Clinical trial NCT04964089
Conditions: Wet Age-related Macular Degeneration
Keywords: AMD Wet AMD neovascularization secondary to age-related macular degeneration KSI-301 Aflibercept Vascular endothelial growth factor VEGF Anti-VEGF Antibody biopolymer conjugate Macular Degeneration wAMD Retinal Degeneration Retinal Diseases Eye Diseases Vision Disorders Vision, Low Kodiak
Sponsor: Kodiak Sciences Inc
Start date: 2021-06-23; Completion date: 2023-04-06
Enrollment: 557 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3 study will evaluate the efficacy and safety of KSI-301 compared to aflibercept, in participants with neovascular (wet) age-related macular degeneration (wAMD)

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 neovascular (wet) age-related macular degeneration (wAMD)

The primary endpoint will be assessed as an average of Weeks 40, 44, and 48; additional secondary endpoints for efficacy will be assessed by visit over time

Arms: arm 1: Intravitreal injection of KSI-301 (5 mg) at Day 1 once every 4 weeks via intravitreal injection through Week 44. arm 2: Intravitreal injection of aflibercept (2 mg) once every 4 weeks for 3 monthly doses followed by intravitreal injection of aflibercept (2 mg) once every 8 weeks from Week 16 to Week 44. Sham injections will be administered at each monthly visit where an active treatment is not administered.
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 documents:
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 Neovascular 
(Wet) Age-related Macular Degeneration (wAMD)
NCT Number: 
NCT04964089
Document Date:  
Protocol Version 2.0, 16 March 2022


CONFIDENTIAL 
Protocol KS301P107, 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 
Neovascular (Wet) Age-related Macular Degeneration (wAMD) 
Protocol Number: 
KS301P107 
Version Date: 
16 March 2022 
Amendment Number: 
2.0 
Supersedes: 
Version 1.1 (Dated: 13 May 2021) 
Test Product: 
KSI-301 
Brief Title: 
A Study to Evaluate the Efficacy and Safety of KSI-301 
Compared to Aflibercept in Participants with Neovascular (Wet) 
Age-related Macular Degeneration (wAMD) 
Study Phase: 
3 
Study Acronym/Name: 
DAYLIGHT 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 USA 
Sponsor Contact & Medical 
Monitor: 
 
 
Kodiak Sciences Inc. 
IND Number: 
136167 
EudraCT Number: 
2021-000225-27 
 
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 KS301P107, 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 
Neovascular (Wet) Age-related Macular Degeneration (wAMD) (DAYLIGHT) 
Protocol Number:  KS301P107 
Version Date: 
16 March 2022 
 
Protocol accepted and approved by: 
 
 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 
 
 
 
 
Signature 
 
Date 
 
 
 


CONFIDENTIAL 
Protocol KS301P107, 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 
Neovascular (Wet) Age-related Macular Degeneration (wAMD) (DAYLIGHT) 
Protocol Number:  KS301P107 
Version Date: 
16 March 2022 
 
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 KS301P107, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
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TABLE OF CONTENTS 
1.0 
PROTOCOL SUMMARY ..............................................................................................12 
1.1 
Synopsis .................................................................................................................12 
1.2 
Schema ...................................................................................................................17 
1.3 
Schedule of Activities (SoA) .................................................................................18 
2.0 
INTRODUCTION............................................................................................................20 
2.1 
Study Rationale ......................................................................................................20 
2.2 
Background ............................................................................................................20 
2.2.1 
Neovascular (Wet) Age-related Macular Degeneration ........................20 
2.2.2 
Vascular Endothelial Growth Factor .....................................................21 
2.2.3 
Description of KSI-301 .........................................................................21 
2.3 
Benefit/Risk Assessment .......................................................................................22 
2.3.1 
Known Potential Benefits .....................................................................22 
2.3.2 
Known Potential Risks ..........................................................................22 
2.3.3 
Overall Benefit/Risk Conclusion ..........................................................25 
3.0 
OBJECTIVES AND ENDPOINTS ................................................................................26 
4.0 
STUDY DESIGN ..............................................................................................................27 
4.1 
Overall Design .......................................................................................................27 
4.1.1 
Screening Period ...................................................................................27 
4.1.2 
Treatment Period ...................................................................................28 
4.1.3 
Administration of Study Intervention ...................................................28 
4.2 
Scientific Rationale for Study Design....................................................................29 
4.2.1 
Choice of Population .............................................................................29 
4.2.2 
Choice of Active Comparator Control ..................................................29 
4.2.3 
Choice of Primary Endpoint and Analysis ............................................29 
4.2.4 
Choice of Duration of Treatment and Follow-up ..................................30 
4.3 
Justification for Dose .............................................................................................30 
4.3.1 
KSI-301 Dose Rationale .......................................................................30 
4.3.2 
Aflibercept Dose Rationale ...................................................................31 
4.3.3 
Sham Injection Rationale ......................................................................31 
4.4 
End of Treatment ...................................................................................................31 
4.5 
End of Study Definition .........................................................................................31 
4.6 
Treatment After End of Study................................................................................31 
5.0 
STUDY POPULATION ..................................................................................................32 
5.1 
Inclusion Criteria ...................................................................................................32 
5.1.1 
Ocular Inclusion Criteria .......................................................................32 


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5.1.2 
General Inclusion Criteria .....................................................................33 
5.2 
Exclusion Criteria ..................................................................................................34 
5.2.1 
Ocular Exclusion Criteria ......................................................................34 
5.2.2 
General Exclusion Criteria ....................................................................35 
5.3 
Lifestyle Considerations ........................................................................................35 
5.4 
Screen Failures .......................................................................................................36 
5.5 
Criteria for Temporarily Delaying Enrollment ......................................................36 
6.0 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ..........................38 
6.1 
Study Intervention(s) Administered .......................................................................38 
6.2 
Preparation/Handling/Storage/Accountability .......................................................39 
6.2.1 
Preparation, Handling, and Storage ......................................................39 
6.2.2 
Study Intervention Accountability and Reconciliation .........................40 
6.3 
Measures to Minimize Bias: Randomization and Masking ...................................41 
6.3.1 
Randomization ......................................................................................41 
6.3.2 
Masking and Unmasking ......................................................................41 
6.4 
Study Intervention Compliance .............................................................................42 
6.5 
Dose Modification .................................................................................................43 
6.6 
Continued Access to Study Intervention after the End of the Study .....................43 
6.7 
Treatment of Overdose ..........................................................................................43 
6.8 
Concomitant Therapy.............................................................................................43 
6.8.1 
Prohibited Therapy ................................................................................44 
6.8.2 
Supportive Care for Adverse Events .....................................................45 
7.0 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................................46 
7.1 
Discontinuation of Study Intervention ...................................................................46 
7.1.1 
Treatment Interruption and/or Discontinuation due to Adverse 
Events or Concomitant Procedures .......................................................46 
7.2 
Participant Discontinuation/Withdrawal from the Study .......................................47 
7.3 
Lost to Follow-up ...................................................................................................48 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................49 
8.1 
Efficacy Assessments.............................................................................................49 
8.1.1 
Medical History and Demographic Data...............................................49 
8.1.2 
Ophthalmic Exams ................................................................................49 
8.1.3 
Injection Procedure ...............................................................................50 
8.1.4 
Post-injection Assessments in the Study Eye .......................................50 
8.1.5 
Best Corrected Visual Acuity (BCVA) 
 
 .................................................................................................51 


