Clinical trial NCT04200248
Conditions: Exudative Age-related Macular Degeneration
Keywords: Fibrosis Edema Neovascularization
Sponsor: Ribomic USA Inc
Start date: 2019-12-02; Completion date: 2021-12-22
Enrollment: 94 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, active-controlled, double masked study assessing the safety, efficacy and durability of four monthly intravitreal (IVT) injections of RBM-007 monotherapy, and four monthly RBM-007 injections in combination with Eylea® dosed at every other month, compared to Eylea® monotherapy dosed at every other month in approximately eighty-one subjects with exudative age-related macular degeneration (AMD).

Detailed description:
RBM-007 is a novel oligonucleotide-based aptamer having potent anti-FGF2 activity and anti-VEGF-expression activity

Arms: arm 1: Sham + RBM-007 intravitreal injection arm 2: RBM-007 + Aflibercept intravitreal injection arm 3: Sham + Aflibercept intravitreal injection
Interventions: intervention 1: RBM-007 Injectable Solution intervention 2: Aflibercept intervention 3: Sham
Intervention descriptions: intervention 1: RBM-007 Injectable Solution intervention 2: EYLEA® (aflibercept) Injection, for Intravitreal Use intervention 3: Sham intravitreal injection

Protocol documents:
Prot_000.pdf: 
Clinical protocol:  
Title:  A Multi-Center, Randomized, Double Masked and Active Controlled Phase II Study 
Assessing the Efficacy and Safety of Intravitreal Injections of RBM-007 monotherapy and RBM-
007 in Combination with Eylea® Compared to Eylea® Monotherapy in Subjects with Wet Age-
related Macular Degeneration – TOFU Study 
NCT04200248 
Date: 15 November 2019 
 








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SYNOPSIS
 
Name of Sponsor/Company:
RIBOMIC USA Inc.
2120 University Ave.
Berkeley, CA 94704
Name of Investigational Product: RBM-007 injectable solution
Name of Active Ingredient: RBM-007
Title of Study: A Multi-Center, Randomized, Double Masked and Active Controlled Phase II 
Study Assessing the Efficacy and Safety of Intravitreal Injections of RBM-007 monotherapy 
and RBM-007 in Combination with Eylea® Compared to Eylea® Monotherapy in Subjects with 
Wet Age-related Macular Degeneration – TOFU Study
Study Period: Approximately 18 months 
Estimated date first subject enrolled: October 2019 
Estimated date last subject completed: March 2021
Phase of Development:
Phase II
Primary Objective:
To assess the safety and efficacy of repeated intravitreal injections of RBM-007 (2.0 mg/eye) 
given as monotherapy and RBM-007 (2.0 mg/eye) in combination with Eylea® in subjects with 
wet age-related macular degeneration (AMD) compared with Eylea® alone.
Secondary Objective:
To evaluate durability of effect for RBM-007 in subjects with exudative age-related macular 
degeneration.
 


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Methodology:
This is a multicenter, active-controlled, double masked study assessing the safety, efficacy 
and durability of four monthly intravitreal (IVT) injections of RBM-007 monotherapy, 
and four monthly RBM-007 injections in combination with Eylea® dosed at every other month, 
compared to Eylea® monotherapy dosed at every other month in approximately eighty-one 
subjects with exudative age-related macular degeneration (AMD).
Subjects who meet all eligibility criteria at Baseline will be randomized to receive 
treatment for up to three months in the study eye.  
Approximately eighty-one subjects with exudative age-related macular degeneration 
(AMD) will be randomized in a 1:1:1 ratio to either:
x
Arm 1: Sham + RBM-007 Injectable Solution (2.0 mg/eye)
x
Arm 2: RBM-007 Injectable Solution (2.0 mg/eye) + Eylea®
x
Arm 3: Sham + Eylea®
The primary endpoint of the study is at one month post the last injection in all treatment 
arms, with safety evaluation through additional two months post the last injection.
For eligibility, subjects age 55 years or older must be diagnosed with active exudative 
AMD in the study eye, for which previous standard treatment with intravitreal anti-
vascular endothelial growth factor (anti-VEGF) agents has demonstrated incomplete 
resolution of exudation, as assessed by spectral domain optical coherence tomography 
(SD-OCT). Other inclusion criteria are: Early Treatment of Diabetic Retinopathy Study 
(ETDRS) best-corrected visual acuity (BCVA) of 78 to 24 letters (≤20/32 and ≥20/320 
Snellen vision equivalent); presence of macular edema or subretinal fluid on SD-OCT; 
absence of central atrophy or retinal epithelial tear in the fovea or any condition preventing 
VA improvement in the study eye.
Eligible subjects who are enrolled in the study will be seen for at least 7 visits that include a 
Screening Visit (Visit 0), Baseline/Day 1 (Visit 1), and Week 1-20 (Visit 2-7).
Subjects are eligible for rescue with Eylea® or other treatment at the discretion of investigator 
anytime during the study except for those visits with Eylea® injection as per protocol, if one of 
the following rescue criteria is met.
Rescue Criteria:
x
BCVA decrease of > 10 letters AND central subfield thickness (CST) increase of > 50 
μm from the last visit
x
The discretion of investigator
Number of Subjects (planned):
Approximately 81 subjects with wet AMD will be enrolled at approximately 15 sites.


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Duration of the Study:
The total study period for each subject will include a screening period (up to 28-days), then a 
treatment and follow up period (up to 20 weeks).
Masking:
This is a double-masked study, with subjects and examiners including the Principal 
Investigator (PI) masked to the treatment regimen. However, the designated injecting physician 
(not the PI) will not be masked to the treatment regimen.
The designated Safety Review Team (SRT) will review the safety data periodically to 
determine if the safety and tolerability of the doses are acceptable. In the event of a serious 
adverse event the SRT may decide to unmask the treatment.
Diagnosis and Main Criteria for Inclusion:
Inclusion Criteria:
At Screening (Day -28 to Day -1) and Visit 1 (Day 1), subjects must meet all of the following 
inclusion criteria:
1. Provide signed written informed consent on the Institutional Review Board (IRB)/Ethics 
Committee (EC) approved Informed Consent Form (ICF) and provide authorization as 
appropriate for local privacy regulations.
2. Male or female 55 years of age or older on the date of signing the ICF and able and 
willing to comply with all treatment and study procedures.
3. Diagnosis of exudative AMD in the study eye, for which previous standard treatment 
with IVT anti-VEGF agents (at least 4 injections over the past 8 months) has 
demonstrated incomplete resolution of exudation, as assessed by spectral domain 
optical coherence tomography (SD-OCT).
4. Presence of macular edema or subretinal fluid on SD-OCT.
5. Absence of central atrophy or retinal epithelial tear in the fovea or any condition 
preventing VA improvement in the study eye.
6. BCVA of 78 to 24 ETDRS letters (20/32 to 20/320) in the study eye.
7. BCVA of 24 ETDRS letters (20/320) or better in the fellow eye.
8. Reasonably clear media and some fixation in the study eye to allow for good quality SD-
OCT and fundus photography.


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Exclusion Criteria:
A subject with any of the following conditions is not eligible to participate in the study:
Ocular:
1. Use of any of the following treatments or anticipated use of any of the following 
treatments to the study eye:
a.
Any IVT treatment for AMD within 4 weeks prior to Baseline (Visit 1).
b. Intravitreal or periocular corticosteroid, within 90 days prior to Visit 1 (Day 1) 
and throughout the study.
c.
Fluocinolone acetonide intravitreal implant, within 12 months prior to Visit 1 
(Day 1) and throughout the study.
d. Visudyne® photodynamic therapy, within 90 days prior to Visit 1 (Day 1) and 
throughout the study.
2. Uncontrolled or advanced glaucoma, evidenced by an intraocular pressure (IOP) of > 21 
mmHg or cup/disc ratio > 0.8 while on medical therapy, or chronic hypotony (< 6 mmHg) 
in the study eye.
3. Evidence of any other ocular disease other than wet AMD in the study eye that may 
confound the outcome of the study (e.g., active diabetic retinopathy, posterior uveitis, 
pseudo vitelliform macular degeneration, moderate/severe myopia).
4. History of vitrectomy in the study eye.
5. Need for ocular surgery in the study eye during the course of the study.
6. YAG laser capsulotomy within 30 days prior to Visit 1 (Day 1) in the study eye.
7. Intraocular surgery, including lens removal or laser, within 90 days prior to Visit 1 (Day 
1) in the study eye.
8. Ocular or periocular infection in either eye.
9. Pupillary dilation inadequate for quality stereoscopic fundus photography in the study 
eye.
10. Media opacity that would limit clinical visualization, intravenous fluorescein 
angiography, or spectral domain optical coherence tomography (SD-OCT) evaluation in 
the study eye.
11. History of herpetic infection in the study eye or adnexa.
12. Presence of known active toxoplasmosis, inactive toxoplasmosis or toxoplasmosis scar 
in either eye.
13. Presence of any form of ocular malignancy including choroidal melanoma in either eye.
Non-Ocular:
14. Prior systemic treatment with RBM-007 injectable solution.


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15. Use of any of the following treatments or anticipated use of any of the following 
treatments during the study:
a.
Systemic treatment with anti-VEGF agents (e.g., bevacizumab)
b. Agents targeting the FGF-2 pathway
16. Allergy or hypersensitivity to study drug product, fluorescein dye, or other study related 
procedures/medications.
17. Major surgery within 90 days prior to Visit 1 (Day 1). Major surgery is defined as any 
surgery involving a risk to the life of the subject, including any operation upon an organ 
within the cranium, chest, abdomen, or pelvic cavity.
18. Therapeutic radiation to the head or neck within 90 days prior to Visit 1 (Day 1).
19. Participation in other investigational drug or device clinical trials within 30 days prior to 
Visit 1 (Day 1) or planning to participate in other investigational drug or device clinical 
trials for the duration of the study. This includes both ocular and non-ocular clinical trials.
20. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease condition that contraindicates 
the use of an investigational drug, might affect the interpretation of the results of the 
study, or renders the subject at high risk for treatment complications.
21. Females who are pregnant or lactating and females of child-bearing potential who are 
not using adequate contraceptive precautions (i.e., IUD, oral contraceptives, barrier 
method, or other contraception deemed adequate by the Clinical Investigator).
22. Unable to comply with study procedures or follow-up visits.
In addition, the Clinical Investigator or RIBOMIC Medical Monitor may declare a subject 
ineligible for any sound reason.




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Criteria for Evaluation:
Efficacy:
The primary efficacy variable assessed at Week 16:
•
Mean change in BCVA from Baseline
The secondary efficacy variables assessed at Week 16:
•
Proportion of patients gaining more than 15 letters as measured by BCVA from Baseline
(3-line gainers)
•
Proportion of subjects with BCVA: 1) gain of ≥10 ETDRS letters; 2) gain of ≥5 ETDRS 
letters; and 3) ≥ 15 letter loss from Baseline
•
Change from Baseline in CST, and macular volume by SD-OCT
•
Change from Baseline in characteristics of subretinal hyper reflective material (SHRM)
•
Change from Baseline in characteristics of fibrosis
•
Proportion of subjects that do not require anti-VEGF treatment during follow-up period
•
Mean numbers of rescue injections in the monotherapy arm
•
Proportion of subjects requiring rescue
Safety:
The safety assessments will include adverse events (AEs), vital signs, pregnancy, physical 
examination, external ocular exam, BCVA, IOP, slit lamp biomicroscopy, indirect 
ophthalmoscopy, SD-OCT, fundus photography and fluorescein angiography.
Statistical Methods:
The primary analysis will be performed at Week 16. All safety and efficacy data will be 
summarized by treatment arms with descriptive statistics. BCVA and CST data will also be 
presented graphically.
Due to the exploratory nature of this study, the sample size was not based on a statistical power.


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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES
TABLE OF CONTENTS
APPROVERS.................................................................................................................................................. 2 
 
PROCEDURES IN CASE OF EMERGENCY ..................................................................................... 3 
 
SYNOPSIS............................................................................................................................................. 4 
 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES...........................................11 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................... 15 
 
INTRODUCTION ............................................................................................................................... 16 
 
OBJECTIVES...................................................................................................................................... 18 
 
INVESTIGATIONAL PLAN............................................................................................................... 19 
 
Overall Study Design and Plan ....................................................................................................... 19 
7.1.1 
Selection of Concentrations in the Study................................................................................... 20 
 
Number of Subjects......................................................................................................................... 21 
 
Treatment Assignment..................................................................................................................... 21 
 
Dose Adjustment Criteria ............................................................................................................... 21 
 
Study Procedures............................................................................................................................. 21 
7.5.1 
Screening Phase....................................................................................................................... 25 
7.5.2 
Treatment/follow-up phase....................................................................................................... 26 
7.5.3 
Study Exit................................................................................................................................ 33 
7.5.4 
Unscheduled Visits................................................................................................................... 33 
 
SELECTION AND WITHDRAWAL OF SUBJECTS......................................................................... 34 
 
Subject Inclusion Criteria............................................................................................................... 34 
 
Subject Exclusion Criteria.............................................................................................................. 34 
 
Subject Withdrawal Criteria........................................................................................................... 36 
 
TREATMENT OF SUBJECTS ........................................................................................................... 37 
 
Description of Study Drug............................................................................................................... 37 
 
Concomitant Medications ............................................................................................................... 37 
9.2.1 
Prohibited Medications or Treatments....................................................................................... 37 
9.2.2 
Rescue Therapy........................................................................................................................ 37 
 
Treatment Compliance.................................................................................................................... 38 
 
Randomization and Masking .......................................................................................................... 38 
 
STUDY DRUG MATERIALS AND MANAGEMENT....................................................................... 39 
 
Study Drug.................................................................................................................................. 39 
10.1.1 
Investigational Drug ............................................................................................................ 39 
10.1.2 
Concomitant drug................................................................................................................ 39 
10.1.3 
Study Drug Complaint Reporting......................................................................................... 39 
10.1.4 
Other Study Supplies........................................................................................................... 39 
 
Study Drug Packaging and Labeling.......................................................................................... 39 
 
Study Drug Storage .................................................................................................................... 39 
 
Study Drug Preparation ............................................................................................................. 39 
 
Loading the Syringe.................................................................................................................... 40 
 
Eye Preparation.......................................................................................................................... 41 
 
Study Drug Administration ........................................................................................................ 41 
 
Study Drug Accountability ......................................................................................................... 42 
 
Study Drug Handling and Return.............................................................................................. 43 
 
ASSESSMENT OF EFFICACY.......................................................................................................... 44 
 
Best Corrected Visual Acuity (BCVA)........................................................................................ 44 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Central Subfield Thickness (CST), Macular Volume (MV), Fibrosis and SHRM..................... 44 
 
ASSESSMENT OF SAFETY............................................................................................................... 45 
 
Adverse Events ........................................................................................................................... 45 
12.1.1 
Definition of Adverse Events............................................................................................... 45 
12.1.2 
Serious Adverse Events........................................................................................................ 47 
12.1.3 
Events of Special Interest..................................................................................................... 48 
12.1.4 
Follow-up of Adverse Events............................................................................................... 49 
12.1.5 
Manual Back-Up Reporting Procedures ............................................................................... 49 
 
Safety Parameters....................................................................................................................... 49 
12.2.1 
Physical Examination .......................................................................................................... 49 
12.2.2 
Vital Signs........................................................................................................................... 50 
12.2.3 
Best Corrected Visual Acuity ............................................................................................... 50 
12.2.4 
External ocular exam........................................................................................................... 50 
12.2.5 
Slit-lamp Biomicroscopy ..................................................................................................... 50 
12.2.6 
Intraocular Pressure............................................................................................................. 50 
12.2.7 
Indirect Ophthalmoscopy..................................................................................................... 50 
12.2.8 
Urine Pregnancy Test........................................................................................................... 50 
12.2.9 
Fundus Photography............................................................................................................ 50 
12.2.10 
Fluorescein Angiography..................................................................................................... 50 
12.2.11 
Spectral Domain Optical Coherence Tomography (SD-OCT) ............................................... 51 
12.2.12 
Adverse Events.................................................................................................................... 51 
 
OTHER ASSESSMENTS.................................................................................................................... 52 
 
Demographics and Baseline Characteristics .............................................................................. 52 
 
OCT Angiography...................................................................................................................... 52 
 
STATISTICAL METHODS ................................................................................................................ 52 
 
Analysis Time Points................................................................................................................... 52 
14.1.1 
Primary Analysis ................................................................................................................. 52 
 
General Considerations .............................................................................................................. 53 
14.2.1 
Sample Size......................................................................................................................... 53 
14.2.2
Statistical Hypotheses and Level of Significance.................................................................. 53
14.2.3 
Randomization .................................................................................................................... 53 
14.2.4 
Study Eye............................................................................................................................ 53 
 
Study Populations....................................................................................................................... 53 
 
Handling of Missing Values ........................................................................................................ 53 
 
Demographics and Baseline Characteristics .............................................................................. 54 
 
Efficacy Analyses ........................................................................................................................ 54 
14.6.1 
Analysis of Primary Efficacy Endpoints............................................................................... 54 
14.6.2 
Analysis of Secondary Efficacy Endpoints........................................................................... 54 
 
Safety Analysis............................................................................................................................ 54 
 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.................................................................... 55 
 
Study Monitoring........................................................................................................................ 55 
 
Audits and Inspections................................................................................................................ 56 
 
Institutional Review Board......................................................................................................... 56 
 
QUALITY CONTROL AND QUALITY ASSURANCE..................................................................... 56 
 
Quality Control........................................................................................................................... 56 
 
Quality Assurance....................................................................................................................... 56 
 
ETHICS ............................................................................................................................................... 57 
 
Ethics Review.............................................................................................................................. 57 
 
Ethical Conduct of the Study...................................................................................................... 57 
 
Written Informed Consent ......................................................................................................... 57 
 
DATA HANDLING AND RECORDKEEPING .................................................................................. 58 
 
Inspection of Records ................................................................................................................. 58 
 
Retention of Records .................................................................................................................. 58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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18.2.1 
Source Documents............................................................................................................... 58 
18.2.2 
Data Collection.................................................................................................................... 59 
 
PUBLICATION POLICY.................................................................................................................... 60 
 
REFERENCES .................................................................................................................................... 61 
 
APPENDICES ..................................................................................................................................... 63 
 
Appendix A - Obligations of Investigators.................................................................................. 63 
 
Appendix B - Elements of Informed Consent............................................................................. 65 
21.2.1 
Elements of Informed Consent............................................................................................. 65 
21.2.2 
Additional Elements of Informed Consent............................................................................ 65 
 
Appendix C - Declaration of Helsinki......................................................................................... 67 
 
Appendix D - Procedures for Examinations............................................................................... 73 
21.4.1 
Demographics/Eligibility, Medical/Surgical History and Concomitant Medication................ 73 
21.4.2 
Physical Examination .......................................................................................................... 73 
21.4.3 
Vital Signs........................................................................................................................... 73 
21.4.4 
Urine pregnancy test............................................................................................................ 74 
21.4.5 
Best Corrected Visual Acuity............................................................................................... 74 
21.4.6 
External Ocular Examination ............................................................................................... 74 
21.4.7 
Slit-Lamp Biomicroscopy.................................................................................................... 74 
21.4.8 
Intraocular Pressure............................................................................................................. 75 
21.4.9 
Indirect Ophthalmoscopy..................................................................................................... 77 
21.4.10 
Spectral Domain Optical Coherence Tomography ................................................................ 77 
21.4.11 
Optical Coherence Tomography Angiography...................................................................... 77 
21.4.12 
Fundus Photography............................................................................................................ 78 
21.4.13 
Fluorescein Angiography..................................................................................................... 78 
 
 
 
 
 
 
 
 


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LIST OF TABLES
TABLE 1: EMERGENCY CONTACT INFORMATION ........................................................................................... 3 
TABLE 2: SCHEDULE OF EVENTS ............................................................................................................... 23 
TABLE 3: RBM-007 DOSING..................................................................................................................... 39 
LIST OF FIGURES
FIGURE 1: STUDY SCHEMATIC ................................................................................................................... 20 
FIGURE 2: DECISION IOP PROCESS FOR TWO INJECTIONS ............................................................................ 28 
FIGURE 3: DECISION IOP PROCESS FOR SINGLE INJECTION .......................................................................... 31 
FIGURE 4: 0.5 ML FILL IN A 2 ML VIAL ....................................................................................................... 41 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this study protocol.
 
