 
Table 3:  Ranges of Study Days Associated With Each Visit for BCVA, Slit-lamp Biomicroscopy, 
Intraocular Pressure, Dilated Ophthalmoscopy, SD-OCT, and Intravitreal Depot Color Fundus 
Photography 
Scheduled Visit 
Planned Study Day 
Targeted 
Range of Study Days 
Analysis 
Range of Study Days 
Screeninga 
-- 
[-30 to -3] 
[-30 to -3] 
Baseline 
1 
1 
1 
Week 2 
14 
[12 to 16] 
[2 to 22) 
Month 1 
30 
[26 to 34] 
[22 to 45) 
Month 2 
60 
[53 to 67] 
[45 to 75) 
Month 3 
90 
[83 to 97] 
[75 to 105) 
Month 4 
120 
[113 to 127] 
[105 to 135) 
Month 5 
150 
[143 to 157] 
[135 to 165) 
Month 6 
180 
[173 to 187] 
[165 to 195) 
Month 7 
210 
[203 to 217] 
[195 to 225) 
Month 8 
240 
[233 to 247] 
[225 to 255) 
Month 9 
270 
[263 to 277] 
[255 to 285) 
Month 10 
300 
[293 to 307] 
[285 to 315) 
Month 11 
330 
[323 to 337] 
[315 to 345) 
Month 12 
360 
[353 to 367] 
[345 to 375) 
a Intravitreal Depot Color Fundus Photograpy is not performed at the Screening Visit 
 


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Table 4:  Ranges of Study Days Associated With Each Visit for Vital Signs 
Scheduled Visit 
Planned Study Day 
Targeted 
Range of Study Days 
Analysis 
Range of Study Days 
Screening 
-- 
[-30 to -3] 
[-30 to -3] 
Baseline 
1 
1 
1 
Week 2 
14 
[12 to 16] 
[2 to 22) 
Month 1 
30 
[26 to 34] 
[22 to 45) 
Month 2 
60 
[53 to 67] 
[45 to 90) 
Month 4 
120 
[113 to 127] 
[90 to 150) 
Month 6 
180 
[173 to 187] 
[150 to 210) 
Month 8 
240 
[233 to 247] 
[210 to 270) 
Month 10 
300 
[293 to 307] 
[270 to 330) 
Month 12 
360 
[353 to 367] 
[330 to 390) 
 
 
Table 5:  Ranges of Study Days Associated With Each Visit for Clinical Laboratory Tests 
Scheduled Visit 
Planned Study Day 
Targeted 
Range of Study Days 
Analysis 
Range of Study Days 
Screening 
-- 
[-30 to -3] 
[-30 to -3] 
Month 4 
120 
[113 to 127] 
[2 to 240) 
Month 12 
360 
[353 to 367] 
[240 to 390) 
 
 


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Table 6:  Ranges of Study Days Associated With Each Visit for Plasma Pharmacokinetic 
Samples 
Scheduled Visit 
Planned Study Day 
Targeted 
Range of Study Days 
Analysis 
Range of Study Days 
Baseline 
1 
1 
1 
Week 2 
14 
[12 to 16] 
[2 to 22) 
Month 1 
30 
[26 to 34] 
[22 to 45) 
Month 2 
60 
[53 to 67] 
[45 to 75) 
Month 3 
90 
[83 to 97] 
[75 to 105) 
Month 4 
120 
[113 to 127] 
[105 to 150) 
Month 6 
180 
[173 to 187] 
[150 to 195) 
Month 7 
210 
[203 to 217] 
[195 to 225) 
Month 8 
240 
[233 to 247] 
[225 to 255) 
Month 9 
270 
[263 to 277] 
[255 to 315) 
Month 12 
360 
[353 to 367] 
[315 to 375) 
 
 
Table 7:  Ranges of Study Days Associated With Each Visit for Fluorescein Angiography and 
Color Fundus Photography 
Scheduled Visit 
Planned Study Day 
Targeted 
Range of Study Days 
Analysis 
Range of Study Days 
Screening 
-- 
[-30 to -3] 
[-30 to -3] 
Month 6 
180 
[173 to 187] 
[2 to 270) 
Month 12 
360 
[353 to 367] 
[270 to 390) 
 
 
 
Pooling of Centers 
Data collected from different study centers will not be pooled for analysis. 
 
Subgroups 
A subgroup analysis of the BCVA strata (< 60 or >= 60 ETDRS letters at randomization) will be conducted 
on the FAS for the following endpoints: time to first rescue treatment/first fulfillment of rescue criteria and 
change from baseline in BCVA and CST. The subgroup analyses will not be conducted on the last-
observation-carried-forward (LOCF) values for BCVA and CST (see Section 8.2 for a description of the 
LOCF analysis).  


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Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
The number of subjects in each analysis set (SS, FAS, PPS, NCFAS and PKS) will be summarized by 
treatment scheme. 
A subject will have fulfilled the requirements for study completion if/when the subject has completed the 
Day 360 visit. The number and percentage of subjects who are randomized, who complete the study, who 
complete each scheduled visit, and who prematurely discontinue the study will be presented for each 
treatment scheme and overall for the Screened Set. 
The primary reasons for study discontinuation as recorded on the disposition pages of the electronic case 
report form (eCRF) will be summarized (number and percentage) by treatment scheme and overall for the 
Screened Set.  
The number and percentage of subjects with major and minor protocol deviations will be summarized 
overall and by treatment scheme for the SS. Deviations related to the following categories will be 
included, with the number of deviations related to COVID-19 in each category also summarized: 
• 
inclusion or exclusion criteria 
• 
withdrawal criteria 
• 
treatment or dose 
• 
concomitant medications 
• 
missing/biased data  
All protocol deviations will be reviewed and documented before database lock and unmasking of 
treatment codes. 
 
Demographic and Other Baseline Characteristics 
Continuous summary statistics will be generated for the quantitative demographic variable (age, in years), 
tabulated by treatment scheme and overall for the SS and PPS. Discrete summary statistics will be 
generated for qualitative demographic variables (age category [<65, ≥ 65 to < 75, and ≥ 75], sex, 
ethnicity, race, and iris color for the study eye) tabulated by treatment scheme for the SS and PPS.  
Baseline clinical characteristics and disease history, including baseline BCVA (continuous summary and 
categories: < 60 ETDRS letters, ≥ 60 ETDRS letters), baseline CST (continuous summary and 
categories:  ≤ 350 µm,> 350 µm), total lesion area, total CNV lesion area, fluorescein leakage area, 
number of previous anti-vegf medications (< 5 medications, ≥ 5 medications), and presence/absence of 
subretinal and intraretinal fluid will also be summarized descriptively by treatment scheme and overall for 
the SS and PPS. 
 
Medical History and Concomitant Diseases 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
22.0. Medical history will be summarized using number and percent of subjects for each MedDRA system 


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organ class (SOC) and preferred term (PT) by treatment scheme for the SS. Medical history will be 
presented separately for ocular conditions in the study eye, ocular conditions in the non-study eye, and 
nonocular conditions. Subjects with multiple medical histories in the same SOC or PT will be counted only 
once for that respective SOC or PT. 
Results of prior SD-OCT and visual acuity assessments for the past 18 months are also collected. These 
will be listed, but not summarized. 
 
Medication 
Prior and concomitant medications will be classified by anatomical therapeutic class 4 (ATC class) and 
PT using the WHO Drug Dictionary, Global B3 March 2019. 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 any time following the first 
administration of study drug. Prior medications are defined as medications initiated prior to the first 
administration of study drug, including both those stopped before the first administration of study drug and 
those continued after the first administration of study drug. Some medications may be classified as both 
concomitant and prior. 
Prior and concomitant medications will be summarized separately using discrete summary statistics for 
each ATC class and PT by treatment scheme for the SS. Medications will be presented separately for 
ocular medications in the study eye, ocular medications in the non-study eye, and nonocular medications. 
Subjects with multiple medications in the same ATC4 or PT will be counted only once for that respective 
ATC4 or PT. 
Separate summaries of on-study anti-VEGF medications and on-study anti-VEGF rescue medications will 
be presented including the number of treatments and the number of subjects on each medication (along 
with percentages) for each ATC class and PT by treatment scheme for the SS. Subjects with multiple 
anti-VEGF medications in the same ATC class or PT will be counted only once for that respective ATC 
class or drug name. 
If the ATC class is not provided, the next lowest classification that is provided in the coding dictionary is 
used. The PT is defined as the active ingredient; if the active ingredient is not provided or includes more 
than two ingredients, then the drug name is used instead of the PT. 
Anti-VEGF medications taken in the 18 months prior to study start and during study conduct are also 
collected. These will be listed, but not summarized.  
 
