Clinical trial NCT05066230
Conditions: Non-proliferative Diabetic Retinopathy
Keywords: Non-proliferative Diabetic Retinopathy Diabetic Retinopathy NPDR KSI-301 VEGF Anti-VEGF Vascular Endothelial Growth Factor Antibody Biopolymer Conjugate Retinal Degeneration Retinal Diseases Eye Diseases Retinopathy Vision Disorders Kodiak
Sponsor: Kodiak Sciences Inc
Start date: 2021-09-07; Completion date: 2023-08-31
Enrollment: 253 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3 Study will evaluate the efficacy and safety of KSI-301 in participants with moderately severe to severe non-proliferative diabetic retinopathy (NPDR).

Detailed description:
This is a Phase 3, prospective, randomized, double-masked, sham-controlled, two-arm, multicenter study evaluating the efficacy and safety of repeated intravitreal dosing of KSI-301 5 mg in participants with moderately severe to severe non-proliferative diabetic retinopathy (NPDR).

The primary endpoint will be assessed at Week 48; additional secondary endpoints for efficacy will be assessed at Week 48, Week 96 and if applicable, over time.

Arms: arm 1: Intravitreal injection of KSI-301 (5 mg): three initiating doses, and then every 24 weeks through Week 92 arm 2: Sham injection on the same schedule as Treatment Group A
Interventions: intervention 1: KSI-301 intervention 2: Sham injection
Intervention descriptions: intervention 1: Intravitreal injection intervention 2: The sham injection 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 is performed to maintain masking of the study.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol KS301P106, Version 1.1 
 
KSI-301 – Kodiak Sciences Inc. 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Prospective, Randomized, Double-masked, Sham-controlled, Multi-
center, Two-arm, Phase 3 Study to Evaluate the Efficacy and Safety of 
Intravitreal KSI-301 in Participants with Moderately Severe to Severe 
Non-proliferative Diabetic Retinopathy (NPDR) 
Protocol Number: 
KS301P106 
Version Date: 
17 May 2021 
Amendment Number: 
1.1 
Supersedes: 
Version 1.0 
Test Product: 
KSI-301 
Brief Title: 
A Study to Evaluate the Efficacy and Safety of KSI-301 Compared 
with Sham Treatment in Participants with Moderately Severe to 
Severe Non-proliferative Diabetic Retinopathy (NPDR) 
Study Phase: 
3 
Study Acronym /Name: 
GLOW 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 USA 
Sponsor Contact & 
Medical Monitor: 
 
 
Kodiak Sciences Inc. 
IND Number: 
136167 
EudraCT Number: 
2020-001064-29 
 
 
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 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 KS301P106, Version 1.1 
 
KSI-301 – Kodiak Sciences Inc. 
2 
PROTOCOL APPROVAL – SPONSOR SIGNATORY 
 
Study Title:  
A Prospective, Randomized, Double-masked, Sham-controlled, Multi-center, 
Two-arm, Phase 3 Study to Evaluate the Efficacy and Safety of Intravitreal 
KSI-301 in Participants with Moderately Severe to Severe Non-proliferative 
Diabetic Retinopathy (NPDR) 
Protocol Number:  KS301P106 
Version Date: 
17 May 2021 
 
Protocol accepted and approved by: 
 
 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 
 
 
 
 
Signature 
 
Date 
 
 
 


CONFIDENTIAL 
Protocol KS301P106, Version 1.1 
 
KSI-301 – Kodiak Sciences Inc. 
3 
PROTOCOL APPROVAL – PRINCIPAL INVESTIGATOR 
SIGNATORY 
 
Study Title:  
A Prospective, Randomized, Double-masked, Sham-controlled, Multi-center, 
Two-arm, Phase 3 Study to Evaluate the Efficacy and Safety of Intravitreal 
KSI-301 in Participants with Moderately Severe to Severe Non-proliferative 
Diabetic Retinopathy (NPDR) 
Protocol Number:  KS301P106 
Version Date: 
17 May 2021 
 
I have read the protocol described above. I agree to conduct the study as described in the 
protocol. I also agree to conduct this study in compliance with Good Clinical Practice (GCP) and 
all applicable national and local laws and regulations, as well as with the requirements of the 
appropriate Institutional Review Board or independent Ethics Committee (IRB/IEC) and any 
other institutional requirements. These are stated in “Guidance for Good Clinical Practice” 
International Council for Harmonisation (ICH) guideline E6 (R1) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, the Declaration of Helsinki, and any other 
applicable regulatory requirements. No changes will be made to the study protocol without prior 
written approval of the Sponsor and the IRB/IEC. 
 
Principal Investigator: 
 
 
 
Print Name of Investigator 
 
 
 
Signature 
 
Date 
 


CONFIDENTIAL 
Protocol KS301P106, Version 1.1 
 
KSI-301 – Kodiak Sciences Inc. 
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TABLE OF CONTENTS 
1.0 
PROTOCOL SUMMARY ..............................................................................................12 
1.1 
Synopsis .................................................................................................................12 
1.2 
Schema ...................................................................................................................17 
1.2.1 
Schema A: All Participants ...................................................................17 
1.2.2 
Schema B: Participants Who Develop Sight-threatening 
Complications of Diabetic Retinopathy ................................................17 
1.3 
Schedule of Activities (SoA) .................................................................................18 
1.3.1 
SoA-A ...................................................................................................18 
1.3.2 
SoA-B ....................................................................................................20 
2.0 
INTRODUCTION............................................................................................................22 
2.1 
Study Rationale ......................................................................................................22 
2.2 
Background ............................................................................................................22 
2.2.1 
Non-proliferative Diabetic Retinopathy ................................................22 
2.2.2 
Vascular Endothelial Growth Factor .....................................................23 
2.2.3 
Description of KSI-301 .........................................................................24 
2.3 
Benefit/Risk Assessment .......................................................................................24 
2.3.1 
Known Potential Benefits .....................................................................24 
2.3.2 
Known Potential Risks ..........................................................................25 
2.3.3 
Overall Benefit/Risk Conclusion ..........................................................27 
3.0 
OBJECTIVES AND ENDPOINTS ................................................................................29 
4.0 
STUDY DESIGN ..............................................................................................................30 
4.1 
Overall Design .......................................................................................................30 
4.1.1 
Screening Period ...................................................................................30 
4.1.2 
Treatment Period ...................................................................................31 
4.1.3 
Administration of Study Intervention ...................................................31 
4.2 
Scientific Rationale for Study Design....................................................................35 
4.2.1 
Choice of Population .............................................................................35 
4.2.2 
Choice of Sham Control ........................................................................35 
4.2.3 
Choice of Primary Endpoint and Analysis ............................................36 
4.2.4 
Choice of Duration of Treatment and Follow-up ..................................36 
4.3 
Justification for Dose .............................................................................................36 
4.3.1 
KSI-301 Dose Rationale .......................................................................36 
4.3.2 
Sham Injection Rationale ......................................................................37 
4.4 
End of Treatment ...................................................................................................37 
4.5 
End of Study Definition .........................................................................................37 


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4.6 
Treatment After End of Study................................................................................37 
5.0 
STUDY POPULATION ..................................................................................................38 
5.1 
Inclusion Criteria ...................................................................................................38 
5.1.1 
Ocular Inclusion Criteria .......................................................................38 
5.1.2 
General Inclusion Criteria .....................................................................38 
5.2 
Exclusion Criteria ..................................................................................................39 
5.2.1 
Ocular Exclusion Criteria ......................................................................39 
5.2.2 
General Exclusion Criteria ....................................................................40 
5.3 
Lifestyle Considerations ........................................................................................41 
5.4 
Screen Failures .......................................................................................................41 
5.5 
Criteria for Temporarily Delaying Enrollment ......................................................42 
6.0 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ..........................43 
6.1 
Study Intervention(s) Administered .......................................................................43 
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 .............................................................................46 
6.5 
Dose Modification .................................................................................................47 
6.6 
Continued Access to Study Intervention after the End of the Study .....................47 
6.7 
Treatment of Overdose ..........................................................................................47 
6.8 
Concomitant Therapy.............................................................................................48 
6.8.1 
Pan-retinal Photocoagulation ................................................................48 
6.8.2 
Prohibited Therapy ................................................................................48 
6.8.3 
Supportive Care for Adverse Events .....................................................49 
7.0 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................................50 
7.1 
Discontinuation of Study Intervention ...................................................................50 
7.1.1 
Treatment Interruption and/or Discontinuation due to Adverse 
Events or Concomitant Procedures .......................................................51 
7.2 
Participant Discontinuation/Withdrawal from the Study .......................................52 
7.3 
Lost to Follow up ...................................................................................................52 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................54 
8.1 
Efficacy Assessments.............................................................................................54 
8.1.1 
Medical History and Demographic Data...............................................54 


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8.1.2 
Ophthalmic Exams ................................................................................54 
8.1.3 
Injection Procedure ...............................................................................55 
8.1.4 
Post Injection Assessments in the Study Eye ........................................55 
8.1.5 
Best Corrected Visual Acuity................................................................56 
8.1.6 
Fundus Photography .............................................................................56 
8.1.7 
Spectral Domain Optical Coherence Tomography ...............................56 
8.1.8 
Fluorescein Angiography ......................................................................56 
8.2 
Safety Assessments ................................................................................................57 
8.2.1 
Vital Signs .............................................................................................57 
8.2.2 
Clinical Safety Laboratory Assessments ...............................................57 
8.2.3 
Pregnancy Testing .................................................................................57 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ................58 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ......................................................58 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events .....58 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events..................59 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events ........59 
8.3.5 
Pregnancy ..............................................................................................59 
8.3.6 
Adverse Events of Special Interest .......................................................60 
8.4 
Pharmacokinetics ...................................................................................................61 
8.5 
Genetics and/or Pharmacogenomics ......................................................................61 
8.6 
Biomarkers .............................................................................................................61 
8.7 
Immunogenicity Assessments ................................................................................61 
8.8 
Health Economics or Medical Resource Utilization and Health Economics ........62 
9.0 
STATISTICAL CONSIDERATIONS ...........................................................................63 
9.1 
Statistical Hypothesis .............................................................................................63 
9.2 
Sample Size Determination....................................................................................63 
9.3 
Analysis Sets ..........................................................................................................64 
9.4 
Statistical Analyses ................................................................................................64 
9.4.1 
General Considerations .........................................................................64 
9.4.2 
Primary Endpoint(s) ..............................................................................65 
9.4.3 
Secondary Endpoint(s) ..........................................................................66 
9.4.4 
Tertiary/Exploratory Endpoint(s) ..........................................................68 
9.4.5 
Safety Analysis .....................................................................................68 
9.4.6 
Pharmacokinetic and Biomarker Analysis ............................................68 
9.5 
Interim Analysis .....................................................................................................68 


