A Phase 3, Multicentre, Double-masked, Randomised Study to Evaluate the Efficacy and Safety of Intravitreal OPT-302 in Combination With Ranibizumab, Compared With Ranibizumab Alone, in Participants With nAMD
Phase: PHASE3
Conditions: Neovascular Age-related Macular Degeneration
Sponsor: Opthea Limited

Document: Study Protocol and Statistical Analysis Plan 
Protocol Number: OPT-302-1004 
Official Title: [ShORe] A Phase 3, Multicentre, Double-masked, Randomised Study to 
Evaluate the Efficacy and Safety of Intravitreal OPT-302 in Combination with Ranibizumab, 
Compared with Ranibizumab Alone, in Participants with Neovascular Age-related Macular 
Degeneration (nAMD) 
NCT Number: NCT04757610 
Document Date: 19 December 2023 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
Confidential 
Study Number: OPT-302-1004 Amendment 1 
 
 
Version: 2.0 (Amendment 1), 19 December 2023  
Page 1 of 113 
 
Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
 
ShORe 
A Phase 3, Multicentre, Double-masked, Randomised Study to Evaluate the 
Efficacy and Safety of Intravitreal OPT-302 in Combination with 
Ranibizumab, Compared with Ranibizumab Alone, in Participants with 
Neovascular Age-related Macular Degeneration (nAMD) 
 
Protocol Number: 
 
 
OPT-302-1004  
EudraCT Number:  
2020-004736-24 
  
 
Investigational Product:  
OPT-302, sozinibercept 
Development Phase:   
3 
Sponsor:  
Opthea 
650 Chapel Street 
South Yarra, VIC 3141 
Australia 
Sponsors’ Clinical Representative:  
  
 
 
 
 
 
 
 
Medical Expert:  
 
 
 
 
CONFIDENTIAL 
This protocol includes information and data that contain trade secrets and privileged or confidential information 
which is the property of Opthea Ltd (“Opthea”). This information must not be made public without written 
permission from Opthea. These restrictions on disclosure will apply equally to all future information supplied to 
you. This material may be disclosed to and used by your staff and associates as may be necessary to conduct the 
clinical study. 
Version / Date 
Version: 2.0 (Amendment 1) 
19th December 2023 
Supersedes 
Version 1.0 
16th December 2020 
 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
Confidential 
Study Number: OPT-302-1004 Amendment 1 
 
 
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Page 2 of 113 
 
Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ................................................................................................. 8 
1. 
PROTOCOL SYNOPSIS .......................................................................................... 11 
2. 
INTRODUCTION...................................................................................................... 20 
 
Background ............................................................................................................ 20 
 
Study Product ......................................................................................................... 21 
 
Pharmacodynamics ................................................................................................ 21 
 
Non-Clinical Safety ............................................................................................... 22 
 
Clinical Studies ...................................................................................................... 22 
 
Rationale ................................................................................................................ 24 
3. 
STUDY OBJECTIVES .............................................................................................. 25 
 
Primary Objective .................................................................................................. 25 
 
Secondary Objectives ............................................................................................. 25 
 
Exploratory Objectives .......................................................................................... 26 
4. 
STUDY OVERVIEW ................................................................................................ 26 
5. 
SELECTION OF STUDY POPULATION ............................................................. 29 
 
Inclusion Criteria ................................................................................................... 29 
5.1.1 
Study Eye ..................................................................................................... 29 
5.1.2 
General ........................................................................................................ 29 
 
Exclusion Criteria .................................................................................................. 29 
5.2.1 
Study Eye ..................................................................................................... 29 
 
 
5.2.3 
General ........................................................................................................ 31 
 
Re-screening .......................................................................................................... 32 
 
Number of Participants .......................................................................................... 32 
 
Participant Identification ........................................................................................ 32 
6. 
STUDY MEDICATION ............................................................................................ 32 
 
Study Arm Allocation, Randomisation and Masking ............................................ 32 
6.1.1 
Study Arm Allocation and Randomisation .................................................. 32 
6.1.2 
Study Masking ............................................................................................. 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Medication Details ....................................................................................... 35 
6.2.1 
Investigational Product - OPT-302 .............................................................. 35 
6.2.1.1 
Investigational Product Excipients ....................................................... 35 
6.2.1.2 
Dose per Administration and Corresponding Justification .................. 36 
6.2.1.3 
Supply, Packaging, and Labelling ........................................................ 36 
6.2.1.4 
Preparation of OPT-302 for Administration ......................................... 37 
6.2.2 
Co-Administered Study Product - Ranibizumab ......................................... 37 
6.2.3 
Control Arm and Sham Injection ................................................................ 37 
 
Dosing Regimens and Corresponding Justifications ............................................. 38 
6.3.1 
Dosing Regimen Justifications .................................................................... 38 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
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6.3.1.1 
Ranibizumab ......................................................................................... 38 
6.3.1.2 
OPT-302 ............................................................................................... 38 
6.3.2 
Standard Dosing Arm .................................................................................. 39 
6.3.3 
Extended Dosing Arm ................................................................................. 39 
6.3.4 
Control Arm ................................................................................................. 40 
 
Administration of Study Medication(s) ................................................................. 40 
6.4.1 
Injection Procedure ...................................................................................... 41 
 
Delay, Pause or Discontinuation of Study Product Treatment(s) .......................... 42 
 
Emergency Unmasking Procedures ....................................................................... 43 
 
Dispensing and Accountability .............................................................................. 44 
 
Assessment of Adherence to Study Medication .................................................... 44 
 
Investigator Initiated Rescue Medication .............................................................. 44 
 
Other Concomitant Medication/Treatments .......................................................... 45 
 
Risk Assessment .................................................................................................... 45 
6.11.1 
Ocular TEAEs ............................................................................................. 46 
 
 
 
 
6.11.3 
Precautions .................................................................................................. 49 
7. 
STUDY PROCEDURES AND EVALUATIONS ................................................... 51 
 
Assessment Periods and Study Procedures ............................................................ 51 
7.1.1 
Overview of Study Visits and Procedures ................................................... 51 
7.1.2 
Visit Windows ............................................................................................. 52 
7.1.3 
Selection of the Study Eye .......................................................................... 52 
7.1.4 
Screening Evaluation ................................................................................... 52 
 
 
 
 
7.1.5 
Baseline Visit (Visit 2, Day 0)..................................................................... 54 
7.1.6 
EFFICACY PHASE
 
