Conditions: Macular Edema Retinal Vein Occlusion
Keywords: RVO Kodiak KSI-301 Vascular endothelial growth factor Anti-VEGF VEGF Antibody biopolymer conjugate Retinal Degeneration Retinal Diseases Eye Diseases Vision Disorders Vision, low Aflibercept Eylea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 568
Healthy volunteers: no

Brief summary:
This Phase 3 study will evaluate the efficacy, durability, and safety of KSI-301 compared to aflibercept, in participants with macular edema due to treatment-naïve branch (BRVO) or central retinal vein occlusion (CRVO).

Detailed description:
This is a Phase 3, prospective, randomized, double-masked, two-arm, multi-center non-inferiority study evaluating the efficacy and safety of repeated intravitreal dosing of KSI-301 5 mg in participants with visual impairment due to treatment-naïve macular edema secondary to RVO (either branch or central type).

The primary endpoint will be assessed at Week 24; additional secondary endpoints for efficacy will be assessed at Week 24 and Week 48.

Arms:
arm 1: Intravitreal injection of KSI-301 (5 mg) at Day 1, Week 4, and once every 8 weeks through Week 20 followed by an individualized dosing regimen of Intravitreal injection of KSI-301 (5 mg) from Week 24 to Week 44.

In the Extension Phase, participants randomized to KSI-301 (5 mg) in the Primary Study will continue to receive KSI-301 (5 mg) based on protocol-defined disease activity criteria. arm 2: Intravitreal injection of aflibercept (2 mg) once every 4 through Week 20 followed by an individualized dosing regimen of Intravitreal injection of Aflibercept (2 mg) once every 4 weeks from Week 24 to Week 44.

In the Extension Phase, participants randomized to aflibercept in the Primary Study will cross over to treatment with KSI-301 (5 mg). They will receive their first dose of KSI-301 (5 mg) at Week 48 and will receive additional treatment with KSI-301 (5 mg) based on protocol-defined disease activity criteria.

Interventions: intervention 1: KSI-301 intervention 2: Aflibercept intervention 3: Sham Procedure
Intervention descriptions: intervention 1: Intravitreal Injection intervention 2: Intravitreal Injection intervention 3: The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

Protocol document:
Prot_000.pdf: 
Official Title:  
A Prospective, Randomized, Double-masked, Active 
Comparator-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate 
the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal 
Aflibercept in Participants with Visual Impairment Due to Treatment-naïve 
Macular Edema Secondary to Retinal Vein Occlusion (RVO)
NCT Number:  
NCT04592419
Document Date: 
Protocol Version 2.0, 02 June 2021


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
KSI-301 – Kodiak Sciences Inc. 
1 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Prospective, Randomized, Double-masked, Active 
Comparator-controlled, Multi-center, Two-arm, Phase 3 Study to 
Evaluate the Efficacy and Safety of Intravitreal KSI-301 
Compared with Intravitreal Aflibercept in Participants with 
Visual Impairment Due to Treatment-naïve Macular Edema 
Secondary to Retinal Vein Occlusion (RVO) 
Protocol Number: 
KS301P103 
Version Date: 
02 June 2021 
Amendment Number: 
2.0 
Supersedes: 
Version 1.1 
Test Product: 
KSI-301 
Brief Title: 
A Study to Evaluate the Efficacy and Safety of KSI-301 
Compared to Aflibercept in Participants with Macular Edema 
Secondary to Retinal Vein Occlusion (RVO) 
Study Phase: 
3 
Study Acronym /Name: 
BEACON 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 USA 
Sponsor Contact & Medical 
Monitor: 
 
 
Kodiak Sciences Inc. 
IND Number: 
136167 
EudraCT Number: 
2020-001061-37 
CONFIDENTIAL 
The information in this document is confidential and may not be disclosed to others in whole or in part without 
express, written authorization from Kodiak Sciences Inc., except to the extent necessary to obtain informed 
consent from persons receiving the investigational drug or their legal guardians, or for discussions with local 
regulatory authorities, institutional review boards (IRB), or persons participating in the conduct of the trial. 
FOR MEDICAL EMERGENCIES CONTACT: 
 
 
 
 
 
 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
2 
PROTOCOL APPROVAL – SPONSOR SIGNATORY 
 
Study Title:  
A Prospective, Randomized, Double-masked, Active Comparator-controlled, 
Multi-center, Two-arm, Phase 3 Study to Evaluate the Efficacy and Safety of 
Intravitreal KSI-301 Compared with Intravitreal Aflibercept in Participants with 
Visual Impairment Due to Treatment-naïve Macular Edema Secondary to Retinal 
Vein Occlusion (RVO) (BEACON) 
Protocol Number:  KS301P103 
Version Date: 
02 June 2021 
 
Protocol accepted and approved by: 
 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 
 
 
 
 
Signature 
 
Date 
 
 
 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
3 
PROTOCOL APPROVAL – PRINCIPAL INVESTIGATOR 
SIGNATORY 
 
Study Title:  
A Prospective, Randomized, Double-masked, Active Comparator-controlled, 
Multi-center, Two-arm, Phase 3 Study to Evaluate the Efficacy and Safety of 
Intravitreal KSI-301 Compared with Intravitreal Aflibercept in Participants with 
Visual Impairment Due to Treatment-naïve Macular Edema Secondary to Retinal 
Vein Occlusion (RVO) (BEACON) 
Protocol Number:  KS301P103 
Version Date: 
02 June 2021 
 
I have read the protocol described above. I agree to conduct the study as described in the 
protocol. I also agree to conduct this study in compliance with Good Clinical Practice (GCP) and 
all applicable national and local laws and regulations, as well as with the requirements of the 
appropriate Institutional Review Board or independent Ethics Committee (IRB/IEC) and any 
other institutional requirements. These are stated in “Guidance for Good Clinical Practice” 
International Council for Harmonisation (ICH) guideline E6(R1) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, the Declaration of Helsinki, and any other 
applicable regulatory requirements. No changes will be made to the study protocol without prior 
written approval of the Sponsor and the IRB/IEC. 
 
Principal Investigator: 
 
 
 
Print Name of Investigator 
 
 
 
Signature 
 
Date 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
4 
TABLE OF CONTENTS 
1.0 
PROTOCOL SUMMARY ..............................................................................................11 
1.1 
Synopsis .................................................................................................................11 
1.2 
Schema ...................................................................................................................17 
1.3 
Schedule of Activities (SoA) .................................................................................18 
1.3.1 
Primary Study SoA ...............................................................................18 
1.3.2 
Optional Open-Label Extension Phase SoA .........................................20 
2.0 
INTRODUCTION............................................................................................................22 
2.1 
Study Rationale ......................................................................................................22 
2.2 
Background ............................................................................................................22 
2.2.1 
Retinal Vein Occlusion .........................................................................22 
2.2.2 
Vascular Endothelial Growth Factor .....................................................23 
2.2.3 
Description of KSI-301 .........................................................................24 
2.3 
Benefit/Risk Assessment .......................................................................................24 
2.3.1 
Known Potential Benefits .....................................................................24 
2.3.2 
Known Potential Risks ..........................................................................24 
2.3.3 
Overall Benefit/Risk Conclusion ..........................................................27 
3.0 
OBJECTIVES AND ENDPOINTS ................................................................................28 
4.0 
STUDY DESIGN ..............................................................................................................29 
4.1 
Overall Design .......................................................................................................29 
4.1.1 
Screening Period ...................................................................................29 
4.1.2 
Treatment Period ...................................................................................30 
4.1.3 
Administration of Study Intervention ...................................................30 
4.2 
Scientific Rationale for Study Design....................................................................32 
4.2.1 
Choice of Population .............................................................................32 
4.2.2 
Choice of Active Comparator Control ..................................................33 
4.2.3 
Choice of Primary Endpoint and Analysis ............................................33 
4.2.4 
Choice of Duration of Treatment and Follow-up ..................................34 
4.3 
Justification for Dose .............................................................................................34 
4.3.1 
KSI-301 Dose Rationale .......................................................................34 
4.3.2 
Aflibercept Dose Rationale ...................................................................35 
4.3.3 
Sham Injection Rationale ......................................................................35 
4.4 
End of Treatment ...................................................................................................36 
4.5 
End of Study Definition .........................................................................................36 
4.6 
Treatment After End of Study................................................................................36 
5.0 
STUDY POPULATION ..................................................................................................37 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
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5.1 
Inclusion Criteria ...................................................................................................37 
5.1.1 
Ocular Inclusion Criteria .......................................................................37 
5.1.2 
General Inclusion Criteria .....................................................................37 
5.2 
Exclusion Criteria ..................................................................................................38 
5.2.1 
Ocular Exclusion Criteria ......................................................................38 
5.2.2 
General Exclusion Criteria ....................................................................39 
5.3 
Lifestyle Considerations ........................................................................................40 
5.4 
Screen Failures .......................................................................................................40 
5.5 
Criteria for Temporarily Delaying Enrollment ......................................................40 
6.0 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ..........................42 
6.1 
Study Intervention(s) Administered .......................................................................42 
6.2 
Preparation/Handling/Storage/Accountability .......................................................43 
6.2.1 
Preparation, Handling, and Storage ......................................................43 
6.2.2 
Study Intervention Accountability and Reconciliation .........................44 
6.3 
Measures to Minimize Bias: Randomization and Masking ...................................45 
6.3.1 
Randomization ......................................................................................45 
6.3.2 
Masking and Unmasking ......................................................................45 
6.4 
Study Intervention Compliance .............................................................................46 
6.5 
Dose Modification .................................................................................................47 
6.6 
Continued Access to Study Intervention after the End of the Study .....................47 
6.7 
Treatment of Overdose ..........................................................................................47 
6.8 
Concomitant Therapy.............................................................................................48 
6.8.1 
Pan-retinal Photocoagulation (PRP) .....................................................48 
6.8.2 
Prohibited Therapy ................................................................................48 
6.8.3 
Supportive Care for Adverse Events .....................................................49 
7.0 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................................50 
7.1 
Discontinuation of Study Intervention ...................................................................50 
7.1.1 
Treatment Interruption and/or Discontinuation due to Adverse 
Events or Concomitant Procedures .......................................................51 
7.2 
Participant Discontinuation/Withdrawal from the Study .......................................52 
7.3 
Lost to Follow-up ...................................................................................................52 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................54 
8.1 
Efficacy Assessments.............................................................................................54 
8.1.1 
Medical History and Demographic Data...............................................54 
8.1.2 
Ophthalmic Exams ................................................................................54 
8.1.3 
Injection Procedure ...............................................................................55 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
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8.1.4 
Post-injection Assessments in the Study Eye .......................................55 
8.1.5 
Best Corrected Visual Acuity (BCVA) .................................................56 
8.1.6 
Fundus Photography (FP) .....................................................................56 
8.1.7 
Spectral Domain Optical Coherence Tomography (SD-OCT) .............56 
8.1.8 
Fluorescein Angiography (FA) .............................................................56 
8.1.9 
Disease Activity Assessments ...............................................................56 
8.2 
Safety Assessments ................................................................................................56 
8.2.1 
Vital Signs .............................................................................................57 
8.2.2 
Clinical Safety Laboratory Assessments ...............................................57 
8.2.3 
Pregnancy Testing .................................................................................57 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ................58 
8.3.1 
Time Period and Frequency for Collecting AE and SAE 
Information ............................................................................................58 
8.3.2 
Method of Detecting AEs and SAEs .....................................................58 
8.3.3 
Follow-up of AEs and SAEs .................................................................59 
8.3.4 
Regulatory Reporting Requirements for SAEs .....................................59 
8.3.5 
Pregnancy ..............................................................................................59 
8.3.6 
Adverse Events of Special Interest .......................................................60 
8.4 
Pharmacokinetics ...................................................................................................61 
8.5 
Genetics and/or Pharmacogenomics ......................................................................61 
8.6 
Biomarkers .............................................................................................................61 
8.7 
Immunogenicity Assessments ................................................................................61 
8.8 
Health Economics or Medical Resource Utilization and Health Economics ........62 
9.0 
STATISTICAL CONSIDERATIONS ...........................................................................63 
9.1 
Study Hypothesis ...................................................................................................63 
9.2 
Sample Size Determination....................................................................................63 
9.3 
Analysis Sets ..........................................................................................................64 
9.4 
Statistical Analyses ................................................................................................64 
9.4.1 
General Considerations .........................................................................64 
9.4.2 
Primary Endpoint(s) ..............................................................................66 
9.4.3 
Secondary Endpoint(s) ..........................................................................66 
9.4.4 
Tertiary/Exploratory Endpoint(s) ..........................................................68 
9.4.5 
Safety Analysis .....................................................................................68 
9.4.6 
Pharmacokinetic and Biomarker Analysis ............................................68 
 
 
9.5 
Interim Analysis .....................................................................................................68 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
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10.0 
APPENDICES WITH SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS ........................................................................69 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................70 
10.1.1 
Regulatory and Ethical Considerations .................................................70 
10.1.2 
Financial Disclosure and Financial Obligations ...................................70 
10.1.3 
Informed Consent Process ....................................................................71 
10.1.4 
Data Protection ......................................................................................71 
10.1.5 
Committees Structure ............................................................................72 
10.1.6 
Data Quality Assurance.........................................................................72 
10.1.7 
Source Documents ................................................................................73 
10.1.8 
Study and Site Start and Closure ...........................................................73 
10.1.9 
Publication Policy .................................................................................74 
10.2 
Appendix 2: Clinical Laboratory Tests ..................................................................75 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...................................................................76 
10.3.1 
Definition of AE ....................................................................................76 
10.3.2 
Definition of SAE .................................................................................77 
10.3.3 
The Recording and Follow-Up of AE and/or SAE ...............................78 
10.3.4 
Reporting of SAEs ................................................................................80 
10.4 
Appendix 4: Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreous Cells or Haze. ................................................................................81 
10.4.1 
Grading Scales for Anterior Chamber Cells or Flare ............................81 
10.4.2 
Grading Scale for Vitreous Cells ..........................................................82 
10.4.3 
Grading Scale for Vitreous Haze ..........................................................82 
10.5 
Appendix 5: Unscheduled Safety Assessment Visits ............................................83 
10.6 
Appendix 6: Contraceptive and Barrier Guidance .................................................84 
10.6.1 
Definitions .............................................................................................84 
10.6.2 
Contraception Guidance ........................................................................85 
10.6.3 
Collection of Pregnancy Information ....................................................85 
10.7 
Appendix 7: Liver Safety .......................................................................................87 
10.8 
Appendix 8: Protocol Amendment History ...........................................................88 
11.0 
REFERENCES .................................................................................................................89 
 
 
 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
8 
LIST OF TABLES 
Table 1:  
Protocol KS301P103: Risk Assessment ....................................................25 
Table 2:  
Protocol KS301P103: Study Interventions ................................................43 
Table 3:  
Protocol KS301P103: Treatment Interruption Criteria ..............................51 
Table 4:  
Protocol KS301P103: Required Safety Laboratory Tests .........................75 
Table 5: 
Protocol KS301P103: Amendment History ...............................................88 
 
 
LIST OF FIGURES 
Figure 1: 
Protocol KS301P103: Primary Study Schema ...........................................17 
Figure 2: 
Protocol KS301P103: Optional Open-Label Extension Phase Schema ....17 
 
 
 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
9 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AAO 
American Academy of Ophthalmology 
ABC 
Antibody biopolymer conjugate 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
APAC 
Asia-Pacific 
AST 
Aspartate aminotransferase 
ATE 
Arterial thromboembolic events 
BCVA 
Best corrected visual acuity 
BP 
Blood pressure 
BRVO 
Branch retinal vein occlusion  
BUN 
Blood urea nitrogen 
CFR 
Code of federal regulations 
CI 
Confidence interval 
CIOMS 
Council for international organizations of medical sciences 
CONSORT 
Consolidated standards of reporting trials 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CRVO 
Central retinal vein occlusion  
CST 
Central subfield thickness 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy  
ECG 
Electrocardiograph 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
ET 
Early termination 
ETDRS 
Early treatment diabetic retinopathy study 
EMEA 
Europe, Middle East, Africa 
FA 
Fundus fluorescein angiography  
FDA 
Food and drug administration  
FP 
Fundus photography  
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
hCG 
Human chorionic gonadotropin 
HIPAA 
Health insurance portability and accountability act 
HRT 
Hormonal replacement therapy 
HRVO 
Hemiretinal vein occlusion  
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IDMC 
Independent Data Monitoring Committee 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
10 
IEC 
Independent or institutional ethics committee 
IMP 
Investigational medicinal product 
IOP 
Intraocular pressure 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
Intent to treat 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
ME 
Macular edema 
MedDRA 
Medical dictionary for regulatory activities 
NA 
North America 
NAB 
Neutralizing antibody 
NIMP 
Non-investigational medical product 
NME 
New molecular entity  
NOAEL 
No observed adverse effect level 
OCT 
Optical coherence tomography  
OTC 
Over the counter 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PRP 
Pan-retinal photocoagulation  
Q4W 
Every four weeks 
Q8W 
Every eight weeks 
QTL 
Quality tolerance limits 
RBC 
Red blood cells 
RVO 
Retinal vein occlusion  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan  
SAR 
Serious adverse reaction  
SD-OCT 
Spectral domain optical coherence tomography  
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SmPC 
Summary of product characteristics  
SoA 
Schedule of activities  
SUN 
Standardization of uveitis nomenclature  
SUSAR 
Suspected unexpected serious adverse reactions 
ULN 
Upper limits of normal 
USPI 
U.S. prescribing information 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 
VEGFR1 
Vascular endothelial growth factor receptor 1 
VEGFR2 
Vascular endothelial growth factor receptor 2 
wAMD 
Wet (neovascular) age-related macular degeneration  
WBC 
White blood cells 
WOCBP 
Women of childbearing potential  
 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
11 
1.0 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Number: KS301P103 
Version:  2.0 
For National Authority 
Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001061-
37 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Due to Treatment-naïve Macular Edema Secondary to Retinal Vein Occlusion 
(RVO) (BEACON) 
Brief Title: 
A Study to Evaluate the Efficacy and Safety of KSI-301 Compared to Aflibercept in Participants with Macular 
Edema Secondary to Retinal Vein Occlusion (RVO) 
Brief Study Rationale: 
KSI-301 is a novel, potent, long-acting biopharmaceutical that inhibits vascular endothelial growth factor (VEGF). 
Compared to aflibercept, KSI-301 has an extended ocular half-life, which may result in a less frequent treatment 
regimen. Thus, this study has been designed to evaluate a less frequent treatment regimen of KSI-301 5 mg 
compared to aflibercept 2 mg in participants with macular edema (ME) secondary to branch (BRVO) or central 
RVO (CRVO). 
Development Phase: 3 
Countries/ Regions: NA (North America), 
EMEA (Europe, Middle-East, Africa), and 
APAC (Asia-Pacific) 
Study Period: Approximately 2.5 years 






CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
14 
Protocol Number: KS301P103 
Version:  2.0 
For National Authority 
Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001061-
37 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Due to Treatment-naïve Macular Edema Secondary to Retinal Vein Occlusion 
(RVO) (BEACON) 
Total Participant Duration: 
Primary Study: 55 weeks 
Primary + Extension Phase: 79 weeks 
Duration of Treatment:  
Primary Study: 44 weeks  
Primary + Extension Phase: 68 weeks 
Study Intervention (Investigational Medicinal Product), Dose, and Route of Administration: 
Treatment Arm A:  
• 
Day 1 to Week 20: KSI-301 5 mg once every 8 weeks after two monthly doses via intravitreal injection; 
• 
Week 24 to Week 44: KSI-301 5 mg using an individualized dosing regimen via intravitreal injection; 
• 
Week 48 to Week 68 (Extension Phase): KSI-301 5 mg using an individualized dosing regimen via intravitreal 
injection.  
Sham injections will be administered at every monthly visit if an active treatment is not administered. 
Study Intervention (Active Control/ Investigational Medicinal Product), Dose, and Route of Administration: 
Treatment Arm B: 
• 
Day 1 to Week 20: Aflibercept 2 mg once every 4 weeks via intravitreal injection; 
• 
Week 24 to Week 44: Aflibercept 2 mg using an individualized dosing regimen via intravitreal injection. 
• 
Week 48 to Week 68 (Extension Phase): All participants originally randomized to the aflibercept arm will be 
crossed over to receive KSI-301 5 mg at Week 48, followed by KSI-301 5 mg using an individualized dosing 
regimen via intravitreal injection. 
Sham injections will be administered at every monthly visit if an active treatment is not administered. 
Efficacy Evaluation: 
Unless stated otherwise, all efficacy analyses will be performed on the intent to treat (ITT) population. The primary 
endpoint is mean change in BCVA from Day 1 to Week 24 using the ETDRS method. The primary assessment of 
efficacy will be based on a pairwise comparison in mean change in BCVA between treatment arm A (KSI-301 
5 mg) and treatment arm B (aflibercept 2 mg). Other efficacy outcomes will be evaluated using ophthalmic 
assessments (including tonometry), fundus photography, spectral domain (SD)-OCT, and fluorescein angiography 
(FA). Secondary endpoints for efficacy will be assessed at Weeks 24, 48, and 72. Planned time points for all 
efficacy assessments are provided in the Schedule of Activities (SoA) (Section 1.3). 


