Phase 1b/2a Study of OPT-302 in Combination With Aflibercept for Persistent Central-involved Diabetic Macular Edema
Phase: PHASE1
Conditions: Diabetic Macular Edema
Sponsor: Opthea Limited



Product:  OPT-302 
Protocol Number:  OPT-302-1003 
Date:  02 August 2018 
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Investigator’s Agreement 
I have read the attached protocol entitled “Phase 1b/2a study of OPT-302 in combination with 
aflibercept for persistent central-involved diabetic macular edema”, dated 02 August 2018, and 
agree to abide by all provisions set forth therein. 
I agree to comply with the protocol, International Council on Harmonisation Tripartite Guideline on 
Good Clinical Practice and applicable regulatory requirements, and will make every reasonable effort 
to complete the study in a timely manner. 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of Opthea Ltd.  I will provide all study personnel under my supervision who participate in the 
conduct of this study with copies of the protocol and the investigator’s brochure, and with access to 
all relevant information provided by Opthea. I will discuss this material with them to ensure that they 
are fully informed about the investigational product and the study.   
I agree that Opthea, or their representatives will have direct access to any source documents from 
which electronic Case Report Form (eCRF) information has been derived.  The eCRFs and other 
data pertinent to this study are the property of Opthea and Opthea may utilize the data in various 
ways such as, for example, submission to government regulatory authorities, or in publication of the 
results of the study. 
 
  
 
 
 
Principal Investigator Signature 
 
Date (DD Month YYYY) 
 
 
Name of Principal Investigator 
 
Site name 
 

Product:  OPT-302 
Protocol Number:  OPT-302-1003 
Date:  02 August 2018 
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PROTOCOL SYNOPSIS 
Protocol Number 
OPT-302-1003 
Title 
Phase 1b/2a study of OPT-302 in combination with aflibercept for persistent central-
involved diabetic macular edema  
Sponsor 
Opthea Ltd 
Indication 
Diabetic macular edema (DME) 
Study Phase  
1b/2a 
Primary Objective(s) 
Phase 1b and Phase 2a: 
• 
Evaluate the safety and tolerability of OPT-302 intravitreal (IVT) injection in 
combination with IVT aflibercept in participants with central-involved DME  
Phase 2a: 
• 
Assess the response rate (≥ 5 letter gain in Best Corrected Visual Acuity [BCVA] 
from baseline to week 12according to ETDRS criteria) in participants with persistent 
central-involved DME receiving combination OPT-302 and aflibercept treatment  
Secondary Objective(s) 
To assess:  
• 
the mean change from baseline in BCVA  
• 
the mean change from baseline in central subfield thickness (CST) and macular 
volume (by spectral domain optical coherence tomography [SD-OCT]) 
• 
the percent of eyes with ≥ 50% reduction in excess foveal thickness (SD-OCT) 
• 
the percent of eyes with CST < 300 µm on SD-OCT  
• 
the percent of participants with a ≥ 2 step improvement in ETDRS Diabetic 
Retinopathy Severity Score  
• 
the mean time to, and number of, retreatment injections of aflibercept anti-VEGF-A 
therapy during long term follow-up (week 12 to 24)  
• 
the pharmacokinetics (PK) of OPT-302  
• 
anti-OPT-302 antibody formation 
Exploratory Objective(s) 
To evaluate: 
• 
the CST area under the curve (AUC) 
• 
the percent of eyes with resolution of fluid (sub-retinal fluid and intraretinal cysts) on 
SD-OCT 
 
 
Hypothesis 
The combination of OPT-302 with aflibercept administered by repeat IVT injections will 
achieve acceptable safety / tolerability with clinical activity in participants with persistent 
center-involving DME.   
Study Design 
Two part multi-center study consisting of a Phase 1b open-label, sequential dose 
escalation followed by a Phase 2a randomized, double-masked, dose expansion 
evaluating intravitreal OPT-302 in combination with aflibercept in participants with 
persistent central-involved DME.  
Planned No. of Subjects 
Approximately 117-126   
Dose Regimens  
Phase 1b dose escalation: The Phase 1b comprises 3 sequential treatment cohorts of 3 
to 4 participants per group receiving escalating dose levels of OPT-302 (0.3, 1 or 2 mg) 
each used in combination with aflibercept (2 mg).  OPT-302 and aflibercept will be 
administered as separate IVT injections (each 0.05 mL) every 4 weeks at Day 1, 29 and 
57.  When used in combination, the OPT-302 IVT injection will be given after IVT 
aflibercept, once a post injection safety check has been performed (which will include a 
check of optic nerve head perfusion, intraocular pressure [IOP] and visual function). 
The dose regimens for the 3 treatment cohorts in the Phase 1b are as follows: 
Cohort 1: 2 mg aflibercept and 0.3 mg OPT-302 
Cohort 2: 2 mg aflibercept and 1 mg OPT-302  
Cohort 3: 2 mg aflibercept and 2 mg OPT-302  
There will be no intra-subject dose escalation in this study. Phase 1b cohorts will enroll 
sequentially, starting with cohort 1.  The patient safety data will be reviewed by the data 

Product:  OPT-302 
Protocol Number:  OPT-302-1003 
Date:  02 August 2018 
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All participants that are enrolled or randomized and receive at least one administration of 
OPT-302 (i.e. the safety population) will be included in the analysis for PK. The PK 
parameters of OPT-302 will be estimated using standard non-compartmental PK 
methods and summarized using means, standard deviations, medians, minimums and 
maximums. Descriptive statistics will also be provided for selected demographic, safety, 
PK and imaging by dose and time as appropriate.  Descriptive statistics on continuous 
data will include means, medians, standard deviations, and ranges, while categorical 
data will be summarized using frequency counts and percentages.  Graphical summaries 
of the data may be presented.  Full details of the statistical analysis will be provided in the 
Statistical Analysis Plan. 

Product:  OPT-302 
Protocol Number:  OPT-302-1003 
Date:  02 August 2018 
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STUDY GLOSSARY 
Abbreviation or Term 
Definition/Explanation 
oC 
Degrees Celsius 
µm 
Micron(s) 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody Dependent Cell Mediated Cytotoxicity 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ARPE-19 
Human Retinal Pigmented Epithelial cell line 
AUC 
Area Under Curve 
AUC(0-∞) 
Area Under Curve from time zero to infinity 
BCVA 
Best Corrected Visual Acuity 
cm 
Centimeter(s) 
Cmax 
Maximum serum concentration 
CMC 
Complement Mediated Cytotoxicity 
CST 
Central Subfield Thickness 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DME 
Diabetic Macular Edema (Oedema) 
DR 
Diabetic Retinopathy 
DRCR.net 
Diabetic Retinopathy Clinical Research Network 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FA 
Fluorescein Angiography 
FDA 
Food and Drug Administration 
FIH 
First-in-Human 
GLP 
Good Laboratory Practice 
HbA1c 
Glycated Hemoglobin   
hr 
Hour 
HUVEC 
Human Umbilical Vein Endothelial Cell 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG1 
Immunoglobulin G1 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRC 
Independent Reading Center 
ITT 
Intent to Treat 
IV 
Intravenous 
IVT 
Intravitreal 
kg 
Kilogram(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
min 
Minute(s) 
mL 
Milliliter(s) 
mm 
Millimeter(s) 
mmHg 
Millimeters of mercury 
mOsmol 
Milliosmole(s) 
mRNA 
Messenger Ribonucleic Acid 
MTD 
Maximum Tolerated Dose 
nAMD 
Neovascular Age-Related Macular Degeneration 
ng 
Nanogram(s) 
NOAEL 
No Observed Adverse Effect Level 
OCT 
Optical Coherence Tomography 
OD 
Oculus Dextrus (right eye) 
OS 
Oculus Sinister (left eye) 
OU 
Oculus Uterque (both eyes) 
PC-3 
Prostate Cell line – human 

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Abbreviation or Term 
Definition/Explanation 
pg 
Picogram(s) 
PIGF 
Placental Growth Factor 
PK 
Pharmacokinetics 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-life 
TEAE 
Treatment Emergent Adverse Event 
tmax 
Time to maximal concentration 
VA 
Visual Acuity 
VAE 
Visual Acuity Examiner 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
YAG 
Yttrium Aluminium Garnet  

Product:  OPT-302 
Protocol Number:  OPT-302-1003 
Date:  02 August 2018 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................. 3 
STUDY DESIGN AND TREATMENT SCHEMA .............................................................. 8 
STUDY GLOSSARY ....................................................................................................... 9 
1. 
OBJECTIVES ....................................................................................................... 15 
1.1 
Primary ..................................................................................................... 15 
1.2 
Secondary ................................................................................................ 15 
1.3 
Exploratory ............................................................................................... 15 
2. 
BACKGROUND AND RATIONALE ...................................................................... 16 
2.1 
Disease .................................................................................................... 16 
2.2 
OPT-302 Background ............................................................................... 18 
2.2.1 
Vascular endothelial growth factors C and D ............................. 18 
2.2.2 
OPT-302 ................................................................................... 19 
 
 
 
 
 
 
 
 
 
 
2.3 
Clinical studies .......................................................................................... 22 
2.3.1 
Safety and tolerability ................................................................ 22 
 
 
2.4 
Risk Assessment ...................................................................................... 24 
2.5 
Rationale .................................................................................................. 25 
2.5.1 
Rationale for OPT-302 dose selection ....................................... 26 
2.6 
Clinical Hypothesis ................................................................................... 27 
3. 
EXPERIMENTAL PLAN ....................................................................................... 28 
3.1 
Study Design ............................................................................................ 28 
3.1.1 
Run-in Phase for Potential Participants receiving Prior 
Intravitreal Bevacizumab. .......................................................... 28 
3.1.2 
Phase 1b – Dose Escalation ..................................................... 28 
3.1.3 
Phase 2a – Randomized Dose Expansion ................................ 29 
3.2 
Number of Centers ................................................................................... 30 
3.3 
Number of Participants ............................................................................. 30 
3.4 
Estimated Study Duration ......................................................................... 31 
3.4.1 
End of Study ............................................................................. 31 
 
 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 32 
4.1 
Inclusion Criteria ....................................................................................... 32 
4.2 
Exclusion Criteria ...................................................................................... 33 
5. 
SUBJECT ENROLLMENT / RANDOMIZATION ................................................... 34 
6. 
INVESTIGATIONAL PRODUCT / STUDY INTERVENTION(S) ............................ 35 
6.1 
OPT-302 ................................................................................................... 35 
 
 
6.1.2 
Dosage, Administration, and Schedule ..................................... 37 

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10.5.1 
Phase 1b - Dose Escalation ...................................................... 70 
10.5.2 
Phase 2a - Dose Expansion ...................................................... 70 
10.6 
Statistical Analysis Plan ............................................................................ 71 
10.7 
Planned Methods of Analysis of Key Study Endpoints .............................. 71 
10.7.1 
Efficacy Endpoints .................................................................... 71 
10.7.2 
Safety Endpoints ....................................................................... 72 
10.7.2.1 
Adverse Events....................................................... 72 
10.7.2.2 
Dose Limiting Toxicities .......................................... 73 
10.7.2.3 
Clinical Laboratory Tests ........................................ 73 
10.7.2.4 
Vital Signs ............................................................... 73 
10.7.2.5 
Electrocardiograms ................................................. 73 
10.7.2.6 
Anti-OPT-302 Antibodies ........................................ 73 
10.7.3 
Pharmacokinetic (PK) Analyses ................................................ 73 
11. 
REGULATORY OBLIGATIONS ............................................................................ 73 
11.1 
Informed Consent ..................................................................................... 73 
11.2 
Regulatory Considerations ........................................................................ 74 
11.3 
Institutional Review Board / Independent Ethics Committee ..................... 74 
 
 
11.5 
Subject Confidentiality .............................................................................. 75 
11.6 
Investigator Signatory Obligations ............................................................ 76 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 76 
12.1 
Clinical Trial Agreement ............................................................................ 76 
12.2 
Protocol Amendments and Study Termination .......................................... 76 
12.3 
Study Documentation and Archive ............................................................ 77 
12.4 
Study Monitoring, Data Collection and Quality Management .................... 77 
12.5 
Language ................................................................................................. 79 
12.6 
Transfer of Sponsor Obligations ............................................................... 80 
12.7 
Publication Policy ...................................................................................... 80 
 
 
13. 
REFERENCES ..................................................................................................... 82 
14. 
APPENDICES ...................................................................................................... 86 
Appendix A.  Phase 1b Schedule of Assessments ........................................................ 87 
Appendix B.  Phase 2a Schedule of Assessments ........................................................ 89 
 
Appendix D.  Refraction and Vision Testing Protocol (ETDRS) ..................................... 92 
 