7.1.7 
Week 52 
 57 
7.1.8 
SAFETY PHASE: 
 58 
7.1.9 
Final Study Visit: 
 60 
 
 
7.1.11 
Interim Visits and Contact ........................................................................... 61 
7.1.12 
Study Product Treatment Discontinuation .................................................. 61 
 
 
 
 
 
 
 
 
7.1.13 
Study Participation Discontinuation ............................................................ 63 
 
 
 
 
 
Observations and Measurements ........................................................................... 65 
7.2.1 
Demographics, Medical and Surgical History ............................................. 65 
7.2.1.1 
Demographics ....................................................................................... 65 
7.2.1.2 
Medical and Surgical History ............................................................... 65 
7.2.1.3 
Previous Ocular Treatments ................................................................. 66 
7.2.1.4 
Prior Medication ................................................................................... 66 
 
 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
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Study Number: OPT-302-1004 Amendment 1 
 
 
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Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
By signing this protocol, the Principal Investigator acknowledges and agrees: 
The protocol contains all necessary details for conducting the study. The Principal Investigator will 
conduct this study as detailed herein, in compliance with Good Clinical Practice1 (GCP) and the 
applicable regulatory requirements, and will make every reasonable effort to complete the study 
documentation within a timely manner. The Principal Investigator is responsible for the medical care 
of each study participant enrolled from the study site, and all study-related medical decisions. 
 
The protocol and the Investigator’s Brochure (IB)2 containing all relevant information on the drug 
relating to pre-clinical and prior clinical experience will be made available to all physicians, nurses and 
other personnel who participate in the conduct of this study. The Principal Investigator will discuss this 
material with these individuals to assure that they are fully informed regarding the study drug(s) and 
the conduct of the study. 
 
This document contains information that is privileged or confidential. Persons to whom any of this 
information is to be disclosed must first be informed that the information is confidential and must agree 
to maintain confidentiality. These restrictions on disclosure will apply equally to all future information 
supplied that is indicated as privileged or confidential or which it is apparent from the context and 
subject matter is confidential in nature. 
Opthea will have 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 utilise the data in various ways such as, for example, submission to government 
regulatory authorities, or in publication of the results of the study. 
 
 
 
 
 
Site Principal Investigator Signature 
 
Date 
 
 
 
 
Site Principal Investigator Name 
 
Site Name 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
Confidential 
Study Number: OPT-302-1004 Amendment 1 
 
 
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Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
LIST OF ABBREVIATIONS 
 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse event / Adverse experience 
 
 
AMD 
Age-related Macular Degeneration 
 
 
 
 
BCVA 
Best-corrected Visual Acuity 
 
 
 
 
 
 
 
 
cGMP 
Current Good Manufacturing Practice 
 
 
 
  
 
 
 
 
 
) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trials Facilitation and Coordination Group 
 
 
 
 
 
 
eCRF 
Electronic Case Report Form 
 
 
 
 
 
 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
 
 
FDA 
Food and Drug Administration 
FA 
Fluorescein Angiography 
 
 
GCP 
Good Clinical Practice 
 
 
GMP 
Good Manufacturing Practice 
 
 
HMA 
Heads of Medicines Agencies 
IB  
Investigators’ Brochure  
 
  
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent or Institutional Ethics Committee 
 
 
 
l 
IRB 
Institutional Review Board 
 
 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
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Study Number: OPT-302-1004 Amendment 1 
 
 
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Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
VEGF Receptor 
UADR 
Unexpected Adverse Drug Reaction 
 
 
 
 
 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
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Study Number: OPT-302-1004 Amendment 1 
 
 
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Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
Study Design: Phase 3, multicentre, randomised, parallel-group, sham-controlled, double-masked, superiority 
study 
Investigational 
Product: 
2.0 mg OPT-302 intravitreal injection 
Co-
administered 
anti-VEGF-A 
therapy: 
0.5 mg ranibizumab intravitreal injection 
Control: Sham intravitreal injection 
Study Arms: 
 
Three study arms, randomised in a 1:1:1 ratio (see Figure 1-1): 
• Standard Dosing 2.0 mg OPT-302 (50 µl) intravitreal injection with 0.5 mg ranibizumab 
(50 µl) intravitreal injection, both administered 4-weekly (q4w). 
• Extended Dosing 2.0 mg OPT-302 (50 µl) intravitreal injection (3 doses at 4-weekly 
intervals, and then 8-weekly [q4w x 3 then q8w]) with sham injection at visits when OPT-
302 is not administered, with 0.5 mg ranibizumab (50 µl) intravitreal injection 4-weekly 
(q4w). 
• Control Sham intravitreal injection with 0.5 mg ranibizumab (50 µl) intravitreal injection, 
both administered 4-weekly (q4w). 
Treatment 
Regimen: 
Efficacy Phase: 
Study treatment administered per randomised treatment group, commencing at the Baseline 
visit for a period of 48 weeks. The last dose prior to efficacy assessments at Week 52 will be 
administered at Week 48. 
Safety Phase: 
Continuing study treatment administered per randomised treatment group, commencing after 
all efficacy assessments have been completed at Week 52, for a period of 48 weeks to Week 
96. 
Masking: The participant, BCVA examiners, assessing Clinical Investigators, and image graders from 
the Independent Reading Centre (IRC), will be masked to study treatment allocation. 
Stratification: 
 
 
  
 
 
 
 
Planned Sample 
Size: 
Approximately 330 participants per treatment group, approximately 990 in total 
Key Eligibility 
Criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
Key Inclusion Criteria  
• Male or female participants at least 50 years of age. 
• Active subfoveal CNV lesion or juxtafoveal CNV lesion (1-199 µm from the fovea) with 
foveal involvement (demonstrated by leakage on FA and/or IR fluid or SRF on SD-OCT) 
that is secondary to AMD in the Study Eye. 
 
