Clinical trial NCT04603937
Conditions: Diabetic Macular Edema
Keywords: DME Kodiak Vascular endothelial growth factor Anti-VEGF VEGF Antibody biopolymer conjugate Retinal Degeneration Retinal Diseases Eye Diseases Vision Disorders Vision, low Aflibercept Eylea Diabetes mellitus Diabetes Diabetic retinopathy Diabetic macular edema Macular edema KSI-301
Sponsor: Kodiak Sciences Inc
Start date: 2020-09-30; Completion date: 2023-08-31
Enrollment: 459 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3 study will evaluate the efficacy, durability, and safety of KSI-301 compared to aflibercept in participants with treatment-naïve DME.

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 treatment-naïve DME.

The primary endpoint will be assessed at Year 1; additional secondary endpoints for efficacy will be assessed at Years 1 and 2.

Arms: arm 1: Intravitreal injection of KSI-301 (5 mg) once every 4 weeks for 3 monthly doses followed by an individualized dosing regimen (every 8 to 24 weeks) via intravitreal injection from Week 16 to Week 100. arm 2: Intravitreal injection of aflibercept (2 mg) once every 4 weeks for 5 monthly doses followed by aflibercept (2 mg) once every 8 weeks via intravitreal injection from Week 24 to 100.
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: 
CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
1 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Prospective, Randomized, Double-masked, Active 
Comparator-controlled, Multi-center, Two-arm, Phase 3 Study to 
Evaluate the Efficacy and Safety of Intravitreal KSI-301 
Compared with Intravitreal Aflibercept in Participants with 
Visual Impairment Secondary to Treatment-naïve Diabetic 
Macular Edema (DME) 
Protocol Number: 
KS301P105 
Version Date: 
15 March 2022 
Amendment Number: 
2.0 
Supersedes:  
Version 1 
Test Product: 
KSI-301 
Brief Title: 
A Study to Evaluate the Efficacy and Safety of KSI-301 
Compared to Aflibercept in Participants with Diabetic Macular 
Edema (DME) 
Study Phase: 
3 
Study Acronym/Name: 
GLIMMER 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 USA 
Sponsor Contact & Medical 
Monitor: 
 
Kodiak Sciences Inc. 
IND Number: 
136167 
EudraCT Number: 
2020-001063-82 
 
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 KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
2 
PROTOCOL APPROVAL – SPONSOR SIGNATORY 
 
Study Title:  
A Prospective, Randomized, Double-masked, Active Comparator-
controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate the Efficacy 
and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept 
in Participants with Visual Impairment Secondary to Treatment-naïve 
Diabetic Macular Edema (DME) (GLIMMER) 
Protocol Number:  KS301P105 
Version Date: 
15 March 2022 
 
Protocol accepted and approved by: 
 
 
 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 
 
 
 
 
 
Signature 
 
Date 
 
 
 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
3 
PROTOCOL APPROVAL – PRINCIPAL 
INVESTIGATOR SIGNATORY 
 
Study Title:  
A Prospective, Randomized, Double-masked, Active Comparator-
controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate the Efficacy 
and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept 
in Participants with Visual Impairment Secondary to Treatment-naïve 
Diabetic Macular Edema (DME) (GLIMMER) 
Protocol Number:  KS301P105 
Version Date: 
15 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 KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
4 
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............................................................................................................21 
2.1 
Study Rationale ......................................................................................................21 
2.2 
Background ............................................................................................................21 
2.2.1 
Diabetic Macular Edema .......................................................................21 
2.2.2 
Vascular Endothelial Growth Factor .....................................................22 
2.2.3 
Description of KSI-301 .........................................................................22 
2.3 
Benefit/Risk Assessment .......................................................................................23 
2.3.1 
Known Potential Benefits .....................................................................23 
2.3.2 
Known Potential Risks ..........................................................................23 
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....................................................................32 
4.2.1 
Choice of Population .............................................................................32 
4.2.2 
Choice of Active Comparator Control ..................................................33 
4.2.3 
Choice of Primary Endpoint and Analysis ............................................33 
4.2.4 
Choice of Duration of Treatment and Follow-up ..................................34 
4.3 
Justification for Dose .............................................................................................34 
4.3.1 
KSI-301 Dose Rationale .......................................................................34 
4.3.2 
Aflibercept Dose Rationale ...................................................................35 
4.3.3 
Sham Injection Rationale ......................................................................35 
4.4 
End of Treatment ...................................................................................................35 
4.5 
End of Study Definition .........................................................................................36 
4.6 
Treatment After End of Study................................................................................36 
5.0 
STUDY POPULATION ..................................................................................................37 
5.1 
Inclusion Criteria ...................................................................................................37 
5.1.1 
Ocular Inclusion Criteria .......................................................................37 


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Protocol KS301P105 Version 2.0 
 
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5.1.2 
General Inclusion Criteria .....................................................................37 
5.2 
Exclusion Criteria ..................................................................................................38 
5.2.1 
Ocular Exclusion Criteria ......................................................................38 
5.2.2 
General Exclusion Criteria ....................................................................39 
5.3 
Lifestyle Considerations ........................................................................................40 
5.4 
Screen Failures .......................................................................................................40 
5.5 
Criteria for Temporarily Delaying Enrollment ......................................................41 
6.0 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ..........................42 
6.1 
Study Intervention(s) Administered .......................................................................42 
6.2 
Preparation/Handling/Storage/Accountability .......................................................44 
6.2.1 
Preparation, Handling, and Storage ......................................................44 
6.2.2 
Study Intervention Accountability and Reconciliation .........................44 
6.3 
Measures to Minimize Bias: Randomization and Masking ...................................45 
6.3.1 
Randomization ......................................................................................45 
6.3.2 
Masking and Unmasking ......................................................................45 
6.4 
Study Intervention Compliance .............................................................................47 
6.5 
Dose Modification .................................................................................................47 
6.6 
Continued Access to Study Intervention after the End of the Study .....................47 
6.7 
Treatment of Overdose ..........................................................................................47 
6.8 
Concomitant Therapy.............................................................................................48 
6.8.1 
Pan-retinal Photocoagulation (PRP) .....................................................48 
6.8.2 
Prohibited Therapy ................................................................................48 
6.8.3 
Supportive Care for Adverse Events .....................................................49 
7.0 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................................50 
7.1 
Discontinuation of Study Intervention ...................................................................50 
7.1.1 
Treatment Interruption and/or Discontinuation due to Adverse 
Events or Concomitant Procedures .......................................................50 
7.2 
Participant Discontinuation/Withdrawal from the Study .......................................51 
7.3 
Lost to Follow up ...................................................................................................52 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................53 
8.1 
Efficacy Assessments.............................................................................................53 
8.1.1 
Medical History and Demographic Data...............................................53 
8.1.2 
Ophthalmic Exams ................................................................................53 
8.1.3 
Injection Procedure ...............................................................................54 
8.1.4 
Post Injection Assessments in the Study Eye ........................................54 
8.1.5 
Best Corrected Visual Acuity (BCVA) .................................................55 


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8.1.6 
Fundus Photography (FP) .....................................................................55 
8.1.7 
Spectral Domain Optical Coherence Tomography (SD-OCT) .............55 
8.1.8 
Optical Coherence Tomography – Angiography (OCT-A) ..................55 
8.1.9 
Fluorescein Angiography (FA) .............................................................55 
8.1.10 
Disease Activity Assessments ...............................................................56 
8.2 
Safety Assessments ................................................................................................56 
8.2.1 
Vital Signs .............................................................................................56 
8.2.2 
Clinical Safety Laboratory Assessments ...............................................56 
8.2.3 
Pregnancy Testing .................................................................................57 
8.3 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting................................................................................................................57 
8.3.1 
Time Period and Frequency for Collecting AE and SAE 
Information ............................................................................................57 
8.3.2 
Method of Detecting AEs and SAEs .....................................................58 
8.3.3 
Follow-up of AEs and SAEs .................................................................58 
8.3.4 
Regulatory Reporting Requirements for SAEs .....................................58 
8.3.5 
Pregnancy ..............................................................................................58 
8.3.6 
Adverse Events of Special Interest .......................................................59 
8.4 
Pharmacokinetics ...................................................................................................60 
8.5 
Genetics and/or Pharmacogenomics ......................................................................60 
8.6 
Biomarkers .............................................................................................................60 
8.7 
Immunogenicity Assessments ................................................................................60 
8.8 
Health Economics or Medical Resource Utilization and Health Economics ........61 
9.0 
STATISTICAL CONSIDERATIONS ...........................................................................62 
9.1 
Study Hypothesis ...................................................................................................62 
9.2 
Sample Size Determination....................................................................................62 
9.3 
Analysis Sets ..........................................................................................................63 
9.4 
Statistical Analyses ................................................................................................63 
9.4.1 
General Considerations .........................................................................64 
9.4.2 
Primary Endpoint(s) ..............................................................................64 
9.4.3 
Secondary Endpoint(s) ..........................................................................65 
9.4.4 
Tertiary/Exploratory Endpoint(s) ..........................................................66 
9.4.5 
Safety Analysis .....................................................................................66 
9.4.6 
Pharmacokinetic and Biomarker Analysis ............................................67 
9.4.7 
China Subpopulation Analyses .............................................................67 
9.5 
Interim Analysis .....................................................................................................67 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
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10.0 
APPENDICES WITH SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS ........................................................................68 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................69 
10.1.1 
Regulatory and Ethical Considerations .................................................69 
10.1.2 
Financial Disclosure and Financial Obligations ...................................69 
10.1.3 
Informed Consent Process ....................................................................70 
10.1.4 
Data Protection ......................................................................................70 
10.1.5 
Committees Structure ............................................................................71 
10.1.6 
Data Quality Assurance.........................................................................71 
10.1.7 
Source Documents ................................................................................72 
10.1.8 
Study and Site Start and Closure ...........................................................72 
10.1.9 
Publication Policy .................................................................................73 
10.2 
Appendix 2: Clinical Laboratory Tests ..................................................................74 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...................................................................75 
10.3.1 
Definition of AE ....................................................................................75 
10.3.2 
Definition of SAE .................................................................................76 
10.3.3 
The Recording and Follow-Up of AE and/or SAE ...............................76 
10.3.4 
Reporting of SAEs ................................................................................78 
10.4 
Appendix 4: Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreous Cells or Haze. ................................................................................80 
10.4.1 
Grading Scales for Anterior Chamber Cells or Flare ............................80 
10.4.2 
Grading Scale for Vitreous Cells ..........................................................81 
10.4.3 
Grading Scale for Vitreous Haze ..........................................................81 
10.5 
Appendix 5: Unscheduled Safety Assessment Visits ............................................82 
10.6 
Appendix 6: Contraceptive and Barrier Guidance .................................................83 
10.6.1 
Definitions .............................................................................................83 
10.6.2 
Contraception Guidance ........................................................................84 
10.6.3 
Collection of Pregnancy Information ....................................................84 
10.7 
Appendix 7: Liver Safety .......................................................................................86 
10.8 
Appendix 8: Protocol Amendment History ...........................................................87 
11.0 
REFERENCES .................................................................................................................88 
 
 
 


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LIST OF TABLES 
Table 1:  
Protocol KS301P105: Risk Assessment ....................................................24 
Table 2:  
Protocol KS301P105: Study Interventions ................................................43 
Table 3:  
Protocol KS301P105: Treatment Interruption Criteria ..............................51 
Table 4:  
Protocol KS301P105: Required Safety Laboratory Tests .........................74 
Table 5: 
Protocol KS301P105: Amendment History ...............................................87 
 
LIST OF FIGURES 
Figure 1: 
Protocol KS301P105: Schema ...................................................................17 
Figure 2: 
Protocol KS301P105: Masked Dosing Regimens by Week ......................29 
Figure 3: 
Protocol KS301P105: Determination of the Base Treatment Interval 
for Patients Randomized to KSI-301 5 mg ................................................30 
Figure 4: 
Protocol KS301P105: Modification of Base Treatment Interval for 
Patients Randomized to KSI-301 5 mg ......................................................31 
 
 
 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ABC 
Antibody biopolymer conjugate 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AMD 
Age-related macular degeneration 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATE 
Arterial thromboembolic events 
BCVA 
Best corrected visual acuity 
BP 
Blood pressure 
BRVO 
Branch retinal vein occlusion 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CFP 
Color fundus photographs 
CFR 
Code of federal regulations 
CIOMS 
Council for international organizations of medical sciences 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CRVO 
Central retinal vein occlusion 
CST 
Central subfield thickness 
DM 
Diabetes mellitus 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy  
ECG 
Electrocardiograph 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMEA 
Europe, Middle East, Africa 
ET 
Early termination 
ETDRS 
Early treatment diabetic retinopathy study 
FA 
Fluorescein angiography  
FDA 
Food and drug administration  


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Protocol KS301P105 Version 2.0 
 
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FP 
Fundus photography  
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
hCG 
Human chorionic gonadotropin 
HIPAA 
Health insurance portability and accountability act 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent or institutional ethics committee 
IMP 
Investigational medicinal product 
IOP 
Intraocular pressure 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
Intent to treat 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
ME 
Macular edema 
MedDRA 
Medical dictionary for regulatory activities 
NA 
North America 
NAB 
Neutralizing antibody 
NI 
Non-inferiority 
NIMP 
Non-investigational medical product 
NME 
New molecular entity  
NPDR 
Non-proliferative diabetic retinopathy 
OCT 
Optical coherence tomography  
OTC 
Over the counter 
PDR 
Proliferative diabetic retinopathy 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PRP 
Pan-retinal photocoagulation  


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
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QxW 
Once every x weeks; x = 4, 8, 12, 16, 20, or 24 
QTL 
Quality tolerance limits 
RBC 
Red blood cells 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan  
SAR 
Serious adverse reaction  
SD-OCT 
Spectral domain optical coherence tomography  
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SmPC 
Summary of product characteristics  
SoA 
Schedule of activities  
SUN 
Standardization of uveitis nomenclature  
SUSAR 
Suspected unexpected serious adverse reactions 
ULN 
Upper limits of normal 
USPI 
U.S. Prescribing Information 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 
VEGFR1 
Vascular endothelial growth factor receptor 1 
VEGFR2 
Vascular endothelial growth factor receptor 2 
wAMD 
Wet (neovascular) age-related macular degeneration  
WBC 
White blood cells 
WOCBP 
Women of childbearing potential  
 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
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1.0 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Number: KS301P105 
Version: 2.0 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001063-82 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA  94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Secondary to Treatment-naïve Diabetic Macular Edema (DME) (GLIMMER) 
Brief Title: 
A Study to Evaluate the Efficacy and Safety of KSI-301 Compared to Aflibercept in Participants with Diabetic 
Macular Edema (DME) 
Brief Study Rationale: 
KSI-301 is a novel, potent, long-acting biopharmaceutical that inhibits vascular endothelial growth factor (VEGF). 
Compared to aflibercept, KSI-301 has an extended ocular half-life, which may result in a less frequent treatment 
regimen. Thus, this study has been designed to evaluate a less frequent treatment regimen of KSI-301 5 mg 
compared to aflibercept 2 mg in participants with DME. 
Development Phase: 3 
Countries/ Regions: NA (North America), EMEA (Europe, 
Middle-East, Africa), and APAC (Asia-Pacific) 
Study Period: Approximately 3 years 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
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Protocol Number: KS301P105 
Version: 2.0 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001063-82 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA  94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Secondary to Treatment-naïve Diabetic Macular Edema (DME) (GLIMMER) 
Objectives and Key Endpoints: 
Objectives 
Key Endpoints 
Primary 
To demonstrate that KSI-301 5 mg is non-inferior to 
aflibercept 2 mg with respect to mean change in best 
corrected visual acuity (BCVA) from Day 1 to Year 1 
(average of Weeks 60 and 64). 
• 
Mean change in BCVA from baseline (Day 1) to 
the average of Weeks 60 and 64 (Year 1) in Early 
Treatment Diabetic Retinopathy Study (ETDRS) 
Letters. 
Secondary 
To evaluate the efficacy of KSI-301 5 mg compared to 
aflibercept 2 mg over the study duration by assessing 
visual parameters. 
• 
Mean change in BCVA (ETDRS Letters) from 
baseline (Day 1) by visit over time.  
• 
Proportion of participants who gain ≥ 5, ≥10 and 
≥15 letters from baseline by visit over time. 
• 
Proportion of participants who lose ≥ 5, ≥10 and 
≥15 letters from baseline by visit over time. 
To evaluate the efficacy of KSI-301 5 mg compared to 
aflibercept 2 mg over the study duration by assessing 
anatomical parameters. 
• 
Mean change in optical coherence tomography 
(OCT) central subfield thickness (CST) and other 
morphological parameters from baseline to the 
average of Weeks 60 and 64 (Year 1) and over 
time.  
• 
Proportion of patients with a ≥ 2-step improvement 
from baseline on the ETDRS DRSS at Week 52. 
To evaluate the durability of KSI-301 5 mg compared to 
aflibercept 2 mg over the study duration. 
• 
Mean number of intravitreal injections over the 
duration of the study. 
• 
Mean number of intravitreal injections from 
baseline to Week 60 and from Week 64 to 104. 
• 
Mean time to first re-treatment after the last 
monthly dose. 
To evaluate the safety and tolerability of KSI-301 5 mg 
compared to aflibercept 2 mg. 
• 
Incidence of ocular and systemic adverse events up 
to Week 64 and Week 108. 
To assess the systemic pharmacokinetics (exposure) and 
immunogenicity of KSI-301. 
• 
Systemic pharmacokinetic profile over time. 
• 
Systemic anti-drug antibody status over time. 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
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Protocol Number: KS301P105 
Version: 2.0 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001063-82 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA  94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Secondary to Treatment-naïve Diabetic Macular Edema (DME) (GLIMMER) 
Design/Methodology/Masking: 
This is a prospective, randomized, double-masked, two-arm, multi-center Phase 3 study to demonstrate that KSI-
301 5 mg is non-inferior to aflibercept 2 mg, with respect to mean change in BCVA from Day 1 to Year 1 (average 
of Weeks 60 and 64), in participants with DME that has not been previously treated.  
One eye per participant will be enrolled in the study.  
Participants will be randomized 1:1 into one of two treatment arms: KSI-301 or aflibercept. Randomization will be 
stratified by 
 