Abbreviations and Terms 
 
Abbreviation
Expression (Name) in full
AE(s)
adverse event(s)
AMD
age-related macular degeneration
BCVA
best corrected visual acuity
CNV
choroidal neo-vascularization
CRF
Case report form
CST
central subfield thickness
eCRF(s)
Electronic Case Report Form(s)
EDC
EC
Electronic Data Capture
Ethics Committee
ESI(s)
event(s) of special interest
ETDRS
Early Treatment of Diabetic Retinopathy Study
FDA
Food and Drug Administration
FGF
fibroblast growth factor
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug Application
IOP
intraocular pressure
IRB
Institutional Review Board
ITT
intent-to-treat
IVT
intravitreal
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
mg
NOAEL
milligram
no observed adverse effect level
μL
microliter
mL
milliliter
mmHg
millimeter of mercury
SAE(s)
serious adverse event(s)
SAP
statistical analysis plan
SD-OCT
SHRM
spectral domain optical coherence tomography
subretinal hyper reflective material
SRT
Safety Review Team
VEGF
vascular endothelial growth factor
 


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INTRODUCTION
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in 
developed countries. AMD is characterized by extracellular matrix deposits, known as drusen, 
accumulating between the retinal pigment epithelium and Bruch’s membrane. In exudative or wet 
AMD unwanted blood vessels grow into the macula which leads to hemorrhage and subretinal 
fluid. In addition, retinal pigment epithelial detachment, retinal tears, fibrovascular scarring and 
vitreous hemorrhage may occur. The aberrant growth of leaky vessels is the result of local 
inflammatory responses leading to disruption of the balance of cytokines that control angiogenesis 
(Lim et al., 2008)
Angiogenesis is a complex and coordinated process of the growth and sprouting of new blood 
vessels from pre-existing vasculature. Although several angiogenic factors have been identified, 
VEGF family proteins, their receptors and intracellular signaling molecules appear to be the key 
mediators of angiogenesis (Kane et al., 2008).
Approximately 1.2 million persons in the United States are estimated to have neovascular AMD 
and 970 000 to have geographic atrophy; >8 million have at least large drusen in 1 eye and 3.6 
million of these have bilateral large drusen. These prevalence figures are expected to increase by 
approximately 50% (Chew et al, 2012; Friedman et al, 2004). From the initial stage of dry AMD, 
characterized by lipofuscin deposits under the retina known as drusen, 10% are at risk for severe, 
acute loss of central vision due to the onset of wet AMD, characterized by the growth of abnormal 
CNV in the macula, which leads to subretinal bleeding, fluid exudation, and fibrotic scar 
formation. Over 200,000 new patients each year in the U.S. develop wet AMD (Ferris, et al, 1984).
Current FDA-approved therapies for AMD are pegaptanib (Macugen®), ranibizumab (Lucentis®) 
and aflibercept (Eylea®). All of these molecules act against the same target: vascular endothelial 
growth factor (VEGF). VEGF, a potent endothelial cell mitogen and vascular permeability factor, 
is a major contributor to the pathogenesis of neovascular AMD. Treatments with anti-VEGF drugs, 
which are delivered by frequent intravitreal injections, have shown dramatic visual benefits for 
AMD patients (Brown et al, 2006; Heier et al, 2012; Martin et al, 2012). However, there are some 
critical limitations; in formal clinical trials, despite consistent monthly treatment, 23% of eyes 
treated monthly with ranibizumab proceeded to vision worse than 20/200, and 20% to 40% fail to 
resolve macular fluid even after 2 years of therapy (Brown et al, 2006; Heier et al, 2012). 
Furthermore, in the “real-world” setting, patients receive intravitreal injections at much lower 
frequency than the established protocols, so that on average, long-term visual outcomes in AMD 
treatment are poor (Rofagha et al, 2013; Maguire et al, 2016). Factors associated with poor vision 
outcomes, in addition to persistent exudation, include macular atrophy and submacular fibrotic 
scar formation. Thus, there is a need for additive or alternative therapy to anti-VEGF treatments 
for wet AMD.
Fibroblast growth factor (FGF) has been implicated in the pathophysiology of both angiogenesis 
and fibrosis in retinal diseases (Schultz and Grant, 1991; Vinding, 1990). FGF comprises a family 
of 22 members, including FGF2, having many biological activities (Bikfalvi et al., 1997). FGF2 
promotes growth of vascular endothelial cells and tubular structure formation (Strutz et al, 2002), 
and stimulates both VEGF production and scar formation in retina. 
RBM-007 injectable solution is a novel oligonucleotide-based aptamer having potent anti-FGF2 
activity (Jin et al, 2016) and anti-VEGF-expression activity (Belgore et al, 2003). In the rat and 
 


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mouse models of laser-induced choroidal neovascularization, it showed activity after intravitreal 
injection at doses as low as 5 μg/eye (Matsuda et al., 2019). In the laser-induced choroidal 
neovascularization (CNV) fibrosis model in rats, it showed activity after intravitreal injection at 
doses as low as 15 μg/eye (Matsuda et al., 2019). It is hypothesized to have potential effects in the 
treatment of wet AMD because of these activities. Thus, the Sponsor plans to evaluate the safety 
and bioactivity of RBM-007 Injectable Solution as an intravitreal treatment for exudative AMD.
RIBOMIC has conducted a Phase I/II, open-label, dose-escalating, sequential cohort study 
assessing the safety, tolerability and bioactivity of a single IVT injection of RBM-007 injectable 
solution in the study eye of nine subjects with refractory wet AMD (Protocol RBM-007-001). 
Three dose levels of RBM-007 have been assessed in this Phase I/II study, 0.2 mg/eye, 1.0 mg/eye 
and 2.0 mg/eye. In this study (SUSHI), there were no reported SAEs. No dose-dependent events 
were reported and no safety concerns were identified at all investigated doses. Ocular AEs were 
reported in 3 subjects (33.3%). Most common AE was subconjunctival hemorrhage (2 subjects) 
and these were considered to be due to the injection procedure. Only one drug related AE was mild 
iritis that was resolved after one day of topical steroid eye drops.
RIBOMIC believes that the Phase I/II study results mentioned above, in addition to the results of 
the non-clinical studies, support the use of repeated IVT injections of the 2.0 mg concentrations of 
RBM-007 in humans in the Phase II clinical trial, namely TOFU (Protocol RBM-007-002).


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OBJECTIVES
Primary Objective:
To assess the safety and efficacy of repeated intravitreal injections of RBM-007 (2.0 mg/eye) 
given as monotherapy and RBM-007 (2.0 mg/eye) in combination with Eylea® in subjects with 
wet AMD compared with Eylea® alone.
Secondary Objective:
To evaluate durability of effect for RBM-007 in subjects with exudative age-related macular 
degeneration.
 
 


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INVESTIGATIONAL PLAN
Overall Study Design and Plan
This is a multicenter, active-controlled, double masked study assessing the safety, efficacy 
and durability of four monthly IVT injections of RBM-007 monotherapy, and four monthly 
RBM-007 injections in combination with Eylea® dosed at every other month, compared to 
Eylea® monotherapy dosed at every other month in approximately eighty-one subjects with 
exudative AMD.
Subjects who meet all eligibility criteria at Baseline will be randomized to receive treatment 
for up to three months in the study eye.  
Approximately eighty-one subjects with exudative AMD will be randomized in a 1:1:1ratio 
to either:
x
Arm 1: Sham + RBM-007 Injectable Solution (2.0 mg/eye) 
x
Arm 2: RBM-007 Injectable Solution (2.0 mg/eye) + Eylea®
x
Arm 3: Sham + Eylea®
For eligibility, subjects age 55 years or older must be diagnosed with active exudative AMD in 
the study eye, for which previous standard treatment with intravitreal anti-VEGF agents has 
demonstrated incomplete resolution of exudation, as assessed by spectral domain optical 
coherence tomography (SD-OCT). Other inclusion criteria are: Early Treatment of Diabetic 
Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) of 78 to 24 letters (≤20/32 
and ≥20/320 Snellen vision equivalent); presence of macular edema or subretinal fluid on SD-
OCT; absence of central atrophy or retinal epithelial tear in the fovea or any condition 
preventing VA improvement in the study eye.
Eligible subjects who are enrolled in the study will be seen for at least 7 visits that include a 
Screening Visit (Visit 0), Baseline/Day 1 (Visit 1), and Weeks 1to20 (Visits 2-7).The Primary 
Analysis is planned when all subjects complete the Week 16 visit. The Follow-up Analysis is 
planned at Week 20 to assess the number of Eylea® injections used for Rescue in addition to 
efficacy and safety data.
Subjects are eligible for rescue with Eylea® or other treatment at the discretion of investigator 
anytime during the study except for those visits with Eylea® injection as per protocol, if one of 
the following rescue criteria is met:
Rescue Criteria:
x
BCVA decrease of > 10 letters AND central subfield thickness (CST) increase of > 50 μm
from the last visit.
x
The discretion of investigator.
If rescue is performed, the following assessments must be performed after the administration of 
Rescue treatment: (all ophthalmic procedures to be performed in the treated eye)
- Within 30 minutes following Rescue treatment
 
 




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A wide range of animal toxicology studies were conducted with RBM-007 Injectable Solution by 
both systemic and ocular routes. Systemic toxicity was seen only with high doses far above those 
doses contemplated for ocular administration. The NOAEL in Good Laboratory Practice (GLP) 
intravitreal monkey studies is 1 mg/eye. Using a volume of vitreous of 2.2 mL for monkey, this is 
a concentration of 0.45 mg/mL (Atsumi et al, 2013). The intended human doses for the first in 
human study (RBM-007-001) are 1.0 mg and 2.0 mg per eye administered once. Considering a 
value of human vitreous to be 5.2 mL (Panda-Jonas, 1994), these concentrations are 0.038, 0.19 
and 0.38 mg/mL for these clinical doses. Therefore, the NOAEL in monkey is 11-fold higher than 
the intended starting clinical dose and 1.1-fold higher than intended maximum human dose. The 
safety factor would have been even higher if the viscosity and injectable volume for RBM-007 
Injectable Solution in animals (monkey and rabbit) were not limiting parameters. Additionally, the 
current long-term ocular monkey study with monthly injection of RBM-007 at 1 mg/eye 
monotherapy and RBM-007 at 0.5 or 1 mg/eye in addition to Eylea® at 2 mg/eye for up to five 
injections (by Week 20 of dosing as interim report) has not shown any treatment-related adverse 
effect. This study is still ongoing.
With regard to systemic exposure, the highest concentration of RBM-007 seen in plasma after 
single intravitreal dosing was 2,100 ng/mL at a dose of 1 mg/eye in monkey and 65.1 ng/mL at a 
dose of 0.5 mg/eye (injection to both eyes at a dose of 0.5 mg/eye, total 1 mg/body) in rabbit. 
Toxicokinetic evaluation in GLP systemic studies in monkey suggests that blood level at which 
toxicity might occur is 691,000 ng/mL. Thus, even without correcting for the body weight 
differences between animals and humans, the safety margin is 165–5,207 at the maximum dose of 
2.0 mg/eye for human. If the body weight for animals is taken into account (rabbit and monkey at 
3 kg and human at 70 kg.), the safety margin is 3,850–123,830. 
Thus, the Sponsor contends that the preclinical toxicology studies support the planned clinical 
studies.
Number of Subjects
Approximately 81 subjects (Arm 1: 27 subjects, Arm 2: 27 subjects, Arm 3: 27 subjects) with wet 
AMD will be enrolled at approximately 15 sites. The final number of subjects enrolled may be 
adjusted based on drop-out rate.
Treatment Assignment
RBM-007 (2.0 mg) and Eylea® will be administered by IVT injection in the study eye.
•
RBM-007 injectable solution 2.0 mg (100 μL of 20 mg/mL)
•
Eylea® 2.0 mg (50 μL of 40 mg/mL)
Dose Adjustment Criteria
The Safety Review Team will review safety parameters periodically and in the event of any SAE 
for adjusting or stopping doses.
Study Procedures
All subjects must sign a written ICF before participating in any study-related activity. Central 
randomization will occur after a subject meets all eligibility requirements at Screening. Each 
 
 
 
 


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randomized subject will be assigned a unique subject number. If a subject is discontinued from the 
study for any reason, the subject number will remain in effect and will not be reused.
A Schedule of Events can be found below and detailed procedures for examinations can be found 
in Section 21.4, Appendix D – Procedures for Examinations.




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f
Urine pregnancy tests are to be performed on all women of child-bearing potential.
g
Schematic for injections is shown in Figure 1.


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7.5.1
Screening Phase
Visit 0/Screening (Day -28 to Day -1)
•
Treatment History Review:
-
Ascertain the patient has exudative AMD that has not resolved with anti-VEGF therapy:
-
Minimum of 4 prior anti-VEGF injections within the past 8 months and last treatment
received at least 4 weeks ago.
-
SD-OCT has shown recurrent or persistent macular fluid despite this anti-VEGF
treatment, defined as the presence of subretinal fluid or cystoid macular edema.
•
Explain the purpose and details of the study to the subject and obtain written informed
consent prior to the subject’s participation in any study related activity.
•
Obtain subject’s demographic information, medical, surgical and medication history.
•
If the subject continues to be eligible for the study, ask female subject whether they are
postmenopausal (Section 21.4.4). Perform urine pregnancy test to the subject who answered
“No” to the question.
•
Perform the following assessments: (all ophthalmic procedures to be performed on both eyes)
-
Physical examination
-
Vital signs
-
BCVA (ETDRS)
-
External ocular exam
-
IOP
-
Slit-lamp biomicroscopy
-
Indirect ophthalmoscopy
-
SD-OCT
-
Fundus photography
•
Review the inclusion and exclusion criteria. Do not continue screening any subject who does
not meet the screening eligibility requirements.
•
Upload case report form (CRF) and collected images (Fundus photography and SD- OCT) of
both eyes to EDC for confirmation of subject eligibility.
•
After confirmation of eligibility and selection of the Study Eye, the subject should be
scheduled for Visit 1 (Day 1).
 
 
 
 
 
 
 
 
 
 
 


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7.5.2
Treatment/follow-up phase
Visit 1 (Day 1)
•
Perform the following assessments prior to administration of study drugs to confirm
eligibility and obtain Baseline characteristics: (all ophthalmic procedures to be performed on
both eyes)
-
Query for AEs
-
Update medical history and medications
-
Perform urine pregnancy test to the subject who answered “No” to the question on 
postmenopausal at Screening Visit
-
BCVA (ETDRS)
-
External Ocular exam
-
IOP
-
Slit-lamp biomicroscopy
-
Indirect ophthalmoscopy
-
SD-OCT
-
OCT-angiography (for selected sites)
-
Fundus photography
-
Fluorescein angiography
•
After review, if the subject continues meeting all eligibility criteria, confirm the study eye,
and proceed for the first injection that will be administered as per drug labeling. The injection
order is shown in Figure 1.
•
The following will be performed after the first injection (only on the treated Study Eye):
-
IOP will be measured at 40 (±10) minutes post-injection.
-
If post-injection IOP is ≤ 21 mmHg and there is no concern regarding retinal artery
perfusion, the second injection will be administered.
-
If post-injection IOP is > 21 mmHg after eye massage and/or aqueous tap performed per
investigator discretion, IOP measurement will be repeated at 60 (±10) minutes post-
injection.
-
If post-injection IOP at 60 (±10) minutes is ≤ 21 mmHg and there is no concern regarding 
retinal artery perfusion, the second injection will be administered.
-
If post-injection IOP at 60 (±10) minutes is > 21 mmHg after eye massage and/or
aqueous tap performed per investigator discretion, IOP measurement will be repeated at
90 (±10) minutes post-injection.
-
If post-injection IOP at 90 (±10) minutes is ≤ 21 mmHg and there is no concern regarding 
retinal artery perfusion, the second injection will be administered.
-
If there is an increase of ≥ 10 mmHg at 90 (±10) minutes post- injections compared to
pre-injections IOP, the subject should be prescribed a topical IOP-lowering medication
until he or she returns for follow-up per the Clinical Investigator’s discretion (an 
unscheduled visit may apply).
-
On the other hand, a subject with IOP measurement of > 21 mmHg will be managed
according to the discretion of the Clinical Investigator.
 


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-
In both these cases, the Clinical Investigator has the discretion on whether to have the
subject continue or exit the study.
-
The IOP increase of ≥ 10 mmHg from Baseline AND IOP measurement of > 21 mmHg 
will be reported as an AE.
x
Aqueous tap can be performed at any time per the Clinical Investigator`s discretion for
treatment or prevention of increasing in the IOP.
•
The following assessments must be performed after the second injection (only on the treated
Study Eye):
-
Within 30 minutes post-injection:
9 Slit-lamp biomicroscopy
9 Indirect ophthalmoscopy
-
IOP will be measured at 40 (±10) minutes post-injection.
-
If post-injection IOP is > 21 mmHg after eye massage and/or aqueous tap performed per
investigator discretion, IOP measurement will be repeated at 60 (±10) minutes post-
second injection.
-
If post-injection IOP at 60 (±10) minutes is > 21 mmHg after eye massage and/or
aqueous tap performed per investigator discretion, IOP measurement will be repeated at
90 (±10) minutes post-injection.
-
If there is an increase of ≥ 10 mmHg at 90 (±10) minutes post-injections compared to
Baseline IOP, the subject should be prescribed a topical IOP-lowering medication until he
or she returns for follow-up per the Clinical Investigator’s discretion (an unscheduled 
visit may apply).
-
On the other hand, a subject with IOP measurement of > 21 mmHg will be managed
according to the discretion of the Clinical Investigator.
-
The IOP increase of ≥ 10 mmHg from Baseline AND IOP measurement of > 21 mmHg
will be reported as an AE.
•
Aqueous tap can be performed at any time per the Clinical Investigator`s discretion for
treatment or prevention of increasing in the IOP.
•
AE assessments must be performed after each IVT injection.
 


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Figure 2: Decision IOP Process for Two Injections
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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•
Upload collected images (SD-OCT, Fundus photography, and Fluorescein angiography) of
the study eye to EDC.
•
Schedule the subject to return for Visit 2 (Day 8s1).
Visit 2 (Week 1 (D8±1))
•
Perform the following assessments: (all ophthalmic procedures to be performed on both eyes)
-
Query for AEs
-
Update medical history and medications
-
BCVA (ETDRS)
-
External ocular exam
-
IOP
-
Slit-lamp biomicroscopy
-
Indirect ophthalmoscopy
-
SD-OCT
•
Upload collected images (SD-OCT) of the study eye to EDC.
•
Schedule the subject to return for Visit 3 (Week 4 (D29±4)).
 
Visit 3 (Week 4 (D29±4))
•
Perform the following assessments: (all ophthalmic procedures to be performed on both eyes)
-
Query for AEs
-
Update medical history and medications
-
BCVA (ETDRS)
-
External ocular exam
-
IOP
-
Slit-lamp biomicroscopy
-
Indirect ophthalmoscopy
-
SD-OCT
-
Fundus photography
•
Administer IVT RBM-007 or Sham per drug labeling.
•
The following assessments must be performed after the injection (only on the treated Study
Eye):
 
-
Within 30 minutes post-injection:
9 Slit-lamp biomicroscopy
9 Indirect ophthalmoscopy
-
IOP will be measured at 40 (±10) minutes post-injection.
 
 


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-
If post-injection IOP is > 21 mm Hg after eye massage and/or aqueous tap performed per
investigator discretion, IOP measurement will be repeated at 60 (±10) minutes post-
injection.
-
If post-injection IOP at 60 (±10) minutes is > 21 mmHg after eye massage and/or
aqueous tap performed per investigator discretion, IOP measurement will be repeated at
90 (±10) minutes post-injection.
-
If there is an increase of ≥ 10 mmHg at 90 (±10) minutes post-injections compared to
Baseline IOP, the subject should be prescribed a topical IOP-lowering medication until he
or she returns for follow-up per the Clinical Investigator’s discretion (an unscheduled 
visit may apply).
-
On the other hand, a subject with IOP measurement of > 21 mmHg will be managed
according to the discretion of the Clinical Investigator.
-
The IOP increase of ≥ 10 mmHg from Baseline AND IOP measurement of > 21 mmHg
will be reported as an AE.
•
Aqueous tap can be performed at any time per the Clinical Investigator`s discretion for
treatment or prevention of increasing in the IOP.
AE assessments must be performed after IVT injection.
 