 
 
 
 
 
 
• An ETDRS BCVA score between 60 and 25 (inclusive) letters in the Study Eye. 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
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Study Number: OPT-302-1004 Amendment 1 
 
 
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Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
 
 
 
 
 
Key Exclusion Criteria 
Study Eye: 
• Any previous treatment for neovascular AMD, 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
• Clinically significant ocular disorders (other than neovascular AMD), which may, in the 
investigator’s opinion, interfere with assessment of BCVA, assessment of safety, or fundus 
imaging. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
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Study Number: OPT-302-1004 Amendment 1 
 
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Study Number: OPT-302-1004 Amendment 1 
 
 
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Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
2. INTRODUCTION 
 
Background 
Age-related macular degeneration (AMD) is a chronic degenerative eye disease of the central retina, 
that causes a progressive, irreversible, severe loss of central vision. In developed nations it is by far the 
leading cause of vision loss in both men and women.3 In many countries, AMD leads to as many blind 
registrations than all other eye diseases combined. There are two main types of AMD: dry-AMD and 
neovascular AMD. Although neovascular AMD is less common, affecting only 10% of AMD patients, 
it is more likely to lead to significant vision loss and blindness. Neovascular AMD is associated with 
choroidal neovascularisation (CNV), in which new blood vessels from the choroid break through to the 
neural retina, leaking fluid, lipids and blood, and leading to fibrous scarring and loss of vision.4 Visual 
deterioration associated with neovascular AMD can be rapid, generally severe, and significantly 
deteriorates patients’ quality of life.5  
Vascular endothelial growth factor A (VEGF-A) is a heparin-binding glycoprotein with potent 
angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells.6 
Although the underlying aetiology of neovascular AMD is complex, it has been established that VEGF-
A plays a pivotal role in the growth of the abnormal blood vessels (ie. CNV lesions), and therefore 
inhibiting VEGF-A has become a key target for effectively controlling neovascular AMD.7 Currently 
four therapies that primarily target VEGF-A inhibition have been approved by global regulatory 
agencies for the treatment of neovascular AMD: pegaptanib, ranibizumab, aflibercept and recently 
brolucizumab (although pegaptanib is not often used in clinical practice).8,9,10,11,12,13,14,15,16 Off-label use 
of bevacizumab (approved for use in oncology indications), an anti-VEGF-A therapy with similar 
properties to ranibizumab, has also become common.17 These therapies have revolutionised the 
treatment for neovascular AMD over the last decade, where initial disease stabilisation with the first 
agent, pegaptanib,18 was then exceeded by reversal of disease and significant vision gains with 
ranibizumab,19,20,21 bevacizumab,22 and aflibercept.23  
Mean vision gains observed over 12-months in the pivotal studies for these anti-VEGF-A therapies 
ranged from +6.1 to +11.3 Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual 
acuity (BCVA) letters. The MARINA study reported a gain of +6.5 to +7.2 letters,20 ANCHOR +8.5 to 
+11.3,21 VIEW (control groups) +8.1 to +9.4,23 and CATT (control group) reported a gain of +8.5 with 
monthly ranibizumab.22 The CATT study reported a gain of +8.0 letters with monthly bevacizumab.22 
The VIEW studies reported gains of +6.9 to +10.9 letters with 1-2 monthly aflibercept,23 and the HAWK 
and HARRIER studies reported gains of +6.1 to +6.9 letters with 1-3 monthly brolucizumab. 24 
Despite these significant gains or stabilisation of vision, at least 45% of patients with neovascular AMD 
exhibit some degree of resistance (characterised by failure to gain or maintain vision) to therapies that 
selectively target VEGF-A.25,26 Newer agents have focussed on non-inferiority to existing anti-VEGF-
A therapies with extended treatment intervals, rather than providing superior vision gains.24 It is thought 
that treatment resistance occurs as selective VEGF-A inhibitors do not fully address the multifactorial 
pathogenesis of CNV formation.27,28 Combination therapy targeting alternative mediators of 
neovascular disease progression, is expected to play an increasing role in treating neovascular AMD to 
help improve visual acuity (VA) outcomes, and prevent chronic decline in VA. This may lead to longer 
treatment free intervals and thus translate to a lesser treatment burden for many patients.  

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
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Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
OPT-302 is a recombinant fusion protein that binds to and neutralises the activity of VEGF-C and 
VEGF-D by preventing ligand binding to the endogenous receptors, VEGFR-2, and VEGFR-3. It is 
highly specific for VEGF-C and VEGF-D and does not bind to VEGF-A.2 Both VEGF-C and VEGF-
D have been shown to induce vessel growth in several in vivo models,29,30,31,32 and levels of VEGF-C 
and/or VEGF-D are upregulated in response to inhibition of VEGF-A with bevacizumab, ranibizumab 
or aflibercept.33,34,35,36,37 
Additionally, VEGF-C has been specifically shown to play a critical role in the formation of the retinal 
vasculature.38 VEGF-C is upregulated by inflammatory mediators that are implicated in the 
pathogenesis of the disease,39 and elevated in the circulation of neovascular AMD patients compared to 
healthy volunteers.40
 
 
 
 
 
 
 
 
  
 
 
 
 
Study Product 
 
 
 OPT-302 binds and neutralises the activity of VEGF-C and VEGF-D by preventing ligand 
binding to endogenous VEGFR-2 and VEGFR-3. 
Full details of the product (in terms of structure, formulation and mechanism of action) may be found 
in the Investigators’ Brochure (IB).2  
 
Pharmacodynamics 
The molecular targets of OPT-302, VEGF-C and VEGF-D, are members of the VEGF family of 
secreted glycoproteins that are critical mediators of blood vessel growth (angiogenesis), lymphatic 
vessel growth (lymphangiogenesis) and vascular permeability. The vascular endothelial growth factors 
(VEGFs) bind to VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and/or VEGFR-3 (Flt-4), a family of 
structurally-related receptor tyrosine kinases that are predominantly expressed on the endothelial cells 
of blood and/or lymphatic vessels.44,45 OPT-302 binds and neutralises the activity of both VEGF-C and 
VEGF-D, with high specificity, by preventing ligand binding to endogenous VEGFR-2 and VEGFR-3.  
VEGF-C and VEGF-D induce angiogenesis via the activation of both VEGFR-2 and VEGFR-3, and 

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Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
each study are outlined in Table 2-1 below. 
Table 2-1 
Clinical Studies to Date 
Protocol No. 
Study Design 
Treatment Groups 
Study 
Population 
N 
 