 Treatment arm randomization at Day 1 and treatment or 
sham assignment for the duration of the study will be provided by the interactive response technology (IRT) 
system. 
For masking purposes, sham injections will be administered at each monthly visit if an active treatment is not 
administered. To preserve masking, two investigators are required for this study. The masked Investigator will be 
responsible for the examinations and safety assessments, including causality assessments for adverse events. The 
unmasked Investigator (and unmasked assistants, if any) will perform the intravitreal injections (active treatments 
and sham) and post-treatment assessments. 
This study is divided into a three-week screening period and two efficacy and safety assessment periods, as shown 
in the schema (Section 1.2):  
• 
Year 1: from Day 1 to Week 64; and  
• 
Year 2: from Week 68 to Week 108. 
Number of Participants Planned: 
Approximately 450 
Gender: 
Male or female 
Age: 
Adults ≥18 years of age 
Diagnosis and Main Criteria for Eligibility: 
Eligible participants will have treatment-naïve DME, with vision loss primarily due to DME and center 
involvement (if present) diagnosed within 9 months of screening; and Type 1 or Type 2 diabetes mellitus with a 
hemoglobin A1c (HbA1c) ≤12%.  
Total Participant Duration: 
111 weeks 
Duration of Treatment:  
100 weeks 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
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15 
Protocol Number: KS301P105 
Version: 2.0 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001063-82 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA  94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Secondary to Treatment-naïve Diabetic Macular Edema (DME) (GLIMMER) 
Study Intervention (Investigational Medicinal Product), Dose, and Route of Administration: 
Treatment Arm A:  
• 
Day 1 to Week 12: KSI-301 5 mg once every 4 weeks for 3 monthly doses via intravitreal injection, followed 
by a sham injection at Week 12; 
• 
Week 16 to Week 100: KSI-301 5 mg using an individualized dosing regimen via intravitreal injection. The 
minimum interval between KSI-301 treatments is 8 weeks (± 14 days, considering the respective visit 
windows) and the maximum interval is 24 weeks (± 14 days, considering the respective visit windows). Sham 
injections will be administered at each monthly visit if an active treatment is not administered. 
Study Intervention (Active Control/ Investigational Medicinal Product), Dose, and Route of Administration: 
Treatment Arm B: 
• 
Day 1 to Week 20: Aflibercept 2 mg once every 4 weeks for 5 monthly doses via intravitreal injection, 
followed by a sham injection at Week 20; 
• 
Week 24 to Week 100: 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 defined as the mean change in ETDRS BCVA from baseline (Day 1) to Year 1 (average of Weeks 60 
and 64). The primary assessment of efficacy will be based on a pairwise comparison in mean change in BCVA 
between treatment arm A (KSI-301 5 mg) and treatment arm B (aflibercept 2 mg). Other efficacy outcomes will be 
evaluated using ophthalmic assessments (including tonometry), fundus photography, spectral domain optical 
coherence tomography (SD-OCT), and fluorescein angiography (FA). Secondary endpoints for efficacy will be 
assessed at Week 64 and Week 104. 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 will 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 108 or the early 
termination (ET) visit if applicable, as specified in the SoA (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. 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
16 
Protocol Number: KS301P105 
Version: 2.0 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001063-82 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA  94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Secondary to Treatment-naïve Diabetic Macular Edema (DME) (GLIMMER) 
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, 
 
  
Statistical Methods: 
The study hypothesis is that treatment with KSI-301 5 mg will provide a non-inferior mean change in BCVA 
compared to aflibercept 2 mg, while using a less frequent dosing schedule in participants with DME.  
Using ETDRS BCVA data collected up to Year 1, the treatment arms will be compared using a non-inferiority 
analysis, with a margin of 
. Confidence intervals (CIs) will be 100(1-2α)% or 95% CIs. If the 
null hypothesis of inferiority is rejected, testing for superiority will be performed. 
The sample size of approximately 450 participants (225 per arm) was calculated using the following assumptions: 
• 
Overall type I error rate of 
. Testing at the 
 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 
. 
• 
The maximum, clinically acceptable true difference for KSI-301 to be considered non-inferior, or the “non-
inferiority margin” is 
.  
• 
The statistical test used to compare the two treatment arms at Year 1  is an independent t-test on the mean 
change in visual acuity from baseline. 
• 
Lost to follow-up/dropout rate of approximately 
 
Analysis of data for the first period of the study will be performed when all participants have either completed the 
Week 64 visit or have discontinued from the study, all data have been entered into the database, cleaned and 
verified as appropriate and the database for the primary analysis has been frozen. Likewise, analysis of data for the 
second period of the study will be performed when all participants have either completed the Week 108 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: 
15 March 2022 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
17 
1.2 
Schema 
Figure 1: 
Protocol KS301P105: Schema 
 
Abbreviations: Q4W = once every four weeks; Q8W = once every 8 weeks. 
 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
18 
1.3 
Schedule of Activities (SoA) 
Visit 
Screening Day 1 Week 
1 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 
52 
Visit Windows (Days) 
D-21 to D-1 
 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & Ocular History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Review2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs3 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Laboratory4  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Plasma ADA/NAB Samples (pre-
dose) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Plasma PK/Biomarker Samples 
(pre-dose) 
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
Pregnancy Test5 (WOCBP only)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Assessments6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BCVA ETDRS (4 meters)7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Exam (Slit-lamp, IOP8, 
dilated indirect ophthalmoscopy) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT-Angiography9-11 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Color Fundus Photos10,11 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Fluorescein Angiogram10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomized study treatment 
(KSI-301, aflibercept or sham) per 
IRT Designation 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-injection Assessments (vision 
check, IOP) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
19 
 
Visit 
Week 
56 
Week 
60 
Week 
64 
Week 
68 
Week 
72 
Week 
76 
Week 
80 
Week 
84 
Week 
88 
Week 
92 
Week 
96 
Week 
100 
Week 
104/ET 
Week 
10812 
Visit Windows (Days) 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
Concomitant Medication Review1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Review2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 3 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Laboratory4 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Plasma ADA/NAB Samples 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Plasma PK/Biomarker Samples 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Pregnancy Test5 (WOCBP only)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Assessments6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BCVA ETDRS (4 meters)7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ophthalmic Exam (Slit-lamp, 
IOP8, dilated indirect 
ophthalmoscopy) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SD-OCT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
OCT-Angiography 9-11 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Color Fundus Photos 10,11 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Fluorescein Angiogram10 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Randomized Study Treatment 
(KSI-301, aflibercept, or sham) 
per IRT Designation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Post-injection Assessments 
(vision check, IOP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
20 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; BCVA = best corrected visual acuity; ET = early termination; ETDRS = early treatment diabetic 
retinopathy study; IOP = intraocular pressure; NAB = neutralizing antibody; PK = pharmacokinetics; SAE = serious adverse event; SD-OCT = spectral 
domain optical coherence tomography; WOCBP = women of childbearing potential. 
1. Record any concomitant medication used by the participant within 30 days prior to Day 1. Procedural medications administered (e.g., dilating drops, 
fluorescein) will not be recorded. 
2. After informed consent has been obtained but prior to initiation of study intervention, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study intervention (Day 1), all AEs will be reported until the final study visit or the ET visit if applicable. 
See Section 8.3.1.  
3. Height and weight will be recorded at the screening visit only. 
4. Clinical laboratory test as described in Appendix 2 and Table 4. 
5. Urine pregnancy test will be performed locally for women of childbearing potential, prior to fluorescein angiogram and study treatment (if applicable). If 
urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. Local urine testing will be standard for the protocol unless serum testing is 
required by local regulation or IRB/IEC. 
6. Ophthalmic assessments will be performed in both eyes at Screening, Week 52 and Week 104, and in the Study Eye only at all other timepoints. 
7. Perform BCVA before any other ophthalmic assessments and prior to dilation. 
8. Method used to measure IOP must remain consistent throughout study.  
9. OCT-Angiography to be performed at selected sites. 
10. It is mandatory that the same model of device is used for the entire duration of the study. 
11. For visits that are missed where color fundus photos (CFP) and OCT-Angiography (OCT-A) are scheduled, the CFP and OCT-A should be performed at the 
next possible visit. 
12. 
 
 
 
 


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Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
21 
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 diabetic macular edema (DME), as well as 
wet age-related macular degeneration (wAMD) and retinal vein occlusion (RVO; branch and 
central). KSI-301 offers a potential for participants to experience a longer interval between 
consecutive intravitreal injections compared to existing anti-VEGF therapies. Thus, KSI-301 
may have the potential to improve real-world outcomes of anti-VEGF therapy, which are 
currently limited by both the high treatment burden and insufficient durability of effect in 
patients with DME.  
2.1 
Study Rationale 
Although substantial visual acuity benefits have been demonstrated with the approved 
intravitreal VEGF inhibitors (e.g., aflibercept, ranibizumab) in the first-line treatment of DME, 
the gains require frequent intravitreal injections; this high treatment burden challenges patient 
compliance (Ciulla 2020). Therefore, there is a substantial medical need for more durable 
options that reduce treatment burden. Compared to aflibercept, KSI-301 has an extended ocular 
half-life (Section 2.2.3), which may result in a less frequent treatment regimen. In the ongoing 
Phase 1b portion of Study KSI-CL-101, the safety and efficacy outcomes of participants with 
treatment-naïve wAMD, DME/diabetic retinopathy (DR), or RVO (branch (BRVO) and central 
(CRVO)) treated with KSI-301 5 mg have supported a prolonged treatment interval (2 to ≥6 
months in DME/DR and wAMD, and 2 to ≥4 months in RVO). Thus, this study has been 
designed to evaluate a less frequent treatment regimen of KSI-301 5 mg (individualized dosing 
in intervals ranging from 2-6 months based on disease activity after only three monthly doses) 
compared to aflibercept 2 mg (Q8W after five monthly doses) in participants with DME.  
2.2 
Background 
2.2.1 
Diabetic Macular Edema  
Diabetes mellitus (DM) is a chronic disease that exerts pathologic effects on multiple organ 
systems, including the retina. Diabetic eye disease is the most common microvascular 
complication of DM and includes diabetic retinopathy (DR) and diabetic macular edema (DME) 
(Cheloni 2019). Important features of DR are microaneurysms, vascular leakage, and retinal 
hemorrhage. Progressive worsening of DR can lead to retinal neovascularization, vitreous 
hemorrhage, tractional retinal detachment, and severe vision loss due to the development of 
neovascular (proliferative) disease (Cheung 2008; Yau 2012). Vascular leakage results in 
collection of fluid, or edema, in the retina. Diabetic macular edema (DME) occurs when there is 
leakage in the macula, the central region of the retina responsible for fine visual acuity. DME is a 
leading cause of vision loss in the working age population (Cheloni 2019; 
Schmidt-Erfurth 2017).  


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Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
22 
The prevalence of DR and its sight-threatening complications (DME and proliferative diabetic 
retinopathy (PDR)) are rising worldwide. It has been estimated that nearly one in three people 
with diabetes have or will develop DR. (Demirel 2016; Duphare 2020) 
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; diabetic retinopathy (DR), including diabetic macular 
edema (DME); and ME due to CRVO or BRVO (Rubio 2016). Inhibition of pathologic VEGF 
activity is both an “anti-angiogenic” and “anti-permeability” approach to treat choroidal and 
retinal neovascular diseases and has been shown to be effective in preserving and improving 
visual acuity (Campochiaro 2015; Cheung 2010). 
Among the VEGF family members, VEGF-A is the most strongly associated with angiogenesis 
and vascular leakage (Campochiaro 2015). Intravitreal VEGF-A inhibitors such as aflibercept 
and ranibizumab have been approved by regulatory authorities worldwide for use in multiple 
retinal vascular diseases. Both ranibizumab and aflibercept have been evaluated in Phase 3 
studies for the management of ME, including DME, where patients treated with monthly 
ranibizumab or every other month aflibercept (after 5 initial monthly doses) achieved significant 
functional and anatomic improvements after 12 months of treatment (Demirel 2016; Flaxel 2020; 
Schmidt-Erfurth 2017).  
On account of superior visual acuity and anatomic outcomes, intravitreal VEGF-inhibition 
therapy has replaced macular laser photocoagulation as the first-line treatment for DME 
(Flaxel 2020; Schmidt-Erfurth 2017). However, primary concerns with approved anti-VEGF 
therapies are that the visual acuity gains observed in the early intensive treatment phase require a 
high treatment burden (monthly or bimonthly injections) and the visual acuity results achieved 
with frequent therapy are not sustained with less frequent dosing. This is thought to be due to the 
relatively short intravitreal half-lives of the approved products (in rabbits: ~4 days for 
aflibercept, ~2.5 days for ranibizumab (Park 2016); in monkeys: ~2.4 days for aflibercept, ~2.7 
days for ranibizumab (Christoforidis 2017)). In DME, short ocular half-lives translate to narrow 
and burdensome retreatment windows, which then result in a high treatment burden that is 
difficult to successfully maintain (Ciulla 2020). 
2.2.3 
Description of KSI-301 
KSI-301 is an antibody biopolymer conjugate (ABC) developed using the Sponsor’s proprietary 
ABC Platform™ technology. The antibody portion of KSI-301 binds to VEGF-A with high 
affinity and inhibits the ability of VEGF-A to bind and activate its cognate receptors (VEGFR1 
and VEGFR2), thereby acting as an anti-angiogenic and anti-permeability agent. The inert 
biopolymer portion is an ultra-hydrophilic phosphorylcholine polymer that significantly 
increases the overall molecular size of KSI-301, which in turn extends its ocular half-life by a 


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
23 
factor of 
 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 DME, 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 DME are also well-
documented and established (Demirel 2016; Duphare 2020). Based on its molecular design and 
structure, in vitro and in vivo nonclinical testing, and clinical data to date, it is expected that the 
efficacy and safety of KSI-301 should be at least comparable to standard of care. 
Long-term and real-world outcomes of approved anti-VEGF therapies are currently limited by 
the high treatment burden caused by their insufficient durability. Emerging efficacy data from 
the ongoing Phase 1b portion of Study KSI-CL-101 support the extended ocular half-life of 
KSI-301 and a less frequent dose regimen compared to aflibercept. Thus, KSI-301 may provide 
clinically relevant benefits over existing therapies for patients with DME. 
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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Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
24 
Table 1:  
Protocol KS301P105: 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. 
Patients 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. 
Patients 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). Patients 
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). Patients 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). 
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). Patients 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). Patients 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 


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Protocol KS301P105 Version 2.0 
 
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25 
2.3.2.1 
Risks Associated with Exposure to the Virus SARS-CoV-2 
In consideration of the Coronavirus disease (COVID-19) pandemic caused by the virus 
SARS-CoV-2 and the impact it may have on clinical trials, COVID-19 related risks to 
participants are carefully considered and will be documented on an ongoing basis. In DME, early 
diagnosis and treatment with intravitreal anti-VEGF therapy is associated with better functional 
outcomes (Brown 2013; Duphare 2020). Moreover, intravitreal anti-VEGF treatment is 
recognized as an essential healthcare service during the pandemic by ophthalmology physician 
societies worldwide. This trial affords all participants the opportunity to receive anti-VEGF 
therapy for their DME. Measures that prioritize trial participant safety and data integrity have 
been developed in consideration of local guidelines.  
In order to minimize any added risk of exposure associated with trial participation beyond that 
associated with standard of care treatment, the Schedule of Activities (SoA) (Section 1.3) has 
been optimized to allow for an adequate follow-up and assessment of the safety and efficacy of 
KSI-301 without unnecessarily increasing participant exposure beyond that which may already 
exist from their attendance at clinic visits for anti-VEGF treatment of their DME.  
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 of DME with KSI-301 (longer treatment intervals) have been 
considered against both the risks associated with KSI-301 treatment and the COVID-19 
pandemic. Participants in this study will be carefully monitored with special attention to known 
and potential risks and managed as appropriate. Exclusion criteria restrict enrollment of 
participants at higher risk, and routine monitoring and follow-up evaluations will be conducted 
for early detection of any AEs, as noted in Section 8.3. Reassessment of the risks will continue as 
the COVID-19 situation develops and any changes to this approach will be documented 
accordingly. 
In DME, early diagnosis and treatment with intravitreal anti-VEGF therapy is associated with 
better functional outcomes (Duphare 2020). Moreover, intravitreal anti-VEGF treatment is 
recognized as an essential healthcare 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.  