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


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LIST OF TABLES 
Table 1: 
Abbreviated Summary of ETDRS Diabetic Retinopathy Severity Scale 
for Individual Eyes .....................................................................................23 
Table 2:  
Protocol KS301P106: Risk Assessment ....................................................26 
Table 3:  
Protocol KS301P106: Sight-threatening Complications of Diabetic 
Retinopathy: Definitions and Required Documentation for Initial 
Diagnosis....................................................................................................33 
Table 4:  
Protocol KS301P106: Study Interventions ................................................43 
Table 5:  
Protocol KS301P106: Treatment Interruption Criteria ..............................51 
Table 6:  
Protocol KS301P106: Required Safety Laboratory Tests .........................75 
Table 7: 
Protocol KS301P106: Amendment History ...............................................88 
 
 
LIST OF FIGURES 
Figure 1: 
Protocol KS301P106: Masked Dosing Regimens by Week ......................32 
Figure 2: 
Protocol KS301P106: Dosing Regimen by Week for All Participants 
Who Develop Sight-threatening Complication(s) in the Study Eye ..........34 
 
 
 


CONFIDENTIAL 
Protocol KS301P106, Version 1.1 
 
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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 
ANCOVA 
Analysis of covariance 
APD 
Afferent pupillary defect 
AST 
ASNV 
Aspartate aminotransferase 
Anterior segment neovascularization 
ATE 
Arterial thromboembolic events 
BCVA 
Best corrected visual acuity as measured on ETDRS chart 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of federal regulations 
CMH 
Cochran-Manzel Haenszel 
CIOMS 
Council for international organizations of medical sciences 
CONSORT 
Consolidated standards of reporting trials 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CST 
Central subfield thickness 
DME 
Diabetic macular edema 
DR 
DRSS 
Diabetic retinopathy  
Diabetic retinopathy severity scale 
EC 
Ethics committee 
ECG 
Electrocardiograph 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
ET 
Early termination 
ETDRS 
Early treatment diabetic retinopathy study 
FA 
Fluorescein angiography  
FDA 
Food and drug administration  
FP 
Fundus photography  
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
HIPAA 
Health insurance portability and accountability act 
HRT 
Hormonal replacement therapy 
IB 
Investigator brochure 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent or institutional ethics committee 


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Protocol KS301P106, Version 1.1 
 
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IMP 
Investigational medicinal product 
IOP 
Intraocular pressure 
IRB 
Institutional review board 
IRMA 
Intraretinal microvascular abnormalities 
IRT 
Interactive response technology 
ITT 
Intent to treat 
LOCF 
Last observation carried forward 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
ME 
Macular edema 
MedDRA 
Medical dictionary for regulatory activities 
NAB 
Neutralizing antibody 
NIMP 
Non-investigational medical product 
NME 
New molecular entity  
NOAEL 
No observed adverse effect level 
NPDR 
Non proliferative diabetic retinopathy 
NVD 
Neovascularization of the disc 
NVE 
Neovascularization elsewhere 
OECD 
Organisation for Economic Co-operation and Development 
OTC 
PDR  
Over the counter 
Proliferative Diabetic Retinopathy 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PPS 
Per protocol 
PRP 
Panretinal photocoagulation  
Q4W 
Once every 4 weeks 
Q12W 
Once every 12 weeks 
Q24W 
Once every 24 weeks 
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-A 
SoA-B 
Schedule of Activities-A 
Schedule of Activities-B  
SPC 
Scars of photocoagulation for PDR or severe NPDR 
STC 
SUN 
Sight-threatening complications 
Standardization of uveitis nomenclature  
SUSAR 
Suspected unexpected serious adverse reactions 
ULN 
Upper limits of normal 


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VA 
Visual acuity 
VB 
Venous beading 
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 KS301P106, Version 1.1 
 
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1.0 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Number: KS301P106 
Version: 1.1 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001064-29 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Sham-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate 
the Efficacy and Safety of Intravitreal KSI-301 in Participants with Moderately Severe to Severe Non-proliferative 
Diabetic Retinopathy (NPDR) 
Brief Title: 
A Study to Evaluate the Efficacy and Safety of KSI-301 Compared with Sham Treatment in Participants with 
Moderately Severe to Severe Non-proliferative Diabetic Retinopathy (NPDR) 
Brief Study Rationale: 
KSI-301 is a novel, potent, long-acting biopharmaceutical that inhibits vascular endothelial growth factor (VEGF). 
KSI-301 has an extended ocular half-life, which may allow an infrequent treatment frequency suitable for patients 
with NPDR.  
Development Phase: 3 
Countries/ Regions: NA (North America), EMEA (Europe, Middle 
East, Africa), and APAC (Asia-Pacific) 
Study Period: Approximately 3.5 years 


CONFIDENTIAL 
Protocol KS301P106, Version 1.1 
 
KSI-301 – Kodiak Sciences Inc. 
13 
Protocol Number: KS301P106 
Version: 1.1 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001064-29 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Sham-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate 
the Efficacy and Safety of Intravitreal KSI-301 in Participants with Moderately Severe to Severe Non-proliferative 
Diabetic Retinopathy (NPDR) 
Objectives and Key Endpoints: 
Objectives 
Key Endpoints 
Primary 
To demonstrate that KSI-301 5 mg is superior to sham 
treatment, with respect to proportion of eyes improving 
≥2 steps on Diabetic Retinopathy Severity Scale 
(DRSS) from baseline at Week 48. 
• 
The proportion of eyes improving ≥2 steps on 
DRSS from baseline at Week 48. 
Secondary 
To evaluate the effect of KSI-301 5 mg in decreasing 
the incidence and delaying the onset of vision-
threatening complications of diabetes compared to 
sham treatment. 
• 
Time to development of and proportion of eyes 
developing any of the following from baseline 
over time (individually and as a composite): 
- 
Proliferative diabetic retinopathy (PDR) or 
anterior segment neovascularization 
(ASNV); 
- 
Vitreous hemorrhage or tractional retinal 
detachment believed to be due to 
proliferative diabetic retinopathy; or 
- 
Diabetic macular edema (DME). 
To evaluate the efficacy of KSI-301 5 mg compared to 
sham treatment. 
• 
Proportion of eyes improving ≥2 or ≥3 steps on 
DRSS from baseline over time. 
• 
Proportion of eyes worsening ≥2 or ≥3 steps on 
DRSS from baseline over time. 
To evaluate the safety and tolerability of KSI-301 5 mg 
compared to sham treatment. 
• 
Incidence of ocular and systemic adverse events 
over time. 
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 KS301P106, Version 1.1 
 
KSI-301 – Kodiak Sciences Inc. 
14 
Protocol Number: KS301P106 
Version: 1.1 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001064-29 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Sham-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate 
the Efficacy and Safety of Intravitreal KSI-301 in Participants with Moderately Severe to Severe Non-proliferative 
Diabetic Retinopathy (NPDR) 
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 superior to sham treatment, with respect to the proportion of eyes improving ≥2 steps on DRSS 
from baseline at Week 48 in participants with moderately severe to severe NPDR. 
One eye per participant will be enrolled in the study.  
As shown in Section 1.2.1 (Schema A), participants will be randomized 1:1 into one of two treatment arms: (i) 
KSI-301 5 mg Q24W or (ii) sham. 
Randomization will be stratified by 
 
 Treatment group 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. 
Sham injections will be administered for masking purposes. To preserve masking, two Investigators are required 
for this study. The masked Investigator will be responsible for the ocular 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. 
The overall duration of the study is approximately 2 years (100 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 100; thus, participant duration is approximately 103 weeks and includes a screening 
period of up to 21 days (Days -21 to -1), a treatment period of approximately 92 weeks (Day 1 to Week 92), a 
safety/efficacy assessment at Week 96, and a final safety follow-up at Week 100 
 The 
primary endpoint will be assessed at Week 48; secondary endpoints for efficacy will be assessed at Weeks 48 and 
96.  
As shown in Section 1.2.2 (Schema B), participants in either treatment group (KSI-301 5 mg or sham) who develop 
DME, PDR, and/or ASNV in the Study Eye shall be treated with KSI-301 for those complications, according to 
criteria specified in the protocol. If treatment is administered, DRSS values after the development of the vision-
threatening complication will be censored. 
Number of Participants Planned: 
Approximately 240 
Gender: 
Male or female 
Age: 
Adults ≥18 years of age 
Diagnosis and Main Criteria for Eligibility: 
• 
Participants with moderately severe to severe NPDR (ETDRS DRSS levels 47 and 53 on color fundus 
photographs as evaluated by the reading center) in the Study Eye, who have not previously received 
intravitreal medications for diabetic retinopathy (DR), and in whom pan-retinal photocoagulation (PRP) 
can be safely deferred for at least 6 months per the Investigator. 
• 
Participants with Type 1 or Type 2 diabetes mellitus and HbA1c of ≤12%. 


CONFIDENTIAL 
Protocol KS301P106, Version 1.1 
 
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Protocol Number: KS301P106 
Version: 1.1 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001064-29 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Sham-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate 
the Efficacy and Safety of Intravitreal KSI-301 in Participants with Moderately Severe to Severe Non-proliferative 
Diabetic Retinopathy (NPDR) 
Total Participant Duration: 
103 weeks 
Duration of Treatment:  
92 weeks 
Study Intervention (Investigational Medicinal Product), Dose, and Route of Administration: 
Treatment Group A (Group A) 
• 
KSI-301 5 mg via intravitreal injection on Day 1, Week 8, Week 20 and then once every 24 weeks (Q24W) 
through Week 92.  
Study Intervention (Sham Injection): 
Treatment Group B (Group B) 
• 
Sham injection on Day 1, Week 8, Week 20, and then once every 24 weeks (Q24W) through Week 92.   
 