Study Drug Administration 
Data on study drug administration (with differentiation between active and sham injections), post-injection 
assessments, and follow-up calls after each injection will be listed. 


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Efficacy 
All efficacy analyses will be conducted on the FAS. The analyses of the time to first rescue treatment/first 
fulfillment of rescue criteria and the change from baseline on BCVA and CST will also be conducted on 
the PPS and the NCFAS. 
 
Primary Efficacy Endpoint and Analysis 
Aflibercept is allowed as rescue treatment 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 (any of the following criteria): 
o 
≥ 5 ETDRS letter decrease compared with the average of last 2 visit BCVA ETDRS letter 
scores, and/or, 
o 
≥ 10 ETDRS letter decrease compared with best on-study BCVA ETDRS letter score 
• 
Increase in CST (any of the following criteria): 
o 
≥ 75 µm compared with the average of the last 2 visit CST measurements (µm), and/or, 
o 
≥ 100 µm compared with the lowest on-study CST measurement (µm) 
Use of rescue treatment will be recorded in the eCRF. 
The primary efficacy endpoint is the time to first rescue treatment/first fulfillment of at least one rescue 
criterion from Baseline through Month 12.  
Time to first rescue treatment/first fulfillment of at least one rescue criterion will be analyzed in the 
GB-102 treatment schemes using the Kaplan-Meier method. The probability of remaining rescue 
treatment free will be reported for the Month 6 and Month 12 visits with associated 80% confidence 
intervals (CI) based on Greenwood’s standard error estimate. If calculable, estimates of the median time 
to fulfillment of at least one rescue criterion and the 25th and 75th percentiles will be calculated with 
corresponding 80% CIs. 
For this analysis, time to first rescue treatment/first fulfillment of at least one rescue criterion is based on 
interval censoring with regard to the scheduled visits. If a subject receives a rescue treatment/fulfills a 
rescue criterion during an unscheduled visit, then this event is allocated to the visit interval ending at the 
next scheduled visit that occurs after the unscheduled visit. Subjects who do not receive rescue 
medication/fufill rescue criterion will be censored at the last visit interval recorded for the subject. 
The Kaplan-Meier curves will be plotted. 
No confirmatory hypothesis testing of the primary parameter will be conducted.  
To assess the homogeneity (or lack thereof) of the treatment groups regarding the study days on which 
the scheduled visits occur, descriptive statistics (n, mean, standard deviation, minimum, median, and 
maximum) of study day will be presented by study visit for each treatment scheme. 
The consistency between the two endpoints (“time to first rescue treatment” and “time to first fulfillment of 
rescue treatment criterion”) will be assessed based on 2x2 tables of the rescue treatment vs. fulfillment of 


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rescue treatment criterion at each study visit. 
Exploratory comparisons of time to rescue treatment between each GB-102 scheme and aflibercept will 
be conducted using a log-rank test stratified by baseline BCVA (< 60 letters vs ≥ 60 letters), as defined at 
the time of randomization. The Peto method will be used to estimate the hazard ratio and asymptotic 80% 
confidence interval based on the stratified log rank test statistic.  
 
Secondary and Exploratory Efficacy Endpoints and Analyses 
For all secondary and exploratory efficacy endpoints, analyses will be conducted on the observed values 
at each visit, even if rescue treatment was given at a prior visit.  
In addition, all analyses of the BCVA and CST efficacy endpoints will be repeated using a LOCF 
approach for visits after rescue treatment.  For this analysis, the values will be censored at each visit after 
rescue treatment and replaced by the last value recorded prior to receipt of rescue treatment. 
Graphs will be produced to visually compare the two analysis approaches for BCVA and CST.  The 
observed values and the LOCF values will be plotted by visit on the same graph for each treatment 
scheme. The observed values and LOCF values will also be presented on separate graphs. 
 
Time to First Rescue Treatment/First Fulfillment of Rescue Criteria 
The secondary efficacy endpoint related to time to first rescue treatment/first fulfillment of rescue criteria 
is time to first rescue treatment/first fulfillment of at least one rescue criterion starting at the Month 6 visit 
through Month 12. 
This endpoint will be analyzed the same way that the primary efficacy endpoint is analyzed.  The 
probability of not receiving rescue treatment/not fulfilling rescue criteria at Month 12 will be calculated.  
Subjects that do not receive the scheduled dose at the Month 6 visit will be excluded from the analyses of 
time to first rescue treatment/first fulfillment of at least one rescue criterion starting at the Month 6 visit 
through Month 12. 
 
Best Corrected Visual Acuity 
The secondary efficacy endpoints related to BCVA are: 
• 
Change from baseline in BCVA (ETDRS) at all visits 
• 
Categorical change from baseline in BCVA (ETDRS) at all visits 
• 
Frequency of subjects with BCVA worse than 20/200 (Snellen equivalent) at all visits 
The exploratory efficacy endpoints related to BCVA are: 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 9 and 10 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 10 and 11 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 11 and 12 
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summarized using continuous summary statistics, including 80% CIs around the mean for each treatment 
scheme.  
Comparisons of the change from baseline between each GB-102 group and the aflibercept control group 
will be made using a linear model adjusting for the baseline category (< 60 letters, >= 60 letters) as a 
factor and also using 2-sample t-tests. 
The proportion of subjects in each BCVA change from Baseline category (<= -15 letters, -14 to -10 letters, 
-9 to -5 letters, -4 to 4 letters, 5 to 9 letters, 10 to 14 letters, >= 15 letters) and with BCVA worse than 
20/200 (Snellen equivalent) at each visit will be summarized using discrete summary statistics. As BCVA 
is collected only in ETDRS letters, a BCVA worse than 20/200 (Snellen equivalent) is considered 
equivalent to a BCVA of < 34 ETDRS letters. 
Subjects with visual acuity measured by counting fingers or by hand motion will be assigned BCVA of 0 
ETDRS letters. If it is required to convert a visual acuity measurement made using the Snellen chart, the 
following formula will be used: 
ETDRS letters =  85+50*log10(20/xxx), 
where “20/xxx” is the Snellen visual acuity score. 
 
Central Subfield Thickness 
The secondary efficacy endpoint related to CST is the change from baseline in CST (μm) at all visits.  
The exploratory efficacy endpoints related to CST are: 
• 
Change in CST from thickest observed CST (µm) prior to enrollment (thickest pre-enrollment 
baseline) at all visits 
• 
Change in CST from mean observed CST (µm) prior to enrollment (mean pre-enrollment 
baseline) at all visits 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 9 and 10 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 10 and 11 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 11 and 12 
Absolute values at each visit and change from baseline and change from thickest observed CST prior to 
first dose at each follow up visit for CST will be summarized using continuous summary statistics, 
including 80% CIs around the mean for each treatment scheme.  
Comparisons of the change from baseline between each GB-102 group and the aflibercept control group 
and will be made using a linear model adjusting for the baseline category (≤ 350 µm,> 350 µm) as a 
covariate and secondarily using 2-sample t-tests. 
 
Number of Treatments 
Mean number of treatments received (including both rescue and scheduled treatments), mean number of 


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scheduled treatments received, and mean number of rescue treatments received from baseline through 
Month 12, from baseline to Month 6, and from Month 6 to Month 12 will be summarized using continuous 
summary statistics, including 80% CIs around the mean for each treatment scheme. Sham injections will 
not be included. 
Total number of treatments received (including both rescue and scheduled treatments), total number of 
scheduled treatments received, and total number of rescue treatments received from baseline through 
Month 12, from baseline to Month 6, and from Month 6 to Month 12 will also be summarized categorically, 
presenting the number and percentage of subjects receiving each total. Sham injections will not be 
included.The proportion of subjects receiving a scheduled treatment at each visit and the proportion of 
subjects who received rescue treatment through each visit will be summarized separately using discrete 
summary statistics, including 80% asymptotic normal CIs for each treatment scheme. A subject will be 
considered to have received rescue treatment at a particular visit if the rescue treatment was received at 
any time after the previous scheduled visit up to and including the visit of interest. 
 
Fulfillment of Rescue Criteria 
The number of times that a subject meets at least one rescue criterion is a secondary efficacy endpoint. 
Mean number of times that a subject met at least one rescue criterion from baseline through Month 12, 
from baseline to Month 6, and from Month 6 to Month 12 will be summarized using continuous summary 
statistics, including 80% CIs around the mean for each treatment scheme. 
Total number of times that a subject met at least one rescue criterion from baseline through Month 12, 
from baseline to Month 6, and from Month 6 to Month 12 will also be summarized categorically, 
presenting the number and percentage of subjects receiving each total. 
The proportion of subjects that met at least one rescue criterion through each visit will be summarized 
using discrete summary statistics, including 80% asymptotic normal CIs for each treatment scheme. A 
subject will be considered to have met at least one rescue criterion at a particular visit if this occurred at 
any time after the previous scheduled visit up to and including the visit of interest. 
 