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8.1.6 
Fundus Photography (FP) .....................................................................51 
8.1.7 
Spectral Domain Optical Coherence Tomography (SD-OCT) .............51 
8.1.8 
Fluorescein Angiography (FA) .............................................................51 
8.2 
Safety Assessments ................................................................................................52 
8.2.1 
Vital Signs .............................................................................................52 
8.2.2 
Clinical Safety Laboratory Assessments ...............................................52 
8.2.3 
Pregnancy Testing .................................................................................52 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ................53 
8.3.1 
Time Period and Frequency for Collecting AE and SAE 
Information ............................................................................................53 
8.3.2 
Method of Detecting AEs and SAEs .....................................................53 
8.3.3 
Follow-up of AEs and SAEs .................................................................54 
8.3.4 
Regulatory Reporting Requirements for SAEs .....................................54 
8.3.5 
Pregnancy ..............................................................................................54 
8.3.6 
Adverse Events of Special Interest .......................................................55 
8.4 
Pharmacokinetics ...................................................................................................56 
8.5 
Genetics and/or Pharmacogenomics ......................................................................56 
8.6 
Biomarkers .............................................................................................................56 
8.7 
Immunogenicity Assessments ................................................................................56 
8.8 
Health Economics or Medical Resource Utilization and Health Economics ........57 
9.0 
STATISTICAL CONSIDERATIONS ...........................................................................58 
9.1 
Study Hypothesis ...................................................................................................58 
9.2 
Sample Size Determination....................................................................................58 
9.3 
Analysis Sets ..........................................................................................................59 
9.4 
Statistical Analyses ................................................................................................59 
9.4.1 
General Considerations .........................................................................59 
9.4.2 
Primary Endpoint(s) ..............................................................................60 
9.4.3 
Secondary Endpoint(s) ..........................................................................61 
9.4.4 
Tertiary/Exploratory Endpoint(s) ..........................................................62 
9.4.5 
Safety Analysis .....................................................................................62 
9.4.6 
Pharmacokinetic and Biomarker Analysis ............................................62 
9.5 
Interim Analysis .....................................................................................................62 
10.0 
APPENDICES WITH SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS ........................................................................63 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................64 
10.1.1 
Regulatory and Ethical Considerations .................................................64 
10.1.2 
Financial Disclosure and Financial Obligations ...................................64 


CONFIDENTIAL 
Protocol KS301P107, Version 2.0 
 
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10.1.3 
Informed Consent Process ....................................................................65 
10.1.4 
Data Protection ......................................................................................65 
10.1.5 
Committees Structure ............................................................................66 
10.1.6 
Data Quality Assurance.........................................................................66 
10.1.7 
Source Documents ................................................................................67 
10.1.8 
Study and Site Start and Closure ...........................................................67 
10.1.9 
Publication Policy .................................................................................68 
10.2 
Appendix 2: Clinical Laboratory Tests ..................................................................69 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...................................................................70 
10.3.1 
Definition of AE ....................................................................................70 
10.3.2 
Definition of SAE .................................................................................71 
10.3.3 
The Recording and Follow-Up of AE and/or SAE ...............................72 
10.3.4 
Reporting of SAEs ................................................................................74 
10.4 
Appendix 4: Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreous Cells or Haze. ................................................................................75 
10.4.1 
Grading Scales for Anterior Chamber Cells or Flare ............................75 
10.4.2 
Grading Scale for Vitreous Cells ..........................................................76 
10.4.3 
Grading Scale for Vitreous Haze ..........................................................76 
10.5 
Appendix 5: Unscheduled Safety Assessment Visits ............................................77 
10.6 
Appendix 6: Contraceptive and Barrier Guidance .................................................78 
10.6.1 
Definitions .............................................................................................78 
10.6.2 
Contraception Guidance ........................................................................79 
10.6.3 
Collection of Pregnancy Information ....................................................79 
10.7 
Appendix 7: Liver Safety .......................................................................................81 
10.8 
Appendix 8: Protocol Amendment History ...........................................................82 
11.0 
REFERENCES .................................................................................................................83 
 
LIST OF TABLES 
Table 1:  
Protocol KS301P107: Risk Assessment ....................................................23 
Table 2:  
Protocol KS301P107: Study Interventions ................................................39 
Table 3:  
Protocol KS301P107: Treatment Interruption Criteria ..............................47 
Table 4:  
Protocol KS301P107: Required Safety Laboratory Tests .........................69 
Table 5: 
Protocol KS301P107: Amendment History ...............................................82 
 
 


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Protocol KS301P107, Version 2.0 
 
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LIST OF FIGURES 
Figure 1: 
Protocol KS301P107: Schema ...................................................................17 
Figure 2: 
Protocol KS301P107: Masked Dosing Regimens by Week ......................28 
 
 
 


CONFIDENTIAL 
Protocol KS301P107, Version 2.0 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AMD 
Age-related macular degeneration 
ANCOVA 
Analysis of covariance 
AR 
Adverse reaction  
AST 
Aspartate aminotransferase 
ATE 
Arterial thromboembolic events 
AUC 
Area under the curve (total exposure) 
BCVA 
Best corrected visual acuity 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of federal regulations 
Cmax 
Maximum concentration observed 
CNV 
Choroidal neovascularization 
COVID-19 
Coronavirus-19 
CRO 
Contract research organization  
CSR 
Clinical study report 
CST 
Central subfield thickness 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy  
DVD 
Digital Video Disc 
EC 
Ethics committee  
ECG 
Electrocardiograph 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ET 
Early termination  
ETDRS 
Early treatment diabetic retinopathy study 
EU 
European Union 
FA 
Fundus fluorescein angiography 
FAS 
Full-analysis set 
FDA  
Food and Drug Administration  
FP 
Fundus photography 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl-transferase 


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Abbreviation 
Definition 
GLP 
Good laboratory practice 
IB 
Investigator’s Brochure  
ICF 
Informed consent form 
ICH 
International conference on harmonization  
ICMJE 
International committee of medical journal editors 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational medicinal product 
IND 
Investigational new drug (application) 
IOP 
Intraocular pressure 
IP 
Investigational product  
IRB 
Institutional review board 
IEC 
Independent or institutional ethics committee 
IRC 
Intraretinal cysts 
IRF 
Intraretinal fluid 
ITT 
Intent to treat 
IRT 
IUD 
Interactive Response Technology 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IVT 
Intravitreal 
 
 
LPLO 
Last participant, last observation 
ME 
Macular edema 
MedDRA 
The medical dictionary for regulatory activities 
NAB 
Neutralizing antibody 
NOAEL 
No observed adverse effect level 
OCT 
Optical coherence tomography 
OU 
Both eyes 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
Q8W 
Every eight weeks 
RPE 
Retinal pigment epithelium 
RVO 
Retinal vein occlusion  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction  
SAR-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD-OCT 
Spectral domain optical coherence tomography 


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Abbreviation 
Definition 
SDV 
Source data verification  
SE 
Study Eye 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SoA 
Schedule of activities 
SRF 
Subretinal fluid 
SUN 
Standardization of uveitis nomenclature 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAEs 
Treatment emergent adverse events 
ULN 
Upper limits of normal 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 
wAMD 
Wet (neovascular) age-related macular degeneration 
WBC 
White blood cell 
WHODrug 
World health organization drug dictionary 
WOCBP 
Women of childbearing potential 
 


CONFIDENTIAL 
Protocol KS301P107, Version 2.0 
 
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12 
1.0 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Number: KS301P107 
Version: 2.0 
For National Authority Use 
Only 
 
IND Number: 136167 
EudraCT Number: 2021-000225-27 
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 Neovascular (Wet) Age-related Macular Degeneration (wAMD) (DAYLIGHT) 
Brief Title: 
A Study to Evaluate the Efficacy and Safety of KSI-301 Compared to Aflibercept in Participants with Neovascular 
(Wet) Age-related Macular Degeneration (wAMD) 
Brief Study Rationale: 
KSI-301 is a novel, potent, long-acting biopharmaceutical that inhibits vascular endothelial growth factor (VEGF). 
KSI-301 has enhanced retinal bioavailability, a greater inhibitory potency, and an extended ocular half-life, which 
may result in improved efficacy and/or a less frequent treatment regimen. Intensive treatment with aflibercept has 
been shown to provide better visual acuity results in a subset of patients with persistent fluid in the retina. Given 
the enhanced properties of KSI-301, this study has been designed to evaluate an intensive treatment regimen of 
KSI-301 5 mg compared to aflibercept 2 mg in participants with wAMD.  
Development Phase: 3 
Countries/Regions: NA (North America) and EMEA (Europe, 
Middle-East, Africa) 
Study Period: Approximately 2 years 






CONFIDENTIAL 
Protocol KS301P107, Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
15 
Protocol Number: KS301P107 
Version: 2.0 
For National Authority Use 
Only 
 
IND Number: 136167 
EudraCT Number: 2021-000225-27 
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 Neovascular (Wet) Age-related Macular Degeneration (wAMD) (DAYLIGHT) 
Study Intervention (Active Control/Investigational Medicinal Product), Dose, and Route of Administration: 
Treatment Group B: 
• 
Day 1 to Week 12: aflibercept 2 mg once every 4 weeks for 3 monthly doses via intravitreal injection, 
followed by a sham injection at week 12; and 
• 
Week 16 to Week 44: aflibercept 2 mg once every 8 weeks via intravitreal injection. Sham injections will be 
administered at each 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 ETDRS BCVA from Day 1 to the average of Weeks 40, 44, and 48. The primary 
assessment of efficacy will be based on a pairwise comparison in mean change in BCVA between treatment group 
A (KSI-301 5 mg) and treatment group 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 Week 48. Planned time points for all 
efficacy assessments are provided in the Schedule of Activities (SoA) (Section 1.3). 
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 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, as specified in Section 1.3. The safety analysis will use outcomes of all participants who were exposed 
to study treatment, regardless of adherence to the protocol or treatment outcome. 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 (ADAs). For exploratory purposes, 
 