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
15 
Protocol Number: KS301P103 
Version:  2.0 
For National Authority 
Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001061-
37 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Due to Treatment-naïve Macular Edema Secondary to Retinal Vein Occlusion 
(RVO) (BEACON) 
Safety Evaluation: 
After informed consent has been obtained but prior to initiation of study intervention, only serious adverse events 
(SAEs) caused by a protocol-mandated assessment should be reported. After initiation of study intervention 
(Day 1), all AE and SAE information will be collected until the final safety follow-up visit at Week 52 for 
participants who do not participate in the Extension Phase, and Week 76 for participants who do participate in the 
Extension Phase, or the ET visit if applicable, as specified in Section 1.3. All reported adverse events (ocular and 
otherwise) in the safety population will be listed by MedDRA term, frequency, severity, association to the study 
therapy, and treatment group. By-treatment incidence rates will also be calculated for the treatment groups. For 
certain adverse events, per-injection rates will also be described. 
Pharmacokinetic/ Biomarker Evaluation: 
Plasma concentrations of study intervention (KSI-301) will be measured, as specified in the SoA (Section 1.3). 
Blood samples will also be analyzed for anti-drug antibodies. For exploratory purposes, 
 
  


CONFIDENTIAL 
Protocol KS301P103, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
16 
Protocol Number: KS301P103 
Version:  2.0 
For National Authority 
Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001061-
37 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Due to Treatment-naïve Macular Edema Secondary to Retinal Vein Occlusion 
(RVO) (BEACON) 
Statistical Methods: 
The study hypothesis is that treatment with KSI-301 5 mg will provide a non-inferior mean change in BCVA to 
aflibercept 2 mg, while using a less frequent dosing schedule in participants with visual impairment due to ME 
secondary to RVO. Using ETDRS BCVA data collected up to Week 24, the treatment arms will be compared using 
a non-inferiority analysis, with a margin of 4.5 ETDRS letters. Confidence intervals (CI) will be 100(1-2 α) or 
95% CI. If the null hypothesis of inferiority is rejected, testing for superiority will be performed. 
The sample size calculated of approximately 550 (275 per arm) participants was calculated using the following 
assumptions: 
• 
Overall type I error rate of 0.025. Testing at the 0.025 level for non-inferiority corresponds to setting 95% CIs. 
• 
Statistical power of ≥90%. 
• 
Standard deviation of the distribution of change in visual acuity from baseline of 
 letters. 
• 
The maximum, clinically acceptable true difference for KSI-301 to be considered non-inferior, or the “non-
inferiority margin”, is 4.5 letters.  
• 
The statistical test used to compare the two treatment arms at Week 24 is an independent t-test on the mean 
change in visual acuity from baseline. 
• 
Lost to follow-up/dropout rate of approximately 
 
Analysis of data for the first period of the study will be performed when all participants have either completed the 
Week 24 visit or have discontinued from the study, all data have been entered into the database, cleaned and 
verified as appropriate, and the database has been locked. Likewise, analysis of data for the second period of the 
study will be performed when all participants have either completed the Week 52 visit or have discontinued from 
the study, all data have been entered into the database, cleaned and verified as appropriate, and the database has 
been locked.  
Analysis of the data for the Extension Phase will be performed when all participants who participate in the 
Extension Phase have either completed the Week 76 visit or have discontinued from the study, all data have been 
entered into the database, cleaned, and verified as appropriate, and the database has been locked.  
Data Monitoring: 
An Independent Data Monitoring Committee (IDMC) will monitor the study conduct and participant safety on an 
ongoing basis. 
Date of Protocol/ Amendment: 
02 June 2021 
 
 
 
 


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1.2
Schema
Figure 1: 
Protocol KS301P103: Primary Study Schema
Abbreviations: 
PE = primary endpoint; SA = safety assessment (follow-up); SE = secondary endpoints.
Figure 2: 
Protocol KS301P103: Optional Open-Label Extension Phase Schema  
Abbreviations: 
SA = safety assessment (follow-up); SE = secondary endpoints.




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Abbreviations: ADA = anti-drug antibody; AE = adverse event; BCVA = best corrected visual acuity; ETDRS = early treatment diabetic retinopathy study; ET = 
early termination; IOP = intraocular pressure; NAB = neutralizing antibody; PK = pharmacokinetics; SAE = serious adverse event; SD-OCT = spectral 
domain optical coherence tomography; WOCBP = women of childbearing potential. 
1. Record any concomitant medication used by the participant within 30 days prior to Day 1. Procedural medications administered (e.g. dilating drops, 
fluorescein) will not be recorded. 
2. After informed consent has been obtained but prior to initiation of study intervention, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study intervention (Day 1), all AEs will be reported until the final study visit or the ET visit if applicable. 
See Section 8.3.1. 
3. Height and weight will be recorded at the screening visit only. 
4. Clinical laboratory test, as described in Appendix 2 and Table 4. 
5. Urine pregnancy test will be performed locally for women of childbearing potential, prior to fluorescein angiogram and study treatment (if applicable). If 
urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. Local urine testing will be standard for the protocol unless serum testing 
is required by local regulation or IRB/IEC.  
6. BCVA and Ophthalmic Exam will be performed in both eyes at Screening, Week 24 and Week 48, and only in the Study Eye at all other timepoints. 
7. Perform BCVA before any other ophthalmic assessments and prior to dilation.  
8. Method used to measure IOP must remain consistent throughout study.  
9. It is mandatory that the same model of device is used for the entire duration of the study. 
10. Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in Section 7.1. 
11. Post-injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
12. For participants continuing in the Extension Phase, the Week 48 and Week 52 procedures listed in Section 1.3.2 should be performed instead of those listed 
here. 
13. For participants not continuing into the Extension Phase, Week 52 is a final safety assessment that will be done via telephone call for all participants, except 
in WOCBP, in which case a site visit is required for the safety assessment that includes a pregnancy test. 
 
 
 




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Abbreviations: ADA = anti-drug antibody; AE = adverse event; BCVA = best corrected visual acuity; ETDRS = early treatment diabetic retinopathy study; 
ET = early termination; IOP = intraocular pressure; NAB = neutralizing antibody; PK = pharmacokinetics; SAE = serious adverse event; 
SD-OCT = spectral domain optical coherence tomography; WOCBP = women of childbearing potential. 
1. Record any concomitant medication used by the participant within 30 days prior to Day 1. Procedural medications administered (e.g. dilating drops, 
fluorescein) will not be recorded. 
2. After informed consent has been obtained but prior to initiation of study intervention, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study intervention (Day 1), all AEs will be reported until the final study visit or the ET visit if 
applicable. See Section 8.3.1. 
3. Clinical laboratory test, as described in Appendix 2 and Table 4. 
4. Urine pregnancy test will be performed locally for women of childbearing potential, prior to fluorescein angiogram and study treatment (if applicable). If 
urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. Local urine testing will be standard for the protocol unless serum testing 
is required by local regulation or IRB/IEC.  
5. BCVA and Ophthalmic Exam will be performed in both eyes at Week 72 and only in the Study Eye at all different timepoints. 
6. Perform BCVA before any other ophthalmic assessments and prior to dilation.  
7. Method used to measure IOP must remain consistent throughout study.  
8. It is mandatory that the same model of device is used for the entire duration of the study. 
9. Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in Section 7.1. 
10. Post injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
11. For participants in the Extension Phase, the Week 48 and Week 52 procedures listed here should be performed instead of those listed in Section 1.3.1. 
12. For participants in the Extension Phase, Week 76 is a final safety assessment that will be done via telephone call for all participants, except in WOCBP, in 
which case a site visit is required for the safety assessment that includes a pregnancy test. 
 


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2.0 
INTRODUCTION 
KSI-301 is a novel, potent, long-acting biopharmaceutical that inhibits vascular endothelial 
growth factor (VEGF). It is being developed to treat macular edema (ME) secondary to retinal 
vein occlusion (RVO), as well as diabetic macular edema (DME) and wet age-related macular 
degeneration (wAMD). KSI-301 offers the potential for participants to experience a longer 
interval between consecutive intravitreal injections compared to existing anti-VEGF therapies. 
Thus, KSI-301 may have the potential to improve real-world outcomes of anti-VEGF therapy, 
which are currently limited by both the high treatment burden and insufficient durability of effect 
in patients with RVO.  
2.1 
Study Rationale 
Although substantial visual acuity benefits have been demonstrated with the approved 
intravitreal VEGF inhibitors (e.g., aflibercept, ranibizumab) in the first-line treatment of RVO, 
the gains are not sustained without high treatment frequency, which challenges patient 
compliance (Hykin 2019). Therefore, there is a substantial medical need for more durable 
options that reduce treatment burden. Compared to aflibercept, KSI-301 has an extended ocular 
half-life (Section 2.2.3), which may result in a less frequent treatment regimen. In the ongoing 
Phase 1b portion of Study KSI-CL-101, the safety and efficacy outcomes of participants with 
treatment-naïve wAMD, DME/diabetic retinopathy (DR), or RVO (branch and central) treated 
with KSI-301 5 mg have supported a prolonged treatment interval (≥2 months for RVO and 
longer for wAMD and DME/DR). Thus, this study, Study KS301P103, has been designed to 
evaluate a less frequent treatment regimen of KSI-301 5 mg (q8w after two monthly doses) 
compared to aflibercept 2 mg (q4w) in participants with ME secondary to branch RVO/central 
RVO (BRVO/CRVO).  
An optional, open-label Extension Phase of the study will evaluate the long-term efficacy and 
safety of KSI-301 5 mg in participants who complete the Primary Study. Participants who 
received aflibercept during the first year of the Primary Study will receive KSI-301 5 mg in the 
Extension Phase. This will enable collection of information on the effects of KSI-301 5 mg in 
participants with prior anti-VEGF therapy for ME secondary to BRVO/CRVO.  
2.2 
Background 
2.2.1 
Retinal Vein Occlusion  
RVO is an obstruction of the retinal venous system. RVO typically occurs in patients with long-
standing hypertension but can also occur in those with underlying coagulation disorders or other 
systemic conditions such as diabetes mellitus. RVO occurs in two primary clinical forms, 
depending on the location of the venous blockage: branch RVO (BRVO) or central RVO 
(CRVO). Hemiretinal vein occlusion (HRVO) will be classified as CRVO in this study owing to 
clinical similarities. (Cugati 2006; Klein 2008; Klein 2000; McAllister 2011).  


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The prevalence of RVO is strongly associated with increasing age (odds ratio (OR) (95% 
confidence interval (CI) = 1.60 (1.38-1.84) per decade)). RVO prevalence appears to be similar 
between males and females and across ethnic groups. In 2015, the global prevalence of any 
RVO, BRVO, and CRVO in people aged 30-89 years was estimated to be 0.77% 
(95% CI = 0.55-1.08), 0.64% (95% CI = 0.47-0.87), and 0.13% (95% CI = 0.08-0.21), 
respectively. (Song 2019) 
One of most clinically relevant complications of RVO is leakage of fluid out of the retinal 
venous system into retinal tissue. Accumulation of that fluid (edema) in the central portion of the 
retina (the macula) is the major cause of vision loss in patients with RVO (Johnson 2009; Morley 
2009).  
2.2.2 
Vascular Endothelial Growth Factor  
VEGF stimulates vascular endothelial cell growth and induces vascular permeability. These 
biologic activities give it a central role in angiogenesis, both in normal and pathologic 
conditions. VEGF plays a critical role in the pathophysiology of choroidal and retinal 
neovascular diseases such as wAMD; DR, including DME; and ME due to CRVO or BRVO 
(Rubio 2016). Inhibition of pathologic VEGF activity is both an “anti-angiogenic” and “anti-
permeability” approach to treat choroidal and retinal neovascular diseases and has been shown to 
be effective in preserving and improving visual acuity (Campochiaro 2015; Cheung 2010). 
Among the VEGF family members, VEGF-A is the most strongly associated with angiogenesis 
and vascular leakage (Campochiaro 2015). Intravitreal VEGF-A inhibitors such as aflibercept 
and ranibizumab have been approved by regulatory authorities worldwide for use in multiple 
retinal vascular diseases. Both ranibizumab and aflibercept have been evaluated in Phase 3 
studies for the management of ME secondary to RVO, where patients treated with monthly 
injections achieved significant functional and anatomic improvements after 6 months of 
treatment. (Boyer 2012; Brown 2010; Campochiaro 2015; Campochiaro 2010; Holz 2013).  
On account of superior visual acuity and anatomic outcomes, VEGF-inhibition therapy has 
replaced steroids, macular laser photocoagulation, and observation as the first-line treatment for 
RVO (Flaxel 2020; Schmidt-Erfurth 2019). However, a primary concern with approved anti-
VEGF therapies is that the visual acuity gains observed in the early intensive treatment phase 
require a high treatment burden (monthly injections) and the visual acuity results may not be 
sustained with less frequent dosing. For example, the need for monthly dosing in CRVO has 
been demonstrated in a recent UK study where less-than-monthly dosing during the initiation 
phase was associated with loss of maximal treatment effect on both optical coherence 
tomography (OCT) and visual acuity outcomes (Hykin 2019). This is thought to be due to the 
relatively short intravitreal half-lives of the approved products (in rabbits: ~4 days for 
aflibercept, ~2.5 days for ranibizumab; in monkeys: ~2.4 days for aflibercept, ~2.7 days for 
ranibizumab) (Christoforidis 2017; Park 2016). In RVO, short ocular half-lives translate to 
narrow and burdensome retreatment windows, which then result in diminished patient 
compliance (repeated undertreatment) (Callizo 2019). 


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2.2.3 
Description of KSI-301 
KSI-301 is an antibody biopolymer conjugate (ABC) developed using the Sponsor’s proprietary 
ABC Platform™ technology. The antibody portion of KSI-301 binds to VEGF-A with high 
affinity and inhibits the ability of VEGF-A to bind and activate its cognate receptors (VEGFR1 
and VEGFR2) thereby acting as an anti-angiogenic and anti-permeability agent. The inert 
biopolymer portion is an ultra-hydrophilic phosphorylcholine polymer that significantly 
increases the overall molecular size of KSI-301, which in turn extends its ocular half-life by a 
factor 
 and ocular concentrations at three months by a factor of 
 compared to 
aflibercept. Due to the biophysical and biological properties of the ABC Platform on which it is 
built, KSI-301 is designed to have improved ocular durability, bioavailability, biocompatibility, 
and stability, and rapid systemic clearance. These properties make KSI-301 an ideal candidate 
for the management of retinal vascular diseases. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of KSI-301 is 
provided in the Investigator’s Brochure (IB). 
2.3 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of KSI-301 may be found in the IB. A brief overview of known potential benefits 
and risks is provided in the subsections that follow. 
2.3.1 
Known Potential Benefits 
KSI-301, an intravitreal VEGF inhibitor developed to treat RVO, benefits from a well-
documented mechanism of action in retinal vascular disease (Homayouni 2009). The efficacy 
and safety of commercially available intravitreal VEGF inhibitors in ME secondary to RVO 
(both branch and central) is also well-documented and established (Flaxel 2020; Schmidt-Erfurth 
2019). Based on its molecular design and structure, in vitro and in vivo nonclinical testing, and 
clinical data to date, it is expected that the efficacy and safety of KSI-301 should be at least 
comparable to standard of care. 
Long-term and real-world outcomes of approved anti-VEGF therapies are currently limited by 
the high treatment burden caused by their insufficient durability. Emerging efficacy data from 
the ongoing Phase 1b portion of Study KSI-CL-101 support the extended ocular half-life of 
KSI-301 and less frequent dose regimen compared to aflibercept. Thus, KSI-301 may provide 
clinically relevant benefits over existing therapies for patients with ME secondary to RVO. 
2.3.2 
Known Potential Risks 
Potential risks of treatment with KSI-301 were identified based on therapeutic protein class 
effects, VEGF-inhibition class effects, the intravitreal route of administration, nonclinical 
findings, and Phase 1/1b clinical experience. In consideration of the Coronavirus disease 
(COVID-19) pandemic caused by the virus SARS-CoV-2 and the impact it may have on clinical 


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trials, COVID-19 related risks to participants are also carefully considered. A summary of 
known potential risks associated with KSI-301 is provided in Table 1. Risks associated with 
COVID-19 are discussed below in Section 2.3.2.1. 
Table 1:  
Protocol KS301P103: Risk Assessment 
Potential Risk 
of Clinical 
Significance 
Summary of Data/ Rationale for Risk 
Mitigation Strategy 
Study Intervention [KSI-301] 
Immunogenicity 
As with all therapeutic proteins, there is 
a potential for an immune response in 
participants treated with KSI-301. 
Clinical experience with commercially 
available intravitreal VEGF inhibitors 
has shown that SAEs related to 
inflammatory reactions can occur.  
Additional details are provided in 
IB Section 5.4.2.1. 
Participants will be monitored following the 
injection and instructed to report any symptoms 
suggestive of an immune response without delay 
to facilitate early diagnosis and treatment (Section 
8.1.4). 
Participants with known hypersensitivity to 
intravitreal agents such as aflibercept or any 
ingredient of KSI-301 are excluded from this study 
(Section 5.2.2). 
Arterial 
thromboembolic 
events (ATEs) 
ATEs are defined as nonfatal stroke, 
nonfatal myocardial infarction, or 
vascular death (including deaths of 
unknown cause). There is a potential 
risk of ATEs following intravitreal use 
of VEGF inhibitors.  
Additional details are provided in 
IB Section 5.4.2.2. 
Participants with recent history (6 months) of 
myocardial infarction, stroke, transient ischemic 
attack, acute congestive heart failure or any acute 
coronary event are excluded from this study 
(Section 5.2.2). 
Intraocular 
inflammation 
Intraocular inflammation has been 
reported following treatment with 
intravitreal anti-VEGF medicines, 
including KSI-301.  
Additional details are provided in 
IB Section 5.4.2.3. 
Participants will be monitored following the 
injection and instructed to report any symptoms 
suggestive of intraocular inflammation without 
delay to facilitate early diagnosis and treatment 
(Section 8.1.4). Participants with active or 
suspected ocular infection or inflammation in 
either eye (e.g., blepharitis, infectious 
conjunctivitis, keratitis, scleritis, endophthalmitis) 
are excluded from this study (Section 5.2.1). 
Participants with active intraocular inflammation 
will have study treatment interrupted (Section 
7.1.1). 
Hypersensitivity 
Hypersensitivity reactions may manifest 
as rash, pruritus, urticaria, severe 
anaphylactic/ anaphylactoid reactions, or 
severe intraocular inflammation.  
Additional details are provided in 
IB Section 5.4.2.4. 
Participants with known hypersensitivity to 
intravitreal agents such as aflibercept or any 
ingredient of KSI-301 are excluded from this study 
(Section 5.2.2). 
 
 
 


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Table 1:  
Protocol KS301P103: Risk Assessment (Cont’d) 
Potential Risk 
of Clinical 
Significance 
Summary of Data/ Rationale for Risk 
Mitigation Strategy 
Study Procedures 
Risks associated 
with the method 
of 
administration 
These risks include endophthalmitis, 
increases in intraocular pressure, retinal 
detachment, retinal tear, traumatic 
cataract, and intraocular hemorrhage. 
Additional details are provided in 
IB Section 5.4.2.5. 
Proper and aseptic injection technique when 
administering intravitreal injections will be used 
(Section 8.1.3). Participants will be monitored 
following the injection and instructed to report any 
symptoms suggestive of endophthalmitis or retinal 
detachment without delay to facilitate early 
diagnosis and treatment (Section 8.1.4). 
Intraocular pressure and the perfusion of the optic 
nerve head will also be monitored and managed 
(Section 8.1.4). Participants with active ocular 
infection or inflammation in either eye (e.g., 
blepharitis, infectious conjunctivitis, keratitis, 
scleritis, endophthalmitis) are excluded from this 
study (Section 5.2.1). 
Exposure to 
SARS-CoV-2 
virus 
Section 2.3.2.1 
Section 2.3.2.1 
Abbreviations: ATEs = Arterial thromboembolic events; IB = Investigator’s Brochure; SAE = serious adverse event; 
VEGF = vascular endothelial growth factor. 
 
2.3.2.1 
Risks Associated with Exposure to the Virus SARS-CoV-2 
In consideration of the Coronavirus disease (COVID-19) pandemic caused by the virus 
SARS-CoV-2 and the impact it may have on clinical trials, COVID-19 related risks to 
participants are carefully considered and will be documented on an ongoing basis. In ME 
secondary to RVO, early diagnosis and treatment with intravitreal anti-VEGF therapy is 
associated with better functional outcomes (Pielen 2013). Moreover, intravitreal anti-VEGF 
treatment is recognized as an essential health care service during the pandemic by 
ophthalmology physician societies worldwide. This trial affords all participants the opportunity 
to receive anti-VEGF therapy for their RVO. Measures that prioritize trial participant safety and 
data integrity have been developed in consideration of local guidelines.  
In order to minimize any added risk of exposure associated with trial participation beyond that 
associated with standard of care treatment, the Schedule of Activities (SoA) (Section 1.3) has 
been optimized to allow for an adequate follow-up and assessment of the safety and efficacy of 
KSI-301 without unnecessarily increasing participant exposure beyond that which may already 
exist from their attendance at clinic visits for anti-VEGF treatment of their RVO.  
As the pandemic situation develops, the Sponsor will reassess risks, which will be documented 
as part of the Sponsor's trial master file. In the event that escalation of the pandemic during this 


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trial and local circumstances lead to a local change in risk assessment, additional measures may 
be implemented. In this case, an Investigator-driven risk assessment will be conducted and 
documented in the Investigator’s site master file and communicated to the Sponsor. 
2.3.3 
Overall Benefit/Risk Conclusion 
The potential benefits of treatment of RVO with KSI-301 (longer treatment intervals) have been 
considered against both the risks associated with KSI-301 treatment and the COVID-19 
pandemic. Participants in this study will be carefully monitored with special attention to known 
and potential risks and managed as appropriate. Exclusion criteria restrict enrollment of 
participants at higher risk, and routine monitoring and follow-up evaluations will be conducted 
for early detection of any AEs, as noted in Section 8.3. Reassessment of the risks will continue as 
the COVID-19 situation develops and any changes to this approach will be documented 
accordingly. 
In ME secondary to RVO, early diagnosis and treatment with intravitreal anti-VEGF therapy is 
associated with better functional outcomes (Pielen 2013). Moreover, intravitreal anti-VEGF 
treatment is recognized as an essential health care service during the pandemic by physician 
groups worldwide. Therefore, based upon the well-known, clinically demonstrated mechanism of 
action (Homayouni 2009); favorable nonclinical and Phase 1a/1b safety, tolerability and 
bioactivity data; and a study design that includes extensive monitoring and COVID-19 risk 
mitigation, the Sponsor considers that the potential risks of study participation are outweighed by 
the value of the information to be gained and further study is warranted. 