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1. 
OBJECTIVES 
1.1 
Primary  
Phase 1b and Phase 2a: 
• 
Evaluate the safety and tolerability of OPT-302 intravitreal (IVT) injection in combination with 
IVT aflibercept in participants with central-involved DME  
Phase 2a: 
• 
Assess the response rate (≥ 5 letter gain in BCVA according to ETDRS criteria from baseline 
to week 12) in participants with persistent central-involved DME receiving combination OPT-
302 and aflibercept treatment 
1.2 
Secondary  
To assess:  
• 
the mean change from baseline in BCVA  
• 
the mean change from baseline in central subfield thickness (CST) and macular volume (by 
spectral domain optical coherence tomography [SD-OCT]) 
• 
the percent of eyes with ≥ 50% reduction in excess foveal thickness (SD-OCT) 
• 
the percent of eyes with CST < 300 µm on SD-OCT  
• 
percent of participants with ≥ 2 step improvement in EDTRS Diabetic Retinopathy Severity 
Score 
• 
the mean time to, and number of, retreatment injections of aflibercept anti-VEGF-A therapy 
during long term follow-up (week 12 to 24)  
• 
the pharmacokinetics of OPT-302  
• 
anti-OPT-302 antibody formation 
1.3 
Exploratory 
To evaluate:  
• 
the CST Area under the Curve (AUC) 
• 
the percent of eyes with resolution of fluid (sub-retinal fluid and intraretinal cysts) on SD-OCT 
 
 

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2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and is the 
leading cause of vision loss among working age adults in developed countries (Solomon et al., 
2017).  Approximately one-third of patients with DR or up to ~7-10% of diabetics have diabetic 
macular edema (DME) which is characterized by accumulation of fluid and retinal thickening within 
the macula and is responsible for most of the central visual loss experienced in the diabetic 
population (Ding and Wong, 2012; Lee et al., 2015).  A review of the natural history of DME showed 
~50% of eyes lost ≥ 2 lines of visual acuity over two-years, while in the Early Treatment Diabetic 
Retinopathy Study (ETDRS) a third of untreated eyes with center-involved DME experienced ≥ 15 
letter decrease in visual acuity in 3 years (Ferris and Patz, 1984; EDTRS report No.4, 1987).  With 
the increasing prevalence of diabetes worldwide, vision loss from DME represents a significant 
public health issue with considerable socioeconomic burden (Kiss et al., 2016). 
Factors associated with increased risk of DR include diabetes duration, hyperglycemia, hypertension 
and dyslipidemia (Klein et al., 1994; Klein et al., 2010; Lee et al., 2015; Solomon et al., 2017).  While 
management of diabetes with control of blood glucose, blood pressure, and serum lipid levels in 
conjunction with scheduled eye examinations can delay the onset and progression of DR and 
decrease the risk of vision loss, a significant proportion of those affected with diabetes will develop 
DME or proliferative changes that require intervention. (UK prospective diabetes study group, 1998; 
Chew et al., 2010).  
Central involved DME is classified as retinal thickening including edema in the macula affecting the 
central subfield region that is 1 mm in diameter.  The pathophysiological mechanisms leading to 
DME are multifactorial, complex and still to be fully elucidated.  However, it is known that 
hyperglycemia can cause vascular endothelial damage and induce microvascular leakage 
secondary to breakdown of the inner blood-retinal barrier which leads to thickening or swelling of the 
macula and potential loss of sight if the edema involves the center of the fovea (Klaassen et al., 
2013).  In addition, ischemia secondary to capillary non-perfusion, caused by diabetic microvascular 
damage stimulates the release of vascular endothelial growth factor-A (VEGF-A) which is a major 
contributor to neovascularization, vascular permeability and may also have pro-inflammatory 
properties (Aiello et al., 1994; Senger et al., 1990; Ishida et al., 2003).  Expression of VEGF-A and 
its receptor, VEGFR-2, have been shown to be greater in diabetic than non-diabetic retinal tissues in 
humans and VEGFR-2 is concentrated in microvascular epithelial cells, including those in the 
macula (Sun et al., 2014; Witmer et al., 2002; Zhao et al., 2007).  Ocular levels of inflammatory 
factors which are also regulated and produced by endothelial cells are increased in patients with 

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DME indicating an important role for inflammation in the disease process (Shin et al., 2014; 
Kocabora et al., 2016). 
The treatment of central-involved DME has markedly changed over the last decade, from the 
primary use of focal / grid laser photocoagulation, to the current era of intravitreal pharmacotherapy 
including anti-VEGF-A agents and corticosteroids.  The role of VEGF-A in the pathophysiology of 
retinal diseases, including wet age-related macular degeneration and DME, has led to the 
breakthrough development of several inhibitor drugs that target this ligand.  The positive clinical data 
and approval of these drugs have validated the importance of the VEGF family of ligands and 
receptors in the pathogenesis of DR and DME.   
Following the regulatory approval of aflibercept (Eylea®; Regeneron), and ranibizumab (Lucentis®; 
Genentech), as well as the off-label use of bevacizumab (Avastin®, Genentech), the treatment 
landscape has significantly altered for patients and currently anti-VEGF-A therapy is the first-line 
standard of care for central-involved DME (Jampol et al., 2014).  Aflibercept is a soluble decoy 
receptor fusion protein created using Trap technology, which targets VEGF-A, placental growth 
factor (PIGF) and VEGF-B (Regeneron, BLA 125387, 2011).  The DA VINCI, VISTA and VIVID 
studies demonstrated that treatment with aflibercept yielded greater visual gains than macular laser 
treatment in patients with central involved DME (Korobelnik et al., 2014; Payne and Clarke, 2015).  
The binding affinity of aflibercept to VEGF-A is substantially greater than that of ranibizumab and 
bevacizumab to VEGF-A, potentially allowing for a less frequent dosing regimen (once every 8 
weeks) following an initial monthly loading dose phase (Stewart and Rosenfeld, 2008).   
Recent data from the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol T 
comparing all three anti-VEGF-A drugs, indicated that at 1 year for eyes with central-involved DME, 
each agent improved visual acuity (VA) (Wells et al., 2015).  There was no difference among the 
three agents in mean change in VA in eyes with baseline vision of 20/32 to 20/40, whereas 
aflibercept had more effective vision outcomes in eyes with baseline VA of 20/50 to 20/320 (Wells et 
al., 2015).  At 2 years, aflibercept remained superior to bevacizumab, but not ranibizumab, among 
eyes with baseline VA of 20/50 or worse, while all three drugs had similar safety profiles (Wells et 
al., 2015; Cai and Bressler, 2017).  Most patients with central involved DME require near-monthly 
administration of intravitreal therapy with these anti-VEGF-A agents during the first 12 months of 
treatment, with fewer injections needed in subsequent years to maintain clinical benefit (Solomon et 
al., 2017). 
Intravitreous steroid therapy has also been evaluated in pivotal Phase 3 studies, and the steroid 
agents dexamethasone and fluocinolone acetonide are approved for use in central involved DME. 
These agents however, are rarely used as first-line therapy due to inferior visual acuity outcomes 

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compared to anti-VEGF-A therapy.  Patients with persistent DME and who are insufficiently 
responsive to anti-VEGF-A therapy have shown some treatment benefit with intravitreal 
corticosteroids (Schwartz et al., 2016; Regillo et al., 2017).  However, as intravitreal corticosteroids 
are associated with high rates of ocular adverse events including cataract progression and 
intraocular pressure elevation, switching to corticosteroids from an anti-VEGF-A agent with a sub-
optimal response needs to be carefully considered in patients with glaucoma and in young phakic 
patients (Shah et al., 2017).  Steroids are therefore preferred in pseudophakic eyes that have 
chronic / persistent or recurrent disease. 
Despite the widespread use of treatments targeting VEGF-A in the management of retinal disorders 
including DME, there is still room for improvement as many patients demonstrate a sub-optimal 
response, remain treatment refractory, or require frequent injections for persistent leakage in the 
macula.  A substantial proportion of patients with central involved DME do not show reductions in 
fluid or clinically significant improvement in visual acuity following anti-VEGF-A treatment (Nguyen et 
al, 2012; Channa et al., 2014; Do et al., 2013).  This resistance may occur as treatment selective 
anti-VEGF-A monotherapies do not fully address the multifactorial pathogenesis of fovea involving 
edema.  Thus potential combination therapies targeting alternative factors and pathways are 
currently being investigated for the treatment of central involved DME (Campochiaro et al., 2016; 
Kaiser, 2017). 
2.2 
OPT-302 Background  
2.2.1 
Vascular endothelial growth factors C and D 
The VEGF-C and VEGF-D members of the VEGF family of secreted glycoproteins are upregulated 
in response to inhibition of VEGF-A with aflibercept or bevacizumab (Cabral et al., 2016; Lieu et al., 
2013; Li et al., 2014; Rose et al., 2010; Fan et al., 2011; Grau et al., 2011).  Such upregulation may 
be an important mechanism contributing to clinical sub-responsiveness reported with VEGF-A 
inhibitors.  Both VEGF-C and VEGF-D induce angiogenic vessel growth in several in vivo models, 
while VEGF-C can also cause the formation of endothelial cell fenestrations, which increases 
vascular permeability (Cao et al., 1998; Witzenbichler et al., 1998; Chung et al., 2009; Stacker et al., 
2001). 
VEGF-C contributes to increased vascular permeability and/or retinal angiogenesis through 
downstream effects of VEGFR-2 and VEGFR-3 activation (Tammela et al., 2011; Joukov et al., 
1998; Joukov et al., 1997; Cao et al., 2004; Gaal et al., 2013; Xu et al., 2013).  Expression of 
VEGFR-2 is greater in human diabetic retina than in non-diabetics and the receptor is concentrated 
in microvascular endothelial cells including those in the macula region (Witmer et al., 2002; Sun et 
al., 2014; Zhao et al., 2007).  Furthermore, VEGF-C can potentiate the angiogenic actions of VEGF-

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A as it’s binding to VEGFR-2 inhibits apoptosis of microvascular endothelial cells induced by the pro-
inflammatory cytokine tumor necrosis factor and hyperglycemia (Zhao et al., 2006; Zhao et al., 
2007).  There is also an increase in VEGF-C and VEGF-A mRNA in microvascular endothelial cells 
of individuals with diabetes (Zhao et al., 2007).  Evaluation of single nucleotide polymorphisms in 
diabetic patients found that genetic variation within the VEGF-C gene is associated with DR and 
DME indicating that VEGF-C and its interaction with VEGFR-2 may play a functional role in the 
pathogenesis of these diseases (Kaidonis et al., 2015). 
2.2.2 
OPT-302 
OPT-302 is a recombinant fusion protein comprising immunoglobulin-like domains 1-3 of the 
extracellular domain of human vascular endothelial growth factor receptor-3 (VEGFR-3) and the Fc 
fragment of human immunoglobulin G1 (IgG1).  It functions by binding and neutralizing the activity of 
VEGF-C and VEGF-D on endogenous VEGFR-2 and VEGFR-3.  
The activity of OPT-302 both as a targeted inhibitor of VEGF-C and VEGF-D, and also the biological 
consequences of such inhibition in the eye, have been investigated in a number of in vitro and in 
vivo studies.  These studies confirm the selective binding of OPT-302 to, and inhibition of, VEGF-C 
and VEGF-D, but not VEGF-A or placenta growth factor (PIGF).  Pre-clinical pharmacology studies 
of an OPT-302 analogue (VGX-300) in the laser-induced choroidal neovascularization mouse model, 
demonstrated that targeted inhibition of VEGF-C/D has significant efficacy when used alone or in 
combination with aflibercept anti-VEGF-A therapy (Lashkari et al., 2014). 
The biological effects to induce angiogenesis by VEGF-C and VEGF-D or vascular permeability by 
VEGF-C, as well as the compensatory upregulation of these two ligands which can occur when 
VEGF-A is inhibited, support the clinical investigation of OPT-302 in combination with existing anti-
VEGF-A therapies for persistent central-involved DME.  Combination therapy with a VEGF-A 
inhibitor and OPT-302 is expected to result in more effective inhibition of central involved macular 
edema in treatment refractory diabetic patients compared to VEGF-A neutralization alone. 
 
 
 
 
 
 
 
 
  

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2.3 
Clinical studies 
2.3.1 
Safety and tolerability 
OPT-302 has demonstrated acceptable safety and tolerability up to 2 mg administered by repeat IVT 
dosing every 4 weeks either alone or in combination with the anti-VEGF-A therapy, ranibizumab (0.5 
mg), in a Phase 1 first in human (FIH) study (OPT-302-1001) in 51 patients with nAMD.  The Phase 
1 study consisted of two parts: Part 1 was an open-label, sequential dose escalation (n=20; 0.3, 1 or 
2 mg OPT-302 with 0.5 mg ranibizumab, or 2 mg OPT-302 monotherapy, in 4 cohorts of 5 patients 
each); Part 2 was a randomized dose expansion (n=31, 2 mg OPT-302 with 0.5 mg ranibizumab 
[n=23] or 2 mg OPT-302 monotherapy [n=8]).  All study drugs were administered by IVT injection for 

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three consecutive dosing cycles at 4 weekly intervals.  Of the 51 patients enrolled, 19 (37%) were 
male, 32 (63%) were female, 10 (20%) had diabetes mellitus and 25 (49%) were treatment naïve, 
while 26 (51%) had received ≥ 3 prior IVT injections of anti-VEGF-A therapy. 
No dose-limiting toxicities (DLTs) were observed with OPT-302 at any IVT dose level up to 2 mg 
either in combination with anti-VEGF-A therapy or as a monotherapy, and the MTD was not reached.  
In addition, there was no evidence of OPT-302 related immunogenicity after IVT administration of 
OPT-302 doses up to 2.0 mg/eye. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
Overall, 100% of evaluable participants at Week 12 (n=49) maintained BCVA, defined as ≤15 letter 
loss from baseline.  In addition, changes from baseline in anatomic measures (CST) on SD-OCT 
through to week 12, demonstrated no adverse safety signals in treatment naïve patients and those 
who showed a sub-optimal response to prior anti-VEGF-A therapy. 