CONFIDENTIAL 
Protocol KS301P105 Version 2.0 
 
KSI-301 – Kodiak Sciences Inc. 
26 
3.0 
OBJECTIVES AND ENDPOINTS  
Objectives 
Endpoints 
Primary 
To demonstrate that KSI-301 5 mg is non-inferior to 
aflibercept 2 mg with respect to mean change in BCVA 
from Day 1 to Year 1 (average of Weeks 60 and 64). 
• 
Mean change in BCVA from baseline (Day 1) to 
the average of Weeks 60 and 64 (Year 1) (ETDRS 
Letters). 
Secondary 
To evaluate the efficacy of KSI-301 5 mg compared to 
aflibercept 2 mg over the study duration by assessing 
visual parameters. 
• 
Mean change in BCVA (ETDRS Letters) from 
baseline (Day 1) by visit over time.  
• 
Proportion of participants who gain ≥ 5, ≥10 and 
≥15 letters from baseline by visit over time. 
• 
Proportion of participants who lose ≥ 5, ≥10 and 
≥15 letters from baseline by visit over time. 
• 
Proportion of participants with BCVA Snellen 
equivalent of 20/40 or better from baseline over 
time. 
• 
Proportion of participants with BCVA Snellen 
equivalent of 20/200 or worse from baseline over 
time. 
To evaluate the efficacy of KSI-301 5 mg compared to 
aflibercept 2 mg over the study duration by assessing 
anatomical parameters. 
• 
Mean change in OCT CST and other 
morphological parameters from baseline to the 
average of Weeks 60 and 64 (Year 1) and over 
time.  
• 
Proportion of patients with a ≥ 2-step 
improvement from baseline on the ETDRS DRSS 
at Week 52. 
To evaluate the durability of KSI-301 5 mg compared 
to aflibercept 2 mg over the study duration. 
• 
Mean number of intravitreal injections over the 
duration of the study. 
• 
Mean number of intravitreal injections from 
baseline to Week 60 and from Week 64 to 104. 
• 
Mean time to first re-treatment after the last 
monthly dose.  
To evaluate the safety and tolerability of KSI-301 5 mg 
compared to aflibercept 2 mg. 
• 
Incidence of ocular and systemic adverse events 
up to Week 64 and Week 108. 
To assess the systemic pharmacokinetics (exposure) 
and immunogenicity of KSI-301. 
• 
Systemic pharmacokinetic profile over time. 
• 
Systemic anti-drug antibody status over time. 
Exploratory 
Additional exploratory endpoints will be further described in the Statistical Analysis Plan (SAP). 


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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 DME. 
The overall duration of the study is approximately 2 years (108 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 108; thus, participant duration 
is approximately 111 weeks and includes a screening period of up to 21 days (Days -21 to -1), a 
treatment period of approximately 100 weeks (Day 1 to Week 100), a 4-week follow-up period 
for safety and efficacy assessments at Week 104, and a final follow-up for safety assessments at 
Week 108 
 The primary endpoint will be assessed at Week 64 
(average of Weeks 60 and 64); additional secondary endpoints for efficacy will be assessed at 
Weeks  64 and 104.  
A single eye per participant will be designated as the Study Eye. If both eyes are eligible to 
become the Study Eye, the eye with worse BCVA at Screening will be selected as the Study Eye. 
If both eyes are eligible and have the same BCVA, the decision of which eye to select as the 
Study Eye will be made by the Investigator. 
Participants will be randomly assigned (1:1) into one of two treatment arms: 
• Group A: KSI-301 5 mg  
• Group B: Aflibercept 2 mg  
Randomization will be stratified by
 
 
Additional details of the randomization methods are described in the 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 (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). 


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When re-screening tests and procedures have been completed and results are available indicating 
that 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 100 and will have an efficacy and safety 
assessment at Week 104 and a final safety assessment at Week 108, 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 
As shown in Section 1.2, all participants will be treated starting on Day 1 through Week 100, 
according to their respective treatment arm (Figure 2). Administration of KSI-301 5 mg is 
described in Section 4.1.3.1. Administration of aflibercept 2 mg is described in Section 4.1.3.2. 
 
 


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Figure 2: 
Protocol KS301P105: Masked Dosing Regimens by Week
Note: For masking purposes, BCVA and OCT CST measurements will be collected and entered in the IRT system 
every month for all participants in both groups, but no modifications to the treatment schedule will be made by 
the IRT system for participants in the aflibercept group.  
4.1.3.1
Administration of KSI-301 5 mg 
As shown in Figure 2 above, KSI-301 will be administered in two separate treatment periods:  
•
Fixed Interval Treatment Period: Day 1 through Week 12 (as described in 
Section 4.1.3.1.1 below); and  
•
Individualized Treatment Period: Week 16 through Week 100 (as described in 
Section 4.1.3.1.2 below). 
4.1.3.1.1
KSI-301 5 mg Fixed Interval Treatment Period (Day 1 Through Week 12) 
Starting on Day 1 through Week 12, participants in this group will initially receive 3 monthly 
(Q4W) doses of KSI-301 5 mg 
 (at Day 1, Week 4, and Week 8), followed by a sham 
injection at Week 12 to preserve masking. The minimum interval between doses is 21 days. 
4.1.3.1.2
KSI-301 5 mg Individualized Treatment Period (Week 16 Through Week 
100) 
Starting at Week 16 until Week 100, participants in this group will be assessed monthly (Q4W) 
and will receive additional administration of KSI-301 5 mg according to protocol-defined 
disease activity criteria (defined below). These criteria are based on changes in OCT CST. The 
minimum interval between active treatments is 8 weeks (± 14 days, considering the respective 
visit windows) and the maximum interval is 24 weeks (± 14 days, considering the respective visit 


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windows). To preserve masking, sham injections are administered at each visit in which no 
active treatment with KSI-301 5 mg is indicated.  
Base Treatment Interval  
At Weeks 16, 20, 24 and 28, participants will be assessed for disease activity criteria to 
determine their base treatment interval (once every 8, 12, 16, 20, or 24 weeks), as shown in 
Figure 3. Participants will receive a KSI-301 5 mg dose at the first visit in which any of the 
disease activity criteria (described in the subsection that follows) are met. If disease activity 
criteria are not met by Week 32, participants will receive a dose of KSI-301 5 mg at that visit, 
which corresponds to the maximum 24-week (Q24W) base treatment interval. The base 
treatment interval is determined by the time between the last loading dose and the first re-
treatment. 
Figure 3: 
Protocol KS301P105: Determination of the Base Treatment Interval 
for Patients Randomized to KSI-301 5 mg  
 
 
 
 
 
 
 
 
 
Once established, the base treatment interval determines when participants receive their next 
KSI-301 5 mg dose. As shown in Figure 3, base treatment intervals are in 4-week increments 
from a minimum of 8 weeks to a maximum of 24 weeks.  


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Modification of the Base Treatment Interval  
As shown in Figure 4, the base treatment interval can be adjusted as follows: 
• Shortened by 4 weeks or more to a minimum of 8 weeks (when one or more disease 
activity criteria are met, indicating that the participant requires an injection before their 
next base treatment interval visit); or 
• Maintained, in two scenarios: 
• When one or more disease activity criteria are met at, but not before, their next base 
treatment interval visit; or 
• When no disease activity criteria are met at their next base treatment interval, but the 
disease stability criterion (see below) is not met; or 
• Extended to a maximum of 24 weeks (when none of the disease activity criteria are met 
and the participant’s DME is stable according to the disease stability criterion below).  
If the base treatment interval is shortened or extended, the new interval will be considered the 
new base treatment interval for that participant and can be modified throughout the 
individualized treatment period based on the adjustments described above.  
Figure 4: 
Protocol KS301P105: Modification of Base Treatment Interval for 
Patients Randomized to KSI-301 5 mg 
 
 
 
 
 
 
 
 
 


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Disease Activity Criteria for KSI-301 5 mg Individualized Treatment Period 
Participants will be administered KSI-301 5 mg if any of the following disease activity criteria 
are met: 
• Increase in OCT CST ≥ 40 µm compared to lowest previous measurement, or 
• OCT CST ≥ 350 µm ; or 
• New or worsening proliferative DR (PDR): progression from NPDR to PDR, vitreous 
hemorrhage, iris neovascularization and/or new or worsening retinal neovascularization. 
Disease activity assessments will be conducted by the masked Investigator (Section 6.3.2). The 
IRT system will make adjustments to the dosing schedule based on disease activity data entered 
by the study site. The IRT will adjust the dosing schedule in consideration of missed visits, out 
of window visits, and missing data during a visit. 
Disease Stability Criterion for KSI-301 5 mg Individualized Treatment Period 
Stable disease for the purposes of extending the base treatment interval is determined by the 
following criterion, which must be met in addition to the absence of any of the disease activity 
criteria: 
• No increase in CST of >30 µm compared to the lowest previous measurement.  
This criterion must be met at each visit where the base treatment interval is being extended. 
4.1.3.2 
Administration of Aflibercept 2 mg 
Participants in this group will initially receive 5 monthly doses of aflibercept 2 mg (50 µL) (at 
Day 1, Week 4, Week 8, Week 12, and Week 16), followed by doses once every 8 weeks (Q8W) 
until Week 108. Participants will receive a sham injection at each visit that aflibercept is not 
administered. The minimum interval between doses is 21 days. 
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 treatment-naïve participants with DME. 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 to treat DME. Thus, 
participants must not have had prior use of an approved or investigational treatment (e.g., anti-
VEGF, intraocular or periocular steroids, macular laser photocoagulation) for DME in the Study 


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Eye. Enrollment of participants who are treatment-naïve for DME also helps minimize biases 
inherent in the inclusion of participants who have failed prior lines of therapy.  
Participants with diabetic macular edema that has been diagnosed within the nine months prior to 
screening and that has not been previously treated, and with best corrected visual acuity (BCVA) 
of 78 to 25 letters (⁓20/25 to 20/320 Snellen equivalent), will be enrolled because they are 
expected to be broadly representative of the general population of patients treated with first-line 
anti-VEGF. Additionally, participants with HbA1c ≤12% will be enrolled because it has been 
demonstrated that the visual and anatomic responses to anti-VEGF therapy are similar 
irrespective of patients’ baseline HbA1c measurements (Singh 2017). 
4.2.1.1 
Recruitment Plan for the People's Republic of China 
This study is a global study that will include participants from multiple geographic regions. 
Because enrollment of a sufficient number of participants to support the potential registration of 
KSI-301 in China will take longer than the global enrollment period, a China-specific enrollment 
plan has been established. Participants will be enrolled and randomized into a China-only cohort 
after the global enrollment phase of the study has been completed. Data from participants 
enrolled into the China extension will not be included in the primary analysis and will be 
reported separately (Section 9.4.7). 
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 European Society of Retina Specialists (EURETINA) and the American Academy of 
Ophthalmology (AAO) both recommend anti-VEGF agents as the preferred pharmacotherapeutic 
method of first-line treatment of DME (Flaxel 2020; Schmidt-Erfurth 2017). Intravitreal 
corticosteroids (triamcinolone and dexamethasone) are considered second-line due to significant 
ocular side effects, such as secondary glaucoma and cataract formation (Schmidt-Erfurth 2017). 
Two anti-VEGF agents are currently approved by the European Medicines Agency (EMA) and 
the US Food and Drug Administration (FDA) for the treatment of DME: ranibizumab 
(Lucentis®) and aflibercept (Eylea®). Aflibercept is chosen as the active comparator for this trial 
because the majority of patients with DME treated in routine clinical practice with an approved 
anti-VEGF receive aflibercept. An additional reason to choose aflibercept as the active 
comparator for this global study is that a single dose strength of aflibercept (2 mg) is the 
approved dose for DME worldwide, whereas for Lucentis, different dose strengths are approved 
for DME in the US versus other regions.  
4.2.3 
Choice of Primary Endpoint and Analysis 
The primary endpoint, mean change in BCVA from baseline to Year 1, was selected based on 
precedent for Phase 3 studies in DME and health authority feedback. 


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A non-inferiority (NI) primary analysis was selected because aflibercept results in significant 
clinical benefit when administered frequently, as in a clinical trial. KSI-301 efficacy outcomes 
are expected to be comparable (non-inferior) to aflibercept but with a substantially improved 
(i.e., less frequent) dosing regimen. 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. As an 
exploratory analysis, superiority will be tested in a hierarchical manner following the primary 
test for NI. 
A NI 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 arms (i.e., KSI-301 and 
aflibercept) and is 100 weeks.  
The primary endpoint will be assessed at Year 1. This time point and associated duration of 
treatment was selected on the basis of precedent for Phase 3 trials in DME and health authority 
feedback. For example, the Phase 3 studies that established the safety and efficacy of aflibercept 
in DME used a one-year primary endpoint and two-year supportive secondary endpoints 
(Korobelnik 2014). Year 1 for this purpose is defined as the average of weeks 60 and 64. This is 
to allow for subjects randomized to the KSI-301 arm to have two full six-month observation 
periods in the individualized dosing phase, such that the durability, efficacy and safety of the 
longer dosing intervals can be evaluated. 
The choice of a safety follow-up 
 
  
4.3 
Justification for Dose 
4.3.1 
KSI-301 Dose Rationale 
The durability of intravitreal anti-VEGF pharmacological effect is proportional to the dose and 
the half-life of the drug. A KSI-301 5 mg dose has approximately 
fold the equivalent molar 
dose of anti-VEGF binding capacity, at the time of injection, relative to 2 mg aflibercept. 
Preclinical modeling suggests that KSI-301 5 mg results in 
fold the equivalent ocular 
concentration of aflibercept 2 mg three months after dosing. Both KSI-301 2.5 mg and KSI-301 
5 mg dose levels that are being evaluated in the ongoing Phase 1b portion of Study KSI-CL-101 
have not resulted in any dose-limiting ocular or systemic toxicities and, as expected, have no 
clear dose-efficacy response relationship. Because the 5 mg dose of KSI-301 may have 
incrementally improved durability compared to the 2.5 mg dose, the 5 mg dose has been selected 
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The 
 injection volume used to deliver a 5 mg dose has been well-tolerated in previous 
KSI-301 studies (additional information can be found in the IB) as well as in other studies for of 
 
The objective of KSI-301 in the treatment of DME is to reduce the number of required 
intravitreal injections while providing non-inferior efficacy outcomes to aflibercept. The ongoing 
Phase 1b portion of Study KSI-CL-101 has thus far supported a prolonged dose regimen 
compared to other anti-VEGF medicinal products approved to treat DME. Therefore, during the 
fixed treatment period (Day 1 through Week 12), KSI-301 5 mg will be administered three times: 
at Day 1, Week 4, and Week 8. A sham injection will be administered in Week 12 to participants 
randomized to treatment with KSI-301 5 mg. During the individualized treatment period (Week 
16 to Week 100), the potential for treatment burden reduction will be explored with an 
individualized dosing approach that is based on disease activity.  
4.3.2 
Aflibercept Dose Rationale 
In both the EU and US, the recommended dose for aflibercept in the treatment of DME is 2 mg 
(50 µL) administered by intravitreal injection every 4 weeks (± 7 days) (i.e., monthly) for the 
first 5 injections followed by 2 mg via intravitreal injection once every 8 weeks (2 months). In 
the EU, but not in the US, the treatment interval after the first 12 months of treatment with 
aflibercept may be extended, based on visual and/or anatomic outcomes, such as with a treat-
and-extend dosing regimen, where the treatment intervals are gradually increased to maintain 
stable visual and/or anatomic outcomes. Therefore, the Sponsor considers that the following 
aflibercept posology in this study provides the maximum possible treatment effect and best 
enables a head-to-head comparison with KSI-301 without undue risk:  
• Day 1 to Week 20: participants will receive 5 monthly doses of aflibercept 2 mg at Day 1, 
Week 4, Week 8, Week 12, and Week 16, followed by a sham injection at Week 20.  
• Week 24 to Week 100: participants will receive aflibercept 2 mg once every 8 weeks (Q8W). 
Sham injections will be administered at each monthly visit when an active treatment is not 
administered. 
4.3.3 
Sham Injection Rationale 
Sham injections are used to preserve study masking and minimize bias.  
Participants in both treatment arms 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 
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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 108 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 arm only if they meet all the inclusion 
criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or participant safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. Prospective approval 
of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or 
exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the criteria in Sections 5.1.1 and 
5.1.2 apply. 
5.1.1 
Ocular Inclusion Criteria 
Where applicable inclusion criteria will be confirmed or assessed by the independent, masked 
image Reading Center.  
1. Treatment-naïve diabetic macular edema, with vision loss and center involvement (if present) 
diagnosed within 9 months of screening.  
2. BCVA ETDRS letter score ≤78 and ≥ 25 (⁓20/25 to 20/320 Snellen equivalent) in the Study 
Eye at Screening and confirmed at Day 1. 
3. CST of ≥ 320 microns on SD-OCT (Heidelberg Spectralis or equivalent on other OCT 
instruments) as determined by the Reading Center at the screening visit. 
4. Decrease in vision in the Study Eye determined by the Investigator to be primarily the result 
of DME. 
In cases where both eyes are eligible, the eye with the worse BCVA at the Screening Visit will 
be selected as the Study Eye. If both eyes are eligible and have the same BCVA, the decision of 
which eye to select as the Study Eye will be made by the Investigator. Only one eye per 
participant can be included in the study.  
5.1.2 
General Inclusion Criteria  
5. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the protocols and restrictions listed in the informed consent form (ICF) and 
in this protocol. 
6. Male or female ≥ 18 years of age with Type 1 or Type 2 diabetes mellitus and a HbA1c of 
≤12%. 