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4.0 
STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 3, prospective, randomized, double-masked, two-arm, multi-center study 
evaluating the efficacy and safety of repeated intravitreal dosing of KSI-301 5 mg in participants 
with visual impairment due to treatment-naïve ME secondary to RVO (both branch and central). 
The overall duration of the study is approximately 1 year (52 weeks) after the last participant is 
randomized to the study. Participant duration is defined as the date a signed written informed 
consent is provided through the last safety follow-up visit at Week 52; thus, participant duration 
is approximately 55 weeks and includes a screening period of up to 21 days (Days -21 to -1), a 
treatment period of approximately 44 weeks (Day 1 to Week 44), a 4-week follow-up period for 
safety and efficacy assessments at Week 48, and a final follow-up for safety assessments at 
Week 52 (8 weeks after the final dose). The primary endpoint will be assessed at Week 24; 
additional secondary endpoints for efficacy will be assessed at Week 24 and 48.  
A single eye per participant will be designated as the Study Eye. If both eyes are eligible to 
become the Study Eye, the eye with worse BCVA at Screening will be selected as the Study Eye. 
If both eyes are eligible and have the same BCVA, the decision of which eye to select as the 
Study Eye will be made by the Investigator. 
Participants will be randomly assigned (1:1) into one of two treatment arms: 
• KSI-301 5 mg  
• Aflibercept 2 mg  
Randomization will be stratified by
 
 
Additional details of the randomization methods 
are described in the statistical analysis plan (SAP). 
Participants who complete the Primary Study are eligible to participate in an optional, open-
label, two-arm, Extension Phase.  
4.1.1 
Screening Period 
Participants will provide written informed consent to participate in the study before completing 
any protocol-specified procedures or evaluations not considered to be part of the participant’s 
standard care. After providing informed consent, participants will be evaluated for eligibility 
criteria during the screening period within 21 days before administration of study intervention(s).  
Participants who do not meet eligibility criteria within the 21-day screening period will not be 
eligible for randomization and will be considered as screen-failed. However, a participant may 
be re-screened up to one additional time at the discretion of the Investigator and in consultation 


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with the Sponsor (Section 5.4). Instructions for participants who meet all eligibility criteria at 
the Screening visit but do not meet the BCVA and/or SD-OCT CST eligibility criteria when they 
return for the planned Day 1 visit are provided in Section 5.5. 
When re-screening tests and procedures have been completed and results are available indicating 
the participant is eligible for study participation, the participant may be enrolled. When re-
screening a participant, a new screening/enrollment number will be generated by the IRT system 
to ensure that there is an audit trail for the screen-failed participant.  
4.1.2 
Treatment Period 
Participants in this study will be treated until Week 44 and will have an additional safety follow-
up at Week 52, unless the Investigator decides to discontinue treatment, the Sponsor decides to 
terminate the study or until any of the reasons for withdrawal/ discontinuation provided in 
Section 7.2 are met. For participants who decide to continue in the optional open-label Extension 
Phase, treatment will continue until Week 68 and they will have a final Safety follow-up at 
Week 76, unless the Investigator decides to discontinue treatment, the Sponsor decides to 
terminate the study or until any of the reasons for withdrawal/ discontinuation provided in 
Section 7.2.  
4.1.3 
Administration of Study Intervention 
Fixed Interval Treatment Period (Day 1 through Week 20): 
As shown in Section 1.2, all participants will be treated on a fixed dosing regimen from Day 1 
through Week 20, according to randomized treatment arm, as follows: 
• Group A - KSI-301 5 mg:  
Following two initial doses of KSI-301 5 mg at Day 1 and Week 4, participants will 
receive one additional dose every 8 weeks (i.e., at Week 12 and Week 20) and will 
receive sham injections (to preserve study masking) at Week 8 and Week 16.  
• Group B - aflibercept 2 mg  
Participants will be treated every 4 weeks with aflibercept 2 mg (i.e., at Day 1, Week 4, 
Week 8, Week 12, Week 16, and Week 20).  
Individualized Treatment Period (Week 24 through Week 44): 
Starting at Week 24, participants in both treatment arms will be assessed monthly (every 4 
weeks) and will receive additional administration of KSI-301 5 mg or aflibercept 2 mg, as per 
their assigned treatment arm, according to protocol-defined disease activity assessment criteria. 
These criteria are based on changes in BCVA and/or OCT CST. The minimum interval between 
active treatments is 4 weeks (± 7 days) for all treatment arms. There are no mandatory active 
injections at any assessment visits and thus, no upper limit to the treatment interval. To preserve 


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study masking, sham injections are administered at visits in which no active treatment is 
indicated. The disease activity assessment criteria are as follows: 
• Increase in OCT CST ≥ 50 µm compared to lowest previous measurement AND a decrease 
in BCVA of ≥ 5 letters compared to the average of the two best previous BCVA assessments, 
due to worsening of RVO disease activity, or 
• Increase in OCT CST ≥ 75 µm compared to lowest previous measurement due to worsening 
of RVO disease activity. 
On visits when either of these criteria are met, the participant is treated with KSI-301 or 
aflibercept as per their assigned treatment arm. On visits when these criteria are not met, the 
participant is treated with sham.  
Optional Extension Phase (Week 48 – Week 72): 
Participants who complete the Primary Study are eligible to participate in the Extension Phase.  
There is no active comparator in the Extension Phase. The Extension Phase will evaluate the 
long-term efficacy and safety of KSI-301 5 mg. Participants who received aflibercept during the 
first year of the Primary Study will receive KSI-301 5 mg in the Extension Phase to enable 
collection of information on the effects of KSI-301 5 mg in participants with prior anti-VEGF 
therapy for ME secondary to BRVO/CRVO.  
KSI-301 5 mg will be administered to all participants in the Extensions Phase, as follows:  
• Primary Study Group A (KSI-301 5 mg) Participants: 
Participants randomized to Group A (KSI-301 5 mg) in the Primary Study will continue 
to receive KSI-301 5mg during the Extension Phase. They will continue to be assessed 
every 4 weeks for disease activity and will receive additional treatment with KSI-301 
(starting at Week 48) if protocol-defined disease activity criteria are met.  
• Primary Study Group B (aflibercept 2 mg) Participants: 
Participants randomized to Group B (aflibercept 2 mg) in the Primary Study will cross 
over to treatment with KSI-301 5 mg in the Extension Phase. They will receive their first 
dose of KSI-301 5 mg at Week 48 and will then be assessed every 4 weeks for disease 
activity; additional treatment with KSI-301 5 mg will be based on protocol-defined 
disease activity criteria (defined below).  
The minimum interval between treatments with KSI-301 5 mg is 4 weeks (± 7 days). There is no 
upper limit to the treatment interval. To preserve study masking, sham injections are 
administered at visits in which KSI-301 5 mg is not administered. 


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The disease activity criteria for the Extension Phase are the same as in the Primary Study, as 
follows:  
• Increase in OCT CST ≥ 50 µm compared to lowest previous measurement AND a decrease 
in BCVA of ≥ 5 letters compared to the average of the two best previous BCVA assessments, 
due to worsening of RVO disease activity, or 
• Increase in OCT CST ≥ 75 µm compared to lowest previous measurement due to worsening 
of RVO disease activity. 
Participants will be followed for an additional 24 weeks at the following time points: Weeks 56, 
60, 64, 68, and 72, with a final safety assessment at Week 76. 
Disease activity assessments will be conducted by the masked Investigator. The IRT system will 
make adjustments to the dosing schedule based on disease activity data entered by the study site. 
The IRT system will adjust the dosing schedule in consideration of missed visits, out of window 
visits, and missing data during a visit. 
4.2 
Scientific Rationale for Study Design 
This is a randomized, active comparator-controlled, double-masked, multi-center, Phase 3 study 
to evaluate the efficacy and safety of intravitreal KSI-301 compared with intravitreal aflibercept 
in participants with visual impairment and treatment-naïve ME due to RVO. A randomized, 
double-masked design minimizes bias and is well-established for demonstrating the safety and 
efficacy of an investigational treatment. The rationales for other key design features are provided 
below. 
4.2.1 
Choice of Population 
This study will enroll participants with treatment-naïve ME and secondary visual impairment of 
≤ 6 months secondary to either CRVO (including HRVO) or BRVO. Because CRVO is ~3-4x 
less common than BRVO, 20% to 35% of the overall study population will be participants with 
CRVO.  
KSI-301 is being evaluated as a first-line anti-VEGF medicinal product to treat ME secondary to 
RVO. Thus, participants must not have had prior use of an approved or investigational treatment 
(e.g., anti-VEGF, intraocular or periocular steroids, macular laser photocoagulation) for ME 
secondary to RVO in the Study Eye. Enrollment of participants who are treatment-naïve for 
RVO also helps minimize biases inherent in the inclusion of participants who have failed prior 
lines of therapy.  
Treatment-naïve participants with best corrected visual acuity (BCVA) of 80 to 25 letters (20/25 
to 20/320 Snellen equivalent) will be enrolled because they are expected to be broadly 
representative of the general population of patients treated with first-line anti-VEGF within 6 
months of diagnosis of BRVO or CRVO.  




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a clinically meaningful change. Therefore, 4.5 letters as an upper threshold excludes the potential 
for clinically meaningful treatment effect differences between KSI-301 and aflibercept. 
4.2.4 
Choice of Duration of Treatment and Follow-up 
The duration of treatment in the Primary Study will be the same for both arms (i.e., KSI-301 and 
aflibercept) and is divided into two intervals: (i) a 20-week fixed-dose interval and (ii) a 24-week 
individualized treatment period.  
The primary endpoint will be assessed at Week 24, 4 weeks after the last dose in the first, fixed-
dose interval and prior to the first dose in the individualized treatment period. This time point 
and associated duration of treatment was selected on the basis of health authority feedback and 
precedent for Phase 3 trials in RVO. For example, the Phase 3 studies which established the 
safety and efficacy of aflibercept and ranibizumab in RVO used a 24-week primary endpoint.  
The optional Extension Phase will provide additional information on the long-term efficacy and 
safety of KSI-301 5 mg in both treatment-naïve and previously treated patients with ME 
secondary to RVO. 
The choice of a safety follow-up interval of 8 weeks after the last dose in both the Primary Study 
and the Extension Phase is based on the expected duration of effect for KSI-301 and aflibercept.  
4.3 
Justification for Dose 
4.3.1 
KSI-301 Dose Rationale 
The durability of intravitreal anti-VEGF pharmacological effect is proportional to the dose and 
the half-life of the drug. A KSI-301 5 mg dose has approximately 
fold the equivalent molar 
dose of anti-VEGF binding capacity, at the time of injection, relative to 2 mg aflibercept. 
Preclinical modeling suggests that KSI-301 5 mg results in 
-fold the equivalent ocular 
concentration of aflibercept 2 mg three months after dosing. Both KSI-301 2.5 mg and KSI-301 
5 mg that are being evaluated in the ongoing Phase 1b portion of Study KSI-CL-101 have not 
resulted in any dose limiting ocular or systemic toxicities and, as expected, have no clear dose-
efficacy response relationship. Because the 5 mg dose of KSI-301 may have incrementally 
improved durability compared to the 2.5 mg dose, the 5 mg dose has been selected for this study.  
The 
 injection volume used to deliver a 5 mg dose has been well-tolerated in previous 
KSI-301 studies (additional information can be found in the IB) as well as in other studies for of 
 
The objective of KSI-301 in the treatment of RVO is to reduce the number of required 
intravitreal injections – for example from six with aflibercept to four with KSI-301 during the 
first 20 weeks of treatment - while providing non-inferior efficacy outcomes to aflibercept. In the 
ongoing Phase 1b portion of Study KSI-CL-101, all participants with RVO who were treated 
with KSI-301 5 mg did not require retreatment based on disease activity assessments for at least 


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8 weeks; and just over half of the participants had ≥3-month retreatment intervals. Therefore, 
during the 20-week fixed-dose interval (Day 1 to Week 20), KSI-301 5 mg will be administered 
four times: at Day 1, Week 4, Week 12, and Week 20. During the individualized treatment 
period (Week 24 to Week 44), the potential for additional treatment burden reduction will be 
explored with an individualized dosing approach that is based on disease activity.  
In the Extension Phase (Week 48 to Week 76), additional safety, efficacy and durability data will 
be obtained for KSI-301 5 mg using an individualized dosing approach.  
4.3.2 
Aflibercept Dose Rationale 
In the US, the recommended dose for aflibercept in RVO is 2 mg (0.05 mL) administered by 
intravitreal injection every 4 weeks (± 7 days) (i.e., monthly).  
In the EU, the recommended dose for aflibercept is 2 mg monthly after the first injection. 
Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs 
of disease activity. Three or more consecutive, monthly injections may be needed. Thereafter, 
treatment may be continued on a “treat and extend” regimen with empirically determined 
treatment intervals.  
In the absence of a recommended posology that is consistent between regions, the Sponsor 
considers that the following aflibercept posology in this study provides the maximum possible 
treatment effect and best enables a head-to-head comparison with KSI-301 without undue risk:  
• During the 20-week fixed-dose interval (Day 1 to Week 20) in this study,  
aflibercept 2 mg will be administered six times via intravitreal injection (once every 4 weeks) 
at Day 1, Week 4, Week 8, Week 12, Week 16, and Week 20.  
• During the individualized treatment period (Week 24 to Week 44), participants will be 
treated according to protocol-guided retreatment criteria based on changes in BCVA and/or 
OCT. The retreatment criteria are the same for both aflibercept and KSI-301.  
4.3.3 
Sham Injection Rationale 
Sham injections are used to preserve study masking and minimize bias.  
During the 20-week fixed-dose interval (Day 1 to Week 20), participants randomized to 
treatment with KSI-301 will receive sham injections at Weeks 8 and 16 to preserve study 
masking, and participants randomized to treatment with aflibercept will not receive any sham 
injections, because they receive active injections monthly through Week 20. During the 
individualized dosing treatment period (Week 24 to Week 44), participants in both treatment 
arms will receive sham injections at every monthly visit when an active treatment is not 
administered. 
During the Extension Phase (Week 48 to Week 76), all patients will be treated with 
KSI-301 5 mg. To maintain masking of the randomization from the Primary Study, a sham 


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injection will be administered at visits through Week 68 in which KSI-301 5 mg is not dispensed 
by the IRT system.  
4.4 
End of Treatment  
Participants may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the Investigator or at the study site. Every effort should be made to 
keep participants in the study. The reasons for end-of-treatment/early termination are provided in 
Section 7.0. 
4.5 
End of Study Definition 
The end of the study is defined as the last follow-up visit of the last participant enrolled (i.e., the 
last enrolled participant’s final visit) or a Sponsor decision to terminate the study, whichever 
comes first.  
A participant is considered to have completed the Primary Study if he/she has completed all 
phases of the Primary Study, including the Week 52 safety follow-up assessment.  
For participants who participate in the Extension Phase, study completion will occur when the 
Week 76 assessments are completed. 
4.6 
Treatment After End of Study 
All participants will return to standard of care treatment, at the discretion of their Treating 
Physician, after completion of their final follow-up visit or once they discontinue from the study 
prematurely. The Sponsor will not provide continued access to study treatment following the end 
of the study or the end of each participant’s study treatment period. 


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5.0 
STUDY POPULATION 
Participants will be randomized to a specified treatment arm only if they meet all the inclusion 
criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or participant safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. Prospective approval 
of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or 
exemptions, are not permitted. 
Participants who complete the Primary Study will be eligible to participate in the Extension 
Phase. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the criteria in Sections 5.1.1 and 
5.1.2 apply. 
5.1.1 
Ocular Inclusion Criteria 
Where applicable, inclusion criteria will be confirmed or assessed by the independent, masked 
image Reading Center.  
1. Treatment-naïve macular edema and visual impairment of ≤ 6 months secondary to CRVO or 
BRVO. Participants with HRVO will also be considered eligible for this study and will be 
included as a CRVO. Eyes classified as having CRVO or HRVO will comprise at least 20% 
and not more than 35% of the total planned sample size. 
2. BCVA ETDRS letter score ≤ 80 and ≥ 25 (20/25 to 20/320 Snellen equivalent) in the Study 
Eye at Screening and confirmed at Day 1. 
3. CST of ≥ 320 microns on SD-OCT (Heidelberg Spectralis or equivalent on other OCT 
instruments) as determined by the Reading Center at the screening visit and confirmed by the 
Investigator at Day 1. 
4. Decrease in vision in the Study Eye determined by the Investigator to be primarily the result 
of ME secondary to RVO. 
In cases where both eyes are eligible, the eye with the worse BCVA at the Screening Visit will 
be selected as the Study Eye. If both eyes are eligible and have the same BCVA, the decision of 
which eye to select as the Study Eye will be made by the Investigator. Only one eye per 
participant can be included in the study.  
5.1.2 
General Inclusion Criteria  
5. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the protocols and restrictions listed in the informed consent form (ICF) and 
in this protocol. 


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6. Male or female ≥ 18 years of age. 
7. For women of childbearing potential: agreement to remain as abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per 
year during the treatment period 
 
.  
a. A woman is considered of childbearing potential if she is postmenarchal, has not reached 
a postmenopausal state (≥ 12 months of amenorrhea with no identified cause other than 
menopause), and has not undergone surgical sterilization (removal of ovaries and/or 
uterus). The definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements. 
b. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, established, proper use of hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. 
c. Contraception methods that do not result in a failure rate of <1% per year such as cap, 
diaphragm, or sponge with spermicide, or male or female condom with or without 
spermicide, are not acceptable. 
d. The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception. 
8. For men: agreement to remain abstinent or use contraceptive measures and agreement to 
refrain from donating sperm, as defined below: 
a. With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of < 
1% per year during the treatment period 
 
 after the last dose of study intervention. Men must refrain from 
donating sperm during this same time period. 
9. Ability and willingness to undertake all the scheduled visits and assessments. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the criteria in Sections 5.2.1 and 5.2.2 apply. 
5.2.1 
Ocular Exclusion Criteria  
Where applicable, exclusion criteria will be confirmed or assessed by the independent, masked 
image Reading Center. 
1. Macular edema in the Study Eye considered to be secondary to a cause other than RVO (e.g. 
diabetic macular edema, Irvine-Gass syndrome). 
2. Active iris or angle neovascularization, neovascular glaucoma, neovascularization of the 
optic disc, retinal neovascularization or vitreous hemorrhage in the Study Eye. 


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3. Uncontrolled glaucoma (defined as intraocular pressure ≥ 25 mmHg despite treatment with 
antiglaucoma medication) in the Study Eye. 
4. History of glaucoma-filtering surgery in the Study Eye.  
5. History of retinal detachment or treatment or surgery for retinal detachment in the Study Eye. 
6. History of uveitis in either eye.  
7. Significant media opacities, including cataract, in the Study Eye that might interfere with 
visual acuity, assessment of safety, optical coherence tomography or fundus photography.  
8. Cataract in the Study Eye that in the judgment of the Investigator is expected to require 
surgical extraction within 6 months of screening. 
9. Prior vitrectomy in the Study Eye. 
10. Active retinal disease other than the condition under investigation in the Study Eye.  
11. Any history or evidence of a concurrent ocular condition present, that in the opinion of the 
Investigator could require either medical or surgical intervention or affect macular edema or 
alter visual acuity during the study (e.g. vitreomacular traction).  
12. Active or suspected ocular or periocular infection or inflammation in either eye at Day 1. 
13. Any prior use of an approved or investigational treatment for macular edema secondary to 
RVO in the Study Eye (e.g. anti-VEGF, intraocular or periocular steroids, macular laser 
photocoagulation).  
5.2.2 
General Exclusion Criteria 
14. Women who are pregnant or lactating or intending to become pregnant during the study.  
15. Women of childbearing potential must have a negative urine pregnancy test result within 28 
days prior to Day 1. If the urine pregnancy test is positive, it must be confirmed with a serum 
pregnancy test. 
16. Uncontrolled blood pressure defined as a systolic value ≥180 mmHg or diastolic value ≥100 
mmHg while at rest at Screening or on Day 1. 
a. If a participant’s initial blood pressure measurement exceeds these values, additional 
readings may be taken later the same day or on a different day during the screening 
period. If a participant’s blood pressure is controlled by antihypertensive medications, 
the participant must be on a stable medication regimen continuously for 21 days prior 
to Day 1. 
17. Recent history (within the 6 months prior to screening) of myocardial infarction, stroke, 
transient ischemic attack, acute congestive heart failure or any acute coronary event. 
18. History of a medical condition that, in the judgment of the Investigator, would preclude 
scheduled study visits, completion of the study, or a safe administration of investigational 
product. 
19. History of hypersensitivity to any component of KSI-301, aflibercept, ophthalmic dye 
(fluorescein), dilating drops, or any of the anesthetic or antimicrobial preparations used 
during the study, as assessed by the Investigator. 