Participants in either treatment arm (KSI-301 5 mg or sham) who develop DME, PDR, or ASNV shall be treated 
with KSI-301 5 mg once every 4 weeks for two doses and at Q12W intervals thereafter. More frequent treatment 
with KSI-301 5 mg and/or subsequent PRP are at the discretion of the Investigator.  
Efficacy Evaluation: 
Unless stated otherwise, all efficacy analyses will be performed on the intent to treat (ITT) population. The primary 
endpoint is the proportion of eyes improving ≥2 steps on DRSS from baseline at Week 48. The primary assessment 
of efficacy will be based on a pairwise comparison in the proportion of eyes improving ≥2 steps on DRSS between 
the KSI-301 5 mg treatment group and the sham group. DRSS score is based on fundus photographs graded by the 
masked independent reading center. Other evaluations include time from baseline to development of and 
proportion of eyes developing PDR, DME, and/or ASNV; proportion of eyes with ≥2 or ≥3 step improvement or 
worsening in DRSS; change in BCVA over time; and change in retinal thickness assessed using spectral domain 
optical coherence tomography (SD-OCT). Secondary endpoints for efficacy will be assessed at Week 48, Week 96, 
and, if applicable, over time. 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 assessment should be reported. After initiation of study intervention (Day 
1), all adverse event (AE) and SAE information will be collected until the final safety follow-up visit at Week 100 
or the Early Termination (ET) visit if applicable, as specified in the SoA-A (Section 1.3.1) and the SoA-B 
(Section 1.3.2). 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. 


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Protocol KS301P106, Version 1.1 
 
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16 
Protocol Number: KS301P106 
Version: 1.1 
For National Authority Use Only 
 
IND Number: 136167 
EudraCT Number: 2020-001064-29 
Sponsor: 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 (USA) 
Investigational Product: 
KSI-301 
Title of Study: 
A Prospective, Randomized, Double-masked, Sham-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate 
the Efficacy and Safety of Intravitreal KSI-301 in Participants with Moderately Severe to Severe Non-proliferative 
Diabetic Retinopathy (NPDR) 
Pharmacokinetic/ Biomarker Evaluation: 
Plasma concentrations of study interventions (KSI-301) will be measured, as specified in the SoA-A 
(Section 1.3.1) and the SoA-B (Section 1.3.2). Blood samples will also be analyzed for anti-drug antibodies. For 
exploratory purposes, 
  
Statistical Methods:  
The study hypothesis is that the proportion of eyes improving ≥2 steps on DRSS from baseline at Week 48 among 
participants treated with KSI-301 5 mg will be superior to that in the sham group. 
A sample size of approximately 240 participants with a target enrollment of approximately 120 participants in each 
treatment group (1:1 ratio) was calculated using the following assumptions: 
• 
 of participants with a ≥2-step improvement from baseline in DRSS score in the KSI-301 5 mg group 
versus 
 in the sham group.  
• 
Statistical power of ≥90%. 
• 
Overall Type I error rate of 0.05. 
• 
The statistical method used to compare the proportion with a ≥2-step improvement from baseline in DRSS 
score for the KSI-301 treatment group at Week 48 compared with sham will be the Cochran-Manzel Haenszel 
(CMH) method
 
• 
Loss to follow-up/drop-out rate of approximately 
 
Analysis of data for the Week 48 primary and secondary endpoints will be performed when all participants have 
either completed the Week 48 visit or have discontinued from the study, all data have been entered into the 
database, cleaned, and verified as appropriate, and the database has been locked. Likewise, analysis of data for the 
Week 96 secondary endpoints and for safety will be performed when all participants have either completed the 
Week 100 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: 17 May 2021 
 
 
 
 


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Protocol KS301P106, Version 1.1
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1.2
Schema
1.2.1
Schema A: All Participants
Schema A applies to all participants unless they are diagnosed with DME, PDR, and/or ASNV in 
their Study Eye during the study. Upon diagnosis of these sight-threatening complication(s) of 
DR in their Study Eye, Schema B applies.
Abbreviations: 
ASNV = anterior segment neovascularization; DME = diabetic macular edema; 
PDR = proliferative diabetic retinopathy; Q24W = once every 24 weeks.
1.2.2
Schema B: Participants Who Develop Sight-threatening Complications of 
Diabetic Retinopathy
Schema B applies to all participants who are diagnosed with DME, PDR, and/or ASNV in their 
Study Eye during the study.
Abbreviations: ASNV = anterior segment neovascularization; DME = diabetic macular edema; Dx Visit = the first 
study visit where a sight-threatening complication of diabetic retinopathy (DME, PDR, and/or ASNV) is 
diagnosed; PDR = proliferative diabetic retinopathy; Q4W = once every 4 weeks; Q12W = once every 
12 weeks.


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Protocol KS301P106 Version 1.1 
 
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1.3 
Schedule of Activities (SoA) 
1.3.1 
SoA-A 
The following schedule of activities, SoA-A, shall be followed for all visits unless a participant is diagnosed with sight-threatening 
complication(s) of DR, as defined in Table 3 (Section 4.1.3.1), in their Study Eye. Upon diagnosis of sight-threatening complication(s) 
of DR in their Study Eye, participants shall then follow SoA-B (Section 1.3.2) instead of SoA-A. 
Visit 
Screening 
Day  
1 
Week  
8 
Week  
20 
Week  
32 
Week  
44 
Week  
48 
Week  
56 
Week  
68 
Week 
80 
Week  
92 
Week 
96/ET 
Week 
10012 
Visit Windows (Days) 
D-21 to D-1 
 
+/-7 
+/-14 
+/-14 
+/-14 
+/-7 
+/-14 
+/-14 
+/-14 
+/-14 
+/-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 
AE/SAE Review2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs3 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
Laboratory4 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Plasma ADA/NAB Samples (pre-injection) 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Plasma PK/Biomarker Samples (pre-injection) 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Pregnancy Test5 (WOCBP only)  
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 
 
Ophthalmic Exam (Slit lamp, IOP8, dilated 
indirect ophthalmoscopy) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SD-OCT9 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fundus Photos9 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fluorescein Angiogram9 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
Randomized study treatment (KSI-301 or sham) 
per IRT Designation10 
 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
 
Post-injection Assessments (vision check, IOP8)11 
 
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 SAEs caused by a protocol-mandated assessment 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 tests as described in Appendix 2 and Table 5. 
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 48 and Week 96, and only in the Study Eye at all other timepoints. 
7 
Perform BCVA before any other ophthalmic assessments and prior to dilation. 
8 
Method used to measure IOP must remain consistent throughout study.  
9 
It is mandatory that the same model of device is used for the entire duration of the study. 
10 
Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in Section 7.1. 
11 
Post injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
12 
 
 


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Protocol KS301P106 Version 1.1 
 
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1.3.2 
SoA-B 
The following schedule of activities, SoA-B, shall be followed once a participant is diagnosed with sight-threatening complication(s) 
of DR, as defined in Table 3 (Section 4.1.3.1), in their Study Eye. Upon diagnosis of sight-threatening complication(s) of DR in their 
Study Eye, participants will be treated with open-label KSI-301 5 mg, regardless of the treatment group that they were originally 
randomized into, and SoA-B will be followed instead of SoA-A. Additional details are provided in Section 4.1.3.1. 
Visit 
Dx Visit1 
Dx Visit 
+ 4 Weeks 
Dx Visit  
+ 16 Weeks 
Dx Visit  
+ 28 Weeks 
Dx Visit 
 + 40 Weeks 
Dx Visit  
+ […]12 Weeks 
Week 
96/ET 
Week 
10013 
Visit Windows (Days) 
  
+/-7 
+/-14 
+/-14 
+/-14 
+/-14 
+/-7 
+/-7 
Concomitant Medication Review2  
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Review 
X 
X 
X 
X 
X 
X 
X 
X 
General Assessments 
 
 
 
 
 
 
 
 
Vital Signs3 
 
 
 
 
 
 
X 
 
Laboratory4 
 
 
 
 
 
 
X 
 
Plasma ADA/NAB Samples 
(pre-injection) 
X 
 
 
X 
 
 
X 
 
Plasma PK/Biomarker Samples (pre-
injection) 
X 
 
 
X 
 
 
X 
 
Pregnancy Test5 (WOCBP only) 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Assessments6 
 
 
 
 
 
 
 
 
BCVA ETDRS (4 meters)7 
X 
X 
X 
X 
X 
X 
X 
 
Ophthalmic Exam (Slit lamp, IOP8, dilated 
indirect ophthalmoscopy) 
X 
X 
X 
X 
X 
X 
X 
 
SD-OCT9 
X 
X 
X 
X 
X 
X 
X 
 
Fundus Photos9 
X 
X 
X 
X 
X 
X 
X 
 
Fluorescein Angiogram9 
X 
 
 
X 
 
 
X 
 
KSI-301 5 mg (Open-label)10 
X 
X 
X 
X 
X 
X 
 
 
Post-injection Assessments (Vision check, 
IOP8)11 
X 
X 
X 
X 
X 
X 
 
 


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Protocol KS301P106 Version 1.1 
 
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Abbreviations: ADA = anti-drug antibody; AE = adverse event; ASNV = anterior segment neovascularization; BCVA = best corrected visual acuity; 
Dx Visit = the first study visit where a sight-threatening complication of diabetic retinopathy (DME, PDR, and/or ASNV) is diagnosed; DME = diabetic 
macular edema; ET=Early Termination; ETDRS = early treatment diabetic retinopathy study; IOP = intraocular pressure; NAB = neutralizing antibody; 
PK = pharmacokinetics; PDR = proliferative diabetic retinopathy; Q12W = once every 12 weeks; SAE = serious adverse event; SD-OCT = spectral domain 
optical coherence tomography; WOCBP = women of childbearing potential. 
1 
Dx Visit is the first study visit where a sight-threatening complication of diabetic retinopathy (DME, PDR, and/or ASNV, as defined in Section 4.1.3.1) is 
diagnosed in the Study Eye; open-label KSI-301 treatment will be initiated at this visit.  
2 
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. 
3 
Height and weight will be recorded at the screening visit only. 
4 
Clinical laboratory tests as described in Appendix 2 and Table 5. 
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 Week 96, and only in the Study Eye at all other timepoints. 
7 
Perform BCVA before any other ophthalmic assessments and prior to dilation. 
8 
Method used to measure IOP must remain consistent throughout study.  
9 
It is mandatory that the same model of device is used for the entire duration of the study. 
10 
Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in Section 7.1. 
11 
Post injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
12 
Continue visits Q12W until Week 92. 
13 
Week 100 is a final safety assessment that will be done via telephone call for all participants, except in WOCBP, in which case a site visit is required for the 
safety assessment that includes a pregnancy test. 