Absence of Exudation 
The secondary efficacy endpoint related to absence of exudation is the frequency of subjects with 
absence of exudation (absence of intra-retinal and sub-retinal fluid) at each visit. 
The proportion of subjects with absence of exudation, as well as the proportion of subjects with each 
finding for intra- and sub-retinal fluid (eg, abset, definite with cystoid involvement, etc) will be summarized 
at each scheduled visit where this data is collected using discrete summary statistics.   
 
Response to First Rescue Treatment 
The exploratory efficacy endpoints associated with assessing the response to first rescue treatment are 
the absolute values and change in BCVA and CST compared to the values at the time of the first rescue 
treatment. 
Only subjects that received at least one rescue treatment will be included in this analysis.  For this 


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analysis, the rescue baseline for BCVA and CST will be defined as last values obtained prior to the 
administration of the first rescue treatment. 
The timepoints of interest are: 
• 
2 months prior to rescue treatment. Includes subjects with data collected between 46 and 75 days 
prior to the first rescue treatment.  If there are multiple values, the value collected closest to 60 
days prior to the first rescue treatment will be used. 
• 
1 month prior to rescue treatment. Includes subjects with data collected between 15 and 45 days 
prior to the first rescue treatment.  If there are multiple values, the value collected closest to 30 
days prior to the first rescue treatment will be used. 
• 
1 month after rescue treatment. Includes subjects with data collected between 15 and 45 days 
after the first rescue treatment.  If there are multiple values, the value collected closest to 30 days 
after the first rescue treatment will be used. 
• 
2 months after rescue treatment. Includes subjects with data collected between 46 and 75 days 
after the first rescue treatment.  If there are multiple values, the value collected closest to 60 days 
after the first rescue treatment will be used. 
Absolute values at each visit and change from rescue baseline for BCVA and CST will be summarized 
using continuous summary statistics at rescue baseline and at each timepoint of interest, including 80% 
CIs around the mean for each treatment scheme.  
Change from baseline will be plotted over time for the timepoints of interest and the rescue baseline. 
The number and percentage of subjects that received another treatment (either rescue or scheduled) 
within 1 month and 2 months of the first rescue treatment will also be summarized. 
 
Other Endpoints 
The other exploratory efficacy endpoints are:  
• 
Change from baseline in total lesion area (mm2) at Months 6 and 12 
• 
Change from baseline in CNV lesion area (mm2) at Months 6 and 12 
• 
Change from baseline in fluorescein leakage area (mm2) at Months 6 and 12 
• 
ALTISSIMO (Core Study) Subject Exit Questionnaire 
Observed values at each visit and change from baseline values at each follow up visit for total lesion 
area, CNV lesion area, and fluorescein leakage area will be summarized using continuous summary 
statistics, including 80% CIs around the mean for each treatment scheme.  
The responses to the Subject Exit Quesitonnaire will be listed, but not summarized. 


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Safety 
The population used for safety analyses will be the Safety Set (SS).  Safety will be assessed on the basis 
of ocular treatment-emergent adverse events (TEAEs) in the study eye, ocular TEAEs in the non-study 
eye, and non-ocular TEAEs, study drug exposure, concomitant medication use, laboratory results, vital 
signs, intra-ocular pressure, slit-lamp biomicroscopy, dilated ophthalmoscopy, physical examination 
results, and plasma concentrations of sunitinib. 
 
Extent of Exposure and Treatment Compliance 
Descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) for the number of 
scheduled treatments received will be presented by treatment scheme. In addition, a frequency table of 
the number of scheduled treatments received will be presented by treatment scheme.  The number and 
percentage of subjects that received all treatments per pharmacy manual and the number and 
percentage of subjects that were treated according to the treatment scheme assigned will also be 
summarized by treatment scheme. 
 
Adverse Events 
The safety of GB-102 will primarily be assessed by the incidence of TEAEs. An AE will be considered a 
TEAE if it occurs or worsens on or after initiation of study drug through the Month 12 visit. An AE with a 
missing start date will be considered a TEAE. If an AE has a partial start date where the partial 
information does not clearly indicate if the AE started before or after the initiation of study drug, then the 
AE will be considered a TEAE (eg, if the AE start date is 3 Jan 2019 and the date and time of study drug 
initiation is 3 Jan 2019 07:31, then the AE would be considered a TEAE). 
TEAE summaries will be presented separately for ocular TEAEs in the study eye, ocular TEAEs in the 
non-study eye, and non-ocular TEAEs. 
An overall summary of TEAEs will be presented including the number of events and the number of 
subjects with at least one event (along with percentages) by treatment scheme for TEAEs in several 
categories based on severity, relationship to study drug, and relationship to study procedure. Serious 
TEAEs, TEAEs leading to study drug discontinuation, arteriothromboembolic TEAEs will also be included 
in the overall summary. 
All AEs will be coded to SOC and PT using MedDRA version 22.0. The number of TEAEs and the 
number and percentage of subjects with any TEAEs will be tabulated overall and by SOC and PT within 
each SOC by treatment scheme. 
The following categories of adverse events will be summarized: 
• 
TEAEs 
• 
Treatment related TEAEs 
• 
Procedure-related TEAEs 
• 
Serious TEAEs 
• 
Serious treatment related TEAEs 
• 
TEAEs leading to discontinuation of study drug 


Statistical Analysis Plan for Interventional Studies 
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• 
TEAEs by maximum severity 
• 
TEAEs by day of onset (Day 1 to Month 6 and Month 6 to Month 12) 
For day of onset, TEAEs that occur on the same date as the Month 6 dose will be included in the Month 6 
to Month 12 interval if they are considered related to the procedure; otherwise, they will be included in the 
Day 1 to Month 6 interval. 
Listings will be provided for serious TEAEs, TEAEs leading to discontinuation of study drug, 
arteriothromboembolic TEAEs, and AEs that occurred prior to treatment exposure. 
 
Laboratory Evaluations 
Blood and urine samples for routine clinical laboratory tests will be collected. Samples should be obtained 
prior to administration of study drug. Screening laboratory tests may be repeated once at the discretion of 
the investigator. The minimum tests to be performed include the following: 
• 
Nonfasting chemistry (blood): sodium, potassium, chloride, bicarbonate, albumin, alkaline 
phosphatase, aspartate amino transferase, alanine amino transferase, bilirubin direct, bilirubin 
indirect, total bilirubin, creatinine, blood urea nitrogen, total protein, calcium, phosphorus, and 
hemoglobin A1c 
• 
Hematology (complete blood count with differential): white blood cell count, red blood cell count, 
hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, red cell distribution width, platelet count, and mean 
platelet volume 
• 
Urinalysis (dipstick): glucose, protein, and pH 
• 
Urine drug screen (Screening visit only) 
Chemistry, hematology, and urinalysis results and change from baseline will be summarized by treatment 
scheme at baseline and at each scheduled post-baseline visit. The number and percentage of subjects 
with low/normal/high or normal/abnormal values according to the lab normal ranges from baseline to each 
scheduled post-baseline visit and from baseline to the last visit will be presented in shift tables. Worst 
case values will also be summarized for chemistry and hematology assessments. 
 
Vital Signs  
Vitals signs will consist of blood pressure and heart rate measurements. Systolic and diastolic blood 
pressure (mmHg) and heart rate (bpm) will be measured after subjects have been at rest (seated) for at 
least 5 minutes. Along with the vital signs, height (without shoes) will be measured at Screening and body 
weight will be measured at Screening and Month 12. 
Change from baseline will be summarized by treatment scheme at each scheduled post-baseline visit for 
applicable parameters.  
 