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20. Participation in an investigational study within 30 days prior to the screening visit that 
involved treatment with any drug (excluding vitamins and minerals) or devices. 
5.3 
Lifestyle Considerations 
No specific lifestyle restrictions are required.  
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse events (SAE) caused by a 
protocol-mandated intervention that occur during the screening period. 
Participants who do not meet eligibility criteria within the 21-day screening period will not be 
eligible for randomization and will be screen-failed. However, a participant may be re-screened 
up to one additional time at the discretion of the Investigator and in consultation with the 
Sponsor. When re-screening, the participant must be re-consented if more than 30 days have 
elapsed since the date of the last informed consent. In the event of re-screening, screening 
procedures need not be repeated if they fall within the 21-day screening window. If the re-
screening occurs outside the 21-day window, all assessments performed at the initial screening 
visit should be repeated during the re-screening visit except fluorescein angiogram (FA). If the 
re-screening visit is more than 8 weeks after the original screening visit, FA should be repeated. 
For re-screening visit occurring fewer than 8 weeks after the original screening visit, although a 
new FA will not be required, the previously acquired FA will need to be re-submitted to the 
Reading Center labeled with the new participant number, along with the new screening images 
from the other modalities. This will ensure that all images from the participant are properly 
labeled, kept within the same directory and that eligible transmission numbers and audit trails are 
maintained. 
When re-screening tests and procedures have been completed and results are available indicating 
the participant is eligible for study participation, the participant may be enrolled. When re-
screening a participant, a new screening/enrollment number will be generated by IRT system to 
ensure there is an audit trail for the screen-failed participant.  
5.5 
Criteria for Temporarily Delaying Enrollment 
Inclusion/Exclusion criteria will be assessed at Screening and on Day 1 to determine a 
participant’s eligibility for the study.  
If a participant meets all eligibility criteria (Sections 5.1 and 5.2) at the Screening visit but does 
not meet BCVA and/or SD-OCT CST eligibility criteria due to expected variability and 


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fluctuation in the BCVA and/or SD-OCT CST values when they return for the planned Day 1 
visit, the Sponsor will allow the participant to return one additional time to reassess the BCVA 
and/or SD-OCT CST, provided the assessment still occurs within the 21-day screening 
window. This repeat measurement for Day 1 visit (Repeat Day 1) is not considered a 
rescreen. Women of childbearing potential who return for a Repeat Day 1 Visit must have a 
negative pregnancy test during the Repeat Day 1 Visit (i.e., the pregnancy test must be 
performed and documented as negative on the same day as randomization/first injection). Day 1 
and Repeat Day 1 Visit data shall be used in the eCRF and IRT as follows:  
• eCRF: In the event that a participant has a Repeat Day 1 Visit, data from 
assessments conducted at the planned randomization (Day 1) visit shall be clearly 
documented in the participant’s source data. If the participant meets the eligibility criteria 
at the Repeat Day 1 visit, all data for assessments performed at that visit is entered into 
the eCRF under Day 1, and the original non-qualifying data will be entered as 
Unscheduled Visit assessments.  
• IRT: In the event that a participant has a Repeat Day 1 Visit and is eligible for this study, 
the BCVA and SD-OCT values from the Repeat Day 1 visit must be used for participant 
randomization into the IRT system. If the participant does not meet eligibility at the 
Repeat Day 1 visit, the participant must be recorded as a screen failure (Section 5.4) in 
the IRT system at that time.  
 


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6.0 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1 
Study Intervention(s) Administered 
Study interventions are summarized in Table 2. For full information regarding the administration 
of study intervention and the contents of the kit, refer to the Pharmacy Manual. For additional 
information regarding the administration of aflibercept, refer to the approved prescribing 
information for aflibercept in your country, such as the Summary of Product Characteristics 
(SmPC) or U.S. Prescribing Information (USPI). The full instructions for administration of sham 
are described in the Pharmacy Manual. 
 
 


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Table 2:  
Protocol KS301P103: Study Interventions 
Arm Name 
A 
B 
A or B 
Intervention Name 
KSI-301 5 mg 
Aflibercept 2 mg 
Sham 
Type  
Biological medicinal 
product 
Biological medicinal 
product 
Sham 
Dose Formulation 
Sterile liquid for intravitreal 
injection in single-use vials  
Sterile liquid for intravitreal 
injection in single-use vials 
or prefilled syringes 
Empty vial 
Unit Dose Strength(s) 
 mg/mL (based on 
antibody mass) 
40 mg/mL 
N/A 
Dosage Level(s) 
5 mg 
 
2 mg (50 µL) 
N/A 
Route of Administration 
Intravitreal injection 
Intravitreal injection 
Sham injection 
Use 
Experimental 
Active control 
Sham (to maintain study 
masking) 
IMP and NIMP 
IMP 
IMP 
NIMP 
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Storage 
In the original packaging, as 
provided, until the time of 
use. Store at 2-8°C before 
use.  
In the original packaging, as 
provided, until the time of 
use. Store at 2-8°C before 
use.  
In the original packaging, as 
provided, until the time of 
use. Store at 2-8°C before 
use.  
Packaging and Labeling KSI-301 will be provided in 
vials that will be labeled as 
required per country 
requirement. 
Aflibercept will be provided 
in vials or prefilled syringes 
that will be labeled as 
required per country 
requirement. 
Sham will be provided in 
vials that will be labeled as 
required per country 
requirement. 
Reconstitution and 
Handling 
KSI-301 is an aqueous 
solution that is provided in 
vials and filled into syringes 
by unmasked site personnel 
without reconstitution or 
dilution.  
 
Aflibercept is an aqueous 
solution that is provided in 
vials and filled into syringes 
by unmasked site personnel 
without reconstitution or 
dilution or provided in 
prefilled syringes. 
 
Sham is provided as empty 
glass vials, which will 
remain empty throughout the 
sham treatment procedure. A 
sham injection mimics an 
intravitreal injection. It 
involves pressing the blunt 
end of an empty syringe, 
without a needle, against an 
anesthetized eye. 
Current/Former 
Name(s) or Alias(es) 
N/A 
Eylea 
N/A 
 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Preparation, Handling, and Storage 
Study interventions (KSI-301 and aflibercept) are aqueous solutions provided in vials (or 
prefilled syringes for aflibercept) and filled into syringes by unmasked site personnel without 
reconstitution or dilution. 


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Study drug kits must be stored in a secure refrigerator at a controlled temperature of 2°C to 8°C. 
All study drug vials or prefilled syringes (for aflibercept) should be stored in the original 
packaging, as provided, until the time of use.  
Please refer to Pharmacy Manual for additional instructions. 
6.2.2 
Study Intervention Accountability and Reconciliation 
Study intervention packaging will be overseen by the Sponsor or their designee and bear a label 
with the identification required by local law, the protocol number, drug identification, and 
dosage. The packaging and labeling of the study medication will be in accordance with local 
regulations. 
The investigational site will acknowledge receipt of the study intervention, to confirm the 
shipment condition and content. Any damaged shipments will be replaced. Upon arrival of the 
study intervention at the site, site personnel will complete the following: 
• Check the shipment for damage. 
• Verify proper identity, quantity, integrity of seals and temperature conditions. 
• Report any deviations or product complaints to the Sponsor or their designee upon discovery. 
Any study intervention under investigation for integrity or temperature excursion should be 
quarantined in the IRT and at the site, pending final assessment by the Sponsor or its 
designee. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
The pharmacist responsible for dispensing study treatment, or the designated site personnel, will 
select the correct study intervention as assigned through the IRT. Instructions for the preparation 


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of KSI-301, aflibercept, or sham for administration, mandatory materials to be used, and 
pretreatment and post-treatment procedures are detailed in the Pharmacy Manual.  
For more detailed information on the formulation, preparation, and handling of KSI-301, 
aflibercept, and sham, see the Pharmacy Manual. 
6.3 
Measures to Minimize Bias: Randomization and Masking 
6.3.1 
Randomization  
All participants will be centrally assigned to a randomized study intervention using an IRT 
system. Before the study is initiated, login information and directions for the IRT will be 
provided to each site.  
Study intervention will be dispensed at the study visits as summarized in the Study intervention 
will be dispensed at the study visits as summarized in the SoA (Section 1.3). 
6.3.2 
Masking and Unmasking 
This is a double-masked study. There must be a minimum of two investigators per site to fulfill 
the masking requirements of this study, as follows: 
• Masked Evaluating Physician(s): At least one Investigator will be designated as the 
evaluating physician who will be masked to participants’ treatment assignments and will 
evaluate all ocular assessments (other than the immediate post-injection assessments done by 
unmasked personnel, as described below).  
• Unmasked Treating Physician(s): At least one other Investigator will be designated as the 
treating (injecting) physician who will be unmasked to participants’ treatment assignments 
and will administer study intervention (KSI-301, aflibercept, or sham). This physician or an 
unmasked assistant will also conduct the immediate post-injection assessments, including 
tonometry, in the Study Eye (Section 8.1.4). The unmasked Treating Physician and 
unmasked staff must not divulge treatment assignment to anyone. 
In the Extension Phase, the study masking procedures remain unchanged, to avoid unmasking of 
the participant’s original treatment assignment.  
As shown in Section 6.1, there are three study interventions: (1) KSI-301 (the investigational 
medicinal product); (2) aflibercept (the active comparator); and (3) sham (for which an injection 
procedure is simulated but not actually performed). All three study interventions are provided in 
masked cartons (also referred to as kits).  
• Masked Cartons: All study interventions are provided in cartons that are identical in 
appearance and weight, making them indistinguishable from each other. 
Each carton is labeled with an identical carton label that includes a unique kit number. The 
IRT system will direct site personnel which specific carton to pull from inventory and use for 


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a specific participant at a given visit based on the unique kit number printed on the carton 
label and that participant’s treatment at that given visit.  
• Unmasked Vials or Prefilled Syringes Within the Masked Cartons: Owing to differences 
among vials, syringes, dose-preparation procedures, and treatment procedures that cannot be 
masked, the treating (injecting) physician is unmasked to study treatment as are any 
assistants to the treating (injecting) physician. Only unmasked site staff are allowed to open 
the masked cartons. 
Participants, study site personnel (except for the Treating Physician(s), assistant(s), and 
pharmacist if any), the designated evaluating physician(s), central Reading Center personnel, and 
the Sponsor and its agents will be masked to treatment assignment.  
The visual acuity (VA) examiner (performing the refraction, BCVA examination) will be 
masked to the participant treatment assignment. The BCVA examiner will have no access to the 
VA scores of a participant’s previous visits and may have access only to a participant’s 
refraction data from previous visits.  
A participant’s treatment assignment will not be unmasked until the end of the study unless 
medical treatment of the participant depends on knowing the study treatment the participant 
received. Emergency code break is available to the Investigator online in the IRT. If unmasking 
is necessary for participant management (for example, in the case of a serious adverse event for 
which participant management might be affected by knowledge of the treatment assignment), the 
Investigator will be able to break the treatment code by accessing the IRT system. Treatment 
codes must not be broken except in emergency situations. If the Investigator wishes to know a 
participant’s treatment assignment for any other, non-emergency reasons, he or she should 
consult with the Medical Monitor. The Investigator should document and provide an explanation 
for any non-emergency unmasking (for example, accidental unmasking). 
For regulatory reporting purposes and if required by local health authorities, the Sponsor or its 
agents (e.g., contract research organization (CRO) pharmacovigilance personnel) will break the 
treatment code for all serious, unexpected suspected adverse reactions (SUSARs) that are 
considered by the Investigator or Sponsor to be related to study intervention. The participant may 
continue to receive treatment, and the Investigator, participant, and Sponsor or CRO personnel, 
except for the pharmacovigilance personnel who must have access to participant treatment 
assignments to fulfill their roles, will remain masked to treatment assignments. 
Additional information regarding masking and unmasking will be outlined in the Masking 
Manual. 
6.4 
Study Intervention Compliance 
Only participants enrolled in the study may receive study treatment and only ophthalmologists 
who have experience administering intravitreal injections may administer study treatment. 


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The unmasked Investigator is responsible for administering the correct dose of KSI-301 or 
aflibercept and for the sham administration, according to the study protocol. The date and time of 
each dose administered in the clinic will be recorded in the source documents and electronic case 
report form (eCRF). To avoid medication dispensing errors, the study intervention, study 
participant and Study Eye identification will be confirmed at the time of dosing by a member of 
the unmasked study site team. 
6.5 
Dose Modification 
During the Primary Study, participants can only receive the specified dose for the intervention 
arm, as follows: 
A. KSI-301: 5 mg 
  
B. Aflibercept: 2 mg (50 µL).  
In the Extension Phase, all participants will receive KSI-301 5 mg 
 
Alterations of the dosage are not allowed.  
6.6 
Continued Access to Study Intervention after the End of the Study 
After participants complete their final follow-up visit or discontinue from the study prematurely, 
they will return to standard of care treatment at the discretion of their Treating Physician. The 
Sponsor will not provide continued access to study treatment following the end of the study or 
the end of each participant’s study treatment period. 
6.7 
Treatment of Overdose 
For this study, any dose of KSI-301 greater than 5 mg or aflibercept greater than 2 mg at a single 
study visit will be considered an overdose. 
The Sponsor does not recommend any specific treatment for an overdose.  
In the event of an accidental overdose, the Investigator/Treating Physician should: 
• Contact the Medical Monitor immediately. 
• Evaluate the participant to determine, in consultation with the Medical Monitor, 
whether additional steps should be taken. 
• Closely monitor the participant for any AE/SAE. 
• Document the quantity of the excess dose. 
In addition to overdosing, an increased injection volume may cause an increase in intraocular 
pressure. In case of overdose, intraocular pressure should be monitored and if deemed necessary 
by the Treating Physician, adequate treatment should be initiated, including performing pressure 
lowering procedures (i.e., anterior chamber paracentesis). 


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6.8 
Concomitant Therapy 
Use of all concomitant medications will be recorded in the participant’s eCRF, except for 
medications required for carrying out procedures in the SoA (Section 1.3) (e.g., dilating drops, 
anesthetics, antiseptic, fluorescein, etc.) related with this study. Concomitant medications will 
include all prescription drugs, herbal products, vitamins, minerals, and over the counter (OTC) 
medications as used by the participant within 30 days prior to Day 1 through Week 52, for 
participants who chose not to continue into the Extension Phase, and through Week 76 for 
participants who continued through the Extension Phase. Any changes in concomitant 
medications also will be recorded in the participant’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the participant during the 
study may be given at the discretion of the Investigator. However, it is the responsibility of the 
Investigator to ensure that all relevant details regarding the medication are recorded in the eCRF. 
Participants who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. 
In case the fellow (non-study) eye requires anti-VEGF treatment during the conduct of the study, 
the participant may be treated at the discretion of the Investigator and according to the standard 
of care in the respective country. The treatment of the fellow (non-study) eye may be 
implemented at any time once the Day 1 injection has been administered. Fellow (non-Study 
Eye), anti-VEGF treatment, including the date of each administration, must be documented as a 
concomitant medication on the appropriate eCRF. If the non-Study Eye requires treatment at the 
same visit as the Study Eye, the Study Eye should be treated first, and the non-Study Eye should 
be treated by the unmasked physician to preserve masking.  
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1 
Pan-retinal Photocoagulation (PRP) 
Pan-retinal photocoagulation laser is permitted in the Study Eye, if clinically indicated for the 
treatment of new, active retinal or iris neovascularization in association with ischemic 
complications of RVO. PRP will be reported as a concomitant procedure in the appropriate 
eCRF. 
6.8.2 
Prohibited Therapy 
At the discretion of the Investigator, during the Study participants may start or continue to 
receive all medications and standard treatments administered for other conditions, except for the 
following: 
• Investigational therapies in the non-Study Eye; 


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• Intravitreal anti-VEGF drugs other than study-assigned aflibercept or KSI-301 in the 
Study Eye; 
• Systemic anti-VEGF therapy; 
• Intravitreal or periocular steroids or steroid implants in the Study Eye; 
• Concurrent use of macular laser photocoagulation in the Study Eye; and/or 
• Investigational treatment with any drug (other than vitamins and minerals) or device. 
Participants whose medical care requires use of a prohibited therapy must have study treatment 
interrupted in order to receive that therapy. After discussion with the Sponsor, participants whose 
study treatment has been interrupted but no longer need a prohibited therapy may resume study 
treatment. 
6.8.3 
Supportive Care for Adverse Events 
Supportive care for the known potential risks associated with anti-VEGF treatment and KSI-301 
(summarized in Table 1) should be as per the standard of care in the respective country. No 
specific prophylactic therapies are recommended. 
 


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7.0 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
Participants may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the Investigator or at the study site. Every effort should be made to 
keep participants in the study.  
If study intervention is discontinued during either the Primary Study or the Extension Phase, an 
end-of-treatment visit should occur 28 +/- 7 days after study treatment is discontinued or before a 
new treatment regimen begins. Participants who discontinue study drug should NOT be 
considered withdrawn from the study. Unless they withdraw consent or there is additional risk to 
the participant, participants who have discontinued study treatment should be encouraged to stay 
in the study and undergo as many scheduled visits as possible, with emphasis on the Week 24 
(primary endpoint), Week 48 (secondary endpoint), and Week 72 (for Extension Phase 
participants only) visits.  
The reasons for study treatment discontinuation and/or withdrawal from the study (study 
discontinuation) will be recorded on the appropriate eCRF. 
A participant may be withdrawn from the study for any of the following reasons: 
1. The participant is noncompliant with the protocol. 
2. The participant has a serious or intolerable adverse event(s) (AE[s]) that in the 
Investigator’s opinion requires withdrawal from the study. 
3. The participant has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal. 
4. The participant is lost to follow-up. 
5. Any medical condition that the Investigator or Sponsor determines may jeopardize the 
participants’ safety if they remain in the study. 
6. The participant withdraws consent, or the Investigator or Sponsor decides to discontinue 
the participant’s participation in the study. 
7. Pregnancy. 
The Investigator will also withdraw a participant if the Sponsor terminates the study. Upon 
occurrence of a serious or intolerable AE, the Investigator will confer with the Sponsor. If a 
participant is discontinued because of an AE, the event will be followed until it is resolved, or no 
additional improvement is expected by the Investigator (based on a follow-up period of not less 
than 3 months). Any participant may withdraw his or her consent at any time. 


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7.1.1 
Treatment Interruption and/or Discontinuation due to Adverse Events or 
Concomitant Procedures 
Study treatment interruption and/or participant discontinuation from the study treatment due to 
certain adverse events or concomitant procedures in the Study Eye will be determined using the 
criteria provided in Table 3. If any of these are met, treatment will be interrupted (or 
discontinued if applicable) and notification will be sent to the Medical Monitor. Treatment may 
be resumed after resolution of the adverse event and upon agreement with both the Investigator 
and Medical Monitor. The reason for study treatment interruption or discontinuation should be 
recorded on the appropriate eCRF and, if applicable, on the adverse event eCRF. 
Table 3:  
Protocol KS301P103: Treatment Interruption Criteria 
Event 
(MedDRA Preferred Term) 
Study Treatment Interruption Criteria 
Vision loss 
Interrupt study treatment for treatment-related decrease of ≥30 letters in 
BCVA in the Study Eye compared with the most recent prior visit.  
Intraocular inflammation  
Interrupt study treatment if any active intraocular inflammation is present in 
the Study Eye. 
Intraocular surgery 
Interrupt study treatment for intraocular surgery in the Study Eye, for 
example cataract surgery. 
Treatment may resume no earlier than 10 days after uncomplicated cataract 
surgery, provided there is no evidence of postoperative intraocular 
inflammation. For complicated cataract surgery or following other 
intraocular surgery, study treatment may be resumed as determined by the 
Investigator following discussion with the Medical Monitor.  
Elevated intraocular pressure 
Interrupt study treatment if the pre-injection IOP is >30 mmHg in the Study 
Eye. 
Retinal tear or break 
Interrupt study treatment if a retinal tear or break is present in the Study Eye.  
Treatment may be resumed no earlier than 10 days after successful laser 
retinopexy, as determined by the Investigator. 
Retinal detachment or 
macular hole 
Interrupt study treatment if rhegmatogenous retinal detachment or Stage 3 or 
Stage 4 macular hole occurs in the Study Eye. 
Treatment may be resumed no earlier than 14 days after successful 
treatment, as determined by the Investigator, following discussion with the 
Medical Monitor. 
Active infection 
Interrupt study treatment if infectious cellulitis, conjunctivitis, keratitis, 
scleritis, or endophthalmitis occurs in or around either eye. 
Infections should be treated as per the local standard of care. 
 