OPT-302-1001 
Phase 1 open-label, dose 
escalation study  
• Ranibizumab + OPT-302 0.3, 1.0 or 
2.0 mg, q4w x 3 
• 2.0 mg OPT-302 monotherapy, q4w 
x 3 
nAMD 
51 
OPT-302-1002 
Phase 2b dose ranging, 
multicentre, double-
masked, sham controlled 
study 
• Ranibizumab + OPT-302 0.5 or 2.0 
mg, q4w x 6 
• Ranibizumab + sham, q4w x 6 
nAMD 
366 
OPT-302-1003 
Phase 1b/2a dose 
escalation study 
• Aflibercept + OPT-302 0.3, 1.0 or 
2.0 mg, q4w x 3 
• Aflibercept + sham, q4w x 3 
DME 
153 
Ranibizumab = 0 5 mg ranibizumab; q4w = administered every 4 weeks; nAMD = neovascular age-related macular degeneration; DME = 
diabetic macular oedema/edema; aflibercept = 2.0 mg aflibercept; N = number of participants 
In the completed first-in-human clinical study (OPT-302-1001, n=51) in treatment-naïve or previously 
treated participants with neovascular AMD,50 OPT-302 was well tolerated when administered every 4 
weeks (total 3 doses) by intravitreal injection up to the highest dose tested (2.0 mg) in combination with 
0.5 mg ranibizumab and as a monotherapy (2.0 mg OPT-302). No dose-limiting toxicities (DLTs) were 
observed, and the maximum tolerated dose (MTD) was not reached. In addition, preliminary signals of 
efficacy were observed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
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Study Number: OPT-302-1004 Amendment 1 
 
 
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Opthea Limited, 650 Chapel Street, South Yarra, VIC 3141, Australia 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Based on the positive Phase 2b study results in neovascular AMD, Opthea is conducting a prospective 
Phase 3 programme in treatment-naïve participants with neovascular AMD, of 2.0 mg OPT-302 in 
combination with 0.5 mg ranibizumab (OPT-302-1004) and of 2.0 mg OPT-302 in combination with 
2.0 mg aflibercept (OPT-302-1005), compared with 0.5 mg ranibizumab or 2.0 mg aflibercept, with 
sham control in each trial respectively.  
Full details of the outcomes for the completed clinical studies are provided in the IB.2 
 
Rationale 
The compensatory upregulation of VEGF-C and VEGF-D, and incomplete inhibition of the pathways 
mediating vascular growth, may be implicated in the sub-optimal responses seen with VEGF-A 
monotherapy. Therefore, combining OPT-302 with a VEGF-A inhibitor is expected to result in a more 
complete and effective inhibition of angiogenesis and vascular leakage in eyes with neovascular AMD 
compared to VEGF-A inhibition alone.  
There is a high unmet medical need for more effective treatments in participants with sub-optimal 
responses to current treatments for neovascular AMD. 
 
 

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3. STUDY OBJECTIVES 
The criteria for evaluation of the study objectives are laid out in Section 10.1. 
 
Primary Objective 
To determine the efficacy of intravitreal 2.0 mg OPT-302 when administered in combination with 
intravitreal 0.5 mg ranibizumab, in participants with neovascular AMD. 
 
Secondary Objectives 
The secondary objectives of the study are to determine the effects of intravitreal 2.0 mg OPT-302 when 
administered in combination with intravitreal 0.5 mg ranibizumab from Baseline to (and at) Week 52 
as determined by: 
Efficacy: 
• 
Changes in ETDRS BCVA letter score  
• 
Changes in anatomical parameters (CNV area, SRF and IR cysts) 
 
Safety: 
 
 
 
 
 
 
 
 
 

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3. 
Clinically significant ocular disorders (other than neovascular AMD), which may, in the 
Investigator’s opinion, interfere with assessment of BCVA, assessment of safety, or fundus 
imaging. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.2.3 
General 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13. 
Any current (or history of a) social, psychological, or medical condition that, in the 
Investigator’s opinion, should preclude enrolment into the study. 
 
 
 
 
 

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Re-screening 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Participants 
It is anticipated that approximately 990 eligible participants will be recruited into the study, with 
approximately 330 per study arm. 
 
Participant Identification 
Participants will be allocated a unique Participant Identification Number (PIN) at screening, and this 
number will be used to identify the participant for the duration of the study. 
6. STUDY MEDICATION  
 
Study Arm Allocation, Randomisation and Masking 
6.1.1 
Study Arm Allocation and Randomisation 
 
 
 
 
  
 
 
 
 
 

ShORe Phase 3 study of OPT-302 with ranibizumab in neovascular AMD 
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6.2.1.2 
Dose per Administration and Corresponding Justification 
OPT-302 is administered at a dose of 2.0 mg per injection. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
6.2.1.3 
Supply, Packaging, and Labelling 
OPT-302 is manufactured and packaged by Opthea, under current Good Manufacturing Practice 
(cGMP) conditions.  
 
 
 
 
 
Each vial, and outer box, is packaged and labelled according to GMP and all regulatory requirements 
in each country participating in the study. 
 
  
 

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6.2.1.4 
Preparation of OPT-302 for Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Co-Administered Study Product - Ranibizumab 
Ranibizumab will be administered as an intravitreal injection, at a dose of 0.5 mg (50 µL volume). The 
ranibizumab will be provided in commercial packaging and labelled for clinical trial use, and is to be 
stored, prepared, and administered as per the package insert. 
 
 
 
6.2.3 
Control Arm and Sham Injection 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

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6.3.2 
Standard Dosing Arm 
Study products are to be administered from Baseline to 
(Week 96) according to the following 
regimen, 
 
• 
0.5 mg ranibizumab is administered at 4-weekly intervals from Baseline up to and including 
Week 96 
• 
2.0 mg OPT-302 is administered at 4-weekly intervals from Baseline up to and including Week 
96. 
6.3.3 
Extended Dosing Arm 
Study products are to be administered from Baseline to 
Week 96) according to the following 
regimen, 
 
• 
0.5 mg ranibizumab is administered at 4-weekly intervals from Baseline up to and including 
Week 96 
• 
2.0 mg OPT-302 is administered at 4-weekly intervals for three treatments 
 
 and then at 8-weekly intervals up to and including Week 96
 
 

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6.4.1 
Injection Procedure 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

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Delay, Pause or Discontinuation of Study Product Treatment(s) 
A delay in study treatments is defined as administration of one or both study products one or more days 
after the scheduled study visit has been completed. A pause in study treatments is defined as a temporary 
cessation of one or both study products for one or more of the study visits, with an intention to resume 
study treatment at the next or a subsequent study visit. Discontinuation is defined as a permanent 
cessation of one or both study products with no intention to restart treatment at a later study visit.  

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Emergency Unmasking Procedures 
Emergency unmasking may only occur if the PI considers that knowledge of study medication is 
essential to properly treat a severe AE or an SAE, and the Treating Investigator cannot adequately treat 
the (S)AE. 
 