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


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b. Neovascularization at optic disc ≥1/3 of the disc area. 
c. Neovascularization elsewhere ≥1/2 of the disc area. 
4. Structural damage to the center of the macula in the Study Eye that is likely to preclude 
improvement in BCVA following the resolution of macular edema including atrophy of the 
retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or 
organized hard exudates in the foveal center. 
5. History of cataract surgery and/or minimally invasive glaucoma surgery (MIGS) in the Study 
Eye within 2 months of screening. 
6. History of Yttrium-Aluminum Garnet (YAG) laser capsulotomy in the Study Eye within 2 
months of screening. 
7. History of Pan-retinal Photocoagulation (PRP) laser in the Study Eye within 3 months of 
screening. 
8. Tractional retinal detachment in the Study Eye.  
9. Uncontrolled glaucoma (defined as intraocular pressure ≥ 25 mmHg despite treatment with 
antiglaucoma medication) in the Study Eye. 
10. History of glaucoma-filtering surgery (trabeculectomy or tube shunt) in the Study Eye.  
11. History of retinal detachment or treatment or surgery for retinal detachment in the Study Eye. 
12. History of uveitis in either eye.  
13. Significant media opacities, including cataract, in the Study Eye that might interfere with 
visual acuity, assessment of safety, OCT or fundus photography.  
14. Cataract in the Study Eye that in the judgment of the Investigator is expected to require 
surgical extraction within 12 months of screening. 
15. Aphakia in the Study Eye. 
16. Prior vitrectomy in the Study Eye. 
17. Active retinal disease other than the condition under investigation in the Study Eye.  
18. Any history or evidence of a concurrent ocular condition present, that in the opinion of the 
Investigator could require either medical or surgical intervention or affect macular edema or 
alter visual acuity during the study (e.g., vitreomacular traction, epiretinal membrane).  
19. Active or suspected ocular or periocular infection or inflammation in either eye at Day 1. 
20. Any prior use of an approved or investigational treatment for DME in the Study Eye (e.g., 
anti-VEGF, intraocular or periocular steroids, macular laser photocoagulation).  
5.2.2 
General Exclusion Criteria 
21. Women who are pregnant or lactating or intending to become pregnant during the study.  
22. 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. 


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23. 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, a second reading may be taken later the same day or a 
different day during the screening period. If the participant’s blood pressure is controlled by 
antihypertensive medications, the participant should be on a stable medication regimen 
continuously for 30 days prior to Day 1. 
24. 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. 
25. Kidney failure requiring renal transplant, hemodialysis or peritoneal dialysis or expected to 
require renal transplant, hemodialysis or peritoneal dialysis during the study. 
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 drug (excluding vitamins and minerals) or devices. 
5.3 
Lifestyle Considerations 
No specific lifestyle restrictions are required.  
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse events (SAE) caused by a 
protocol-mandated intervention that occur during the screening period. 
Participants who do not meet eligibility criteria within the 21-day screening period will not be 
eligible for randomization and will be screen-failed. However, a participant may be re-screened 
up to one additional time at the discretion of the Investigator and in consultation with the 
Sponsor. When re-screening, the participant must be re-consented if more than 30 days have 
elapsed since the date of the last informed consent. In the event of re-screening, screening 
procedures need not be repeated if they fall within the 21-day screening window. If the re-
screening occurs outside the 21-day window, all assessments performed at the initial screening 
visit should be repeated during the re-screening visit except fluorescein angiogram (FA). If the 
re-screening visit is more than 8 weeks after the original screening visit, the FA should be 
repeated. For re-screening visits 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 


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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 to 
ensure there is an audit trail for the screen-failed participant.  
5.5 
Criteria for Temporarily Delaying Enrollment 
There are no specific criteria for temporarily delaying enrollment into the study. 
Inclusion/Exclusion criteria will be assessed at Screening and on Day 1 to determine a 
participant’s eligibility for the study.  


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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 KS301P105: Study Interventions 
Arm Name 
A 
B 
A or B 
Intervention Name 
KSI-301 5 mg 
Aflibercept 2 mg 
Sham 
Type  
Biological medicinal product Biological medicinal product Sham 
Dose Formulation 
Sterile liquid for intravitreal 
injection in single-use vials 
Sterile liquid for intravitreal 
injection in single-use vials 
or prefilled syringes 
Empty vial 
Unit Dose Strength(s) 
 mg/mL (based on 
antibody mass) 
40 mg/mL 
N/A 
Dosage Level(s) 
5 mg 
 
2 mg (50 µL) 
N/A 
Route of 
Administration 
Intravitreal injection 
Intravitreal injection 
Sham injection 
Use 
Experimental 
Active control 
Sham (to maintain study 
masking) 
IMP and NIMP 
IMP 
IMP 
NIMP 
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Storage 
In the original packaging, as 
provided, until the time of 
use. Store at 2-8°C before 
use.  
In the original packaging, as 
provided, until the time of 
use. Store at 2-8°C before 
use.  
In the original packaging, as 
provided, until the time of 
use. Store at 2-8°C before 
use.  
Packaging and 
Labeling 
KSI-301 will be provided in 
vials that will be labeled as 
required per country 
requirement. 
Aflibercept will be provided 
in vials or prefilled syringes 
that will be labeled as 
required per country 
requirement. 
Sham will be provided in 
vials that will be labeled as 
required per country 
requirement. 
Reconstitution and 
Handling 
KSI-301 is an aqueous 
solution that is provided in 
vials and filled into syringes 
by unmasked site personnel 
without reconstitution or 
dilution. 
Aflibercept is an aqueous 
solution that is provided in 
vials and filled into syringes 
by unmasked site personnel 
without reconstitution or 
dilution or provided in 
prefilled syringes. 
Sham is provided as empty 
glass vials, which will 
remain empty throughout the 
sham treatment procedure. A 
sham injection mimics an 
intravitreal injection. It 
involves pressing the blunt 
end of an empty syringe, 
without a needle, against an 
anesthetized eye.  
Current/Former 
Name(s) or Alias(es) 
N/A 
Eylea 
N/A 
 
 


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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. 
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 its 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 its designee upon discovery. 
Any study intervention under investigation for integrity or temperature excursion should be 
quarantined in the IRT and at the site, pending final assessment by the Sponsor or its 
designee. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 


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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 pre-
treatment and post-treatment procedures are detailed in the Pharmacy Manual.  
For more detailed information on the formulation, preparation, and handling of KSI-301, 
aflibercept, and sham, see the Pharmacy Manual. 
6.3 
Measures to Minimize Bias: Randomization and Masking 
6.3.1 
Randomization  
All participants will be centrally assigned to a randomized study intervention using an IRT 
system. Before the study is initiated, login information and directions for the IRT will be 
provided to each site.  
Study intervention will be dispensed at the study visits as summarized in the 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 
masked cartons (also referred to as kits).  
• Masked Cartons: All study interventions are provided in cartons that are identical in 
appearance and weight, making them indistinguishable from each other. 


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


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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, 
anesthetics, antiseptic, fluorescein, etc.) related with this study. Concomitant medications will 
include all prescription drugs, herbal products, vitamins, minerals, and over the counter (OTC) 
medications as used by the participant within 30 days prior to Day 1 through Week 108. Any 
changes in concomitant medications also will be recorded in the participant’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the participant during the 
study may be given at the discretion of the Investigator. However, it is the responsibility of the 
Investigator to ensure that all relevant details regarding the medication are recorded in the eCRF. 
Participants who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. 
In case the fellow (non-study) eye requires anti-VEGF treatment during the conduct of the study, 
the participant may be treated at the discretion of the Investigator and according to the standard 
of care in the respective country. The treatment of the fellow (non-study) eye may be 
implemented at any time once the Day 1 injection has been administered. Fellow (non-Study 
Eye) anti-VEGF treatment, including the date of each administration, must be documented as a 
concomitant medication on the appropriate eCRF. If the non-Study Eye requires treatment at the 
same visit as the Study Eye, the Study Eye should be treated first, and the non-Study Eye should 
be treated by the unmasked physician to preserve masking.  
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1 
Pan-retinal Photocoagulation (PRP) 
Pan-retinal photocoagulation laser is permitted in the Study Eye, if clinically indicated for the 
treatment of new, active retinal or iris neovascularization due to worsening diabetic retinopathy. 
PRP will be reported as a concomitant procedure in the appropriate eCRF. 
6.8.2 
Prohibited Therapy 
At the discretion of the Investigator, during the Study participants may start or continue to 
receive all medications and standard treatments administered for other conditions, except for the 
following: 
• Investigational therapies in the non-Study Eye 


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• Intravitreal anti-VEGF drugs other than study-assigned aflibercept or KSI-301 in the 
Study Eye 
• Systemic anti-VEGF therapy 
• Intravitreal or periocular steroids or steroid implants in the Study Eye 
• Concurrent use of macular laser photocoagulation in the Study Eye 
• 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, subjects whose study treatment has been interrupted but no longer need a 
prohibited therapy may resume study treatment. 
6.8.3 
Supportive Care for Adverse Events 
Supportive care for the known potential risks associated with anti-VEGF treatment and KSI-301 
(summarized in Table 1) should be as per the standard of care in the respective country. No 
specific prophylactic therapies are recommended. 
 


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7.0 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
Participants may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the Investigator or at the study site. Every effort should be made to 
keep participants in the study. If study intervention is discontinued, an end-of-treatment visit 
should occur 28 +/- 7 days after study treatment is discontinued or before a new treatment 
regimen begins. The reasons for 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 
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. 


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Table 3:  
Protocol KS301P105: 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 post-operative 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 14 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 visits at Week 12, 36, 48, 52, 60, 64, 76, 104, and 108 at 
which key efficacy and safety assessments are performed. However, participants are free to 
withdraw from the study or study treatment at any time upon request. Participant participation in 
the study may be stopped at any time at the discretion of the Investigator or at the request of the 
Sponsor. 
Participants who discontinue study treatment or active participation in the study will no longer 
receive study intervention. When a participant discontinues from study treatment or active 
participation in the study, the reason(s) for study treatment discontinuation or withdrawal shall 
be recorded by the Investigator or designee on the relevant page of the eCRF. Whenever 
possible, all participants who discontinue study treatment or withdraw from the study 


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prematurely will undergo an Early Termination visit. Participants who fail to return for final 
assessments must be contacted by the site by phone and in writing to obtain follow-up. 
If a participant exits early from the study between visits, the Investigator or designee must 
attempt to contact the participant and advise the participant to return for a final visit to complete 
the exit procedures. If the participant is unable or unwilling to return for the Early Termination 
visit, the ‘date of exit’ will be the date that the participant was last seen at the site or contacted by 
other communication.  
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
a) The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
b) Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods) and discuss the situation with the Sponsor. These contact attempts 
should be documented in the participant’s medical record. 
c) Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 


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8.0 
STUDY ASSESSMENTS AND PROCEDURES 
• Before undertaking any study procedures, all potential participants will sign an ICF. 
Participants will have the opportunity to have any questions answered before signing the 
ICF. The Investigator must address all questions raised by the participant. The 
Investigator or designee will also sign the ICF.  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Assessments 
performed in the event of an unscheduled safety visit (Appendix 5) are at the discretion 
of the Investigator. Adherence to the study design requirements, including those specified 
in the SoA, is essential and required for study conduct. All screening evaluations must be 
completed and reviewed to confirm that potential participants meet all eligibility criteria. 
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure, as applicable. 
• Protocol waivers or exemptions are not allowed.  
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
8.1 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1 
Medical History and Demographic Data 
Medical history (general and ophthalmic) includes clinically significant diseases, surgeries and 
reproductive status. All medications (e.g., prescription drugs, OTC drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the participant regularly or within 30 days preceding 
Day 1 must be recorded. A full ocular history including prior ocular treatments will be noted. 
Demographic data will include age, sex, and self-reported race and ethnicity.  
8.1.2 
Ophthalmic Exams 
Unless otherwise noted, ophthalmic assessments are captured for the Study Eye only. 
Slit-lamp examination, which will include the following:  
• Inspection of the eyelids, 
• Inspection of the cornea, 
• Examination of the anterior chamber, 
• Examination of the pupil, 
• Examination of the iris, 
• Inspection of the lens, 
• Inspection of the vitreous body, and 


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• 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 Investigational Medicinal 
Product (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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The method of post-injection IOP measurement (such as Goldmann tonometry or Tonopen) must 
be the same as the pre-injection method and remain the same throughout the study for each 
participant. 
8.1.5 
Best Corrected Visual Acuity (BCVA) 
BCVA will be measured utilizing the ETDRS method by certified, masked personnel at the study 
sites. The measurement should be performed following refraction, and prior to any examination 
requiring contact with the eye and prior to dilating the eyes. A BCVA Testing Procedure Manual 
and training materials will be provided to all sites by the third-party VA Examiner certification 
vendor. 
8.1.6 
Fundus Photography (FP) 
Fundus photography will be performed at the study sites by certified, masked personnel. It is 
mandatory that the same model of device is used for the entire duration of the study. 
Additional specifications and instructions regarding acceptable equipment and imaging 
techniques will be provided by the Reading Center. 
8.1.7 
Spectral Domain Optical Coherence Tomography (SD-OCT) 
SD-OCT will be performed at the study sites by certified, masked personnel on a qualified 
instrument. It is mandatory that the same model of device is used for the entire duration of the 
study.  
Additional specifications and instructions regarding acceptable equipment and imaging 
techniques will be provided by the Reading Center. 
8.1.8 
Optical Coherence Tomography – Angiography (OCT-A) 
OCT-A will be performed at select study sites by certified, masked personnel on a qualified 
instrument. It is mandatory that the same model of device is used for each participant for the 
entire duration of the study.  
Additional specifications and instructions regarding acceptable equipment and imaging 
techniques will be provided by the Reading Center. 
8.1.9 
Fluorescein Angiography (FA) 
FA will be performed at all the study sites by certified, masked personnel. It is mandatory that 
the same model of device is used for the entire duration of the study.  
Additional specifications and instructions regarding acceptable equipment imaging and imaging 
techniques will be provided by the Reading Center. 


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8.1.10 
Disease Activity Assessments 
The IRT will make the necessary adjustments to the dosing schedule based on disease activity 
data from the study site. Details of the disease activity assessments are described in  
Section 4.1.3. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 
Vital Signs 
The following vital signs will be assessed taken with the participant in a seated position after 
resting for 5 minutes: blood pressure (BP), pulse rate, and body temperature. Height and weight 
will be recorded at the screening visit only. 
8.2.2 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and refer to the SoA 
(Section 1.3) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
• If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
• All protocol-required laboratory tests, as defined in Appendix 2, must be conducted in 
accordance with the SoA (Section 1.3). 
• If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 


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8.2.3 
Pregnancy Testing 
Participant samples for pregnancy testing will be taken at the Screening and Day 1 visits and 
then monthly in women of childbearing potential only, as specified in the SoA (Section 1.3). 
Prior to enrollment in the study, female participants of childbearing potential and male 
participants must be advised of the importance of avoiding pregnancy or partner pregnancy, 
respectively, during the trial and the potential risks associated with an unintentional pregnancy. 
Contraceptive and barrier guidance and collection of pregnancy information is described in 
Appendix 6. 
8.3 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting 
The definitions of AEs and serious AEs (SAEs) can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7.0). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
After informed consent has been obtained but prior to initiation of study intervention, only SAEs 
caused by a protocol-mandated intervention should be reported. After initiation of study 
intervention (Day 1), all AE and SAE information will be collected until the final safety follow-
up visit at Week 108 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 AE or SAE 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 
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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). 
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 Investigator’s Brochure 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, 


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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 
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 adverse events may be serious or non-
serious. Applicable adverse events 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 timeframe (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 letters in BCVA compared with the last VA 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 
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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. 
8.4 
Pharmacokinetics 
To understand the pharmacokinetic (PK) profile of the study intervention following intravitreal 
injection (i.e., systemic exposure), the 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 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 ADAs 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 


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intervention(s) (neutralizing antibodies (NAB)). All samples collected for detection of antibodies 
to study intervention will also be evaluated for KSI-301 plasma concentration to enable 
interpretation of the antibody data.  
Samples may be stored for a maximum of 5 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of immune responses to KSI-301.  
8.8 
Health Economics or Medical Resource Utilization and Health Economics 
These parameters are not evaluated in this study. 