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7.2 
Participant Discontinuation/Withdrawal from the Study 
Participants should be strongly encouraged to stay in the study and undergo as many scheduled 
visits as possible, with emphasis on the Week 24 (primary endpoint), Week 48 (secondary 
endpoint), and Week 52 (final safety assessment) visits. Similarly, for participants who 
participate in the Extension Phase, completion of as many scheduled visits is encouraged, with 
emphasis on the Week 72 and Week 76 (final safety assessment) visits. However, participants 
are free to withdraw from the study or study treatment at any time upon request. Participant 
participation in the study may be stopped at any time at the discretion of the Investigator or at the 
request of the Sponsor. 
Participants who discontinue study treatment or active participation in the study will no longer 
receive study intervention. When a participant discontinues from study treatment or active 
participation in the study, the reason(s) for study treatment discontinuation or withdrawal shall 
be recorded by the Investigator or designee on the relevant page of the eCRF. Whenever 
possible, all participants who discontinue study treatment or withdraw from the study 
prematurely will undergo an Early Termination visit. Participants who fail to return for final 
assessments must be contacted by the site by phone and in writing to obtain follow-up. 
If a participant exits early from the study between visits, the Investigator or designee must 
attempt to contact the participant and advise the participant to return for a final visit to complete 
the exit procedures. If the participant is unable or unwilling to return for the Early Termination 
visit, the ‘date of exit’ will be the date that the participant was last seen at the site or contacted by 
other communication.  
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
a) The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 


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b) Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods) and discuss the situation with the Sponsor. These contact attempts 
should be documented in the participant’s medical record. 
c) Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 


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8.0 
STUDY ASSESSMENTS AND PROCEDURES 
• Before undertaking any study procedures, all potential participants will sign an ICF. 
Participants will have the opportunity to have any questions answered before signing the 
ICF. The Investigator must address all questions raised by the participant. The 
Investigator or designee will also sign the ICF.  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Assessments 
performed in the event of an unscheduled safety visit (Appendix 5) are at the discretion 
of the Investigator. Adherence to the study design requirements, including those specified 
in the SoA, is essential and required for study conduct. All screening evaluations must be 
completed and reviewed to confirm that potential participants meet all eligibility criteria. 
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure, as applicable. 
• Protocol waivers or exemptions are not allowed.  
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
8.1 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1 
Medical History and Demographic Data 
Medical history (general and ophthalmic) includes clinically significant diseases, surgeries and 
reproductive status. All medications (e.g., prescription drugs, OTC drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the participant regularly or within 30 days preceding 
Day 1 must be recorded. A full ocular history including prior ocular treatments will be noted. 
Demographic data will include age, sex, and ethnic origin (also referred to as self-reported race 
and ethnicity in some regions of the world).  
8.1.2 
Ophthalmic Exams 
Unless otherwise noted, ophthalmic assessments are captured for the Study Eye only. 
Slit-lamp examination, which will include the following:  
• Inspection of the eyelids; 
• Inspection of the cornea; 
• Examination of the anterior chamber; 
• Examination of the pupil; 
• Examination of the iris; 
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• Inspection of the vitreous body; and 
• Inspection of the retina and optic disc. 
Dilated indirect ophthalmoscopy will include examination of the peripheral retina. 
Tonometry shall be conducted as part of the ophthalmic exam. The method of IOP measurement 
(such as Goldmann tonometry or Tonopen) must remain the same throughout the study for each 
participant. Pre-injection tonometry should be performed prior to pupil dilation.  
Participants will be instructed to report any signs or symptoms of intraocular inflammation 
(uveitis) or endophthalmitis such as pain, photophobia, redness, or reduced vision.  
8.1.3 
Injection Procedure 
The unmasked injecting Investigator must be qualified and trained in administering intravitreal 
injections and follow standard injection procedures in adherence to specific institutional or local 
policies associated with intravitreal injections. Aseptic technique must be observed by clinic staff 
involved in the assembly of the injection tray, study intervention preparation, anesthetic 
preparation, and study treatment administration. To minimize the risk of infection the periocular 
skin, eyelid and conjunctiva of the Study Eye must be disinfected, as outlined in the Syringe 
Preparation and Injection Procedure Guidelines found in the Pharmacy Manual.  
The unmasked injecting Investigator will choose one of the acceptable methods of ocular 
anesthesia on a per participant basis. Subconjunctival anesthesia is recommended (but not 
required) to maximize participant comfort. In order to maintain masking, the selected method of 
anesthesia for an individual participant must remain constant for the duration of the trial and at 
all visits irrespective of the study treatment assigned during the study visit (KSI-301, aflibercept 
or sham). 
Please refer to the Pharmacy Manual for additional instructions on IMP preparation and 
administration. 
8.1.4 
Post-injection Assessments in the Study Eye  
Within 5 minutes after the injection, check vision for count fingers or hand motion.  
• Tonometry (between 30 and 50 minutes after injection):  
If the IOP is >30 mmHg or has increased by ≥ 10 mmHg from pre-injection, the IOP will 
be measured again at 60−80 minutes post-injection. If there are no safety concerns, the 
participant will be permitted to leave the clinic. If the IOP value is of concern to the 
Investigator, the participant will remain in the clinic and will be managed in accordance 
with the Investigator’s clinical judgment. The latest post-injection IOP measured (prior to 
any intervention for increased IOP, if applicable) will be recorded on the post-treatment 
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The method of post-injection IOP measurement (such as Goldmann tonometry or Tonopen) must 
be the same as the pre-injection method and remain the same throughout the study for each 
participant. 
8.1.5 
Best Corrected Visual Acuity (BCVA) 
BCVA will be measured utilizing the ETDRS method by certified, masked personnel at the study 
sites. The measurement should be performed following refraction, and prior to any examination 
requiring contact with the eye and prior to dilating the eyes. A BCVA Testing Procedure Manual 
and training materials will be provided to all sites by the third-party VA Examiner certification 
vendor. 
8.1.6 
Fundus Photography (FP) 
Fundus photography will be performed at the study sites by certified, masked personnel. It is 
mandatory that the same model of device is used for the entire duration of the study. 
Additional specifications and instructions regarding acceptable equipment and imaging 
techniques will be provided by the Reading Center. 
8.1.7 
Spectral Domain Optical Coherence Tomography (SD-OCT) 
SD-OCT will be performed at the study sites by certified, masked personnel on a qualified 
instrument. It is mandatory that the same model of device is used for the entire duration of the 
study.  
Additional specifications and instructions regarding acceptable equipment and imaging 
techniques will be provided by the Reading Center. 
8.1.8 
Fluorescein Angiography (FA) 
FA will be performed at all the study sites by certified, masked personnel. It is mandatory that 
the same model of device is used for the entire duration of the study.  
Additional specifications and instructions regarding acceptable equipment imaging and imaging 
techniques will be provided by the Reading Center. 
8.1.9 
Disease Activity Assessments 
The IRT will make the necessary adjustments to the dosing schedule based on disease activity 
data from the study site. Details of the disease activity assessments are described in  
Section 4.1.3. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 


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8.2.1 
Vital Signs 
The following vital signs will be assessed taken with the participant in a seated position after 
resting for 5 minutes: blood pressure (BP), pulse rate, and body temperature. Height and weight 
will be recorded at the screening visit only. 
8.2.2 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and refer to the SoA 
(Section 1.3) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
• If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
• All protocol-required laboratory tests, as defined in Appendix 2, must be conducted in 
accordance with the SoA (Section 1.3). 
• If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.2.3 
Pregnancy Testing 
Participant samples for pregnancy testing will be taken at the Screening and Day 1 visits and 
then monthly in women of childbearing potential only as specified in the SoA (Section 1.3). 
Prior to enrollment in the study, female participants of childbearing potential and male 
participants must be advised of the importance of avoiding pregnancy or partner pregnancy, 
respectively, during the trial and the potential risks associated with an unintentional pregnancy. 
Contraceptive and barrier guidance and collection of pregnancy information is described in 
Appendix 6. 


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8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
After informed consent has been obtained but prior to initiation of study intervention, only SAEs 
caused by a protocol-mandated intervention should be reported. After initiation of study 
intervention (Day 1), all AE and SAE information will be collected until the final safety follow-
up visit at Week 52 or the ET visit if applicable for participants who are not participating in the 
Extension Phase. For those participants who continue into the Extension Phase, all AE and SAE 
information will continue to be collected until the final visit at Week 76 or the ET visit if 
applicable. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. At every study visit, 
open-ended and nonleading verbal questioning of the participant is the preferred method to 
inquire about AE occurrences. The participant will also be asked if they have been hospitalized, 
had any accidents, used any new medications, or changed concomitant medication regimens 
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In addition to participant observations, AEs identified from any study data (e.g., laboratory 
values, ophthalmic examination findings) or identified from review of other documents that are 
relevant to participant safety will be documented on the AE page in the eCRF. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AEs of special interest (as defined in 
Section 8.3.6), will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is provided in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
intervention under clinical investigation are met. The Sponsor has a legal responsibility to notify 
both the local regulatory authority and other regulatory agencies about the safety of a study 
intervention under clinical investigation. The Sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary. 
8.3.5 
Pregnancy 
During the study, female and male participants are to be instructed to contact the Investigator 
immediately if they suspect they might be pregnant or if their partner becomes pregnant, 
respectively, and details will be collected. Additional urine or serum pregnancy testing may be 
performed during the study at the discretion of the Investigator, or in accordance with local 
requirements or regulations.  
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs during study participation must be reported using the same procedures as an SAE on a 
Sponsor prepared form. To ensure participant safety, each pregnancy must be reported to the 
Sponsor or its designee immediately (within 24 hours) after learning of its occurrence. The 


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pregnancy must be followed up to determine outcome (including spontaneous miscarriage, 
elective termination, normal birth, or congenital abnormality) and status of mother and child, 
even if the participant was discontinued from the study. Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE. Spontaneous miscarriages 
must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the Investigator’s attention after 
the participant has completed the study, and considered by the Investigator as possibly related to 
the study treatment, must be promptly reported to the Sponsor. 
Pregnancy is considered a criterion for discontinuation from the study, please refer to Section 7.1 
for additional information. Contraceptive and barrier guidance and collection of pregnancy 
information is described in Appendix 6. 
8.3.6 
Adverse Events of Special Interest 
An adverse event of special interest (AESI) is one of scientific and medical concern specific to 
the Sponsor’s product or program where ongoing monitoring and rapid communication by the 
Investigator to the Sponsor may be appropriate. These AEs may be serious or non-serious. 
Applicable AEs may require additional investigation in order to characterize and understand, and 
depending upon the nature of the event, rapid communication by the Sponsor to other parties 
may also be required. 
These AESIs must be reported by the Investigator using the same mechanism (Electronic data 
capture (EDC) or fax) and time frame (i.e., within 24 hours after learning of the event) as 
described previously for SAEs. The AESIs include the following: 
• AEs resulting from medication error, including overdose, incorrect dose, incorrect drug, 
incorrect administration, or incorrect kit. 
• AEs with sight-threatening potential, meeting one or more of the following criteria: 
o Causes a decrease ≥ 30 letter in BCVA compared with the last visual acuity 
assessment; 
o It is associated with severe intraocular inflammation (i.e., endophthalmitis, Grade 
4 aqueous flare/aqueous cells, Grade 4 vitreous haze/vitreous cells; see 
Appendix 4 for grading scales); or 
o Requires surgical intervention to prevent permanent loss of sight. 
• Cases of potential liver injury (Appendix 7). 
As with all AEs occurring in a study participant, a decision will be made by the Investigator 
concerning additional exposure to study treatment and further participation in the study. 


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8.4 
Pharmacokinetics 
To understand the pharmacokinetic (PK) profile of the study intervention following intravitreal 
injection (i.e., systemic exposure), plasma concentration of KSI-301 will be measured. For 
exploratory purposes, 
 
. Plasma samples of comparator may also be analyzed for systemic PK and systemic 
biomarkers. 
Blood samples of approximately 4 mL will be collected from participants for measurement of 
plasma concentrations of KSI-301, as specified in the SoA (Section 1.3). 
Instructions for the collection and handling of biological samples will be included in the Central 
Laboratory Manual. The actual date and time when each sample is collected will be recorded. 
8.5 
Genetics and/or Pharmacogenomics 
Genetics and/or pharmacogenomics are not evaluated in this study. 
8.6 
Biomarkers 
Blood samples that were collected from participants for systemic PK analysis (Section 8.4) may 
also be analyzed for measurement of plasma biomarkers, as specified in the SoA (Section 1.3). 
Instructions for the collection and handling of biological samples will be provided by the Central 
Laboratory Manual. The actual date and time when each sample is collected will be recorded. 
8.7 
Immunogenicity Assessments 
Blood samples of approximately 4 mL will be collected for detection and confirmation of anti-
drug antibodies (ADAs), as well as assays to further characterize the anti-drug antibodies as 
specified in the SoA (Section 1.3). Additionally, plasma samples should also be collected and 
evaluated at the final visit from participants who discontinued study intervention or were 
withdrawn from the study as per the SoA.  
The detection and characterization of ADAs to KSI-301 will be performed using a validated 
assay method. Plasma samples will be screened for antibodies binding to KSI-301 and the titre of 
confirmed positive samples will be reported. Specificity analyses may be performed to further 
characterize the immunogenicity of KSI-301. Anti-KSI-301 antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study 
intervention(s) (neutralizing antibodies NAB). All samples collected for detection of antibodies 
to study intervention will also be evaluated for KSI-301 plasma concentration to enable 
interpretation of the antibody data.  


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Samples may be stored for a maximum of 5 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of immune responses to KSI-301.  
8.8 
Health Economics or Medical Resource Utilization and Health Economics 
These parameters are not evaluated in this study. 


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9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Hypothesis 
Treatment with KSI-301 5 mg will provide a non-inferior mean change in BCVA compared to 
aflibercept 2 mg while using a less frequent dosing schedule in participants with visual 
impairment due to ME secondary to RVO. 
9.2 
Sample Size Determination 
The sample size for the comparison of BCVA between treatment arm A (KSI-301 5 mg q8w 
after 2 monthly doses) and treatment arm B (aflibercept 2 mg q4w) at Week 24 is based on a 
non-inferiority approach. The following assumptions were made in order to calculate the sample 
size: 
• Overall Type I error rate of 0.025. Testing at the 0.025 level for non-inferiority 
corresponds to setting 95% CIs. 
• Statistical power of ≥90%. 
• Standard deviation of the distribution of change in visual acuity from baseline of 
 
letters. 
• The maximum clinically acceptable true difference for KSI-301 to be considered non-
inferior, or the “non-inferiority margin”, is 4.5 letters.  
• The statistical test used to compare the two treatment arms at Week 24 is an independent 
t-test on the mean change in visual acuity from baseline. 
• Lost to follow-up/dropout rate of approximately 
. 
The sample size calculated using the above assumptions is approximately 550 participants (275 
per treatment arm). 
 
 
 
 
 
 
Note: “enrolled” means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process and 
screening and completing the Day 1 visit. Potential participants who are screened for the purpose 
of determining eligibility for the study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.  
 


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9.3 
Analysis Sets 
For the purpose of analysis, the following analysis sets are defined:  
Population 
Description 
Randomized/ intent to treat set 
(ITT) 
The ITT will be comprised of all participants who were randomized into one 
of the study arms. 
For analyses based on this population, participants will be grouped according 
to the study intervention assigned at randomization. 
Evaluable / Per protocol set 
(PPS) 
The PPS will consist of all ITT participants who fulfill all inclusion/exclusion 
criteria and have no significant protocol deviations that are expected to have a 
significant impact on the assessment of efficacy, including lack of compliance 
with study treatment, missing data, and having taken any prohibited 
medication. All analyses using the PPS will group participants according to 
the study intervention they actually received. 
Safety 
All participants randomly assigned to study intervention and who receive at 
least one dose of study intervention. Participants will be analyzed according to 
the intervention they actually received. 
Pharmacokinetic/ Biomarker/ 
ADA-evaluable  
The PK/biomarker evaluable data set will consist of all participants in the ITT 
Population with at least one post-Day 1 evaluable sample. The ADA-
evaluable data set will consist of all participants in the ITT Population with at 
least one evaluable sample. 
 
9.4 
Statistical Analyses 
The study SAP will fully specify the statistical methodology and reporting for all aspects of the 
planned analyses. The SAP will be finalized prior to database lock and executed thereafter, and it 
will include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints.  
Additional unplanned analyses may be required after all planned analyses have been completed, 
and additional analyses of key efficacy metrics may be performed between the primary and final 
analyses to support marketing applications for various jurisdictions. Any unplanned analyses will 
be clearly identified in the clinical study report. 
Results of the Week 24 analyses may be reported to the public and to health authorities prior to 
completion of the Week 52 portion of the study. Participants, masked study site staff, and the 
Reading Center will remain masked to treatment assignments until the entire study is completed, 
the database is locked, and the Week 76 analyses are completed.  
9.4.1 
General Considerations 
At baseline (Day 1), participants will be randomized 1:1 into one of two treatment arms: 


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A. KSI-301: two monthly doses of KSI-301 5 mg followed by every 8 weeks until the 
primary endpoint.  
B. Aflibercept: six monthly doses of aflibercept 2 mg.  
The Primary Study is divided into two efficacy and safety assessment periods (Section 1.2) for 
participants who are not participating in the Extension Phase, as follows: 
• Day 1 to Week 24, which corresponds to the fixed interval treatment period (Day 1 through 
Week 20); and 
• Week 24 to Week 52, which corresponds to the individualized treatment period (Week 24 to 
Week 44). 
For participants who participate in the Extension Phase, an additional efficacy and safety 
assessment period is added, as follows:  
• Week 48 to Week 76 (Extension Phase), which corresponds to a KSI-301 5 mg 
individualized treatment period (Week 48 to Week 68).  
Using ETDRS BCVA data collected up to Week 24, the treatment arms will be compared using a 
non-inferiority analysis, with a margin of 4.5 ETDRS letters. Confidence intervals will be 
100(1-2 α) or 95%CI. If the null hypothesis of inferiority is rejected, testing for superiority will 
be performed. That is, if the lower confidence limit for the difference in mean BCVA lies within 
(-4.5, ∞), the null hypothesis of inferiority will be rejected, and non-inferiority will be 
established. Furthermore, if the lower confidence limit lies within (0, ∞), superiority will be 
established.  
Analysis of data for the first period of the study will be performed when all participants have 
either completed the Week 24 visit or have discontinued from the study, all data have been 
entered into the database, cleaned and verified as appropriate, and the database has been locked; 
likewise, analysis of data for the second period of the study will be performed when all 
participants have either completed the Week 52 visit or have discontinued from the study, all 
data have been entered into the database, cleaned and verified as appropriate, and the database 
has been locked. Additionally, analysis of data for the Extension Phase of the study will be 
performed when all participants who participate have either completed the Week 76 visit or have 
discontinued from the study, all data have been entered into the database, cleaned and verified as 
appropriate, and the database has been locked.  
Details of all preplanned analyses, including imputation approaches for the handling of missing 
data, subgroup analyses (for example, across key demographic and ocular baseline 
characteristics), and sensitivity analyses, will be included in the SAP. The results of all analyses 
detailed in the SAP will appear in the final clinical study report.  


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9.4.2 
Primary Endpoint(s) 
The primary endpoint is defined as the mean change in ETDRS BCVA from baseline (Day 1) to 
Week 24. The primary assessment of efficacy will be based on a pairwise comparison in mean 
change in BCVA between treatment arm A (KSI-301 5 mg) and treatment arm B (aflibercept 
2 mg). 
Unless stated otherwise, all analyses described will be performed on the ITT Population.  
Analysis of the primary endpoint data will be performed when the following occur: 
• all participants have either completed the Week 24 visit or have discontinued from the study 
prior to the Week 24 visit, whichever comes later; 
• all data up to and including the Week 24 visit have been entered into the database, and have 
been cleaned, and verified as appropriate; and  
• the database for the primary analysis locked. 
If there are no imbalances on important prognostic factors at baseline, a simple independent t-test 
and corresponding CIs will be used for evaluation of treatment differences. If there are 
imbalances in key prognostic factors at baseline (e.g., BCVA) generalized linear models or other 
statistical models (such as mixed effects models) will be used to estimate the difference in mean 
change in BCVA between treatment arms and CIs derived from the corresponding standard error 
of the estimate. These models will also include indicator variables for stratification variables. An 
alpha level of 0.025 will be used for hypothesis testing and CIs will be 100(1-2α) or 95% CI. If 
the null hypothesis of inferiority is rejected, testing for superiority will be performed.  
Full details on the statistical testing procedures along with supplementary and sensitivity 
analyses will be provided in the SAP. 
9.4.3 
Secondary Endpoint(s) 
In the Primary Study, key secondary endpoints will be assessed at Week 24, and Week 48 (for 
efficacy) or Week 52 (for safety). In the Extension Phase, additional exploratory endpoints will 
be evaluated at Week 72 (for efficacy) or Week 76 (for safety). Secondary endpoints include the 
following:  
• Mean change in BCVA (ETDRS Letters) from baseline (Day 1) by visit over time.  
• Proportion of participants who gain ≥ 5, ≥10, and ≥15 letters from baseline by visit over 
time. 
• Proportion of participants who lose ≥ 5, ≥10, and ≥15 letters from baseline by visit over time. 
• Proportion of participants with BCVA Snellen equivalent of 20/40 or better from baseline 
over time. 