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2.0 
INTRODUCTION 
KSI-301 is a novel, potent, long-acting biopharmaceutical that inhibits vascular endothelial 
growth factor (VEGF) and is being developed to treat non-proliferative diabetic retinopathy 
(NPDR). KSI-301 has an extended ocular half-life, which may offer the potential for participants 
to experience a longer interval between consecutive intravitreal injections compared to existing 
anti-VEGF therapies. 
2.1 
Study Rationale 
Although substantial improvements in diabetic retinopathy (DR) severity have been 
demonstrated in patients with NPDR following treatment with intravitreal VEGF inhibitors, 
aflibercept and ranibizumab, the use of intravitreal VEGF inhibitors for the treatment of NPDR 
is not considered standard of care (Flaxel 2020). NPDR is a slowly progressive asymptomatic 
condition that affects adults of a working age. Approved intravitreal VEGF inhibitors require a 
high treatment frequency for improving the severity of NPDR, and the burden of treatment is 
such that they are not considered standard of care treatment for NPDR in the absence of sight-
threatening complications such as diabetic macular edema (DME) or proliferative diabetic 
retinopathy (PDR) (Flaxel 2020). There is a substantial medical need for a more durable 
therapeutic option that allows a lower treatment frequency that may be more suitable as a 
treatment for NPDR. 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-CL101, the 
safety and efficacy outcomes of participants with diabetic macular edema treated with KSI-301 
5 mg have supported a prolonged (2 to 6 months) treatment interval. Study KS301P106 has been 
designed to evaluate extended treatment intervals of KSI-301 5 mg in participants with NPDR.  
2.2 
Background 
2.2.1 
Non-proliferative Diabetic Retinopathy  
Diabetes mellitus (diabetes) is a chronic disease that exerts pathologic effects on multiple organ 
systems, including the microvasculature of the retina. All patients with diabetes are at risk of 
developing DR, a progressive condition that can result in severe vision loss. DR is a leading 
cause of vision loss in the working-age population and is classified in routine clinical practice 
according to the International Clinical Diabetic Retinopathy Disease Severity Scale in order of 
increasing severity (Flaxel 2020; Wu 2013), as follows:  
a) No apparent retinopathy (no diabetic fundus changes);  
b) Mild NPDR (few microaneurysms); 
c) Moderate NPDR (microaneurysms, intraretinal hemorrhages or venous beading that do 
not reach the severity of the reference photographs); 
d) Severe NPDR (fundus changes consistent with reference photographs); and  


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e) PDR (neovascularization of the disc, retina, iris, and angle; vitreous hemorrhage; or 
tractional retinal detachment). 
In clinical trials, DR severity is described according to the well-characterized and validated 
ETDRS Diabetic Retinopathy Severity Scale (DRSS), which divides the above clinical scale into 
additional, more discrete categories based on standardized grading of retinal color fundus 
photographs.  
Table 1: 
Abbreviated Summary of ETDRS Diabetic Retinopathy Severity 
Scale for Individual Eyes 
Level 
Severity 
10 
DR absent 
20 
Micro-aneurisms only 
35 
Mild NPDR (HE, SE, and/or mild H) 
43 
Moderate NPDR (mild IRMA or moderate H) 
47 
Moderately severe NPDR (mild VB, moderate IRMA, or severe H) 
53 
Severe or very severe NPDR (moderate/severe VB, severe IRMA, and/or very severe H) 
60 
Scars of photocoagulation for PDR or severe NPDR (SPC) 
61 
Mild PDR 
65 
Moderate PDR 
71, 75 
High risk PDR 
Abbreviations: H = Hemorrhage; HE = hard exudates; SE = soft exudates; IRMA = intraretinal microvascular 
abnormalities; VB = venous beading; DR = diabetic retinopathy; NPDR = non proliferative diabetic 
retinopathy; PDR = proliferative diabetic retinopathy.  
Levels 35-53 require presence of microaneurysms in addition to specified abnormalities. The definition for each 
level assumes that the definition for any higher level is not met. Severities of abnormalities are defined in 
References 2 and 6. 
Source: Adapted from: Supplementary Appendix from (ACCORD Study Group 2010). 
 
According to the World Health Organization, the global prevalence of diabetes among adults 
over 18 years of age rose from 4.7% in 1980 to 8.5% in 2014. Concomitant with the rising 
prevalence of diabetes, the prevalence of diabetic retinopathy (DR) in patients with diabetes is 
also increasing. DR and its clinical sequelae are responsible for vision loss in as many as 2.6-3.7 
million patients with diabetes worldwide (Cheloni 2019). The risk of DR increases with diabetes 
duration. The current global estimate of any DR prevalence among patients with diabetes is 
approximately 35% (Leasher 2016). 
2.2.2 
Vascular Endothelial Growth Factor  
VEGF stimulates vascular endothelial cell growth and induces vascular permeability. Several 
mechanisms are involved in the regulation of VEGF gene expression, and hypoxia is a key factor 
that induces VEGF production. In addition, changes in glucose levels also contribute to VEGF 
expression and intraocular VEGF levels are elevated in patients with diabetes. In nonclinical 


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Protocol KS301P106, Version 1.1 
 
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24 
models, over-expression of VEGF leads to retinal pathologic events common in diabetic macular 
edema and DR. For example, retinal VEGF mRNA and protein levels were increased in rats with 
background diabetic retinopathy and correlated with the breakdown of the blood-retinal barrier. 
In addition, experimental injections of VEGF protein into non-human primate eyes recapitulate 
the DR phenotype including nonperfusion, microaneurysm formation, and preretinal 
neovascularization. (Aiello 1994; Durham 2011; Lu 1999; Tolentino 2002) 
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. Phase 3 studies of intravitreal administration of ranibizumab and 
aflibercept in patients with DR demonstrated clinically significant improvements in DRSS and 
lower rates of DRSS worsening relative to sham control. (Bressler 2017; Stewart 2017; Wells 
2015; Wells 2016)  
2.2.3 
Description of KSI-301 
KSI-301 is an antibody biopolymer conjugate (ABC) developed using the Sponsor’s proprietary 
ABC Platform™ technology. The antibody portion of KSI-301 binds to VEGF-A with high 
affinity and inhibits the ability of VEGF-A to bind and activate its cognate receptors (VEGFR1 
and VEGFR2) thereby acting as an anti-angiogenic and anti-permeability agent. The inert 
biopolymer portion is an ultra-hydrophilic phosphorylcholine polymer that significantly 
increases the overall molecular size of KSI-301, which in turn extends its ocular half-life by a 
factor 
 and ocular concentrations at three months by a factor of 
 compared to 
aflibercept. Due to the biophysical and biological properties of the ABC Platform on which it is 
built, KSI-301 is designed to have improved ocular durability, bioavailability, biocompatibility, 
and stability, and rapid systemic clearance. These properties make KSI-301 an ideal candidate 
for the management of retinal vascular diseases. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of KSI-301 is 
provided in the Investigator’s Brochure. 
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 Investigator’s Brochure (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 NPDR, benefits from a well-
documented mechanism action in retinal vascular disease (Homayouni 2009). The efficacy and 
safety of commercially available intravitreal VEGF inhibitors in retinal vascular disease is also 
well-documented and established. 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 


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KSI-301 should be at least comparable to other anti-VEGF biologics such as ranibizumab or 
aflibercept. 
Patients with NPDR are treated for underlying hyperglycemia, hyperlipidemia, and hypertension 
as clinically indicated. The adoption of approved anti-VEGF therapies for NPDR is constrained 
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 KSI-301’s extended ocular half-life 
and less frequent dose regimens. Thus, KSI-301 may provide clinically relevant benefits as an 
intravitreal therapy for NPDR. 
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 2. Risks associated with 
COVID-19 are discussed below in Section 2.3.2.1. 
 
 


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Table 2:  
Protocol KS301P106: 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 serious adverse events (SAEs) 
related to inflammatory reactions can 
occur.  
Additional details are provided in IB 
Section 5.4.2.1. 
Participants will be monitored following the 
injection and instructed to report any symptoms 
suggestive of an immune response without delay 
to facilitate early diagnosis and treatment 
(Section 8.1.4). 
Participants with known hypersensitivity to 
intravitreal agents such as aflibercept or 
ranibizumab or any ingredient of KSI-301 are 
excluded from this study (Section 5.2.2). 
Arterial 
thromboembolic 
events (ATEs) 
ATEs are defined as nonfatal stroke, 
nonfatal myocardial infarction, or 
vascular death (including deaths of 
unknown cause). There is a potential risk 
of ATEs following intravitreal use of 
VEGF inhibitors.  
Additional details are provided in IB 
Section 5.4.2.2. 
Participants with recent history (6 months) of 
myocardial infarction, stroke, transient ischemic 
attack, acute congestive heart failure or any 
acute coronary event are excluded from this 
study (Section 5.2.2). 
Intraocular 
inflammation 
Intraocular inflammation has been 
reported following treatment with 
intravitreal anti-VEGF medicines, 
including KSI-301.  
Additional details are provided in IB 
Section 5.4.2.3. 
Participants will be monitored following the 
injection and instructed to report any symptoms 
suggestive of intraocular inflammation without 
delay to facilitate early diagnosis and treatment 
(Section 8.1.4). Participants with active ocular 
infection or inflammation in either eye (e.g., 
blepharitis, infectious conjunctivitis, keratitis, 
scleritis, endophthalmitis) are excluded from 
this study (Section 5.2.1). Participants with 
active intraocular inflammation will have study 
treatment interrupted (Section 7.1.1) 
Hypersensitivity 
Hypersensitivity reactions may manifest 
as rash, pruritus, urticaria, severe 
anaphylactic/ anaphylactoid reactions, or 
severe intraocular inflammation.  
Additional details are provided in IB 
Section 5.4.2.4. 
Participants with known hypersensitivity to 
intravitreal agents such as aflibercept or 
ranibizumab or any ingredient of KSI-301 are 
excluded from this study (Section 5.2.2). 
 