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9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Hypothesis 
Treatment with KSI-301 5 mg will provide a non-inferior mean change in BCVA compared to 
aflibercept 2 mg while using a less frequent dosing schedule in participants with DME. 
9.2 
Sample Size Determination 
The sample size for the comparison of BCVA between treatment arm A (KSI-301 5 mg) and 
treatment arm B (aflibercept 2 mg) at Year 1 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 
 Testing at the 
 level for non-inferiority corresponds 
to setting 95% confidence intervals (CIs). 
• Statistical power of ≥90%. 
• Standard deviation of the distribution of change in visual acuity from baseline of 
. 
• The maximum, clinically acceptable true difference for KSI-301 to be considered non-
inferior, or the “non-inferiority margin,” is 
.  
• The statistical test used to compare the two treatment arms at Year 1 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 450 participants (225 
per treatment arm). 
 
 
 
 
 
 
 Additional details will be provided in the SAP. 
Note: “enrolled” means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process and 
screening and completing the Day 1 visit. Potential participants who are screened for the purpose 
of determining eligibility for the study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.  


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9.3 
Analysis Sets 
For the purpose of analysis, the following analysis sets are defined:  
Population 
Description 
Randomized/ Intent to treat set 
(ITT) 
The ITT will be comprised of all participants who were randomized into one 
of the study arms. 
For analyses based on this population, participants will be grouped according 
to the treatment assigned at randomization. 
Evaluable / Per protocol set 
(PPS) 
The PPS will consist of all ITT participants who fulfill all inclusion/exclusion 
criteria and have no significant protocol deviations that are expected to have a 
significant impact on the assessment of efficacy, including lack of compliance 
with study treatment, missing data, and having taken any prohibited 
medication. All analyses using the PPS will group participants according to 
the treatment they actually received. 
Safety 
All participants randomly assigned to study intervention and who receive at 
least 1 dose of study intervention. Participants will be analyzed according to 
the intervention they actually received. 
Pharmacokinetic/ Biomarker/ 
ADA Evaluable  
The PK/biomarker evaluable data set will consist of all participants in the ITT 
Population with at least one post-Day 1 evaluable sample. The ADA evaluable 
data set will consist of all participants in the ITT Population with at least one 
evaluable sample. 
 
9.4 
Statistical Analyses 
The study SAP will fully specify the statistical methodology and reporting for all aspects of the 
planned analyses. The SAP will be finalized prior to database lock and executed thereafter, and it 
will include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints.  
Additional unplanned analyses may be required after all planned analyses have been completed, 
and additional analyses of key efficacy metrics may be performed between the primary and final 
analyses to support marketing applications for various jurisdictions. Any unplanned analyses will 
be clearly identified in the clinical study report. 
Results of the Year-1 analyses may be reported to the public and to health authorities prior to the 
completion of the Week 108 portion of the study. Participants, masked study site staff, and the 
Reading Center will remain masked to treatment assignments until the entire study is completed, 
the database is locked, and the Week 108 analyses are completed.  


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9.4.1 
General Considerations 
At baseline (Day 1), participants will be randomized 1:1 into one of two treatment arms: 
A. KSI-301 5 mg.  
B. Aflibercept 2 mg.  
This study is divided into two efficacy and safety assessment periods (Section 1.2), as follows:  
• Year 1: from Day 1 to Week 64; and 
• Year 2: from Week 68 to Week 108. 
Using the average ETDRS BCVA data collected at Weeks 60 and 64, the treatment arms will be 
compared using a non-inferiority analysis, with a margin of 
. Confidence 
intervals will be 100(1-2 α)% or 95% CIs. 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 
, ∞), the null hypothesis of inferiority will be rejected, and non-inferiority 
will be established. Furthermore, if the lower confidence limit lies within (0, ∞), superiority will 
be established.  
Analysis of data for the first period of the study will be performed when all participants have 
either completed the Week 64 visit or have discontinued from the study, all data have been 
entered into the database, cleaned and verified as appropriate, and the database for the primary 
analysis has been frozen; likewise, analysis of data for the second period of the study will be 
performed when all participants have either completed the Week 108 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 
Year 1 (average of Weeks 60 and 64). The primary assessment of efficacy will be based on a 
pairwise comparison in mean change in BCVA between treatment arm A (KSI-301 5 mg) and 
treatment arm B (aflibercept 2 mg). 
Unless stated otherwise, all analyses described will be performed on the ITT population.  
Analysis of the primary endpoint data will be performed when the following occur: 


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• all participants have either completed the Week 64 visit or have discontinued from the study 
prior to the Week 64 visit, whichever comes later; 
• all data up to and including the Week 64 visit have been entered into the database, and have 
been cleaned, and verified as appropriate; and  
• the database for the primary analysis locked. 
If there are no imbalances on important prognostic factors at baseline, a simple independent t-test 
and corresponding CIs will be used for evaluation of treatment differences. If there are 
imbalances in key prognostic factors at baseline 
 generalized linear models or other 
statistical models (such as mixed effects models) will be used to estimate the difference in mean 
change in BCVA between treatment arms and CIs derived from the corresponding standard error 
of the estimate. These models will also include indicator variables for stratification variables. An 
alpha level of 0.025 will be used for hypothesis testing and CIs will be 100(1-2α)% or 95% CIs. 
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 64 and Week 104:  
• Mean change in BCVA (ETDRS Letters) from baseline (Day 1) by visit over time.  
• Proportion of participants who gain ≥ 5, ≥10 and ≥15 letters from baseline by visit over time. 
• Proportion of participants who lose ≥ 5, ≥10 and ≥15 letters from baseline by visit over time. 
• Proportion of participants with BCVA Snellen equivalent of 20/40 or better from baseline 
over time.  
• Proportion of participants with BCVA Snellen equivalent of 20/200 or worse from baseline 
over time. 
• Mean change in OCT central subfield retinal thickness (CST) from baseline to the average of 
Weeks 60 and 64 and over time. 
• Proportion of patients with a ≥ 2-step improvement from baseline on the ETDRS DRSS at 
Week 52. 
• Mean number of intravitreal injections from Day 1 to Week 60, from Week 64 to Week 104, 
and over the duration of the study.  
• Mean time to first re-treatment in the individualized treatment period.  
• Distribution of intravitreal injections from Week 16 to Week 104. 
• Incidence of ocular and systemic adverse events up to Week 64 and Week 108. 
• Systemic anti-drug antibody status over time (in the ADA-evaluable population). 


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• 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 
ANCOVA will be reported as 95% CI for the difference in adjusted means for the grouping 
determined by the fixed effects of interest. 
For categorical variables, the number and percentage of responders will be presented by 
treatment group for each time period and will be evaluated among treatment groups using chi-
square tests of proportions supplemented with logistic regression models. The distribution of the 
need for intravitreal injections over the individualized treatment period will be computed and 
compared using the Kolmogorov-Smirnov test for the equality of distribution functions. The 
probability of receiving intravitreal injections over time during the individualized treatment 
period will be compared using a generalized linear model or generalized linear mixed model with 
appropriate link function (e.g., logit, beta-binomial, etc.). 
Additional endpoints and full details on statistical considerations will be provided in the SAP. 
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 adverse events 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. 


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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. 
9.4.7 
China Subpopulation Analyses 
China subpopulation analyses will include all participants enrolled from China during the China-
only extension. Additional details regarding these analyses will be included in the SAP. 
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 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies, and all other applicable local regulations 
10.1.2 
Financial Disclosure and Financial Obligations 
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements to the appropriate 
regulatory authorities. In addition, Investigators must provide to the Sponsor a commitment to 
promptly update this information if any relevant changes occur during the investigation and for 1 
year following the completion of the study. 
Neither the Sponsor nor their CRO partner is financially responsible for additional testing or 
treatment of any medical condition that may be detected during the screening process. In 
addition, in the absence of specific arrangements, neither the Sponsor nor their CRO are 
financially responsible for further treatment of the participant’s disease. 


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


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confidentiality. All records will be kept in a secure storage area with limited access. Upon the 
participant’s permission, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
All information provided by the Sponsor, verbally and in writing, is confidential. The 
Investigator agrees not to disclose any such information without prior written permission of the 
Sponsor. This document may be disclosed to study personnel under the PI’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 
CRF. 


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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 contract research organization(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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10.2 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 4 will be performed by the central laboratory. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time.   
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or as required by local regulations. 
Investigators must document their review of each laboratory safety report. 
Table 4:  
Protocol KS301P105: Required Safety Laboratory Tests 
Laboratory 
Tests 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
 
White blood cell (WBC) 
count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) 
Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Blood urea 
nitrogen (BUN) 
Potassium 
Aspartate 
Aminotransferase (AST)/ 
Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine Aminotransferase 
(ALT)/ Serum Glutamic-
Pyruvic Transaminase 
(SGPT) 
Total Protein 
 
Glucose  
Calcium 
Alkaline phosphatase 
Hemoglobin A1c 
Pregnancy 
testing 
Highly sensitive [serum or urine] human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)1 
Other Screening 
Tests 
Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only) 
NOTES: 
1. Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/IEC. 
 
 


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10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of 
study intervention, whether or not considered related to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. 
 
Events Meeting the AE Definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments 
(e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the Investigator (i.e., not related to progression of 
underlying disease). 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition. 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention interaction. 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant 
medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose taken with 
possible suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae. 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or SAE. 
Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE or 
SAE. 
 
Events NOT Meeting the AE Definition 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the 
participant’s condition. 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being 
studied, unless more severe than expected for the participant’s condition. 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is the 
AE. 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the 
study that do not worsen. 
 
 
 


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10.3.2 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have caused death if it 
were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d. Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
Medical or scientific judgment should be exercised by the Investigator in deciding whether SAE reporting is 
appropriate in other situations such as significant medical events that may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment for allergic 
bronchospasm, blood dyscrasias, convulsions  
 
10.3.3 
The Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (e.g., hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
The Investigator or designee will then record all relevant AE/SAE information. 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to the Sponsor in 
lieu of completion of the AE/SAE required form. 
There may be instances when copies of medical records for certain cases are requested by the Sponsor. In this 
case, all participant identifiers, with the exception of the participant number, will be redacted on the copies of the 
medical records before submission to the Sponsor. 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical 
information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 
The Medical Monitor or other Sponsor representative may contact the PI or investigational site personnel to 
request additional information regarding the event or to confirm information. 
For the purposes of reporting events of infection and inflammation of the eye, the following terms and definitions 
should be used: 
• 
Iritis: the presence of inflammatory cells in the anterior chamber 


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• 
The presence of aqueous flare alone will not constitute iritis but should be documented as an anterior 
chamber flare for AE reporting purposes. 
• 
Iridocyclitis: the presence of inflammatory cells in both the aqueous and vitreous 
• 
Vitritis: the presence of active inflammation in the vitreous, demonstrated by the presence of inflammatory 
cells (trace or greater) 
• 
Endophthalmitis: diffuse intraocular inflammation predominantly involving the vitreous cavity but also 
involving the anterior chamber, implying a suspected underlying infectious cause 
Active inflammation in the vitreous should be clinically differentiated from cellular debris from prior episodes of 
inflammation, hemorrhage, or other causes. 
Note: Trace benign, aqueous pigmented cells visible on slit-lamp examination that are caused by dilation and are 
not red blood cells or white blood cells or the result of any ocular disorder should not be recorded as an AE. 
For the purposes of reporting events of elevated intraocular pressure, the following terms and definitions should 
be used: 
• 
An AE of high IOP after the injection should be recorded as “Increased or Elevated IOP”. 
• 
Ocular Hypertension is a syndrome characterized by chronic elevated IOP with no optic nerve damage. 
Ocular hypertension should not be used to refer to a transient increase in IOP following the injection. 
• 
Glaucoma is a condition with nerve damage, which may or may not have a concomitant high IOP.  
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign 
it to one of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering with 
everyday activities. 
• 
Moderate: An event that causes sufficient discomfort to interfere with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should not be 
confused with an SAE. Severe is a category utilized for rating the intensity of an event; and both AEs and 
SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the definition 
of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
The Investigator is obligated to assess the relationship between study intervention and each occurrence of each 
AE/SAE. 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or arguments to suggest a 
causal relationship, rather than a relationship cannot be ruled out. 
The Investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration will be considered and investigated. 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for marketed 
products, in his/her assessment. 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the AE/SAE and 
has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to include 
in the initial report to the Sponsor. However, it is very important that the Investigator always make an assessment 
of causality for every event before the initial transmission of the SAE data to the Sponsor. 
The Investigator may change his/her opinion of causality in light of follow-up information and send an SAE 
follow-up report with the updated causality assessment. 


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The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
The relationship to the intravitreal injection procedure or to study intervention will be assessed using the 
following definitions: 
• 
Not Related - There is not a reasonable possibility that the AE is related to the injection procedure or to the 
study intervention. 
• 
Related - There is a reasonable possibility that the AE is related to the injection procedure or to the study 
intervention. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by the Sponsor to elucidate the nature and/or causality of 
the AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, the Investigator 
will provide the Sponsor with a copy of any post-mortem findings including histopathology if applicable.  
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of the 
information. 
 
10.3.4 
Reporting of SAEs 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to the Sponsor will be the electronic data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool (see next 
section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken off-line to 
prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken off-line, then the site can report this 
information on a paper SAE form (see next section) or to the Sponsor/medical monitor/SAE coordinator by 
telephone. 
• 
Contacts for SAE reporting are as follows:  
  
 
 
  
 
 
 
SAE Reporting to the Sponsor via Paper Data Collection Tool 
• 
Facsimile transmission of the SAE paper data collection tool is the preferred method to transmit this 
information to the Sponsor/Medical Monitor or the SAE coordinator. 


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• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is acceptable with 
a copy of the SAE data collection tool sent by overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete and sign the SAE 
data collection tool within the designated reporting time frames. 
• 
Contacts for SAE reporting are as follows:  
  
 
 
  
 
 
 
 


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


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10.6.2 
Contraception Guidance 
Participants who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. 
2) 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 for
 
  
a. Examples of contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation, male sterilization, established, proper use 
of hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices and copper intrauterine devices. 
b. Contraception methods that do not result in a failure rate of <1% per year 
such as cap, diaphragm, or sponge with spermicide, or male or female 
condom with or without spermicide, are not acceptable. 
c. The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
or postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
3) For men: agreement to remain abstinent or use contraceptive measures and agreement to 
refrain from donating sperm, as defined below: 
d. 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 and 
 
 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.  
• 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. 


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• 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 still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in Section 8.3.4. 
While the Investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive any study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure.  
 
 
 


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


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10.8 
Appendix 8: Protocol Amendment History 
Table 5: 
Protocol KS301P105: Amendment History 
Version 
Version Date 
Description 
2.0 
15 March 2022 
Changes from Version 1.0 include the following: 
• 
  
• 
Change in timing of the primary efficacy endpoint assessment, and 
• 
Addition of a China-specific enrollment plan. 
1 
31 July 2020 
Original Protocol 
 


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11.0 
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Campochiaro PA, Clark WL, Boyer DS, et al. 2015. Intravitreal Aflibercept for Macular 
Edema Following Branch Retinal Vein Occlusion. Ophthalmology, 122: 538-44. 
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Cheloni R, Gandolfi SA, Signorelli C, et al. 2019. Global prevalence of diabetic 
retinopathy: protocol for a systematic review and meta-analysis. BMJ open, 9: e022188. 
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Cheung N, and Wong TY. 2008. Diabetic retinopathy and systemic vascular 
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Christoforidis JB, Briley K, Binzel K, et al. 2017. Systemic biodistribution and 
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Ciulla TA, Pollack JS, and Williams DF. 2020. Visual acuity outcomes and anti-VEGF 
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Demirel S, Argo C, Agarwal A, et al. 2016. Updates on the clinical trials in diabetic 
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Duphare C, Desai K, and Munjal A. 2020. 'Diabetic Macular Edema.' in, StatPearls 
[Internet] (StatPearls Publishing). 
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Flaxel CJ, Adelman RA, Bailey ST, et al. 2020. Diabetic Retinopathy Preferred Practice 
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Foster CS, and Vitale AT. 2013. Diagnosis & Treatment of Uveitis (JP Medical Ltd). 
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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. 
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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 
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Homayouni M. 2009. Vascular endothelial growth factors and their inhibitors in ocular 
neovascular disorders. Journal of ophthalmic & vision research, 4: 105. 
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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. 