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• Proportion of participants with BCVA Snellen equivalent of 20/200 or worse from baseline 
over time. 
• Mean change in OCT CST from baseline to Week 24 and over time.  
• Mean number of intravitreal injections over the duration of the study. 
• Mean number of intravitreal injections from Week 24 to Week 44 and from Week 48 to 
Week 68 (Extension Phase).  
• Mean time to first retreatment after the last monthly dose (from Week 24 to Week 44). 
• Distribution of intravitreal injections from Week 24 to Week 48 and from Week 48 to 
Week 68. 
• Probability of receiving intravitreal injections over time between Week 24 to Week 48. 
• Incidence of ocular and systemic AEs up to Week 24, Week 52, and Week 76. 
• Systemic pharmacokinetic profile (i.e., systemic exposure) over time (in the PK-evaluable 
population). 
• Systemic anti-drug antibody status over time (in the ADA-evaluable population). 
Unless stated otherwise, all analyses described will be performed on the ITT Population.  
For continuous key secondary efficacy endpoints, the between-group changes from baseline in 
BCVA at each time point will be computed and compared using t-tests, generalized linear 
models, mixed effects models, or other approaches as documented in the SAP. In addition, 
comparisons between groups determined by fixed effects of interest will be performed by 
analysis of covariance (ANCOVA) in which the dependent variable is the continuous variable of 
interest at the specified time point, the covariate is the baseline value of the variable of interest. 
Treatment group as well as stratification variables will be entered as fixed effects. Results of the 
t-test will be reported as 95% Cis for within group mean change from baseline. Results of 
ANCOVA will be reported as 95% CIs for the difference in adjusted means for the grouping 
determined by the fixed effects of interest. 
For categorical variables, the number and percentage of responders will be presented by 
treatment group for each time period and will be evaluated among treatment groups using chi-
square tests of proportions supplemented with logistic regression models. The distribution of the 
need for intravitreal injections over the individualized treatment period will be computed and 
compared using the Kolmogorov-Smirnov test for the equality of distribution functions. The 
probability of receiving intravitreal injections over time during the individualized treatment 
period will be compared using a generalized linear model or generalized linear mixed model with 
appropriate link function (e.g., logit, beta-binomial, etc.). 
Additional endpoints and full details on statistical considerations will be provided in the SAP. 




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10.0 
APPENDICES WITH SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
Appendix 2:  Clinical Laboratory Tests 
Appendix 3:  AEs and SAEs: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting 
Appendix 4:  Grading Scale for Assessment of Anterior Chamber Flare or Cells, Vitreous Cells 
or Haze 
Appendix 5: Unscheduled Safety Assessment Visits 
Appendix 6:  Contraceptive and Barrier Guidance 
Appendix 7:  Liver Safety 
Appendix 8:  Protocol Amendment History 
 
 


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10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines; 
• Applicable ICH Good Clinical Practice (GCP) Guidelines; and 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC; 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures; and 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies, and all other applicable local regulations. 
10.1.2 
Financial Disclosure and Financial Obligations 
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements to the appropriate 
regulatory authorities. In addition, Investigators must provide to the Sponsor a commitment to 
promptly update this information if any relevant changes occur during the investigation and for 1 
year following the completion of the study. 
Neither the Sponsor nor their CRO partner is financially responsible for additional testing or 
treatment of any medical condition that may be detected during the screening process. In 
addition, in the absence of specific arrangements, neither the Sponsor nor their CRO are 
financially responsible for further treatment of the participant’s disease. 


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10.1.3 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
If required by the IRB/EC, participants must be re-consented to the most current version of the 
ICF(s) during their participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
Participants who are re-screened are required to sign a new ICF if it has been more than 30 days 
from the initial consent date. 
The ICF will contain a separate section that addresses the use of remaining samples for optional 
exploratory research. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to participate 
in this optional research will not provide this separate signature. 
10.1.4 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.  
Participant medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. All laboratory specimens, evaluation forms, 
reports, and other records will be identified in a manner designed to maintain participant 


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confidentiality. All records will be kept in a secure storage area with limited access. Upon the 
participant’s permission, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
All information provided by the Sponsor, verbally and in writing, is confidential. The 
Investigator agrees not to disclose any such information without prior written permission of the 
Sponsor. This document may be disclosed to study personnel under the Investigator’s 
supervision and to the IRB under the condition that they also agree to maintain its 
confidentiality. Any supplemental information (e.g., protocol amendment) that may be added to 
this document is confidential and must also be handled accordingly. The information obtained 
from the Sponsor may be disclosed to obtain informed consent from participants who wish to 
participate in the study. 
Study documents provided by the Sponsor (protocols, IB, etc.) will be stored appropriately to 
ensure their confidentiality.  
The Investigator and all employees and co-workers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the Sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. 
10.1.5 
Committees Structure 
10.1.5.1 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will monitor the study conduct and safety 
on an ongoing basis. Members of the IDMC will be external to the Sponsor and will follow a 
charter that outlines the IDMC membership and responsibilities, the timing of IDMC meetings, 
the content of the analysis report for the IDMC meetings, and the communication with the 
Sponsor. The IDMC can recommend changes to the conduct of the study based on the evaluated 
data and may recommend stopping the study early for safety reasons. Nominal Type I error 
penalties for IDMC reviews will be outlined in the SAP. 
10.1.6 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 


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The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 10 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
10.1.7 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the eCRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.8 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 


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Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the Investigator 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
10.1.9 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multi-center studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
 














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10.4 
Appendix 4: Grading Scale for Assessment of Anterior Chamber Flare or Cells, 
Vitreous Cells or Haze.  
10.4.1 
Grading Scales for Anterior Chamber Cells or Flare 
The SUN Working Group Grading Scale for Anterior Chamber Cells 
Grade 
Cells in Field1 
0 
< 1 
0.5+ 
1-5 
1+ 
6-15 
2+ 
16-25 
3+ 
26-50 
4+ 
>50 
Abbreviations: SUN = Standardization of uveitis nomenclature. 
1 
Field size is a 1 mm by 1 mm slit beam. 
Source: (Jabs 2005) 
 
The SUN Working Group Grading Scale for Anterior Chamber Flare 
Grade 
Cells in Field1 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens details clear) 
3+ 
Marked (iris and lens details hazy) 
4+ 
Intense (fibrin or plastic aqueous)  
Abbreviations: SUN = Standardization of uveitis nomenclature. 
2 
Field size is a 1 mm by 1 mm slit beam. 
Source: (Jabs 2005) 
 
 
 


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10.4.2 
Grading Scale for Vitreous Cells 
Source: (Foster 2013) 
 
10.4.3 
Grading Scale for Vitreous Haze 
Score 
Description 
Clinical Findings 
0 
Nil 
None 
1 
Minimal  
Posterior pole clearly visible 
2 
Mild 
Posterior pole details slightly hazy 
3 
Moderate 
Posterior pole details very hazy 
4 
Marked 
Posterior pole details barely visible 
5 
Severe 
Fundal details not visible 
Source: (Nussenblatt 1985) 
 
Grade 
Description 
0 
No Cells 
½+  
1-10 
1 + 
11-20 
2 + 
21- 30 
3 + 
31 - 100 
4+ 
Greater than 100 


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10.5 Appendix 5: 
Unscheduled Safety Assessment Visits 
Assessments performed at unscheduled safety visits are at the discretion of the Investigator. The 
following safety assessments are recommended: 
• Vital signs (blood pressure, respiration rate, pulse, temperature); 
• Hematology, serum chemistry panel, and coagulation panel; 
• Best corrected visual acuity (BCVA); 
• Slit-lamp examination (both eyes); 
• Tonometry (both eyes); 
• Indirect ophthalmoscopy (both eyes); 
• Adverse events; 
• Concurrent ocular procedures; and 
• Concomitant medications. 
The causality of adverse events is to be evaluated by a masked physician. 
 
 


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10.6 
Appendix 6: Contraceptive and Barrier Guidance 
10.6.1 
Definitions 
Women of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal female with one of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Müllerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
Postmenopausal Female 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation 
with more than one FSH measurement is required. The Screening Visit FSH will be processed 
using the chemistry tube and the Day 1 FSH will need to be collected separately and sent to the 
central lab for analysis. A pregnancy test is required until both FSH measurements have been 
collected and results have been received that verify the post-menopausal state of the female 
participant. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
estrogen hormonal highly effective contraception methods if they wish to continue their HRT 


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during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
10.6.2 
Contraception Guidance 
Participants who use oral contraceptives, HRT, or other maintenance therapy should continue 
their use. 
1) For women of childbearing potential: agreement to remain as abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per 
year during the treatment period 
 
  
a. Examples of contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation, male sterilization, established, proper use 
of hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices and copper intrauterine devices. 
b. Contraception methods that do not result in a failure rate of <1% per year 
such as cap, diaphragm, or sponge with spermicide, or male or female 
condom with or without spermicide, are not acceptable. 
c. The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
or postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
2) For men: agreement to remain abstinent or use contraceptive measures and agreement to 
refrain from donating sperm, as defined below: 
a. With female partners of childbearing potential, men must remain abstinent 
or use a condom plus an additional contraceptive method that together 
result in a failure rate of < 1% per year during the treatment period 
 
 after the last dose 
of study intervention. Men must refrain from donating sperm during this 
same time period. 
10.6.3 
Collection of Pregnancy Information 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a participant's 
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• The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor, as described in Section 8.3.4. 
While the Investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive any study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure.  
 
 
 


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10.7 
Appendix 7: Liver Safety  
Investigators must report to the Sponsor immediately (within 24 hours) the following laboratory 
findings as an AE indicative of severe liver injury (as defined by Hy’s Law): 
• Treatment-emergent ALT or AST more than 3 times the Upper Limits of Normal (ULN) in 
combination with an elevated total bilirubin (more than 2 times the ULN) 
• Treatment-emergent ALT or AST more than 3 times the ULN in combination with clinical 
jaundice 
The most appropriate diagnosis or (if the diagnosis cannot be established) the abnormal 
laboratory values should be recorded in the eCRF. 
 
 
 


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10.8 
Appendix 8: Protocol Amendment History 
The amendment history for Protocol KS301P103 is provided in Table 5. 
Table 5: 
Protocol KS301P103: Amendment History 
Version 
Version Date 
Description 
2.0 
02 June 2021 
Changes from Version 1.1 include the following: 
• 
Minor editorial and administrative revisions;  
• 
Addition of a 20-week Extension Phase; and 
• 
 
1.1 
22 July 2020 
Changes from Version 1.0 include the following: 
• 
Minor editorial revisions to improve consistency, grammar, and 
readability; and  
• 
Administrative revisions based on IRB pre-submission feedback of 
Version 1.0. 
1.0 
16 June 2020 
Original protocol; used for pre-submission review with a US Central IRB. 
This version was not submitted to any health authorities, nor was it 
implemented. 
 


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11.0 
REFERENCES 
1. 
Boyer D, Heier J, Brown DM, et al. 2012. Vascular Endothelial Growth Factor Trap-Eye 
for Macular Edema Secondary to Central Retinal Vein Occlusion. Ophthalmology, 119: 
1024-32. 
2. 
Brown DM, Campochiaro PA, Singh RP, et al. 2010. Ranibizumab for Macular Edema 
following Central Retinal Vein Occlusion. Ophthalmology, 117: 1124-33.e1. 
3. 
Callizo J, Ziemssen F, Bertelmann T, et al. 2019. Real-World Data: Ranibizumab 
Treatment For Retinal Vein Occlusion In The OCEAN Study. Clinical Ophthalmology, 
Volume 13: 2167-79. 
4. 
Campochiaro PA, Heier JS, Feiner L, et al. 2010. Ranibizumab for Macular Edema 
following Branch Retinal Vein Occlusion. Ophthalmology, 117: 1102-12.e1. 
5. 
Campochiaro PA, Clark WL, Boyer DS, et al. 2015. Intravitreal Aflibercept for Macular 
Edema Following Branch Retinal Vein Occlusion. Ophthalmology, 122: 538-44. 
6. 
Cheung N, Mitchell P, and Wong TY. 2010. Diabetic retinopathy. The Lancet, 376: 124-
36. 
7. 
Christoforidis JB, Briley K, Binzel K, et al. 2017. Systemic biodistribution and 
intravitreal pharmacokinetic properties of bevacizumab, ranibizumab, and aflibercept in a 
nonhuman primate model. Investigative ophthalmology & visual science, 58: 5636-45. 
8. 
Cugati S. 2006. Ten-Year Incidence of Retinal Vein Occlusion in an Older Population. 
Archives of Ophthalmology, 124: 726. 
9. 
Flaxel CJ, Adelman RA, Bailey ST, et al. 2020. Retinal Vein Occlusions Preferred 
Practice Pattern®. Ophthalmology, 127: P288-P320. 
10. 
Foster CS, and Vitale AT. 2013. Diagnosis & Treatment of Uveitis (JP Medical Ltd). 
11. 
Gragoudas ES, Adamis AP, Cunningham Jr ET, et al. 2004. Pegaptanib for neovascular 
age-related macular degeneration. New England Journal of Medicine, 351: 2805-16. 
12. 
Holz FG, Roider J, Ogura Y, et al. 2013. VEGF Trap-Eye for macular oedema secondary 
to central retinal vein occlusion: 6-month results of the phase III GALILEO study. British 
Journal of Ophthalmology, 97: 278-84. 
13. 
Holz FG, Sadda SR, Busbee B, et al. 2018. Efficacy and safety of lampalizumab for 
geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 
randomized clinical trials. JAMA ophthalmology, 136: 666-77. 
14. 
Homayouni M. 2009. Vascular endothelial growth factors and their inhibitors in ocular 
neovascular disorders. Journal of ophthalmic & vision research, 4: 105. 
15. 
Hykin P, Prevost AT, Vasconcelos JC, et al. 2019. Clinical Effectiveness of Intravitreal 
Therapy With Ranibizumab vs Aflibercept vs Bevacizumab for Macular Edema 
Secondary to Central Retinal Vein Occlusion. JAMA ophthalmology, 137: 1256. 


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16. 
Jabs D, Nussenblatt R, and Rosenbaum J. 2005. Standardization of uveitis nomenclature 
for reporting clinical data. Results of the First International Workshop. American Journal 
of Ophthalmology, 140: 509-16. 
17. 
Johnson MW. 2009. Etiology and Treatment of Macular Edema. American Journal of 
Ophthalmology, 147: 11-21.e1. 
18. 
Klein R, Klein BE, Moss SE, et al. 2000. The epidemiology of retinal vein occlusion: the 
Beaver Dam Eye Study. Transactions of the American Ophthalmological Society, 98: 
133. 
19. 
Klein R. 2008. The 15-Year Cumulative Incidence of Retinal Vein Occlusion. Archives 
of Ophthalmology, 126: 513. 
20. 
McAllister IL. 2011. Central retinal vein occlusion: a review. Clinical & Experimental 
Ophthalmology, 40: 48-58. 
21. 
Morley MG, and Heier JS. 2009. "Venous Obstructive Disease of the Retina." In 
Ophthalmology, 597-605. Elsevier. 
22. 
Nussenblatt RB, Palestine AG, Chan C-C, et al. 1985. Standardizatlon of Vitreal 
inflammatory Activity in Intermediate and Posterior Uveitis. Ophthalmology, 92: 467-71. 
23. 
Park SJ, Choi Y, Na YM, et al. 2016. Intraocular Pharmacokinetics of Intravitreal 
Aflibercept (Eylea) in a Rabbit Model. Invest Ophthalmol Vis Sci, 57: 2612-7. 
24. 
Pielen A, Feltgen N, Isserstedt C, et al. 2013. Efficacy and safety of intravitreal therapy 
in macular edema due to branch and central retinal vein occlusion: a systematic review. 
PLoS One, 8. 
25. 
Rubio RG, and Adamis AP. 2016. 'Ocular angiogenesis: vascular endothelial growth 
factor and other factors.' in, Retinal Pharmacotherapeutics (Karger Publishers). 
26. 
Schmidt-Erfurth U, Garcia-Arumi J, Gerendas BS, et al. 2019. Guidelines for the 
management of retinal vein occlusion by the European Society of Retina Specialists 
(EURETINA). Ophthalmologica, 242: 123-62. 
27. 
Song P, Xu Y, Zha M, et al. 2019. Global epidemiology of retinal vein occlusion: a 
systematic review and meta-analysis of prevalence, incidence, and risk factors. Journal of 
global health, 9. 
 

SAP_001.pdf: 
Official Title:   
A Prospective, Randomized, Double-masked, Active
Comparator-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate
the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal
Aflibercept in Participants with Visual Impairment Due to Treatment-naïve
Macular Edema Secondary to Retinal Vein Occlusion (RVO)
NCT Number:  
NCT04592419
Document Date:  
SAP Version 1.0, 22 June 2022






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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .............................................................................................1 
SPONSOR SIGNATORY .............................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF TABLES .........................................................................................................................5 
LIST OF ABBREVIATIONS .......................................................................................................6 
1.0 
INTRODUCTION..............................................................................................................8 
2.0 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................8 
3.0 
INVESTIGATIONAL PLAN ...........................................................................................9 
3.1 
Study Design ............................................................................................................9 
3.2 
Disease Activity Assessment Criteria ....................................................................10 
3.3 
Study Interventions ................................................................................................11 
3.4 
Randomization and Stratification ..........................................................................11 
4.0 
TYPES OF PLANNED ANALYSES .............................................................................11 
4.1 
Data Monitoring Committee Analyses ..................................................................11 
4.2 
Interim Analyses ....................................................................................................11 
4.3 
Primary Analysis ....................................................................................................11 
4.3.1 
Timing of the Primary Analysis ............................................................11 
4.3.2 
Data to be Analyzed for the Primary Analysis Period ..........................12 
4.4 
Individualized Treatment Period (ITP) Analysis ...................................................12 
4.4.1 
Timing of the ITP Analysis ...................................................................12 
4.4.2 
Data to be Analyzed for the ITP ...........................................................12 
4.5 
Open Label Extension Phase (OLEP) Analysis .....................................................13 
5.0 
GENERAL STATISTICAL METHODS ......................................................................13 
5.1 
Reporting Conventions ..........................................................................................13 
5.2 
Standard Calculations ............................................................................................14 
5.3 
Study Definitions and Derived Variables ..............................................................15 
5.3.1 
Patient Baseline Values .........................................................................15 
5.4 
Analysis Sets ..........................................................................................................15 
5.4.1 
Randomized...........................................................................................15 
5.4.2 
Safety Analysis Set (SAF) ....................................................................15 
5.4.3 
Safety Analysis Set (SAFOLE) .............................................................15 
5.4.4 
Full Analysis Set Week 24 (FASW24) .................................................15 


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5.4.5 
Full Analysis Set Week 48 (FASW48) .................................................16 
5.5 
Examination of Subgroups .....................................................................................16 
5.6 
Multiple Comparisons/Multiplicity .......................................................................17 
5.7 
Multicenter Studies ................................................................................................17 
5.8 
Analysis Visit .........................................................................................................17 
5.9 
Disposition of Subjects ..........................................................................................18 
5.10 
Demographic and Other Baseline Characteristics .................................................18 
5.10.1 
Demographics and Baseline Characteristics .........................................18 
5.10.2 
Ocular and Other Medical History ........................................................19 
5.10.3 
Prior and Concomitant Medications/Procedures ...................................20 
5.11 
Protocol Deviations ................................................................................................21 
6.0 
EFFICACY ANALYSES ................................................................................................21 
6.1 
Primary Efficacy Analysis .....................................................................................21 
6.1.1 
Primary Estimand ..................................................................................21 
6.1.2 
Analysis of Primary Efficacy Endpoint ................................................23 
6.1.3 
Sensitivity Analysis 1 ............................................................................24 
6.1.4 
Tipping Point Sensitivity Analysis of the Primary Endpoint ................24 
6.2 
Secondary Efficacy Analyses ................................................................................25 
6.2.1 
Analysis of Binary Data ........................................................................25 
6.3 
Subgroup Analyses ................................................................................................28 
6.4 
Exploratory Analyses .............................................................................................28 
7.0 
SAFETY EVALUATION ................................................................................................28 
7.1 
Exposure to Study Medication ...............................................................................28 
7.2 
Adverse Events ......................................................................................................29 
7.3 
Deaths, Serious Adverse Events, and other Significant Adverse Events ..............30 
7.4 
Pregnancies ............................................................................................................30 
7.5 
Intraocular Pressure ...............................................................................................30 
7.6 
Clinical Laboratory Evaluations ............................................................................30 
7.7 
Vital Signs ..............................................................................................................30 
8.0 
SAMPLE SIZE CONSIDERATIONS ...........................................................................31 
9.0 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ..................................................................................................31 
10.0 
REFERENCES .................................................................................................................32 
11.0 
APPENDICES ..................................................................................................................32 
Appendix 1: Schedule of Activities ...................................................................................33 




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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ANCOVA 
Analysis of covariance 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATE 
Arteriothromboembolic 
BCVA 
Best-corrected visual acuity 
BP 
Blood pressure 
BRVO 
Branch retinal vein occlusion 
CMH 
Cochran-Mantel-Haenszel  
CNV 
Choroidal Neovascularization 
CRVO 
Central retinal vein occlusion 
CSR 
Clinical Study Report 
CST 
Central Subfield Thickness 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ET 
Early Termination 
ETDRS 
Early treatment diabetic retinopathy study 
FA 
Fluorescein angiography 
FASW24 
Full-Analysis Set Week 24 
FASW48 
Full-Analysis Set Week 48 
FDA 
Food and Drug Administration 
FP 
Fundus photography 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
ILM 
Inner Limiting Layer 
IND 
Investigational New Drug (application) 
ICE 
Intercurrent event 
IOI 
Intraocular inflammation 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITP 
Individualized Treatment Period 
LOQ 
Level of Quantification 
MAR 
Missing at Random 
ME 
Macular Edema 
MNAR 
Missing not at Random 
MedDRA 
The Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
OCT 
Optical Coherence Tomography 


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Abbreviation 
Definition 
OLEP 
Open Label Extension Phase 
Q8W 
Every eight weeks 
RPE 
Retinal Pigment Epithelium 
RVO 
Retinal vein occlusion 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAFOLE 
Safety Analysis Set Open-Label Extension 
SAP 
Statistical Analysis Plan 
ULN 
Upper Limits of Normal 
VA 
Visual acuity 
VEGF 
Vascular Endothelial Growth Factor 
 
 
 






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The Primary Study is divided into a 21-day screening period (Days -21 to -1) and two efficacy 
and safety assessment periods, as follows: 
• Day 1 to Week 24, which corresponds to the fixed interval treatment period of Day 1 
through Week 20 followed by assessment of the primary efficacy and safety endpoints at 
Week 24;  
• KSI-301 5 mg: Following two initial doses at Day 1 and Week 4, patients will receive 
one additional dose every 8 weeks (i.e., at Week 12 and Week 20) and will receive 
sham injections, to preserve study masking, at Week 8 and Week 16 
• Aflibercept 2 mg: Patients will receive treatment every 4 weeks, i.e., at Day 1, Week 
4, Week 8, Week 12, Week 16, and Week 20 
• Week 24 to Week 52, which corresponds to the individualized treatment period (Week 24 
to Week 44) followed by assessment of the secondary efficacy endpoints at Week 48 and 
the follow-up safety endpoints at Week 52. 
• Starting at Week 24, patients in both treatment arms will be assessed monthly (every 
4 weeks) and will receive additional administration of KSI-301 5 mg or aflibercept 2 
mg, as per their assigned treatment arm, according to protocol-defined disease 
activity assessment criteria. 
• These criteria are based on changes in BCVA and/or OCT central subfield thickness 
(CST). The minimum interval between active treatments is 4 weeks (± 7 days) for all 
treatment arms. There are no mandatory active injections at any assessment visits and 
thus, no upper limit to the treatment interval. To preserve study masking, sham 
injections are administered at visits in which no active treatment is indicated.  
Patients who complete the Primary Study are eligible to participate in an optional, open-label, 
single-arm Extension Phase (Week 48 – Week 72).  There is no active comparator in this open-
label portion of the study (Week 48 to Week 68).  The Extension Phase will evaluate the long-
term efficacy and safety of KSI-301 5 mg.  Patients who received aflibercept during the first 48-
week of the Primary Study will receive KSI-301 5 mg in the Extension Phase to enable 
collection of information on the effects of KSI-301 5 mg in patients who had previously (i.e. 
from Day 1 through Week 44) received a defined course of prior anti-VEGF therapy for ME 
secondary to BRVO/CRVO.  
 