  


CONFIDENTIAL 
Protocol KS301P107, Version 2.0 
 
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Protocol Number: KS301P107 
Version: 2.0 
For National Authority Use 
Only 
 
IND Number: 136167 
EudraCT Number: 2021-000225-27 
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 Neovascular (Wet) Age-related Macular Degeneration (wAMD) (DAYLIGHT) 
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 in participants with wAMD. Using ETDRS BCVA data collected up to Week 48, the treatment 
groups will be compared using a non-inferiority analysis, with a margin 
. Confidence intervals 
(CI) will be 100(1-2 α) or 95% CI. 
The sample size of approximately 500 (250 per group) 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”, 
.  
• 
The statistical test used to compare the two treatment groups at Week 48 is an independent t-test on the mean 
change in visual acuity from baseline. 
• 
Lost to follow-up/dropout rate of approximately 
. 
Analysis of study data will be performed when all participants have either completed the Week 48 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: 
16 March 2022 
 
 


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Protocol KS301P107, Version 2.0 
 
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1.2 
Schema 
Figure 1: 
Protocol KS301P107: Schema 
 
Abbreviations: Q4W = once every four (4) weeks; Q8W = once every eight (8) weeks.  
 
 






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Protocol KS301P107, Version 2.0 
 
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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 neovascular (wet) age-related macular 
degeneration (wAMD), as well as macular edema (ME) secondary to retinal vein occlusion 
(RVO), diabetic macular edema (DME), and diabetic retinopathy (DR). 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 in patients with wAMD, is currently 
limited by both the high treatment burden and insufficient durability of effect.  
2.1 
Study Rationale 
Although substantial visual acuity benefits have been demonstrated with the approved 
intravitreal VEGF inhibitors (e.g., aflibercept and ranibizumab) in the first-line treatment of 
wAMD, some patients have an insufficient response to treatment, with continued loss of visual 
acuity and/or persistent retinal fluid (Brown 2006; Heier 2012; Rosenfeld 2006). 
Pharmacokinetic modeling suggests that more frequent dosing with anti-VEGF therapy could be 
beneficial for such patients (Stewart 2012), and intensive treatment with aflibercept has shown to 
provide better visual acuity results in a subset of patients with persistent fluid in the retina (Jaffe 
2016). With enhanced retinal bioavailability, a greater inhibitory potency, and an extended 
ocular half-life (Section 2.2.3), KSI-301 may lead to improved treatment outcomes. The ongoing 
Phase 2b/3 Study of KSI-301 versus aflibercept in participants with wAMD, Study KSI-CL-102, 
evaluates dosing regimens of KSI-301 at intervals of every 12 weeks or longer. Thus, this study, 
Study KS301P107, has been designed to evaluate an intensive treatment regimen of KSI-301 5 
mg (Q4W) compared to aflibercept 2 mg (Q8W after 3 monthly loading doses) in participants 
with wAMD.  
2.2 
Background 
2.2.1 
Neovascular (Wet) Age-related Macular Degeneration  
Age-related macular degeneration (AMD) is a progressive disease that affects the macula, which 
is the central portion of the retina and is the region of the eye responsible for sharp, central vision 
and color perception. AMD affects people 50 years of age and older and the likelihood of AMD 
progression and associated vision loss increases with age. Population-based studies have shown 
that AMD accounts for 8.7% of all blindness worldwide and is the most common cause of 
blindness in developed countries. (Wong 2014) 
Neovascular (wet) AMD (wAMD) is an advanced form of AMD that is characterized by 
choroidal neovascularization and fluid leakage within and under the retina. In the United States 
and the European Union (EU), wAMD is the leading cause of severe vision loss in people over 
the age of 50. In the United States, the prevalence of wAMD is approximately 1.25 million, with 
an annual incidence of approximately 148,000 new cases (Wong 2014). Like AMD, the 


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likelihood of disease progression of wAMD increases with age, and both the prevalence and 
incidence of wAMD are projected to accelerate worldwide.  
Approximately 50% of patients presenting with wAMD in one eye will develop wAMD in the 
fellow eye within five years, leading to a substantial number of patients requiring treatment in 
both eyes (Chew 2014). In many eyes with wAMD, the disease can progress quickly, with rapid 
loss of central vision needed for activities such as reading and driving. Untreated or undertreated 
wAMD can result in subretinal scarring with irreversible photoreceptor damage and loss, and 
ultimately permanent vision impairment or blindness. 
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 RVO (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 2015b; Cheung 2010). 
Among the VEGF isoforms, VEGF-A is the most strongly linked to angiogenesis and vascular 
leakage (Campochiaro 2015a). Intravitreal VEGF-A inhibitors such as aflibercept and 
ranibizumab have been approved by regulatory authorities worldwide for use in these retinal 
vascular diseases. Phase 3 clinical trials of ranibizumab demonstrated that monthly injections of 
ranibizumab for DME and wAMD resulted in substantial visual acuity gains (Brown 2006; 
Nguyen 2012; Rosenfeld 2006). Similarly, the Phase 3 clinical trials of aflibercept in patients 
with wAMD demonstrated that every 8-week (Q8W) dosing of aflibercept (after 3 once-monthly 
loading doses) was non-inferior to monthly ranibizumab (Heier 2012). 
The anti-VEGF therapy is well-established for the treatment of wAMD (Schmidt-Erfurth 2014). 
However, some patients have an insufficient response to treatment, with continued loss of BCVA 
and/or persistent retinal fluid using the approved posologies (Brown 2006; Heier 2012; 
Rosenfeld 2006). Pharmacokinetic modeling suggests that more frequent dosing with anti-VEGF 
therapy could be beneficial for such patients (Stewart 2012), and intensive treatment with 
aflibercept has shown to provide better visual acuity results in a subset of patients with persistent 
fluid in the retina (Jaffe 2016). 
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 


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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 wAMD, 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 wAMD is also well-
documented and established (Schmidt-Erfurth 2014). 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. 
The use of anti-VEGF therapy is a well-established treatment for wAMD (Schmidt-Erfurth 
2014). However, some patients have an insufficient response to treatment, with continued loss of 
BCVA and/or persistent retinal fluid using the approved posologies (Brown 2006; Heier 2012; 
Rosenfeld 2006). Pharmacokinetic modeling suggests that more frequent dosing with anti-VEGF 
therapy could be beneficial for such patients (Stewart 2012), and intensive treatment with 
aflibercept has been shown to provide better visual acuity results in a subset of patients with 
persistent fluid in the retina (Jaffe 2016). Thus, an intensive treatment regimen of KSI-301 may 
provide clinically relevant benefits over existing therapies for patients with wAMD. 
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 
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. 
 
 


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Table 1:  
Protocol KS301P107: 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 KS301P107: 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. Because 
wAMD is an acute onset, rapidly progressing disease, early diagnosis and treatment with 
intravitreal anti-VEGF therapy is associated with better functional outcomes, including 
prevention of irreversible vision loss (Schmidt-Erfurth 2014). 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 wAMD. 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 
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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 
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 for wAMD with KSI-301 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. 
Because wAMD is an acute onset, rapidly progressing disease, early diagnosis and treatment 
with intravitreal anti-VEGF therapy is associated with better functional outcomes, including 
prevention of irreversible vision loss (Schmidt-Erfurth 2014). 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 treatment-naïve wAMD. 
The overall duration of the study is approximately 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 
  
The primary endpoint is defined as the mean change in ETDRS BCVA from baseline (Day 1) to 
the average of Weeks 40, 44, 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 groups: 
• KSI-301 5 mg, or 
• Aflibercept 2 mg. 
Randomization will be stratified by
 
Additional details of 
the randomization methods are described in the statistical analysis plan (SAP). 
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 
with the Sponsor (Section 5.4). Instructions for participants who meet all eligibility criteria at the 


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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 efficacy 
and/or safety follow-up at Weeks 48 and 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. 
4.1.3 
Administration of Study Intervention 
All participants will be treated starting on Day 1 through Week 36 according to their respective 
treatment group, as shown in Figure 2.  
Participants randomized to the KSI-301 treatment group will receive KSI-301 5 mg 
 
once every four (4) weeks from Day 1 to Week 44.  
Participants randomized to the aflibercept treatment group will initially receive three (3) monthly 
doses of aflibercept 2 mg (50 µL) at Day 1, Week 4, and Week 8, followed by aflibercept 2 mg 
(50 µL) once every 8 weeks (Q8W) until Week 44. Participants randomized to the aflibercept 
treatment group will receive a sham injection at each visit that aflibercept is not administered 
(i.e., at Weeks 12, 20, 28, and 36).  
Figure 2: 
Protocol KS301P107: Masked Dosing Regimens by Week 
  
Abbreviations: PE = primary endpoint; Q4W = once every four (4) weeks; Q8W = once every eight (8) weeks; 
SA = safety assessment.  
 