 
 


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Table 2:  
Protocol KS301P106: Risk Assessment (Cont’d) 
Study Procedures 
Risks associated 
with the method 
of administration 
These risks include endophthalmitis, 
increases in intraocular pressure, retinal 
detachment, retinal tear, traumatic 
cataract, and intraocular hemorrhage. 
Additional details are provided in IB 
Section 5.4.2.5. 
Proper and aseptic injection technique when 
administering intravitreal injections will be used 
(Section 8.1.3). Participants will be monitored 
following the injection and instructed to report 
any symptoms suggestive of endophthalmitis or 
retinal detachment without delay to facilitate 
early diagnosis and treatment (Section 8.1.4). 
Intraocular pressure and the perfusion of the 
optic nerve head will also be monitored and 
managed (Section 8.1.4). Participants with 
active ocular infection or inflammation in either 
eye (e.g., blepharitis, infectious conjunctivitis, 
keratitis, scleritis, endophthalmitis) are excluded 
from this study (Section 5.2.1). 
Exposure to 
SARS-CoV-2 
virus 
Section 2.3.2.1 
Section 2.3.2.1 
 
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. Studies 
suggest that intravitreal anti-VEGF treatment improved diabetic retinopathy and prevented 
disease progression in eyes with moderately severe to severe NPDR in patients without DME 
(Lim 2020). This trial affords participants the opportunity to potentially receive anti-VEGF 
therapy for their NPDR and potential sight-threatening complications of DME, PDR, and/or 
anterior segment neovascularization (ASNV) that develop during the study period. Measures that 
prioritize trial participant safety and data integrity have been developed in consideration of local 
guidelines.  
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 of escalation of the pandemic during this 
trial and local circumstances leading 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 NPDR 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 


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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 adverse events (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 eyes with moderately severe to severe NPDR, intravitreal anti-VEGF treatment improved 
diabetic retinopathy and prevented disease progression (Lim 2020). Therefore, based upon the 
well-known, clinically demonstrated mechanism of action (Homayouni 2009); favorable 
nonclinical and Phase 1a/1b safety, tolerability and bioactivity data; and a study design that 
includes extensive monitoring and COVID-19 risk mitigation, the Sponsor considers that the 
potential risks of study participation are outweighed by the value of the information to be gained 
and further study is warranted. 


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3.0 
OBJECTIVES AND ENDPOINTS  
Objectives 
Endpoints 
Primary 
To demonstrate that KSI-301 5 mg is superior to sham 
treatment, with respect to proportion of eyes improving 
≥2 steps on DRSS from baseline at Week 48. 
• 
The proportion of eyes improving ≥2 steps on 
DRSS from baseline at Week 48. 
Secondary 
To evaluate the effect of KSI-301 5 mg in decreasing 
the incidence and delaying the onset of vision-
threatening complications of diabetes compared to 
sham treatment. 
• 
Time to development of and proportion of eyes 
developing any of the following from baseline 
over time (individually and as a composite): 
- 
PDR or ASNV; 
- 
Vitreous hemorrhage or tractional retinal 
detachment believed to be due to proliferative 
diabetic retinopathy; or 
- 
DME. 
To evaluate the efficacy of KSI-301 5 mg compared to 
sham treatment. 
• 
Proportion of eyes improving ≥2 or ≥3 steps on 
DRSS from baseline over time. 
• 
Proportion of eyes worsening ≥2 or ≥3 steps on 
DRSS from baseline over time. 
To evaluate the safety and tolerability of KSI-301 5 mg 
compared to sham treatment. 
• 
Incidence of ocular and systemic adverse events 
over time. 
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 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 dosing of KSI-301 5 mg administered by 
intravitreal injections in participants with treatment-naïve NPDR. 
The overall duration of the study is approximately 2 years (100 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 100; thus, participant duration 
is approximately 103 weeks and includes a screening period of up to 21 days (Days -21 to -1), a 
treatment period of approximately 92 weeks (Day 1 to Week 92), a safety/efficacy assessment at 
Week 96, and a final follow-up for safety assessments at Week 100 
 
. The primary endpoint will be assessed at Week 48; secondary endpoints for efficacy will 
be assessed at Weeks 48 and 96.  
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 and/or worse DR severity at Screening will be 
selected as the Study Eye. If both eyes are eligible and have the same BCVA and/or DR severity 
or one eye has worse BCVA and the fellow eye has worse DR, 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 via intravitreal injection at  
Day 1, Week 8, Week 20, and every 24 weeks thereafter through Week 92.  
• Group B: Sham injection at  
Day 1, Week 8, Week 20, and every 24 weeks thereafter through Week 92. 
Randomization will be stratifie
 
Additional details of the randomization methods are described 
in the statistical analysis plan (SAP). 
Participants who develop sight-threatening complications of DME, PDR, or ASNV in the study 
eye will be managed as outlined in Section 4.1.3.1. 
4.1.1 
Screening Period 
Participants will provide written informed consent to participate in the study before completing 
any protocol-specified procedures or evaluations not considered to be part of the participant’s 
standard care. After providing informed consent, participants will be evaluated for eligibility 
criteria during the screening period within 21 days before administration of study intervention(s).  


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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 rescreened up to one additional time at the discretion of the Investigator and in consultation 
with the Sponsor (Section 5.4). Instructions for participants who meet all eligibility criteria at the 
Screening visit but do not meet the BCVA eligibility criteria when they return for the planned 
Day 1 visit are provided in Section 5.5. 
When rescreening tests and procedures have been completed and results are available indicating 
the participant is eligible for study participation, the participant may be enrolled. When 
rescreening a participant, a new screening/enrollment number should be selected to ensure there 
is an audit trail for the screen failed participant.  
4.1.2 
Treatment Period 
Participants in this study will be treated until Week 92 and will have additional efficacy and/or 
safety follow-up visits at Weeks 96 and 100, unless the Investigator decides to discontinue 
treatment, the Sponsor decides to terminate the study or until any of the reasons for withdrawal/ 
discontinuation provided in Section 7.2 are met. 
4.1.3 
Administration of Study Intervention 
All participants will be treated starting on Day 1 through Week 92 according to their respective 
treatment group. The IRT will determine the dosing schedule and adjust it in consideration of 
missed visits, out of window visits, and missing data during a visit. If a visit is missed at which 
study treatment is scheduled to be administered, the missed dose should be made up as close to 
the originally scheduled visit as possible using an unscheduled visit. Adjustments to study 
intervention due to development of sight-threatening complications of DR are described in 
Section 4.1.3.1. 
As shown in the dosing regimen schematic provided in Figure 1, participants will be treated 
according to the group to which they were randomized, as follows: 
• Group A - KSI-301 5 mg via Intravitreal Injection:  
Intravitreal KSI-301 5 mg injection will be administered on Day 1, Week 8, Week 20, 
Week 44, Week 68, and Week 92. 
• Group B - Sham Injection: 
To preserve study masking, sham injections are administered to Group B participants 
at visits in which KSI-301 is administered to Group A participants. Thus, sham 
injections will be administered on Day 1, Week 8, Week 20, Week 44, Week 68, and 
Week 92. 


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For all study participants, non-treatment study visits will occur on Week 32, Week 48, Week 56, 
Week 80, and Week 96. A final safety assessment will occur on Week 100 and will be done via 
telephone call for all participants, except in WOCBP, in which case a site visit is required to 
administer a pregnancy test. 
Figure 1: 
Protocol KS301P106: Masked Dosing Regimens by Week
Abbreviations: PE = primary endpoint; Q24W = once every 24 weeks; SA = safety assessment; SE = secondary 
endpoint.
a
Week 100 is a final safety assessment that will be done via telephone call for all participants, except in 
WOCBP, in which case a site visit is required for the safety assessment that includes a pregnancy test. 
4.1.3.1
Sight-threatening Complications of Diabetic Retinopathy in the Study Eye 
Definitions and Documentation of Sight-threatening Complications 
In this study, sight-threatening complications of DR in the Study Eye include DME, PDR, and/or 
ASNV. The protocol definition of each sight-threatening complication in the Study Eye is 
provided in Table 3. The diagnosis of DME, PDR, and/or ASNV will be made by the masked 
Investigator.  
Because the treatment schedule changes for participants who develop these complications (as 
described below), it is very important that the imaging and/or clinical documentation described 
in Table 3 is collected at the time of diagnosis. It is also very important that the color fundus 
photographs are submitted to the reading center, because the color fundus photographs from this 
visit will be used for DRSS endpoint assessment. 


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Table 3:  
Protocol KS301P106: Sight-threatening Complications of Diabetic 
Retinopathy: Definitions and Required Documentation for Initial 
Diagnosis 
Sight-threatening 
Complication 
Definition 
Required Documentation 
Diabetic Macular 
Edema (DME) 
• 
CST of ≥320 microns on SD-OCT and 
at least 5-letter decrease in best 
corrected visual acuity from Day 1 due 
to DME (as assessed by the 
Investigator); or  
• 
CST of ≥350 microns on SD-OCT due 
to DME (as assessed by the 
Investigator). 
A fundus photograph and OCT 
(Section 8.1.6) of the Study Eye must 
be obtained prior to the first treatment 
of DME. 
Proliferative Diabetic 
Retinopathy (PDR) 
• 
Neovascularization of the disc (NVD) 
or neovascularization elsewhere 
(NVE);  
• 
Vitreous hemorrhage; or  
• 
Pre-retinal hemorrhage. 
PDR must be documented with fundus 
photography (Section 8.1.6) [and, 
optionally, fluorescein angiography 
(Section 8.1.8)] of the Study Eye prior 
to initiation of the first treatment of 
PDR. 
Anterior segment 
neovascularization 
(ASNV) 
• 
Neovascularization of the iris (at least 
two cumulative clock hours);  
• 
Neovascularization in the iridocorneal 
angle (as assessed clinically by 
gonioscopy); or  
• 
Neovascular glaucoma. 
A fundus photograph of the Study Eye 
must be obtained prior to the first 
treatment of ASNV. ASNV must be 
documented by clinical exam. Anterior 
segment photographic documentation is 
preferred if possible, but not required. 
 