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In summary, OPT-302 was well tolerated at doses up to 2 mg when administered by repeat 
intravitreal injections once every 4 weeks, either in combination with anti-VEGF-A therapy (0.5 mg 
ranibizumab) or as a monotherapy. 
 
 
 
 
 
 
 
 
 
  
2.4 
Risk Assessment 
Dose selection for this study is based on the current safety and PK data of OPT-302, assessed in a 
Phase 1 FIH study in 51 patients with nAMD and in nonclinical studies 
.  Based on 
the available data, administration of 0.3, 1 or 2 mg OPT-302 by IVT injection once every 4 weeks on 
Days 1, 29 and 57 is anticipated to have an acceptable risk benefit profile with acceptable safety and 
tolerability in participants with central involved DME. 
The other study drug to be used in the study is aflibercept which has been approved and is widely 
used globally for retinal vascular diseases including central involved DME.  Overall, IVT aflibercept is 
a highly effective and safe therapy for improving vision and reducing vision loss in patients with 
DME.  Cumulative safety data to date do not show an increased risk of any ocular or systemic 
adverse events with this anti-VEGF-A agent compared to other similar drugs used to treat these 
indications (Wells et al., 2015; Wells et al., 2016).  There is therefore no additional risk to the use of 
this drug over and above standard care and the participants would likely be treated in the clinic with 
IVT injections of aflibercept or a similar anti-VEGF-A agent, even if not enrolled in this study  
 
  
 
 
 
 

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Participants enrolled in this study will be monitored closely in the clinic following dosing with 
aflibercept and OPT-302. 
 
 
  Further details of the safety data for aflibercept may be 
found in the package insert and the approved label for the drug. 
2.5 
Rationale 
Intravitreal anti-VEGF-A therapy has become the standard of care for most cases of center involving 
DME.  However, even with monthly or near monthly IVT injections for the first 12 months utilized in 
controlled clinical trials, > 35 % of patients with DME treated with anti-VEGF-A therapy fail to achieve 
≥ 2 lines improvement in VA from baseline at 2 years, while approximately a third or more of eyes 
still had CST ≥ 300 µm at 1 year, or did not have complete resolution of retinal thickening (< 250 µm 
on time domain OCT) by 2 years (Elman et al., 2011; Rajendram et al., 2012; Nguyen et al., 2012).  
In addition, data suggest that sub-optimally responding eyes may be identified after as few as 3 anti-
VEGF injections and should be considered for alternate therapies (Gonzalez et al., 2016).  A post 
hoc analysis of the DRCR network Protocol I study showed that ~40% of eyes had a poor mean 
BCVA response of < 5 letter gain from baseline, while ~23% of eyes showed a moderate mean VA 
gain of 5 - 9 letters from baseline after 3 monthly injections of ranibizumab, and both groups then 
only achieved a further mean VA improvement of < 3 letters at 1 and 3 years (Gonzalez et al., 2016).  
Within the subset of patients with a poor BCVA of < 5 letter at 12 weeks, a minority of eyes (23%) 
continuing to receive regular monthly anti-VEGF-A therapy slowly improved their response to at least 
a 10 letter gain from baseline at 52 weeks (Gonzalez et al., 2016).   
Tolerance or tachyphylaxis, differences in drug levels between patients and resistance have all been 
proposed as potential reasons for suboptimal results in retinal diseases treated with anti-VEGF-A 

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therapy (Schaal et al., 2008; Eghoj and Sorensen 2012).  Various reasons for this, including 
differences in individual VEGF-A gene expression, up-regulation of alternative factors and pathways, 
and a shift to chronic inflammation mechanisms have been implicated (Forooghian et al., 2011).  To 
overcome this suboptimal response, strategies involving more intensive dosing regimens or 
switching drugs within the same anti-VEGF-A pharmacologic group have been used with alternative 
anti-VEGF-A agents reportedly showing further anatomic improvements but limited changes in VA 
(Lim et al., 2015; Rahimy et al., 2016; Spooner et al., 2017; Mira et al., 2017).  However, many of 
these studies have either been retrospective and / or employ varied methodologies including 
differing retreatment regimens, variable entry criteria and non-standardized VA measurements.  
Thus, refractory eyes responding sub-optimally to first-line therapy characterized by persistent or 
recurrent retinal thickening and/or poor gains in VA represent a therapeutic challenge with a high 
unmet medical need. 
Since treatment selective anti-VEGF-A monotherapies do not fully address the multifactorial 
pathogenesis of center involving DME, potential adjunctive therapies targeting alternative factors 
and pathways are currently being investigated (Campochiaro et al., 2016; Kaiser, 2017).  Increased 
levels of the ligands VEGF-C/D upregulated in response to inhibition of VEGF-A with aflibercept or 
bevacizumab may represent an alternate mechanism contributing to sub-responsiveness reported 
with VEGF-A inhibitors (Cabral et al., 2016; Lieu et al., 2013; Li et al., 2014; Rose et al., 2010; Fan 
et al., 2011; Grau et al., 2011).  In the Phase 1 FIH study (OPT-302-1001), nAMD patients (n=19) 
showing a sub-optimal response to prior IVT anti-VEGF-A therapy (mean number of prior injections 
= 17 [range 3 to 76]), and subsequently receiving combination OPT-302 with ranibizumab for 3 
monthly IVT injections, had a change from baseline to week 12 in mean BCVA of +4.9 letters and a 
reduction in mean CST of -54 µm.  A total of 10/19 (53%) of these patients receiving combination 
OPT-302 with ranibizumab had a ≥ 5 letter gain from baseline at week 12 in BCVA despite being 
treatment refractory to prior anti-VEGF-A therapy. 
OPT-302 which blocks the alternative VEGF-C/D angiogenesis and vascular leakage ligand 
pathways, therefore represents a novel therapeutic candidate to be used in combination with the 
anti-VEGF-A inhibitor, aflibercept as a potential treatment of center involved DME. 
2.5.1 
Rationale for OPT-302 dose selection 
OPT-302 in combination with aflibercept will be investigated in the Phase 1b / 2a study.  The pre-
specified nominal doses of OPT-302 for use in the dose escalation are a starting dose at 0.3 mg, 
escalating to 1 mg and a potential maximum dose of 2 mg, administered by IVT injection once every 
4 weeks for a total of 3 injections.  
 
  The doses for OPT-302 were selected based on 

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the clinical and non-clinical safety data 
 and PK modelling derived from 
 clinical 
PK samples.  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The clinical and non-clinical data support the proposed dosing regimen for OPT-302 at dose levels 
up to 2 mg when used in combination with intravitreal anti-VEGF-A therapy (aflibercept) 
administered by sequential intravitreal injection once every 4 weeks. 
2.6 
Clinical Hypothesis 
The combination of OPT-302 with aflibercept administered by repeat IVT injections will achieve 
acceptable safety / tolerability with clinical activity in participants with persistent center-involving 
DME. 

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• 
Cohort 3: 2 mg aflibercept and 2 mg OPT-302 
Following the third IVT injection participants will have a 4 week treatment free follow-up through 
week 12 and an additional longer-term follow-up through week 24 when standard of care IVT 
aflibercept retreatment will be based on protocol-specified retreatment criteria for persistent DME if 
visual acuity (VA) or central subfield thickness (CST) on SD-OCT worsens (defined as a ≥ 10% 
decrease increase in CST or a ≥ 5 letter decline in VA from the last study treatment phase visit [Day 
57]).   
Dose escalation cohorts in the Phase 1b will enroll sequentially, starting with cohort 1.  
 
 
 
 
At least 3 patients must 
complete the 14 day DLT period at each dose level before the data review team can consider dose 
escalation. 
 
 
 
3.1.3 
Phase 2a – Randomized Dose Expansion 
The Phase 2a randomized dose expansion will begin dependent upon agreement by the data review 
team based on their review of emerging safety data from the Phase 1b dose escalation phase (once 
all participants have completed the 14 day DLT window).   
In the Phase 2a, at least 108 participants will be assigned randomly in a 2:1 ratio to one of the 
following two treatment groups: 
• 
Cohort 4: 2 mg aflibercept + OPT-302 (at MTD or highest dose tested from the Phase 1b) 
• 
Cohort 5: aflibercept + sham 
Cohort 4 will dose a minimum of 72 participants using IVT aflibercept (2 mg in 0.05 mL) in 
combination with OPT-302 (0.05 mL) at the MTD or highest tested dose from the Phase 1b, given 
once every 4 weeks (Day 1, 29 and 57) for a total of 3 sequential injections.  
Cohort 5 will dose a minimum of 36 participants with IVT aflibercept (2 mg in 0.05 mL) + sham once 
every 4 weeks (Day 1, 29 and 57) for a total of 3 injections.  Randomization to cohorts 4 and 5 will 
continue until 72 evaluable participants are available in the aflibercept + OPT-302 experimental arm. 
The OPT-302 IVT injection (or sham) is given sequentially after IVT aflibercept by the unmasked 
injecting investigator once a post injection safety check has been performed (which will include a 

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check of optic nerve head perfusion, intraocular pressure and visual function).  
 
 
 
 
 
 
 
 
Participants will have a further 4 week treatment free follow-up through week 12 and an additional 
longer-term follow-up through week 24 when standard of care IVT aflibercept retreatment will be 
based on protocol-specified retreatment criteria for persistent DME if VA or CST on SD-OCT 
worsens (defined as a ≥ 10% increase in CST or a ≥ 5 letter decline in VA from the last study 
treatment phase visit [Day 57]).   
In the Phase 2a randomized dose expansion the investigator ophthalmologist and VA examiners will 
be “masked” to the individual treatment assignments.  Evaluation of SD-OCT scans, color fundus 
photographs and FA images will be performed by a masked observer, unaware of participant 
treatment assignment, both at the site and at the Independent Reading Center. 
The overall study design is described by a study design and treatment schema at the end of the 
protocol synopsis section. 
3.2 
Number of Centers 
The study will be conducted at up to ~25-50 Ophthalmology sites with expertise in retinal disorders. 
3.3 
Number of Participants 
In the Phase 1b dose escalation, at least 9 adult participants ≥ 18 years with persistent central-
involved DME who have received prior IVT anti-VEGF-A therapy with the need for additional therapy 
are expected to be enrolled. The sample size for the Phase 1b dose escalation was determined 
empirically and is consistent with historical precedence for initial human clinical study of therapies 
including in retinal eye disease.  In the Phase 2a dose expansion, at least 108 participants will be 
randomized in a 2:1 ratio to two treatment groups of (i) OPT-302 at the MTD or highest dose tested 
from the Phase 1b, in combination with aflibercept (2 mg) or (ii) aflibercept (2 mg + sham.  
The rationale for the number of participants in the Phase 2a study is detailed in Section 10.3. 

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3.4 
Estimated Study Duration 
It is estimated that the study duration for participants in the active treatment phase will be 6 months 
consisting of 14 days for screening, 2 months of treatment (at Day 1, 29 and 57) depending on 
tolerability to aflibercept ± OPT-302 (or sham) and week 12 and 24 follow-up visits.  For the study 
participants who enter the run-in phase, there will be an additional ~4 to 6 weeks prior to entry into 
the active treatment phase.  
3.4.1 
End of Study 
Primary Completion:  The primary completion of study will occur when target enrollment or 
randomization is complete and each participant does at least one of the following: 
• 
Has had the opportunity to complete the week 12 visit on study, or 
• 
Withdraws from study 
End of Trial:  The end of trial will occur when target enrollment or randomization is complete and 
each participant either withdraws from study or completes the week 12 follow up visit or the week 24 
long-term follow-up. 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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4. 
SUBJECT ELIGIBILITY 
Adult participants ≥ 18 years with diabetes mellitus with central-involved macular edema with a 
suboptimal response despite prior intravitreal anti-VEGF-A therapy which in the opinion of the 
investigator might benefit from additional treatment.  
 