 


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Figure 3: Decision IOP Process for Single Injection
 
 
•
Upload collected images (SD-OCT and Fundus photography) of the study eye to EDC.
•
Schedule the subject to return for Visit 4 (Week 8 (D57±4)).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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Visit 4 (Week 8 (D57±4))
•
Perform the following assessments: (all ophthalmic procedures to be performed on both eyes)
-
Query for AEs
-
Update medical history and medications
-
BCVA (ETDRS)
-
External ocular exam
-
IOP
-
Slit-lamp biomicroscopy
-
Indirect ophthalmoscopy
-
SD-OCT
-
Fundus photography
Injection/ IOP control procedures are same as Visit 1 (Day 1) as described in Section 7.5.2.1
 •
Upload collected images (SD-OCT and Fundus photography) of the study eye to EDC.
•
Schedule the subject to return for Visit 5 (Week 12 (D85±4))
 
Visit 5 (Week 12 (D85±4))
•
Perform the following assessments: (all ophthalmic procedures to be performed on both eyes)
-
Query for AEs
-
Update medical history and medications
-
BCVA (ETDRS)
-
External ocular exam
-
IOP
-
Slit-lamp biomicroscopy
-
Indirect ophthalmoscopy
-
SD-OCT
-
Fundus photography
Injection/ IOP control procedures are same as Visit 3 (Week 4 (D29±4)) as described in 
Section 7.5.2.3
•
Upload collected images (SD-OCT and Fundus photography) of the study eye to EDC.
•
Schedule the subject to return for Visit 6 (Week 16 (D113±7))
 
 
 


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Visit 6 (Week 16 (D113±7))
•
Perform the following assessments: (all ophthalmic procedures to be performed on both eyes)
-
Query for AEs
-
Update medical history and medications
-
BCVA (ETDRS)
-
External ocular exam
-
IOP
-
Slit-lamp biomicroscopy
-
Indirect ophthalmoscopy
-
SD-OCT
-
OCT-angiography (for selected sites)
-
Fundus photography
-
Fluorescein angiography
•
Upload collected images (SD- OCT, Fundus photography and Fluorescein angiography) of
the study eye to EDC.
•
Schedule the subject to return for Visit 7 (Week 20 (D141±7)).
7.5.3
Study Exit
Visit 7/Exit (Week 20 (D141±7))
•
Perform the following assessments:
-
Query for AEs
-
Update medical history and medications
-
Perform urine pregnancy test to the subject who answered “No” to the question on 
postmenopausal at Screening Visit
-
BCVA (ETDRS)
-
External ocular exam
-
IOP
-
Slit-lamp biomicroscopy
-
Indirect ophthalmoscopy
-
SD-OCT
-
Fundus photography
•
Upload collected images (SD-OCT and Fundus photography) of the study eye to EDC.
 
7.5.4
Unscheduled Visits
If a subject requires evaluation between scheduled visits, complete all applicable study specified 
procedures as necessary and record the information on the Unscheduled Visit form(s).
 
 


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SELECTION AND WITHDRAWAL OF SUBJECTS
Eligible subjects must meet all eligibility criteria described in Section 8.1 and Section 8.2.
Subject Inclusion Criteria
At Screening (Day -28 to Day -1) and Visit 1 (Day 1), subjects must meet all of the following 
inclusion criteria:
1.Provide signed written informed consent on the Institutional Review Board (IRB)/Ethics 
Committee (EC) approved Informed Consent Form (ICF) and provide authorization as 
appropriate for local privacy regulations.
2.Male or female 55 years of age or older on the date of signing the ICF and able and willing 
to comply with all treatment and follow-up study procedures.
3.Diagnosis of exudative AMD in the study eye, for which previous standard treatment 
with IVT anti-VEGF agents (at least 4 injections over the past 8 months) has 
demonstrated incomplete resolution of exudation, as assessed by spectral domain 
optical coherence tomography (SD-OCT).
4.Presence of macular edema or subretinal fluid on SD-OCT.
5.Absence of central atrophy or retinal epithelial tear in the fovea or any condition 
preventing VA improvement in the study eye.
6.BCVA of 78 to 24 ETDRS letters (20/32 to 20/320) in the study eye.
7.BCVA of 24 ETDRS letters (20/320) or better in the fellow eye.
8.Reasonably clear media and some fixation in the study eye to allow for good quality SD-
OCT and fundus photography.
Subject Exclusion Criteria
A subject with any of the following conditions is not eligible to participate in the study:
Ocular:
1.Use of any of the following treatments or anticipated use of any of the following treatments 
to the study eye:
a.
Any IVT treatment for AMD within 4 weeks prior to Baseline (Visit 1).
b. Intravitreal or periocular corticosteroid, within 90 days prior to Visit 1 (Day 1) and 
throughout the study.
c.
Fluocinolone acetonide intravitreal implant, within 12 months prior to Visit 1 (Day 
1) and throughout the study.
d. Visudyne® photodynamic therapy, within 90 days prior to Visit 1 (Day 1) and 
throughout the study.
2.Uncontrolled or advanced glaucoma, evidenced by an IOP of > 21 mmHg or cup/disc ratio 
> 0.8 while on medical therapy, or chronic hypotony (< 6 mmHg) in the study eye.
 
 
 
I 


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3.Evidence of any other ocular disease other than wet AMD in the study eye that may confound 
the outcome of the study (e.g., active diabetic retinopathy, posterior uveitis, pseudo 
vitelliform macular degeneration, moderate/severe myopia).
4.History of vitrectomy in the study eye.
5.Need for ocular surgery in the study eye during the course of the study.
6.YAG laser capsulotomy within 30 days prior to Visit 1 (Day 1) in the study eye.
7.Intraocular surgery, including lens removal or laser, within 90 days prior to Visit 1 (Day 1) 
in the study eye.
8.Ocular or periocular infection in either eye.
9.Pupillary dilation inadequate for quality stereoscopic fundus photography in the study eye.
10. Media opacity that would limit clinical visualization, intravenous fluorescein angiography, 
or SD-OCT evaluation in the study eye.
11. History of herpetic infection in the study eye or adnexa.
12. Presence of known active toxoplasmosis, inactive toxoplasmosis or toxoplasmosis scar in 
either eye.
13. Presence of any form of ocular malignancy including choroidal melanoma in either eye.
 
Non-Ocular:
14. Prior systemic treatment with RBM-007 injectable solution.
15. Use of any of the following treatments or anticipated use of any of the following treatments 
during the study:
a.
Systemic treatment with anti-VEGF agents (e.g., bevacizumab)
b. Agents targeting the FGF-2 pathway
16. Allergy or hypersensitivity to study drug product, fluorescein dye, or other study related 
procedures/medications.
17. Major surgery within 90 days prior to Visit 1 (Day 1). Major surgery is defined as any 
surgery involving a risk to the life of the subject, including any operation upon an organ 
within the cranium, chest, abdomen, or pelvic cavity.
18. Therapeutic radiation to the head or neck within 90 days prior to Visit 1 (Day 1).
19. Participation in other investigational drug or device clinical trials within 30 days prior to 
Visit 1 (Day 1) or planning to participate in other investigational drug or device clinical 
trials for the duration of the study. This includes both ocular and non-ocular clinical trials.
20. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease condition that contraindicates 
the use of an investigational drug, might affect the interpretation of the results of the study, 
or renders the subject at high risk for treatment complications.


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21. Females who are pregnant or lactating and females of child-bearing potential who are not 
using adequate contraceptive precautions (i.e., IUD, oral contraceptives, barrier method, 
or other contraception deemed adequate by the Clinical Investigator).
22. Unable to comply with study procedures or follow-up visits.
In addition, the Clinical Investigator or RIBOMIC Medical Monitor may declare a subject 
ineligible for any sound reason.
 
Subject Withdrawal Criteria
An early termination occurs when a subject who provides written informed consent ceases 
participation in the study, regardless of circumstances, before the completion of the study. Subjects 
may voluntarily withdraw from the study at any time for any reason. In addition, the Clinical 
Investigator or the Medical Monitor may terminate a subject’s study participation for reasons 
related to the best interest of the subject. Subjects who terminate from the study may be replaced. 
Subjects may be terminated from the study due to any of the following reasons:
•
Non-compliance
•
Lost to follow-up
•
Protocol violation
•
Withdrawal by subject
•
AEs
•
Death
•
Other
If a subject is discontinued from the study before completing Visit 7/Exit (Week 20 (D141±7)),
then to the extent possible, all assessments, including safety, that are scheduled to be performed at 
Visit 7/Exit should be performed on the day of discontinuation.
 


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TREATMENT OF SUBJECTS
Description of Study Drug
RBM-007 is a pegylated oligonucleotide-based aptamer. RBM-007 injectable solution is a 
formulation designed for intravitreal injection. RBM-007 has an approximate molecular weight of 
54kDa. 
Concomitant Medications
The use of any concomitant prescription or over-the-counter medication will be recorded during 
the study. Therapy considered necessary for the subject’s welfare may be given at the discretion 
of the Clinical Investigator during the study. Whenever possible, concomitant medications should 
be administered in dosages that remain constant throughout the study. The generic name, 
indication, route of administration, frequency, dose, start date and stop date (if applicable) will be 
recorded for each medication.
9.2.1
Prohibited Medications or Treatments
Any treatments for wet AMD in the study eye other than RBM-007 and Eylea® are prohibited 
during the study.
Any systemic treatments with anti-VEGF agents (e.g., bevacizumab) are prohibited during the 
study.
The decision to administer a prohibited concomitant medication or treatment during the study 
should be made with the safety of the subject as the primary consideration. Whenever possible, 
RIBOMIC should be notified before any prohibited medication or treatment is administered or if 
the permissibility of a specific medication or treatment is in question
9.2.2
Rescue Therapy
Rescue therapy is defined as IVT injection of Eylea® or other treatment at the discretion of 
investigator in the study eye. The rescue should be considered anytime during the study except 
for those visits with Eylea® injection as per protocol. Assessing Physician should determine the 
need for Rescue and refer the subject to the Injecting Physician to decide about what to use for 
Rescue. 
Eligibility criteria for Rescue are as follow:
x
BCVA decrease of > 10 letters AND central subfield thickness (CST) increase of > 50 μm
from the last visit.
x
The discretion of investigator.
If rescue is performed, the following assessments must be performed after the administration of 
Rescue treatment: (all ophthalmic procedures to be performed in the treated eye)
- Within 30 minutes following Rescue treatment
o
Slit-lamp biomicroscopy
o
Indirect ophthalmoscopy
 
 
 


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- IOP: 40 (±10) minutes following Rescue treatment 
Treatment Compliance
In order to obtain efficacy and safety data, it is critical that the treatment regimen and visit schedule 
specified in this protocol are followed. The Clinical Investigator is required to administer the 
RBM-007 injection and Eylea® and is responsible for scheduling the subject for follow-up visits 
as specified in the protocol. Study monitors will verify pertinent data to confirm the study is 
conducted according to the protocol.
Randomization and Masking
Two arms in the study will have Sham injection which is a mimic procedure of a real intravitreal 
injection but does not penetrate the eye. To keep masking of the clinical trial, investigator and 
authorized study staffs must follow the points below.
•
The designated injecting physician and the designated injection staff must ensure any
information regarding clinical study drugs injection during the study is inaccessible to other
study staff.
•
The designated injecting physician and the designated injection staff cannot perform any
assessments, examinations, or procedures for the study other than clinical study drug
injection procedures and examinations post drug injections.
•
Study staff not designated to study drug injections, including investigators, examiner and
other clinical site staff, cannot participate in any procedures for clinical study drug injections
and examinations post drug injections.
In case of a medical emergency, the Principal Investigator or site staff may reveal the treatment 
information by unmasking to know which treatment the subject has received. The Principal 
Investigator should contact RIBOMIC, or RIBOMIC’s designee, before taking this measure, if 
there is sufficient time. RIBOMIC, or RIBOMIC’s designee, must be informed of all instances 
where the code is broken and of the reasons for such instances.
Additionally, the adverse event or serious adverse event for which study treatment was unmasked 
should be reported to RIBOMIC (see Section 12.1).
 
 




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Once an investigational drug vial number has been assigned to the subject, the vial of 
investigational drug with the assigned vial number will be removed from the freezer. The contents 
should be thawed by rotating the vials between the palms of the hands, or by setting the vial at 
room temperature. Care should be taken to protect the product from light. 
Investigational drug should be used for intravitreal injection in the study subject within 1 hour 
after removing the vial from the freezer.
Study drug preparation should be performed by the designated injecting physician.
Each vial contains enough RBM-007 to inject one subject. Each vial will be used one time only. 
Write the subject number on the carton label. After use, return the vial in the carton, seal and initial 
the carton.
<Investigational drug: Sham>
The study drug preparation for Sham injection is same as RBM-007.
Loading the Syringe
<Concomitant drug: Eylea®>
Eylea® administration to be done as per Eylea® drug labeling.
<Investigational drug: RBM-007>
1.A sterile, single-use 250 μL syringe with several custom marking including 0.1 mL (100 μL) 
will be provided separately for IVT injection of RBM-007. Instructions for filling the 
syringe are as follows:
2.Remove the sterile, single-use 250 μL syringe from the packaging.
3.Attach a 19-gauge x 1 ½ inch filter needle to the syringe. RBM-007 is dispensed in a 0.5 ml 
fill in a 2 mL vial. See Figure 4.
4.Using sterile technique, carefully draw up approximately 200 μL of RBM-007 into the 
syringe. (Sufficiently larger volume than 100 μL is needed to allow for dead space in 
syringe and needles prior to IVT injection).
5.Remove the 19-gauge x 1½ inch filter needle from the syringe and replace with a 30-gauge 
x 0.5 inch needle for the IVT injection.
A. Ensure that the 30-gauge x 0.5 inch needle is affixed tightly to the syringe.
B. Align the top edge of the red O-ring of the plunger with the 100 μL black mark on the 
syringe, expelling the excess fluid drawn up.
C. Ensure there are no air bubbles within the syringe or the needle hub prior to injection, 
and prior to expelling the excess fluid drawn up.
 


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Figure 4: 0.5 mL fill in a 2 mL vial
 
<Investigational drug: Sham>
Loading syringe procedure for Sham injection is similar to RBM-007; no drug product will be 
drawn up into the syringe.
Eye Preparation
< Concomitant drug: Eylea®>
Eye preparation for Eylea® administration to be done as per Eylea® drug labeling.
<Investigational drug: RBM-007>
Prior to RBM-007 administration, the study eye should be prepared as follows:
1.Dilate pupil (1 % mydriacyl and 2.5 % phenylephrine or equivalent applied topically) 
approximately 10 minutes prior to injection.
2.Administer 1 eye drop of topical anesthetic (0.5 % proparacaine hydrochloride ophthalmic 
solution or an equivalent topical ophthalmic anesthetic).
3.Administer 10 % povidone iodine.
4.Use a sterile cotton-tipped applicator to remove excess fluid from the lower conjunctival sac.
5.Take 2 sterile cotton tipped applicators and thoroughly soak with 0.5 % proparacaine topical 
anesthetic eye drops or an equivalent topical ophthalmic anesthetic. Place the soaked 
applicators, side by side, gently but firmly on the conjunctival surface at the area of the 
entry site described below in Step 2 (Section 10.7) and hold in place for approximately 1 
minute.
6.Insert sterile eyelid speculum.
<Investigational drug: Sham>
Eye preparation for Sham injection is the same as RBM-007.
Study Drug Administration
<Concomitant drug: Eylea®>
Eylea® administration to be done as per Eylea® drug labeling.
 
 


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<Investigational drug: RBM-007>
1. Prior to starting the injection procedure, RBM-007 should have been prepared as described in
Section 10.4 and Section 10.5, and the study eye should have been prepared as described in
Section 10.6.
2. The entry site for injection is 4.0 mm posterior to the corneal limbus. A caliper may be used
to identify the needle entry site.
3. Insert the needle perpendicular to the eye wall at the location specified in Step 2 (Section
10.7) to inject the study solution into the vitreous cavity. Note: If aqueous tap is considered
necessary, it should be performed preferably prior to injection of the RBM-007 and noted in
the source documents.
4. Very slowly, inject the entire RBM-007 dose volume (100 μL) and slowly withdraw the
needle. Do not pull back on the plunger at any time prior to withdrawing the needle.
5. Briefly apply pressure for approximately 30 seconds to the needle entry site with sterile
cotton tipped applicator (may be skipped per Clinical Investigator's discretion).
6. Remove the eyelid speculum and rinse the eye with sterile eye wash solution.
7. Patch the study eye at the Clinical Investigator's discretion.
8. Prescribe topical antibiotic per PI discretion.
<Investigational drug: Sham>
Sham is injection that simulates RBM-007/Eylea® drug administration. Sham intravitreal 
injections will be administered to subjects according to the same dosing schedule and procedure 
as RBM-007/ Eylea® injections. However the Sham intravitreal injection procedure will only 
mimic RBM-007/Eylea® intravitreal injection in that the blunt end of an empty syringe is pressed 
against an anesthetized eye, instead of a needle attached to RBM-007/Eylea® syringe injected into 
the anesthetized eye. Therefore Step 3 and 4 of RBM-007 (Section 10.7) and corresponding steps 
of Eylea® administration procedure will be skipped for the Sham injection.
To keep masking of the study, investigator and authorized staff must follow the points described 
in Section 9.4.
Study Drug Accountability
The Principal Investigator is responsible for ensuring that an inventory is conducted upon receipt 
of the clinical supplies. The temperature recorder from the shipment will be deactivated and 
authorized study staff will verify that the temperature was maintained at -20°C during transit. The 
clinical supplies shipment form should be completed, signed, and returned as directed. A copy 
must be maintained at the site for the Principal Investigator's records.
The Principal Investigator will keep a current record of the inventory, storage conditions and 
dispensing of all study drugs. This record will be made available to RIBOMIC (or designee) for 
accounting for all clinical supplies. Any significant discrepancy and/or deficiency must be 
recorded with an explanation.
All supplies sent to the Principal Investigator must be accounted for and in no case will study drugs 
be used in any unauthorized situation. It is the responsibility of the Principal Investigator to ensure 
that any used and unused supplies are available to RIBOMIC (or designee) throughout the study.
 
 
 


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Study Drug Handling and Return
All investigational products including unused vials of RBM-007 will be fully accounted for by the 
monitor with the help of the unmasked person responsible for dispensing the RBM-007 and will 
be returned to RIBOMIC/Representative or designee. Accountability will be documented by use 
of drug accountability forms. 
The used vials of RBM-007/ Eylea® will be stored at the investigational site upon completion of 
accountability procedures and returned to RIBOMIC or designee after the trial is completed.
Refer to Study Drug Manual for study drug handling.
 


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ASSESSMENT OF EFFICACY
Best Corrected Visual Acuity (BCVA)
Mean change in BCVA from Baseline at Week 16 is the primary efficacy variable for this study, 
Proportion of subjects with BCVA: 1) gain of ≥15 ETDRS letters (3-line gainers); 2) gain of ≥10 
ETDRS letters; 3 )  gain of ≥5 ETDRS letters and 4) ≥ 15 letter loss from Baseline at Week 16 are 
other secondary endpoints.
The visual acuity will be recorded using the ETDRS chart and total number of letters at 4 meter 
and 1 meter will be recorded. If a subject could not read ETDRS chart, Finger Counts, Hand 
Motion, Light Perception, or No Light Perception will be recorded.
Central Subfield Thickness (CST), Macular Volume (MV), Fibrosis and SHRM
CST, MV, fibrosis and SHRM are secondary efficacy variables, and change in CST, MV, fibrosis 
and SHRM from Baseline at Week 16 are secondary endpoints. 
 