 
 
 

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Whenever possible, the PI should discuss each case with the Medical Monitor and notify the Sponsor 
prior to unmasking - when this is not possible both the Medical Monitor and Sponsor must be notified 
as soon as is practical, and within 24 hours of unmasking taking place. The site’s Independent/Research 
Ethics Committee (IEC/REC) / Institutional Review Board (IRB) should also be notified according to 
local regulations. 
 
Dispensing and Accountability 
The Unmasked Technician is responsible for ensuring accurate records of receipt, distribution, 
reconciliation, and return of study product. Accurate records must be kept regarding when and how 
much of each study product was administered to each participant in the study and what product was 
returned, with associated study product kit numbers and expiry dates. 
At completion of the study, all unused study product must be reconciled via detailed records itemising 
all movement of study product to, from and within study sites, and dispensing records. Once 
reconciliation of study product has been performed, unused product (either returned dispensed or un-
dispensed study product) may be destroyed or returned to the Sponsor or designee as per the Pharmacy 
Manual and written instructions issued by the Sponsor at the end of the study. 
 
Assessment of Adherence to Study Medication 
 
 
 
 
 
 
 
 
Investigator Initiated Rescue Medication 
 
 
 

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Other Concomitant Medication/Treatments 
Permitted and prohibited concomitant medications and ocular treatments are outlined in detail in 
Section 7.3. 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
  
. 
 
Risk Assessment 
 
 
 
 
 
. 
There appears to be no significant additional safety risks associated with the addition of OPT-302 to 
ranibizumab or aflibercept intravitreal therapy over and above those identified after intravitreal injection 
of anti-VEGF-A therapies, as observed to date 
 
 
. The safety data is provided in more detail in the IB with a full benefit/risk evaluation.2 
There are no anticipated additional risks to a participant relating to participation in this clinical trial due 
to the COVID-19 health emergency. Patients would require regular in-clinic treatment whether or not 
they were participating in a clinical trial, given the serious nature of neovascular AMD. 

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6.11.1 
Ocular TEAEs  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

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Table 6-4 below presents the AEs that have been reported during clinical experience with intravitreal 
administration of well-established anti-VEGF-A therapies.10,11,12,13  
Table 6-4 
AEs Related to Intravitreal Anti-VEGF-A Therapies 
Frequency 
Rate* 
Event(s) 
Very Common 
≥ 10% people 
Ocular: Vitritis; vitreous detachment; retinal haemorrhage; visual 
disturbance; eye pain; vitreous floaters; conjunctival haemorrhage; eye 
irritation; foreign body sensation in eye; lacrimation increased; blepharitis; 
dry eye; ocular hyperaemia; eye pruritus; increased intraocular pressure. 
Non-ocular: sore throat; nasopharyngitis; headache and arthralgia. 
Common 
< 10% to ≥ 1% 
people 
Ocular: Retinal degeneration; retinal disorder; retinal detachment; retinal 
tear; detachment of the retinal pigment epithelium; retinal pigment 
epithelium tear; visual acuity reduced; vitreous haemorrhage; vitreous 
disorder; uveitis; iritis; iridocyclitis; cataract; cataract cortical; cataract 
nuclear; cataract subcapsular; posterior capsule opacification; punctuate 
keratitis; corneal erosion; corneal abrasion; anterior chamber flare; vision 
blurred; injection site haemorrhage; eye haemorrhage; conjunctivitis; 
conjunctivitis allergic; eye discharge; photopsia; photophobia; ocular 
discomfort; eyelid oedema; eyelid pain; conjunctival hyperaemia. 
Non-ocular: urinary tract infection; anaemia; anxiety; cough; nausea; 
hypersensitivity; allergic reactions (rash, urticaria, pruritus, erythema). 
Uncommon 
< 1% to ≥ 0.1% 
people 
Ocular: Hypopyon; hyphaema; keratopathy; iris adhesion; corneal deposits; 
corneal oedema; corneal striae; corneal epithelium defect; injection site pain; 
injection site irritation; abnormal sensation in eye; eyelid irritation; lenticular 
opacities. 
Serious 
 
 
Common 
< 10% to ≥ 1% 
people 
Detachment or tear of the layer in the back of the eye, resulting in flashes of 
light with floaters progressing to a temporary loss of sight, or cataract. 
Uncommon 
< 1% to ≥ 0.1% 
people 
Blindness, endophthalmitis with inflammation of the inside of the eye. 
*CIOMS Definition; data sources: Lucentis® label and SmPC,10,11 Eylea® label and SmPC.12,13 
Full details of the non-clinical and clinical safety data for ranibizumab may be found in the package 
insert and the approved label for the product. 

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7. STUDY PROCEDURES AND EVALUATIONS 
 
Assessment Periods and Study Procedures 
7.1.1 
Overview of Study Visits and Procedures 
After screening assessments have been completed, eligibility has been confirmed, and Baseline 
assessments have been completed, participants will be randomised
 
 
 
During the Efficacy Phase (Baseline to Week 52), study medication will be administered according to 
the randomised schedule, commencing at the Baseline visit, to Week 48. The primary endpoint will be 
determined at Week 52 
Once all study assessments have been completed at Week 52, the 
participant will continue the study in the Safety Phase (Week 52 to Week 100). Each participant will 
continue to receive study medication (per the schedule allocated at Baseline), resuming after all study 
assessments at Week 52, and continuing to Week 96 
except no loading doses are 
administered in the Extended Dosing OPT-302 arm. A final follow-up visit will be conducted at Week 
100 
, approximately 4 weeks after the last administration of study medication. 
 
 
 
 
 
 
 
 
 
 

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7.1.2 
Visit Windows  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
7.1.3 
Selection of the Study Eye 
Only one eye may be “enrolled” into the study, and this eye will be designated the “Study Eye”. This 
will be the eye that will be administered study medication and be assessed according to the protocol. 
 
 
 
 
 
The Study Eye will be documented in the eCRF as either OD or OS. 
7.1.4 
Screening Evaluation  
The screening evaluation period should be kept as short as possible so as to promptly commence 
medication for an eligible participant. 
 
 
 
 
 
 
 
 

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7.1.5 
Baseline Visit (Visit 2, Day 0) 
The Baseline visit (Day 0) is to occur as soon as possible after eligibility has been confirmed, 
 
 
 

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7.1.7 
Week 52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.1.8 
SAFETY PHASE: 
  
 
 
  

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7.1.9 
Final Study Visit: 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.1.11 
Interim Visits and Contact 
Interim contact and visits between scheduled study visits may occur at any time during the study if 
requested by the participant, for the assessment of an AE, or as deemed necessary by the Investigator. 
 