Treatment of Sight-threatening Complications of Diabetic Retinopathy 
Participants who develop any of the sight-threatening complications of DR in the Study Eye that 
are described in Table 3 will be treated with open-label KSI-301 5 mg, irrespective of the 
treatment group that they were originally randomized into (KSI-301 5 mg or sham). The original 
treatment group randomization will remain masked throughout the study. 
At the visit that a sight-threatening complication of DR (DME, PDR and/or ASNV) is diagnosed 
(i.e., the “Dx Visit”), treatment with open-label KSI-301 5 mg will be initiated. Starting at the 
Dx Visit, participants will no longer follow the study visits and assessments outlined in 
Section 1.3.1 (SoA-A), nor receive further masked treatments. Instead, they will follow the study 
visits and assessments outlined in Section 1.3.2 (SoA-B), which is specific to the participants 
who develop DME, PDR, and/or ASNV.  
As shown in Figure 2, treatment of DME, PDR, and/or ASNV will consist of the following: 


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•
Two doses of KSI-301 5 mg, given four weeks apart (+/- 7 days), followed by 
KSI-301 5 mg once every 12 weeks (Q12W; +/-14 days). Thus, the first dose shall 
occur during the study visit in which DME, PDR, and/or ASNV was diagnosed, and 
the second dose shall occur 4 weeks (+/- 7 days) later. Thereafter, subsequent doses 
shall occur Q12W (+/-14 days).  
More frequent visits and more frequent treatments with KSI-301 5 mg and/or pan-
retinal photocoagulation (PRP) are at the discretion of the Investigator if the sight-
threatening complication(s) as described in Table 3 are still present. Treatment with 
KSI-301 5 mg may not be given more often than monthly (28 ± 7 days).  
End of Study Considerations 
For participants who develop any of the sight-threatening complications described in Table 3, the 
following shall be considered:
•
Participants shall not receive any treatment with KSI-301 5 mg after Week 92 (i.e., 92 
weeks after the day of randomization (Day 1)). 
•
Weeks 96 and 100 (relative to the day of randomization (Day 1)) include final safety 
assessments that are mandatory and shall also be conducted according to the SoA-B
(Section 1.3.2).
Figure 2: 
Protocol KS301P106: Dosing Regimen by Week for All Participants 
Who Develop Sight-threatening Complication(s) in the Study Eye
Abbreviations: Dx Visit = the first study visit where a sight-threatening complication of diabetic retinopathy (DME, 
PDR, and/or ASNV) is diagnosed; Q4W = once every 4 weeks; Q12W = once every 12 weeks; SA = safety 
assessment; SE = secondary endpoint.
a
All participants who develop sight-threatening complication(s) of DME, PDR, and/or ASNV will be treated 
with open-label KSI-301 5 mg, irrespective of the treatment group that they were originally randomized into. 
The participant’s ‘as randomized’ treatment group will remain masked. Participants shall not receive any 
KSI-301 5 mg dose for sight-threatening complications after Week 92. 
b
Week 100 is a final safety assessment that will be done via telephone call for all participants, except in 
WOCBP, in which case a site visit is required for the safety assessment that includes a pregnancy test.


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4.1.3.2 
Sight-threatening Complications in the Fellow Eye (non-Study Eye) 
Treatment of DME, PDR, or ASNV in the fellow eye may be conducted at any time and at the 
discretion of the Investigator (Section 6.8). 
4.2 
Scientific Rationale for Study Design 
This is a randomized, sham-controlled, double-masked, multi-center, Phase 3 study to evaluate 
the efficacy and safety of intravitreal KSI-301 in participants with moderately severe to severe 
treatment-naïve NPDR. A randomized, double-masked design minimizes bias and is well-
established for demonstrating the safety and efficacy of an investigational treatment. The 
rationale for other key design features is provided below. 
4.2.1 
Choice of Population 
This study will enroll participants with moderately severe to severe NPDR (DRSS levels 47 and 
53), who have not previously received intravitreal medications for DR in the study eye.  
KSI-301 is being evaluated as a first-line anti-VEGF medicinal product to treat NPDR. Thus, 
participants must not have had prior use of an approved or investigational treatment (e.g., anti-
VEGF or intraocular steroids) for DR in the Study Eye. Enrollment of participants who have not 
previously received intravitreal medications for DR in the study eye helps minimize biases 
inherent in the inclusion of participants who have failed prior lines of therapy.  
Moderately severe to severe NPDR (DRSS levels 47 and 53) is a disease level that is most 
amenable to anti-VEGF therapeutic intervention (Ip 2012), while not meeting the threshold of 
alternative therapeutic interventions (e.g., panretinal photocoagulation in the case of proliferative 
DR) (Flaxel 2020). Additionally, and importantly, patients with moderately severe to severe 
NPDR are at higher risk of sight-threatening DR complications than patients with earlier stages 
of disease. 
4.2.2 
Choice of Sham Control 
A sham comparator was selected for this trial to demonstrate that treatment with KSI-301 5 mg is 
superior to standard of care for NPDR, which includes standard-of-care therapeutics for 
treatment of the patient’s underlying hyperglycemia, hyperlipidemia, and hypertension due to 
diabetes, as clinically indicated. Intravitreal anti-VEGF treatment has improved diabetic 
retinopathy and prevented disease progression in eyes with moderately severe to severe NPDR in 
patients without DME (Lim 2020). However, the regulatory status of intravitreal anti-VEGFs as 
a treatment for NPDR is not globally uniform, and, even more importantly, anti-VEGF has not 
been established as standard of care therapy for NPDR. For example, ranibizumab and 
aflibercept are both approved in the US for the treatment of DME and DR (NPDR and DR), 
however in Europe, only ranibizumab is approved for PDR, and neither is approved in Europe 
for NPDR. Furthermore, in the US where the intravitreal anti-VEGFs are approved for the 
treatment of adult patients with DR, they are not standard of care for NPDR (Flaxel 2020). 


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Hence, the choice of sham comparator does not deprive participants in the control group of 
access to accepted, standard-of-care therapy. As described in Section 4.1.3.1, all participants 
with progression of NPDR to the sight-threatening complications of DME, PDR, or ASNV will 
be identified and treated with KSI-301. 
4.2.3 
Choice of Primary Endpoint and Analysis 
The primary endpoint, the proportion of eyes improving ≥2 steps on DRSS from baseline at 
Week 48, as measured using color fundus photographs graded by an independent, central reading 
center, was selected based on precedent for Phase 3 studies in NPDR (Lim 2020).  
4.2.4 
Choice of Duration of Treatment and Follow-up 
The duration of treatment in this study will be approximately 92 weeks. The primary endpoint 
will be assessed at Week 48; secondary endpoints for efficacy will be assessed at Week 48, 
Week 96, and over time. These endpoints and associated duration of treatment were selected 
based on precedent for Phase 3 trials in NPDR (Lim 2020).  
The choice of a safety follow-up interval of 8 weeks after the last dose is based on the expected 
duration of effect for KSI-301.  
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 aflibercept 2 mg. 
Preclinical modeling suggests that KSI-301 5 mg results in 
-fold the equivalent ocular 
concentration of aflibercept 2 mg three months after dosing. Both KSI-301 2.5 mg and 
KSI-301 5 mg that are being evaluated in the ongoing Phase 1b portion of Study KSI-CL-101 
have not resulted in any dose limiting ocular or systemic toxicities and, as expected, have no 
clear dose-efficacy response relationship. Because the 5 mg dose of KSI-301 may have 
incrementally improved durability compared to the 2.5 mg dose, the 5 mg dose has been selected 
for this study. Interim efficacy data from 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. 
The dosing regimen of KSI-301 5 mg intravitreal injection at Day 1, Week 8, Week 20, and 
every 24 weeks thereafter through Week 92 was selected in consideration of the increased 
durability of KSI-301 relative to existing intravitreal anti-VEGF therapies that have been studied 
in patients with NPDR.  
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 studies of 
 


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4.3.2 
Sham Injection Rationale 
Sham injections are used as a comparator to KSI-301 and to preserve study masking and 
minimize bias. Additional details are provided in Section 4.2.2.  
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 (ET) are 
provided in Section 7.0. 
4.5 
End of Study Definition 
The end of the study is defined as the last follow-up visit of the last participant enrolled (i.e., the 
last enrolled participant’s final visit) or a Sponsor decision to terminate the study, whichever 
comes first.  
A participant is considered to have completed the study if he/she has completed all phases of the 
study, including the Week 100 safety follow-up assessment.  
4.6 
Treatment After End of Study 
All participants will return to standard of care treatment, at the discretion of their treating 
physician, after completion of their final follow-up visit or once they discontinue from the study 
prematurely. The Sponsor will not provide continued access to study treatment following the end 
of the study or the end of each participant’s study treatment period. 