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89 
16. 
Korobelnik J-F, Do DV, Schmidt-Erfurth U, et al. 2014. Intravitreal aflibercept for 
diabetic macular edema. Ophthalmology, 121: 2247-54. 
17. 
Nussenblatt RB, Palestine AG, Chan C-C, et al. 1985. Standardizatlon of Vitreal 
inflammatory Activity in Intermediate and Posterior Uveitis. Ophthalmology, 92: 467-71. 
18. 
Park SJ, Choi Y, Na YM, et al. 2016. Intraocular Pharmacokinetics of Intravitreal 
Aflibercept (Eylea) in a Rabbit Model. Invest Ophthalmol Vis Sci, 57: 2612-7. 
19. 
Rubio RG, and Adamis AP. 2016. 'Ocular angiogenesis: vascular endothelial growth 
factor and other factors.' in, Retinal Pharmacotherapeutics (Karger Publishers). 
20. 
Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al. 2017. Guidelines for the 
management of diabetic macular edema by the European Society of Retina Specialists 
(EURETINA). Ophthalmologica, 237: 185-222. 
21. 
Singh RP, Wykoff CC, Brown DM, et al. 2017. Outcomes of diabetic macular edema 
patients by baseline hemoglobin A1c: analyses from VISTA and VIVID. Ophthalmology 
Retina, 1: 382-88. 
22. 
Yau JW, Rogers SL, Kawasaki R, et al. 2012. Global prevalence and major risk factors of 
diabetic retinopathy. Diabetes Care, 35: 556-64. 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
For Studies KS301P104 (GLEAM) and KS301P105 (GLIMMER), each entitled: 
 
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two- 
arm, Phase 3 Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with 
Intravitreal Aflibercept in Participants with Visual Impairment Secondary to Treatment-naïve 
Diabetic Macular Edema (DME) 
 
 
 
 
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: 
KS301P104 and KS301P105 
EUDRACT Number: 
2020-001062-11 
2020-001063-82 
Test Product: 
tarcocimab tedromer (KSI-301) 
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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SPONSOR SIGNATORY 
 
Study Title: 
A Prospective, Randomized, Double-masked, Active 
Comparator-controlled, Multi-center, Two-arm, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravitreal 
KSI-301 Compared with Intravitreal Aflibercept in 
Participants with Visual Impairment Secondary to 
Treatment-naïve Diabetic Macular Edema (DME) 
(GLEAM and GLIMMER) 
Protocol Code: 
KS301P104 and KS301P105 
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 ......................................................................................................................... 5 
LIST OF ABBREVIATIONS ........................................................................................................ 6 
1.0 
INTRODUCTION .............................................................................................................. 8 
2.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 8 
3.0 
INVESTIGATIONAL PLAN .......................................................................................... 10 
3.1 
Study Design .......................................................................................................... 10 
3.2 
KSI-301 5 mg Individualized Treatment ............................................................... 11 
3.2.1 
Base Treatment Interval ........................................................................ 11 
3.2.2 
Modification of the Base Treatment Interval ........................................ 11 
3.2.3 
Disease Activity Criteria ....................................................................... 11 
3.2.4 
Disease Stability Criteria ....................................................................... 12 
3.3 
Study Interventions................................................................................................. 12 
3.4 
Randomization and Stratification ........................................................................... 12 
4.0 
TYPES OF PLANNED ANALYSES .............................................................................. 12 
4.1 
Data Monitoring Committee Analyses ................................................................... 12 
4.2 
Interim Analyses .................................................................................................... 12 
4.3 
Primary Analysis (Week 64) .................................................................................. 13 
4.3.1 
Timing of the Primary Analysis ............................................................ 13 
4.3.2 
Data to be Analyzed for the Primary Analysis Period .......................... 13 
4.4 
Final Analysis (Week 108) ..................................................................................... 13 
4.4.1 
Timing of the Final Analysis ................................................................. 13 
4.4.2 
Data to be Analyzed for the Final Analysis ........................................... 14 
5.0 
GENERAL STATISTICAL METHODS ....................................................................... 14 
5.1 
Reporting Conventions ........................................................................................... 14 
5.2 
Standard Calculations ............................................................................................. 15 
5.3 
Study Definitions and Derived Variables ............................................................... 16 
5.4 
Analysis Sets .......................................................................................................... 16 
5.4.1 
Full Analysis Set (FAS) ......................................................................... 16 
5.4.2 
Safety Analysis Set (SAF) ..................................................................... 16 


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5.5 
Examination of Subgroups ..................................................................................... 17 
5.6 
Multiple Comparisons/Multiplicity ........................................................................ 17 
5.7 
Multicenter Studies ................................................................................................ 18 
5.8 
Analysis Visit ......................................................................................................... 18 
6.0 
BASELINE ANALYSES ................................................................................................. 18 
6.1 
Disposition of Subjects .......................................................................................... 18 
6.2 
Demographic and Other Baseline Characteristics .................................................. 19 
6.2.1 
Demographics and Baseline Characteristics .......................................... 19 
6.2.2 
Ocular and Other Medical History ........................................................ 20 
6.2.3 
Prior and Concomitant Medications/Procedures ................................... 20 
6.3 
Protocol Deviations ................................................................................................ 21 
7.0 
EFFICACY ANALYSES ................................................................................................. 22 
7.1 
Primary Efficacy Analysis ..................................................................................... 22 
7.1.1 
Primary Estimand .................................................................................. 22 
7.1.2 
Analysis of Primary Efficacy Endpoint ................................................. 23 
7.1.3 
Sensitivity Analysis 1 ............................................................................ 24 
7.1.4 
Sensitivity Analysis 2 (Trimmed Mean Analysis) ................................ 24 
7.1.5 
Sensitivity Analysis 3 (Tipping Point Analysis) ................................... 25 
7.2 
Key Secondary Efficacy Analyses ......................................................................... 26 
7.3 
Secondary Efficacy Analyses ................................................................................. 27 
7.3.1 
Analysis of Binary Data ........................................................................ 27 
7.4 
Exploratory Analyses ............................................................................................. 30 
7.5 
Subgroup Analyses ................................................................................................. 32 
7.6 
Additional Pooled Analyses ................................................................................... 32 
8.0 
SAFETY EVALUATION ................................................................................................ 33 
8.1 
Exposure to Study Medication ............................................................................... 33 
8.2 
Adverse Events ....................................................................................................... 33 
8.3 
Deaths, Serious Adverse Events, and other Significant Adverse Events ............... 34 
8.4 
Pregnancies ............................................................................................................. 34 
8.5 
Intraocular Pressure ................................................................................................ 35 
8.6 
Clinical Laboratory Evaluations ............................................................................. 35 
8.7 
Vital Signs .............................................................................................................. 35 
9.0 
SAMPLE SIZE CONSIDERATIONS ............................................................................ 35 
10.0 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ...................................................................................................................... 36 


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11.0 
REFERENCES ................................................................................................................. 36 
12.0 
APPENDICES .................................................................................................................. 37 
Appendix 1: Schedule of Activities ................................................................................... 38 
Appendix 2: Sample SAS Code ......................................................................................... 41 
Mixed Model for Repeated Measures .................................................................... 41 
Cochran–Mantel–Haenszel (CMH) Test Adjusting Randomization Strata ........... 43 
Reference for Weighted Percentages Based on Weighted Average of Observed 
Estimates Across Strata Using CMH Weights ...................................... 44 
 
LIST OF TABLES 
Table 1: Objectives and Endpoints................................................................................................... 9 
Table 2: Subgroups 
17 
Table 3: Windows for Unscheduled Visit ...................................................................................... 18 
Table 4: Secondary Efficacy Endpoints and Analysis Methods .................................................... 29 
Table 5: Exploratory Efficacy Endpoints and Analysis Methods .................................................. 31 
Table 6: Pooled analysis parameters .............................................................................................. 32 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ANCOVA 
Analysis of covariance 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATE 
Arteriothromboembolic 
BCVA 
Best-corrected visual acuity 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
CST 
Central Subfield Thickness 
DME 
Diabetic Macular Edema 
DR 
Diabetic retinopathy 
DRSS 
Diabetic Retinopathy Severity Scale 
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 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
ILM 
Inner Limiting Layer 
IND 
Investigational New Drug (application) 
ICE 
Intercurrent event 
IOI 
Intraocular inflammation 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
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 
NPDR 
Non-proliferative diabetic retinopathy 
OCT 
Optical Coherence Tomography 


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Abbreviation 
Definition 
PDR 
Proliferative diabetic retinopathy 
PT 
Preferred Term 
Q4W 
Every four weeks 
Q8W 
Every eight weeks 
Q12W 
Every twelve weeks 
Q16W 
Every sixteen weeks 
Q20W 
Every twenty weeks 
Q24W 
Every twenty-four weeks 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
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 
 
 
WHO 
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 Studies KS301P104 and KS301P105 
(Protocol Amendment 2.0, dated 15 March 2022), each entitled A Prospective, Randomized, Double- 
masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate the Efficacy 
and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in Participants with Visual 
Impairment Secondary to Treatment-naïve Diabetic Macular Edema (DME). (Study KS301P104 is also 
referred to as ‘GLEAM’ and Study KS301P105 as ‘GLIMMER.’) These studies are 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 key 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). Details about the unmasking plan for study treatment assignment, including the procedures and 
guidelines that Kodiak, study sites, and vendors will follow to ensure that masking of the study is 
appropriately maintained during the conduct of the study, will be detailed in a separate document. 
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 CSRs. Minor changes or deviations from 
the templates for tables, figures, and listings need not be documented in the CSRs. 
Since the studies are identically designed, a single analysis plan has been developed that includes 
analyses of both individual study outcomes and selected outcomes from pooled data of studies 
KS301P104 and KS301P105. 
 
 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
Table 1 lists the primary and secondary study objectives, along with their corresponding endpoints. 


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Table 1: Objectives and Endpoints 
Objectives 
Corresponding Endpoints 
Primary 
To demonstrate that KSI-301 5 mg is non-inferior to 
aflibercept 2 mg with respect to mean change in BCVA 
from Day 1 to the average of Weeks 60 and 64 
Mean change in BCVA from baseline to the average of 
Weeks 60 and 64 (using Early Treatment Diabetic 
Retinopathy Study (ETDRS) Letters) 
Key Secondary 
To evaluate the efficacy of KSI-301 5 mg compared to 
aflibercept 2 mg over the study duration by assessing 
anatomical parameters (focusing on the ETDRS DRSS) 
Proportion of subjects with a ≥ 2-step worsening from 
baseline on the ETDRS DRSS at Week 52 in Studies 
KS301P104 and KS301P105 combined 
Proportion of subjects with a ≥ 2-step worsening from 
baseline on the ETDRS DRSS at Week 52 in individual 
Study KS301P104/KS301P105 
Secondary 
To evaluate the efficacy of KSI-301 5 mg compared to 
aflibercept 2 mg over the study duration by assessing 
visual parameters 
Mean change in BCVA (ETDRS Letters) from baseline 
over time 
Proportion of subjects who gain ≥ 5, ≥10 and ≥15 letters 
from baseline by visit over time 
Proportion of subjects who lose ≥ 5, ≥10 and ≥15 letters 
from baseline by visit over time 
Proportion of subjects with BCVA Snellen equivalent of 
20/40 (69 or more ETDRS letters) or better over time 
Proportion of subjects with BCVA Snellen equivalent of 
20/200 (38 or less ETDRS letters) or worse over time 
To evaluate the efficacy of KSI-301 5 mg compared to 
aflibercept 2 mg over the study duration by assessing 
anatomical parameters 
Mean change in optical coherence tomography (OCT) 
central subfield thickness (CST) and other 
morphological parameters from baseline to the average 
of Weeks 60 and 64 and over time. 
Proportions of patients with a ≥ 2-step improvement or 
worsening from baseline on the ETDRS DRSS over time 


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Objectives 
Corresponding Endpoints 
To evaluate the durability of KSI-301 5 mg over the 
study duration 
Mean/Median number of intravitreal injections over the 
duration of the study 
Mean/Median number of intravitreal injections from 
baseline through Week 60 and from Week 64 until end 
of study 
Mean/Median time to first retreatment after the last 
monthly dose 
Proportion of patients in the KSI-301 arm on a Q8W, 
Q12W, Q16W, Q20W or Q24W treatment interval 
through the duration of exposure 
To evaluate the safety and tolerability of KSI-301 5 mg 
compared to aflibercept 2 mg. 
Incidence of ocular and systemic adverse events up to 
Week 64 and Week 108. 
 
 
3.0 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
These are phase 3, prospective, randomized, double-masked, two-arm, multi-center studies evaluating 
the efficacy and safety of repeated intravitreal dosing of KSI-301 5 mg in patients with treatment naïve 
DME. A brief description of the study design and study treatment regimen appears below; additional 
details can be found in the study protocols. 
The schedule of activities is provided in Appendix 1. 
The studies are divided into a 3-week screening period, a 104-week treatment period, and a final 4-week 
follow-up period. At baseline, subjects will be randomized 1:1 into two treatment arms: KSI-301 5 mg 
and aflibercept 2 mg. 
KSI-301 5 mg 
Patients randomized in KSI-301 5 mg group will initially receive 3 monthly (Q4W) doses of KSI-301 5 
mg 
 (at Day 1, Week 4, and Week 8), followed by a sham injection at Week 12 to preserve 
masking. Starting at Week 16 until Week 100, patients in this group will be assessed monthly (Q4W) 
and will receive additional administration of KSI-301 5 mg according to disease activity criteria defined 
below. The minimum interval between active treatments is 8 weeks (± 14 days, considering the 
respective visit windows) and the maximum interval is 24 weeks (± 14 days, considering the respective 
visit windows). To preserve masking, sham injections are administered at each visit in which no active 
treatment with KSI-301 5 mg is indicated. 
Aflibercept 2 mg 
Patients in this group will initially receive 5 monthly doses of aflibercept 2 mg (50 µL) (at Day 1, Week 
4, Week 8, Week 12, and Week 16), followed by doses once every 8 weeks (Q8W) until Week 108. 
Patients will receive a sham injection at each visit that aflibercept is not administered. 


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3.2 
KSI-301 5 mg Individualized Treatment 
3.2.1 Base Treatment Interval 
At Weeks 16, 20, 24 and 28, patients will be assessed for disease activity criteria to determine their base 
treatment interval (once every 8, 12, 16, 20, or 24 weeks). Patients will receive a KSI-301 5 mg dose at 
the first visit in which any of the disease activity criteria are met. If disease activity criteria are not met 
by Week 32, participants will receive a dose of KSI-301 5 mg at that visit, which corresponds to the 
maximum 24-week (Q24W) base treatment interval. The base treatment interval is determined by the 
time between the last loading dose and the first re-treatment. Once established, the base treatment 
interval determines when participants receive their next KSI-301 5 mg dose. 
 
3.2.2 Modification of the Base Treatment Interval 
The base treatment interval can be adjusted as follows: 
• Shortened by 4 weeks or more to a minimum of 8 weeks (when one or more disease activity 
criteria are met, indicating that the participant requires an injection before their next base 
treatment interval visit); or 
• Maintained, in two scenarios: 
- 
When one or more disease activity criteria are met at, but not before, their next base treatment 
interval visit; or 
- 
When no disease activity criteria are met at their next base treatment interval, but the disease 
stability criterion is not met; or 
• Extended to a maximum of 24 weeks (when none of the disease activity criteria are met and the 
participant’s DME is stable according to the disease stability criterion below). 
If the base treatment interval is shortened or extended, the new interval will be considered the new base 
treatment interval for that participant and can be modified throughout the individualized treatment 
period based on the adjustments described above. 
 
3.2.3 Disease Activity Criteria 
Under protocol version 2, patients are administered KSI-301 5 mg if any of the following disease 
activity criteria are met: 
• Increase in OCT CST ≥ 40 µm compared to lowest previous measurement, or 
• OCT CST ≥ 350 µm; or 
• New or worsening proliferative DR (PDR): progression from NPDR to PDR, vitreous 
hemorrhage, iris neovascularization and/or new or worsening retinal neovascularization. 


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Disease activity assessments will be conducted by the masked Investigator. The IRT system will adjust 
the dosing schedule based on disease activity data entered by the study site. The IRT will adjust the 
dosing schedule in consideration of missed visits, out of window visits, and missing data during a visit. 
 
3.2.4 Disease Stability Criteria 
Stable disease for the purposes of extending the base treatment interval is determined by the following 
criterion, which must be met in addition to the absence of any of the disease activity criteria: 
• No increase in CST of >30 µm compared to the lowest previous measurement. 
This criterion must be met at each visit where the base treatment interval is being extended. 
 
3.3 
Study Interventions 
Study interventions are summarized in the Protocol Table 2. 
 
3.4 
Randomization and Stratification 
Patients who meet all inclusion criteria and none of the exclusion criteria will be centrally assigned to a 
randomized study intervention using an Interactive Response Technology (IRT) system. Randomization 
will be stratified by
 
 
 
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 
Primary Analysis (Week 64) 
4.3.1 Timing of the Primary Analysis 
The primary analysis will be performed when all patients have either completed the Week 64 visit or 
have discontinued from the study prior to the Week 64 visit, whichever comes later, the data up to and 
including the Week 64 visit have been entered, cleaned and verified as appropriate, and the database for 
the primary analysis is frozen. 
Safeguards will be put in place to ensure that the unmasking does not introduce operational biases in the 
conduct of the ongoing study. Details of the unmasking plan are described in a separate document. 
 