 
 


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ASSESSMENT OF SAFETY
Adverse Events
12.1.1 Definition of Adverse Events
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with the study drug(s). An AE, therefore, 
can be an unintended sign (including an abnormal laboratory finding), symptom, or disease that 
has clinical significance and is temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product.
In clinical studies, an undesirable medical condition occurring at any time, including Baseline or 
pre-treatment period, may be recorded as an AE even if no study drug has been administered.
Any significant adverse change in a subject’s condition from Baseline, regardless of causality, is 
to be considered an AE, unless the change is determined to be a continuation of a pre-existing 
condition that is documented in the subject’s medical history. However, a clinically significant 
worsening in severity, intensity, or frequency of a pre-existing condition may indicate an AE. In 
addition, all conditions that lead to hospitalizations, defined as an overnight hospital stay, are 
considered as AEs. This includes planned elective surgeries.
Lack of efficacy of the study drug(s) for the condition being investigated is not considered an AE 
unless a clinically significant change is assessed by the Clinical Investigator.  An elective surgical 
procedure scheduled or planned prior to study entry is not considered an AE if an overnight 
hospital stay is not required, and the underlying diagnosis for which surgery is to be performed 
should be captured in the medical history as a pre-existing condition. The surgical procedure 
should also include the term “elective” in all reports.
Assessment of Adverse Events
Clinical Investigators will seek information on AEs at each subject contact. Subjects should be 
asked, using a general, non-direct question, if there has been any change in their general health. 
Direct questioning and examination should then be performed as appropriate.
Severity of the AE should be assessed according to the following criteria:
•
Mild: No interference with the subject’s daily activities; no medical intervention/therapy
required
•
Moderate: Possible interference with the subject’s daily activities; no or minimal medical
intervention/therapy required
•
Severe: Considerable interference with the subject’s daily activities; medical 
intervention/therapy required
Regardless of severity, some AEs may also meet regulatory serious criteria. Refer to definitions 
and reporting of serious adverse events (SAEs) in Section 12.1.2.
A Clinical Investigator who is qualified in medicine must make the determination of the 
relationship of the study drug(s) to each AE (related or not related). The Clinical Investigator 
should decide whether, in his or her medical judgment, there is a reasonable possibility that the 
 
 
  
 


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RBM-007, Eylea® or the Sham injection could have caused the AE/SAE based on facts, evidence, 
scientific rationales, and clinical judgment. When assessing causality, the Clinical Investigator 
may consider the following information when determining the relationship to the study drug(s) for 
each AE: mechanism of action, biologic plausibility, confounding risk factors (i.e., medical history, 
concomitant medications), temporal relationship, dechallenge/rechallenge, and lack of alternative 
explanation. It should be specified if the AE is related to the injection procedure and not the study 
drug.
x
The AE may be recorded as Related to the study drug(s) if there is a plausible temporal 
relationship between the onset of the AE and administration of the study drug(s), and the AE 
cannot be readily explained by the subject’s clinical state, concurrent illness, or concomitant 
therapies; and/or the AE follows a known pattern of response to the study drug(s),; and/or 
the AE abates or resolves upon discontinuation of the study drug(s),.
x
Reporting the AE as Not Related to study drug(s), may be considered if, for example, there 
is good evidence that the AE has an etiology other than the study drug(s) (e.g., pre-existing 
medical condition, underlying disease, concurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to administration of the study drug(s) 
(e.g., cancer diagnosed 2 days after dose of study drug(s)).
Reporting Adverse Events
AEs, whether spontaneously reported by the subject or noted by authorized study personnel, will 
be recorded in the subject’s medical record and on the appropriate AE eCRF. Each recorded AE 
will be described by its duration (i.e., start and end dates), frequency, severity, regulatory 
seriousness criteria if applicable, suspected relationship to the study drug(s), relation to injection 
procedure, location, actions taken and outcome.
AEs that occur after any subject has provided written informed consent, before treatment, during 
treatment, or within 30 days following the cessation of treatment, whether or not they are related 
to the study, must be recorded. To improve the quality and precision of acquired AE data, Clinical 
Investigators should observe the following guidelines:
x
Whenever possible, use recognized medical terms when recording. Do not use 
colloquialisms and/or abbreviations.
x
If known, record the diagnosis (i.e., disease or syndrome) rather than component signs and 
symptoms and /or laboratory or test findings (e.g., record congestive heart failure rather than 
dyspnea, rales, and cyanosis, and enlarged heart on chest x-ray). However, other events that 
are considered unrelated to an encountered syndrome or disease should be recorded as 
individual AEs (e.g., if congestive heart failure and severe headache are observed at the same 
time and are clinically unrelated, each event should be recorded as an individual AE).
x
If the diagnosis is not known, then record the leading component sign, symptom or test 
finding and describe the other clinically related findings in the narrative description of the 
case. A suspected diagnosis can be used and described as such
x
(e.g., record suspected or probable myocardial infarction); this has to be updated in the 
clinical database once the diagnosis is confirmed.
 


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x
AEs occurring secondary to other events (e.g., sequelae) should be identified by the primary 
cause. A primary AE, if clearly identifiable, generally represents the most accurate clinical 
term. If a primary AE is recorded, events occurring secondary to the primary event should 
be described in the narrative description of the case. For example:
x
The subject developed orthostatic hypotension and subsequently fainted and fell to the floor 
wherein she experienced a head trauma and neck pain.
x
The primary AE in this example is orthostatic hypotension. The fall, head trauma and neck 
pain should be described in the narrative description of the case.
x
For intermittent events (e.g., intermittent headache), the event onset date should be recorded 
as the date the subject first started to experience the event and resolution date should reflect 
when the last occurrence resolved or stopped. Separate AEs for each event should not be 
recorded. For example, if a subject experienced headache on 14SEP2015 lasting for three 
hours, then subsequently experienced intermittent episodes of headache every day for 
approximately 3 hours until 21SEP2015, then the AE date of onset is 14SEP2015 and the 
resolution date is 21SEP2015.
x
For intermittent events, record the maximum severity of the individual events. For example, 
if a subject complains of intermittent headaches for one week and the severity of each 
headache ranges from mild to moderate, then the severity would be moderate.
x
For intermittent hospitalizations occurring for a primary AE (e.g., in a subject with multiple 
sclerosis, commonly known for its relapsing and remitting course, in some cases leading to 
multiple hospital confinements), the subsequent hospitalizations should be described in the 
narrative description of the case.
x
If treatment was initiated, include the treatment and duration of the medication(s) in the 
eCRF.
12.1.2 Serious Adverse Events
SAEs are defined as any findings that suggest a significant hazard, contraindication, side effect, or 
precaution. Any adverse event is considered a serious adverse event if it results in any of the 
following outcomes:
x
Death
x
Life threatening:
A life-threatening event is any event that places the subject at immediate risk of 
death from the event as it occurred; it does not refer to an event that hypothetically 
might have caused death if it were more severe.
x
Hospitalization, at the minimum an overnight stay
x
A persistent or significant disability/incapacity
x
A congenital anomaly/birth defect
x
Other medically significant events:


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Other medically significant events are events that may not result in death, be life- 
threatening, or require hospitalization but may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
x
Sight threatening event:
A sight-threatening event is any event that places the subject at immediate risk of 
permanently losing vision in either eye as a direct result of the event. It is defined 
as a loss of ≥ 30 letters or 6 lines of vision from Baseline.
Reporting Serious Adverse Events
A SAE eCRF must be completed with as much information available within 24 hours of knowledge 
of the event.
To improve the quality and precision of acquired SAE data, Clinical Investigators should observe 
the following guidelines:
x
Death - Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported as a SAE.
x
Hospitalizations for Surgical or Diagnostic Procedures - The illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure itself. The 
procedure should be captured in the case narrative as part of the action taken in response to 
the illness.
When new significant information (including the outcome of the event) is obtained, the Clinical 
Investigator should enter the information directly into the eCRF within 24 hours or as soon as 
possible after knowledge of the information.
Depending on the nature and seriousness of the AE, RIBOMIC may request additional 
documentation, for example, copies of the ophthalmic and medical record of the subject as well as 
results of laboratory tests. If the subject was hospitalized, the site should summarize the hospital 
discharge summary and provide to RIBOMIC upon request.
Expedited Reporting of Serious Adverse Events
RIBOMIC (or designee) will provide the Principal Investigator with a reporting cover letter and 
an anonymized MedWatch 3500A or CIOMs form as appropriate for expedited reporting of SAEs 
to the IRB or IEC. The Principal Investigator is responsible for receiving and reviewing expedited 
safety reports, submitting expedited safety reports to the IRB or IEC, and maintaining copies of 
expedited safety reports in the study records.
12.1.3 Events of Special Interest
Events of Special Interest (ESIs) are events that may require special attention for the purposes of 
on-going patient safety review during this study. The following are considered ESIs and should be 
reported on the appropriate eCRF with as much information as available within 24 hours of 
knowledge of the event:
  
 
 




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12.2.2 Vital Signs
Blood pressure and heart rate will be measured using an automated or manual blood pressure 
monitor. Systolic and diastolic blood pressures will be recorded in millimeters of mercury 
(mmHg), and heart rate will be recorded in beats per minute (bpm).
12.2.3 Best Corrected Visual Acuity
The BCVA will be recorded using the ETDRS chart and total number of letters at 4 meters and 1 
meter will be recorded. If a subject could not read ETDRS chart, Finger Counts, Hand Motion, 
Light Perception, or No Light Perception will be recorded.
12.2.4 External ocular exam
The Clinical Investigator will assess external ocular examination evaluating lid and lashes.
12.2.5 Slit-lamp Biomicroscopy
The Clinical Investigator will assess Slit-lamp biomicroscopy examination using Slit-lamp 
microscope. On the visit of any IVT treatment, a biomicroscopy examination will be performed 
prior to the first injection and a second one within 30 minutes after the second injection. This will 
be also applied for the post IVT injection of Rescue treatment.
12.2.6 Intraocular Pressure
IOP will be measured in each visit as described in Section 7.5.2.
The IOP for the post IVT injection of Rescue treatment will be measured as described in Section 
21.4.8.
12.2.7 Indirect Ophthalmoscopy
The Clinical Investigator will assess indirect ophthalmoscopy using indirect ophthalmoscope. On 
the visit of any IVT treatment, an ophthalmoscopy examination will be performed prior to the first 
injection and a second one within 30 minutes after the second injection. This will be also applied 
for the post IVT injection of Rescue treatment.
12.2.8 Urine Pregnancy Test
A urine pregnancy test will be conducted for all females of childbearing potential.
12.2.9 Fundus Photography
Digital color fundus photography will be taken following the procedure provided by the sponsor. 
It will be performed prior to any intravitreal injections.
12.2.10 Fluorescein Angiography
Fundus fluorescein angiography will be taken on visit 1 (Day 1) and visit 6 (Week 16), following 
the procedure provided by the sponsor.


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12.2.11 Spectral Domain Optical Coherence Tomography (SD-OCT)
SD-OCT images will be taken following the procedure provided by the sponsor. It will be 
performed prior to any intravitreal injections.
12.2.12 Adverse Events
AEs will be elicited from the subjects starting at the Screening through study exit. The information 
will include at least a description of the event, whether or not it is serious, onset and duration, 
frequency, severity, relation to masked study therapy, relation to injection procedure, location (OD, 
OS, OU or NA), action taken and outcome. Prior to evaluating the incidences, all AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA, 2013).
Ocular and non-ocular AEs will be summarized separately. See Section 12.1 for complete 
information regarding AE reporting.


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OTHER ASSESSMENTS
Demographics and Baseline Characteristics
Subject demographics include age, race, sex, and ethnicity. Baseline characteristics include 
medical history, prior medications, and Baseline results of physical examination, vital signs, 
BCVA, slit-lamp biomicroscopy, IOP, indirect ophthalmoscopy, SD-OCT, urine pregnancy test, 
fundus photography, and fluorescein angiography. For assessments performed multiple times 
before the IVT injection of RBM-007, the last pre-injection value will be used as the Baseline 
value.
OCT Angiography
For future exploratory research, OCT angiography will be taken at selected sites on Visit 1 
(Day 1) and Visit 6 (Week 16) in subjects showing SHRM on the screening SD-OCT.
STATISTICAL METHODS
Analysis Time Points
One primary analysis (Week 16) and follow-up analysis (Week 20) will be performed.
14.1.1 Primary Analysis
Descriptive summaries of the following efficacy and safety measures will be provided by treatment 
arms at the Week 16:
•
Mean change in BCVA from Baseline
•
Proportion of subjects with BCVA: 1) gain of ≥15 ETDRS letters (3-line gainers); 2) gain
of ≥10 ETDRS letters; 3 ) gain of ≥5 ETDRS letters and 4) ≥ 15 letter loss from Baseline
at Week 16 are other secondary endpoints.
•
Change from Baseline in CST, and macular volume by SD-OCT
•
Change from Baseline in characteristics of SHRM
•
Change from Baseline in characteristics of fibrosis
•
Proportion of subjects that do not require anti-VEGF treatment during follow-up period
•
Mean numbers of rescue injections in the monotherapy arm
•
Proportion of subjects requiring rescue
•
Safety assessment include AEs, physical examination, vital signs, external ocular exam,
BCVA, IOP, slit lamp biomicroscopy, indirect ophthalmoscopy, SD-OCT, fundus
photography, fluorescein angiography and pregnancy.
•
Additional variables of interest will also be provided.
 
 
 
 
 


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General Considerations
All study parameters will be listed and a selected list of parameters will be summarized 
descriptively. The descriptive statistics will include number of observations (n), mean, standard 
deviation, minimum, and maximum for continuous parameter and frequency (n) and percent (%) 
for categorical parameters.
Details about the statistical analyses for this study will be provided in the statistical analysis plan 
(SAP).
All data manipulations and descriptive summaries will be implemented using SAS®, Version 9.1.3 
or later.
14.2.1 Sample Size
Approximately 81 subjects (Arm 1: 27, Arm 2: 27, and Arm 3: 27) with wet AMD will be enrolled 
at approximately 15 sites. The final number of subjects enrolled may be adjusted based on the 
judgments from Safety Review Team. 
14.2.2 Statistical Hypotheses and Level of Significance
No statistical hypothesis is defined for this study.
14.2.3 Randomization
All subjects will be randomized to a 1:1:1 ratio. 
14.2.4 Study Eye
The study eye must meet all inclusion and exclusion criteria. If both eyes are eligible based on 
inclusion and exclusion criteria, the study eye is defined as the eye with worse vision. If both eyes 
have the same vision, the right eye (OD) should be determined as the study eye.
Study Populations
The following study populations are defined for analysis: Intention-to-treat (ITT) and Safety.
x
ITT Population: The ITT population will include all randomized subjects in the study.
x
Safety Population: The Safety population will include all randomized subjects who 
received at least one study medication. It will be the study population for safety analyses.
x
Full Analysis Set: The Full Analysis Set (FAS) will include all randomized subjects who 
received at least one study medication and provided at least one post-Baseline BCVA 
measurement. The efficacy analysis will be performed on the FAS or a subset of the FAS.
x
Per-Protocol Population: The Per-Protocol (PP) Population is a subset of the FAS. It 
includes all FAS subjects without major protocol violations that could affect the primary 
efficacy endpoint.
Handling of Missing Values
For safety measures, missing scores will not be imputed for data summaries.
 
 
 


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Completely or partially missing onset and resolution dates for AEs and completely or partially 
missing start and end dates of concomitant medications will be imputed in a conservative fashion 
that will be detailed in the SAP.
For efficacy endpoints, missing post-injection values will be imputed using the last-observation- 
carried-forward (LOCF) approach.
Demographics and Baseline Characteristics
Age, sex, race, ethnicity, and Baseline assessments will be summarized descriptively by treatment 
arms.
Subjects with abnormal medical history will be tabulated by treatment arm and body system.
Subjects using any prior medications will be tabulated by treatment arms, Anatomical Therapeutic 
Chemical levels, and preferred term specified in the World Health Organization Drug Dictionary 
Enhanced (World Health Organization Drug Dictionary, 2011).
Efficacy Analyses
14.6.1 Analysis of Primary Efficacy Endpoints
•
Mean change in BCVA from Baseline at Week 16 will be analyzed using descriptive
statistics. Observed BCVA in the study eye will be presented descriptively and graphically
by study visit.
The primary analysis will be based on the FAS and repeat analysis will be performed on the PP 
Population.
14.6.2 Analysis of Secondary Efficacy Endpoints
The following will be analyzed at Week 16:
•
Proportion of subjects with BCVA: 1) gain of ≥15 ETDRS letters (3-line gainers); 2) gain of
≥10 ETDRS letters; 3 ) gain of ≥5 ETDRS letters and 4) ≥ 15 letter loss from Baseline
•
Change from Baseline in CST, and macular volume by SD-OCT
•
Change from Baseline in characteristics of SHRM
•
Change from Baseline in characteristics of fibrosis
•
Proportion of subjects that do not require anti-VEGF treatment during follow-up period
•
Mean numbers of rescue injections in the monotherapy arm
•
Proportion of subjects requiring rescue
Safety Analysis
All safety outcome measures will be summarized descriptively for the Safety Population. The 
safety outcome measures include adverse events (AEs), external ocular exam, BCVA, slit-lamp 
biomicroscopy, indirect ophthalmoscopy, intraocular pressure (IOP), vital signs, pregnancy, 
physical examination, fundus photography, fluorescein angiography, and SD-OCT.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).
 
 
 


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Subjects with any AEs will be tabulated by system organ classification and preferred term specified 
in the MedDRA. Similarly, subjects with any ocular and non-ocular AEs and ESIs will be tabulated 
separately. AEs, ocular and non-ocular, as well as ESIs will also be summarized by relationship to 
treatment and maximum severity. In addition, SAEs and discontinuations due to AEs will be 
summarized.
Ocular safety outcome measures will be summarized using descriptive statistics.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The Principal Investigator will allow representatives of RIBOMIC’s monitoring team (or 
designee), the governing institutional review board (IRB), the FDA, and other applicable 
regulatory agencies to inspect all study records, eCRFs, recruitment materials and corresponding 
portions of the subject’s medical records at regular intervals throughout the study. These 
inspections are for the purpose of verifying adherence to the protocol, completeness, and exactness 
of the data being entered onto the eCRF, and compliance with the FDA or other regulatory agency 
regulations.
Study Monitoring
Before an investigational site can enter a subject into the study, RIBOMIC or a representative of 
RIBOMIC (or designee) will evaluate the investigational study site to:
•
Determine the adequacy of the study facilities.
•
Review with the Principal Investigator(s) and authorized study staff their responsibilities
with regard to protocol procedures adherence, and the responsibilities of RIBOMIC (or
designee).
During the study, RIBOMIC (or designee) will have regular contact with the investigational site, 
for the following:
•
Provide information and support to the Principal Investigator(s).
•
Confirm that facilities remain acceptable.
•
Assess adherence to the protocol and Good Clinical Practice (GCP).
•
Perform investigational product accountability checks and quality control procedures.
•
Ensure the on-going implementation of accurate data entry in the eCRF.
•
Perform source data verification, including a comparison of the data in the eCRFs with the
subject’s medical records and other records relevant to the study. This will require direct
access to all original records for each subject (e.g., clinic charts).
•
Record and report any protocol deviations not previously sent to RIBOMIC.
•
Confirm AEs and SAEs have been properly documented on eCRFs and confirm any SAEs
have been forwarded to RIBOMIC and those SAEs that met criteria for reporting have been
forwarded to the IRB or IEC.
RIBOMIC (or designee) may remotely access the eCRFs at any time during the study for 
centralized monitoring. RIBOMIC (or designee) will be available between visits if authorized 
study staff needs study related information or support.
 
 


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Audits and Inspections
The Principal Investigator will allow RIBOMIC (or designee), the governing IRB or IEC, and 
applicable regulatory agencies to audit and inspect any aspect of the study, including all study 
records, eCRFs, recruitment materials, and corresponding portions of the subject’s charts and 
medical records at any time during the study. These study records must be retained at the study 
site and made available for audits and inspections. The purpose of these audits and inspections is 
to verify adherence to the protocol, completeness and accuracy of the eCRF data, and compliance 
with Good Clinical Practice (GCP) guidelines and applicable regulatory requirements.
The Principal Investigator or authorized study staff will notify RIBOMIC (or designee) should the 
site be audited or inspected by the governing IRB or IEC, and applicable regulatory agencies. 
RIBOMIC (or designee) will also notify the investigational site of any known pending site audits 
or inspections planned by RIBOMIC (or designee), governing IRB or IEC and regulatory agencies.
Institutional Review Board
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the subject consent form and 
recruitment materials must be maintained by the Principal Investigator and made available for 
inspection.
QUALITY CONTROL AND QUALITY ASSURANCE
Quality Control
RIBOMIC (or designee) will provide instructional material to the study sites, as appropriate; 
including but not limited to instruction on the protocol, the completion of eCRFs, and study 
procedures. RIBOMIC (or designee) will communicate regularly with site personnel via mail, 
email, telephone, and/or fax; and make periodic visits to the study site. During those visits, 
RIBOMIC (or designee) will perform source data verification with the subject’s medical records 
and other records relevant to the study. Upon receiving the eCRFs, RIBOMIC (or designee) will 
review and evaluate eCRF data and use standard system edits and may use centralized monitoring 
to detect errors in data collection.
Quality Assurance
RIBOMIC (or designee) may conduct a quality assurance audit at any time.
 