3.2 
Disease Activity Assessment Criteria 
In the individualized treatment period, protocol-defined disease activity assessments are 
performed every 4 weeks, starting at Week 24 (See Appendix 1 for details).  The disease activity 
assessment criteria are as follows: 


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• Increase in OCT CST ≥ 50 µm compared to lowest previous measurement AND a 
decrease in BCVA of ≥ 5 letters compared to the average of the two best previous BCVA 
assessments, due to worsening of RVO disease activity, or 
• Increase in OCT CST ≥ 75 µm compared to lowest previous measurement due to 
worsening of RVO disease activity. 
 
3.3 
Study Interventions 
Study interventions are summarized in the Protocol Table 2. 
 
3.4 
Randomization and Stratification 
Patients who meet all inclusion criteria and none of the exclusion criteria will be centrally 
assigned to a randomized study intervention using an Interactive Response Technology (IRT) 
system.  Randomization will be stratified by 
 
 Randomization uses a permuted block design.  
 
4.0 
TYPES OF PLANNED ANALYSES 
4.1 
Data Monitoring Committee Analyses  
An Independent Data Monitoring Committee (IDMC) will monitor study conduct and safety on 
an ongoing basis.  Members of the IDMC will be external to the Sponsor and will follow a 
charter that outlines the IDMC membership and responsibilities, the timing of IDMC meetings, 
the content of the analysis report for the IDMC meetings, and the communication with the 
Sponsor.  The IDMC can recommend changes to the conduct of the study based on the evaluated 
data and may recommend stopping the study early for safety reasons only as detailed in the 
charter.  
 
4.2 
Interim Analyses 
No interim analyses were planned or performed.  
4.3 
Primary Analysis 
4.3.1 Timing of the Primary Analysis 
The primary analysis will be performed when all patients have either completed the Week 24 
visit or have discontinued from the study prior to the Week 24 visit, whichever comes later, the 
data up to and including the Week 24 visit have been entered, cleaned and verified as 
appropriate, and the database for the primary analysis is frozen.  


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Safeguards will be put in place to ensure that the unmasking does not introduce operational 
biases in the conduct of the ongoing study.  Details of the unmasking plan are described in a 
separate document. 
4.3.2 Data to be Analyzed for the Primary Analysis Period 
The following data (up to Week 24) will be included in the primary analyses: 
• Demographics and Baseline Ocular and Non-Ocular Characteristics  
• Subject Disposition at Week 24 
• Primary Efficacy Analyses 
• Sensitivity and Subgroup Analyses for the Primary Efficacy Endpoint  
• Selected Secondary Efficacy Analyses up to Week 24 
• Interventions 
• Study Treatment and Exposure 
• Safety  
• AEs (including SAEs and AESIs), by Event Type (i.e., Study Eye, Fellow-Eye, 
Non-Ocular) 
• Clinical laboratory 
• Vital signs 
• Concomitant Medications and Procedures 
 
4.4 
Individualized Treatment Period (ITP) Analysis 
4.4.1 Timing of the ITP Analysis 
The analysis will be performed when all patients have either completed the Primary Study (Week 
52 visit) or have discontinued from the study prior to the Week 52 visit, whichever comes later, 
the data up to and including the Week 52 visit have been entered, cleaned and verified as 
appropriate, and the database for the individualized treatment period (ITP) analysis is frozen.   
4.4.2 Data to be Analyzed for the ITP 
The following data (up to Week 52) will be included in the analyses.   
• Subject Disposition at Week 48 
• Descriptive Efficacy Analyses up to Week 48 
• Interventions up to Week 48 
• Study Treatment and Exposure 
• Safety up to Week 52 
• Incidence of ocular and systemic AEs (including SAEs and AESIs) by Event Type 
(i.e,, Study Eye, Fellow-Eye, Non-Ocular) 
• Clinical laboratory 
• Vital signs 
• Concomitant Medications and Procedures 
 


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4.5 
Open Label Extension Phase (OLEP) Analysis 
The Analysis of the OLEP will be performed when all patients have either completed the Week 
76 visit or have discontinued from the study, and all data have been entered into the database, 
cleaned and verified as appropriate, and the database locked.  The same relevant endpoints as 
described in Section 4.4.2 will be subsequently analyzed in the OLEP. 
 
5.0 
GENERAL STATISTICAL METHODS 
SAS (SAS Institute Inc., Cary NC, USA) Version 9.4 or higher will be used for the study 
analyses. 
 
5.1 
Reporting Conventions 
Tables and figures will be summarized by treatment group. Tables summarizing demographics 
and other baseline characteristics will also include a column for all patients combined.  In 
general, all data collected and any derived data will be presented in subject data listings, for all 
randomized patients. Listings will be ordered by treatment group, subject number, and 
assessment or event date. The treatment groups will be displayed in the same order as the 
summary tables. The treatment groups presented in listings will be based on the planned 
assignment, unless otherwise noted. 
In general, continuous variables will be summarized to indicate the study population sample size 
(N), number of subjects with available data (n), mean, SD, median, 25th (Q1) and 75th (Q3) 
quartiles, minimum, and maximum values.  Categorical variables will be summarized by the 
population size (N), number of subjects with available data (n), number of subjects in each 
category, and the percentage of subjects in each category.  Unless otherwise noted, the 
denominator to determine the percentage of subjects in each category will be based on the 
number of subjects with available data.  The denominator for percentages for incidence data 
(such as adverse events) will be based on the number of subjects in the analysis population “at 
risk.”  Select ordinal data may be summarized using both descriptive statistics and counts and 
percentages of subjects in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Percentages that round down to 0 or 
up to 100% will be displayed as “<0.1%” and “>99.9%”, respectively. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form e.g., on the electronic case report form 
(eCRF) and are outlined as follows: 
The mean and median will be rounded to an additional decimal place than the precision of the 
variable of summarization;  


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Measures of variability (e.g., SD, SE) will be rounded to two additional decimal places than the 
precision of the variable of summarization; and 
Minimum and maximum values will be presented using the same precision as the variable of 
summarization. 
Other statistics (e.g., CIs) will be presented using the same general rules outlined above or 
assessed for the most appropriate presentation based on the underlying data. 
Unless noted otherwise, statistical significance testing will be two-sided and performed using 
α=0.05. Confidence intervals (CIs) will be calculated at the 95% level, reflecting a type I error 
rate of 0.05. P-values will be reported for all statistical tests, rounded to four decimal places. P-
values less than 0.0001 will be displayed as “<0.0001”; p-values greater than 0.9999 will be 
displayed as “>0.9999”.  
 
5.2 
Standard Calculations 
Where appropriate, the calculated study day will be presented with the assessment or event date 
on subject data listings.  Study day will be determined as: 
• The assessment/event date minus the date of first dose of study drug, if the 
assessment/event date is prior to the date of first dose; and 
• The assessment/event date minus the date of first dose of study drug, plus one, if the 
assessment/event date is on or after the date of first dose. 
Start and stop dates will be imputed when partial dates are present as needed, to determine 
treatment emergent events and concomitant medications/procedures.  No imputations will be 
done for a completely missing start/stop date or for subjects who did not receive study treatment. 
Start dates with a missing day but with month and year available will be imputed such that: 
• If the provided month and year match the month and year for that subject’s first dose 
date, then the Day 1 date will be used. 
• In all other cases the 1st of the month will be used with the provided month and year. 
Start dates with a missing day and month but with available year will be imputed such that: 
• If the provided year matches the year for that subject’s first dose date, then the first dose 
date will be used. 
• In all other cases the 1st of January will be used with the provided year. 
Stop dates will be imputed as follows: 
• Missing day with a provided year and month will use the last day of the month. 
• Missing day and month with provided year will use December 31. 
If the imputed stop date is greater than the last study date for the subject, then the imputed date 
will be replaced with the last available event date for the subject in the study. 


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Other variables requiring calculations will be derived using the following formulas: 
• Days: A duration between two dates expressed in days will be calculated using the 
following conventions: 
- 
Later date – earlier date + 1. 
• Months: A duration expressed in months will be calculated by dividing the duration in 
days by (365.25 /12). 
• Years: A duration expressed in years will be calculated by dividing the duration in days 
by 365.25. 
 
5.3 
Study Definitions and Derived Variables 
5.3.1 Patient Baseline Values 
Baseline values are defined as the most recent values prior to the first dose of study treatment.  
Baseline (Week 48) for aflibercept patients who opt to continue in the open-label extension 
phase of the study and receive KSI-301 is defined as the last value prior to the first dose of KSI-
301 5 mg. 
 
5.4 
Analysis Sets 
The efficacy and safety analyses that are specified in Sections 6.0 and 7.0 will utilize the 
Analysis Sets as specified in this section.   
5.4.1 Randomized  
The Randomized Analysis Set includes all patients who were randomized into one of the study 
arms.  For analyses based on this population, patients will be analyzed according to the study 
intervention assigned at randomization.  
5.4.2 Safety Analysis Set (SAF) 
The Safety Analysis Set includes all patients who received any study treatment.  Subjects will be 
analyzed according to the study treatment they actually received.  
5.4.3 Safety Analysis Set (SAFOLE) 
The Safety Analysis Set SAFOLE includes all patients who received any study treatment and 
who have at least one study treatment in the optional Open-Label Extension phase.  Subjects will 
be analyzed according to the study treatment they actually received. 
5.4.4 Full Analysis Set Week 24 (FASW24) 
The Full Analysis Set Week 24 (FASW24) includes all patients who received any study 
treatment (KSI-301 or aflibercept) during the fixed interval treatment period.  Subjects will be 
analyzed according to their randomized treatment.  The FASW24 will be used in the primary 
analyses of efficacy. 


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5.4.5 Full Analysis Set Week 48 (FASW48) 
The Full Analysis Set Week 48 (FASW48) includes all patients who did not discontinue study 
treatment prior to week 24 and have at least one BCVA assessment during the individualized 
treatment period.  Subjects will be analyzed according to the treatment received.  The FASW48 
will be used for descriptive efficacy analyses of the ITP. 
5.5 
Examination of Subgroups 
The primary efficacy endpoints will be summarized in the following subgroups of baseline 
characteristics. 
Table 2: Subgroups 
 
Characteristics 
Subgroup 
Age 
• 
< 65 years of age 
• 
≥ 65 years of age 
• 
< 75 years of age 
• 
≥ 75 years of age 
Sex 
• 
Female 
• 
Male 
Ethnicity 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
RVO subtype* 
• 
CRVO 
• 
BRVO 
BCVA* 
• 
BCVA: ≥ 70 letters 
• 
BCVA: 69-50 letters 
• 
BCVA: < 50 letters 
Disease duration* 
• 
< 3 months 
• 
≥ 3 months 
Geographic location* 
• 
North America 
• 
Rest of World 
Race 
• 
White 
• 
Black or African American 
• 
Asian 
• 
American Indian or Alaska Native 
• 
Native Hawaiian or other Pacific 
Islander 
• 
Other 
Lens status 
• 
Phakic  
• 
Pseudophakic 
• 
Aphakic 
 
Other subgroup analyses may be explored. 
 


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5.6 
Multiple Comparisons/Multiplicity 
 
 
 
 
 
  
 
5.7 
Multicenter Studies 
This is a multicenter, international study.  Efficacy data collected from all study sites will be 
pooled for data analysis.  The effect of study site on the efficacy analysis results may be 
explored, as needed. 
 
5.8 
Analysis Visit  
For efficacy analyses, unscheduled or early termination visits will be assigned a study day and 
then mapped to the appropriate analysis window as detailed in Table 3.  In the event where more 
than one record falls in the same analysis window, the following rules will be used in sequential 
order to determine the record that will be used for data analysis: 
• If there is a scheduled visit in the analysis window, then the scheduled visit’s data will be 
used. 
• If there is no scheduled visit in the analysis visit window, the record that is the closest to 
the scheduled study day at a given visit will be used. 
• If there is no scheduled visit in the analysis visit window and there is a tie between the 
two records with regards to the number of days before and after the scheduled study day, 
the later record will be used. 
Analysis visit windows will not apply to subject data listings.  Prior to any missing data 
imputations or analysis, the analysis visit windows will be applied to the data. 
Table 3: Windows for Unscheduled Visit 
Nominal Visit 
Scheduled 
Study Day 
Starting Day for 
Nominal Visit 
Ending Day for 
Nominal Visit 
Day 1 
1 
1 
1 
Week 1 
7 
4 
14 
Week 4 
28 
15 
42 
Week 8 – Week 76 
Week×7 
(Week×7)-13 
(Week×7)+14 
Note: Nominal visits are at Day 1, Weeks 1, 4, 8, … every 4 weeks from Week 8 until Week 76. 
 


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5.9 
Disposition of Subjects 
Subject disposition will be summarized by treatment group, RVO type (BRVO, 
) and 
overall.  The following will be summarized: 
• First 24 Weeks 
o The number of patients screened 
o The number of patients randomized 
o The number of subjects (%) in the Full Analysis set (FAS24) 
o The number (%) in the Safety set (SAF)  
o The number (%) completing the study treatment  
o The number (%) discontinuing the study treatment and the reasons for discontinuation 
of study treatment 
 
• First 48 Weeks 
o The number (%) in the FASW48  
o The number (%) completing the study treatment 
o The number (%) discontinuing study treatment early and the reasons for 
discontinuation of study treatment 
o The number (%) discontinuing from the study prior to week 48 and the reasons for 
discontinuation 
 
• Optional Open-Label Extension 
o The number (%) treated in the extension study 
o The number (%) completing the study treatment 
o The number (%) discontinuing study treatment early and the reasons for 
discontinuation 
o The number (%) discontinuing from the study early and the reasons for 
discontinuation 
 
Subject disposition will also be summarized separately for each study site.  Subject completion 
status, date of study completion/discontinuation, study day of discontinuation, and reason for 
discontinuation will be listed.  
Patients who did not meet inclusion or exclusion eligibility criteria will be listed. 
 
5.10 
Demographic and Other Baseline Characteristics 
5.10.1 Demographics and Baseline Characteristics 
The following demographics, baseline characteristics, and randomization stratification variables 
will be summarized by treatment group by treatment group, RVO type (BRVO,
) and 
overall for the randomized patients. 




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5.10.3 Prior and Concomitant Medications/Procedures 
All medications (ocular and non-ocular) will be coded using the World Health Organization 
(WHO) Drug Global Dictionary, Format B3 [Version September 2020 (or a later version if 
updated during the study)], Anatomical Therapeutic Chemical (ATC) Classification codes.  
Medications will be summarized by treatment group and overall for the SAF Analysis Set.  
Medication summaries will be presented by Anatomical Therapeutic Chemical (ATC) class level 
4 and preferred name.  In addition, ocular medications will be presented separately for the study 
eye and fellow eye. 
Prior medications and concomitant medications are defined as follows: 
• Prior medications are those taken prior to the start of the first dose of study treatment 
• Concomitant medications are those with  
• a start date on or before the last dose of study treatment and  
• a stop date after the first dose of study treatment or are ongoing at the end of the study 
 
See Section 5.2 for imputation of missing or partial dates.   
 
Prior and concomitant medications will be separately summarized by ocular and non-ocular for 
the SAF Analysis Set as follows: 
• The number and percentage of patients with at least one prior / concomitant medication / 
procedure will be presented. 
• The number and percentage of patients with at least one prior / concomitant medication / 
procedure within each ATC Level 4, and preferred name will be presented.   
• Patients reporting use of more than one medication / procedure at each level of 
summarization (any medication received, ATC class, and generic drug name) will be 
counted only once. 
• The summary will be sorted using numerical counts by descending order of Therapeutic 
Subgroup, then descending order of preferred name in the total column.  Where groups or 
terms tie these will be sorted alphabetically. 
 
Prior medications and concomitant medications (ocular and non-ocular) will be listed separately 
for the SAF Analysis Set.  
The following will be summarized and listed for concomitant medications and procedures: 
• Ocular (study eye and fellow eye separately) and non-ocular concomitant medications 
that were initiated before start of treatment.  
• Ocular (study eye and fellow eye separately) and non-ocular concomitant medications 
that were initiated after the start of treatment. 
• Medications prescribed after study treatment discontinuation for subjects who remain in 
the study will be listed separately.  
• Concomitant ocular procedures (study eye and fellow eye separately) administered while 
subjects were on study treatment will be summarized and listed.  


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• Concomitant study eye procedures administered after study treatment discontinuation for 
subjects who remain in the study will be listed separately. 
 
In the listings the relative start and stop day of prior / concomitant medication (ocular and non-
ocular) use will be calculated relative to the first dose date of study treatment and will be presented 
for those patients who received at least one dose of treatment.  If the concomitant medication is 
“Ongoing” it will be indicated as such in the listing and the relative stop day will not be calculated.  
Only original dates will be presented in the listing even though the relative day may be based on 
an imputed date. 
 
5.11 
Protocol Deviations 
All major protocol violations will be determined and categorized by the timing of analyses (see 
Section 4.0): 
• From start of the study to the data freeze for the Week 24 Primary Analysis  
• From the start of the study to the data freeze for the individualized treatment period (ITP) 
Analysis 
• From the ITP Analysis to the final database lock (OLEP) 
Major protocol deviations will be summarized by timeframe (see above), treatment group, RVO 
type (BRVO,
) and overall, for analysis sets of FASW24, FASW48, and SAFOLE, as 
appropriate.  The number and percentage of patients with any major protocol deviation as well as 
the number and percentage of patients with deviations within each category of major deviation 
will be presented.  The major protocol deviations will also be summarized by site.  Protocol 
deviations will be listed in a subject data listing.  
6.0 
EFFICACY ANALYSES 
6.1 
Primary Efficacy Analysis 
6.1.1 Primary Estimand 
6.1.1.1 
Target Population 
The population targeted by the scientific question is patients with visual impairment from 
macular edema due to RVO. 
The most relevant aspects of the study eligibility criteria for defining this population include the 
following key inclusion and exclusion criteria: 
Inclusion criteria 
1. Treatment-naïve macular edema and visual impairment of ≤ 6 months secondary to CRVO or 
BRVO. Patients with HRVO will also be considered eligible for this study and will be 
included as CRVO. Eyes classified as having CRVO or HRVO will comprise at least 20% 
and not more than 35% of the total planned sample size. 