4.3.2 Data to be Analyzed for the Primary Analysis Period 
The following data (up to Week 64) will be included in the primary analyses: 
• Demographics and Baseline Ocular and Non-Ocular Characteristics 
• Subject Disposition at Week 64 
• Primary Efficacy Analyses 
- 
Sensitivity and Subgroup Analyses for the Primary Efficacy Endpoint 
• Selected Secondary Efficacy Analyses 
• Interventions 
- 
Study Treatment and Exposure 
• Safety 
- 
AEs (including SAEs and AESIs), by Event Type (i.e., Study Eye, Fellow-Eye, Non-Ocular) 
- 
Clinical laboratory 
- 
Vital signs 
- 
Concomitant Medications and Procedures 
 
4.4 
Final Analysis (Week 108) 
4.4.1 Timing of the Final Analysis 
The analysis will be performed when all patients have either completed the Study (Week 108 visit) or 
have discontinued from the study prior to the Week 108 visit, whichever comes later, the data up to and 
including the Week 108 visit have been entered, cleaned and verified as appropriate, and the database is 
locked. 


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4.4.2 Data to be Analyzed for the Final Analysis 
The following data (up to Week 108) will be included in the analyses. 
• Subject Disposition 
• Descriptive Efficacy Analyses 
• Interventions 
- 
Study Treatment and Exposure 
• Safety 
- 
Incidence of ocular and systemic AEs (including SAEs and AESIs) by Event Type (i.e,, Study 
Eye, Fellow-Eye, Non-Ocular) 
- 
Clinical laboratory 
- 
Vital signs 
- 
Concomitant Medications and Procedures 
 
 
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 


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


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• Missing day with a provided year and month will use the last day of the month. 
• Missing day and month with provided year will use December 31. 
If the imputed stop date is greater than the last study date for the subject, then the imputed date will be 
replaced with the last available event date for the subject in the study. 
Other variables requiring calculations will be derived using the following formulas: 
• Days: A duration between two dates expressed in days will be calculated using the following 
conventions: 
- 
Later date – earlier date + 1. 
• Months: A duration expressed in months will be calculated by dividing the duration in days by 
(365.25 /12). 
• Years: A duration expressed in years will be calculated by dividing the duration in days by 
365.25. 
 
5.3 
Study Definitions and Derived Variables 
• Unless otherwise specified, the duration of Week 64 analysis is defined as Study Day 1 until 
Week 64, as it is meant to be inclusive both of study treatments leading to the primary efficacy 
outcome at Week 64 and of safety assessments in that period. 
• Similarly, the duration of Week 108 analysis is defined as being from Day 1 until week 108, 
unless otherwise specified. 
• 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 (FAS) 
The Full Analysis Set 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 
analyses of efficacy. 
 
5.4.2 Safety Analysis Set (SAF) 
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. 


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5.5 
Examination of Subgroups 
The primary efficacy endpoints will be summarized in the following subgroups of baseline 
characteristics. 
Table 2: Subgroups 
 
 
Characteristics 
Subgroup 
Age 
< 65 years of age 
≥ 65 years of age 
65-74 years of age 
75-84 years of age 
≥ 85 years of age 
< 75 years of age 
≥ 75 years of age 
Sex 
Female 
Male 
Ethnicity 
Hispanic or Latino 
Not Hispanic or Latino 
BCVA  
BCVA: ≥ 69 letters 
BCVA: 68-49 letters 
BCVA: ≤48 letters 
OCT CST  
≤ 420 microns 
> 420 microns 
Geographic location* 
North America 
Rest of World 
Race 
White 
Black or African American 
Asian 
American Indian or Alaska Native 
Native Hawaiian or other Pacific Islander 
Other 
Lens status 
Phakic 
Pseudophakic 
DRSS 
DRSS: less than level 47 
DRSS: level 47 or 53 
DRSS: greater than level 53 
 
Other subgroup analyses may be explored. 
 
5.6 
Multiple Comparisons/Multiplicity 
 
 
 


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5.7 
Multicenter Studies 
This is a multicenter, international study. Efficacy data collected from all study sites will be pooled for 
data analysis. The effect of study site on the efficacy analysis results may be explored, as needed. 
 
5.8 
Analysis Visit 
For efficacy analyses, unscheduled or early termination visits will be assigned a study day and then 
mapped to the appropriate analysis window as detailed in Table 3. In the event where more than one 
record falls in the same analysis window, the following rules will be used in sequential order to 
determine the record that will be used for data analysis: 
• If there is a scheduled visit in the analysis window, then the scheduled visit’s data will be used. 
• If there is no scheduled visit in the analysis visit window, the record that is the closest to the 
scheduled study day at a given visit will be used. 
• If there is no scheduled visit in the analysis visit window and there is a tie between the two 
records with regards to the number of days before and after the scheduled study day, the later 
record will be used. 
Analysis visit windows will not apply to subject data listings. Prior to any missing data imputations or 
analysis, the analysis visit windows will be applied to the data. 
Table 3: Windows for Unscheduled Visit 
Nominal Visit 
Scheduled 
Study Day 
Starting Day for 
Nominal Visit 
Ending Day for 
Nominal Visit 
Day 1 
1 
1 
1 
Week 1 
7 
2 
14 
Week 4 
28 
15 
42 
Week 8 – Week 108 
Week×7 
(Week×7)-13 
(Week×7)+14 
Note: Nominal visits are at Day 1, Weeks 1, 4, 8, … every 4 weeks from Week 8 until Week 108. 
 
 
6.0 
BASELINE ANALYSES 
6.1 
Disposition of Subjects 
Subject disposition will be summarized by treatment group and overall. The following will be 
summarized: 
- 
The number of patients screened 


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The number of patients randomized
-
The number of patients (%) in the Full Analysis set
-
The number (%) in the Safety Analysis set
-
The number (%) completing the study treatment
-
The number (%) discontinuing the study treatment and the reasons for discontinuation of study 
treatment
-
The number of patients (%) discontinuing study and the reasons for discontinuation of study
Subject disposition will also be summarized separately for each study site. Subject completion status, 
date of study completion/discontinuation, study day of discontinuation, and reason for discontinuation 
will be listed.
Patients who did not meet inclusion or exclusion eligibility criteria will be listed.
6.2
Demographic and Other Baseline Characteristics
6.2.1
Demographics and Baseline Characteristics
The following demographics, baseline characteristics, and randomization stratification variables will be 
summarized by treatment group and overall. 
Demographics:
•
Sex
•
Age continuous and by category (<65, ≥ 65, < 75, ≥75, 65-74, 75-84, >85 years)
•
Ethnicity
•
Race
Randomization stratification variables:
•
Other baseline characteristics:
•
Systolic and diastolic blood pressure
Other Baseline Ocular Characteristics:
•
Intraocular pressure in the study eye, continuous and by category (≤21, 22-29, >29 mmHg)
•
Lens status (phakic, pseudophakic, aphakic) 
Ocular Imaging, OCT: 


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• Center Subfield Thickness (CST) 
• Intraretinal fluid 
• Subretinal fluid 
Ocular Imaging, Fundus fluorescein angiography (FA): 
• Foveal Avascular Zone, area in square microns 
• Leakage Intensity: in central mm, in inner subfields, in outer subfields 
 
Ocular Imaging, color fundus photography (FP): 
• Baseline DRSS score 
Individual patients’ demographics and baseline characteristics will be listed. 
 
6.2.2 Ocular and Other Medical History 
Medical history includes non-ocular events and ocular events for the study and fellow (non-study) eyes. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
[version 23.1] and will be summarized by System Organ Class (SOC) and Preferred Term (PT) for the 
Safety Analysis Set. Summaries will be presented by treatment group and overall. Two listings will be 
provided: one listing for all non-ocular medical history and an additional listing for ocular history by 
treatment, subject, and study/non-study eye. 
 
6.2.3 Prior and Concomitant Medications/Procedures 
All medications (ocular and non-ocular) will be coded using the World Health Organization (WHO) 
Drug Global Dictionary, Format B3 [Version September 2020 (or a later version if updated during the 
study)], Anatomical Therapeutic Chemical (ATC) Classification codes. Medications will be 
summarized by treatment group and overall for the Safety Analysis Set. Medication summaries will be 
presented by Anatomical Therapeutic Chemical (ATC) class level 4 and preferred name. In addition, 
ocular medications will be presented separately for the study eye and fellow eye. 
Prior medications and concomitant medications are defined as follows: 
• Prior medications are those taken prior to the start of the first dose of study treatment 
• Concomitant medications are those with 
- 
a start date on or before the last dose of study treatment and 
- 
a stop date after the first dose of study treatment or are ongoing at the end of the study 
 
See Section 5.2 for imputation of missing or partial dates. 
 
Prior and concomitant medications will be separately summarized by ocular and non-ocular for the Safety 
Analysis Set as follows: 


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• The number and percentage of patients with at least one prior / concomitant medication / procedure 
will be presented. 
• The number and percentage of patients with at least one prior / concomitant medication / procedure 
within each ATC Level 4, and preferred name will be presented. 
• Patients reporting use of more than one medication / procedure at each level of summarization 
(any medication received, ATC class, and generic drug name) will be counted only once. 
• The summary will be sorted using numerical counts by descending order of Therapeutic Subgroup, 
then descending order of preferred name in the total column. Where groups or terms tie these will 
be sorted alphabetically. 
Prior medications and concomitant medications (ocular and non-ocular) will be listed separately for the 
Safety Analysis Set. 
The following will be summarized and listed for concomitant medications and procedures: 
• Ocular (study eye and fellow eye separately) and non-ocular concomitant medications that were 
initiated before start of treatment. 
• Ocular (study eye and fellow eye separately) and non-ocular concomitant medications that were 
initiated after the start of treatment. 
• Medications prescribed after study treatment discontinuation for patients who remain in the study 
will be listed separately. 
• Concomitant ocular procedures (study eye and fellow eye separately) administered while patients 
were on study treatment will be summarized and listed. 
• 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-ocular) use 
will be calculated relative to the first dose date of study treatment and will be presented for those patients 
who received at least one dose of treatment. If the concomitant medication is “Ongoing” it will be 
indicated as such in the listing and the relative stop day will not be calculated. Only original dates will be 
presented in the listing even though the relative day may be based on an imputed date. 
 
6.3 
Protocol Deviations 
All major protocol violations will be determined and categorized by the timing of analyses (see 
Section 4.0): 
• From start of the study to the data freeze for the Week 64 Primary Analysis 
• From the start of the study to the data freeze for Week 108 Analysis 
Major protocol deviations will be summarized by treatment group and overall for the Full Analysis set. 
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 


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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 DME. 
The most relevant aspects of the study eligibility criteria for defining this population include the 
following key inclusion and exclusion criteria: 
Inclusion criteria 
1. Treatment-naïve diabetic macular edema, with vision loss and center involvement (if present) 
diagnosed within 9 months of screening. 
2. BCVA ETDRS letter score ≤78 and ≥ 25 (⁓20/25 to 20/320 Snellen equivalent) in the Study Eye at 
Screening and confirmed at Day 1. 
3. CST of ≥ 320 microns on SD-OCT (Heidelberg Spectralis or equivalent on other OCT instruments) 
as determined by the Reading Center at the screening visit. 
4. Decrease in vision in the Study Eye determined by the Investigator to be primarily the result of 
DME. 
Exclusion criteria 
1. Macular edema in the Study Eye considered to be secondary to a cause other than DME (e.g., RVO, 
Irvine-Gass syndrome). 
2. Active iris or angle neovascularization or neovascular glaucoma in the Study Eye. 
3. Structural damage to the center of the macula in the Study Eye that is likely to preclude 
improvement in BCVA following the resolution of macular edema including atrophy of the retinal 
pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or organized hard 
exudates in the foveal center. 
 
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 Weeks 60 and 64. If the Week 60 or Week 64 assessment is missing, the 
available value will be used in the analysis. 


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7.1.1.3 
Hypotheses and Test 
The maximum clinically acceptable true difference between KSI-301 and aflibercept among DME 
patients to be considered non-inferior 
, i.e. the non-inferiority margin (NI) is 
 
 
The hypothesis to be tested is: 
 
H0: μK - μA ≤ 
 
vs 
HA: μK - μA > 
 
Where μK and μA are the mean changes from baseline to the Weeks 60 and 64 average BCVA in the 
KSI-301 and aflibercept groups. 
If the lower limit of the two-sided 95.04% CI for the difference between the two means is 
, 
NI will be demonstrated. Furthermore, superiority will be established if the lower limit of the two-sided 
95.04% 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 (including sham or active treatment) of 1 or more study treatments. 
3. Use of prohibited medications in the study eye. 
4. Premature discontinuation from study treatment due to study eye adverse events or due to lack of 
efficacy. 
5. Premature discontinuation from study treatment due to events unrelated to study treatment such as 
malignancies, systemic infections, trauma, or other systemic adverse events that are not treatment- 
related, including discontinuations related to COVID-19. 
Intercurrent events will be classified by the Sponsor prior to treatment code unmasking to prevent 
potential bias. Intercurrent events will be tabulated by treatment group. Strategies for addressing the 
potential impact of these intercurrent events are described below. 
 
7.1.2 Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint will be estimated based on the FAS, i.e., all randomized subjects who 
received at least one treatment injection and using all available post baseline measurements up to Week 
64 or until the subject discontinues study treatment. The ‘While on-Treatment’ policy will be applied 
for the primary endpoint. 
A Mixed Model for Repeated Measures (MMRM) will be used. The model assumes missing at random 
(MAR) and uses all available data. MMRM balances the benefits of preserving unbiased estimates 
because of randomization with the desire to obtain estimates for a comparison of true biological 
treatment effects. 


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The model will include the change from baseline value as the dependent variable; categorical covariates 
of treatment group, protocol scheduled visit, treatment × visit interaction,
 as 
well as continuous covariates of baseline BCVA value and baseline OCT CST value, as fixed effects; 
and then subject as a random effect. Within-subject correlations will be assumed to follow an 
unstructured covariance matrix. The change from baseline in BCVA score averaged over Weeks 60 and 
64 will be compared between treatment groups. The comparisons will be performed using a contrast 
over Weeks 60 and 64. 
If the model assuming an unstructured covariance matrix does not converge, a heterogeneous compound 
symmetry structure or an AR(1) covariance structure will be fitted. 
 
7.1.3 Sensitivity Analysis 1 
A sensitivity analysis, aimed at assessing the robustness of the assumptions used in the statistical model 
for the main estimator will be conducted to include the FAS patients who did not have any of the 
following intercurrent events: deviations from key inclusion/exclusion criteria as defined above, 
treatment misallocations as defined above, and use of prohibited medications in the study eye during the 
study treatment period. 
The sensitivity analysis based on this set is a type of ‘Hypothetical Policy’ strategy. The same MMRM 
as described for the primary efficacy analyses will be used. 
7.1.4 Sensitivity Analysis 2 (Trimmed Mean Analysis) 
An additional sensitivity analysis using the trimmed mean approach (Permutt and Li 2017) will be 
performed. 
If any of the following event types denoted by E occurred, patients will be considered to have the worst 
outcomes (defined below) and will be trimmed from the analysis: 
• Discontinuation from study treatment due to study eye adverse events or due to lack of efficacy 
at or prior to Week 64 with no BCVA assessments available at Weeks 60 and 64. 
• Administration of prohibited anti-VEGF medication any time during the 64 weeks of treatment. 
The equal trimming fraction denoted by p will be determined based on a masked assessment of the 
intercurrent events percentage in the study. 
Patients will not be considered “to be trimmed” candidates if they have a Week 60 and/or Week 64 
assessments before the occurrence of any event type E above. 
Patients who have no BCVA assessments available at Weeks 60 and 64 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 related to COVID-19, will be considered missing at 
random (MAR) and will be removed from the analysis. 
A 95.04% confidence interval (CI) for the trimmed mean will be based on the permutation test of 30,000 
generated datasets. In each dataset (random sample), the treatment assignments will be randomly 


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permuted according to the study randomization stratification algorithm (blocked randomization stratified 
by 
 
For each generated random sample: 
1. An analysis of covariance (ANCOVA) model with adjustment for treatment, baseline BCVA 
value (continuous), as well as randomization stratification factors will be derived. The dependent 
variable in the ANCOVA model will be the average of non-missing values of Weeks 60 and 64 
BCVA change from baseline, as for the primary analysis and denoted by Y. If only one 
assessment is available, then the value will be used. 
2. The value Z=Y - β' X will be derived for each patient, where Y is defined above, X is the matrix 
for the values of the following covariates— baseline BCVA value (continuous), baseline BCVA 
categorical, baseline OCT CST categorical, and region; β is the ANCOVA estimated coefficient 
matrix for the covariates. 
3. The Z values will be ordered and equal fractions, p, from each treatment arm will be trimmed. 
4. The patients to be trimmed will always be ranked the lowest regardless of whether their adjusted 
values are available and trimmed from the analyses. The best (1 - p)*100 in each group will be 
used for the analysis specified in Step 1. If multiple patients have the same model values, they 
will be ranked randomly relative to each other prior to trimming. 
5. The difference between groups in the trimmed means is derived. 
Steps 1-5 are repeated 30,000 times. 
The empirical permutation distribution of the difference between the trimmed means based on 2.48 and 
97.52 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 
 
decrease 
 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 60 or 64 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. 


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Step 1b: A penalty will be applied to the imputed primary efficacy endpoint for the Weeks 60 and 64 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 treatment difference for the 
average of Week 60 and Week 64. 
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 
. After the tipping point is identified, clinical judgment will determine the 
plausibility of the assumptions underlying this tipping point. 
 