 
 
 
 


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ETHICS
Ethics Review
The final study protocol and the final version of the ICF, and other study related material, as 
appropriate, must be approved or given a favorable opinion in writing by an IRB or IEC as 
appropriate. The Principal Investigator must submit written approval to RIBOMIC (or designee) 
before study initiation. See Section 21.1 Appendix A for a list of obligations of Investigators.
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local regulations and guidelines. In addition, the IRB or IEC must 
approve all advertising used to recruit subjects for the study. The protocol must be re-approved by 
the IRB or IEC upon receipt of amendments and at least annually.
The Principal Investigator is also responsible for providing the IRB or IEC with progress reports 
and notifications of any reportable serious adverse drug reactions from the investigational product.
Ethical Conduct of the Study
This study will be conducted in compliance with IRB or IEC, and regulatory requirements. This 
study will also be conducted in compliance with the protocol, GCP guidelines, International 
Conference on Harmonization (ICH) guidelines, the Declaration of Helsinki.
Written Informed Consent
The Principal Investigator at each center will ensure that the subject is given full and adequate oral 
and written information about the nature, purpose, possible risk and possible benefit of the study. 
Subjects must also be notified that they are free to withdraw from the study at any time. Subjects 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. Before participating in any study-related activity, voluntary informed consent must be 
documented by the use of a written ICF approved by the IRB or IEC and signed and dated by the 
subject or the subject’s legally authorized representative at the time of consent. The original signed 
and dated ICF will be retained with the study records, and a copy of the signed ICF will be given 
to the subject or the subject’s legally authorized representative.
 
  
 
 


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DATA HANDLING AND RECORDKEEPING
Inspection of Records
The Principal Investigator will allow RIBOMIC (or designee), the governing IRB or IEC and 
applicable regulatory agencies to inspect any aspect of the study, including all study records, 
eCRFs, recruitment materials and corresponding portions of the subject’s charts and medical 
records at any time during the study. The purpose of these inspections is to verify adherence to the 
protocol, completeness and accuracy of the eCRF data, and compliance with GCP guidelines and 
applicable regulatory requirements.
Retention of Records
All records relating to the conduct of this study are to be retained by the Principal Investigator 
until notified by RIBOMIC (or designee) that the records may be destroyed.
18.2.1 Source Documents
The Principal Investigator must maintain detailed source documents on all study subjects who 
provide informed consent. Source documents include subject medical records, hospital charts, 
study files, as well as the results of diagnostic tests (e.g., laboratory tests).
The following minimum information should be entered into the subject’s medical record:
•
The date the subject was enrolled and the subject number
•
The study protocol number and the name of RIBOMIC USA Inc.
•
The date that informed consent was obtained
•
Evidence that the subject meets study eligibility requirements (e.g., medical history, study
procedures and/or evaluations)
•
The dates of all study-related subject visits
•
Evidence that required procedures and/or evaluations were completed
•
Use of any concomitant medications
•
Documentation of study drug accountability
•
Occurrence and status of any AEs
•
The date the subject exited the study and a notation as to whether the subject completed or
terminated early from the study, including the reason for early termination
 
 
 


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18.2.2 Data Collection
The Principal Investigator must maintain detailed records on all subjects who provide informed 
consent. Data for screened and enrolled subjects will be entered into eCRFs. Review of the eCRFs 
will be completed remotely by RIBOMIC (or designee). At designated intervals, a study monitor 
will perform source data verification on site. During those visits, RIBOMIC (or designee) will 
monitor the subject data recorded in the eCRF against source documents at the study site. 
RIBOMIC (or designee) will review and evaluate eCRF data and use standard system edits, and 
may use centralized monitoring evaluations, to detect errors in data collection. At the end of the 
study, a copy of the completed eCRFs will be sent to the site to be maintained as study records.


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PUBLICATION POLICY
The existence of this clinical study is confidential, and it should not be discussed with persons 
outside of the study. Additionally, the information in this document and regarding this study 
contains trade secrets and commercially sensitive information that is confidential and may not be 
disclosed unless such disclosure is required by federal or state law or regulations. Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have 
a need to know, but all such persons must be instructed not to further disseminate this information 
to others.  These restrictions of disclosure will apply equally to all future information supplied 
that is indicated as confidential.  Information pertaining to this study will be published on 
www.clinicaltrials.gov. 
The data generated by this clinical study are the property of RIBOMIC and should not be disclosed 
without the prior written permission of RIBOMIC. These data may be used by RIBOMIC now and 
in the future for presentation or publication at RIBOMIC’s discretion or for submission to 
governmental regulatory agencies. RIBOMIC reserves the right of prior review of any publication 
or presentation of data from this study.
In signing this protocol, the Principal Investigator agrees to the release of the data from this study 
and acknowledges the above publication policy.
 


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REFERENCES
1.
Belgore F, Lip GYH, Blann AD. Basic fibroblast growth factor induces the secretion of 
vascular endothelial growth factor by human aortic smooth muscle cells but not by 
endothelial cells. European Journal of Clinical Investigation 2003; 33:833-839.
2.
Bikfalvi A, Klein S, Pintucci G, Rifkin DB. Biological roles of fibroblast growth factor-2. 
Endocr Rev 1997;18(1):26-45.
3.
Brown DM, Kaiser PK, Michels M, et al. ANCHOR Study Group: ranibizumab versus 
verteporfin for neovascular age-related macular degeneration. New England Journal of 
Medicine 2006; 355:2832-44.
4.
Chew EY, Clemons T, Sangiovanni JP, et al. The Age-related Eye Disease Study 2 
(AREDS2): Study Design and Baseline Characteristics (AREDS2 Report Number 1). 
Ophthalmology 2012; 119:2282-89.
5.
Friedman DS, O'Colmain BJ, Munoz B, et al. Prevalence of age-related macular 
degeneration in the United States. Arch Ophthalmol 2004;122(4):564-72.
6.
Gordon, M., Kass, M. (2001). Ocular Hypertension Treatment Study (OHTS), Manual of 
Procedures, Version 3.0. National Technical Information Service.
7.
Heier JS, Brown DM, Chong V, et al. VIEW 1 and VIEW 2 Study Groups: Intravitreal 
aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012; 
119: 2537-48.
8.
Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for 
reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 
280:509-16
9.
Jin L, Nonaka Y, Miyakawa S, Fujiwara M, Nakamura Y. Dual Therapeutic Action of a 
Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain. Mol Ther 2016; 
24:1974-86.
10. Kane, F., Campochiaro, P. Choroidal Neovascularization. In: Lim J, editor. Age-Related 
Macular Degeneration. 2nd edition, 2008. p. 87-95.
11. Matsuda Y, Nonaka Y, Satoshi Futakawa, et al. Anti-Angiogenic and Anti-Scarring Dual 
Action of an Anti-Fibroblast Growth Factor 2 Aptamer in Animal Models of Retinal Disease. 
Mol Ther 2019; 17: 819-832. 
12. Maguire MG, Martin DF, Ying GS, et al. CATT Research Group. Five-year outcomes with 
anti-vascular endothelial growth factor treatment of neovascular age-related macular 
degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. 
Ophthalmology 2016; 123:1751-61.
13. Martin DF, Maguire MG, Fine SL et al. Comparison of Age-Related Macular Degeneration 
Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of 
neovascular age-related macular degeneration: 2-year results. Ophthalmology 2012; 
119:1388-8.
14. MedDra. MedDRA MSSO, Medical Dictionary for Regulatory Activities, Version 16.12013.
 


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15. Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology 1985; 92:467-71.
16. Panda-Jonas S, Jonas JB, Jakobczyk M, Schneider U. Retinal photoreceptor count, retinal 
surface area, and optic disc size in normal human eyes. Ophthalmology 1994; 101:519-23.
17. Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated 
patients in ANCHOR, MARINA, and HORIZON a multicenter cohort study (SEVEN-UP). 
Ophthalmology 2013; 120:2292-99
18. Schultz GS and Grant AB. Neovascular growth factors. Eye 1991; 1:70-80.
19. Sherwood M, Brandt J. Six-month comparison of bimatoprost once-daily and twice-daily 
with timolol twice-daily in patients with elevated intraocular pressure. Surv Ophthalmol 
2001;45(6 Suppl 2):S361-S68.
20. Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-
mesenchymal transformation. Kidney Int 2002; 61:1714–28.
21. Sun Working, G. (2005). PERSPECTIVES Standardization of Uveitis Nomenclature or 
Reporting Clinical Data. Results of the First International Workshop. American Journal of 
Ophthalmology. 280(3):509-16.
22. US_Dept_Health_And_Human_Services. The Seventh Report of the Joint National 
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, 
and Treatment of High Blood Pressure. Bethesda (MD)2004.
23. Vinding T. Occurrence of drusen, pigmentary changes and exudative changes in the macula 
with reference to age-related macular degeneration. An epidemiological study of 1000 aged 
individuals. Acta Ophthalmologica 1990; 68:410–28.
24. World Health Organization Drug Dictionary, E. World Health Organization Drug Dictionary 
Enhanced (WHO-DDE), September 2011 Version2011.


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APPENDICES
Appendix A - Obligations of Investigators
In summary, the Clinical Investigator has agreed to the following obligations:
x Obtaining informed consent from every subject prior to the subject’s participation in any 
study related activity and maintaining records of consent as part of the study records.
x Obtaining approval from the IRB before involving any subject in any study related activity; 
submitting verification of the approval to the Sponsor; submitting periodic progress reports 
(at least annually) and final report to IRB and to the Sponsor.
x Approving the protocol and conducting the study according to the protocol and applicable 
regulations; informing the Sponsor of all deviations from the protocol.
x Informing the IRB of all protocol amendments/modifications; sending the Sponsor a copy 
of the letter from the IRB approving the amendment/modification.
x Reporting to the Sponsor and the IRB any adverse experiences that occur in the course of 
the investigation, this includes Serious Adverse Events within 24 hours.
x Keeping careful and accurate records of all clinical study data (study records must be 
considerably more exact and complete than those kept in ordinary medical practice); 
maintaining records of all materials submitted to the IRB and of all action by the IRB 
regarding the study.
x Making study records available for inspection by the Sponsor and representatives of the Food 
and Drug Administration and other regulatory agencies; keeping records until notified by 
the Sponsor that they may be destroyed.
x Maintaining proper control and documentation of all test and control articles.
x Submitting the following records and reporting to the Sponsor.
 
I.  Prior to the Beginning of the Study 
x A current curriculum vitae (CV) if not submitted to RIBOMIC previously or if updated.
x CVs for all sub-Investigators.
x A letter from the IRB indicating that the protocol was approved, including the name and 
address of the IRB.
x A copy of the consent form approved by IRB.
x A list of current members of the IRB.
 
II.
While the Study Is in Progress 
x Acknowledgment of receipt of the test and control articles; documentation of disposition of 
all test and control articles.
x Original Case Report Forms for each subject enrolled in the study.
 
   


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x Information regarding all deviations from the protocol.
x Information regarding all adverse medical events occurring to a subject while enrolled in the 
study.
x Annual progress report (if study is ongoing for more than one year). Letter from the IRB 
indicating approval of the annual progress report.
 
III.
Once the Study Is Completed 
x Disposition of all used and/or unused test and control articles, as well as documentation of 
all drug accountability.


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Appendix B - Elements of Informed Consent
21.2.1 Elements of Informed Consent
The following information must be provided to each subject in obtaining informed consent. If 
written consent is being obtained, the subject (or subject’s legal representative) should be provided 
with a copy of the signed written ICF.
1.
State that the study involves RESEARCH.
2.
Explain the PURPOSE of the research.
3.
Trial treatments and the probability for random assignment to each treatment.
4.
State the expected DURATION of the subject’s participation.
5.
Describe the PROCEDURES to be followed.
6.
Identify any EXPERIMENTAL procedures.
7.
Describe any reasonably foreseeable RISKS OR DISCOMFORTS to the subject.
8.
Describe any BENEFITS to the subject and responsibility for the subject or to others 
that may reasonably be expected from the research.
9.
Note appropriate ALTERNATIVE procedures or courses of treatment, if any, that might 
be advantageous to the subject.
10. A.
Describe the extent, if any, to which CONFIDENTIALITY of records 
identifying the subject will be maintained.
B.
Note that the FDA MAY INSPECT the records.
11. For research involving more than minimal risk, explain if any COMPENSATION or 
medical treatments are available should injury occur. If so, explain (a) what they consist 
of, OR (b) where further information may be obtained.
12. A.
Tell whom to contact for ANSWERS to pertinent questions about (a) the 
research, and (b) research subjects’ rights.
B.
Tell whom to contact in the event of a research-related INJURY to the subject.
13. State that:
A.
Participation is VOLUNTARY,
B.
Refusal to participate will involve NO PENALTY or loss of benefits to which 
the subject is otherwise entitled
C.
The subject MAY DISCONTINUE participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
21.2.2 Additional Elements of Informed Consent
When appropriate, one or more of the following elements of information shall also be provided to 
each subject:
 


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1.
A statement that particular treatment or procedure may involve risks to the subject (or to the 
embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable.
2.
Anticipated circumstances under which the subject’s participation may be terminated by the 
Investigator without regard to the subject’s consent.
3.
Any additional costs to the subject that may result from participation in the research.
4.
The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
5.
A statement that significant new findings developed during the course of the research, which 
may relate to the subject’s willingness to continue participation, will be provided to the 
subject.
6.
The approximate number of subjects involved in the study.
The informed consent requirements in this protocol are not intended to preempt any applicable 
Federal, State, or local laws which require additional information to be disclosed for informed 
consent to be legally effective.
Nothing in this protocol is intended to limit the authority of a physician to provide emergency 
medical care to the extent the physician is permitted to do so under applicable Federal, State, or 
local law.
REFERENCE: 21 CFR Part 50.25 - PROTECTION OF HUMAN SUBJECTS, Elements of 
Informed Consent.


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Appendix C - Declaration of Helsinki
 
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects 
 
Preamble
1.
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles.
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfilment of this duty.
5.
Medical progress is based on research that ultimately must include studies involving 
human subjects.
6.
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality.
7.
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights.
8.
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects.
9.
It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects must 
always rest with the physician or other health care professionals and never with the research 
subjects, even though they have given consent.
10.
Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
 


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norms and standards. No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration.
11.
Medical research should be conducted in a manner that minimizes possible harm to the 
environment.
12.
Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on patients 
or healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional.
13.
Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research.
14.
Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, diagnostic 
or therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research subjects.
15.
Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured.
Risks, Burdens and Benefits 
16.
In medical practice and in medical research, most interventions involve risks and 
burdens.
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects.
17.
All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by the 
condition under investigation.
Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.
18.
Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed.


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When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or immediately 
stop the study.
Vulnerable Groups and Individuals
19.
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
20.
Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out in a non- 
vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research.
Scientific Requirements and Research Protocols
21.
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal experimentation. 
The welfare of animals used for research must be respected.
22.
The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions.
Research Ethics Committees
23.
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee 
must be transparent in its functioning, must be independent of the researcher, the sponsor and 
any other undue influence and must be duly qualified. It must take into consideration the laws 
and regulations of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration.
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any serious 
adverse events. No amendment to the protocol may be made without consideration and approval 
by the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions.
Privacy and Confidentiality 
24.
Every precaution must be taken to protect the privacy of research subjects and the 


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confidentiality of their personal information.
Informed Consent
25.
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees.
26.
In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits 
and potential risks of the study and the discomfort it may entail, post-study provisions and any 
other relevant aspects of the study. The potential subject must be informed of the right to refuse 
to participate in the study or to withdraw consent to participate at any time without reprisal. 
Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information.
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the non- 
written consent must be formally documented and witnessed.
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study.
27.
When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship.
28.
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorized representative. These 
individuals must not be included in a research study that has no likelihood of benefit for them 
unless it is intended to promote the health of the group represented by the potential subject, the 
research cannot instead be performed with persons capable of providing informed consent, and 
the research entails only minimal risk and minimal burden.
29.
When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorized representative. The potential subject’s 
dissent should be respected.
30.
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. Consent 
to remain in the research must be obtained as soon as possible from the subject or a legally 


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authorized representative.
31.
The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where 
consent would be impossible or impracticable to obtain for such research. In such situations the 
research may be done only after consideration and approval of a research ethics committee.
Use of Placebo
33.
The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable;
or
Where for compelling and scientifically sound methodological reasons the use of any
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive any 
intervention less effective than the best proven one, placebo, or no intervention will not be 
subject to additional risks of serious or irreversible harm as a result of not receiving the best 
proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.
In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention identified 
as beneficial in the trial. This information must also be disclosed to participants during the 
informed consent process.
Research Registration and Publication and Dissemination of Results
35.
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject.
36.
Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable for 
the completeness and accuracy of their reports. All parties should adhere to accepted guidelines 
for ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication.
Unproven Interventions in Clinical Practice
37.
In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert advice, with 


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informed consent from the patient or a legally authorized representative, may use an unproven 
intervention if in the physician's judgment it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available.
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th'Wl'v.IA General Assembly; Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 55th 
WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013


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Appendix D - Procedures for Examinations
21.4.1 Demographics/Eligibility, Medical/Surgical History and Concomitant 
Medication
Demographics/Eligibility, medical/surgical history and concomitant medication will be obtained 
through subject interviews at Screening (Day -28 to Day -1). Medical history and concomitant 
medications will be obtained through subject interviews at each visit.
 
21.4.2 Physical Examination
A full body systematic physical examination will be conducted during Visit 0/Screening (Day - 28 
to Day -1). Clinical Investigator or an external internist will confirm subject’s overall condition 
noting any abnormalities by a review of the following systems: e.g., head, neck, thyroid, ears, nose, 
throat, mouth, tongue, respiratory, cardiovascular, abdomen, neurological and other. 
The Clinical Investigator will assess subject’s overall condition to determine qualification for 
study entry considering possible class effects of RBM-007. 
21.4.3 Vital Signs
Blood pressure and heart rate will be measured at Visit 0/Screening (Day - 28 to Day -1) using an 
automated or manual blood pressure monitor. Systolic and diastolic blood pressures will be 
recorded in millimeters of mercury (mmHg) and heart rate will be recorded in beats per minute 
(bpm).
In accordance with the recommendations of the Joint National Committee on Prevention, 
Detection, 
Evaluation, 
and 
Treatment 
of 
High 
Blood 
Pressure 
(US_Dept_Health_and_Human_Services, 2004), the following measurement procedure will be 
used to measure vital signs:
x
Subject should not smoke or ingest caffeine within the 30-minute period immediately before 
the measurement.
x
Subject should be seated quietly in a chair with the back supported, feet on the floor, arm 
bared, and arm supported at heart level.
x
Begin the measurement after at least 5 minutes of rest.
x
To ensure an accurate measurement, use an appropriately sized cuff. The cuff bladder should 
encircle at least 80 % of the arm. Many adults need a large cuff.
x
Take two (2) systolic/diastolic pressure and heart rate measurements separated by at least 30 
seconds. Record each measurement in the subject’s source document.
x
If the two pressure measurements differ by 5 mmHg or less, then the average of the two 
becomes the recorded pressure. For example, if the two measurements are 120/90 and 
125/95, then 122.5/92.5 is the recorded systolic/diastolic pressure.
 


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x
If the two pressure measurements differ by more than 5 mmHg, then a third reading 
measurement is made, and the average of the three becomes the recorded pressure. For 
example, if the three measurements are 115/90, 124/96, and 120/92, then 119.7/92.7 is the 
recorded systolic/diastolic pressure. The recorded blood pressure will be the average of the 
measurements.
x
Record the heart rate. For heart rate, the average of the two (or three, if performed) 
measurements obtained becomes the recorded heart rate.
21.4.4 Urine pregnancy test
A urine pregnancy test will be conducted before IVT injection at Screening Visit, Visit 1 and 
Visit 7 for all females of childbearing potential. A female is considered of childbearing potential 
unless she is postmenopausal (at least 24 months since last menses occurred), has had her uterus 
and/or both ovaries removed, or has had a bilateral tubal ligation. To obtain the pregnancy test, 
the subject should follow instructions provided by the manufacturer of the urine pregnancy test 
kit. 
21.4.5 Best Corrected Visual Acuity
ETDRS chart will be used to examine and record BCVA at each study visit.
21.4.6 External Ocular Examination
External ocular examination will be done evaluating lid and lashes as normal and abnormal with 
notes if abnormal.
21.4.7 Slit-Lamp Biomicroscopy
Slit-lamp biomicroscopy will be used to examine eye structures at each study visit. Slit-lamp 
biomicroscopy will be performed prior to the (first) injection and then again within 30 minutes 
after the (second) injection on the Visit 1 (Day1), 3 (W4), 4 (W8) and 5 (W12). This will be also 
applied for the post IVT injection of Rescue treatment. The conjunctiva, cornea, and lens will be 
observed with the slit-lamp beam approximately 0.3 mm in width and 1.0 mm in length. 
Conjunctiva, Sclera and Cornea will be described as normal / abnormal with notes if abnormal.
 