. All such unscheduled 
visits must be documented in the participant’s study file and eCRF and any AEs reported during such 
visits will be documented in the eCRF. 
7.1.12 
Study Product Treatment Discontinuation 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Observations and Measurements 
7.2.1 
Demographics, Medical and Surgical History 
Each study participant’s demographic information and medical and surgical history will be taken from 
medical records, clinic notes, and/or during the participant’s interview at the screening evaluation.  
7.2.1.1 
Demographics  
Study participants’ gender, age (at the Screening Visit), race (and additionally ethnicity if in the US), 
 will be collected.  
7.2.1.2 
Medical and Surgical History  
Relevant medical and surgical history will be collected, including: Any ongoing medical conditions or 
relevant conditions, any ocular surgical procedures, any ocular medical interventions, and all 
ophthalmic diagnoses. 

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7.2.1.3 
Previous Ocular Treatments 
All ocular treatments administered within the previous 
 should be recorded, 
with an indication of which eye (OS, OD, OU [Oculus Uterque, both eyes]) the treatment was 
administered to (if applicable).  
Any previous treatment for neovascular AMD in the Study Eye is an exclusion for entry into the study, 
 
7.2.1.4 
Prior Medication 
All prescription and non-prescription medications, non-pharmaceutical therapeutic treatments, 
vitamin/mineral supplements and herbal or other complementary medicines taken or administered at 
Screening are to be recorded as prior medication, with start/stop dates or indicated as “ongoing”. 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

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7.2.4.1 
 Best-corrected Visual Acuity (BCVA) 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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7.2.6 
Adverse Events 
The Investigator(s) and designated study personnel will monitor each participant for AEs during the 
study. All AEs reported between the time consent was obtained and final follow-up is completed will 
be recorded in the eCRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Concomitant Medication and Treatments 
7.3.1 
Recording Concomitant Treatments  
 
 
All medications must be reported and recorded in the eCRF (including prescribed and over-the-counter 
medications, vitamins, herbal remedies, other traditional preparations, and any ocular preparations 
administered of any type) 
 
 
 
 
 
  
 
 
 
 
 
  
7.3.2 
Prohibited and Permitted Concomitant Treatment - Study Eye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.3.3 
Concomitant Treatment - Non-Study Eye 
 
 
 
 
 
 
 
7.3.4 
Other Prohibited Concomitant Treatments  
 
 
  
 
 
 
 
8. SAFETY REPORTING 
The reporting and documentation of AEs 
 
 is an essential component of all clinical studies. Therefore, it is important that all 
investigational staff understand the requirements and responsibilities outlined below. It is the 
responsibility of the Investigator to ensure that all AEs and other clinically significant findings that 
occur during the conduct of a clinical study are documented and reported accurately. 
Adverse event(s) should be documented in terms of a medical diagnosis(es) where possible, rather than 
signs and/or symptoms.  

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Adverse Event Definitions 
8.1.1 
Adverse Event (AE) 
 
 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. An AE (also referred to as an adverse experience) can be any 
unfavourable and unintended sign (eg. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, without any judgment about causality. 
The Investigator will make a judgment regarding whether or not, in their opinion, the AE was related 
to the study product(s). However, even if the Investigator feels there is no relationship to the test 
product, the AE must be recorded. If any clinical AEs have occurred, they will be recorded on the AE 
report page of the eCRF and their severity will be graded. 
Adverse events may include: 
1. 
The significant worsening of a disease or symptoms of a disease. 
2. 
An intercurrent illness. 
3. 
Exacerbation (ie. increase in frequency or intensity) of a pre-existing condition or event. 
An AE does not include a/an: 
1. 
Medical or surgical procedure: but the condition that leads to the procedure is usually an 
AE. 
2. 
Situation where an untoward medical occurrence has not occurred (eg. hospitalisation for 
cosmetic surgery, social and/or convenience admissions). 
3. 
Overdose of either study drug or concomitant medication that does not result in any signs 
or symptoms. If any signs or symptoms of an overdose are present, then these will be 
recorded as an AE. 
8.1.2 
Treatment Emergent Adverse Event (TEAE) 
A TEAE is an AE that was not present prior to treatment with the study product(s), or an event that was 
present prior to treatment, but worsens either in intensity or frequency following treatment. 
8.1.3 
Serious Adverse Event (SAE)  
An SAE is defined as any AE that results in any of the following outcomes: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability / incapacity (including temporary or permanent 

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sight-loss) 
• 
Is a congenital anomaly / birth defect 
• 
Is an Important Medical Event, which includes an event that puts the participant at immediate 
risk of permanent sight loss. 
 
 
 
 
 
 
 
  
The term “life-threatening” in the 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. 
Hospitalisation is defined as the participant being hospitalised > 24 hours, or the participant’s 
hospital stay being prolonged for at least an additional overnight stay. Hospital admissions for 
a pre-existing condition, planned procedures, or for normal disease management procedures 
(eg. routine glycaemic control in a diabetic participant) will not be considered an SAE. 
Complications that occur during hospitalisations are usually AEs. If a complication prolongs 
hospitalisation by at least one night, it is an SAE. 
Important Medical Events that may not result in death, be life-threatening, or require hospitalisation 
may be considered to be SAEs when, based upon appropriate medical judgment, they may jeopardise 
the study participant, may pose a serious risk to the participants vision, or may require urgent medical 
or surgical intervention to prevent one of the outcomes listed in the SAE definition. 
 
 
 
 
8.1.4 
Adverse Drug Reaction (ADR) and Unexpected 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 medication(s) and 
the AE. 
An Unexpected ADR (UADR) is defined as an ADR, the nature, severity, or frequency of which, is not 
consistent with the applicable product information (ie. not listed in the IB for OPT-302 or in the 
Summary of Product Characteristics for ranibizumab [see Section 6.11]). 

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8.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as an SAE that is suspected to 
be an ADR, but is not consistent with the information provided in the Investigators’ Brochure - ie. either 
is not listed as an expected ADR in the Reference Safety Information section of the IB, 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 IEC/REC/IRB by each Investigator 
(see Section 8.9). 
 
Timeframes for Reporting of an Adverse Event 
8.2.1 
Timeframe for Reporting Adverse Events 
 
 
 
 
 
8.2.2 
Timeframe and Timelines for Reporting Serious Adverse Events 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 

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. 