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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 wAMD. 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 
KSI-301 is being evaluated as a first-line anti-VEGF medicinal product for the management of 
wAMD. Thus, participants must not have had prior use of an approved or investigational 
treatment (e.g., anti-VEGF) for wAMD in the Study Eye.  
Enrollment of participants who are treatment-naïve for wAMD helps to 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 83 to 25 letters will be enrolled because 
they are expected to be broadly representative of the general population of patients treated with 
first-line anti-VEGF with diagnosis of wAMD.  
4.2.2 
Choice of Active Comparator Control 
An active comparator was selected for this trial because an effective treatment currently exists, 
rendering placebo (sham injection) control unethical.  
The use of VEGF-inhibition therapy is a well-established treatment for wAMD (Schmidt-Erfurth 
2014). Three highly potent anti-VEGF biologics are currently approved by both the United States 
(US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the 
treatment of wAMD: ranibizumab (Lucentis®), brolucizumab (Beovu®), and aflibercept 
(Eylea®). Aflibercept is chosen as the active comparator for this trial because the majority of 
patients with wAMD treated in routine clinical practice with an approved anti-VEGF receive 
aflibercept.  
4.2.3 
Choice of Primary Endpoint and Analysis 
The primary endpoint, mean change in BCVA, was selected based on health authority feedback 
and precedent for Phase 3 studies in wAMD. 
A non-inferiority primary analysis was selected because aflibercept results in significant clinical 
benefit for most patients, when administered according to the approved posology. KSI-301 
efficacy outcomes are expected to be comparable (non-inferior) to aflibercept, but with the 
potential for improved outcomes in some patients. Consequently, the a priori assumption is that 
it is unlikely that KSI-301 (or any novel anti-VEGF) would demonstrate clinically meaningful 
superiority in vision outcomes to an approved anti-VEGF agent in a well-conducted, head-to-
head trial, for the overall population.  


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A non-inferiority margin of 
 was selected based on health authority feedback. Five letters 
represent one line on the ETDRS visual acuity chart and is considered by many physicians to be 
a clinically meaningful change. Therefore, 
 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 this study will be the same for both groups (i.e., KSI-301 and 
aflibercept) (i.e., 44 weeks).  
The primary endpoint will be assessed using ETDRS data collected up to Week 48. This time 
point and associated duration of treatment was selected on the basis of health authority feedback 
and precedent for other ongoing Phase 3 trials in wAMD.  
The choice of a safety follow-up interval of 8 weeks after the last dose 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 and pharmacological effect of intravitreal anti-VEGF therapy is proportional to 
the concentration, potency, and half-life of the drug. A KSI-301 5 mg dose has approximately 
times 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 pharmacological effects 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 overall development objective of KSI-301 in the treatment of wAMD is to reduce the 
number of required intravitreal injections, and with it the treatment burden for patients, 
clinicians, and health systems. However, establishing the safety and efficacy of an intensive 
treatment approach with KSI-301 is of importance for and of potential benefit to patients who 
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4.3.2 
Aflibercept Dose Rationale 
In the US, the recommended dose for aflibercept in wAMD is 2 mg (0.05 mL) administered by 
intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 12 
weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks 
(2 months).  
In the EU, the recommended dose for aflibercept is 2 mg per month for three consecutive doses. 
The treatment interval is then extended to two months. The treatment interval may then be 
maintained at two months or further extended using a treat-and-extend dosing regimen, where 
injection intervals are increased in 2- or 4-weekly increments to maintain stable visual and/or 
anatomic outcomes.  
In the absence of a recommended posology that is consistent between regions, the Sponsor 
considers that a once every two-month (Q8W) interval after three initial loading doses provides 
the maximum possible treatment effect and best enables a head-to-head comparison with 
KSI-301 without undue risk. 
4.3.3 
Sham Injection Rationale 
Sham injections are used to preserve study masking and minimize bias. Participants in the 
aflibercept treatment group will receive sham injections at each monthly visit when an active 
treatment is not administered. 
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 study if he/she has completed all phases of the 
study, including the Week 52 safety follow-up assessment. 
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 group 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. 
Inclusion/exclusion criteria (Sections 5.1 and 5.2) will be assessed at Screening and on Day 1 to 
determine a participant’s eligibility for the study. 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. 
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. Active, treatment-naïve choroidal neovascularization (CNV) secondary to AMD, including 
subfoveal, juxtafoveal, and extrafoveal lesions, or retinal angiomatous proliferations (RAP) 
lesions with a CNV component that affects the central subfield, as evidenced by FA or OCT 
in the Study Eye at Screening. 
2. The CNV area in the Study Eye must be at least 50% of total lesion size at Screening. 
3. The lesion area in the Study Eye must be <30 mm2 (12-disc areas) and can include any CNV 
lesion subtype. 
4. Intra- and/or subretinal fluid and/or subretinal hyperreflective material (SHRM) affecting the 
central subfield of the Study Eye on OCT at Screening. 
5. BCVA ETDRS score between 83 and 25 letters, inclusive, in the Study Eye at screening and 
reconfirmed at Day 1. 
6. Decrease in vision in the Study Eye determined by the Investigator to be primarily the result 
of wAMD. 


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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 participate in the study.  
5.1.2 
General Inclusion Criteria  
7. 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. 
8. Male or female ≥50 years of age. 
9. 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 
. 
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. 
a. A woman is considered of childbearing potential if she is postmenarcheal, 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. 
10. 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 drug. Men must refrain from 
donating sperm during this same time period. 
11. Ability and willingness to undertake all the scheduled visits and assessments. 


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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. BCVA of hand motion or worse in the non-Study Eye or non-physical presence of a non-
Study Eye (i.e., monocular). 
2. Active or suspected ocular or periocular infection or inflammation in either eye at Screening 
or on Day 1. 
3. CNV secondary to other causes in the Study Eye, including pathologic myopia, angioid 
streaks, prior trauma, ocular histoplasmosis, or others. 
4. Any history of macular pathology unrelated to AMD but affecting vision or contributing to 
subretinal or intraretinal fluid, such as central serous chorioretinopathy.  
5. Fibrosis or atrophy of >50% of the lesion size and/or involving the foveal center of the Study 
Eye at Screening. 
6. Subretinal blood affecting the foveal center of the Study Eye and/or more than 50% of the 
lesion size at Screening. 
7. Retinal pigment epithelium tear or rip in the Study Eye at Screening or on Day 1. 
8. Any approved or investigational treatment for neovascular AMD (other than oral vitamin 
supplements) in the Study Eye at any time. 
9. Prior macular laser (e.g., thermal laser or photodynamic therapy laser) in the Study Eye. 
10. Any history or evidence of a concurrent ocular condition present in the Study Eye, 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, epiretinal 
membrane). 
11. History of cataract surgery and/or minimally invasive glaucoma surgery (MIGS) in the Study 
Eye within 2 months of screening. 
12. History of Yttrium-Aluminum Garnet (YAG) laser capsulotomy in the Study Eye within 2 
months of screening. 
13. Uncontrolled glaucoma (defined as intraocular pressure ≥ 25 mmHg despite treatment with 
antiglaucoma medication) in the Study Eye. 
14. History of glaucoma-filtering surgery (trabeculectomy or tube shunt) in the Study Eye.  
15. History of retinal detachment or treatment or surgery for retinal detachment in the Study Eye. 
16. History of uveitis in either eye.  
17. Significant media opacities, including cataract, in the Study Eye that might interfere with 
visual acuity, assessment of safety, OCT or fundus photography.  