Lens 
The lens will be noted as normal/abnormal, phakic, aphakic, or pseudophakic. Phakic lens 
will be graded for cataract as nuclear, posterior subcapsular, and cortical as described 
below:
None
(0) = No lens discoloration nor opacification
Mild
(1) = Yellow lens discoloration or small lens opacity (axial or peripheral) 
Moderate (2) = Amber lens discoloration or medium lens opacity (axial or peripheral) 
Severe
(3) = Brunescent lens discoloration or complete lens opacification (no red reflex)
Anterior chamber cells and flare will be observed with a 1.0 mm in width and 1.0 mm in length 
slit beam and graded using the Standardization of Uveitis Nomenclature (SUN) scale (Sun 


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Working, 2005). The iris and the pupil will be evaluated for the presence of clinically significant 
abnormalities.
Anterior Chamber Cells 
 
(0) = No cells 
(0.5) = 1-5 cells
(1) = 6-15 cells
(2) = 16-25 cells
(3) = 26-50 cells
(4) = >50 cells
 
Anterior Chamber Flare 
(0) = None
(1) = Fain
(2) = Moderate (iris/lens details clear)
(3) = Marked (iris/lens details hazy)
(4) = Intense (fibrin/plastic aqueous)
 
Iris 
The iris will be evaluated for the presence of any clinically significant abnormalities, and 
graded as either normal (within normal limits) or abnormal (clinically significant abnormality 
present). A description of any clinically significant abnormalities will be noted.
 
Pupil 
The pupil will be evaluated for the presence of any clinically significant abnormalities, and 
graded as either normal (within normal limits) or abnormal (clinically significant abnormality 
present). A description of any clinically significant abnormalities will be noted.
21.4.8 Intraocular Pressure
IOP will be measured by applanation tonometry at each study visit. Procedures in each visit are 
described in Section 7.5.2.


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For Rescue IVT injection, IOP will be measured as follows: 
-
IOP will be measured at 40 (±10) minutes post-injection.
-
If post-injection IOP is > 21 mmHg after eye massage and/or aqueous tap performed per
investigator discretion, IOP measurement will be repeated at 60 (±10) minutes post-
injection.
-
If post-injection IOP at 60 (±10) minutes is > 21 mmHg after eye massage and/or
aqueous tap performed per investigator discretion, IOP measurement will be repeated at
90 (±10) minutes post-injection.
-
If there is an increase of ≥ 10 mmHg at 90 (±10) minutes post-injection compared to
Baseline IOP, the subject should be prescribed a topical IOP-lowering medication until he
or she returns for follow-up per the Clinical Investigator’s discretion (an unscheduled
visit may apply).
-
On the other hand, a subject with IOP measurement of > 21 mmHg will be managed
according to the discretion of the Clinical Investigator.
-
The IOP increase of ≥ 10 mmHg from Baseline AND IOP measurement of > 21 mmHg
will be reported as an AE.
•
Aqueous tap can be performed at any time per the Clinical Investigator`s discretion for
treatment or prevention of increasing in the IOP.
The applanation tonometer must be calibrated for accuracy before the first subject undergoes 
screening, and periodically until the last subject has exited the study. For checking calibration, 
follow the manufacturer’s instructions.
The following IOP measurement procedure is in accordance with the procedure used in the Ocular 
Hypertension Treatment Study (Gordon et al., 2001) at each visit:
At least two, and sometimes three, consecutive measurements are made to obtain a determination 
of intraocular pressure. Each IOP measurement should be recorded in the subject’s source 
document and in the eCRFs.
•
If the two measurements differ by 2 mmHg or less, then the average of the two
measurements becomes the recorded IOP. For example, if the two measurements are 22 and
23, then 22.5 is the final recorded IOP.
•
However, if the two measurements differ by 3 mmHg or more, then a third measurement is
made, and the median of the three measurements becomes the recorded IOP (the median is
the middle measurement after arraying the measurements from low to high).
For example,
if the three measurements are 15, 19, and 16, then 16 is the final recorded IOP.
•
The IOP in the left eye is then measured using the same technique.


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21.4.9 Indirect Ophthalmoscopy
Indirect ophthalmoscopy will be performed for each eye at each visit under pharmacological pupil 
dilation.
Indirect ophthalmoscopy will be used to examine the retina at each study visit. Indirect 
ophthalmoscopy will be performed prior to the (first) injection and then again within 30 minutes 
after the (second) injections on the Visit 1 (Day1),  Visit 3 (Week 4), Visit 4 (Week 8) and Visit 5 
(Week 12). Areas to be assessed include cup to disc ratio, peripheral retina, macula, choroid, and 
vitreous. This will be also applied for the post IVT injection of Rescue treatment.
Cup/Disc Ratio
The cup/disc ratio will be determined by the examiner and recorded using two decimal places 
(e.g., 0.80).
 
Retina, Macula and Choroid
The retina, macula and choroid will be evaluated for the presence of any clinically significant 
abnormalities, and graded as either normal (within normal limits) or abnormal (clinically 
significant abnormality present). A description of any abnormalities will be noted.
Vitreous
The following National Eye Institute Grading Scheme will be used to measure vitreous haze 
and opacification (Nussenblatt et al., 1985).
Vitreous Haze Scale
Step
Description
(0)
Clear
(Trace or 0.5+)
Trace
(1+)
Few opacities, mild blurring
(2+)
Significant blurring but still visible
(3+)
Optic nerve visible, no vessels seen
(4+)
Dense opacity obscures the optic nerve head
21.4.10 Spectral Domain Optical Coherence Tomography
Spectralis, Cirrus or 3D OCT will be utilized to take optical images at each study visit. The images 
may be stored in the EDC and sent to the central reading center at a later date at Sponsor discretion.
21.4.11 Optical Coherence Tomography Angiography
OCT angiography images will be taken only at selected sites at study Visit 1 (Day1) and Visit 6 
(Week 16) in subjects showing SHRM on the Visit 0 (Screening) SD-OCT. The images may be 
stored in the EDC and sent to the central reading center at a later date at Sponsor discretion.


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21.4.12 Fundus Photography
Digital color fundus photography will be taken at each study visit except Visit 2 (Week 1). The 
images may be stored in the EDC and sent to the central reading center at a later date at Sponsor 
discretion.
21.4.13 Fluorescein Angiography
Fundus fluorescein angiography will be taken at Visit 1 (Day 1) and Visit 6 (Week 16). The images 
may be stored in the EDC and sent to the central reading center at a later date at Sponsor discretion.

SAP_001.pdf: 
Statistical analysis plan: 
Title: A Multi-Center, Randomized, Double Masked and Active Controlled Phase II Study 
Assessing the Efficacy and Safety of Intravitreal Injections of RBM-007 monotherapy and RBM- 
007 in Combination with Eylea® Compared to Eylea® Monotherapy in Subjects with Wet Age- 
related Macular Degeneration – TOFU Study 
NCT04200248 
Date: 14 December 2021 


DocuSign Envelope ID: D58307D0-9153-4113-88E4-8C8EAF704F45 
 
 
 
 
 
RIBOMIC USA Inc 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
RBM-007-002 
 
 
 
 
 
 
 
 
 
 
A Multi-Center, Randomized, Double Masked and Active Controlled 
Phase II Study Assessing the Efficacy and Safety of Intravitreal 
Injections of RBM-007 monotherapy and RBM-007 in Combination with 
Eylea® Compared to Eylea® Monotherapy in Subjects with Wet Age- 
related Macular Degeneration – TOFU Study 
 
 
 
 
 
 
 
 
 
Author: 
Version Number and Date of Protocol: Amendment 1, 15 Nov 2019 


DocuSign Envelope ID: D58307D0-9153-4113-88E4-8C8EAF704F45 
Protocol No: RBM-007-002 
Version Number: 
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Statistical Analysis Plan, 
RIBOMIC USA Inc 
Page 2 of 28 
 
 
 
 
Statistical Analysis Plan Signature Page 
 
Statistical Analysis Plan for Protocol RBM-007-002. 
 
Name 
Signature 
Date 
Author: 
 
14 Dec 2021 
Position: 
Biostatistician 
Company: 
Tech Observer 
 
 
Upon review of this document, the undersigned approve this version of the Statistical Analysis 
Plan, authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
12/14/2021 
Position: 
Medical Monitor 
Company: 
RIBOMIC USA, Inc 
Approved By: 
12/14/2021 
Position: 
CEO 
Company: 
RIBOMIC USA, Inc 


DocuSign Envelope ID: D58307D0-9153-4113-88E4-8C8EAF704F45 
Protocol No: RBM-007-002 
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Statistical Analysis Plan, 
RIBOMIC USA Inc 
 
Page 3 of 28 
 
 
 
 
 
Modification History 
 
Version 
Number 
Date of the Document 
Version 
Author 
Significant Changes from 
Previous Version 
1.0 
13 Dec 2021 
 
Not Applicable – First Version 


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Page 4 of 28 
 
 
 
 
Table of Contents 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................................. 5 
2. 
INTRODUCTION ............................................................................................................. 6 
2.1. 
Responsibilities ................................................................................................................................ 6 
2.2. 
Timing of Analyses ........................................................................................................................... 6 
3. 
STUDY OBJECTIVES ..................................................................................................... 6 
3.1. 
Primary Objective(s) ......................................................................................................................... 6 
3.2. 
Secondary Objectives ...................................................................................................................... 6 
4. 
STUDY DESIGN .............................................................................................................. 7 
5. 
TREATMENT ASSIGNMENT AND MASKING ................................................................ 8 
6. 
ANALYSIS POPULATIONS ............................................................................................ 9 
6.1. 
All Enrolled Population ..................................................................................................................... 9 
6.2. 
Safety Population ........................................................................................................................... 10 
6.3. 
Intent-to-Treat (ITT) Population ...................................................................................................... 10 
6.4. 
Full Analysis Set ............................................................................................................................. 10 
6.5. 
Per-Protocol (PP) Population ......................................................................................................... 10 
6.6. 
Prtotocol Deviations ....................................................................................................................... 11 
7. 
GENERAL CONSIDERATIONS .................................................................................... 11 
7.1. 
Reference Start Date and Study Day ............................................................................................. 12 
7.2. 
Baseline ......................................................................................................................................... 12 
7.3. 
Retests, Unscheduled Visits and Early Termination Data .............................................................. 12 
7.4. 
Treatment Period ........................................................................................................................... 12 
7.5. 
Common Calculations .................................................................................................................... 13 
7.6. 
Coding Dictionary ........................................................................................................................... 13 
7.7. 
Software Version ............................................................................................................................ 13 
8. 
SAMPLE SIZE AND POWER CALCULATIONS ........................................................... 13 
9. 
INTERIM ANALYSIS ..................................................................................................... 13 
10. 
SUBJECT CHARACTERISITCS AND STUDY CONDUCT SUMMARIES ..................... 13 
10.1. 
Subject Disposition ......................................................................................................................... 13 


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10.2. 
Demographic and Baseline Characteristics .................................................................................... 14 
10.3. 
Medical and Surgical History .......................................................................................................... 14 
10.4. 
Medications .................................................................................................................................... 15 
11. 
EFFICACY ANALYSIS STRATEGY .............................................................................. 15 
11.1. 
Primary Efficacy Endpoint .............................................................................................................. 15 
11.2. 
Secondary Efficacy Endpoints ........................................................................................................ 16 
11.3. 
Subgroup Analysis ......................................................................................................................... 17 
11.4. 
Multipilicty ....................................................................................................................................... 17 
11.5. 
Imputation of Missing Data ............................................................................................................. 17 
11.6. 
Sensitivity Analysis ......................................................................................................................... 18 
12 
SAFETY ANALYSIS STRATEGY ................................................................................. 18 
12.1 
Extent of Exposure ......................................................................................................................... 19 
12.2 
Adverse Events .............................................................................................................................. 19 
12.3 
Intraocular Pressure ....................................................................................................................... 21 
12.4 
Slit Lamp Examination.................................................................................................................... 22 
12.5 
Indirect Ophthalmoscopy ................................................................................................................ 22 
12.6 
External Ocular Examination .......................................................................................................... 22 
12.7 
Loss in BCVA ................................................................................................................................. 23 
12.8 
Vital Signs ...................................................................................................................................... 23 
12.9 
Physical Examination ..................................................................................................................... 24 
12.10 
Other Assessments ........................................................................................................................ 24 
APPENDIX 1. SCHEDULE OF EVENTS ................................................................................... 1 
APPENDIX 2. MISSING DATE PROCEDURE .......................................................................... 2 
APPENDIX 3. LIST OF TABLES, FIGURES, AND LISTINGS ................................................... 4 


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1. 
GLOSSARY OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AMD 
Age-related Macular Degeneration 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BDRM 
Blinded Data Review Meeting 
BP 
Blood Pressure 
BMI 
Body Mass Index 
CSR 
Clinical Study Report 
CST 
Central Subfield Thickness 
ENR 
Enrolled 
EOT 
End of Treatment 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
ICF 
Informed Consent Form 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
IVT 
Intravitreal 
LOCF 
Last Observation Carried Forward 
LSMEANS 
Least Squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Protocol Deviation 
PT 
Preferred Term 
PP 
Per-Protocol 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SE 
Standard Error 
SOC 
System Organ Class 
SRT 
Safety Review Team 
SHRM 
Subretinal Hyper Reflective Material 
TEAE 
Treatment Emergent Adverse Event 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
WHODrug Global 
World Health Organization Drug Dictionary 


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2. 
INTRODUCTION 
The purpose of this document is to provide a description of the statistical methods and procedures 
to be implemented for the analysis of data from the RBM-007-002 study. This document is based on 
the protocol version Amendment 1, dated 15 November 2019. This Statistical Analysis Plan (SAP) 
has been developed prior to database lock for interim or final analysis for the TOFU study. Any 
changes from the planned analysis as described in the protocol for RBM-007-002 and its 
amendments (as applicable) are detailed here, and any differences described here supersede the 
analysis presented in the protocol. Any additional analyses are conducted to supplement the 
planned analyses and any deviations from the planned analyses described in this SAP will be 
documented in the Clinical Study Report (CSR). 
 
2.1. RESPONSIBILITIES 
Tech Observer will perform the statistical analyses and will be responsible for the production and 
quality control of all tables, figures and listings. This SAP describes the efficacy and safety 
analyses. 
 
2.2. TIMING OF ANALYSES 
The primary analysis of efficacy and safety is planned after all subjects complete the study visit for 
Week 16 or withdraw early from the study. The final analysis is planned after all subjects complete 
the final study visit (Week 20) or withdraw early from the study. No interim analysis is planned for 
this study. 
 
3. 
STUDY OBJECTIVES 
3.1. PRIMARY OBJECTIVE 
The primary objective of this study is to assess the safety and efficacy of repeated intravitreal 
injections of RBM-007 (2.0 mg/eye) given as monotherapy and RBM-007 (2.0 mg/eye) in 
combination with Eylea® in subjects with wet age-related macular degeneration (AMD) compared 
with Eylea® alone. 


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3.2. SECONDARY OBJECTIVES 
The secondary objective of this study is to evaluate durability of effect for RBM-007 in subjects 
with exudative age-related macular degeneration. 
 
4. 
STUDY DESIGN 
This is a multicenter, active-controlled, double masked study assessing the safety, efficacy and 
durability of four monthly intravitreal (IVT) injections of RBM-007 monotherapy, and four monthly 
RBM-007 injections in combination with Eylea® dosed at every other month, compared to Eylea® 
monotherapy dosed at every other month in approximately eighty-one subjects with exudative age- 
related macular degeneration (AMD). 
 
Subjects aged 55 years or older diagnosed with active exudative AMD in the study eye, for which 
previous standard treatment with intravitreal anti-vascular endothelial growth factor (anti-VEGF) 
agents have demonstrated incomplete resolution of exudation assessed by spectral domain optical 
coherence tomography (SD-OCT) will be enrolled. Other inclusion criteria are: Early Treatment of 
Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) of 78 to 24 letters (≤20/32 
to ≥20/320 Snellen vision equivalent); presence of macular edema or subretinal fluid on SD-OCT; 
absence of central atrophy or retinal epithelial tear in the fovea or any condition preventing VA 
improvement in the study eye. 
 
At the Screening Visit, best corrected visual acuity (BCVA), spectral-domain optical coherence 
tomography (SD-OCT) imaging, fluorescein angiography (FA) and color fundus photography will be 
performed and reviewed by a trained technician for the determination of subject eligibility based 
upon the lesion attributes specified in the inclusion criteria. Randomization occurs after the 
Screening Visit when the subject has been determined to be eligible and the study site completes 
the randomization request. 
 
The study eye must meet all inclusion and exclusion criteria. If both eyes are eligible based on 
inclusion and exclusion criteria, the study eye of an eligible subject is defined as the eye with the 
worst vision. If both eyes have the same vision, the right eye (OD) will be determined as the study 
eye. 


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Subjects who meet all inclusion and none of the exclusion criteria will return to the clinic for the 
Baseline Visit 1 (Day 1). Approximately 81 eligible subjects with exudative age-related macular 
degeneration (AMD) will be randomized in a 1:1:1 ratio to receive one of the following treatment 
arms for up to three months in the study eye: 
 
• 
Arm 1: Sham + RBM-007 Injectable Solution (2.0 mg/eye) 
• 
Arm 2: RBM-007 Injectable Solution (2.0 mg/eye) + Eylea® 
• 
Arm 3: Sham + Eylea®. 
 
Subjects are eligible to receive rescue therapy with Eylea® or other treatment anytime during the 
study except for those visits with Eylea® injection as per protocol, if a BCVA decrease of >10 letters 
and a central subfield thickness (CST) increase of >50μm from the last (previous) per-protocol 
scheduled assessment visit or at the discretion of the investigator. 
 
Total duration of the study will be approximately 24 months. The total study period for each subject 
will include a screening period of up to 28-days and a treatment period and a follow up period that 
totals 20 weeks. Study assessment visits include a screening visit (Visit 0), Baseline/Day 1 (Visit 1), 
post treatment visits at Week 1 (Visit 2), Week 4 (Visit 3), Week 8 (Visit 4), Week 12 (Visit 5), Week 
16 (Visit 6) and Week 20 (Visit 7). The schematic for injections is shown below and the schedule of 
assessments is presented in Appendix 1 (Time and Events Schedule). 
 
 
*Follow-up period: Two-month period between Visit 5 (Week 12) and Visit 7 (Week 20) 


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5. 
TREATMENT ASSIGNMENT AND MASKING 
Subjects who satisfy all of the inclusion and none of the exclusion criteria will be randomized in a 
1:1:1 ratio to receive one of the following three treatment arms in the study eye for up to 3 months 
according to a study randomization scheme: 
 
• 
Arm 1: Sham + RBM-007 Injectable Solution (2.0 mg/eye) 
 
• 
Arm 2: RBM-007 Injectable Solution (2.0 mg/eye) + Eylea® 
 
• 
Arm 3: Sham + Eylea®. 
 
This is a double-masked study. The subjects, efficacy assessors (including photographer(s) and 
BCVA technician(s)), Investigators, Sponsor, and any monitors involved in reporting, obtaining 
and/or reviewing the clinical evaluations will be masked to the specific treatment being administered. 
In addition, Biostatistics staff who are directly involved in the analysis of the study results will remain 
masked to the treatment assignment. However, the designated injection physician (not the 
investigator) will not be masked to the treatment regimen. To keep masking of the clinical trial, the 
investigator and authorized study staffs must follow the following procedures: 
 
• The designated injecting physician and the designated injection staff must ensure any information 
regarding clinical study drug injections during the study is inaccessible to other study staff. 
 
• The designated injecting physician and the designated injection staff cannot perform any 
assessments, examinations, or procedures for the study other than clinical study drug injection 
procedures and examinations post drug injections. 
 
• Study staff not designated to do study drug injections, including investigators, examiner, and 
other clinical site staff, cannot participate in any procedures for clinical study drug injections and 
examinations post drug injections. 
 