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Recording an Adverse Event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
8.3.1 
Assessment of Adverse Event Severity 
 
Adverse event severity will be graded as per the current version of the National Institutes of Health 
(NIH) Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0). 
AEs not presented in the CTCAE will be graded as follows: 
Grade 1: Mild 
An AE where there is an awareness of the sign or symptom, but 
no or minimal interference with normal daily activities. 
Grade 2: Moderate 
An AE that causes interference with normal daily activities 

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Grade 3: Severe 
An AE that causes inability to perform normal daily activities. 
 
It should be noted that an AE that is considered to be “severe” may not necessarily be considered to be 
“serious” or of major medical significance. 
8.3.2 
Assessment of Adverse Event Causality 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Follow-up of Adverse Events 
Investigators must monitor participants with an SAE until the event has stabilised or resolved. In the 
case of non-serious AEs, follow-up should occur until the participant completes the study. 
 
Regulatory Reporting Requirements 
Opthea has a legal responsibility to notify the local regulatory authority(ies), and other overseas 
agencies (if applicable) about the safety of the product/drug 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, with a maximum reporting timeline typically of 7 calendar days. 
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. 
 
IEC/REC/IRB Reporting Requirements 
The timeframe within which the Investigators must provide notification of deaths, study product related 
and/or unexpected SAEs is stipulated by the local regulatory authorities. 
It is the Investigators’ responsibility to comply with the requirements for the relevant IEC/REC/IRB 
notification. Each investigator will notify the relevant IEC/REC/IRB of all reportable events, 
 

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9. CLINICAL MANAGEMENT 
 
Participant Completion 
In the context of clinical management, a participant will be deemed to have completed the study once 
all trial procedures have been completed to Week 100 (Visit 27). Any AEs or SAEs still ongoing will 
be followed in accordance with Section 8. 
 
Minimising Study Participant Discontinuation 
The Investigator should make every effort to keep each participant in the study
 
 
 However, 
Investigator’s efforts to retain participants must respect their ethical right to withdraw their consent and 
discontinue the study any time. 
See Section 7.1.12 and Section 7.1.13 for procedures and evaluation of Study Product Treatment 
Discontinuation and Study Participation Discontinuation. 
 
Lost to Follow-Up 
Sites should make every effort to select participants who are motivated and give every indication that 
they will remain in the study to completion. If a participant fails to appear for a scheduled visit, the site 
must make all reasonable attempts to contact the participant, and work through any difficulties that the 
participant may be experiencing in attending the study visit. These attempts should be documented in 
the participant’s study file.  
 
Premature Termination of Study  
The study may be terminated prematurely locally by the Sponsor, ethics, or regulatory authorities, if: 
• 
The number and/or severity of AEs justify discontinuation of the study 
• 
New data become available that raises concern about the safety of the investigational product 
so that continuation might cause unacceptable risks to participants. 
In addition, Opthea reserves the right to discontinue the trial prior to inclusion of the intended number 
of participants, but will only exercise this right for reasons of safety or force majeure events.  
After such a decision to discontinue the trial is made, the Investigator must contact all participants 
within two weeks, and written notification must be sent to the IRB/IEC. 
 
End of the Study  
The study is deemed to have ended once the last study visit has been completed for the last remaining 
participant. 

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11. HUMAN PARTICIPANTS PROTECTION 
 
Regulatory Considerations 
Opthea or their agents will submit the appropriate documents to the local regulatory agencies and 
IEC/REC/IRBs affiliated to each site and will await approval prior to study commencement. 
This study will be conducted in accordance with the following guidelines and regulations as applicable:  
• 
ICH Guidelines for Good Clinical Practice (GCP) 
• 
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). 
 
Independent/Research Ethics Committee (IEC/REC)/Institutional Review 
Board (IRB) 
Prior to the commencement of the clinical study, written approval from the IEC/REC or IRB must be 
received by the Investigator. 
The Investigator or designee must submit the protocol, plus participant information and consent forms, 
for independent review by a recognised IEC/REC/IRB pertinent to the study location. 
The IEC/REC/IRB should be constituted in accordance with local regulatory requirements. 

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Informed Consent 
Written informed consent must be obtained from each potential study participants prior to the initiation 
of any study-related procedures. The Investigator or designee must explain to each participant the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, and any discomfort it may entail, and the alternative treatment options including standard of 
care. The participant should be provided with sufficient time to consider the information, and be given 
the opportunity to ask questions. It is essential that the Investigator or designee fully explores the 
duration of the study with a potential participant and stresses the importance of attending all study visits, 
 
Each participant must be informed that participation in the study is voluntary, that he/she may 
discontinue participation in the study at any time, and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. The information sheet 
accompanying the informed consent is to be given by means of a standard written statement, written in 
non-technical language, and potential participants should be given sufficient time to adequately read 
the information and properly consider the potential risks, benefits, study specific procedures and time 
commitments. The participant is to read and consider the consent statement before personally signing 
and dating it, and should be given a copy of the signed document. The participant must date the 
document, it is inappropriate for the PI or site staff to date the executed consent form. If participants’ 
vision is too poor, participant consents, and provided that this is documented on the consent form, an 
impartial witness may be used to document consent.  In this instance, any impartial witness is to be 
present for the full discussion, the documents are to be read and explained to the participant, and the 
participant (if able) and impartial witness should sign and date the ICF. In obtaining and documenting 
informed consent, the Investigator and his/her designee(s) will comply with applicable local and 
domestic regulatory requirements and will adhere to GCP and to the ethical principles that have their 
origin in the Declaration of Helsinki. 

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Prior to the beginning of the trial, site Investigators will have the IRB/IEC’s written approval of the 
protocol, the ICFs, and any other study-related information to be provided to participants. The Sponsor 
(or designee) must review and confirm in writing that all essential documents have been received, prior 
to commencement of participant screening. 
Participants will document their provision of informed consent by signing their informed consent forms. 
The informed consent process will give individuals all of the relevant information and time they need 
in order to decide whether to participate, or to continue participation, in this study. All study related 
materials distributed to participants including the informed consent forms will be available in the local 
language(s). Potential participants will be permitted to ask questions and to exchange information freely 
with the study Investigators. Only listed study Investigators may obtain informed consent from potential 
study participants. The Investigators will keep research participants fully informed of any new 
information that could affect their willingness to continue study participation.  
 