 
 
 
4.1 
Inclusion Criteria 
4.1.1 
Able and willing to provide written informed consent  
4.1.2 
Age ≥ 18 years of either gender 
4.1.3 
Diabetes mellitus (type 1 or type 2) 
4.1.4 
Edema that involves the center of the macula as confirmed by the reading center 
4.1.5 
Eyes with recurrent / persistent DME despite prior intravitreal anti-VEGF therapy with a 
suboptimal response and defined as meeting all of the following:  
o 
Ophthalmoscopic evidence of center-involved DME  
o 
Retinal thickness ≥ 320 µm in the central 1 mm subfield on Spectralis (Heidelberg) 
SD-OCT (or ≥ 305 µm on Cirrus) as confirmed by the reading center 
o 
DME is the cause of OCT thickening despite ongoing treatment with either aflibercept 
or ranibizumab with ≥ 3 prior IVT injections within 5 months of study Day 1, the most 
recent injection being ≤ 42 days prior to study Day 1 (prior bevacizumab allowed only 
if therapy subsequently switched to intravitreal aflibercept or ranibizumab for ≥ 1 
most recent injection(s) prior to study Day 1) 
4.1.6 
History of center-involved macular edema requiring treatment, including intravitreal ant-
VEGF-A therapy, for ≤ 24 months (maximum number of intravitreal anti-VEGF-A injection 
cycles is ≤ 24) 
4.1.7 
BCVA letter score ≤ 73 and ≥ 24 (approximate Snellen equivalent 20/40 to 20/320; Snellen 
[metric] equivalent 6/12 to 6/96) in the study eye, inclusive 
4.1.8 
If female and of child-bearing potential: Pregnancy test at screening and Day 1 is negative, 
and agrees to use a highly effective method of contraceptive for the duration of the study and 
for at least 3 months following the last dose of study medication.  The following are 
considered “highly effective methods”: i.e. hormonal contraceptive (oral, intravaginal, or 
implant, but excluding progestogen-only oral hormonal contraception where inhibition of 
ovulation is not the primary mode of action); intrauterine device; or documented vasectomy 
of partner.  A participant will not be considered to be of child-bearing potential if she is post-
menopausal and has not had menses for at least 12 months prior to screening (by history), 
or if surgically sterile 
4.1.9 
Only one eye will be enrolled in the study. (If both eyes meet the entry criteria the study eye 
chosen is the worse eye (based on investigator assessment of SD-OCT and / or VA).  If both 
eyes are equal, the participant and investigator will select the eye for entry). 

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4.2 
Exclusion Criteria 
4.2.1 
Eyes in which scatter (panretinal) photocoagulation is needed now or is likely to be needed 
within the next 3 months (e.g. eyes with high risk proliferative diabetic retinopathy [defined as 
neovascularization of the disc > 1/3 disc area or neovascularization elsewhere > 1/2 disc 
area and presence of vitreous hemorrhage regardless of size of neovascularization] not 
already adequately treated with photocoagulation) 
4.2.2 
Macula edema is considered to be due to a cause other than DME in the study eye (e.g. 
clinical exam by investigator and OCT as confirmed by the reading center suggest that 
vitreoretinal interface abnormalities such as taut posterior hyaloid or epiretinal membrane are 
the primary cause of macular edema) 
4.2.3 
Presence of any abnormality that in the opinion of the investigator would be likely to 
confound assessment of visual acuity improvement in the study eye in which macular edema 
resolves, or improves, such as dense subfoveal hard exudates, neovascular glaucoma, or 
presence of chorioretinal / foveal atrophy involving the center of the macula 
4.2.4 
Vitreoretinal traction confirmed by OCT, or seen clinically within 1 disc diameter of the center 
of the macula of the study eye as confirmed by the reading center 
4.2.5 
Any retinal vein occlusion involving the macula in the study eye as confirmed by the reading 
center 
4.2.6 
Any intraocular surgery in the study eye within 4 months of study entry or anticipated within 
the next 3 months following dosing on Day 1. 
4.2.7 
Previous vitrectomy or scleral buckling surgery in the study eye 
4.2.8 
HbA1C level ≥12% and/or recent signs of uncontrolled diabetes (3 or more episodes of 
severe hypoglycemia within 3 months of baseline, or hospitalization for hyperglycemia, or 2 
or more episodes of ketoacidosis within 1 year of baseline, or an episode of ketoacidosis 
within 3 months of baseline). 
4.2.9 
Renal failure, dialysis, or history of renal transplant  
4.2.10 Myocardial infarction, other cardiac event requiring hospitalization, stroke, transient ischemic 
attack, or treatment for congestive heart failure within 6 months prior study Day 1. 
4.2.11 Uncontrolled hypertension ≥180 mmHg systolic or ≥110 mmHg diastolic. (If blood pressure is 
brought below 180/110 mmHg by anti-hypertensive treatment, the individual can become 
eligible.  Participants with a history of controlled hypertension on medication may have their 
blood pressure taken at a second visit to qualify based on the repeat testing). 
4.2.12 Pregnant or lactating 
4.2.13 Major surgery (defined as intra-abdominal or surgery requiring general anesthesia) within 28 
days prior to dosing on study Day 1 or major surgery planned during the next 6 months. 
4.2.14 Previous treatment with photodynamic therapy or external beam radiation in the study eye 
4.2.15 Subjects who have received panretinal or focal / grid photocoagulation, YAG laser, or 
peripheral retinal cryoablation (for retinal tears only) in the study eye within the previous 4 
months 
4.2.16 Concurrent or prior use of systemic anti-VEGF agents 
4.2.17 Concurrent or prior use of intravitreal bevacizumab in the study eye, unless therapy switched 
to intravitreal aflibercept or ranibizumab for ≥ 1 most recent injection(s) prior to Day 1  
4.2.18 Most recent intravitreal injection of aflibercept or ranibizumab less than 28 days or greater 
than or equal to 42 days prior to Day 1 dosing in the study eye 

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4.2.19 Administration of systemic steroids within 4 months prior to Day 1  
4.2.20 Concurrent or prior use of any intravitreal injections of steroids within 4 months prior to Day 1 
in the study eye 
4.2.21 Concurrent or prior use of dexamethasone implant in the study eye 
4.2.22 Concurrent or prior use of fluocinolone implant in the study eye   
4.2.23 Concurrent or prior administration of experimental therapy within 30 days of screening 
4.2.24 Concurrent treatment for active systemic (non-ocular) infection at screening, if in the opinion 
of the investigator, doing so will place the participant at undue risk  
4.2.25 Concurrent treatment in either eye for any ocular condition with an investigational drug or 
device that has not received regulatory approval  
4.2.26 Concurrent or prior use of thiazolidinediones within 6 months prior to Day 1 dosing 
4.2.27 Active or recent (within 4 weeks) intraocular inflammation (grade trace or above) in the study 
eye 
4.2.28 Any active periocular or intraocular infection or inflammation (e.g.  conjunctivitis, keratitis, 
scleritis, uveitis or endophthalmitis) 
4.2.29 Subjects with other ocular diseases that can in the opinion of the investigator compromise 
the visual acuity of the study eye such as amblyopia and anterior ischemic optic neuropathy 
4.2.30 History of idiopathic or autoimmune-associated uveitis in either eye. 
4.2.31 Current vitreous hemorrhage at the screening assessments in the study eye as confirmed by 
the reading center 
4.2.32 Uncontrolled glaucoma (>30 mmHg) either untreated or on anti-glaucoma medication at 
screening 
4.2.33 Known allergy to any component of the study drug(s)  
4.2.34 Prior participation in this clinical trial 
4.2.35 History or evidence of clinically significant disorder, condition or disease (with the exception 
of those outlined above) that, in the opinion of the investigator or medical monitor would pose 
a risk to participant safety or interfere with study evaluation, procedures or completion 
5. 
SUBJECT ENROLLMENT / RANDOMIZATION 
Before participants may be entered into the study, the site must obtain IRB / IEC written approval of 
the protocol, informed consent form, and other participant information and/or recruitment material, if 
applicable 
.  The informed consent form must be signed and dated by the 
participant or by their legal representative and by the person who conducted the informed consent 
discussion before commencement of study-specific procedures.  
 
 
 
 
 

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Participants will be enrolled in the Phase 1b after all screening visit and safety assessments have 
been completed and eligibility criteria have been met.  In the Phase 2a dose expansion a participant 
is considered randomized when they have met all eligibility criteria and have received the 
randomized treatment allocation 
 
. 
 
 
 
  Participants who are 
deemed ineligible will be documented as screen failures.  Screen failures are defined as participants 
who consent to participate in the clinical study but are not subsequently enrolled (Phase 1b) or 
randomized (Phase 2a). 
 
 
 
 
 
 
 
 
 
 
   
6. 
INVESTIGATIONAL PRODUCT / STUDY INTERVENTION(S) 
OPT-302 is the only investigational product administered in this study.  The other study drug to be 
used in the study is aflibercept.  A pharmacy manual containing detailed information regarding the 
storage, preparation, and administration of OPT-302 will be provided as a separate document. 
6.1 
OPT-302  
OPT-302 will be manufactured 
 in accordance with current Good 
Manufacturing Practice.  The investigational product will be supplied 
 at a 
concentration of 40 mg/mL.  
 

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  Each glass vial will contain sufficient study medication to enable a single use only 
treatment for a single eye in one participant. OPT-302 will be given by IVT injection.   
 
 
 
 
  Instructions for the preparation of OPT-302 for IVT administration are specified in the 
pharmacy manual. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.1.2.4 
Phase 1b Dose Escalation 
The Phase 1b dose escalation is open label and eligible participants who enroll will receive OPT-302 
by IVT injection (0.05 mL) at doses of 0.3 mg (Cohort 1), 1 mg (cohort 2) or 2 mg (Cohort 3) once 
every 4 weeks (Day 1, 29 and 57) each used in combination with aflibercept (2 mg) for a total of 3 
injections. The OPT-302 IVT injection is given sequentially after IVT aflibercept once a post injection 
safety check has been performed (which may include a check of optic nerve head perfusion, 
intraocular pressure and/or visual function.  Dose escalation will occur at the planned dose levels 
until the MTD is determined or until the highest dose level is tested.   
 
 
 
 
 
6.1.2.5 
Phase 2a Randomization and Masking 
For the Phase 2a dose expansion, at least 108 eligible participants will be centrally allocated in a 2:1 
ratio to one of the two treatment groups (combination OPT-302 + aflibercept [n=72]: aflibercept + 
sham [n=36]) by a dynamic minimization procedure stratifying by two baseline characteristics: 
ETDRS Best Corrected Visual Acuity (BCVA ≤ 55 or > 55 letters) and Central Subfield Thickness 
(CST ≤ 450 vs. > 450 µm).  The dynamic minimization will use a stochastic treatment allocation 

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algorithm based on the variance method (Pockock and Simon, 1975).  Randomization will continue 
until 72 evaluable participants are randomized to the aflibercept + OPT-302 experimental arm. 
The Phase 2a is double masked: the participant, investigator, VA assessors, image technician 
readers / photographers and other site staff involved in participant care will be masked to study 
medication.  
 
 
  OPT-302 and aflibercept will be administered as separate IVT injections (each 0.05 
mL) every 4 weeks at Day 1, 29 and 57.  The OPT-302 IVT injection (or sham) is given sequentially 
after IVT aflibercept by the unmasked injecting investigator once a post injection safety check has 
been performed (which may include a check of optic nerve head perfusion, intraocular pressure or 
visual function).  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.2 
Phase 2a Sham Control 
In the Phase 2a the control arm will consist of aflibercept IVT injection followed by a sham injection.  
For participants receiving sham injections in the control group, the procedure will be done by the 
injecting ophthalmologist and involves pressing the hub of an identical syringe (but without the 
needle) against the eye wall to mimic the active doses injected into the vitreous cavity, whilst also 
following other standard preparation steps used for OPT-302 such as aseptic techniques etc.  
 
 
 
6.3 
Other Study Drug - Aflibercept 
Aflibercept (Eylea®) is a fusion protein that includes the key binding domains of human VEGF 
receptors 1 and 2 with human IgG Fc and acts by binding and inhibiting all VEGF-A isoforms, 
VEGF-B and placental growth factor, preventing increased permeability and macular edema in 
central involved DME.  Aflibercept will be 
 stored and prepared for IVT 
injection in compliance with the manufacturer’s instructions.  Aflibercept will be administered to the 
study eye at a dose of 2 mg in 0.05 mL.  Refer to the aflibercept package insert for more details 
about the study drug and its physical, chemical and pharmacological properties and formulation. 

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6.3.1 
Aflibercept Retreatment Criteria – Week 12 to Week 24 
Following the dosing period, in the Phase 1b and Phase 2a there will be a 4 week treatment free 
follow-up to week 12 and then a follow-up to week 24 during which the subject will receive as 
needed standard of care IVT aflibercept based on retreatment criteria for persistent DME if visual 
acuity (VA) or central subfield thickness (CST) worsens (defined as a ≥ 10% increase in CST or a ≥ 
5 letter decline in VA from the last study treatment phase visit [Day 57]).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.5 
Dose Escalation / Expansion Safety Review 
 
The Phase 1b dose escalation is aimed at determining the MTD or highest dose tested, and 
evaluating the safety and tolerability of OPT-302 (0.3, 1 or 2 mg) in combination with aflibercept (2 
mg).  Dose limiting toxicity (DLT) and stopping criteria will be incorporated into the Phase 1b of the 
study.  There will be a 14 day DLT window following the first dose for determination of whether 
patient dosing will continue and a data review team will meet to review participant safety to make 
recommendations on dose escalation to the higher dose level cohort.   
 