Intraocular Pressure 
At each study visit, IOP will be measured according to routine clinical practice using Goldmann 
applanation tonometry or Tono-Pen in both eyes at all study visits (must be performed prior to dilation and 
the IVT injection of study drug at dosing visits). A single measurement will be made to obtain a 


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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. 
IOP measurements will be summarized by treatment scheme separately for the study eye and for the 
nonstudy eye. The IOP data will be summarized by visit using both continuous and discrete summaries. 
Changes from baseline will also be summarized continuously and discretely. Discrete categories for IOP 
measurements will include (in mmHg) ≤ 5, 6 to 14, 15 to 21, 22 to 29, and ≥ 30. These categories will be 
used to summarize results by visit and to summarize shifts from baseline IOP for each treatment scheme 
by visit and last visit . Discrete categories for changes from baseline in IOP will include ≤ −5, −4 to  4, 5 to 
9, 10 to 14, and ≥ 15. The numbers and percentages of eyes with an IOP measurement ≥ 30 mmHg and 
with an increase from baseline in IOP measurement ≥ 10 mmHg will also be summarized. 
 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy will be performed for each eye by a qualified assessing investigator at each study 
visit. This procedure will include an assessment of each of the following as normal or abnormal: 
• 
Eyelids 
• 
Conjunctiva 
• 
Cornea 
• 
Anterior chamber 
• 
Iris 
• 
Pupil 
• 
Lens 
If any findings are abnormal, exact findings should be specified and noted as either clinically or not 
clinically significant. 
In addition, the lens will be graded by the assessing investigator for the presence and severity of nuclear, 
cortical, and posterior subcapsular lens opacities using the Age-related Eye Diseases Study (AREDS) 
photographic reference scale. For detailed instructions regarding AREDS lens scoring, refer to the 
separately provided AREDS lens grading scale (Chew 2010) provided in the protocol. 
Abnormal slit-lamp biomicroscopy results will be summarized for each treatment scheme for the study eye 
by visit using discrete summary statistics. 
After the IVT injection, it is possible that the microparticles in the depot formation could migrate away from 
the depot. This migration could result in a higher incidence of AEs or could potentially affect the efficacy 
of the drug. A narrative will be provided for each subject that experiences the presence of the study 
medication in the anterior chamber in the study eye. 
 
Dilated Ophthalmoscopy 
Dilated fundus examination of both eyes will be performed in all subjects by designated qualified study 


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center personnel. The following will be observed for the presence of abnormalities: 
• 
Vitreous body 
• 
Macula 
• 
Peripheral retina 
• 
Choroid 
• 
Optic nerve 
If any findings are abnormal, exact findings should be specified and noted as either clinically or not 
clinically significant. All abnormal findings that are clinically significant will be described. 
Abnormal dilated ophthalmoscopy results will be summarized for each treatment scheme for the study 
eye by visit using discrete summary statistics. 
 
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. 
Abnormal physical examination results will be summarized for each treatment by visit using discrete 
summary statistics. 
 
Plasma Concentrations of Sunitinib 
Blood samples for plasma analysis will be collected from all subjects and an analysis of all subjects 
assigned to each sunitinib group will be performed. Any statistical analysis of these values will be done 
post hoc and is not described in this document. 
 
Fluorescein Angiography and Color Fundus Photography 
The FA imaging of both eyes will be performed to examine the circulation of the retina and characteristics 
of the CNV lesion in the study eye according to standard FA image capture protocol. The FA images will 
be obtained using a digital camera by designated certified study center personnel. 
The CFP of both eyes will be performed to assess characteristics of the retina. The photographs will be 
obtained using a digital fundus camera and will be performed by certified study center personnel.  
Supplemental 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. 


Statistical Analysis Plan for Interventional Studies 
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Changes from Analysis Planned in Protocol 
The following secondary endpoints were modified: 
• 
“Time to fulfillment of at least one rescue criterion starting at the Month 6 visit through to the 
Month 12 visit (excluding any rescue at the Month 12 visit)” was updated to “Time to first rescue 
treatment/first fulfillment of at least one rescue criterion starting at the Month 6 visit through 
Month 12”  
• 
“Number of times that at least one rescue criterion is met” was updated to “Number of visit 
intervals during which at least one rescue criterion is met” 
The following secondary endpoints were added: 
• 
Number and percentage of subjects receiving treatment at each visit, including both rescue and 
scheduled treatments (combined and separate) 
• 
Number of visit intervals during which at least one rescue criterion is met 
• 
Number and percentage of subjects meeting at least one rescue criterion at each visit 
The following exploratory endpoints were added: 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 9 and 10 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 10 and 11 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 11 and 12 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 9 and 10 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 10 and 11 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 11 and 12 
• 
Absolute values and change in BCVA and CST compared to values at the time of first rescue 
treatment (response to first rescue treatment) 
In the protocol, “Plasma levels of sunitinib (ng/mL)” was listed as a safety endpoint. In the SAP, this is 
considered under “Other Endpoints”. 
Per protocol section 9.6.1, “A primary endpoint analysis will be conducted when all subjects complete the 
Month 12 (Day 360) visit.” This was updated to clarify that the analysis will be conducted when all 
subjects complete the Month 12 (Day 360) visit or early terminate. 
Per protocol section 8.1, “A treatment emergent adverse event (TEAE) is an AE with an onset anytime 
from when the subject has received study drug through the end of study and at least 30 days after the last 
dose of study drug, whether or not it is considered causally related to the study drug.” Per protocol 
section 9.7, “An AE will be considered a TEAE if it occurs or worsens on or after initiation of study drug.” 
To resolve the difference in definitions in the protocal, an AE will be considered a TEAE if it occurs or 
worsens on or after initiation of study drug through the Month 12 visit. 
There were no other changes from the analysis planned in the protocol.” 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) 
 
 
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Reference List 
Brown DM, Heier JS, Ciulla T, Benz M, Abraham P, et al. Primary endpoint results of a Phase II study of 
vascular endothelial growth factor trap-eye in wet age-related macular degeneration. 
Ophthalmology. 2011; 118(6): 1089-1097. 
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. 
Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial 
infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. 
Antiplatelet Trialists’ Collaboration. BMJ. 1994;308(6921):81-106. 
Heier JS, Boyer D, Nguyen QD, Marcus D, Roth DB, et al. The 1-year results of CLEAR-IT 2, a Phase 2 
study of the vascular endothelial growth factor trap-eye dosed as-needed after 12-week 
fixed dosing. Ophthalmology. 2011; 118(6):1098-1106. 
Lachin JM and Foulkes MA. 1986. 'Evaluation of Sample Size and Power for Analyses of Survival with 
Allowance for Nonuniform Patient Entry, Losses to Follow-up, Noncompliance, and 
Stratification', Biometrics. 1986;42:507-516. 


Statistical Analysis Plan for Interventional Studies 
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This document is confidential. 
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Page 42 of 47 
 
 
Programming Considerations 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4 (SAS Institute Inc., Cary, NC, USA) or later. Computer-generated table, listing, and figure 
output will adhere to the following specifications.   
 
General Considerations 
• 
One SAS program can create several outputs 
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance  
 
Table, Listing, and Figure Format 
 
General 
• 
All TFLs will be produced in landscape format on American letter size paper size, unless otherwise 
specified. 
• All TFLs will be produced using the Courier New font, Size 8 which is the smallest acceptable point 
size for the Regulatory Authorities. 
• The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
• Headers and footers for figures will be in Courier New font, Size 8 which is the smallest acceptable 
point size for the Regulatory Authorities. 
• Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• TFLs will be in black and white (no color), unless otherwise specified 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
• Only standard keyboard characters will be used in the TFLs. Special characters, such as 
non-printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
Headers 
• All output should have the following header at the top left of each page: 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) 
 
 
This document is confidential. 
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Graybug Vision, Inc., Protocol GBV-102-002 (Syneos Health Study Number 1011627) 
Draft/Final Run DD-MMM-YYYY 
• All output should have Page n of N at the top or bottom right corner of each page. TFLs are 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
• The date output was generated should appear along with the program name as a footer on each 
page. 
 
Display Titles 
• Each TFL is identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering is 
strongly recommended, but sponsor preferences are obtained before final determination. A decimal 
system (x.y and x.y.z) are used to identify TFLs with related contents. The title is centered. The 
analysis set are identified on the line immediately following the title. The title and table designation 
are single spaced. A solid line spanning the margins will separate the display titles from the 
Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT Analysis Set) 
 
 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial 
upper-case characters.  
• In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment scheme columns and total column (if applicable). P-values may be presented 
under the total column or in separate p-value column (if applicable). Within-treatment comparisons 
may have p-values presented in a row beneath the summary statistics for that treatment. 
• For numeric variables, include “unit” in column or row heading when appropriate. 
• Analysis set sizes will be presented for each treatment scheme in the column heading as (N=xx) 
(or in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
• The order of treatments in the tables and listings will be Placebo first in the case of placebo 
controlled studies and Active comparators first in the case of active comparator trials, followed by a 
total column (if applicable). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) 
 
 
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Body of the Data Display 
12.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values are left-justified; 
• Whole numbers (e.g., counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned. 
12.2.5.2. 
Table Conventions 
• Units will be included where available 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment schemes in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups are included. 
• An Unknown or Missing category are added to each parameter for which information is not 
available for 1 or more subjects.  
• Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 


Statistical Analysis Plan for Interventional Studies 
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• P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Every p-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down 
to 0.0.  A common convention is to display as '<0.1', or as appropriate with additional decimal 
places. Unless otherwise noted, for all percentages, the number of subjects in the analysis set for 
the treatment scheme who have an observation will be the denominator. Percentages after zero 
counts should not be displayed and percentages equating to 100% are presented as 100%, without 
decimal places.  
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data are presented by the body system, treatment class, or SOC with the highest 
occurrence in the active treatment scheme in decreasing order, assuming all terms are coded. 
Within the body system, drug class and SOC, medical history (by PT), drugs (by ATC1 code), and 
adverse events (by PT) are displayed in decreasing order. If incidence for more than 1 term is 
identical, they should then be sorted alphabetically. Missing descriptive statistics or p-values which 
cannot be estimated are reported as “-”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment scheme (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Describe details of this in 
footnotes or programming notes. 
• For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, describe in a footnote or programming note if the subject are included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting 
the criteria. 
• Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page.  The 
overall summary statistics for the subheading should only be output on the first relevant page. 
12.2.5.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of treatment schemes as above, subject number, 
visit/collection day, and visit/collection time. 
• Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates are 
represented on subject listings as dashes (--JUL2000). Dates that are missing because they are 
not applicable for the subject are output as “N/A”, unless otherwise specified. 