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18. Cataract in the Study Eye that in the judgment of the Investigator is expected to require 
surgical extraction within 12 months of screening. 
19. Aphakia in the Study Eye. 
20. Prior vitrectomy in the Study Eye. 
21. Prior intraocular or periocular steroids in the Study Eye. 
22. Current vitreous hemorrhage or history of vitreous hemorrhage in the Study Eye within 3 
months of Screening. 
23. History of corneal transplant in the Study Eye. 
5.2.2 
General Exclusion Criteria 
24. Women who are pregnant or lactating or intending to become pregnant during the study  
25. 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.  
26. 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. 
27. 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. 
28. Participation in an investigational study within 30 days prior to the screening visit that 
involved treatment with any investigational drug (excluding vitamins and minerals) or 
device, except for non-therapeutic ophthalmic imaging devices. 
29. Active cancer within the 12 months prior to Screening except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin cancer, and prostate cancer with a 
Gleason score of <6 and stable prostate-specific antigen for >12 months. 
30. Treatment with systemic anti-VEGF therapeutics within 90 days prior to Screening. 
31. Uncontrolled blood pressure defined as a systolic value ≥180 mmHg or diastolic value ≥100 
mmHg while at rest at Screening or on Day 1. 
• 
If a participant’s initial blood pressure measurement exceeds these values, up to 
two 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. 
 
5.3 
Lifestyle Considerations 
No specific lifestyle restrictions are required.  


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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 considered ‘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 a 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 the BCVA eligibility criterion due to expected variability and fluctuation in the BCVA 
value when they return for the planned Day 1 visit, the Sponsor will allow the participant to 
return one additional time to reassess the BCVA, 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 


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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 are 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 KS301P107: Study Interventions 
Group 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 not used until the 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 
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.  


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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 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. 
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 
unmasked vials or prefilled syringes within masked cartons (also referred to as kits), as follows:  
• 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 
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.  


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• 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 or 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. 
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 


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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 
Participants can only receive the specified dose for the intervention group, as follows: 
A. KSI-301: 5 mg 
  
B. Aflibercept: 2 mg (50 µL).  
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). 
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, 


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anesthetics, antiseptic, fluorescein, etc.) related to 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. 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 eye (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 eye (non-Study Eye) may 
be implemented at any time once the Day 1 injection has been administered. Anti-VEGF 
treatment for the fellow eye, including the date of each administration, must be documented as a 
concomitant medication on the appropriate eCRF. If the fellow eye requires treatment during the 
same visit as the Study Eye, the Study Eye should be treated first, and the fellow 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 
Prohibited Therapy 
At the discretion of the Investigator, 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, 
• Intravitreal anti-VEGF drugs in the Study Eye other than study-assigned aflibercept or 
KSI-301 until all assessments are completed at Week 48, 
• Systemic anti-VEGF therapy, 
• Concurrent use of intravitreal or periocular steroids or steroid implants in the Study Eye, 
• Concurrent use of macular photocoagulation or photodynamic therapy with verteporfin in 
the Study Eye, and 
• 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 or be discontinued from the study 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. 


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6.8.2 
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, 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 Weeks 40, 44, and 48 (primary endpoint) 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. 
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 


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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 KS301P107: 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. 
 
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 Weeks 40, 44, and 48 visits. However, participants are 
free to withdraw from the study or study treatment at any time upon request. Participant 


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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: 
• 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. 
• 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. 
• 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 or designee 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 will be recorded. A full ocular history including prior ocular treatments will be noted. 
Demographic data will include age, sex, ethnic origin (also referred to as self-reported race and 
ethnicity in some regions of the world), and smoking status.  
8.1.2 
Ophthalmic Exams 
Unless otherwise noted, ophthalmic assessments are captured for the Study Eye only. 
Slit-lamp examination 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, 
• Inspection of the lens, 


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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 
IOP eCRF.  




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Additional specifications and instructions regarding acceptable equipment imaging and imaging 
techniques will be provided by the Reading Center. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 
Vital Signs 
The following vital signs will be assessed 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 or designee 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). 


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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. 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs are provided in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver or surrogate). 
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 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 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 
(both prescription and OTC medications). 


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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 titer 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 or NABs). All samples collected for detection of 
antibodies to study intervention will also be evaluated for KSI-301 plasma concentration to 
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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 
Intensive treatment with KSI-301 5 mg will provide a non-inferior mean change in BCVA 
compared to aflibercept 2 mg in participants with visual impairment due to wAMD. 
9.2 
Sample Size Determination 
The sample size for the comparison of the change in BCVA between treatment group A 
(KSI-301 5 mg once every 4 weeks) and treatment group B (aflibercept 2 mg once every 8 weeks 
after 3 initial monthly injections) from Day 1 to the average of Weeks 40, 44, and 48 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,” 
; 
• The statistical test used to compare the two treatment groups using ETDRS BCVA data 
collected up to Week 48 is an independent t-test on the mean change in visual acuity from 
baseline (Day 1); and 
• Lost to follow-up/dropout rate of approximately 
. 
The sample size calculated using the above assumptions is approximately 500 participants (250 
per treatment group). 
 
 
 
 
 
 
Note: “enrolled” means a participant's agreement to participate in a clinical study following 
completion of the informed consent process, screening, and the Day 1 visit. Potential participants 
who are screened for the purpose of determining eligibility for the study, but who 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 (ITT) 
set 
The ITT set will be comprised of all participants who were randomized into 
one of the study groups. 
For analyses based on this population, participants will be grouped 
according to the study intervention assigned at randomization. 
Evaluable/per protocol (PP) set 
The PP set will comprise 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 PP set will group 
participants according to the study intervention they actually received. 
Safety set 
The safety set will comprise 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 set 
The PK/biomarker evaluable data set will comprise all participants in the 
ITT set with at least one post-Day 1 evaluable sample. The ADA-evaluable 
data set will consist of all participants in the ITT set 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. 
9.4.1 
General Considerations 
At baseline (Day 1), participants will be randomized 1:1 into one of two treatment groups: 
A. KSI-301 5 mg 
: once every four (4) weeks from Day 1 to Week 44; or 
B. Aflibercept 2 mg (50 µL): three (3) monthly doses at Day 1, Week 4, and Week 8, 
followed by once every 8 weeks (Q8W) until Week 44. Participants randomized to the 


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aflibercept treatment group will receive a sham injection at each visit that aflibercept is 
not administered (i.e., at Weeks 12, 20, 28, 36, and 44).  
This study consists of one efficacy and safety assessment period (Section 1.2), as follows: 
• Day 1 to Week 52, which consists of the treatment period (Day 1 through Week 44), 
4-week efficacy and safety period (to Week 48), and a final 4-week safety assessment at 
Week 52 (8 weeks after the last dose).  
Using ETDRS BCVA data collected up to Week 48, the treatment groups will be compared using 
a non-inferiority analysis, with a margin 
. 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 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.  
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.  
9.4.2 
Primary Endpoint(s) 
The primary endpoint is defined as the mean change in ETDRS BCVA from baseline (Day 1) to 
Weeks 40, 44, and 48. The primary assessment of efficacy will be based on a pairwise 
comparison in mean change in BCVA between treatment group A (KSI-301 5 mg) and treatment 
group 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 48 visit or have discontinued from the 
study prior to the Week 48 visit, whichever comes later; 
• all data up to and including the Week 48 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 


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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 groups 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) 
Key secondary endpoints will be assessed at Week 48 (for efficacy) or Week 52 (for safety):  
• Mean change in BCVA (ETDRS Letters) from baseline (Day 1) by visit over time.  
• Proportion of participants who gain ≥5, ≥10 and ≥15 ETDRS letters from baseline 
(Day 1) by visit over time. 
• Proportion of participants who lose ≥5, ≥10 and ≥15 ETDRS letters from baseline 
(Day 1) by visit over time. 
• Proportion of participants with BCVA Snellen equivalent of 20/40 or better from baseline 
(Day 1) over time. 
• Proportion of participants with BCVA Snellen equivalent of 20/200 or worse from 
baseline (Day 1) over time. 
• Mean change in OCT CST from baseline (Day 1) to Week 48 and over time.  
• Incidence of ocular and systemic AEs up to Week 52. 
• Systemic anti-drug antibody status over time (in the ADA-evaluable population). 
• Systemic pharmacokinetic profile (i.e., systemic exposure) over time (in the 
PK-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 


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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.  
Additional endpoints and full details on statistical considerations will be provided in the SAP. 
9.4.4 
Tertiary/Exploratory Endpoint(s) 
Exploratory endpoints will be described in the SAP. 
9.4.5 
Safety Analysis 
The safety analysis (using the safety set described in Section 9.3) will use outcomes of all 
participants who were exposed to study treatment regardless of adherence to the protocol or 
treatment outcome. Safety analyses will be conducted concurrently with efficacy analyses.  
In addition to analyses of ocular safety events, all reported AEs 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 AEs, per-injection 
rates will also be described. 
9.4.6 
Pharmacokinetic and Biomarker Analysis 
PK analyses will be outlined in the PK Analysis Plan; potential exploratory biomarker analyses 
will be outlined in a Biomarker Analysis Plan. 
9.5 
Interim Analysis 
There is no interim analysis planned for this study.  