7.2 
Key Secondary Efficacy Analyses 
The first key secondary efficacy analysis of interest is DRSS using Color Fundus Photography defined 
as the proportion of subjects with a ≥ 2-step worsening from baseline on the ETDRS DRSS at Week 52 
in the FAS population for studies KS301P104 and KS301P105 combined. 
The maximum clinically acceptable non-inferiority margin between KSI-301 and aflibercept subjects is 
 to be considered non- inferior, or the “non-inferiority margin”, which translates into the following 
null/alternative hypothesis. 
H0: pK - pA ≥ 
 
Vs   HA: pK - pA < 
 
Where pK and pA are the proportion of subjects with a ≥ 2-step worsening from baseline at Week 52 in 
the KSI-301 and aflibercept groups respectively. 
Non-inferiority will be demonstrated if the upper limit of the two-sided 95.04% confidence interval for 
the treatment difference (KSI-301 – aflibercept) is less than the prespecified non-inferiority margin of 
 Furthermore, superiority will be established if the upper limit of the two-sided 95.04% confidence 
interval for the treatment difference (KSI-301 – aflibercept) is less than zero. 
The key secondary endpoints will be estimated based on the FAS, defined as in Section 5.4.1. The 
proportions of “responders” for subjects with a ≥ 2-step worsening will be tested between KSI-301 and 
aflibercept using the Cochran–Mantel–Haenszel (CMH) test by adjusting the baseline randomization 
stratification factors (Section 3.4) and Study (KS301P104 or KS301P105). If the response rate is low, 
an unstratified analysis may also be performed. For subjects who missed the assessment or have 


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ungradable DRSS at Week 52, the last evaluable response prior to week 52 will be used for this analysis. 
Patients with ungradable or missing baseline DRSS will be excluded from the analysis. 
In addition, the weighted percentages difference between the KSI-301 and aflibercept (i.e., KSI-301 – 
aflibercept) and 95.04% CI of the difference will be presented. Percentages are calculated as 
100×number of “responders”/number of patients in FAS. 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. 
The second key secondary efficacy analysis of interest is DRSS using Color Fundus Photography 
defined as the proportion of subjects with a ≥ 2-step worsening from baseline on the ETDRS DRSS at 
Week 52 in the FAS population for study KS301P104 (or KS301P105) individually. The tested non- 
inferiority hypothesis and analysis will be the same as described above for the first key secondary 
endpoint except the study will be excluded from CMH model. If the response rate is low, an unstratified 
analysis may also be performed. 
Together with the primary endpoint point and the key secondary endpoints, this family of tests will be 
conducted hierarchically to maintain a familywise Type I error rate of 4.96%. Each test within this 
family will only be conducted at the 4.96% level if the preceding test was significant at the 4.96% level. 
 
7.3 
Secondary Efficacy Analyses 
As specified in Section 4.0, the Primary Analysis will evaluate the efficacy of KSI-301 compared to 
aflibercept from Day 1 up to Week 64. The Final Analysis will evaluate the KSI-301 efficacy compared 
to aflibercept from Day 1 up to Week 104. 
Table 4 lists the secondary efficacy endpoints, efficacy variable derivations, reporting statistics and 
analysis methods for the Primary Analysis and the Final Analysis. 
 
7.3.1 Analysis of Binary Data 
The number and percentage of patients who gain or lose ≥ 5, ≥10 and ≥15 letters from baseline over 
time will be summarized by treatment group and visit, as will the number and percentage of patients 
with BCVA of 20/40 or better Snellen equivalent, BCVA or 20/200 or worse Snellen equivalent, ≥2-step 
improvement in DRSS, and OCT CST < 325 microns. The group proportions of “responders” for these 
categories of binary outcomes will be compared between KSI-301 and aflibercept using the Cochran– 
Mantel–Haenszel (CMH) test by adjusting the baseline randomization stratification factors (Section 3.4) 
similar to the analysis for the key secondary endpoints. 
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 


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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 
[Primary], up to Wk 64 
[Final], up to Wk 104 
Using the MMRM model (Section 7.1.2) 
used for deriving the primary endpoint 
estimate 
Proportion of subjects with a ≥ 
2-step improvement from 
baseline on the ETDRS DRSS 
over time 
Binary Endpoint 
Patients had a 2-step improvement (yes/no) 
Difference in proportions (%) 
and 95% CI at each scheduled 
time point 
[Primary], up to Wk 64 
[Final], up to Wk 104 
Stratified analysis of the binary endpoint 
using CMH adjusting for randomization 
stratification factors (Section 7.3.1) 
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] 
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] 
Difference in proportions (%) 
and 95% CI at each time point 
[Primary], up to Wk 64 
[Final], up to Wk 104 
Stratified analysis of the binary endpoint 
using CMH adjusting for randomization 
stratification factors (Section 7.3.1) 
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] 


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Secondary Efficacy Endpoint 
Variable Derivation 
[Source] 
Summary Statistics 
[Analysis Set] 
Method of Analysis 
Mean change in OCT central 
subfield retinal thickness (CST) 
from baseline to the average of 
Weeks 60 and 64 and over time 
Continuous Endpoint: 
Change from baseline to each time point 
 
LS Mean difference in change 
from baseline to each time 
point 
[Primary], up to Wk 64 
[Final], up to Wk 104 
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 
Proportion of patients in the 
KSI-301 arm on a Q8W, 
Q12W, Q16W, Q20W or 
Q24W treatment interval 
through the duration of 
exposure 
Categorical Endpoint: 
Patient proportion in each category 
[Exposure/EDC] 
Frequency and proportion 
Descriptive 
Mean/median number of 
intravitreal injections over the 
duration of the study 
Mean/median number of 
intravitreal injections from 
baseline through week 60 and 
from week 64 until the end of 
study 
Mean/median time to first 
retreatment after the last 
monthly dose 
Continuous Endpoints: 
[Exposure/EDC] 
Mean/median 
Descriptive 
7.4 
Exploratory Analyses 
Analysis of the following exploratory endpoints may be undertaken as deemed appropriate. 


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Table 5: Exploratory Efficacy Endpoints and Analysis Methods 
Secondary Efficacy Endpoint 
Variable Derivation 
[Source] 
Summary Statistics 
[Analysis Set] 
Method of Analysis 
Mean change in area of leakage 
on FA from baseline over time 
Continuous Endpoint: 
Change from baseline to each time point 
 
LS Mean difference in change 
from baseline to each time 
point 
[Primary], up to Wk 64 
[Final], up to Wk 104 
MMRM (similar to Section 7.1.2) 
adjusting for baseline area of leakage, 
with time, treatment, and time*treatment 
interaction and randomization 
stratification as factors 
Unstructured covariance matrix 
Proportion of subjects without 
intraretinal fluid on OCT over 
time 
Binary endpoint: 
Subject has no intraretinal fluid (yes/no) 
 
Difference in proportions (%) 
and 95% CI at each time point 
[Primary], up to Wk 64 
[Final], up to Wk 104 
Stratified analysis of the binary endpoint 
using CMH adjusting for randomization 
stratification factors (Section 7.3.1) 
Proportion of subjects without 
subretinal fluid on OCT over 
time 
Binary endpoint: 
Subject has no subretinal fluid (yes/no) 
 


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7.5 
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 60 and 64) 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. 
7.6 
Additional Pooled Analyses 
The efficacy endpoints listed in Table 6 below will be analyzed using data pooled from Studies 
KS301P104 and KS301P105. The same analysis methods and models used for the individual 
studies will be applied. An additional fixed effect for Study (KS301P104 or KS301P105) will be 
added to the models where applicable. 
Table 6: Pooled analysis parameters 
 
 
Parameter 
Endpoints 
BCVA 
Mean change in BCVA (ETDRS Letters) from 
baseline (Day 1) to the average of Weeks 60 and 
64 and over time 
Proportion of subjects who gain ≥ 5, ≥10 and ≥15 
letters from baseline by visit over time 
Proportion of subjects who lose ≥ 5, ≥10 and ≥15 
letters from baseline by visit over time 
Proportion of subjects with BCVA Snellen 
equivalent of 20/40 (69 or more ETDRS letters) 
or better over time 
Proportion of subjects with BCVA Snellen 
equivalent of 20/200 (38 or less ETDRS letters) 
or worse over time 
OCT CST 
Mean change in OCT CST from baseline to the 
average of Weeks 60 and 64 and over time. 
DRSS 
Proportion of subjects with a ≥ 2-step worsening 
from baseline on the ETDRS DRSS over time 
Proportion of subjects with a ≥ 2-step 
improvement from baseline on the ETDRS DRSS 
over time 
Durability 
Proportion of patients in the KSI-301 arm on a 
Q8W, Q12W, Q16W, Q20W or Q24W treatment 
interval through the duration of exposure 


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8.0 
SAFETY EVALUATION 
Safety analyses will be performed for the Safety Analysis Set. In the Primary Analysis, the safety 
data from Day 1 to Week 64 will be summarized by treatment group for the SAF patients. In the 
Final Analysis, the safety data from Day 1 to Week 108 will be summarized by treatment group 
for the SAF patients. 
 
8.1 
Exposure to Study Medication 
Study eye exposure to study medication will be summarized. Summaries will include: 
• Mean (SD) and median number of injections, and number of patients receiving ≥1 
injection, 1, 2, 3, 4, 5, etc. of KSI-301 or aflibercept injections from Day 1 to Week 60, 
from Week 64 to Week 104 and from Day 1 to Week 104. 
• Duration of study drug exposure (mean [SD] and median, in months) for subjects 
receiving KSI-301 5 mg or aflibercept 2 mg. 
• Listings will include treatment (KSI-301, aflibercept, sham) and date of injection. 
A listing of patients who received study treatment other than the one assigned at randomization 
will include the randomized treatment, the actual administered treatment, Visit, and study Day. 
 
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 starting after the first study treatment injection and continuing until 4 weeks (28 
days) after the last study injection will be considered treatment emergent AEs (TEAE). 
If the severity score of an adverse event is missing, the severity score will be imputed as severe. 
If the relatedness of an adverse event is missing, the adverse event will be considered related. 
At each level of summarization (e.g., any AE, system organ class, and preferred term), subjects 
experiencing more than one TEAE will be counted only once. In the summary of TEAEs by 
severity grade, subjects will be counted once at the highest severity reported at each level of 
summarization. 
Frequency tables including patients’ incidence rates will be provided through Week 64 and 
through Week 108 for the following: 


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• Ocular TEAEs and treatment-emergent serious AEs (TESAEs) (study eye and fellow eye 
separately) 
• Non-ocular TEAEs and TESAEs 
• Ocular TEAEs leading to study treatment discontinuation (study eye and fellow eye 
separately) 
• Injection procedure related TEAEs and TESAEs for study eye 
• Ocular TEAEs by severity (study eye and fellow eye separately) 
• Non-ocular TEAEs by severity 
• Related ocular TEAEs (study eye and fellow eye separately) by severity 
• Related non-ocular TEAEs by severity 
• Intraocular inflammation (IOI) TEAEs and TESAEs not associated with infection, 
autoimmunity, drug toxicity, or traumatic etiologies (study and fellow eye separately). 
• IOI TEAEs and TESAEs associated with infection (study and fellow eye separately). 
• IOI TEAEs and TESAEs associated with autoimmune, drug toxicity, or trauma (study 
and fellow eye separately). 
• 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). 
• Adverse events of special interest [AESI] (study eye, fellow eye, and non-ocular 
separately), as defined in the protocol Section 8.3.6 
• Non-serious TEAEs and TESAEs for study eye, fellow eye and non-ocular combined 
Exposure adjusted rates may be derived for selected adverse events. 
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. 
 
8.3 
Deaths, Serious Adverse Events, and other Significant Adverse Events 
All deaths during the study will be listed by treatment group and subject and will include the 
primary cause of death. Serious AEs and other significant AEs, including those that led to 
interruption or withdrawal of the study drug, will be provided in separate subject data listings. 
 
8.4 
Pregnancies 
Listings of pregnancies, if any, and outcomes will be presented. 


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8.5 
Intraocular Pressure 
For study eye, pre and post-injection IOP as well as the change from baseline to post baseline 
values will summarized, using mean, standard deviation, median, and range, by treatment group 
and protocol specified visit. IOP data will be listed by treatment, subject ID, study eye or non- 
study eye, and time point. 
 
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 52 and Week 104. 
Subjects with ALT or AST more than 3 times the Upper Limits of Normal (ULN) in combination 
with an elevated total bilirubin (more than 2 times the ULN); or ALT or AST more than 3 times 
the ULN in combination with clinical jaundice will be listed. 
Other clinical laboratory results through Week 64 and through Week 108 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. 
 
 
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 
. Testing at the 
 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 
 
letters 


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• The maximum clinically acceptable true difference for KSI-301 to be considered 
non- inferior, or the “non-inferiority margin”, is 
. 
• 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 450 patients (225 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. Additional secondary endpoints were pre-specified, including endpoints for 
the combined KS301P104 and KS301P105 studies. Where relevant, these definitions take 
precedence over those defined in the study protocol. 
 
 
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. 
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 


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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 
Error! Reference source not found.: Sample SAS Code 


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Appendix 1: Schedule of Activities 
Visit 
Screening Day 1 Week 
1 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 
52 
Visit Windows (Days) 
D-21 to D-1 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
Informed Consent 
X 
Demographics 
X 
Medical & Ocular History 
X 
Inclusion/Exclusion Criteria Review 
X 
X 
Concomitant Medication Review1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Review2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
General Assessments 
Vital Signs3 
X 
X 
X 
X 
Laboratory4 
X 
X 
Plasma ADA/NAB Samples (pre- 
dose) 
X 
X 
X 
X 
Plasma PK/Biomarker Samples 
(pre-dose) 
X 
X 
X 
X 
X 
X 
Pregnancy Test5 (WOCBP only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Assessments6 
BCVA ETDRS (4 meters)7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Exam (Slit-lamp, IOP8, 
dilated indirect ophthalmoscopy) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT-Angiography9-11 
X 
X 
X 
X 
Color Fundus Photos10,11 
X 
X 
X 
X 
Fluorescein Angiogram10 
X 
X 
Randomized study treatment 
(KSI-301, aflibercept or sham) per 
IRT Designation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-injection Assessments (vision 
check, IOP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Visit 
Week 
56 
Week 
60 
Week 
64 
Week 
68 
Week 
72 
Week 
76 
Week 
80 
Week 
84 
Week 
88 
Week 
92 
Week 
96 
Week 
100 
Week 
104/ET 
Week 
10812 
Visit Windows (Days) 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
Concomitant Medication Review1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Review2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
General Assessments 
Vital Signs 3 
X 
X 
Laboratory4 
X 
Plasma ADA/NAB Samples 
X 
X 
Plasma PK/Biomarker Samples 
X 
X 
Pregnancy Test5 (WOCBP only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Assessments6 
BCVA ETDRS (4 meters)7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Exam (Slit-lamp, 
IOP8, dilated indirect 
ophthalmoscopy) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT-Angiography 9-11 
X 
X 
Color Fundus Photos 10,11 
X 
X 
Fluorescein Angiogram10 
X 
Randomized Study Treatment 
(KSI-301, aflibercept, or sham) 
per IRT Designation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-injection Assessments 
(vision check, IOP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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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; IOP = intraocular pressure; NAB = neutralizing antibody; PK = pharmacokinetics; SAE = serious adverse event; SD-OCT = spectral 
domain optical coherence tomography; WOCBP = women of childbearing potential. 
1. Record any concomitant medication used by the participant within 30 days prior to Day 1. Procedural medications administered (e.g., dilating drops, 
fluorescein) will not be recorded. 
2. After informed consent has been obtained but prior to initiation of study intervention, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study intervention (Day 1), all AEs will be reported until the final study visit or the ET visit if applicable. 
See protocol section 8.3.1. 
3. Height and weight will be recorded at the screening visit only. 
4. Clinical laboratory test as described in protocol. 
5. Urine pregnancy test will be performed locally for women of childbearing potential, prior to fluorescein angiogram and study treatment (if applicable). If 
urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. Local urine testing will be standard for the protocol unless serum testing is 
required by local regulation or IRB/IEC. 
6. Ophthalmic assessments will be performed in both eyes at Screening, Week 52 and Week 104, and in the Study Eye only at all other timepoints. 
7. Perform BCVA before any other ophthalmic assessments and prior to dilation. 
8. Method used to measure IOP must remain consistent throughout study. 
9. OCT-Angiography to be performed at selected sites. 
10. It is mandatory that the same model of device is used for the entire duration of the study. 
11. For visits that are missed where color fundus photos (CFP) and OCT-Angiography (OCT-A) are scheduled, the CFP and OCT-A should be performed at the 
next possible visit. 
12. 
 
 


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Appendix 2: Sample SAS Code 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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base
regpmm(CHG2=
nbiter=25
nbiter=25
nbiter=25 regpmm(CHG5=
CHG3 CHG2
CHG4
CHG4
CHG5
CHG3
CHG4
CHG2
CHG3
CHG5
nbiter=25
regpmm(CHG6=
nbiter=25
nbiter=25
CHG2
regpmm(CHG3=
ntil week 64
CHG20/shift


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Reference for Weighted Percentages Based on Weighted Average of Observed Estimates 
Across Strata Using CMH Weights 
 


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