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• All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
• Units will be included where available 
12.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the footnotes.  
• All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
• Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
• Subject specific footnotes are avoided, where possible. 
• Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page.  
• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan for Interventional Studies 
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Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures, or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
SOP Developing Statistical Programs (3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency, and commenting and by review 
of the produced output. 
 


 
 
 
 
 
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 Statistical Analysis Plan for Interventional Studies 
 
Sponsor Name: Graybug Vision, Inc. 
 
Protocol Number: GBV-102-002 (Phase 2b) 
Protocol Title: A Phase 2b Multicenter Dose-Ranging Study Evaluating the Safety and Efficacy of a 
Long-acting Intravitreal Sunitinib Malate Depot Formulation (GB-102) Compared to Intravitreal Aflibercept 
in Subjects with Neovascular (Wet) Age-related Macular Degeneration (ALTISSIMO Study) 
 
Extension Study Statistical Analysis Plan 
 
Protocol Version and Date: Version 4.0 / 08 September 2020 (Amendment 3) 
 
 
Syneos Health Project Code: 1011627 
 
Authors: 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Graybug Vision, Inc. Acceptance 
of this document constitutes agreement by the recipient that no information contained herein will be 
published or disclosed without prior written authorization from an official of Graybug Vision, Inc. However, 
this document may be disclosed to appropriate Institutional Review Board and Ethics Committees or duly 
authorized representatives of a national regulatory authority under the condition that they are requested 
to keep it confidential. In the event of an actual or suspected breach of this obligation, Syneos Health 
should be notified promptly. 




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Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
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Page 4 of 30 
Table of Contents 
Revision History ............................................................................................................................ 2 
Approvals .................................................................................................................................... 3 
 
Glossary of Abbreviations .................................................................................................... 6 
 
Purpose ................................................................................................................................ 7 
 
Study Objectives .................................................................................................................. 8 
 
Endpoints ........................................................................................................................... 11 
 
Analysis Sets ...................................................................................................................... 12 
 
General Aspects for Statistical Analysis ............................................................................. 13 
 
Demographic, Other Baseline Characteristics and Medication .......................................... 15 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 5 of 30 
 
Efficacy ............................................................................................................................... 17 
 
Safety ................................................................................................................................. 20 
 
Changes from Analysis Planned in Protocol ...................................................................... 23 
 
Reference List .................................................................................................................... 24 
 
Programming Considerations ............................................................................................. 25 
 
Quality Control ................................................................................................................... 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 7 of 30 
 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables, and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives stated in Protocol GBV-102-002 
(Phase 2b), Version 4.0, dated 08 September 2020 (Amendment 3). This document addresses only the 
analyses associated with the extension study. The analyses for the core study have been addressed in a 
separate document (Statistical Analysis Plan, Version 3.0, 08JAN2021). 
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. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality 
control of all tables, figures, and listings. 
 
Timings of Analyses 
An exploratory analysis of safety and efficacy will be performed at the end of the study after database 
lock when all subjects have completed the Month 18 visit, ended the study by receiving rescue treatment, 
or discontinued prematurely from the study. No formal statistical hypothesis testing will be performed. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 8 of 30 
 
Study Objectives 
 
Primary Objective 
The objective of the extension study is to monitor the safety and duration of effect of intravitreal (IVT) 
GB-102 administered every 6 months compared to IVT aflibercept administered every 2 months in 
subjects in ALTISSIMO (Core Study) who complete all core study visits through Month 12 (Day 360) and 
who do not require/receive rescue treatment at the Month 12 (Day 360) final core study visit. 
 
Brief Description 
The Extension Study is a multicenter, visual examiner-masked study, designed to monitor the safety and 
duration of effect of IVT GB-102 administered every 6 months compared to IVT aflibercept administered 
every 2 months in subjects in ALTISSIMO (Core Study) who complete all study visits through Month 12 
(Day 360) and who do not require/receive rescue treatment at the Month 12 (Day 360) final study visit.  
Enrolled subjects will be followed for monthly visits until they receive rescue treatment or for a maximum 
of 180 days (ie, 6 months). There will be no additional treatment with GB-102. 
The assessments to be collected include adverse events (AEs), serious adverse events (SAEs), 
concomitant medications, best corrected visual acuity (BCVA) assessments using the Early Treatment 
Diabetic Retinopathy Study (ETDRS) protocol, slit-lamp biomicroscopy findings, the Age-related Eye 
Diseases Study (AREDS) lens assessments, intraocular pressure (IOP) measurements, dilated 
ophthalmoscopy results, retinal central subfield thickness (CST) using spectral domain optical coherence 
tomography (SD-OCT), color fundus photograpy for depot imaging (ultra-widefield imaging, where 
available), and date of administration of rescue treatment. 
Once a subject meets at least one rescue criterion and all study visit assessments are completed, they 
may receive an injection of aflibercept and exit the study. 
 
Subject Selection 
Subjects eligible for screening and enrollment must complete all study assessments including fluorescein 
angiography at the Month 12 (Day 360) visit and not require/receive a rescue treatment at the Month 12 
(Day 360) final study visit in ALTISSIMO (Core Study).  
The study eye selected in ALTISSIMO (Core Study) will remain the same for the Extension Study. There 
will be no randomization in the Extension Study. 
 
Inclusion Criteria 
1. Verbal and written informed consent for the Extension Study obtained from the subject 
2. Completed all study assessments at Month 12 (Day 360) final study visit including fluorescein 
angiograpy, and did not require/receive a rescue treatment at the Month 12 (Day 360) final study visit 
in ALTISSIMO (Core Study). 
3. Willing and able to give informed consent, comply with all study procedures, and be likely to complete 
the study for the Extension Study. 
 
Exclusion Criteria 
1. Subjects who terminated early from ALTISSIMO (Core Study) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 9 of 30 
2. Subjects who did not complete all study assessments at Month 12 (Day 360) final study visit including 
fluorescein angiography in ALTISSIMO (Core Study). 
3. Subjects who received rescue treatment at the Month 12 (Day 360) final study visit in ALTISSIMO 
(Core Study) 
 
Determination of Sample Size 
The sample size of this study was not selected to support specific statistical hypothesis testing, as all 
comparisons are exploratory. 
 
Treatment Assignment and Masking 
No treatments are scheduled during the Extension Study. Enrolled subjects will remain masked to their 
treatment assignment in ALTISSIMO (Core Study).  
The visual acuity examiners, the Sponsor (other than the Vice President of Global Clinical Development 
Operations), the masked contract research organization personnel, the medical monitor, and other study 
personnel, including individuals at a central reading center, study coordinators, laboratory vendor, etc. will 
remain masked relative to the GB-102 treatment scheme. The visual acuity examiners are not allowed to 
perform any study-related activities other than BCVA assessments to maintain masking including 
obtaining medical histories or attempting to elicit any information regarding treatment, adverse events, or 
clinical information from the subjects. The same BCVA examiner should be utilized for each subject 
throughout the study when possible. 
Each study center will have at least 2 investigators who are retina specialists; one will serve as the 
injecting investigator and the other will serve as the assessing investigator. To maintain study masking, 
the roles of these investigators should not be switched during the conduct of the study. 
• 
Injecting Investigator: An injecting investigator will perform the study drug (GB-102 or aflibercept), 
sham, and/or rescue injections, will supervise the preparation and tracking of study drug, and will 
perform predose and postdose safety assessments for the IVT injections. 
• 
Assessing Investigator: An assessing investigator will supervise and assess the collection of AEs and 
efficacy parameters. The assessing investigator will determine whether rescue treatment is required. 
The SD-OCT, FA, and CFP technicians are masked to treatment scheme; however, collected images 
may reveal to the assessing investigator or technician which subjects received the GB-102 depot (but not 
the treatment scheme) in ALTISSIMO (Core Study). 
 