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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 
• 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 
and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants 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. 
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 
confidentiality. All records will be kept in a secure storage area with limited access. Upon the 


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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. 
14 
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. 
15 
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. 
• 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 and 
 
  
o 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. 
o 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. 
o 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. 
• For men: agreement to remain abstinent or use contraceptive measures and agreement to 
refrain from donating sperm, as defined below: 
o 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 
 
 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 
pregnancy.  


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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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11.0 
REFERENCES 
1. 
Brown DM, Kaiser PK, Michels M, et al. 2006. Ranibizumab versus verteporfin for 
neovascular age-related macular degeneration. New England Journal of Medicine, 355: 
1432-44. 
2. 
Campochiaro PA. 2015a. Molecular pathogenesis of retinal and choroidal vascular 
diseases. Progress in Retinal and Eye Research, 49: 67-81. 
3. 
Campochiaro PA, Clark WL, Boyer DS, et al. 2015b. Intravitreal Aflibercept for Macular 
Edema Following Branch Retinal Vein Occlusion. Ophthalmology, 122: 538-44. 
4. 
Cheung N, Mitchell P, and Wong TY. 2010. Diabetic retinopathy. The Lancet, 376: 124-
36. 
5. 
Chew EY, Clemons TE, Agron E, et al. 2014. Ten-year follow-up of age-related macular 
degeneration in the age-related eye disease study: AREDS report no. 36. JAMA 
Ophthalmol, 132: 272-7. 
6. 
Foster CSVitale AT. 2013. Diagnosis & Treatment of Uveitis (JP Medical Ltd). 
7. 
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. 
8. 
Heier JS, Brown DM, Chong V, et al. 2012. Intravitreal aflibercept (VEGF trap-eye) in 
wet age-related macular degeneration. Ophthalmology, 119: 2537-48. 
9. 
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. 
10. 
Homayouni M. 2009. Vascular endothelial growth factors and their inhibitors in ocular 
neovascular disorders. Journal of ophthalmic & vision research, 4: 105. 
11. 
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. 
12. 
Jaffe G, Kaiser P, Thompson D, et al. 2016. Visual acuity of eyes with early persistent 
retinal fluid from neovascular age-related macular degeneration in the VIEW studies. 
Ophthalmology, 123: 1856-64. 
13. 
Nguyen QD, Brown DM, Marcus DM, et al. 2012. Ranibizumab for diabetic macular 
edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology, 119: 
789-801. 
14. 
Nussenblatt RB, Palestine AG, Chan C-C, et al. 1985. Standardizatlon of Vitreal 
inflammatory Activity in Intermediate and Posterior Uveitis. Ophthalmology, 92: 467-71. 
15. 
Rosenfeld PJ, Brown DM, Heier JS, et al. 2006. Ranibizumab for neovascular age-related 
macular degeneration. New England Journal of Medicine, 355: 1419-31. 


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16. 
Rubio RGAdamis AP. 2016. 'Ocular angiogenesis: vascular endothelial growth factor and 
other factors.' in, Retinal Pharmacotherapeutics (Karger Publishers). 
17. 
Schmidt-Erfurth U, Chong V, Loewenstein A, et al. 2014. Guidelines for the 
management of neovascular age-related macular degeneration by the European Society of 
Retina Specialists (EURETINA). British Journal of Ophthalmology, 98: 1144-67. 
18. 
Stewart MW, Rosenfeld PJ, Penha FM, et al. 2012. Pharmacokinetic rationale for dosing 
every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and 
aflibercept (vascular endothelial growth factor Trap-eye). Retina, 32: 434-57. 
19. 
Wong WL, Su X, Li X, et al. 2014. Global prevalence of age-related macular 
degeneration and disease burden projection for 2020 and 2040: a systematic review and 
meta-analysis. Lancet Glob Health, 2: e106-16. 
 

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 Neovascular 
(Wet) Age-related Macular Degeneration (wAMD)
NCT Number:  
NCT04964089
Document Date:  
SAP Version 1.0, 20 June 2023


 
STATISTICAL ANALYSIS PLAN 
 
 
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 Neovascular (Wet) Age-
related Macular Degeneration (wAMD) (DAYLIGHT) 
 
 
Sponsor: 
Kodiak Sciences Inc. 
1200 Page Mill Road 
Palo Alto, CA 94304 USA 
Sponsor Contact  
& Medical Monitor: 
 
Kodiak Sciences Inc. 
IND Number: 
136167 
Protocol Numbers: 
KS301P107 
EUDRACT Number: 
2021-000225-27 
Test Product: 
KSI-301 (tarcocimab tedromer) 
Statistical Analysis Plan Version: 
1.0 
Statistical Analysis Plan Version 
Date:  
June 20, 2023 
Supersedes:  
N/A 
 
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. 
 
 


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2 
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 Neovascular (Wet) Age-related Macular 
Degeneration (wAMD) (DAYLIGHT) 
Protocol Code: 
KS301P107 
Statistical Analysis Plan Version: 
1.0 
Statistical Analysis Plan Version 
Date: 
June 20, 2023 
Prepared by: 
 
 
Statistical Analysis Plan Accepted and Approved by: 
 
 
 
 
 
Kodiak Sciences Inc. 
1200 Page Mill Rd. 
Palo Alto, CA 94304 
 
Date 
 
 
 
 
 
Kodiak Sciences Inc. 
1200 Page Mill Rd. 
Palo Alto, CA 94304 
 
Date 
 
 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .............................................................................................1 
SPONSOR SIGNATORY .............................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF TABLES .........................................................................................................................4 
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 
Study Interventions ................................................................................................10 
3.3 
Randomization and Stratification ..........................................................................10 
4.0 
TYPES OF PLANNED ANALYSES .............................................................................10 
4.1 
Data Monitoring Committee Analyses ..................................................................10 
4.2 
Interim Analyses ....................................................................................................10 
4.3 
Final Analysis ........................................................................................................11 
5.0 
GENERAL STATISTICAL METHODS ......................................................................11 
5.1 
Reporting Conventions ..........................................................................................11 
5.2 
Standard Calculations ............................................................................................12 
5.3 
Study Definitions and Derived Variables ..............................................................13 
5.4 
Analysis Sets ..........................................................................................................13 
5.4.1 
Full Analysis Set ...................................................................................13 
5.4.2 
Safety Analysis Set ...............................................................................13 
5.5 
Examination of Subgroups .....................................................................................13 
5.6 
Multiple Comparisons/Multiplicity .......................................................................15 
5.7 
Multicenter Study...................................................................................................15 
5.8 
Analysis Visit .........................................................................................................15 
6.0 
BASELINE ANALYSES .................................................................................................16 
6.1 
Disposition of Subjects ..........................................................................................16 
6.2 
Demographic and Other Baseline Characteristics .................................................16 
6.2.1 
Demographics and Baseline Characteristics .........................................16 
6.2.2 
Ocular and Other Medical History ........................................................17 
6.2.3 
Prior and Concomitant Medications/Procedures ...................................17 




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Table 3: Windows for Unscheduled Visit ......................................................................................15 
Table 4: Secondary Efficacy Endpoints and Analysis Methods ....................................................25 
Table 5: Exploratory Efficacy Endpoints and Analysis Methods ..................................................26 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ANCOVA 
Analysis of covariance 
AE 
Adverse event 
AESI 
AI 
Adverse event of special interest 
Artificial intelligence 
ALT 
Alanine aminotransferase 
AMD 
Age-related Macular Degeneration 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATE 
Arteriothromboembolic 
BCVA 
Best-corrected visual acuity 
BP 
Blood pressure 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel  
CNV 
Choroidal Neovascularization 
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 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FP 
Fundus photography 
ICE 
Intercurrent event 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug (application) 
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 
MNAR 
Missing not at Random 
MedDRA 
The Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
NI 
Non-Inferiority 


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Abbreviation 
Definition 
OCT 
Optical Coherence Tomography 
PT 
Preferred Term 
RAP 
Retinal Angiomatous Proliferations 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment Emergent AE 
ULN 
Upper Limits of Normal 
VA 
Visual acuity 
VEGF 
Vascular Endothelial Growth Factor 
VRC 
WHO 
Vienna Reading Center 
World Health Organization 
 