 
 
 
 
 
 
 
 

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Dose escalation will occur at the planned dose levels until the MTD is determined or until the highest 
dose level is tested.  A DLT is defined as any related ocular or systemic adverse event 
 
 occurring during the first 14 days in each dose escalation cohort:  
• 
Any adverse event ≥ grade 3 deemed related to the study drug(s) by the investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
   

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6.6 
Data Review Team 
During the trial, Opthea will assess subject safety and tolerability of investigational product through 
periodic review of individual safety data (unmasked review for the Phase 1b and masked review for 
the Phase 2a).  A data review team will review accumulating safety data and make 
recommendations to the study team regarding the conduct of the study in order to safeguard the 
interest of the trial participants while preserving the integrity of the study.  
 
 
 
 
 
 
 
 
 
 
 
 
6.6.1 
Phase 1b Dose Level and Safety Data Review 
For the Phase 1b dose escalation, a dose level review meeting will be held for each cohort.  
Escalation to a higher dose cohort will only proceed when the previous dose regimen(s) has (have) 
been found to be reasonably tolerated based on available study data through the DLT period for all 
participants enrolled in the cohort 
 
 
 
  

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6.6.2 
Phase 2a Safety Data Review 
For the Phase 2a, the data review team will review masked safety data once 30, 60 and 90 patients 
have been randomized and completed at least 14 days follow-up post first dose.  
 
 
 
6.6.3 
Determination of Adverse Event Severity and Relatedness 
Determination of the severity of adverse events will be consistent with Common Terminology Criteria 
for Adverse Events (CTCAE) v 4.  If the adverse event is not specified in CTCAE, then the severity 
will be assessed on a standard adverse event scoring system 
.  The relationship 
of an adverse event to investigational product will be determined by the investigator. An event 
should be considered related to treatment if, in the Investigator’s medical judgment, there is a 
reasonable possibility that the event may have been caused by OPT-302 and or aflibercept 
 
.  
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.7 
Concomitant Therapy  
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 6.9.  Any 
medication including over the counter or prescription medicines, vitamins and/or herbal supplements 
that the participant is receiving at the time of enrollment / randomization or receives during the study 
through to week 24 must be recorded in the eCRF along with reason for use, dates of administration 
(including start and end dates) and dosage information (e.g. dose).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.8 
Concomitant Therapy for the Non-Study Eye 
Treatment of DME that develops in the non-study eye during the study should follow the 
investigators best medical judgment for the patient. Other investigational agents must not be used 
for treatment of the non-study eye. 
6.9 
Excluded Treatments During or Prior to Study Period  
 The following medications and/or therapies should not be administered within the timeframes 
specified prior to enrollment or randomization or during the study (Day 1 through week 24): 
• 
Eyes in which scatter (panretinal) photocoagulation is needed now or is likely to be needed 
within the next 3 months (e.g. eyes with high risk proliferative diabetic retinopathy [defined as 
neovascularization of the disc > 1/3 disc area or neovascularization elsewhere > 1/2 disc area 
and presence of vitreous hemorrhage regardless of size of neovascularization] not already 
adequately treated with photocoagulation) 
• 
Previous treatment with photodynamic therapy, thermal laser or external beam radiation in the 
study eye 
• 
Subjects who have received panretinal or focal/grid photocoagulation, YAG laser, or peripheral 
retinal cryoablation (for retinal tears only) in the study eye within the previous 4 months  
• 
Concurrent or prior use of systemic anti-VEGF agents 
• 
Concurrent or prior use of intravitreal bevacizumab in the study eye, unless therapy switched to 
intravitreal aflibercept or ranibizumab for ≥ 1 most recent injection(s) prior to study Day 1  
• 
Most recent intravitreal injection of aflibercept or ranibizumab less than 28 days or greater than 
or equal to 42 days prior to Day 1 dosing in the study eye 
• 
Administration of systemic steroids within 4 months prior to Day 1 
• 
Concurrent or prior use of any intravitreal injections of steroids within 4 months prior to Day 1 in 
the study eye 
• 
Concurrent or prior use of dexamethasone implant in the study eye 
• 
Concurrent or prior use of fluocinolone implant in the study eye   
• 
Concurrent or prior administration of experimental therapy within 30 days of screening 
• 
Concurrent treatment for active systemic (non-ocular) infection at screening if in the opinion of 
the investigator, doing so will place the participant at undue risk 
• 
Concurrent treatment in either eye for any ocular condition with an investigational drug or device 
that has not received regulatory approval  
• 
Concurrent or prior use of thiazolidinediones within 6 months prior to Day 1 dosing 
6.10 
Other Procedures  
The following procedures should not be undertaken within the timeframes specified prior to 
enrollment or randomization or during the study (unless otherwise specified below): 
• 
Any intraocular surgery within 6 months of study entry or anticipated within the next 3 months 
following dosing on Day 1 
• 
Previous posterior vitrectomy or scleral buckling surgery 
• 
Major surgery (defined as intra-abdominal or surgery requiring general anesthesia) within 28 
days prior to dosing on study Day 1 or major surgery planned during the next 6 months. 

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6.11 
Contraception  
All women of child bearing potential must have a negative pregnancy test performed at screening 
and at regular intervals throughout the study. 
Women of child bearing potential must agree not to attempt to become pregnant or undergo in vitro 
fertilization and, must use highly effective contraceptive methods during the study and for 3 months 
following the last dose administration of study drug(s).  The following are considered “highly effective 
methods”: e.g. hormonal contraceptive (oral, intravaginal, or implant, but excluding progestogen-only 
oral hormonal contraception where inhibition of ovulation is not the primary mode of action); 
intrauterine device; or documented vasectomy of partner.  Male participants with female partners of 
child bearing potential must agree to use effective contraception (e.g. condom) during the study and 
for 3 months following the last dose administration of study drug(s).    
Note: Women who are postmenopausal for at least 1 year (by history and defined as 12 consecutive 
months with no menses without an alternative medical cause), women with documented total 
hysterectomy, documented bilateral oophorectomy, and women with documented bilateral tubal 
ligation are considered of non-childbearing potential and are not required to use contraception. 
7. 
STUDY PROCEDURES 
7.1 
General Study Procedures  
All assessments for each participant will be performed by the study investigator(s) and / or 
appropriately delegated center staff according to the Schedule of Assessments 
 
 
 Every effort must be made to 
adhere to the Schedule of Assessments.  Participants who are unable to make a required study visit 
should be encouraged to return to the clinic within the specified visit window to complete study 
assessments.  In general, scheduled visits will include assessment of adverse events, concomitant 
medications, treatments and blood samples for various laboratory tests.  All adverse events, 
concomitant medications, treatments and visit assessments will be documented on eCRFs.  
All participants must sign the current IRB / IEC approved, protocol-specific informed consent form 
prior to undergoing any protocol specific evaluations and or procedures.  
 
 
 
 
 
 

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7.2 
Run-In Phase for Participants receiving Prior Intravitreal Bevacizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only potential participants who meet the study inclusion criteria and no exclusion criteria 
 
 may enter the Run-In 
Phase.  
Participants in the Run-in Phase will receive: 
• 
 At least one Intravitreal injection of aflibercept (2mg; 0.05 mL) in the proposed study eye  
• 
 Post injection safety checks will be performed in accordance with local site standard of care 
 
 
 
 
At the end of the run-in phase, participants with persistent DME despite the prior intravitreal 
anti-VEGF-A therapy and who continue to be eligible 
 can be enrolled (Phase 1b) 
/ randomized (Phase 2a) into the study. 
 
 
 
7.3 
Screening 
All screening assessments to determine eligibility must be completed within 14 days prior to study 
Day 1.  
The following assessments will be performed at the screening visit after the informed consent has 
been obtained 
 
• 
Demographics  

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• 
Medical / Ocular / Surgical history including current conditions will be obtained 
• 
Concurrent medications and any medication taken within 14 days prior to study Day 1 
• 
Previous treatments for center involved DME.  
 
• 
Physical Exam 
 
• 
Vital signs measured 
• 
ECG recorded 
• 
Ocular Examination 
 
• 
BCVA by EDTRS 
 
• 
Collection of Hematology, Chemistry and HbA1c samples 
• 
Urine sample for Dipstick Urinalysis and Pregnancy test (women of child bearing potential 
only) 
• 
SD-OCT 
 
• 
Fluorescein angiography 
 
• 
Color Fundus Photography 
 
 
 
Medical, surgical and ocular history will be collected during screening and must include documented 
diagnosis of diabetic macular edema.  
 
 
  Angiographic and / or OCT confirmation of disease status must 
be performed using the same techniques and equipment as are planned throughout the study.  
When all screening procedures have been performed and the investigator has confirmed the 
subject’s eligibility for the study, the participant will return for the Day 1 visit. 
7.4 
Week 1 Day 1 
7.4.1 
Pre-dose / Baseline 
Prior to the participant being enrolled (Phase 1b) or randomized (Phase 2a) into the study the 
following assessment will occur. 
• 
Vital signs measured 
• 
Ocular Examination 
 
• 
BCVA by EDTRS 
 
• 
Collection of Hematology and Chemistry samples 
 
 
• 
Urine sample for Pregnancy test (women of child bearing potential only) 
• 
Any changes in Medical History or concomitant medications 
 
  
Upon completion of screening and pre-dose tests and assessments, and review of all results 
including imaging eligibility performed by the independent reading center, the investigator will 
confirm final subject eligibility.   

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• 
Ocular Examination 
 
• 
BCVA by EDTRS 
 
• 
SD-OCT 
 
• 
OCT-A 
 
• 
Record any adverse event and concomitant medications 
7.7 
Week 5 Day 29 
 
On Day 29 
 the following assessments / procedures will be performed prior to study drug 
administration: 
• 
Vital signs measured 
• 
ECG performed 
• 
Ocular Examination 
 
• 
BCVA by EDTRS 
 
• 
Collection of Hematology and Chemistry samples 
 
 
• 
Urine sample for Dipstick Urinalyses and Pregnancy test (women of child bearing potential 
only) 
• 
SD-OCT 
 
 
 
• 
Record any adverse events and concomitant medications administered 
Study drug(s) Administration: 
• 
Intravitreal injection of aflibercept in study eye 
• 
Post injection safety check must be performed and will include a check of optic nerve head 
perfusion, intraocular pressure and visual function 
• 
Intravitreal injection of OPT-302 (or sham in Phase 2a) to the study eye 
 
 
 
 
 
 
 
 
 
 
7.8 
Week 9 Day 57 
 
On Day 57 
 the following assessments / procedures will be performed prior to study drug 
Administration: 
• 
Vital signs measured 
• 
ECG performed 
• 
Ocular Examination 
 
• 
BCVA by EDTRS 
 
• 
Collection of Hematology and Chemistry samples 

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• 
Urine sample for Dipstick Urinalyses and Pregnancy test (women of child bearing potential 
only) 
• 
SD-OCT 
 
 
 
• 
Record any adverse events and concomitant medications administered 
Study drug Administration: 
• 
Intravitreal injection of aflibercept in study eye 
• 
Post injection safety check must be performed and will include a check of optic nerve head 
perfusion, intraocular pressure and visual function  
• 
Intravitreal injection of OPT-302 (or sham in Phase 2a) to the study eye 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
7.10 
Week 12 Day 85 
 – Follow Up  
On Day 85 
 the following assessments / procedures will be performed: 
• 
Vital signs measured 
• 
ECG recorded 
• 
Ocular Examination 
 
• 
BCVA by EDTRS 
 
• 
Collection of Hematology, Chemistry and HbA1c samples 
• 
Urine sample for Dipstick Urinalysis and Pregnancy test (women of child bearing potential 
only) 
 
 
• 
SD-OCT (both eyes) 
• 
Fluorescein angiography (both eyes) 
• 
Color Fundus Photography (both eyes) 
 
  
• 
Record any adverse events and concomitant medications administered 

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7.11 
Week 24 Day 168 
 – Long Term Follow Up 
On Day 168 
 the following assessments / procedures will be performed: 
• 
Ocular Examination 
 
• 
BCVA by EDTRS 
 
• 
SD-OCT 
 
• 
Fluorescein angiography 
 
• 
Color Fundus Photography 
 
• 
Record any adverse events and concomitant medications administered 
7.12 
Study Assessments 
7.12.1 
Demographics 
Date of birth, gender, and race will be collected for all participants. 
7.12.2 
Medical / Ocular / Surgical History 
Clinically significant medical, ocular and surgical history will be obtained from medical records, the 
physical examination and by interviewing the participant. The original diagnosis of central-involved 
DME must be recorded in the source documents.  If a subject is referred to the study center, a copy 
of all applicable reports and imaging evidence, confirming the diagnosis must be provided to the 
study center before enrollment or randomization. 
7.12.3 
Concomitant Medications 
All prescription and nonprescription medications taken within 14 days prior to treatment until the 
long-term follow-up visit will be recorded with start and stop dates captured or indicated as ongoing. 
All prior IVT anti-VEGF-A therapy administered for central involved DME should also be recorded 
 
At each visit following Day 1 participants will be questioned by study staff to assess if they have 
commenced or had any changes in concomitant medications since the previous visit.  Study staff 
should record all concomitant medications administered to the participant whilst in the clinic. 
7.12.4 
Physical Examination  
A physical examination, including a review of body systems, will be performed at screening. 
 
 
7.12.5 
Vital Signs 
The following vital signs will be measured: 
• 
Body temperature (degrees Celsius [°C]) 
• 
Respiratory rate (breaths / min) 

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• 
Pulse rate (beats / min), 
• 
Blood pressure (mm mercury [mmHg]) 
Blood pressure and pulse are to be recorded after the participant has been resting semi-supine for at 
least 5 minutes.  
 