The designated Safety Review Team (SRT) will review the masked safety data periodically to 
determine if the safety and tolerability of the doses are acceptable. In case of a medical emergency, 
the Principal Investigator or site staff may reveal the treatment information by unmasking to know 
which treatment the subject has received. The Principal Investigator should contact RIBOMIC, or 


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RIBOMIC’s designee, before taking this measure, if there is sufficient time. RIBOMIC, or RIBOMIC’s 
designee, must be informed of all instances where the code is broken and of the reasons for such 
instances. 
 
6. 
ANALYSIS POPULATIONS 
6.1. ALL ENROLLED POPULATION 
The All Enrolled (ENR) population will contain all subjects who signed an informed consent for 
this study. This analysis population will be used to summarize subject disposition and pre- 
treatment adverse events. 
 
6.2. SAFETY POPULATION 
The safety population will include all randomized subjects who received at least one injection of 
study medication. Subjects in the safety population will be analyzed according to the treatment 
received. The safety population will be used for all safety analyses. 
 
6.3. INTENT-TO-TREAT (ITT) POPULATION 
The ITT population will include all subjects who are randomized to a treatment assignment. 
Subjects in the ITT population will be analyzed according to the treatment group to which they 
are assigned at randomization. This analysis population will be used to summarize subject’s 
demographic and baseline characteristics. 
 
6.4. FULL ANALYSIS SET 
The Full Analysis Set (FAS) will include all randomized subjects who received at least one 
injection and provided at least one scheduled post-baseline BCVA measurement. Subjects in the 
FAS will be analyzed according to the treatment group they are assigned at randomization. The 
FAS will censor data after receiving rescue therapy (i.e., all visits/assessments after rescue 
therapy will be excluded while data collected on the date of rescue therapy are considered prior 
to rescue therapy) and use last-observation carried forward (LOCF). The FAS population will be 
the primary analysis population for all efficacy analyses. 


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6.5. PER-PROTOCOL (PP) POPULATION 
The PP population is a subset of FAS. It includes all FAS subjects without any major protocol 
violations that could affect the assessment of primary efficacy endpoint at Week 16. Classification 
of protocol violations as major or minor will be assessed at a Blinded Data Review Meeting 
(BDRM) prior to database lock. The PP population will be the supportive analysis population for 
all efficacy analysis. All assessments after rescue treatment will be excluded from the analysis. 
 
6.6. PROTOCOL DEVIATIONS 
Protocol deviations (PDs) will be documented separately in a stand-alone document before 
database lock which include deviation category (e.g., violation of inclusion and exclusion criteria at 
screening, use of excluded concomitant medications, received the wrong treatment or incorrect 
dose), deviation description, severity (minor/major), visit/time point for each PD. Major PDs are 
defined as those deviations from the protocol that threaten the integrity of the data, adversely affect 
subjects and/or could influence/affect the outcome of the study endpoints(or part of it). 
 
Protocol deviations pertaining to the effects of the COVID-19 pandemic and related measures may 
be seen on this trial, and there may be an increase in the number of PDs seen due to the pandemic. 
All discussions pertaining to the COVID-19 pandemic and related PDs affecting inclusion/exclusion 
of Analysis Populations, and any adjustments to data handling and/or analysis of data will be 
documented in the BDRM Report. Both the BDRM Report and this document (SAP) will be finalized 
before database lock. A by-subject listing of major and minor PDs will be provided for the safety 
population. 
 
7. 
GENERAL CONSIDERATIONS 
Continuous data will be summarized using the number of observations (n), arithmetic mean (mean), 
standard deviation (SD), median, minimum value (min), and maximum value (max). 
 
The number of observations (n) will be presented with no decimal place, mean and median will be 
presented up to one decimal place from the original value, standard deviation up to two decimal places 
from the original value, and min and max as an original value. 


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Categorical variables will be summarized using the frequency count (n) and percentage (%) for each 
possible value. The frequencies will be presented up to 0 decimal places and percentage up to 1 
decimal place, unless specified otherwise. For all percentage calculations, the denominator will be the 
number of subjects in the analysis population for the treatment group, unless otherwise stated. 
 
All data will be summarized by treatment group unless otherwise specified. Only data from protocol 
scheduled visits will be included in the summary tables. All data entered into the database will be 
included in the subject data listings. 
 
Unless otherwise specified, all discussion of efficacy endpoints and analyses are specific to outcomes 
in the study eye. 
 
7.1. REFERENCE START DATE AND STUDY DAY 
The study day will be calculated from the reference start date, defined as the day of the first 
injection, and will appear in every listing where an assessment date or event date appears. 
If the date of the event is on or after the reference date, then: Study Day = (date of event – 
reference date) + 1. 
 
If the date of the event is prior to the reference date, then: Study Day = (date of event – reference 
date). 
If the event date is partial or missing, study day, and any corresponding durations will appear 
partial or missing in the listings. 
 
7.2. BASELINE 
Baseline is defined as the last non-missing measurement taken prior to the first injection of the 
study drug (including unscheduled assessments). If the last non-missing measurement and the 
reference start date coincide, that measurement will be considered pre-baseline, but AEs and 
medications commencing on the reference start date will be considered post-baseline. It will be 
assumed that all assessments on Day 1 (Baseline) occur prior to the injection of the study drug, 
except those assignments that are designated as post-injection. 


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7.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
Unscheduled measurements and retests will not be included in by-visit summaries but will 
contribute to incidence of significant abnormality tables. 
In the case of a retest (same visit number assigned), the last available measurement for that visit 
will be used for by-visit summaries. Early discontinuation data will be mapped to the End of 
Treatment (EoT) visit for by-visit summaries. Listings will include scheduled, unscheduled, retest 
and early discontinuation data. 
 
7.4. TREATMENT PERIOD 
The treatment period includes the duration that a subject is under treatment in the study between 
the date of first injection received and the date of last injection received. 
 
7.5. COMMON CALCULATIONS 
For quantitative measurements, change from baseline values will be calculated as test value at 
post-treatment visit X – Baseline value. 
Percent change from baseline values will be calculated as (test value at post-treatment visit X – 
Baseline value)*100/Baseline value. 
 
7.6. CODING DICTIONARY 
Where applicable, safety data will be coded using the following coding dictionaries: 
 
Dictionary 
Version 
Medical Dictionary for Regulatory Activities (MedDRA) 
23.0 
World Health Organization Drug Dictionary (WHODrug Global) 
March 2020 
 
7.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher. 


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8. 
SAMPLE SIZE AND POWER CALCULATIONS 
Due to the exploratory nature of this study, the sample size was not based on a statistical power. 
Approximately 81 subjects (Arm 1: 27 subjects, Arm 2: 27 subjects, and Arm 3: 27 subjects) with 
wet AMD will be enrolled at 8 sites. 
 
9. 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 
 
10. SUBJECT CHARACTERISITCS AND STUDY CONDUCT SUMMARIES 
10.1. SUBJECT DISPOSITION 
Subject disposition table will be summarized based on all enrolled subjects who are consented to 
participate in the study. The following summaries will be included in the disposition table: total 
number of subjects screened in the study, number of subjects who failed screening, number of 
subjects who were randomized, number of subjects received treatment, number of subjects who 
completed the study, and number and percentage of subjects who discontinued from the study with 
reason for discontinuation. Percentages will be based on the number of subjects who are 
randomized. This tabulation will be done overall as well as by treatment assignment. In addition, the 
number of subjects included in each of the analysis population (ITT, FAS, PP and Safety) will be 
presented. A by-subject listing of disposition will be provided for the ENR population. 
 
10.2. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Subjects’ demographics and baseline characteristics will be summarized overall and by treatment 
group for the Safety, ITT, FAS and PP populations. 
 
Continuous variables (e.g., age and weight) will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum). Qualitative variables (e.g., sex, race, 
and ethnicity) will be summarized with counts and percentages. 
 
The demographic parameters will include age category (55 to 64, 65 to 74, 75 to 84 and ≥85 years), 
gender, race, and ethnicity. Age will also be summarized as a continuous variable. The baseline 
parameters include, time since diagnosis for the study eye, BCVA (both as a continuous variable 


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and using categories (<55 and ≥55 letters), central subfield thickness (CST) (both as a continuous 
variable and using categories (<400, ≥400 µm) and total macular volume. 
 
By-subject listings of demographic and other baseline characteristics will be provided for the safety 
populations. 
 
10.3. MEDICAL AND SURGICAL HISTORY 
Medical and surgical (ocular and non-ocular) history will be coded using a central coding dictionary, 
the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
 
Medical and surgical history will be defined as any significant past medical conditions that ended 
before screening or current medical conditions that were ongoing at Screening. Medical and surgical 
histories (ocular and non-ocular) will be summarized by system organ class (SOC) and preferred term 
(PT) overall and for each treatment group for the Safety population. Ocular histories will be presented 
by study and non-study eye. Summaries will be sorted alphabetically by SOC, and by descending 
order of frequency for PTs according to the total column. Subjects with more than one of the same 
PTs within an SOC will be counted only once. A by-subject listing will be provided for the safety 
population. 
 
10.4. MEDICATIONS 
Prior medications are medications which started and stopped before the first IVT injection. Any 
changes to prior medications (dose, regimen, etc.) during the study will be considered a new 
concomitant medication. Prior and concomitant medications will be coded using the Anatomical 
Therapeutic Chemical (ATC) classification text from the World Health Organization Drug Dictionary 
and summarized separately. The counts and percentage of subjects taking a medication will be 
displayed by therapeutic class (ATC Level 3) and preferred name. If a therapeutic subgroup or 
preferred term is unavailable, ‘Not coded’ will be used. Summaries will be sorted alphabetically by 
ATC-Level 3, and by descending order of frequency for preferred name according to the total 
column. Subjects with more than one of the same preferred name within an ATC-Level 3 will be 
counted only once. Ocular medications will be presented separately for the study eye and non-study 
eye. 


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A by-subject listing of prior and concomitant medications will be provided for the safety population. 
 
11. EFFICACY ANALYSIS STRATEGY 
11.1. PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is the mean change in BCVA from Baseline at Week 16. 
 
11.1.1. Hypothesis 
This is an exploratory study. No formal testing of hypothesis is planned. 
 
11.1.2. Statistical Methods 
The analysis for the primary efficacy end point, BCVA change from baseline at Week 16 will be 
performed using analysis of covariance model, including visit and treatment as factors and baseline 
value as a covariate. A separate analysis will be conducted between Arm 1 (Sham + RBM-007) versus 
Arm 3 (Sham + Eylea®) and Arm 2 (RBM-007 + Eylea®) versus Arm 3 (Sham + Eylea®). The estimate 
of LS Means for the treatment differences (Arm 1 and Arm 2 versus Arm 3) and two-sided 95% 
confidence interval of the LSMEANS difference will be presented. Observed and change from 
baseline values in BCVA will be summarized descriptively at each visit by treatment group. The 
following figures will be provided for BCVA: 
• 
Line plot for actual BCVA by visit and treatment (Mean ± SE) 
• 
Line plot for change from baseline in BCVA by visit and treatment (Mean ± SE) 
 
11.2. SECONDARY EFFICACY ENDPOINTS 
The secondary efficacy endpoints are: 
 
• 
Proportion of subjects with BCVA gain of ≥5, ≥10 and ≥15 ETDRS letters and BCVA loss 
of ≥15 ETDRS letters relative to baseline at Week 16. 
• 
Change from Baseline in CST at Week 16 by SD-OCT 
 
• 
Change from Baseline in macular volume at Week 16 by SD-OCT 
 
• 
Change from Baseline in characteristics of SHRM 
 
• 
Change from Baseline in characteristics of fibrosis 


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• 
Proportion of subjects that do not require anti-VEGF treatment during follow-up period 
 
• 
Mean numbers of rescue injections in the monotherapy arm (Arm 1) 
 
• 
Proportion of subjects requiring rescue therapy 
 
11.2.1. Statistical Methods 
Counts and percentage of subjects with the categorical improvement of BCVA relative to baseline (≥1 
letter gain, ≥5 letters gain, ≥10 letters gain and ≥15 letters gain) and categorical worsening of BCVA 
(≥5 letters loss, ≥10 letters loss and ≥15 letters loss) will be presented by visit and treatment group. 
Analysis of change from baseline in CST and Macular Volume at Week 16 will be performed similar 
to the primary efficacy endpoint analysis. Observed and change from baseline values in CST and 
Macular Volume will be summarized descriptively at each visit by treatment group. Characteristics of 
SHRM/fibrosis will be evaluated in post-hoc analyses. Counts and percentage of subjects that do not 
require anti-VEGF treatment and counts and percentage of subjects who received rescue injections 
in the RBM-007 monotherapy arm (Arm 1) during the study period will be presented. In addition, the 
number of subjects that received rescue injections will be summarized descriptively. The following 
figures will be provided for the secondary efficacy endpoints. 
• 
Bar-diagram for categorical changes in BCVA by visit and treatment 
• 
Line plot of actual CST by visit and treatment (Mean ± SE) 
• 
Line plot of change from baseline in CST by visit and treatment (Mean ± SE) 
• 
Line plot of Macular Volume by visit and treatment (Mean ± SE) 
• 
Line plot of change from baseline in Macular volume by visit and treatment (Mean ± SE) 
 
11.3. SUBGROUP ANALYSIS 
The following sub populations will be investigated for BCVA and CST parameters to assess the 
impact of these sub populations on overall study results, and to assess the efficacy in each sub 
population. These analyses will be performed for the FAS population with LOCF. 
• 
Age category (<75 years and ≥75 years) 
• 
Gender (Male and Female). 
• 
Baseline BCVA categories (<55 and ≥55 letters) 


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• 
Baseline CST categories (<400, ≥400 µm). 
 
Descriptive summaries will be presented for change from baseline in BCVA and CST by visit and 
treatment. In addition, forest plots for treatment differences in change from BCVA and CST at Week 
16 will be presented. 
 
11.4. MULTIPILICTY 
 
Not applicable. This study is descriptive in nature. No formal testing of hypothesis will be conducted. 
 
11.5. IMPUTATION OF MISSING DATA 
Every effort will be made to prevent subjects early terminating the study. Where missing data exist 
for primary and secondary efficacy endpoints, imputation will occur where specified. 
 
For the primary analysis based on the FAS, a last observation carried forward (LOCF) approach will 
be used to handle missing or in-valid data. No baseline observation will be carried forward for the 
missing data. 
 
11.6. SENSITIVITY ANALYSIS 
A sensitivity analysis to explore the robustness of the efficacy results with respect to the protocol 
deviations will be performed using the per-protocol population. In addition, the results from the 
primary efficacy analysis using the FAS population will be compared to the results using all 
observed data irrespective of rescue treatment and observed data excluding data collected after 
rescue treatment without imputation. 
 
The three analyses (all data censoring post rescue measurements and using LOCF, all observed 
data irrespective of rescue treatment, and observed data excluding measurements collected after 
rescue treatment without imputation) will be repeated using the PP population. 


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12 SAFETY ANALYSIS STRATEGY 
All analyses described in this section will be performed on the Safety Population and will be 
presented by treatment group. The results will be descriptive in nature. There will be no statistical 
comparisons between the treatment groups for safety data, unless otherwise specified within the 
relevant section. All data will be summarized and listed. 
 
Safety will be assessed based on the following assessments: 
• 
Extent of Exposure 
• 
Adverse Events 
• 
Slit-lamp Biomicroscopy 
• 
Indirect Ophthalmoscopy 
• 
Intraocular Pressure 
• 
External Ocular Exam (Lid and Lashes) 
• 
Loss in BCVA 
• 
Physical Examination Findings at Screening Visit 
• 
Vital Signs at Screening Visit 
 
12.1 EXTENT OF EXPOSURE 
Extent of exposure to study drug is calculated as the number of injections received during the study 
period. Counts and percentages will be provided for the number of injections received by treatment 
group. 
 
12.2 ADVERSE EVENTS 
The applicable definition of an Adverse Event (AE) is in the study protocol Section 12.1. All AEs 
occurring from when a subject signed informed consent to when a subject exits the study will be 
accounted for in the reporting. 
 
A pre-treatment AE is defined as any AE with an onset date before the date of first injection of the 
study drug. A treatment-emergent AE is an event not present prior to exposure to the study drug or 
any pre-existing event that worsens following exposure to study drug. The period for treatment- 


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emergent AE analysis starts from the first injection of the study drug until the subject exits the study. 
 
All AEs will be coded using the MedDRA coding dictionary (version 23.0). See Appendix 2 for 
imputation of partial dates for AEs. Imputed dates will be used to determine treatment emergent 
status. For the treatment-emergent AE analyses, analyses will be performed for study eye and non- 
study eye separately. 
 
Summaries of number and percentage of subjects within each of the categories described in the 
sub-sections below, will be provided by treatment group for the safety population. A by-subject 
listing will include TEAEs and pre-treatment AEs for the safety population. 
 
Overall summary of TEAEs: 
 
• 
Subjects with at least one TEAE 
• 
Subjects with at least one ocular AE 
• 
Subjects with at least one non-ocular AE 
• 
Subjects with at least one TEAE related to study drug 
• 
Subjects with at least one TEAE related to injection procedure 
• 
Subjects with at least one Serious TEAE 
• 
Subjects with at least one serious TEAE related to study drug 
• 
Subjects with at least one serious TEAE related to injection procedure 
• 
Subjects with at least one TEAE leading to premature discontinuation 
• 
Subjects with at least one TEAE leading to death 
 
 
12.2.1. All Treatment-emergent Adverse Events 
The incidence of TEAEs will be presented by system organ class (SOC) and preferred term (PT), 
and also be broken down further by maximum severity and relationship to study drug. A separate 
summary of TEAEs in descending order of preferred terms will be provided. 
 
12.2.2. Severity 
A summary of ocular and non-ocular TEAEs by SOC/PT and highest severity will be provided. If a 
subject reports a TEAE more than once within that SOC/PT, the AE with the worst-case severity will 


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be used in the corresponding severity summaries. An adverse event with an unknown severity will 
be considered as missing. 
 
12.2.3. Relationship to Study Drug 
Relationship, as indicated by the Investigator, is classified as not related, possibly related, related 
and related to the injection procedure. A ‘related’ TEAE is defined as a TEAE with a relationship of 
‘possibly related’ or ‘related’ to study drug. A summary of TEAEs by SOC/PT and highest 
relationship to study drug will be provided. If a subject reports the same AE more than once within 
that SOC/PT, the AE with the worst-case relationship to study drug will be used in the corresponding 
relationship summaries. An adverse event with an unknown relationship to study drug will be 
considered as missing. 
 
12.2.4. TEAEs Leading to Discontinuation of Study Drug 
The incidence of TEAEs leading to discontinuation of study drug will be presented by SOC and PT. 
 
12.2.5. Serious Adverse Events 
The incidence of treatment-emergent SAEs will be presented by SOC and PT. Serious AEs are 
those events recorded as ‘Serious’ on the AEs page of the eCRF. 
 
12.2.6. Adverse Events Leading to Death 
The incidence of AEs leading to death will be presented by SOC and PT. The TEAEs leading to 
death are those events which are recorded as ‘Fatal’ as the outcome variable on the AE page of the 
eCRF. 
 
12.3 INTRAOCULAR PRESSURE 
Intraocular pressure (IOP) measurements will be recorded in mmHg and rounded to the nearest 
integer in mmHg. IOP measurements will be conducted at Screening, Baseline (Day 1), Week 1, 
Week 4, Week 8, Week 12, Week 16 and Week 20. Post-injection IOP assessments will be 
conducted on the injection days. 


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Descriptive summaries of observed values and change from baseline values will be presented at 
each study visit by treatment. Line plots of the mean observed values and change in IOP values 
with error bars representing +/- 1 standard error by visit and treatment will be presented using the 
study eye. 
 
A summary table with counts and percentages of subjects in each category of IOP change from 
baseline to last on-treatment IOP assessment, maximum IOP increase from baseline to any post- 
baseline assessment visit and maximum IOP decrease from baseline to any post-baseline 
assessment visit for the study eye will be presented according to the following categories: >30 
mmHg increase, 21 to 30 mmHg increase, 11 to 20 mmHg increase, 6 to 10 mmHg increase, 5 
mmHg increase to 5 mmHg decrease, 6 to 10 mmHg decrease, 11 to 20 mmHg decrease, 21 to 30 
mmHg decrease, and > 30 mmHg decrease. For the presentation of maximum increase, subjects 
who did not have an increase in IOP will be summarized under the category “≤ 5 mmHg increase”. 
For the presentation of maximum decrease, subjects who did not have a decrease in IOP will be 
summarized under the category “≤ 5 mmHg decrease”. 
 