 
 


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1.0 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide a comprehensive and detailed 
description of the methods and presentation of data analyses for Study KS301P107 (Protocol 
Amendment 2.0, dated 16 March 2022), 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 
Neovascular (Wet) Age-related Macular Degeneration (wAMD) (DAYLIGHT).  This study is 
conducted in accordance with the protocols, Good Clinical Practice, the Declaration of Helsinki, 
and any other applicable regulatory requirements. 
Descriptions of planned analyses are provided a priori to preserve the validity of the 
interpretation of the statistical analysis results pertaining to the primary and secondary efficacy 
endpoints.  The statistical methods applied in the design and planned analyses are consistent with 
the International Council for Harmonisation (ICH) guidelines Statistical Principles for Clinical 
Trials (E9) (1998) and ICH E9 (R1) Addendum on Estimands and Sensitivity Analysis in Clinical 
Trials to the Guideline on Statistical Principles for Clinical Trials (2020).  
This SAP provides details of the statistical analysis results to be presented in the clinical study 
reports (CSR).  Analyses of pharmacokinetics, biomarkers, and anti-drug antibodies will be 
addressed in separate analysis plan(s). 
Any changes between the statistical methods and study endpoints provided in the clinical study 
protocol and this SAP will be described and explained in Section 10.0; any changes or deviations 
from this SAP relative to the final analyses will be fully documented in the CSR.  Minor changes 
or deviations from the templates for tables, figures, and listings need not be documented in the 
CSR. 
 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
Table 1 lists the primary and secondary study objectives, along with their corresponding 
endpoints. 




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safety and efficacy assessments at Week 48, and a final follow-up for safety assessments at 
Week 52 
  
The primary endpoint is defined as the mean change in ETDRS BCVA from baseline (Day 1) to 
the average of Weeks 40, 44, 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 groups: 
o KSI-301 5 mg, or 
o Aflibercept 2 mg. 
 
3.2 
Study Interventions 
Study interventions are summarized in the Protocol Table 2. 
 
3.3 
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 
 
   
 
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.  
 


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4.3 
Final Analysis 
The final analysis will be performed when all patients have either completed all phases of the 
study or have discontinued the study prematurely.   
 
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: 


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o The mean and median will be rounded to an additional decimal place than the 
precision of the variable of summarization;  
o Measures of variability (e.g., SD, SE) will be rounded to two additional decimal 
places than the precision of the variable of summarization; and 
o 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: 
o 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 
o 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: 
o 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. 
o 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: 
o If the provided year matches the year for that subject’s first dose date, then the 
first dose date will be used. 
o In all other cases the 1st of January will be used with the provided year. 
Stop dates will be imputed as follows: 


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o Missing day with a provided year and month will use the last day of the month. 
o 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. 
Other variables requiring calculations will be derived using the following formulas: 
o Days: A duration between two dates expressed in days will be calculated using 
the following conventions: 
- 
Later date – earlier date + 1. 
o Months: A duration expressed in months will be calculated by dividing the 
duration in days by (365.25 /12). 
o 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 
Baseline values are defined as the most recent values prior to the first dose of study treatment.  
 
5.4 
Analysis Sets 
The efficacy and safety analyses that are specified in Sections 7.0 and 8.0 will utilize the analysis 
sets as specified in this section.   
 
5.4.1 Full Analysis Set 
The Full Analysis Set (FAS) includes all patients who received any study treatment (KSI-301 or 
aflibercept).  Patients will be analyzed according to their randomized treatment.  The FAS will 
be used in the primary analysis of efficacy. 
 
5.4.2 Safety Analysis Set  
The Safety Analysis Set includes all patients who received any study treatment (KSI-301 or 
aflibercept).  Patients will be analyzed according to the study treatment they actually received.  
 
5.5 
Examination of Subgroups 
The primary efficacy endpoints will be summarized in the following subgroups of baseline 
characteristics. 










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o Prior medications are those taken prior to the start of the first dose of study 
treatment 
o 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 Safety 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 KSI-301 group.  Where groups 
or terms tie will be sorted by descending order in the Aflibercept group, then alphabetically. 
 
Prior medications and concomitant medications (ocular and non-ocular) will be listed separately 
for the Safety Analysis Set.  
The following will be summarized and listed for concomitant medications and procedures: 
o Ocular (study eye and fellow eye separately) and non-ocular concomitant 
medications that were initiated before start of treatment.  
o Ocular (study eye and fellow eye separately) and non-ocular concomitant 
medications that were initiated after the start of treatment. 
o Medications prescribed after study treatment discontinuation for patients who 
remain in the study will be listed separately.  
o Concomitant ocular procedures (study eye and fellow eye separately) 
administered while patients were on study treatment will be summarized and 
listed.  
o Concomitant study eye procedures administered after study treatment 
discontinuation for patients 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-
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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. 
 
6.3 
Protocol Deviations 
All major protocol deviations will be determined and summarized by treatment group and 
overall.  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.  
 
7.0 
EFFICACY ANALYSES 
7.1 
Primary Efficacy Analysis 
7.1.1 Primary Estimand 
7.1.1.1 
Target Population 
The population targeted by the scientific question is treatment-naïve patients with visual 
impairment from wAMD. 
The most relevant aspects of the study eligibility criteria for defining this population include the 
following key inclusion and exclusion criteria: 
Inclusion criteria: 
1. Active, treatment-naïve choroidal neovascularization (CNV) secondary to AMD, including 
subfoveal, juxtafoveal, and extrafoveal lesions, or retinal angiomatous proliferations (RAP) 
lesions with a CNV component that affects the central subfield, as evidenced by FA or OCT 
in the Study Eye at Screening. 
2. The lesion area in the Study Eye must be <30 mm2 (12-disc areas) and can include any CNV 
lesion subtype. 
3. Intra- and/or subretinal fluid and/or subretinal hyperreflective material (SHRM) affecting the 
central subfield of the Study Eye on OCT at Screening. 
4. BCVA ETDRS score between 83 and 25 letters, inclusive, in the Study Eye at screening and 
reconfirmed at Day 1. 
Exclusion criteria: 
1. CNV secondary to other causes in the Study Eye, including pathologic myopia, angioid 
streaks, prior trauma, ocular histoplasmosis, or others. 


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2. Any history of macular pathology unrelated to AMD but affecting vision or contributing 
to subretinal or intraretinal fluid, such as central serous chorioretinopathy.  
3. Prior treatment with any approved or investigational treatment for neovascular AMD 
(other than oral vitamin supplements) in the Study Eye at any time. 
 
7.1.1.2 
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 the average of non-missing BCVA values of Weeks 40, 44 and 48. 
 
7.1.1.3 
Hypotheses and Test 
The maximum clinically acceptable true difference between KSI-301 and aflibercept among 
wAMD patients to be considered non-inferior is 4.5 ETDRS letters, i.e. the non-inferiority 
margin (NI) is 4.5 letters. 
The hypothesis to be tested is:  
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 Weeks 40, 44 and 48 average BCVA 
in the KSI-301 and aflibercept groups. 
 
If the lower limit of the two-sided 95.03% CI for the difference between the two means is >-4.5 
letters, NI will be demonstrated.  Furthermore, superiority will be established if the lower limit of 
the two-sided 95.03% confidence interval for the treatment difference (KSI-301 – aflibercept) is 
greater than zero. 
 
7.1.1.4 
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 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. 






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The empirical permutation distribution of the difference between the trimmed means based on 
2.485 and 97.515 percentiles will be derived. 
 
If the proportion of patients “to be trimmed” in either treatment group in the permuted datasets 
exceeds the planned trimmed fraction p, the trimming fraction will be the maximum of the 
proportions of the "patients to be trimmed" in the two treatment groups. 
 
7.1.5 Sensitivity Analysis 3 (Tipping Point Analysis) 
A tipping point analysis will be performed 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 FAS 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 40, 44 or 48 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 penalty will be applied to the imputed primary efficacy endpoint for the Weeks 40, 44 
and 48 in step 1a. 
Fifteen complete data sets will be generated. The proposed number of imputed datasets will 
ensure an efficiency of at least 99% assuming a maximum of 12% rate of missing primary 
efficacy endpoint data using Rubin’s approximation (Rubin 1987). 
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 average of Weeks 40, 44 
and 48 treatment difference. 
Steps 1-3 are repeated for each of the two scenario 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 penalty 
value that will render the lower bound of the confidence interval for mean treatment differences 
to be less than or equal to -4.5 letters.  After the tipping point is identified, clinical judgment will 
determine the plausibility of the assumptions underlying this tipping point. 
 