 
7.12.6 
Electrocardiograms 
ECG assessments will be collected in participants who have been supine for no less than 5 minutes.  
The following parameters will be reported: QRS, QT, QTcF, RR and PR intervals. 
 
 
  Repeat measurements will be 
performed if there are any clinical abnormalities observed or artifacts are present.  
 
 
 
7.12.7 
Ocular Examination 
A standard ophthalmic examination using slit lamp biomicroscopy and dilated fundus examination, 
will be performed on the study eye at all visits and fellow eye at selected visits by a study certified 
ophthalmologist. 
 
 
 
 
 
 
 
 
 
   
7.12.8 
Best Corrected Visual Acuity 
Visual acuity tests will be performed in the study eye and fellow eye by certified assessors using 
validated vision charts according to the ETDRS refraction 
.  In the Phase 2a dose 
expansion, visual acuity examiners will be masked to the participants’ treatment assignments.  
 
  

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7.12.9 
Clinical Laboratory Assessments 
All laboratory samples are to be obtained by venipuncture before study drug(s) administration.  All 
analyses will be performed by the study central laboratory unless otherwise indicated 
 
 
 
  Required clinical safety laboratory tests are as follows: 
Biochemistry: Sodium; potassium; chloride; bicarbonate; albumin; calcium; magnesium; 
phosphorous; glucose; blood urea nitrogen; creatinine; creatinine kinase; total bilirubin; aspartate 
aminotransferase; alanine transferase; alkaline phosphatase. 
Hematology: Red blood cells; hemoglobin; hematocrit; mean corpuscular volume; mean corpuscular 
hemoglobin; platelets; white blood cells with differential (absolute count or percentage of: 
neutrophils, eosinophils, basophils, lymphocytes and monocytes). 
HbA1c: Glycated hemoglobin 
Urine: Urine pregnancy testing (using a standard pregnancy kit) for women of child bearing potential 
only and urinalysis (dipstick testing) will be performed in the clinic.   
 
  
 
  All testing materials will be provided as kits by the central laboratory.  Each study site will 
follow the laboratory manual for proper collection, processing, labelling, and transport to the central 
laboratory. 
 
 
 
 
 
 
 
 
 
 
 

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7.12.10.1 
Pharmacokinetics Samples 
The PK parameters of OPT-302 will be estimated using standard non-compartmental methods.  
Pharmacokinetics data will include, but may not be limited to, Cmax, tmax and area under the curve 
(AUC), and half-life (t1/2), where feasible.  
 
 
   
 
 
 
The handling and processing of laboratory samples is described in detail in the study Laboratory 
Manual.  All testing materials will be provided as kits to the site. 
7.12.10.2 
Anti-OPT-302 Antibody Analysis 
Blood samples will be collected from all participants for the measurement of anti-OPT-302 binding 
antibodies.  
 
 
  
 
 
 
 
 
The handling and processing of laboratory samples is described in detail in the study laboratory 
manual.  All testing materials will be provided as kits to the site. 
7.12.11 
Spectral Domain Optical Coherence Tomography (SD-OCT) 
SD-OCT scans of both the study eye and fellow eye will be taken at each pre-determined time-point 
throughout the study by a masked and certified OCT technician, according to the IRC imaging 
standardized procedures.  
 
 
 
 

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7.12.12 
Fundus Fluorescein Angiography (FA) 
A study IRC certified photographer (masked) will perform FA in both the study eye and fellow eye at 
each pre-determined time-point throughout the study according to the IRC imaging standardized 
procedures. 
 
 
 
 
 
7.12.13 
Color Fundus Photography 
A study IRC certified photographer (masked) will perform color fundus photography in both the study 
eye and fellow eye at each pre-determined time-point throughout the study according to the IRC 
imaging procedures.  
 
 
 
 
 
 
 
 
 
 
 
 
 
7.12.15 
Independent Reading Center (IRC) 
An Independent Reading Center (IRC) will conduct independent review of all imaging for the study to 
reduce variability of interpretation, and for the Phase 2a dose expansion will be masked to study 
treatment allocation.  These masking procedures will avoid both performance and detection bias.  

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The IRC will assess and register / certify all imaging equipment and each technician involved in 
imaging at each site.  
 
 
 The images will be anonymized prior to submission to the IRC.  
 
 
 
  
Confirmation of eligibility is to be provided by the IRC prior to enrollment of any participant into the 
study.  Determination of on study clinical management by imaging of participants will be assessed at 
the local site. 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
8. 
REMOVAL AND REPLACEMENT OF PARTICIPANTS 
8.1 
Removal of Participants 
Participants have the right to withdraw fully or partially from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Participants may decline to continue receiving investigational product(s) or other protocol-required 
therapies at any time during the study.  If this occurs, the investigator will discuss with the participant 

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appropriate procedures for withdrawal from investigational product(s) or other protocol-required 
therapies.  
 
 
 
 
Should a participant (or a legally acceptable representative) request or decide to withdraw from the 
study, all efforts will be made to complete and report the observations as thoroughly as possible up 
to the date of withdrawal.  
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
The investigator’s clinical judgment will be used to determine whether a participant should be 
removed from treatment or from the study due to an adverse event.  A participant may also 
voluntarily withdraw from treatment or from the study due to an adverse event.   
 
 
 
 
 
 
     
 
 
 

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9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
It is the responsibility of the Investigator to ensure that all adverse events and other clinically 
significant findings that occur during the clinical study are documented and reported accurately. 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Events  
An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial subject.  The 
event does not necessarily have a causal relationship with study treatment.  The investigator is 
responsible for ensuring that any AEs observed or reported by the participant are recorded in the 
medical record 
   
The definition of AEs includes worsening of a pre-existing medical condition.  Worsening indicates 
the pre-existing medical condition (e.g., diabetes, migraine headaches, gout) has increased in 
severity, frequency, and/or duration, and/or has an association with a significantly worse outcome.  
An AE does not include: medical / surgical procedures (but the condition that leads to the procedure 
may be and AE; situation where an untoward medical occurrence has not occurred (e.g. 
hospitalization for cosmetic surgery); overdose of study drug(s) or concomitant medication that does 
not result in any signs or symptoms (if signs or symptoms are present, then will be recorded as an 
AE); or underlying disease progression (DME in the study eye). 
A treatment emergent adverse event (TEAE) is an AE that was not present prior to treatment with 
the study drug(s), or an event that was present prior to treatment, but worsens either in intensity or 
frequency following treatment. 
9.1.2 
Reporting Procedures for Adverse Events  
The investigator is responsible for ensuring that all AEs observed or reported by the subject that 
occur after signing of the informed consent throughout the study until the final study visit are 
reported.   
 
 
 
   
At each visit, the investigator / delegate will determine whether any AEs have occurred.  
 
 
 

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If known, the medical diagnosis of an adverse event should be recorded in preference to the listing 
of individual signs and symptoms.  The investigator will evaluate any changes in laboratory values if 
laboratory testing is performed, and make a determination as to whether or not the change is 
clinically important to be reported as an adverse event, and whether or not the changes were related 
to the study drug(s).  In general, abnormal laboratory findings without clinical significance (based on 
the investigator's judgment) should not be recorded as AEs.  However, laboratory value changes 
that the investigator considers clinically significant or requiring treatment / adjustment in current 
therapy are considered AEs.  Where applicable, the clinical sequelae (not the laboratory 
abnormality) should be recorded as the adverse event.  
Every adverse event must be assessed and the eCRF entry reviewed and confirmed by the 
investigator. 
All ocular AEs should indicate which eye the adverse event occurred (Oculus sinister (OS) [left], 
oculus dextrus (OD) [right], oculus uterque (OU) [both]). 
The investigator has overall responsibility to ensure that the following adverse event attributes are 
assigned: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
• 
Dates of onset and resolution 
• 
Severity [and/or toxicity per protocol] 
• 
Assessment of relatedness to study drug(s) 
• 
Action taken 
If any AEs are present when a participant completes the study or when a participant is discontinued 
from the study, the Investigator / delegate should make every effort to follow-up the participant until 
the adverse event has resolved or stabilized.  All follow-up information (and attempted follow-up 
contacts) should be documented in the participant’s medical records. 
If an adverse event changes in severity, it should be a single entry in the eCRF, and assigned the 
highest severity experienced.  The adverse event toxicity grading scale used will be the National 
Institutes of Health Common Terminology Criteria for Adverse Events (CTCAE, Version 4).   
If the adverse event is not specified in the CTCAE, the severity will be assessed on the following 
scale with appropriate clinical definitions: 

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Medically significant AEs considered related to the study drug(s) by the investigator or the sponsor 
will be followed until resolved or considered stable. 
9.2 
Adverse Drug Reaction (ADR)  
An adverse drug reaction (ADR) is defined by the International Council for Harmonisation (ICH) as 
any noxious and unintended response to a medicinal product related to any dose.  Therefore, it is 
any AE where there is reasonable possibility of a causal relationship between the study drug(s) and 
the AE.  An unexpected ADR is defined as an ADR, the nature, severity or frequency of which, is not 
consistent with the applicable drug information (i.e. not listed in the investigator’s brochure for OPT-
302 or in the summary of product characteristics for aflibercept). 
9.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A suspected unexpected serious drug reaction (SUSAR) is defined as a SAE that is suspected to be 
an ADR, but is not consistent with the information as provided in the Investigators’ Brochure - i.e. 
either is not listed as an expected ADR in the Investigator’s Brochure, occurred at a greater severity 
than was listed, or there is an increase in the rate of occurrence that is judged to be clinically 
important.  All SUSARs must be reported to the applicable regulatory agencies within the timelines 
as stipulated by local law and guidelines by the Sponsor, and reported to each IRB / IEC by each 
Investigator. 
9.4 
Serious Adverse Events  
9.4.1 
Definition of Serious Adverse Events  
A serious adverse event (SAE) is defined as an AE that meets at least one of the following serious 
criteria: 
• 
Results in death; 
• 
Is life-threatening; 
• 
Requires in-participant hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability / incapacity; 
• 
Is a congenital anomaly / birth defect; 
• 
Is an important medical event. 
Death is an outcome of a SAE, and not a SAE in itself.  All deaths must be reported for participants 
on study and for deaths occurring within 30 days of last study drug(s) administration or within 30 
days of last study evaluation, whichever is longer, to 
 
ensure immediate 
 reporting to all appropriate regulatory bodies within the required 
timelines as applicable.  The Investigator should provide any additional requested information as 
available (e.g. autopsy reports and terminal medical reports).  The term “life-threatening” in the 

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definition of “serious” refers to an event in which the participant was at immediate risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have caused death if it 
were more serious. 
Hospitalization is defined as the participant being hospitalized overnight, or the participant’s hospital 
stay being prolonged for at least an additional overnight stay.  Hospital admissions for a pre-existing 
condition or for normal disease management procedures (e.g. chemotherapy) will not be considered 
a SAE.  
 
 
 
  Complications that occur during hospitalizations, prolonging hospitalization 
by ≥ 24 hrs are an SAE.   
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered to be SAEs when, based upon appropriate medical judgment, they may 
jeopardize the study participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias, or 
convulsions, or the development of drug dependency or drug abuse. 
9.4.2 
Reporting Procedures for Serious Adverse Events  
The investigator is responsible for ensuring that all SAEs observed by the investigator or reported by 
the subject that occur after signing of the informed consent through the week 24 follow-up visit are 
recorded in the participant’s medical record.  Any SAE (including death) that occurs during the 
course of the study, whether or not related to the study drug(s) due to any cause, must be reported 
immediately on the SAE form (within 24 hours of the investigator becoming aware of the event) 
 
  
 
 
The investigator (or designee) will be requested to complete the SAE form associated with the study 
including as much information regarding the event that is available at the time of the initial report.  
 
 
 
 
The investigator must review and sign-off each SAE report to confirm that they have 
reviewed the SAE and the details are correct; however, this sign-off must not delay the initial 
reporting and may be undertaken after the initial report has been made.  Prompt notification is 

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essential so that legal requirements and ethical obligations to the participants participating in the 
study can be met.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
The Investigator must also: 
• 
Report all SAEs to the reviewing IEC / IRB within the time-line specified by the reviewing 
body per the respective reporting requirements; 
 
 
Opthea will report SAEs and / or SUSARs as required to regulatory authorities, investigators / 
institutions, and IRBs / IECs as applicable in compliance with all reporting requirements according to 
local regulations and good clinical practice.  
9.5 
Regulatory Reporting Requirements 
Opthea has a legal responsibility to notify local regulatory authorities, about the safety of the study 
drug(s) under clinical investigation.  Prompt notification of SAEs by the investigator is essential so 
that legal obligations and ethical responsibilities towards the safety of other participants are met.  All 
SUSARs qualify for expedited reporting as soon as possible after Sponsor confirmation that the case 
meets the criteria for expedited reporting, and no later than the timelines stipulated by each relevant 
regulatory authority.  Fatal or life-threatening SUSARs must be reported very rapidly by Sponsor (or 
designee) to the Regulatory authorities
 

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  Therefore, it is essential that all SAEs are reported as soon as the site becomes aware that 
the event has taken place, in order for rapid triaging and notification to occur. 
9.6 
Institutional Review Board / Independent Ethics Committee Reporting 
It is the Investigators’ responsibility to comply with the requirements for IRB / IEC notification.  
 