Ethical Considerations 
The study involves intravitreal injections into the Study Eye which may cause anxiety and/or 
discomfort. In addition, since the study population comprises older participants, there may be some 
people with impairment of hearing, comprehension, or other disability. The Investigator and study staff 
must fully assess each potential participant to ensure that he/she is fully aware and fully understands 
the procedures and risks of the study. Potential participants who do not have the mental capacity to fully 
understand the nature of the study and potential risks must not be enrolled into the study. 
 
Confidentiality 
Members of the study site staff must all maintain participant confidentiality. The log of study participant 
names and other protected health information will be kept secured. 
 
 
 
 
 
 
  
Participant medical records pertaining to this study may be inspected/audited at any time by Opthea 
employees or their duly authorised representatives, a regulatory authority, or the IEC/REC/IRB. All 
records accessed will be strictly confidential. Consent to participate in this study includes consent to 
these inspections/audits. 
The study will be conducted in accordance with data privacy regulations relevant to each participating 
country. 

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12. ADMINISTRATIVE ASPECTS 
 
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 Sponsors and will form 
the contractual basis under which the clinical trial will be conducted.  
 
Study File 
All associated study correspondence will be filed by the Investigator and will be available for inspection 
by the study monitor and/or appropriate representatives of Opthea and/or regulatory authorities to 
determine that all documentation is present. It will be the responsibility of the Investigator to provide 
adequate means for organisation and filing of study documentation at the study centres.  
 
Initiation of the Study 
Prior to the commencement of the study, a designated representative of Opthea will visit the 
investigational site to ensure adequacy of facilities and to discuss with the Investigator, and other 
personnel involved with the study, their responsibilities with regard to protocol adherence. This visit 
may be waived in the event that there has been recent experience with the investigational site, and there 
has been no change to site facilities or key site staff.  
The investigational staff may not enrol any participants prior to Opthea receiving written approval from 
the IEC/REC/IRB, and completion of a formal Site Initiation Meeting (SIV) conducted by an Opthea 
representative with key investigational site staff in attendance. This meeting will include an inventory 
of study supplies and a detailed review of the protocol and eCRFs. 
 
Participant Reimbursement 
Participants will be reimbursed according to the guidelines of the relevant IEC/REC/IRB in order to 
compensate them for items such as travel, meals, the inconvenience, and their time as appropriate. 
 
Participant Identification and PIN 
All participants who provide consent for the Study will be assigned a unique PIN. The PIN of the 
participant will be entered on all pages of the eCRF and any study specific documents and will be the 
participant’s primary identification number.  
 
Recording of Data 
The Investigator should maintain the individual participant files 
 
 
 This constitutes ‘source 

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data’. All entries on the eCRFs must be backed up by source data, unless agreed that the eCRF will 
constitute source data. 
 
 
 
 
 
 
 
 
 
 
 
 
Monitoring of the Study 
Monitoring for this study will be conducted both during monitoring visits and via centralised review of 
eCRF data. 
The Investigator will permit Opthea and their 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 reasonable access to the related source documents 
for monitoring purposes as frequently as the sponsor deems necessary. 
 
 
 
 
 
 
 
 
 
 
 
 

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Quality Management 
Prior to study start, all risks to critical study processes and data will be identified, both at the system 
level, and clinical trial level. A risk review and control process will be implemented, and risks will be 
monitored throughout the study to ensure that appropriate actions and processes are instigated. 
Throughout the Study, the data will be monitored (both locally and remotely) and the eCRFs checked 
against the participant’s medical record for completeness and accuracy. This will be performed by 
Opthea or its legally contracted agents. 
Following completion of the eCRFs, the data will be electronically checked for consistency and range. 
Queries will be generated for spurious data and clarification sought from the responsible Investigator 
or delegate at the Study site. These data queries must be resolved in a timely manner by the Study site. 
 
Quality Assurance Audit/Inspection 
The Study may be subject to an audit by an authorised representative of Opthea and/or an authorised 
Regulatory Authority (eg. FDA, Medicines and Healthcare Products Regulatory Agency [MHRA]).  
Regulatory authorities may request access to all study documentation, including source documents for 
inspection and copying, in keeping with local regulations. Opthea will immediately notify the 
Investigator of an upcoming audit/inspection. The PI 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. 
 
Study and Site Closure 
Opthea reserves the right to prematurely discontinue or suspend the study either at a particular site for 
significant quality or compliance issues, or at a particular site or all sites at any time for safety reasons 
or due to a force majeure event. 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 is responsible for advising the 
IEC/REC/IRB overseeing the study at their site of any study and/or site closure. 
 

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. 
 
Record Retention 
All study documents, including the protocol and IB, are the confidential property of Opthea and should 
be regarded as such. 
 
 
Following completion of the study the Investigator will retain copies of the approved protocol, approved 
protocol amendments, completed eCRFs, informed consent documents, relevant source documents, and 
all other supporting documentation related to the project in accordance with the applicable 
IEC/REC/IRB, ICH and regulatory requirements (whichever is the longer). 
 
 
 
 
 
 
 
 
Study Report 
A complete study report and its results shall be written on completion of the study and will include any 
conclusions drawn with respect to the safety and efficacy of the study product (refer to ICH Topic E3 - 
Note for Guidance on Structure and Content of Clinical Study Reports [CPMP/ICH/137/95]). 
 
  
 
13. SPONSOR RESPONSIBILITIES 
In addition to preparing the study protocol Opthea or their agents will also be responsible for the conduct 
of the activities listed below. 

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Funding 
Opthea will fund the study as outlined in the clinical trial agreements. All direct costs associated with 
the conduct of the study and laboratory investigations will be paid for by Opthea as outlined in the 
clinical trial agreements.  
 
Supply of Study Materials and Study Documentation 
Opthea or their agents will supply all the study materials and templates and other associated 
documentation required for the study. 
 
Compliance with Regulatory Requirements 
Opthea will ensure that the Investigator is conducting the study in accordance with the local and 
international regulatory requirements as stipulated in the protocol. 
 
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 the Sponsor of the obligation to ensure proper oversight of all aspects of the 
study. 
14. USE OF DATA AND PUBLICATIONS 
Opthea may disclose data derived from the study to other Investigators and regulatory authorities in one 
or more geographical regions. 
The principles for publication of results of this study will be addressed in clinical trial agreements 
between Opthea and the study site, and Opthea and the subcontractors performing the study. Results 
means any and all information and know-how (whether patentable or not) which is discovered, invented 
or developed or which arises in the course of or as a result of the conduct of the Study, including any 
and all improvements to the products being studied. 
 

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