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7.2 
Secondary Efficacy Analyses 
Table 4 lists the secondary efficacy endpoints, efficacy variable derivations, reporting statistics 
and analysis methods for the Final Analysis. 
 
7.2.1 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 well the number and percentage of 
patients with BCVA of 20/40 or better Snellen equivalent, BCVA or 20/200 or worse Snellen 
equivalent.  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 3.3). 
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 
[FAS], up to Wk 48 
 
Using the MMRM model (Section 7.1.2) 
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  
[FAS], up to Wk 48 
Stratified analysis of the binary endpoint 
using CMH adjusting for randomization 
stratification factors (Section 7.2.1) 
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] 
Mean change in OCT central 
subfield retinal thickness (CST) 
from baseline to the average of 
Weeks 40, 44 and 48 and over 
time 
Continuous Endpoint: 
Change from baseline to each time point  
[
]  
 
LS Mean difference in change 
from baseline to each time 
point 
[FAS], up to Wk 48 
MMRM (similar to Section 7.1.2) 
adjusting for baseline CST, with time, 
treatment, and time*treatment 
interaction and randomization 
stratification as factors 
Unstructured covariance matrix 


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7.3 
Exploratory Analyses 
Analysis of the following exploratory endpoints may be undertaken as deemed appropriate. Intraretinal fluid (IRF) and subretinal fluid (SRF) 
data using AI-based grading algorithms may be explored. 
Table 5: Exploratory Efficacy Endpoints and Analysis Methods 
Exploratory Efficacy 
Endpoint 
Variable Derivation  
[Source] 
Summary Statistics  
[Analysis Set] 
Method of Analysis 
Proportion of subjects with 
OCT central subfield retinal 
thickness (CST) < 325 microns 
over time 
Binary endpoint: 
Subject with OCT CST < 325 microns (yes/no) 
[
] 
Difference in proportions (%) 
and 95% CI at each time point  
[FAS], up to Wk 48 
Stratified analysis of the binary endpoint 
using CMH adjusting for randomization 
stratification factors (Section 7.2.1) 
Mean change from baseline in 
BCVA (ETDRS Letters) to the 
average of non-missing BCVA 
values of Weeks 40, 44 and 48 
by: ≥ median vs. < median of 
baseline OCT-CST 
Continuous endpoint:  
Change from baseline to average of non-
missing BCVA values of Weeks 40, 44 and 48  
[Visual Acuity Score/EDC] 
LS Mean difference in change 
from baseline to the average of 
non-missing values of Weeks 
40, 44 and 48 
[FAS], Wks 40-48 average 
 
Using the MMRM model (Section 7.1.2) 
used for deriving the primary endpoint 
estimate 
 
 
 
 


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7.4 
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 the average of Weeks 40, 44 and 48) will be analyzed using an MMRM 
that is described in Section 7.1.2.  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. 
8.0 
SAFETY EVALUATION 
Safety analyses will be performed for the Safety Analysis Set.  In the Final Analysis, the safety 
data will be summarized by treatment group. 
 
8.1 
Exposure to Study Medication 
Study eye exposure to study medication will be summarized.  Summaries will include: 
o 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. 
o Duration of study drug exposure (mean [SD] and median, in months) for subjects 
receiving KSI-301 5 mg or aflibercept 2 mg defined as treatment end date minus 
treatment start date + 1. 
o 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.  
 
8.2 
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 with onset date on or after the initiation of study drug through the last dose date 
of study drug + 28 days or non-study anti-VEGF start date in study eye on or after last dose date 
are considered treatment-emergent AEs (TEAEs), whichever occurs first.  
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 
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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 for the following: 
o Ocular TEAEs and treatment-emergent serious AEs (TESAEs) (study eye and 
fellow eye separately) 
o Non-ocular TEAEs and TESAEs  
o Ocular TEAEs leading to study treatment discontinuation (study eye and fellow 
eye separately) 
o Ocular TEAEs by severity (study eye and fellow eye separately) 
o Non-ocular TEAEs by severity  
o Related ocular TEAEs (study eye and fellow eye separately) by severity 
o Related non-ocular TEAEs by severity  
o Intraocular inflammation TEAEs and TESAEs not associated with infection, 
autoimmunity, drug toxicity, or traumatic etiologies (study and fellow eye 
separately)  
o IOI TEAEs and TESAEs associated with infection (study and fellow eye 
separately)  
o IOI TEAEs and TESAEs associated with autoimmune, drug toxicity, or trauma 
(study and fellow eye separately) 
o Arteriothromboembolic (ATE) Adverse Events. ATEs will be tabulated as those 
events meeting the Anti-Platelet Trialists’ Collaboration criteria (i.e., nonfatal 
myocardial infarction, nonfatal stroke, and vascular death, including deaths of 
unknown cause) 
o Adverse events of special interest [AESI] (study eye, fellow eye, and non-ocular 
separately), as defined in the protocol Section 8.3.6 
o Injection procedure related TEAEs and TESAEs (study eye) 
o Non-serious TEAEs and TESAEs (study eye, fellow eye and non-ocular 
combined) 
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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8.3 
Deaths, Serious Adverse Events, and other Significant Adverse Events 
All deaths during the study will be listed by treatment group 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. 
 
8.4 
Pregnancies 
Listings of pregnancies, if any, and outcomes will be presented.  
 
8.5 
Intraocular Pressure 
For the 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. 
 
8.6 
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 48. 
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 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. 
 
8.7 
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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9.0 
SAMPLE SIZE CONSIDERATIONS 
The sample size for this study 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. 
• Actual expected mean treatment difference between treatments of at most -0.3 
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 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 500 patients (250 per 
treatment arm).  
  
10.0 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES 
No changes in the conduct of the study have occurred relative to the latest version of the protocol 
at this time.  
In this SAP, the Sponsor has defined the primary estimand, analysis populations, and strategies 
for addressing intercurrent events, missing data, and a set of sensitivity analyses for the primary 
efficacy outcome.  Where relevant, these definitions take precedence over those defined in the 
study protocol. 
Also in this SAP, the Sponsor has clarified that the non-inferiority margin will be 4.5 letters for 
the primary efficacy endpoint and corresponding sensitivity analyses per the FDA’s draft 
guidance on wAMD drug development dated February 2023.  
 


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11.0 
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. 
US Food and Drug Administration Draft Guidance Document – Neovascular Age-Related 
Macular Degeneration: Developing Drugs for Treatment (February 2023). Available at 
https://www.fda.gov/media/165606/download.  
Rubin, D.B. (1987) Multiple Imputation for Nonresponse in Surveys, New York, John Wiley and 
Sons. 
Littell, Ramon C., George Milliken, Walter W. Stroup, Russell D. Wolfinger, and Oliver 
Schabenberger (2006) SAS(R) for Mixed Models, 2nd Edition (2006), SAS Institute, Cary NC.  
Little, R.J.A. and Rubin, D.B. (2002). Statistical Analysis with Missing Data, 2nd edition, New 
York: John Wiley.  
SAS/STAT® 14.1 User’s Guide The MIANALYZE Procedure, SAS institute, Cary, NC, 
available online at https://support.sas.com/documentation/onlinedoc/stat/141/mianalyze.pdf  
SAS/STAT® 14.1 User’s Guide The MI Procedure, SAS institute, Cary, NC, available online at 
https://support.sas.com/documentation/onlinedoc/stat/141/mi.pdf.  
van Buuren, Stef Flexible Imputation of Missing Data, 2nd Edition (2018). 
Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat. 2017 
 
12.0 
APPENDICES 
Appendix 1: Schedule of Activities 
 
 






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Abbreviations: ADA = anti-drug antibody; AE = adverse event; BCVA = best corrected visual acuity; ET = early termination; ETDRS = early treatment diabetic 
retinopathy study; IRT = interactive response technology; 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 protocol Section 8.3.1. 
3 
Height and weight are taken at screening only. 
4 
Clinical laboratory test as described in Appendix 2 and Table 4. 
5 
Blood draws for ADA, plasma PK, and biomarker samples are to be taken pre-injection.  
6 
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. 
7 
Ophthalmic assessments will be performed in both eyes at Screening and Week 48, and in the Study Eye only at all other timepoints. 
8 
Perform BCVA before any other ophthalmic assessments and prior to dilation. 
9 
Method used to measure IOP must remain consistent throughout study. 
10 
It is mandatory that the same model of device is used for the entire duration of the study. 
11 
Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in protocol Section 7.1. 
12 
Post injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
13 
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.