Administration of Study Medication 
No study medication will be administered during the Extension Study. 
 
Study Procedures 
The schedule of assessments is provided in Table 1, and includes the expected study day relative to the 
date of first dose in ALTISSIMO (Core Study), acceptable ranges of study days for each visit, and visit 
nomenclature. 
 




Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 11 of 30 
 
 
Endpoints 
 
Exploratory Efficacy Endpoints 
All safety and efficacy data collected beyond Month 12 (Day 360) will be presented in listings and 
summarized as appropriate using descriptive statistics.  
The exploratory efficacy endpoints for the Extension Study include, but are not limited to:  
• 
Time to first rescue treatment/first fulfillment of at least one rescue criterion from Baseline through 
Month 18 
• 
Time to first rescue treatment/first fulfillment of at least one rescue criterion starting at the Month 
6 visit through Month 18 
• 
Observed values and change from baseline in BCVA (ETDRS) at all visits 
• 
Categorical change from baseline in BCVA (ETDRS) at all visits 
• 
Frequency of subjects with BCVA worse than 20/200 (Snellen equivalent) at all visits 
• 
Observed values and change from baseline in CST (µm) at all visits 
• 
Number and percentage of subjects receiving rescue treatment at each visit 
• 
Number of visit intervals during which at least one rescue criterion is met 
• 
Number and percentage of subjects meeting at least one rescue criterion at each visit 
 
Safety Endpoints 
The main safety endpoint is the occurrence of ocular and nonocular AEs and serious AEs. Other safety 
endpoints include intraocular pressure, slit-lamp biomicroscopy, dilated ophthalmoscopy, and the 
presence and severity of nuclear sclerosis, cortical opacities, and posterior subcapsular opacities. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 12 of 30 
 
 
Analysis Sets 
Protocol deviation management at Syneos Health is detailed in “Processing and Management of Protocol 
Deviations” (3101.W02). For details on the process for defining analysis datasets refer to “(Blind) Data 
Review and Definition of Analysis Sets” (SOP 3911). 
Analysis sets are defined in the following sections. Subjects to be included within and excluded from each 
analysis set will be determined at a Data Review Meeting (DRM) prior to database lock. 
 
Extension Set 
The Extension Set will include all subjects enrolled in the Extension Study; ie, all subjects that met study 
entry criteria and were determined to be accepatable to the investigator. This set will be used for all of the 
analyses in the Extension Study. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 13 of 30 
 
 
General Aspects for Statistical Analysis 
 
General Methods 
Statistical programming and analyses will be performed using SAS® Version 9.4 or higher. 
All safety and efficacy data collected beyond Month 12 (Day 360) will be presented in listings and 
summarized as appropriate using descriptive statistics.  
Summaries for continuous variables will include the number of observations (n), arithmetic mean, 
standard deviation, 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 1 additional decimal place than 
reported in the raw values. Standard deviations will be presented to 2 additional decimal places than 
reported in the raw values. Summaries for discrete variables will include the number of observations (n), 
frequencies and percentages by categories. All percentages will be rounded to one decimal place (i.e., 
XX.X%).  
The unit of analysis in this study will be the study eye for all efficacy and safety summaries. According to 
protocol the study eye is selected as the study eye in ALTISSIMO (Core Study).  
All summaries will be presented according to the actual treatment scheme from ALTISSIMO (Core Study) 
and, where appropriate, by visit. When presenting by treatment scheme, each individual treatment 
scheme (aflibercept, 1 mg GB-102 followed by 1 mg and 2 mg GB-102 followed by 1 mg dosing) will be 
presented. 
Differences between treatment schemes will be calculated as GB-102 minus aflibercept and change from 
baseline will be calculated as the value at follow-up study visit minus the value at baseline. 
All relevant subject data will be included in listings. 
 
Key Definitions 
Study day, for a particular date, relative to the date of first injection of study medication in ALTISSIMO 
(Core Study) will be computed as (particular date – date of first injection of study medication in 
ALTISSIMO (Core Study)) + 1 day if the particular date is on or after the date of first injection of study 
medication. As a result of this definition, the date of first injection of study medication will by Study Day 1, 
and the date immediately preceding the date of first injection of study medication will be Study Day -1, 
thus there will be no Study Day 0. 
Baseline is defined as the last nonmissing measurement prior to the first injection of study medication in 
ALTISSIMO (Core Study). 
Change from baseline will be computed as follow-up value minus baseline value. 
 
Missing Data 
The handling of missing or partial dates related to adverse events is detailed in Section 9.3. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
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SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
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Page 14 of 30 
 
No other imputation of missing data will be performed. 
 
Visit Windows and Allocation 
For parameters which will be summarized by visit, parameters that are associated with a scheduled visit 
in the CRF will remain allocated to that study visit. If data is missing at a scheduled visit and there is an 
unscheduled visit or end of study visit (conducted when a subject has early terminated the study) that 
occurred in the analysis range of study days (Table 2) for the missed visit, then the data from the 
unscheduled visit will be assigned to the missing visit. For ranges associated with ALTISSIMO (Core 
Study) visits, see the SAP Version 3.0, 08Jan2021. 
A listing of all such imputed visits will be presented, including the study day of the unscheduled or end of 
study visit used in place of the missing visit. 
Table 2: Ranges of Study Days Associated With Each Visit for BCVA, Slit-lamp Biomicroscopy, 
Intraocular Pressure, Dilated Ophthalmoscopy, SD-OCT, and Intravitreal Depot Color Fundus 
Photography 
Scheduled Visit 
Planned Study Day 
Targeted 
Range of Study Days 
Analysis 
Range of Study Days 
Month 13 
390 
[383 to 397] 
[375 to 405) 
Month 14 
420 
[413 to 427] 
[405 to 435) 
Month 15 
450 
[443 to 457] 
[435 to 465) 
Month 16 
480 
[473 to 487] 
[465 to 495) 
Month 17 
510 
[503 to 517] 
[495 to 525) 
Month 18 
540 
[533 to 547] 
[525 to …) 
a Intravitreal Depot Color Fundus Photograpy is not performed at the Screening Visit 
 
Pooling of Centers 
Data collected from different study centers will not be pooled for analysis. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 15 of 30 
 
 
Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
A subject will have fulfilled the requirements for study completion if/when the subject has completed the 
Month 18 visit or when the subject receives rescue treatment. The number and percentage of subjects 
who enter the Extension Study, who complete the Extension Study, and who prematurely discontinue the 
Extension Study will be presented for each treatment scheme and overall. 
The primary reasons for study discontinuation as recorded on the disposition pages of the electronic case 
report form (eCRF) will be summarized (number and percentage) by treatment scheme and overall.  
The number and percentage of subjects with major and minor protocol deviations will be summarized 
overall and by treatment scheme. Deviations related to the following categories will be included, with the 
number of deviations related to COVID-19 in each category also summarized: 
• 
inclusion or exclusion criteria 
• 
withdrawal criteria 
• 
treatment or dose 
• 
concomitant medications 
• 
missing/biased data  
All protocol deviations will be reviewed and documented before database lock. 
 
Demographic and Other Baseline Characteristics 
Continuous summary statistics will be generated for the quantitative demographic variable (age, in years), 
tabulated by treatment scheme and overall. Discrete summary statistics will be generated for qualitative 
demographic variables (age category [<65, ≥ 65 to < 75, and ≥ 75], sex, ethnicity, race, and iris color for 
the study eye) tabulated by treatment scheme.  
Baseline clinical characteristics and disease history, including baseline BCVA (continuous summary and 
categories: < 60 ETDRS letters, ≥ 60 ETDRS letters), baseline CST (continuous summary and 
categories:  ≤ 350 µm,> 350 µm), total lesion area, total CNV lesion area, fluorescein leakage area, 
number of previous anti-vegf medications (< 5 medications, ≥ 5 medications), and presence/absence of 
subretinal and intraretinal fluid will also be summarized descriptively by treatment scheme and overall. 
 
Medication and Procedures 
Concomitant medications will be classified by anatomical therapeutic class 4 (ATC class) and PT using 
the WHO Drug Dictionary, Global B3 March 2019. Concomitant medications are defined as those 
medications which were on-going at the time of the Month 12 visit in the Core Study or that were initiated 
during the Extension Study. 
Concomitant medications will be summarized using discrete summary statistics for each ATC class and 
PT by treatment scheme. Medications will be presented separately for ocular medications in the study 
eye, ocular medications in the non-study eye, and nonocular medications. Subjects with multiple 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 16 of 30 
 
medications in the same ATC4 or PT will be counted only once for that respective ATC4 or PT. Ocular 
concomitant procedures will be summarized similarly. 
A summary of on-study anti-VEGF medications (eg rescue medications) will be presented including the 
number of treatments and the number of subjects on each medication (along with percentages) for each 
PT by treatment scheme. Subjects with multiple anti-VEGF medications in the same PT will be counted 
only once for that drug name. An anti-VEGF medication is considred on-study if it was administered after 
the Month 12 ALTISSIMO (Core Study) visit. 
The PT is defined as the active ingredient; if the active ingredient is not provided or includes more than 
two ingredients, then the drug name is used instead of the PT. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
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Page 17 of 30 
 
 
Efficacy 
All efficacy analyses will be conducted on the Extension Set. 
 