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5.0 
STUDY POPULATION 
Participants will be randomized to a specified treatment group only if they meet all the inclusion 
criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or participant safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. Prospective approval 
of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or 
exemptions, are not permitted. 
Inclusion/exclusion criteria (Sections 5.1 and 5.2) will be assessed at Screening and on Day 1 to 
determine a participant’s eligibility for the study. Instructions for participants who meet all 
eligibility criteria at the Screening visit but do not meet the BCVA and/or SD-OCT CST 
eligibility criteria when they return for the planned Day 1 visit are provided in Section 5.5. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the criteria in Sections 5.1.1 and 
5.1.2 apply. 
5.1.1 
Ocular Inclusion Criteria 
Where applicable, ocular inclusion criteria will be confirmed or assessed by the independent, 
masked image reading center.  
1. Participants with moderately severe to severe NPDR in the Study Eye (DRSS levels 47 and 
53 as determined by the reading center based on color fundus photographs), who have not 
previously received intravitreal medications for DR or DME, and in whom pan-retinal 
photocoagulation (PRP) can be safely deferred for at least 6 months per the Investigator. 
2. BCVA ETDRS letter score in the Study Eye of ≥69 letters (approximate Snellen equivalent of 
20/40 or better) in the Study Eye at Screening and confirmed at Day 1.  
Only one eye per participant is eligible to participate in the study. If both eyes are eligible to 
become the Study Eye, the eye with worse BCVA and/or worse DR severity at Screening will be 
selected as the Study Eye. If both eyes are eligible and have the same BCVA and/or DR severity 
or one eye has worse BCVA and the fellow eye has worse DR, the decision of which eye to 
select as the Study Eye will be made by the Investigator. 
5.1.2 
General Inclusion Criteria  
3. Male or female ≥18 years of age. 
4. Capable of giving signed informed consent, as described in Appendix 1, which includes 
compliance with the protocols and restrictions listed in the informed consent form (ICF) and 
in this protocol.  


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5. Type 1 or 2 diabetes mellitus and HbA1c of ≤12%. 
6. 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 at least 90 days after the last dose of study 
intervention.  
a. A woman is considered of childbearing potential if she is post-menarchal, has not reached 
a post-menopausal 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 post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
7. 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 and for at least 
 
 after the last dose of study intervention. Men must refrain from 
donating sperm during this same time period. 
8. 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 or 5.2.2 apply. 
5.2.1 
Ocular Exclusion Criteria  
Where applicable, ocular exclusion criteria will be determined by an independent, masked image 
reading center. 
1. Presence of center-involved DME in the study eye, defined for this purpose as CST of ≥320 
microns on SD-OCT (Heidelberg Spectralis or equivalent value on other OCT instruments). 
2. Prior PRP in the Study Eye. 


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3. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional 
retinal detachment in the Study Eye.  
4. Prior intravitreal anti-VEGF treatment in the Study Eye for DR or DME. 
5. Prior intravitreal or periocular steroid in the Study Eye for DR or DME. 
6. Prior use of an investigational intravitreal treatment for DR or DME in the Study Eye. 
7. History of vitreoretinal surgery in the Study Eye 
8. History of retinal detachment or treatment or surgery for retinal detachment in the Study Eye. 
9. History of cataract surgery in the Study Eye within 2 months of screening. 
10. History of YAG laser capsulotomy in the Study Eye within 2 months of screening. 
11. Uncontrolled glaucoma (defined as intraocular pressure ≥25 mmHg despite treatment with 
antiglaucoma medication) in the Study Eye. 
12. History of glaucoma-filtering surgery (trabeculectomy or tube shunt) in the Study Eye.  
13. History of uveitis in either eye.  
14. Significant media opacities, including cataract, in the Study Eye that might interfere with 
visual acuity, assessment of safety, OCT, or FP.  
15. Cataract in the Study Eye that in the judgment of the Investigator is expected to require 
surgical extraction within 12 months of screening. 
16. Aphakia 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 in the Study Eye, that in the 
opinion of the Investigator could require either medical or surgical intervention 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. BCVA of hand motion or worse in the non-Study Eye or non-physical presence of a non-
Study Eye (i.e., monocular). 
 
5.2.2 
General Exclusion Criteria 
21. Women who are pregnant or lactating or intending to become pregnant during the study.  
22. Women of child-bearing 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. 
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.  


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• If a participant’s initial blood pressure measurement exceeds these values, up to two 
additional readings may be taken later the same day or on a different day during the 
screening period. If a participant’s blood pressure is controlled by antihypertensive 
medications, the participant must be on a stable medication regimen continuously for 21 
days prior to Day 1. 
24. Kidney failure requiring renal transplant, hemodialysis or peritoneal dialysis or expected to 
require renal transplant, hemodialysis or peritoneal dialysis during the study. 
25. Recent history (within the 6 months prior to screening) of myocardial infarction, stroke, 
transient ischemic attack, acute congestive heart failure, or any acute coronary event. 
26. History of a medical condition that, in the judgment of the Investigator, would preclude 
scheduled study visits, completion of the study, or a safe administration of investigational 
product. 
27. History of hypersensitivity to intravitreal agents such as aflibercept or ranibizumab or to any 
component of KSI-301, ophthalmic dye (fluorescein), dilating drops, or any of the anesthetic 
or antimicrobial preparations used during the study, as assessed by the Investigator. 
28. Active cancer within the 12 months prior to Screening except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin cancer, and prostate cancer with a 
Gleason score of <6 and stable prostate-specific antigen for >12 months. 
29. Participation in an investigational study within 30 days prior to the screening visit that 
involved treatment with any investigational drug (excluding vitamins and minerals) or 
investigational devices, except for non-therapeutic ophthalmic imaging 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 considered ‘screen-failed’. However, a participant may be 
rescreened up to one additional time at the discretion of the Investigator and in consultation with 
the Sponsor. When rescreening, 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 rescreening, 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 


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visit should be repeated during the re-screening visit except fluorescein angiogram (FA). If the 
rescreening visit is more than 8 weeks after the original screening visit, FA should be repeated. 
For a rescreening visit occurring fewer than 8 weeks after the original screening visit, although a 
new FA will not be required, the previously acquired FA will need to be re-submitted to the 
Reading Center labeled with the new participant number, along with the new screening images 
from the other modalities. This will ensure that all images from the participant are properly 
labeled, kept within the same directory and that eligible transmission numbers and audit trails are 
maintained. 
When rescreening tests and procedures have been completed and results are available indicating 
the participant is eligible for study participation, the participant may be enrolled. When 
rescreening a participant, a new screening/enrollment number will be generated by IRT system to 
ensure there is an audit trail for the screen-failed participant.  
5.5 
Criteria for Temporarily Delaying Enrollment 
Inclusion/Exclusion criteria will be assessed at Screening and on Day 1 to determine a 
participant’s eligibility for the study.  
If a participant meets all eligibility criteria (Sections 5.1 and 5.2) at the Screening visit but does 
not meet BCVA eligibility criteria due to expected variability and fluctuation in the BCVA when 
they return for the planned Day 1 visit, the Sponsor will allow the participant to return one 
additional time to reassess the BCVA, provided the assessment still occurs within the 21-day 
screening window. This repeat measurement for Day 1 visit (Repeat Day 1) is not considered a 
rescreen. Women of childbearing potential who return for a Repeat Day 1 Visit must have a 
negative pregnancy test during the Repeat Day 1 Visit (i.e., the pregnancy test must be 
performed and documented as negative on the same day as randomization/first injection). Day 1 
and Repeat Day 1 Visit data shall be used/entered in the eCRF and IRT as follows: 
• eCRF: In the event that a participant has a Repeat Day 1 Visit, data from assessments 
conducted at the planned randomization (Day 1) visit shall be clearly documented in 
the participant’s source data. If the participant meets the eligibility criteria at the 
Repeat Day 1 visit, all data for assessments performed at that visit are entered into the 
eCRF under Day 1 and the original non-qualifying data will be entered as 
Unscheduled Visit assessments. 
• IRT: In the event that a participant has a Repeat Day 1 Visit and is eligible for this 
study, the BCVA and SD OCT values from the Repeat Day 1 visit must be used for 
participant randomization into the IRT system. If the participant does not meet 
eligibility at the Repeat Day 1 visit, the participant must be recorded as a screen 
failure (Section 5.4) in the IRT system at that time. 


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6.0 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1 
Study Intervention(s) Administered 
Study interventions are summarized in Table 4. For full information regarding the administration 
of study intervention and the contents of the kit, refer to the Pharmacy Manual. The full 
instructions for administration of sham are also described in the Pharmacy Manual. 
Table 4:  
Protocol KS301P106: Study Interventions 
Group Name 
A 
B 
Intervention Name 
KSI-301 5 mg 
Sham 
Type  
Biological medicinal product 
Sham 
Dose Formulation 
Sterile liquid for intravitreal injection 
in single-use vials  
Empty vial 
Unit Dose Strength(s) 
 mg/mL (based on antibody mass) 
N/A 
Dosage Level(s) 
5 mg 
 
N/A 
Route of Administration 
Intravitreal injection 
Sham injection 
Use 
Experimental 
Sham (to maintain study masking) 
IMP and NIMP 
IMP 
NIMP 
Sourcing 
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. Refer to Pharmacy Manual 
for additional instructions. 
In the original packaging, as provided, 
until the time of use. Store at 2-8°C 
before use. Refer to Pharmacy Manual 
for additional instructions. 
Packaging and Labeling 
KSI-301 will be provided in vials 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 vial and filled into a 
syringe by unmasked site personnel 
without reconstitution or dilution.  
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 
N/A 
 


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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Preparation, Handling, and Storage 
KSI-301 is an aqueous solution provided in vials 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 should be stored in the original packaging, as provided, until the time of use.  
Please refer to the 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 and document 
receipt in IRT system. 
• Report any deviations or product complaints to the Sponsor or its delegate upon discovery. 
Any study intervention under investigation for integrity or temperature excursion should be 
quarantined in the IRT, and not used until the final assessment by the Sponsor or its designee. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 


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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. Detailed stepwise instructions 
for the preparation of KSI-301 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 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 assessment 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 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 two study interventions: (1) KSI-301 (the investigational 
medicinal product); and (2) sham (for which an injection procedure is simulated but not actually 
performed). The two study interventions are provided are provided in unmasked vials 
within masked cartons (also referred to as kits), as follows: 
• Masked Cartons: All study interventions are provided in cartons that are identical in 
appearance and weight, making them indistinguishable from each other. 
Each carton is labeled with an identical carton label that includes a unique kit number. The 
IRT system will direct site personnel which specific carton to pull from inventory and use for 


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


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The unmasked Investigator is responsible for administering the correct dose of KSI-301 or 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 group, as follows: 
A. KSI-301: 5 mg 
  
B. Sham injection  
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 at a single study visit will be considered 
an overdose. 
The Sponsor does not recommend any specific treatment for an overdose.  
In the event of an accidental overdose, the Investigator/treating physician should: 
• Contact the Medical Monitor immediately. 
• Evaluate the participant to determine, in consultation with the Medical Monitor, 
whether additional steps should be taken. 
• Closely monitor the participant for any AE/SAE. 
• Document the quantity of the excess dose. 
In addition to overdosing, an increased injection volume may cause an increase in intraocular 
pressure. In case of overdose, intraocular pressure should be monitored and if deemed necessary 
by the treating physician, adequate treatment should be initiated, including performing pressure 
lowering procedures (i.e., anterior chamber paracentesis). 