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2. BCVA ETDRS letter score ≤ 80 and ≥ 25 (20/25 to 20/320 Snellen equivalent) in the Study 
Eye at Screening and confirmed at Day 1. 
3. CST of ≥ 320 microns on SD-OCT (Heidelberg Spectralis or equivalent on other OCT 
instruments) as determined by the Reading Center at the screening visit and confirmed by the 
Investigator at Day 1. 
4. Decrease in vision in the Study Eye determined by the Investigator to be primarily the result 
of macular edema secondary to RVO. 
Exclusion criteria 
1. Macular edema in the Study Eye considered to be secondary to a cause other than RVO (e.g. 
diabetic macular edema, Irvine-Gass syndrome). 
2. Active iris or angle neovascularization, neovascular glaucoma, neovascularization of the 
optic disc, retinal neovascularization or vitreous hemorrhage in the Study Eye. 
3. Significant media opacities, including cataract, in the Study Eye that might interfere with 
visual acuity, assessment of safety, optical coherence tomography or fundus photography. 
4. Prior vitrectomy in the Study Eye. 
5. Active retinal disease other than the condition under investigation in the Study Eye. 
6. Any history or evidence of a concurrent ocular condition present that in the opinion of the 
Investigator could require either medical or surgical intervention or affect macular edema or 
alter visual acuity during the study (e.g. vitreomacular traction). 
 
6.1.1.2 
Primary Efficacy Endpoint/Variable of Interest 
The primary efficacy variable of interest is BCVA, a continuous variable measured at each study 
visit using the ETDRS BCVA approach.  The primary efficacy endpoint is the mean change in 
BCVA from Day 1 to Week 24. 
6.1.1.3 
Hypotheses and Test 
The maximum clinically acceptable true difference between KSI-301 and aflibercept among 
RVO patients to be considered non-inferior is 4.5 ETDRS letters, i.e. the non-inferiority margin 
(NI) is 4.5 letters. 
Two analyses will be conducted: 
1. First, non-inferiority will be assessed in BRVO patients.  Hypothesis 1: 
H0: μK - μA ≤ -4.5 letters  
Vs 
HA: μK - μA > -4.5 letters 
Where μK and μA are the mean changes from baseline to the Week 24 BCVA in the KSI-301 
and aflibercept groups of in BRVO patients, respectively. 
 
If the lower limit of the two-sided 95.02% CI for the difference between the two means is >-
4.5 letters, NI will be demonstrated. 
 
2. If NI is demonstrated in BRVO patients, a second analysis will assess NI in BRVO+CRVO 
patients.  Hypothesis 2: 


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H0: μK - μA ≤ -4.5 letters  
Vs 
HA: μK - μA > -4.5 letters 
Where μK and μA are the mean changes from baseline to the Week 24 BCVA in the KSI-301 
and aflibercept groups of in BRVO+CRVO patients, respectively. 
 
If the lower limit of the two-sided 95.02% CI for the difference between the two means is >-4.5 
letters, NI will be demonstrated. 
The analyses will be conducted hierarchically to maintain a familywise Type I error rate of 
4.98%.  Each test within this family will be conducted at the 4.98% level if the preceding test 
was significant at the 4.98% level. 
Furthermore, superiority will be established if the lower limit of the two-sided 95.02% 
confidence interval for the treatment difference (KSI-301 – aflibercept) is greater than zero. 
 
6.1.1.4 
Intercurrent Events 
The following intercurrent events (ICEs) may impact the assessment of the primary efficacy 
endpoint: 
1. Deviations from key inclusion/exclusion criteria as defined above. 
2. Treatment misallocation (including sham or active treatment) of 1 or more study treatments. 
3. Use of prohibited medications in the study eye. 
4. Premature discontinuation from study treatment due to study eye adverse events or due to 
lack of efficacy. 
5. Premature discontinuation from study treatment due to events unrelated to study treatment 
such as malignancies, systemic infections, trauma, or other systemic adverse events that are 
not treatment-related, including discontinuations due to COVID-19. 
Intercurrent events will be classified by the Sponsor prior to treatment code unmasking to 
prevent potential bias.  Intercurrent events will be tabulated by treatment group.  Strategies for 
addressing the potential impact of these intercurrent events are described below. 
 
6.1.2 Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint will be estimated based on the FASW24, i.e., all randomized 
subjects who received at least one treatment injection in the first 24 weeks and using all available 
post baseline measurements up to Week 24 or until the subject discontinues study treatment.  The 
‘While on-Treatment’ policy will be applied for the primary endpoint. 
A Mixed Model for Repeated Measures (MMRM) will be used.  The model assumes missing at 
random (MAR) and uses all available data.  MMRM balances the benefits of preserving unbiased 
estimates because of randomization with the desire to obtain estimates for a comparison of true 
biological treatment effects. 
The model will include the change from baseline value as the dependent variable; treatment 
group, protocol scheduled visit, treatment × visit interaction as fixed effects; subject as a random 


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effect; and the randomization stratification factors (i.e., RVO subtype as assessed by the 
investigator [for Hypothesis 2 only], baseline BCVA, disease duration, and geographical 
location) as covariates.  Within-subject correlations will be assumed to follow an unstructured 
covariance matrix.  If the model assuming an unstructured covariance matrix does not converge, 
a heterogeneous compound symmetry structure or an AR(1) covariance structure will be fitted. 
 
6.1.3 Sensitivity Analysis 1 
A sensitivity analysis will be conducted to include the FASW24 patients who did not have any of 
the following intercurrent events: deviations from key inclusion/exclusion criteria as defined 
above, treatment misallocations as defined above, and use of prohibited medications in the study 
eye during the study treatment period. 
The sensitivity analysis based on this set is a type of ‘Hypothetical Policy’ strategy.  The same 
MMRM as described for the primary efficacy analyses will be used. 
 
6.1.4 Tipping Point Sensitivity Analysis of the Primary Endpoint 
A tipping point analysis where an offset (Delta based imputation penalty) is applied to the MAR 
imputation distribution applying a range of BCVA penalties ranging from 0.5 letter to 4.5 letters 
decrease (-4.5 is the non-inferiority threshold) in 0.5 letter decrements. The Delta-based multiple 
imputations method will pertain to the following FASW24 patients: 
1. Subjects randomized to the KSI-301 arm with missing data considered missing not at random 
(MNAR), i.e. subjects who prematurely discontinue from study treatment due to study eye 
adverse events or due to lack of efficacy.  
2. All KSI-301 treated patients with missing Week 24 assessments.  
The following steps will be undertaken (see Appendix 4 for the SAS syntax used and additional 
details).  
Step 1a: A fully conditional imputation model (FCS) with predictive mean matching will be 
applied to all subjects’ missing change from baseline BCVA values.  
Step 1b: A delta-adjusted imputation will be applied to missing values in step 1a for missing 
subjects’ change from baseline BCVA values post study treatment discontinuation.  
Step 2: a mixed model identical to the one used for the primary analysis will be run for each 
imputed data set. 
Step 3: the mixed model mean treatment difference estimates from step 2 for all imputations are 
combined and Rubin’s method is applied to derive an estimate of the Week 24 treatment 
difference. 
Steps 1-3 are repeated for each of the two potential MNAR groups in the KSI-301 treatment arm 
and for the range of penalties in the BCVA change from baseline. The tipping point will be the 


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penalty value that will render the lower bound of the confidence interval for mean treatment 
differences to be greater than -4.5 letters.   
 
6.2 
Secondary Efficacy Analyses 
As specified in Section 4.0, the Primary Analysis will evaluate the efficacy of KSI-301 compared 
to aflibercept from Day 1 up to Week 24.  The ITP Analysis will evaluate the KSI-301 efficacy 
comparing to aflibercept using the secondary endpoint data from Day 1 up to Week 48.  The 
OLEP Analysis will evaluate the KSI-301 efficacy using the secondary endpoint data from 
Week 48 up to Week 68. 
Table 4 lists the secondary efficacy endpoints, efficacy variable derivations, reporting statistics 
and analysis methods for the Primary Analysis and the ITP Analysis.   
In the OLEP, because aflibercept treated patients will be treated with KSI-301 from Week 48 to 
week 68, the baseline for these patients will be recalculated for the purpose of data analysis in 
the extension phase.  In the OLEP Analysis, the treatment group will be dropped from statistical 
models, as appropriate. 
6.2.1 Analysis of Binary Data 
The number and percentage of patients who gain or lose ≥ 5, ≥10 and ≥15 letters from baseline 
over time will be summarized by treatment group and visit, as will the number and percentage of 
patients with BCVA of 20/40 or better Snellen equivalent, BCVA or 20/200 or worse Snellen 
equivalent, and OCT CST < 325 microns.  The group proportions of “responders” for these 
categories of binary outcomes will be compared between KSI-301 and aflibercept using the 
Cochran–Mantel–Haenszel (CMH) test by adjusting the baseline randomization stratification 
factors (Section 3.4).   
The number (%) of patients who fall into these categories from baseline at each post-baseline 
visit will be presented by treatment group, along with the weighted percentages.  In addition, the 
weighted percentages difference between the KSI-301 and aflibercept (i.e., KSI-301 – 
aflibercept) and 95% CI of the difference will be presented by protocol specified visit.  
Percentages are calculated as 100×number of “responders”/number of patients with data at a 
visit.  Weighted percentages are based on weighted average of observed estimates across strata 
using CMH weights.  The CI are based on the normal approximation to the binomial proportions. 
 


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Table 4: Secondary Efficacy Endpoints and Analysis Methods 
Secondary Efficacy Endpoint 
Variable Derivation  
[Source] 
Summary Statistics  
[Analysis Set] 
Method of Analysis 
Mean change from baseline in 
BCVA (ETDRS Letters) by 
visit over time  
Continuous endpoint:  
Change from Day 1 to each time point  
[Visual Acuity Score/EDC] 
LS Mean difference in change 
from baseline at each time 
point 
[FASW24], up to Wk 24 
[FASW48], up to Wk 48 
[SAFOLE], Wk 48 to Wk 68 
Using the MMRM model (Section 6.1.2) 
used for deriving the primary endpoint 
estimate 
Proportion of patients who gain 
≥ 5, ≥10 and ≥15 letters from 
baseline over time 
 
Binary endpoints:  
patients had a BCVA gain ≥ 5 (yes/no); 
patients had a BCVA gain ≥ 10 (yes/no); 
patients had a BCVA gain ≥ 15 (yes/no).  
[Visual Acuity Score/EDC] 
Difference in proportions (%) 
and 95% CI at each time point  
[FASW24], up to Wk 24 
[FASW48], up to Wk 48 
[SAFOLE], Wk 48 to Wk 68 
Stratified analysis of the binary endpoint 
using CMH adjusting for randomization 
stratification factors (Section 6.2.1) 
Proportion of patients who lose 
≥ 5, ≥10 and ≥15 letters from 
baseline over time 
Binary endpoints:  
patients had a BCVA loss ≥ 5 (yes/no); patients 
had a BCVA loss ≥ 10 (yes/no); patients had a 
BCVA loss ≥ 15 (yes/no).  
[Visual Acuity Score/EDC] 
Proportion of patients with 
BCVA Snellen equivalent of 
20/40 or better over time (≥69 
ETDRS letters) 
Binary endpoints:  
patients had a BCVA Snellen 20/40 or better  
(yes/no) 
[Visual Acuity Score/EDC] 
Proportion of patients with 
BCVA Snellen equivalent of 
20/200 or worse (≤ 38 ETDRS 
letters) over time 
Binary endpoints:  
patients had a BCVA Snellen 20/200 or worse  
(yes/no) 
[Visual Acuity Score/EDC] 
Proportion of patients with 
absence of macular edema 
(defined as OCT CST < 325 
microns) over time 
Binary endpoints: 
Patient had a OCT CST < 325 microns (yes/no) 
[
] 


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Secondary Efficacy Endpoint 
Variable Derivation  
[Source] 
Summary Statistics  
[Analysis Set] 
Method of Analysis 
Mean change in OCT central 
subfield retinal thickness (CST) 
from baseline to Week 24 and 
over time 
Continuous Endpoint: 
Change from baseline to each time point  
[
]  
 
LS Mean difference in change 
from baseline to each time 
point 
[FASW24], up to Wk 24 
[FASW48], up to Wk 48 
[SAFOLE], Wk 48 to Wk 68 
MMRM (similar to Section 6.1.2) 
adjusting for baseline CST, with time, 
treatment, and time*treatment 
interaction and randomization 
stratification as factors 
Unstructured covariance matrix 
Mean change in OCT center 
point retinal thickness (CPT) 
from baseline to Week 24 and 
over time 
Continuous Endpoint: 
Change from baseline to each time point  
[
]  
 
LS Mean difference in change 
from baseline to each time 
point 
[FASW24], up to Wk 24 
[FASW48], up to Wk 48 
[SAFOLE], Wk 48 to Wk 68 
MMRM (similar to Section 6.1.2) 
adjusting for baseline CPT, with time, 
treatment, and time*treatment 
interaction and randomization 
stratification as factors 
Unstructured covariance matrix 


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6.3 
Subgroup Analyses 
For each of the subgroups listed in Table 2, the primary efficacy endpoint (i.e., the change in 
BCVA from Day 1 to Week 24) will be analyzed using an MMRM that is described in Section 
6.1.2.  When a subgroup is a part of the randomization stratification variable, the corresponding 
stratification variable will be removed from the MMRM model as a covariate. 
A forest plot will be provided to present the treatment effect of these subgroups. 
 
6.4 
Exploratory Analyses 
Exploratory analysis may be conducted to include the FASW24 patients who received 4 or more 
does of active study treatment (KSI-301 or aflibercept). Additionally, an exploratory analysis 
may be conducted to include the FASW24 patients who 1) received 4 or more does of active 
study treatment (KSI-301 or aflibercept), 2) did not have any of the intercurrent events as defined 
for Sensitivity Analysis 1, and 3) did not discontinue assigned study treatment prematurely 
except for reasons related to study eye adverse events or lack of efficacy. 
The same MMRM as described for the primary efficacy analyses will be used. 
Additional exploratory analyses may be conducted. 
 
7.0 
SAFETY EVALUATION 
Safety analyses will be performed for the SAF patients and SAFOLE patients, as appropriate. In 
the Primary Analysis, the safety data from Day 1 to Week 24 will be summarized by treatment 
group for the SAF patients.  In the ITP Analysis, the safety data from Day 1 to Week 48/52 will 
be summarized by treatment group for the SAF patients.  In the OLEP Analysis, the safety data 
from Week 48 to Week 68/72 will be summarized for the SAFOLE patients.  The safety 
summaries will be presented by RVO type (BRVO, 
) and overall. 
 
7.1 
Exposure to Study Medication 
Study eye exposure to study medication will be summarized.  Summaries will include: 
• Mean (SD) and median number of injections, and number of patients receiving ≥1 
injection, 1, 2, 3, 4, 5, etc. of KSI-301 or aflibercept injections from Day 1 to Week 20, 
from Week 24 to Week 44, and from Week 48 to Week 68.   
• Duration of study drug exposure (mean [SD] and median, in months) for subjects 
receiving KSI-301 5 mg or aflibercept 2 mg. 
Listings will include treatment (KSI-301, aflibercept, sham) and date of injection. 
A listing of patients who received study treatment other than the one assigned at randomization 
will include the randomized treatment, the actual administered treatment, Visit, and study Day.  


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7.2 
Adverse Events 
Adverse events (AEs) will be coded to a MedDRA version 23.1 or later.  AEs and Serious AEs 
(SAEs) will be summarized and listed by ocular events for the treated eye (or study eye), ocular 
events for the non-treated eye (or fellow eye), and non-ocular (systemic) events. 
Adverse events starting after the first study treatment injection and continuing until 4 weeks (28 
days) after the last study injection will be considered treatment emergent AEs (TEAE).  
If the severity score of an adverse event is missing, the severity score will be imputed as severe. 
If the relatedness of an adverse event is missing, the adverse event will be considered related. 
At each level of summarization (e.g., any AE, system organ class, and preferred term), subjects 
experiencing more than one TEAE will be counted only once.  In the summary of TEAEs by 
severity grade, subjects will be counted once at the highest severity reported at each level of 
summarization.  
Frequency tables including patients’ incidence rates will be provided through Week 24, from 
Week 28 to Week 52 and through Week 52, separately; and from Week 52 to Week 76 for the 
following: 
• Ocular TEAEs and treatment-emergent serious AEs (TESAEs) (study eye and fellow eye 
separately) 
• Non-ocular TEAEs and TESAEs  
• Ocular TEAEs leading to study treatment discontinuation (study eye and fellow eye 
separately) 
• Ocular TEAEs by severity (study eye and fellow eye separately) 
• Non-ocular TEAEs by severity  
• Related ocular TEAEs (study eye and fellow eye separately) by severity 
• Related non-ocular TEAEs by severity  
• Intraocular Inflammation TEAEs (study and fellow eye separately). See Appendix 3 for 
preferred terms used to identify events of intraocular inflammation (IOI) 
• Intraocular Inflammation TESAEs (study and fellow eye separately) 
• Arteriothromboembolic (ATE) Adverse Events. See Appendix 2 for preferred terms used 
to identify ATEs. 
• Adverse events of special interest [AESI], as defined in the protocol Section 8.3.6 
 
Adverse event data will be presented in data listings by treatment group, subject ID, and event 
date.  Serious AEs, AEs leading to discontinuation of the study drug, intraocular inflammation 
events, and ATE events will be presented in separate data listings. 
Adverse events from patients who remain in the study after study treatment discontinuation will 
be listed.  


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7.3 
Deaths, Serious Adverse Events, and other Significant Adverse Events 
All deaths during the study will be listed by treatment group and subject and will include the 
primary cause of death. Serious AEs and other significant AEs, including those that led to 
interruption or withdrawal of the study drug, will be provided in separate subject data listings. 
 
7.4 
Pregnancies 
Listings of pregnancies, if any, and outcomes will be presented.  
 
7.5 
Intraocular Pressure 
For study eye, pre and post-injection IOP as well as the change from baseline to post baseline 
values will summarized, using mean, standard deviation, median, and range, by treatment group 
and protocol specified visit.  IOP data will be listed by treatment, subject ID, study eye or non-
study eye, and time point. 
 
7.6 
Clinical Laboratory Evaluations 
Continuous laboratory parameters will be summarized, using mean, standard deviation, median, 
and range by treatment group and protocol specified visit.  Laboratory parameters as well as 
change from baseline for each parameter will be presented at Week 24, Week 48, and Week 72. 
Subjects with ALT or AST more than 3 times the Upper Limits of Normal (ULN) in combination 
with an elevated total bilirubin (more than 2 times the ULN); or ALT or AST more than 3 times 
the ULN in combination with clinical jaundice will be listed. 
Other clinical laboratory results through Week 24, from Week 24 to Week 48, and from Week 48 
to Week 72 will be listed and values outside the normal ranges will be flagged along with the 
clinical significance. 
For summary of continuous laboratory parameters, values that are lower than the LOQ will be 
assigned a value that is 1 unit less than the LOQ. Values that are above the LOQ will be assigned 
a value that is 1 unit higher than the LOQ. 
 
7.7 
Vital Signs  
Vital signs including pulse, systolic/diastolic blood pressure, body temperature, height, weight, 
and BMI will be summarized by treatment group and protocol specified visit.  Descriptive 
statistics will be presented for results and change from baseline at each visit.  Vital signs will be 
listed by treatment group, subject, and visit date.  




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10.0 
REFERENCES 
US Food and Drug Administration Guidance Document - E9(R1) Statistical Principles for 
Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials (May 2021). 
Available at https://www.fda.gov/media/148473/download.  
US Food and Drug Administration Guidance Document – Non-Inferiority Clinical Trials to 
Establish Effectiveness (November 2016). Available at 
https://www.fda.gov/media/78504/download. Accessed November 13, 2021. 
 
11.0 
APPENDICES 
Appendix 1: Schedule of Activities 
 
  
 
 




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1. 
Record any concomitant medication used by the patient within 30 days prior to Day 1. Procedural medications administered (e.g. dilating drops, 
fluorescein) will not be recorded. 
2. 
After informed consent has been obtained but prior to initiation of study intervention, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study intervention (Day 1), all AEs will be reported until the final study visit or the ET visit if 
applicable. See Protocol Section 8.3.1. 
3. 
Height and weight will be recorded at the screening visit only. 
4. 
Clinical laboratory test, as described in Protocol Appendix 2 and Table 4. 
5. 
Urine pregnancy test will be performed locally for women of childbearing potential, prior to fluorescein angiogram and study treatment (if applicable). If 
urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. Local urine testing will be standard for the protocol unless serum testing 
is required by local regulation or IRB/IEC. 
6. 
BCVA and Ophthalmic Exam will be performed in both eyes at Screening, Week 24 and Week 48, and only in the Study Eye at all other timepoints. 
7. 
Perform BCVA before any other ophthalmic assessments and prior to dilation. 
8. 
Method used to measure IOP must remain consistent throughout study. 
9. 
It is mandatory that the same model of device is used for the entire duration of the study. 
10. 
Patients who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in Protocol Section 7.1. 
11. 
Post-injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
12. 
For patients continuing in the Extension Phase, the Week 48 and Week 52 procedures listed in Protocol Section 1.3.2 should be performed instead of those 
listed here. 
13. 
For patients not continuing into the Extension Phase, Week 52 is a final safety assessment that will be done via telephone call for all patients, except in 
WOCBP, in which case a site visit is required for the safety assessment that includes a pregnancy test. 
 
 




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8. 
It is mandatory that the same model of device is used for the entire duration of the study. 
9. 
Patients who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in Section 7.1. 
10. 
Post injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
11. 
For patients in the Extension Phase, the Week 48 and Week 52 procedures listed here should be performed instead of those listed in Section 1.3.1. 
12. 
For patients in the Extension Phase, Week 76 is a final safety assessment that will be done via telephone call for all patients, except in WOCBP, in which 
case a site visit is required for the safety assessment that includes a pregnancy test.