Exploratory Efficacy Endpoints and Analyses 
For all exploratory efficacy endpoints, analyses will be conducted on the observed values at each visit, 
even if rescue treatment was given at a prior visit.  
 
Time to First Rescue Treatment/First Fulfillment of Rescue Criteria 
The exploratory efficacy endpoints related to time to first rescue treatment/first fulfillment of rescue criteria 
are  
• 
Time to first rescue treatment/first fulfillment of at least one rescue criterion starting from Baseline 
through Month 18. 
• 
Time to first rescue treatment/first fulfillment of at least one rescue criterion starting at the Month 
6 visit through Month 18. Subjects that did not receive the scheduled dose at the Month 6 visit will 
be excluded from this analysis. 
These endpoints will be analyzed similarly to the primary efficacy endpoint in ALTISSIMO (Core Study).  
Aflibercept is allowed as rescue treatment at any visit following the Day 30 study assessments in 
ALTISSIMO (Core Study) in subjects who meet any of the following criteria regarding decrease in BCVA 
and/or increase in CST: 
• 
Decrease in BCVA (any of the following criteria): 
o 
≥ 5 ETDRS letter decrease compared with the average of last 2 visit BCVA ETDRS letter 
scores, and/or, 
o 
≥ 10 ETDRS letter decrease compared with best on-study BCVA ETDRS letter score 
• 
Increase in CST (any of the following criteria): 
o 
≥ 75 µm compared with the average of the last 2 visit CST measurements (µm), and/or, 
o 
≥ 100 µm compared with the lowest on-study CST measurement (µm) 
Use of rescue treatment will be recorded in the eCRF. 
Time to first rescue treatment/first fulfillment of at least one rescue criterion will be analyzed in the 
GB-102 treatment schemes using the Kaplan-Meier method. The probability of remaining rescue 
treatment free/not fulfilling rescue criteria through Month 18 will be calculated with associated 80% 
confidence intervals (CI) based on Greenwood’s standard error estimate. If calculable, estimates of the 
median time to fulfillment of at least one rescue criterion and the 25th and 75th percentiles will be 
calculated with corresponding 80% CIs. 
For this analysis, time to first rescue treatment/first fulfillment of at least one rescue criterion is based on 
interval censoring with regard to the scheduled visits. If a subject receives a rescue treatment/fulfills a 
rescue criterion during an unscheduled visit, then this event is allocated to the visit interval ending at the 
next scheduled visit that occurs after the unscheduled visit. Subjects who do not receive rescue 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 18 of 30 
 
medication/fufill rescue criterion will be censored at the last visit interval recorded for the subject. 
The Kaplan-Meier curves will be plotted. 
To assess the homogeneity (or lack thereof) of the treatment groups regarding the study days on which 
the scheduled visits occur, descriptive statistics (n, mean, standard deviation, minimum, median, and 
maximum) of study day will be presented by study visit for each treatment scheme. 
The consistency between the two endpoints (“time to first rescue treatment” and “time to first fulfillment of 
rescue treatment criterion”) will be assessed based on 2x2 tables of the rescue treatment vs. fulfillment of 
rescue treatment criterion at each study visit. 
 
Best Corrected Visual Acuity 
The exploratory efficacy endpoints related to BCVA are: 
• 
Observed values and change from baseline in BCVA (ETDRS) at all visits 
• 
Categorical change from baseline in BCVA (ETDRS) at all visits 
• 
Frequency of subjects with BCVA worse than 20/200 (Snellen equivalent) at all visits 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 9 and 10 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 10 and 11 
• 
Change from baseline in BCVA (EDTRS) to the average of the scores at Month 11 and 12 
Absolute values at each visit and change from baseline values at each follow up visit for BCVA will be 
summarized using continuous summary statistics, including 80% CIs around the mean for each treatment 
scheme.  
The proportion of subjects in each BCVA change from Baseline category (<= -15 letters, -14 to -10 letters, 
-9 to -5 letters, -4 to 4 letters, 5 to 9 letters, 10 to 14 letters, >= 15 letters) and with BCVA worse than 
20/200 (Snellen equivalent) at each visit will be summarized using discrete summary statistics. As BCVA 
is collected only in ETDRS letters, a BCVA worse than 20/200 (Snellen equivalent) is considered 
equivalent to a BCVA of < 34 ETDRS letters. 
Subjects with visual acuity measured by counting fingers or by hand motion will be assigned BCVA of 0 
ETDRS letters. If it is required to convert a visual acuity measurement made using the Snellen chart, the 
following formula will be used: 
ETDRS letters =  85+50*log10(20/xxx), 
where “20/xxx” is the Snellen visual acuity score. 
 
Central Subfield Thickness 
The exploratory efficacy endpoints related to CST are: 
• 
Observed values and change from baseline in CST (μm) at all visits.  


Statistical Analysis Plan for Interventional Studies 
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• 
Change from baseline in CST (μm) to the average of the measurements at Month 9 and 10 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 10 and 11 
• 
Change from baseline in CST (μm) to the average of the measurements at Month 11 and 12 
Absolute values at each visit and change from baseline at each follow up visit for CST will be summarized 
using continuous summary statistics, including 80% CIs around the mean for each treatment scheme.  
 
Number of Rescue Treatments 
Mean number of rescue treatments received from Month 12 to Month 18 will be summarized using 
continuous summary statistics, including 80% CIs around the mean for each treatment scheme. 
Total number of rescue treatments received will also be summarized categorically, presenting the number 
and percentage of subjects receiving each total. The proportion of subjects who received rescue 
treatment through each visit will be summarized separately using discrete summary statistics, including 
80% asymptotic normal CIs for each treatment scheme. A subject will be considered to have received 
rescue treatment at a particular visit if the rescue treatment was received at any time after the previous 
scheduled visit up to and including the visit of interest. 
 
Fulfillment of Rescue Criteria 
The number of times that a subject meets at least one rescue criterion is an exploratory efficacy endpoint. 
Mean number of times that a subject met at least one rescue criterion from Month 12 to Month 18 will be 
summarized using continuous summary statistics, including 80% CIs around the mean for each treatment 
scheme. 
Total number of times that a subject met at least one rescue criterion from Month 12 to Month 18 will also 
be summarized categorically, presenting the number and percentage of subjects receiving each total. 
The proportion of subjects that met at least one rescue criterion through each visit will be summarized 
using discrete summary statistics, including 80% asymptotic normal CIs for each treatment scheme. A 
subject will be considered to have met at least one rescue criterion at a particular visit if this occurred at 
any time after the previous scheduled visit up to and including the visit of interest. 


Statistical Analysis Plan for Interventional Studies 
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Safety 
The population used for safety analyses will be the Extension Set. Safety will be assessed on the basis of 
ocular extension-onset adverse events (EOAEs) in the study eye, ocular EOAEs in the non-study eye, 
and non-ocular EOAEs, concomitant medication use, intra-ocular pressure, slit-lamp biomicroscopy, and 
dilated ophthalmoscopy,. 
 