A subject listing of all IOP measurements will be presented by visit. In addition, a listing of all 
subjects with an increase or decrease in IOP of more than 10 mmHg at any visit compared to the 
same eye at Baseline will be presented. 
 
Measurements taken at the post-injection assessments (40, 60 and 90 minutes after injection) will 
not be included in the summary tables, but will be included in the subject listings. 
 
12.4 SLIT LAMP EXAMINATION 
A slit-lamp examination will be performed at Screening, Baseline (Day 1), Week 1, Week 4, Week 8, 
Week 12, Week 16 and Week 20 to evaluate the anterior segment of the eye, including, conjunctiva, 
sclera, cornea, lens and iris. Findings on conjunctiva, cornea, and iris that are deemed clinically 
significant by the investigator will be reported as adverse events. 
 
For each slit-lamp parameter, counts and percentages of subjects in each grading category will be 
presented by visit. A shift table showing fundus grade at baseline relative to last post-baseline will 
be presented 


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A listing will be provided for all slit-lamp parameters. An additional listing will be provided which 
presents all subjects with a worsening of any slit-lamp parameter status at any visit in the study eye 
compared to the status of the same eye at Baseline. 
 
12.5 INDIRECT OPHTHALMOSCOPY 
The indirect ophthalmoscopy will be performed to evaluate the health of the retina, macula, optic 
nerve, and vitreous. Findings on retina, macula, vitreous or optic nerve deemed to be clinically 
significant by the investigator will be reported as adverse events. Fundus examination will be 
conducted at Screening, Baseline (Day 1), Week 1, Week 4, Week 8, Week 12, Week 16, and Week 
20. 
 
For each fundus parameter, counts and percentages of subjects in each grading category will be 
presented by visit. A shift table showing fundus grade at baseline relative to last post-baseline will 
be presented. 
 
A listing will be provided for all indirect ophthalmoscopy parameters. An additional listing will be 
provided which presents all subjects with an increase in any fundus parameter at any visit compared 
to the grade for the same eye at Baseline. 
 
12.6 EXTERNAL OCULAR EXAMINATION 
An external ocular exam will be performed at Screening, Baseline (Day 1), Week 1, Week 4, Week 
8, Week 12, Week 16, and Week 20 to evaluate the anterior segment of the eye, including lids, 
lashes and pupils. Findings on lids, lashes and pupils that are deemed clinically significant by the 
investigator will be reported as adverse events. 
 
For each external ocular examination parameter, counts and percentages of subjects in each 
grading category will be presented by visit. A shift table showing fundus grade at baseline relative to 
last post-baseline will be presented 
 
A listing will be provided for all external ocular examination parameters. An additional listing will be 
provided which presents all subjects with a worsening of any external ocular examination parameter 
status at any visit in the study eye compared to the status of the same eye at Baseline. 


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12.7 LOSS IN BCVA 
Counts and percentages of subjects who experience a pre-specified category of change from 
Baseline to last on-treatment assessment and maximum loss from Baseline to any post-baseline 
assessment visit will be presented according to the following mutually categories: <5 letter loss, ≥5 
letter loss, ≥10 letter loss and ≥15 letter loss. 
 
A listing of all BCVA values by visit will be presented. In addition, a listing of all subjects with a ≥15 
letter loss in BCVA from baseline to any post-baseline visit will be presented. For subjects who had 
≥15 letters loss at any visit, BCVA values at all visits will be presented. 
 
12.8 VITAL SIGNS 
The following vital signs measurements will be assessed at the screening visit: 
 
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Pulse Rate (Beats per min) 
• 
Respiratory Rate (Breaths per min) 
• 
Temperature (F) 
A by-subject listing for all the above parameters will be provided for the safety population. No 
summaries will be provided for the vital sign parameters. 
 
12.9 PHYSICAL EXAMINATION 
The physical examination assessment will be conducted at the screening visit. A by-subject 
listing of physical examination results will be provided including specification of any abnormalities 
observed for the safety population. No summaries will be provided for the physical examination 
results. 
 
12.10 
OTHER ASSESSMENTS 
A listing of urine pregnancy test data will be provided for the safety population. 


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APPENDIX 1. 
SCHEDULE OF EVENTS 
 
 


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APPENDIX 2. 
MISSING DATE PROCEDURE 
Prior/Concomitant Medications 
 
For the purpose of assessing whether a medication is prior or concomitant, if a medication has a 
completely missing start date it will be considered a prior medication, and if a medication has a 
completely missing stop date it will be considered a concomitant medication. If a partial start or stop 
date occurs, the following imputation process will be implemented: 
 
Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for 
Stop Date 
Day missing, month 
and year present 
• 
Month and/or year different to month and year of first 
study drug dose: Impute day with “01” 
• 
Month and/or year same as month and year of first 
study drug dose: Impute day with same day as first 
dose of study drug. 
Impute day with last 
day of the month 
Day and month 
missing, year 
present 
• 
Year different to year of first study drug dose: Impute 
day and month with “01JAN” 
• 
Year same as year of first study drug dose: Impute 
month and day with same month and day as first dose 
of study drug. 
Impute day and 
month with 
“31DEC” 
Month missing, day 
and year present 
• 
Year different to year of first study drug dose: Impute 
month with “JAN” 
• 
Year same as year of first study drug dose: Impute 
month with same month as first dose of study drug. 
Impute with “DEC” 
Caveats 
• 
If any imputed start date leads to a start date that is after the stop date, then 
the start date will be imputed with the date of the stop of medication. 
• 
No stop date will be imputed if the treatment is ongoing. 
 
 
Adverse Events 
For the purpose of assessing whether an AE is treatment emergent, if an AE has a completely missing start and 
stop date, it will be considered treatment emergent; if the stop date is not missing, but the start date is completely 
missing, it will be considered treatment emergent unless the stop date occurs prior to the first dose of study 
drug. 
For assessing treatment emergence or for calculation of duration of AE, if a partial start or stop date occurs, the 
following imputation process will be implemented: 
 
Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for Stop 
Date 
Day missing, month 
and year present 
• 
Month and/or year different to month and year of 
first study drug dose: Impute day with “01”. 
Impute day with last 
day of the month 


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Protocol No: RBM-007-002 
Version Number: 
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Statistical Analysis Plan, 
RIBOMIC USA Inc 
 
Page 28 of 28 
 
 
 
 
Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for Stop 
Date 
• 
Month and/or year same as month and year of first 
study drug dose: Impute day with same day as first 
dose of study drug. 
Day and month 
missing, year 
present 
• 
Year different to year of first study drug dose: 
Impute day and month with “01JAN”. 
• 
Year same as year of first study drug dose: Impute 
month and day with same month and day as first 
dose of study drug. 
Impute day and 
month with “31DEC” 
Month missing, day 
and year present 
• 
Year different to year of first study drug dose: 
Impute month with “JAN”. 
• 
Year same as year of first study drug dose: Impute 
month with same month as first dose of study drug. 
Impute with “DEC” 
Caveats 
• 
If any imputed start date leads to a start date that is after the stop date, then 
the start date will be imputed with the date of the stop of AE. 


DocuSign Envelope ID: D58307D0-9153-4113-88E4-8C8EAF704F45 
 
 
 
 
 
 
APPENDIX 3. 
LIST OF TABLES, FIGURES, AND LISTINGS 
 
List of Tables 
RIBOMIC USA Inc 
 
Table 
Number 
Table Title 
14.1.1.1 
Subject Disposition 
14.1.1.2 
Subject Enrollment by Investigational Site (Safety Population) 
14.1.2.1 
Summary of Demographic and Baseline Characteristics (Intent-to-Treat Population) 
14.1.2.2 
Summary of Demographic and Baseline Characteristics (Full Analysis Set) 
14.1.2.3 
Summary of Demographic and Baseline Characteristics (Per-Protocol Population) 
14.1.2.4 
Summary of Demographic and Baseline Characteristics (Safety Population) 
14.1.3.1 
Summary of Ocular Medical History (Safety Population) 
14.1.3.2 
Summary of Non-Ocular Medical History (Safety Population) 
14.1.4.1 
Summary of Prior Medications (Safety Population) 
14.1.4.2 
Summary of Concomitant Medications (Safety Population) 
14.1.5.1 
Summary of Treatment Exposure (Safety Population) 
14.1.5.2 
Summary of Treatment Received (Safety Population) 
14.2.1.1.1 
Analysis of Change from Baseline in Best Corrected Visual Acuity (No. of Letters) at Week 16 (Full 
Analysis Set) 
14.2.1.1.2 
Analysis of Change from Baseline in Best Corrected Visual Acuity (No. of Letters) at Week 16 
(Per-Protocol Population) 
14.2.1.2.1 
Summary of Best Corrected Visual Acuity (No. of Letters) By Visit (Full Analysis Set) 
14.2.1.2.2 
Summary of Best Corrected Visual Acuity (No. of Letters) By Visit (Per-Protocol Population) 
14.2.1.3.1 
Categorical Improvement of Best Corrected Visual Acuity at Week 16 Relative to Baseline (Full 
Analysis Set) 
14.2.1.3.2 
Categorical Improvement of Best Corrected Visual Acuity at Week 16 Relative to Baseline (Per- 
Protocol Population) 
14.2.1.4.1 
Sensitivity Analysis of Change from Baseline in BCVA (No. of Letters) at Week 16 Using All 
Observed Data Irrespective of the Rescue Therapy (Full Analysis Set) 
14.2.1.4.2 
Sensitivity Analysis of Change from Baseline in BCVA (No. of Letters) at Week 16 Using All 
Observed Data Irrespective of the Rescue Therapy (Per-Protocol Population) 
14.2.2.1.1 
Analysis of Change from Baseline in Central Subfield Thickness (m) at Week 16 (Full Analysis 
Set) 
14.2.2.1.2 
Analysis of Change from Baseline in Central Subfield Thickness (m) at Week 16 (Per-Protocol 
Population) 
14.2.2.2.1 
Summary of Central Subfield Thickness (m) by Visit (Full Analysis Set) 
14.2.2.2.2 
Summary of Central Subfield Thickness (CST) (m) by Visit (Per-Protocol Population) 
14.2.2.3.1 
Sensitivity Analysis of Change from Baseline in Central Subfield Thickness(µm) at Week 16 Using 
All Observed Data Irrespective of the Rescue Therapy (Full Analysis Set) 
14.2.2.3.2 
Sensitivity Analysis of Change from Baseline in Central Subfield Thickness(µm) at Week 16 Using 
All Observed Data Irrespective of the Rescue Therapy (Per-Protocol Population_ 
14.2.3.1.1 
Analysis of Change from Baseline in Macular Volume (mm3) at Week 16 (Full Analysis Set) 
14.2.3.1.2 
Analysis of Change from Baseline in Macular Volume (mm3) at Week 16 (Per-Protocol Population) 
14.2.3.2.1 
Summary of Macular Volume (mm3) by Visit (Full Analysis Set) 
14.2.3.2.2 
Summary of Macular Volume (mm3) by Visit (Per-Protocol Population) 
14.2.3.3.1 
Sensitivity Analysis of Change from Baseline in Macular Volume (mm&ssuper3) at Week 16 Using 
All Observed Data Irrespective of the Rescue Therapy (Full Analysis Set) 
14.2.3.3.2 
Sensitivity Analysis of Change from Baseline in Macular Volume (mm&ssuper3) at Week 16 Using 
All Observed Data Irrespective of the Rescue Therapy (Per-Protocol Population) 
14.2.4.1 
Cumulative Number of Subjects Who Met Rescue Therapy Criteria by Visit (Full Analysis Set) 
14.2.4.2 
Cumulative Number of Subjects Who Met Rescue Therapy Criteria by Visit (Per-Protocol 
Population) 
14.2.4.3 
Cumulative Number of Subjects Who Received Rescue Treatment by Visit (Full Analysis Set) 
14.2.4.4 
Cumulative Number of Subjects Who Received Rescue Treatment by Visit (Per-Protocol 


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Protocol No: RBM-007-002 
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Population) 
14.2.5.1.1 
Summary of Best Corrected Visual Acuity by Age Categories (Full Analysis Set) 
14.2.5.1.2 
Summary of Best Corrected Visual Acuity by Age Categories (Per-Protocol Population) 
14.2.5.2.1 
Summary of Best Corrected Visual Acuity by Gender (Full Analysis Set) 
14.2.5.2.2 
Summary of Best Corrected Visual Acuity by Gender (Per-Protocol Population) 
14.2.5.3.1 
Summary of Best Corrected Visual Acuity by Baseline BCVA Categories (Full Analysis Set) 
14.2.5.3.2 
Summary of Best Corrected Visual Acuity by Baseline BCVA Categories (Per-Protocol Population) 
14.2.5.4.1 
Summary of Best Corrected Visual Acuity by Baseline CST Categories (Full Analysis Set) 
14.2.5.4.2 
Summary of Best Corrected Visual Acuity by Baseline CST Categories (Per-Protocol Population) 
14.2.6.1.1 
Summary of Central Subfield Thickness (m) by Age Categories (Full Analysis Set) 
14.2.6.1.2 
Summary of Central Subfield Thickness (m) by Age Categories (Per-Protocol Population) 
14.2.6.2.1 
Summary of Central Subfield Thickness (m) by Gender (Full Analysis Set) 
14.2.6.2.2 
Summary of Central Subfield Thickness (m) by Gender (Per-Protocol Population) 
14.2.6.3.1 
Summary of Central Subfield Thickness (m) by Baseline BCVA Categories (Full Analysis Set) 
14.2.6.3.2 
Summary of Central Subfield Thickness (m) by Baseline BCVA Categories (Per-Protocol 
Population) 
14.2.6.4.1 
Summary of Central Subfield Thickness (m) by Baseline CST Categories (Full Analysis Set) 
14.2.6.4.2 
Summary of Central Subfield Thickness (m) by Baseline CST Categories (Per-Protocol 
Population) 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events (Safety Population) 
14.3.1.2 
Summary of Ocular Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term (Safety Population) 
14.3.1.3 
Summary of Non-Ocular Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
14.3.1.4 
Summary of Ocular Treatment-Related Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term (Safety Population) 
14.3.1.5 
Summary of Non-Ocular Treatment-Related Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Population) 
14.3.1.6 
Summary of Ocular Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
and Maximum Severity in the Study Eye (Safety Population) 
14.3.1.7 
Summary of Ocular Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
and Maximum Severity in the Non-Study Eye (Safety Population) 
14.3.1.8 
Summary of Non-Ocular Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term and Maximum Severity (Safety Population) 
14.3.1.9 
Summary of Ocular Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
and Highest Relationship to the Study Drug in the Study Eye (Safety Population) 
14.3.1.10 
Summary of Non-Ocular Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term and Highest Relationship to the Study Drug (Safety Population) 
14.3.1.11 
Summary of Treatment Emergent Adverse Events Related to the Injection Procedure by System 
Organ Class and Preferred Term (Safety Population) 
14.3.1.12 
Summary of Ocular Treatment Emergent Adverse Events Leading to Study Discontinuation by 
System Organ Class and Preferred Term (Safety Population) 
14.3.1.13 
Summary of Non-Ocular Treatment Emergent Adverse Events Leading to Study Discontinuation 
by System Organ Class and Preferred Term (Safety Population) 
14.3.2.1 
Summary of Ocular Treatment Emergent Serious Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
14.3.2.2 
Summary of Non-Ocular Treatment Emergent Serious Adverse Events by System Organ Class 
and Preferred Term (Safety Population) 
14.3.3.1 
Summary of Intraocular Pressure (mmHg) by Visit (Safety Population) 
14.3.3.2 
Categorical Changes of Intraocular Pressure (mmHg) from Baseline (Safety Population) 
14.3.4 
Summary of Slit Lamp Examination Findings (Safety Population) 
14.3.5 
Summary of Indirect Ophthalmoscopy Findings (Safety Population) 
14.3.6 
Summary of External Ocular Exam Parameter Findings (Safety Population) 
14.3.7 
Summary of Worsening of BCVA by Visit (Safety Population) 


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List of Figures 
 
Figure Number 
Figure Title 
14.4.1.1 
Best Corrected Visual Acuity (BCVA) by Visit (Full Analysis Set) 
14.4.1.2 
Best Corrected Visual Acuity (BCVA) by Visit (Per-Protocol Population) 
14.4.1.3 
Best Corrected Visual Acuity (BCVA) Change from Baseline by Visit (Full Analysis Set) 
14.4.1.4 
Best Corrected Visual Acuity (BCVA) Change from Baseline by Visit (Per-Protocol Population) 
14.4.2.1 
Central Subfield Thickness (CST) by Visit (Full Analysis Set) 
14.4.2.2 
Central Subfield Thickness (CST) by Visit (Per-Protocol Population) 
14.4.2.3 
Central Subfield Thickness (CST) Change from Baseline by Visit (Full Analysis Set) 
14.4.2.4 
Central Subfield Thickness (CST) Change from Baseline by Visit (Per-Protocol Population) 
14.4.3.1 
Macular Volume by Visit (Full Analysis Set) 
14.4.3.2 
Macular Volume by Visit (Per-Protocol Population) 
14.4.3.3 
Macular Volume Change from Baseline (mL) by Visit (Full Analysis Set) 
14.4.3.4 
Macular Volume Change from Baseline by Visit (Per-Protocol Population) 
14.4.4.1 
Forest Plot for Treatment Differences in Change form Baseline in BCVA at Week 16 (Full 
Analysis Set) 
14.4.4.2 
Forest Plot for Treatment Differences in Change form Baseline in CST at Week 16 (Full 
Analysis Set) 
14.4.5.1 
Intraocular Pressure (IOP) by Visit (Safety Population) 
14.4.5.2 
Intraocular Pressure (IOP) Change from Baseline by Visit (Safety Population) 
 
 
List of Listings 
 
Listing Number 
Listing Title 
16.1.7 
Randomization Schedule 
16.2.1.1 
Study Disposition (All Enrolled Population) 
16.2.1.2 
Inclusion/Exclusion Criteria Not Met (All Enrolled Population) 
16.2.1.3 
Subjects included in the Analysis Populations (All Enrolled Population) 
16.2.2 
Protocol Deviations (Safety Population) 
16.2.4.1 
Demographic and Baseline Characteristics (ITT Population) 
16.2.4.2 
Medical History (Safety Population) 
16.2.4.3 
Surgical History (Safety Population) 
16.2.4.4 
Prior AMD Treatment History (Safety Population) 
16.2.4.5 
Prior Medications (Safety Population) 
16.2.4.6 
Concomitant Medications (Safety Population) 
16.2.5.1 
Study Drug Exposure (Safety Population) 
16.2.5.2 
Rescue Treatments (Safety Population) 
16.2.6 
Efficacy Parameters (Full Analysis Set) 
16.2.7.1 
Adverse Events (Safety Population) 
16.2.7.2 
Adverse Events Related to Study Drug (Safety Population) 
16.2.7.3 
Adverse Events Related to Injection Procedure (Safety Population) 
16.2.7.4 
Serious Adverse Events (Safety Population) 
16.2.7.5 
Adverse Events Leading to Study Discontinuation (Safety Population) 
16.2.7.6 
Adverse Events Leading to Death (Safety Population) 
16.2.8 
Best Corrected Visual Acuity >=15 Letters Loss Relative to Baseline at Any Visit (Safety 
Population) 
16.2.9.1 
Intraocular Pressure Measurements (Safety Population) 
16.2.9.2 
Change in IOP of >=10 mmHg at any Visit Relative to Baseline (Safety Population) 
16.2.10.1 
Slit-lamp Parameter Results (Safety Population) 
16.2.10.2 
Worsening of Slit-Lamp Parameter at any Visit Relative to Baseline (Safety Population) 
16.2.11.1 
Indirect Ophthalmoscopy Parameters (Safety Population) 


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16.2.11.2 
Increase in Indirect Ophthalmoscopy Parameter at any Visit Relative to Baseline (Safety 
Population) 
16.2.12.1 
External Ocular Examination Parameters (Safety Population) 
16.2.12.2 
Worsening of External Ocular Examination Parameters at Any Visit Relative to Baseline (Safety 
Population) 
16.2.13 
Vital Signs Parameters at Screening (Safety Population) 
16.2.14 
Physical Examination Findings at Screening (Safety Population) 
16.2.15 
Pregnancy Test Results (Safety Population)