 
 
9.7 
Pregnancy Reporting 
Participants who become pregnant during the study period up to and including 30 days after the last 
use of study drug(s) are to be instructed that they immediately notify the Investigator, and must not 
receive any further study drug(s).  
 
 
 
  
 
 
 
 
10. 
STATISTICAL CONSIDERATIONS 
All statistical considerations and analyses will be fully described in the statistical analysis plan, which 
will be finalized prior to database lock (and un-masking for the Phase 2a).  
 
 
10.1 
Study Design 
This is a two part (Phase 1b open-label, sequential dose escalation followed by a Phase 2a double 
masked, randomized, dose expansion) study evaluating OPT-302 in combination with aflibercept in 
participants with central-involved DME.   
10.2 
Study Endpoints, Subsets, and Covariates 
10.2.1 
Primary Endpoints 
Phase 1b and Phase 2a: 
• 
Safety: Subject incidence of adverse events, DLTs and clinically significant changes in vital 
signs, ECGs and clinical laboratory tests 
Phase 2a: 

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• 
Efficacy: Response rate as defined by proportion of participants receiving combination OPT-
302 and aflibercept achieving at least a 5 letter gain in BCVA compared to baseline at week 
12 according to ETDRS criteria  
10.2.2 
Secondary Endpoints 
• 
Mean change in BCVA from baseline to week 12 according to standardized ETDRS criteria 
• 
Mean change from baseline to week 12 in CST and macular volume on SD-OCT 
• 
Percent of eyes with ≥ 50% reduction in excess foveal thickness from baseline to week 12 on 
SD-OCT 
• 
Percent of eyes with CST < 300 µm on SD-OCT through week 12 
• 
Percent of participants with a ≥ 2 step improvement from baseline to week 12 in ETDRS 
Diabetic Retinopathy Severity Score 
• 
The mean time to, and number of, retreatment injections of aflibercept anti-VEGF-A therapy 
based on protocol specified criteria during week 12 to 24 follow-up  
• 
OPT-302 PK parameters  
• 
Incidence of anti-OPT-302 antibody formation  
10.2.3 
Exploratory Endpoints 
• 
CST area under the curve (AUC) 
• 
Percent of eyes with resolution of fluid (sub-retinal fluid and intraretinal cysts) through week 
12 on SD-OCT 
 
 
Additional details on endpoints will be included in the statistical analysis plan. 
10.2.4 
Analysis Subsets 
10.2.4.1 
Intent-to-treat (ITT) Analysis Set  
The Intent-to-Treat (ITT) analysis sets will include all participants enrolled (Phase 1b) or randomized 
(Phase 2a) into the study, irrespective of whether study drug(s) was administered or not. These 
analysis sets will be used to report participant disposition and to provide a sensitivity analysis of the 
safety and efficacy endpoints only. 
10.2.4.2 
Safety Analysis Set 
The safety analysis sets will comprise all participants in the ITT analysis sets, but excluding those 
not receiving at least one dose of study drug(s) (aflibercept or OPT-302). These analysis sets will be 
employed to determine the safety endpoints.  Note that this population includes the ‘unevaluable’ 
participants (see per protocol population below) in the Phase 2a that received at least one 
administration of study drugs.  

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10.2.4.3 
Dose Escalation Analysis Set 
The analysis of dose limiting toxicity (DLT) will be conducted on the Phase 1b dose escalation 
analysis set defined as all DLT evaluable participants. A participant is classified as DLT-evaluable if 
they have had the opportunity to complete the DLT interval (Days 1 to 14) and received 1 dose of 
planned OPT-302 or experienced a DLT at any time during the first 14 days on study.  
 
 
   
10.2.4.4 
Per-Protocol Analysis Set 
The Per-Protocol (PP) analysis sets will comprise participants in the safety dataset who were 
compliant with study medication, and who are considered sufficiently compliant with the protocol. 
The participants pertaining to the PP datasets are considered ‘evaluable’ participants. Efficacy 
analyses performed using the PP datasets will be considered as primary analysis.  The PP analysis 
sets are intended to represent the subset of participants who were in the intended study population, 
received the intended study medication (a total of 3 scheduled IVT injections once every 4 weeks), 
and could be evaluated for study outcomes.   
10.2.5 
Covariates 
Due to the small sample size, the impact of baseline characteristics on study outcomes will not be 
explored, and no subgroup analyses will be performed in the primary analyses of safety and efficacy 
endpoints. Covariates could be included in secondary analyses for these purposes and will be 
defined in the statistical analysis plan. 
10.3 
Sample Size Considerations 
In the Phase 1b dose escalation, at least 9 participants are expected to be enrolled. The sample size 
was determined empirically and is consistent with those used in this type of initial human clinical 
study.  A total of at least 108 additional participants are expected to be treated in the Phase 2a (dose 
expansion) with OPT-302 at the MTD or highest dose tested from the Phase 1b, in combination with 
aflibercept (72 participants) or with aflibercept alone (36 participants). 
Increasing numbers of participants will be exposed in the various phases of the trial: 
• 
In the Phase 1b dose escalation, if 3 participants will be treated with OPT-302 per cohort 
(without dose limiting toxicity), a total of at least 9 participants will be treated in this phase of 
the trial. 
• 
In the Phase 2a dose expansion, 72 additional participants will be enrolled at the MTD or the 
highest dose level of OPT-302 (determined from the Phase 1b).  In case one or more of 
these 72 participants are not evaluable, randomization will continue and more patients will 
receive the same dose. 

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• 
A total of up to at least 81 participants receiving OPT-302 is anticipated to be enrolled in the 
trial (9 in Phase 1b and 72 in Phase 2a). 
The table below shows the true proportion of patients with an AE that can be ruled out at various 
confidence levels, assuming no such event is observed in the trial.  
Number of participants 
without adverse event 
Confidence level 
80% 
90% 
95% 
3 
0.48 
0.57 
0.63 
9 
0.24 
0.30 
0.35 
81* 
0.04 
0.05 
0.06 
* If more than 72 participants are randomized to the experimental arm (aflibercept + OPT-302) in Phase 2a, the 
confidence levels of the total group of participants receiving OPT-302 will be higher than N=81. 
In the Phase 2a dose expansion, subjects will be allocated in a 2:1 ratio to one of two treatment 
groups, aflibercept with OPT-302 or aflibercept with sham, with minimization for two baseline 
characteristics: BCVA (≤ 55 vs. > 55 letters) and CST (≤ 450 vs. > 450 µm).  The primary outcome of 
the Phase 2a is the proportion of evaluable patients with a response of ≥ 5 letter gain in BCVA from 
baseline to week 12 according to ETDRS criteria in the combination aflibercept + OPT-302 group. 
The design of the trial is non-comparative in so far as the sample size is calculated for the aflibercept 
+ OPT-302 arm only. A one-stage design is used for the primary outcome (Sargent 2001) of the 
aflibercept + OPT-302 arm. A formal rule allows for the assessment of the observed response rate 
as compared with pre-specified “low” and high response rates. Specifically, the hypotheses of 
interest are H0: r ≤ r0 (“low” response rate) against HA: r ≥ rA (“high” response rate). 
The following assumptions were made for sample size calculations: 
o 
the pre-specified “low” and “high” response rates are r0 = 0.28 and rA = 0.45 
o 
the type I error rate (α, probability of accepting a treatment whose true response rate is lower 
than r0, a false positive outcome) is set to 5% 
o 
the type II error rate (ß, probability of rejecting a treatment whose true response rate is 
higher than rA, a false negative outcome) is set to 5% 
o 
the probability of correctly rejecting a treatment whose true response rate is lower than 
r0 is set to at least 90% 
o 
the probability of correctly accepting a treatment whose true response rate is higher 
than rA is set to at least 90% 
Under these assumptions, a total of 72 evaluable subjects need to be randomized to the aflibercept 
+ OPT-302 arm. With the 2:1 randomization, a sample size of at least 108 subjects is randomized 
between aflibercept + OPT-302 (n=72) or aflibercept + sham (n=36). Non-evaluable participants will 

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be replaced.  The conclusions based on the results of 72 evaluable participants in the combination 
aflibercept + OPT-302 arm will be: 
• 
clinical activity if ≥ 27 of 72 patients have a ≥ 5 letter gain in BCVA from baseline to week 12 
according to ETDRS criteria in the aflibercept + OPT-302 group 
• 
insufficient clinical activity if ≤ 25 of 72 patients have a ≥ 5 letter gain in BCVA from baseline 
to week 12 according to ETDRS criteria in the aflibercept + OPT-302 group  
 
 
10.4 
Access to Individual Subject Treatment Assignments 
The study will be conducted in 2 parts: Phase 1b open label dose escalation and Phase 2a 
randomized dose expansion.  Participants in this study will either receive aflibercept + OPT-302, or 
aflibercept + sham.  The Phase 2a is a double-masked trial. The sponsor, investigator, VA assessor, 
imaging readers and subject will be masked to the treatment to which the subject was randomized. 
10.5 
Interim Analysis, Safety Review 
 
No formal interim analysis is planned.  A data review team will advise on periodic safety review of 
the study  
  
 
  If concerns 
arise from either planned or unplanned safety reviews, the data review team may request additional 
review or recommend that the study at any time be modified or discontinued due to documented 
safety findings. 
10.5.1 
Phase 1b - Dose Escalation 
In the open label Phase 1b, the unmasked patient safety data for each cohort will be reviewed by the 
data review team 
  After reviewing at least 14 days of safety data 
(DLT window) for a cohort, the data review team will decide on escalation to the next dose level for 
the subsequent cohort (or whether to stop dose escalation).  Dose escalation will occur at the 
planned dose levels of OPT-302 until the MTD is determined or until the highest dose level is 
tested.  On completion of Phase 1b the MTD or highest dose tested will be used to inform the OPT-
302 dose selected for Phase 2a dose expansion. 
10.5.2 
Phase 2a - Dose Expansion 
No interim analyses or stopping rules are planned based on the evaluation of efficacy.  During the 
Phase 2a randomized dose expansion, there will be masked reviews of safety data by the data 
review team once 30, 60 and 90 participants have been randomized, received OPT-302 treatment 
and completed at least 14 days on study
  If concerns arise from either 

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planned or unplanned safety reviews, the data review team may request additional review or 
recommend that the study at any time be modified or discontinued due to documented safety 
findings.   
10.6 
Statistical Analysis Plan 
A final statistical analysis plan will be developed and approved by both Opthea and the study 
biostatistician prior to database lock.  The primary efficacy analysis will occur when target enrollment 
or randomization is complete and each participant either completes the week 12 follow-up visit or 
withdraws from the study. The final analysis for all other endpoints will occur after all participants 
complete the week 24 follow-up visit. 
 
 
 The following is a summary of the planned analyses; full 
details are captured in the statistical analysis plan. 
Continuous variables will be summarized using descriptive statistics (N, mean, standard deviation, 
median, minimum and maximum), while categorical variables will be summarized as counts and 
percentages of participants in each category.  Results will be presented by study arm as appropriate. 
The primary efficacy analysis will be presented using the PP analysis set.  Secondary efficacy 
analyses will be presented using the PP and ITT populations. For efficacy analyses, no missing 
values will be imputed as the primary efficacy analysis is on the PP population. Safety analyses will 
be presented using the safety and ITT populations. 
All baseline and demographic summaries will be based on the ITT dataset. 
10.7 
Planned Methods of Analysis of Key Study Endpoints 
10.7.1 
Efficacy Endpoints 
The primary efficacy endpoint of the Phase 2a is the proportion of evaluable participants (i.e. in the 
PP set) with a response of ≥ 5 letter gain in BCVA from baseline to week 12 according to ETDRS 
criteria in the combination aflibercept + OPT-302 group.  Based on the results of 72 evaluable 
participants in the aflibercept + OPT-302 arm the combination therapy will be considered to have 
clinical activity if ≥ 27 of 72 participants have a ≥ 5 letter gain in BCVA from baseline to week 12 
according to ETDRS criteria in the aflibercept + OPT-302 group.  Likewise the combination therapy 
will be considered to have insufficient clinical activity if ≤ 25 of 72 participants have a ≥ 5 letter gain 
in BCVA from baseline to week 12 according to ETDRS criteria in the aflibercept + OPT-302 group.  
 
 

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The difference in the mean change from baseline to week 12 between treatments will be tested for 
three secondary efficacy endpoints: mean BCVA, mean CST and mean macular volume.  A model 
for repeated measures, fitted by restricted maximum likelihood method, will be used for the analysis.  
This model takes into account the presence of missing data and yields valid estimates under the 
assumption of data missing at random.  
 