Adverse Events 
The safety of GB-102 will primarily be assessed by the incidence of EOAEs. An AE will be considered an 
EOAE if it occurs or worsens on or after the Month 12 ALTISSIMO (Core Study) visit through study exit. 
An AE with a missing start date will be considered an EOAE. If an AE has a partial start date where the 
partial information does not clearly indicate if the AE started before or after the Month 12 visit, then the 
AE will be considered an EOAE (eg, if the AE start date is 3 Jan 2019 and the date of the Month 12 visit 
is 3 Jan 2019, then the AE would be considered an EOAE). 
EOAE summaries will be presented separately for ocular EOAEs in the study eye, ocular EOAEs in the 
non-study eye, and non-ocular EOAEs. 
An overall summary of EOAEs will be presented including the number of events and the number of 
subjects with at least one event (along with percentages) by treatment scheme for EOAEs in several 
categories based on severity, relationship to study drug, and relationship to study procedure. Serious 
EOAEs, EOAEs leading to study drug discontinuation, arteriothromboembolic EOAEs will also be 
included in the overall summary. 
All AEs will be coded to SOC and PT using MedDRA Version 22.0. The number of EOAEs and the 
number and percentage of subjects with any EOAEs will be tabulated overall and by SOC and PT within 
each SOC by treatment scheme. 
The following categories of adverse events will be summarized: 
• 
EOAEs 
• 
Treatment related EOAEs 
• 
Serious EOAEs 
• 
Serious treatment related EOAEs 
• 
EOAEs by maximum severity 
• 
Non-serious EOAEs 
 
Intraocular Pressure 
At each study visit, IOP will be measured according to routine clinical practice using Goldmann 
applanation tonometry or Tono-Pen in both eyes at all study visits (must be performed prior to dilation and 
the IVT injection of study drug at dosing visits). 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 


Statistical Analysis Plan for Interventional Studies 
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subject. 
IOP measurements will be summarized by treatment scheme separately for the study eye and for the 
nonstudy eye. The IOP data will be summarized by visit using both continuous and discrete summaries. 
Changes from baseline will also be summarized continuously and discretely. Discrete categories for IOP 
measurements will include (in mmHg) ≤ 5, 6 to 14, 15 to 21, 22 to 29, and ≥ 30. These categories will be 
used to summarize results by visit for each treatment scheme by visit and last visit . Discrete categories 
for changes from baseline in IOP will include ≤ −5, −4 to  4, 5 to 9, 10 to 14, and ≥ 15. The numbers and 
percentages of eyes with an IOP measurement ≥ 30 mmHg and with an increase from baseline in IOP 
measurement ≥ 10 mmHg will also be summarized. 
 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy will be performed for each eye by a qualified assessing investigator at each study 
visit. This procedure will include an assessment of each of the following as normal or abnormal: 
• 
Eyelids 
• 
Conjunctiva 
• 
Cornea 
• 
Anterior chamber 
• 
Iris 
• 
Pupil 
• 
Lens 
If any findings are abnormal, exact findings should be specified and noted as either clinically or not 
clinically significant. 
In addition, the lens will be graded by the assessing investigator for the presence and severity of nuclear, 
cortical, and posterior subcapsular lens opacities using the Age-related Eye Diseases Study (AREDS) 
photographic reference scale. For detailed instructions regarding AREDS lens scoring, refer to the 
separately provided AREDS lens grading scale (Chew 2010) provided in the protocol. 
Abnormal slit-lamp biomicroscopy results will be summarized for each treatment scheme for the study eye 
by visit using discrete summary statistics. 
After the IVT injection, it is possible that the microparticles in the depot formation could migrate away from 
the depot. This migration could result in a higher incidence of AEs or could potentially affect the efficacy 
of the drug. A narrative will be provided for each subject that experiences the presence of the study 
medication in the anterior chamber in the study eye. 
 
Dilated Ophthalmoscopy 
Dilated fundus examination of both eyes will be performed in all subjects by designated qualified study 
center personnel. The following will be observed for the presence of abnormalities: 
• 
Vitreous body 
• 
Macula 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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• 
Peripheral retina 
• 
Choroid 
• 
Optic nerve 
If any findings are abnormal, exact findings should be specified and noted as either clinically or not 
clinically significant. All abnormal findings that are clinically significant will be described. 
Abnormal dilated ophthalmoscopy results will be summarized for each treatment scheme for the study 
eye by visit using discrete summary statistics. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
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Changes from Analysis Planned in Protocol 
There were no changes from the analysis planned in the protocol for the Extension Study.  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
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Filing requirements: TMF 
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Reference List 
Brown DM, Heier JS, Ciulla T, Benz M, Abraham P, et al. Primary endpoint results of a Phase II study of 
vascular endothelial growth factor trap-eye in wet age-related macular degeneration. 
Ophthalmology. 2011; 118(6): 1089-1097. 
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. 
Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial 
infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. 
Antiplatelet Trialists’ Collaboration. BMJ. 1994;308(6921):81-106. 
Heier JS, Boyer D, Nguyen QD, Marcus D, Roth DB, et al. The 1-year results of CLEAR-IT 2, a Phase 2 
study of the vascular endothelial growth factor trap-eye dosed as-needed after 12-week 
fixed dosing. Ophthalmology. 2011; 118(6):1098-1106. 
Lachin JM and Foulkes MA. 1986. 'Evaluation of Sample Size and Power for Analyses of Survival with 
Allowance for Nonuniform Patient Entry, Losses to Follow-up, Noncompliance, and 
Stratification', Biometrics. 1986;42:507-516. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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Programming Considerations 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4 (SAS Institute Inc., Cary, NC, USA) or later. Computer-generated table, listing, and figure 
output will adhere to the following specifications.  
 
General Considerations 
• 
One SAS program can create several outputs 
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance  
 
Table, Listing, and Figure Format 
 
General 
• 
All TFLs will be produced in landscape format on American letter size paper size, unless otherwise 
specified. 
• All TFLs will be produced using the Courier New font, Size 8 which is the smallest acceptable point 
size for the Regulatory Authorities. 
• The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
• Headers and footers for figures will be in Courier New font, Size 8 which is the smallest acceptable 
point size for the Regulatory Authorities. 
• Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• TFLs will be in black and white (no color), unless otherwise specified 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
• Only standard keyboard characters will be used in the TFLs. Special characters, such as 
non-printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
Headers 
• All output should have the following header at the top left of each page: 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
SAP Version: Extension 1.0, 31MAR2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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Graybug Vision, Inc., Protocol GBV-102-002 (Syneos Health Study Number 1011627) 
Draft/Final Run DD-MMM-YYYY 
• All output should have Page n of N at the top or bottom right corner of each page. TFLs are 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
• The date output was generated should appear along with the program name as a footer on each 
page. 
 
Display Titles 
• Each TFL is identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering is 
strongly recommended, but sponsor preferences are obtained before final determination. A decimal 
system (x.y and x.y.z) are used to identify TFLs with related contents. The title is centered. The 
analysis set are identified on the line immediately following the title. The title and table designation 
are single spaced. A solid line spanning the margins will separate the display titles from the 
Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT Analysis Set) 
 
 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial 
upper-case characters.  
• In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment scheme columns and total column (if applicable). P-values may be presented 
under the total column or in separate p-value column (if applicable). Within-treatment comparisons 
may have p-values presented in a row beneath the summary statistics for that treatment. 
• For numeric variables, include “unit” in column or row heading when appropriate. 
• Analysis set sizes will be presented for each treatment scheme in the column heading as (N=xx) 
(or in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
• The order of treatments in the tables and listings will be Placebo first in the case of placebo 
controlled studies and Active comparators first in the case of active comparator trials, followed by a 
total column (if applicable). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
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Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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Body of the Data Display 
12.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values are left-justified; 
• Whole numbers (e.g., counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned. 
12.2.5.2. 
Table Conventions 
• Units will be included where available 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment schemes in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups are included. 
• An Unknown or Missing category are added to each parameter for which information is not 
available for 1 or more subjects.  
• Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 


Statistical Analysis Plan for Interventional Studies 
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This document is confidential. 
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Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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• P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Every p-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down 
to 0.0. A common convention is to display as '<0.1', or as appropriate with additional decimal 
places. Unless otherwise noted, for all percentages, the number of subjects in the analysis set for 
the treatment scheme who have an observation will be the denominator. Percentages after zero 
counts should not be displayed and percentages equating to 100% are presented as 100%, without 
decimal places.  
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data are presented by the body system, treatment class, or SOC with the highest 
occurrence in the active treatment scheme in decreasing order, assuming all terms are coded. 
Within the body system, drug class and SOC, medical history (by PT), drugs (by ATC1 code), and 
adverse events (by PT) are displayed in decreasing order. If incidence for more than 1 term is 
identical, they should then be sorted alphabetically. Missing descriptive statistics or p-values which 
cannot be estimated are reported as “-”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment scheme (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Describe details of this in 
footnotes or programming notes. 
• For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, describe in a footnote or programming note if the subject are included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting 
the criteria. 
• Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page. The 
overall summary statistics for the subheading should only be output on the first relevant page. 
12.2.5.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of treatment schemes as above, subject number, 
visit/collection day, and visit/collection time. 
• Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates are 
represented on subject listings as dashes (--JUL2000). Dates that are missing because they are 
not applicable for the subject are output as “N/A”, unless otherwise specified. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
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Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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• All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
• Units will be included where available 
12.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the footnotes.  
• All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
• Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
• Subject specific footnotes are avoided, where possible. 
• Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page.  
• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Graybug Vision, Inc.; Protocol No.: GBV-102-002 (Phase 2b) – Extension Study 
 
 
This document is confidential. 
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Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures, or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
SOP Developing Statistical Programs (3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency, and commenting and by review 
of the produced output.