 
In addition, the following secondary outcomes will be estimated in the Phase 2a by treatment arm, 
and their 95% confidence intervals will be obtained: 
• 
Percent of eyes with ≥ 50% reduction in excess foveal thickness from baseline to week 12 on 
SD-OCT 
• 
Percent of eyes with CST < 300 µm on SD-OCT through week 12 
• 
Percent of participants with a ≥ 2 step improvement from baseline to week 12 in ETDRS 
Diabetic Retinopathy Severity Score 
• 
The mean time to, and number of, retreatment injections of aflibercept anti-VEGF-A therapy 
based on protocol specified criteria during week 12 to week 24 follow-up 
Further details of the analysis methods will be provided in the statistical analysis plan. 
10.7.2 
Safety Endpoints 
10.7.2.1 
Adverse Events  
All safety summaries will be presented by study arm using the safety dataset.  The extent of 
exposure to study medication will be quantified using total dose (mg), number of doses, and duration 
of exposure (days).  Total dose and duration of exposure will be summarized using descriptive 
statistics (mean, median, standard deviation, minimum and maximum); number of doses and 
duration of exposure will be presented by counts and percentages. Percent compliance and the 
number of missed doses will be summarized using descriptive statistics. Compliance will also be 
presented according to range categories and summarized by counts and percentages. 
The number of participants reporting AEs and TEAEs will be summarized by system organ class and 
preferred term; a participant will only be counted once per system organ class and once per 
preferred term within a study arm.  Participant counts and percentages and event counts will be 
presented for each study arm by decreasing frequency and presented as all AEs, ocular AEs and 
non-ocular AEs for the following summaries: all TEAE, all SAEs, all TEAE by maximum severity, all 
TEAE by relationship to study medication, all TEAE related to study medication. 
Participant listings will also be presented for all AEs as well as for SAEs leading to discontinuation 
from the study and AEs leading to discontinuation from study medication.  These listings will include 
study arm and study period along with variables describing the nature, duration, and resolution of the 
event. 

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Adverse events will be coded using Medical Dictionary for Regulatory Activities 
 
 The number and percentage of participants reporting AEs will be evaluated for each dose and 
across doses and will also be tabulated by relationship to study drug(s).  AEs resulting in treatment 
discontinuation will be identified.  
Adverse events will be listed for participants enrolled in the study.  
10.7.2.2 
Dose Limiting Toxicities 
A listing and summary of the subject incidence of DLTs will be provided should they occur.  
10.7.2.3 
Clinical Laboratory Tests  
Clinical laboratory data will be listed for each subject.  Values outside the normal laboratory 
reference ranges will be flagged as high or low on the listings. 
10.7.2.4 
Vital Signs  
Vital signs data will be listed for each subject.  
10.7.2.5 
Electrocardiograms  
ECG data will be listed for each subject and summarized.   
10.7.2.6 
Anti-OPT-302 Antibodies  
Anti-OPT-302 antibody data will be listed for each subject and summarized. 
10.7.3 
Pharmacokinetic (PK) Analyses 
The PK parameters of OPT-302 will be estimated using standard non-compartmental methods and 
summarized by cohort and dose level using means, standard deviations, medians, minimum and 
maximums.  Individual serum / time profiles will be summarized by dose level.  OPT-302 
concentrations at each time point along with PK parameter values may be listed for each subject.  
Summary statistics will be computed for each sampling time and parameter as appropriate.  
Additional analyses of OPT-302 concentration-time data using compartmental methods may be 
performed.   
 
 
 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
Before a subject’s participation in the clinical study, the investigator or delegate (e.g. sub-
investigator) is responsible for obtaining written informed consent from the subject or legally 
acceptable representative after adequate explanation of the aims, methods, anticipated benefits, and 

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potential hazards of the study and before any protocol-specific screening procedures or any study 
drug(s) are administered.  A legally acceptable representative is an individual or other body 
authorized under applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study.   
The investigator is also responsible for asking the subject if they have a primary care physician and 
if the subject agrees to have his/her primary care physician informed of their participation in the 
clinical study.  If the subject agrees to such notification, the investigator shall inform the subject’s 
primary care physician of the subject’s participation in the clinical study.  If the subject does not have 
a primary care physician and the investigator will be acting in that capacity, the investigator should 
document such in the subject’s medical record.  The original signed informed consent form should 
be retained in accordance with institutional policy, and a copy of the signed consent form should be 
provided to the subject or legally acceptable representative. 
If a potential subject is illiterate and does not have a legally acceptable representative, the 
investigator must provide an impartial witness to read the informed consent form to the subject and 
must allow for questions.  Thereafter, both the subject and the witness must sign the informed 
consent form to attest that informed consent was freely given and understood.  
11.2 
Regulatory Considerations 
Opthea or their agents will submit appropriate documents for review and approval to the local 
regulatory agencies and IRB / IECs affiliated to each site prior to study commencement.  This study 
will be conducted in accordance with the following guidelines and regulations:  
• 
International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice; 
• 
The Declaration of Helsinki; 
• 
US Food and Drug Administration (FDA) Human Participant Protection Regulations (Title 21 
Code of Federal Regulations, Parts 50, 54, 56 & 312). 
11.3 
Institutional Review Board / Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject information, and any 
proposed advertising material must be submitted to the IRB / IEC for written approval.  A copy of the 
written approval of the protocol and informed consent form must be received before recruitment of 
participants into the study and shipment of Opthea investigational product (OPT-302). 
The investigator must submit and, where necessary, obtain approval from the IRB / IEC for all 
subsequent protocol amendments and changes to the informed consent document.  The investigator 
should notify the IRB / IEC of important deviations from the protocol or SAEs occurring at the site 
and other AE reports received from Opthea, in accordance with local procedures. 

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The investigator will be responsible for obtaining annual IRB / IEC approval /renewal throughout the 
duration of the study.  The investigator must also notify the IRB / IEC of the end of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.5 
Subject Confidentiality 
The investigator and members of the site staff must ensure that the subject’s confidentiality is 
maintained:   
 
 
 
 
   
 
 
  All 
electronic information regarding study participants will be kept on a password protected computer.  
 
  The study sites’ data management and clinical staff will be the only personnel with 
access to the protected health information of the study participant.  All research records will be kept 
according to ethics committee, ICH and regulatory requirements (whichever is the longer duration) 
following closure of the study.  Identifiable information will not be stored in the eCRF and will not 
leave the site.  
 
 
Original records pertaining to this study may be inspected / audited at any time by Opthea 
employees or their duly authorized representatives, a regulatory authority or the IEC / IRB.  All 
records accessed will be strictly confidential.  Consent to participate in this study includes consent to 
direct access to records and these inspections / audits. 

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11.6 
Investigator Signatory Obligations 
For multicenter studies the clinical study report should be signed by the coordinating investigator 
identified by Opthea, who will either be: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to the design or interpretation of the study 
• 
an investigator contributing a high number of eligible participants 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Clinical Trial Agreement 
Prior to commencement of the study, the principal investigator must sign a clinical trial agreement 
that will clearly delineate the responsibilities and obligations of the investigator and Sponsor and will 
form the contractual basis under which the clinical trial will be conducted.  
 
 
 
 
12.2 
Protocol Amendments and Study Termination 
If Opthea amends the protocol, agreement from the investigator must be obtained.  The IRB / IEC 
must be informed of all amendments and give approval. 
Opthea reserves the right to terminate the study at any time either at a particular site or at all sites at 
any time and for any reason.  Both Opthea and the investigator reserve the right to terminate the 
investigator’s participation in the study according to the study contract.  If such action is taken, 
Opthea will discuss this with the investigator(s) at that time and notify the investigator(s) in writing.  If 
the study is suspended or terminated for safety reasons all investigators conducting the study will be 
immediately notified of the action as well as the reason for it, as will the relevant regulatory agencies.  
The Investigator will advise the IRB / IEC overseeing the study at their site. 
Upon closure of the study (whether at the expected conclusion or prematurely), the following 
activities will be performed by the Sponsor in conjunction with the Investigator: 
• 
Return of all study data 
• 
Data clarification and resolution of queries 
• 
Study drug accountability, reconciliation and final disposition 
• 
Review of site study records for completeness  
• 
Shipment of all relevant samples to the central laboratory 
The investigator should notify the IRB / IEC in writing of the study’s completion or early termination 
and send a copy of the notification to Opthea. 

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12.3 
Study Documentation and Archive 
The investigator should maintain a list of appropriately qualified persons to whom he / she has 
delegated study duties.  All persons authorized to make entries and / or corrections on eCRFs will be 
included on the Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, images, microfiches, radiographs, and correspondence.  The 
principal investigator will be responsible for ensuring that source documents are filed in a suitably 
secure location to ensure source data verification can be undertaken throughout the study. 
The investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system of all study-related (essential) documentation, suitable for inspection at any time by 
representatives from Opthea and / or applicable regulatory authorities.   
In addition, all original source documents supporting entries in the eCRFs must be maintained and 
be readily available.   
Following completion of the study the investigator will retain copies of the approved protocol, 
completed eCRFs, informed consent documents, relevant source documents, and all other 
supporting documentation related to the project in accordance with the applicable institutional review 
board, ethics committee, ICH and regulatory requirements (whichever is the longer).  Documents 
must be retained for a minimum of 15 years from the date of termination of the study or for at least 2 
years after the last approval of a marketing application in an ICH region, or at least 2 years after the 
formal discontinuation of the clinical development of an investigational product in accordance with 
local regulatory requirements. 
In the event that the investigator retires or relocates, custody of the records may be transferred to 
another suitable person who will accept responsibility for the records.  Notice of such transfer should 
be given to Opthea in writing.  The investigator must notify Opthea prior to destroying any study 
related documents. 
12.4 
Study Monitoring, Data Collection and Quality Management 
Monitoring for this study will be conducted both during monitoring visits (both masked and 
unmasked) and via centralized review of eCRF data.  The investigator will permit Opthea and their 

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agents to monitor the study as frequently as Opthea deems necessary to determine that data 
recording and protocol adherence are satisfactory.  A designated representative of Opthea in the 
form of a study monitor will verify participant data on the eCRFs for the purpose of analysis.  The 
investigator will allow Opthea and their agents direct access to the related source documents for 
monitoring purposes as frequently as the sponsor deems necessary.  This includes tests performed 
as a requirement for participation in this study and may also include other medical records required 
to confirm information contained in the eCRF such as past history and secondary diagnoses. 
At each participant visit, the Investigator or delegate should record all data generated since the last 
visit on the eCRF.  The Investigator and his / her staff will be expected to cooperate with the monitor 
to assist in providing any missing information.  The study monitor will require access to the 
investigator’s study file to ensure completeness of all study-related documentation. 
The date the study monitor visits the study site will be recorded in the site visit log.  During 
monitoring visits, the study site co-coordinator and Investigator should be available, the source 
documentation will be accessible and a suitable environment will be provided for the study monitor to 
review study related documentation. 
The Opthea monitor is responsible for verifying the eCRFs at regular intervals throughout the study 
to verify adherence to the protocol; completeness, accuracy, and consistency of the data; and 
adherence to local regulations on the conduct of clinical research.  The monitor should have access 
to subject medical records and other study-related records needed to verify the entries on the 
eCRFs. The key purposes for monitoring visits by the study monitor include the following: 
• 
Review of all study documentation for completion, adherence to the protocol  
• 
Notation of inconsistencies or missing data. 
• 
Ensuring all study materials are correctly stored and dispensed. 
• 
Verification of study data with source documents as per monitoring guidelines. 
• 
Checking fulfilment of the obligations of the Investigator. 
• 
Review of consent forms and date of consent. 
• 
Inspection of investigational product (storage, labelling and documentation). 
 
 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing eCRFs, are resolved. 
The study may be subject to an audit by an authorized representative of Opthea and / or an 
authorized Regulatory Authority (e.g. Food and Drug Administration [FDA]).  Regulatory authorities 
may request access to all study documentation, including source documents for inspection and 

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copying, in keeping with local regulations.  Opthea will immediately notify the Investigator of an 
upcoming audit / inspection.  The principal investigator must also notify Opthea if they are made 
aware of an audit that may involve this study, or the facilities. 
In the event of an audit, all pertinent study-related documentation must be made available.  If an 
audit or inspection occurs, the Investigator will permit the auditor/inspector direct access to all 
relevant documents and allocate his / her time as well as the time of relevant staff to discuss the 
findings and any relevant issues. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  A 
detailed monitoring plan and data management plan will be developed detailing the quality control 
and quality assurance checks to be undertaken. 
12.5 
Language 
All written information and other material to be used by participants and investigative staff must use 
vocabulary and language that are clearly understood.   

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12.6 
Transfer of Sponsor Obligations 
Transfer of Sponsor obligations may occur for certain activities such as project management, 
monitoring and data management.  Such transfer of obligations will be outlined in a specific 
agreement, and will not discharge Sponsor of the obligation to ensure proper oversight of all aspects 
of the study. 
12.7 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International Committee of 
Medical Journal Editors)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

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13. 
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deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011; 
118:609–614. 
Fan F, Samuel S, Gaur P, et al. Chronic exposure of colorectal cancer cells to bevacizumab 
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Ferris FL, Patz A.  Macula edema.  A complication of diabetic retinopathy.  Surv Ophthalmol 1984; 
28 Suppl: 452-61. 
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14. 
APPENDICES  
 

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Appendix D.  Refraction and Vision Testing Protocol (ETDRS)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

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