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6.8 
Concomitant Therapy 
Use of all concomitant medications will be recorded in the participant’s eCRF, except for 
medications required for carrying out procedures in the SoA (Section 1.3) (e.g., dilating drops, 
anesthetics, antiseptic, fluorescein, etc.) related to this study. Concomitant medications will 
include all prescription drugs, herbal products, vitamins, minerals, and over the counter (OTC) 
medications as used by the participant within 30 days prior to Day 1 through Week 100. Any 
changes in concomitant medications also will be recorded in the participant’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the participant during the 
study may be given at the discretion of the Investigator. However, it is the responsibility of the 
Investigator to ensure that all relevant details regarding the medication are recorded in the eCRF. 
Participants who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. 
In case the fellow eye (non-Study Eye) requires anti-VEGF treatment during the conduct of the 
study, the participant may be treated at the discretion of the Investigator and according to the 
standard of care in the respective country. The treatment of the fellow eye (non-Study Eye) may 
be implemented at any time once the Day 1 injection has been administered. Anti-VEGF 
treatment for the fellow eye, including the date of each administration, must be documented as a 
concomitant medication on the appropriate eCRF. If the fellow eye requires treatment during the 
same visit as the Study Eye, the Study Eye should be treated first, and the fellow eye should be 
treated by the unmasked physician to preserve masking.  
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1 
Pan-retinal Photocoagulation 
Pan-retinal photocoagulation (PRP) laser is permitted in the Study Eye if PDR or ASNV 
develops. 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; 
• Intravitreal anti-VEGF drugs other than study-assigned KSI-301 in the Study Eye; 
• Systemic anti-VEGF therapy; 
• Intravitreal or periocular steroids or steroid implants in the Study Eye; 


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• Concurrent use of macular laser photocoagulation in the Study Eye; and 
• Investigational treatment with any drug (other than vitamins and minerals) or device. 
Participants whose medical care requires use of a prohibited therapy must have study treatment 
interrupted or be discontinued from the study in order to receive that therapy. After discussion 
with the Sponsor, participants whose study treatment has been interrupted but no longer need a 
prohibited therapy may resume study treatment. 
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 2) 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 treatment is discontinued, an end-of-treatment visit should occur 28 +/- 7 days after 
study treatment is discontinued or before a new treatment regimen begins. Participants who 
discontinue study drug should NOT be considered withdrawn from the study. Unless they 
withdraw consent or there is additional risk to the participant, participants who have discontinued 
study treatment should be encouraged to stay in the study and undergo as many scheduled visits 
as possible, with emphasis on the Week 48 (primary endpoint) and Week 96 (secondary 
endpoint) visits.  
The reasons for study treatment discontinuation and/or withdrawal from the study (study 
discontinuation) will be recorded on the appropriate eCRF. 
A participant may be withdrawn from the study for any of the following reasons: 
1. The participant is non-compliant 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; or 
7. Pregnancy. 
The Investigator will also withdraw a participant if the Sponsor terminates the study. Upon 
occurrence of a serious or intolerable AE, the Investigator will confer with the Sponsor. If a 
participant is discontinued because of an AE, the event will be followed until it is resolved, or no 
additional improvement is expected by the Investigator (based on a follow-up period of not less 
than 3 months). Any participant may withdraw his or her consent at any time. 


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7.1.1 
Treatment Interruption and/or Discontinuation due to Adverse Events or 
Concomitant Procedures 
Study treatment interruption and/or participant discontinuation from the study treatment due to 
certain adverse events or concomitant procedures in the Study Eye will be determined using the 
criteria provided in Table 5. If any of these are met, treatment will be interrupted (or 
discontinued if applicable) and notification will be sent to the medical monitor. Treatment may 
be resumed after resolution of the adverse event and upon agreement with both the Investigator 
and medical monitor. The reason for study treatment interruption or discontinuation should be 
recorded on the appropriate eCRF and, if applicable, on the Adverse Event eCRF. 
Table 5:  
Protocol KS301P106: 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 10 days after successful laser 
retinopexy, as determined by the Investigator. 
Retinal detachment or 
macular hole 
Interrupt study treatment if rhegmatogenous retinal detachment or Stage 3 or 
Stage 4 macular hole occurs in the Study Eye. 
Treatment may be resumed no earlier than 14 days after successful 
treatment, as determined by the Investigator, following discussion with the 
Medical Monitor. 
Active infection 
Interrupt study treatment if infectious cellulitis, conjunctivitis, keratitis, 
scleritis, or endophthalmitis occurs in or around either eye. 
Infections should be treated as per the local standard of care. 
 
 


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7.2 
Participant Discontinuation/Withdrawal from the Study 
Participants should be strongly encouraged to stay in the study and undergo as many scheduled 
visits as possible, with emphasis on the Weeks 48, 96, and 100 safety assessments. However, 
participants are free to withdraw from the study or study treatment at any time upon request. 
Participant participation in the study may be stopped at any time at the discretion of the 
Investigator or at the request of the Sponsor. 
Participants who discontinue study treatment or active participation in the study will no longer 
receive study intervention. When a participant discontinues from study treatment or active 
participation in the study, the reason(s) for study treatment discontinuation or withdrawal shall 
be recorded by the Investigator or designee on the relevant page of the eCRF. Whenever 
possible, all participants who discontinue study treatment or withdraw from the study 
prematurely will undergo an ET visit. Participants who fail to return for final assessments must 
be contacted by the site by phone and in writing to obtain follow-up. 
If a participant exits early from the study between visits, the Investigator or designee must 
attempt to contact the participant and advise the participant to return for a final visit to complete 
the exit procedures. If the participant is unable or unwilling to return for the Early Termination 
visit, the ‘date of exit’ will be the date that the participant was last seen at the site or contacted by 
other communication.  
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
a) The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 


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


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


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• Inspection of the vitreous body, 
• Inspection of the retina, and 
• Inspection of the optic disc. 
Dilated indirect ophthalmoscopy will include examination of the peripheral retina and vessels. 
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 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 or sham) 
and documented in the site’s source documents. Per Section 4.1.3.1, upon initiation of treatment 
of DME, PDR, and/or ASNV, the method of anesthesia is not required to remain constant.  
Please refer to the Pharmacy Manual for 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 


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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.  
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 
Best corrected visual acuity (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 
Fundus photography (FP) will be performed at the study sites by certified, masked personnel. 
Where wide-field devices qualified by the Reading Center are available, wide-field FP should be 
performed. 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 
Spectral domain optical coherence tomography (SD-OCT) will be performed at the study sites by 
certified, masked personnel on a qualified instrument. It is mandatory that the same model of 
device is used for the entire duration of the study.  
Additional specifications and instructions regarding acceptable equipment and imaging 
techniques will be provided by the Reading Center. 
8.1.8 
Fluorescein Angiography  
Fluorescein angiography (FA) will be performed at all the study sites by certified, masked 
personnel. Where wide-field devices qualified by the Reading Center are available, wide-field 
FA should be performed. 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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8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 
Vital Signs 
The following vital signs will be assessed with the participant in a seated position after resting 
for 5 minutes: blood pressure, pulse rate, and body temperature. Height and weight will be 
recorded at the screening visit only. 
8.2.2 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and refer to the SoA 
(Section 1.3) for the timing and frequency. 
The Investigator or designee must review the laboratory report, document this review, and record 
any clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or medical monitor. 
• If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified, and the 
Sponsor notified. 
• All protocol-required laboratory tests, as defined in Appendix 2, must be conducted in 
accordance with the SoA (Section 1.3). 
• If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.2.3 
Pregnancy Testing 
Participant samples for pregnancy testing will be taken starting at the Screening visit and then at 
each visit through the end of the study 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 


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unintentional pregnancy. Contraceptive and barrier guidance and collection of pregnancy 
information is described in Appendix 6. 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs are provided in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, 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 (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 Adverse Event and Serious Adverse 
Event Information 
After informed consent has been obtained but prior to initiation of study intervention, only SAEs 
caused by a protocol-mandated assessment should be reported. After initiation of study 
intervention (Day 1), all AE and SAE information will be collected until the final safety follow-
up visit at Week 100 or the ET visit, if applicable. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. At every study visit, 
open-ended and nonleading verbal questioning of the participant is the preferred method to 
inquire about AE occurrences. The participant will also be asked if they have been hospitalized, 
had any accidents, used any new medications, or changed concomitant medication regimens 
(both prescription and OTC medications). 


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In addition to participant observations, AEs identified from any study data (e.g., laboratory 
values, ophthalmic examination findings) or identified from review of other documents that are 
relevant to participant safety will be documented on the AE page in the eCRF. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
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 Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
intervention under clinical investigation are met. The Sponsor has a legal responsibility to notify 
both the local regulatory authority and other regulatory agencies about the safety of a study 
intervention under clinical investigation. The Sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and Investigators. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators, as necessary. 
8.3.5 
Pregnancy 
During the study, female and male participants are to be instructed to contact the Investigator 
immediately if they suspect they might be pregnant or if their partner becomes pregnant, 
respectively, and details will be collected. Additional urine or serum pregnancy testing may be 
performed during the study at the discretion of the Investigator, or in accordance with local 
requirements or regulations.  
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs during study participation must be reported using the same procedures as an SAE on a 
Sponsor prepared form. To ensure participant safety, each pregnancy must be reported to the 
Sponsor or its designee immediately (within 24 hours) after learning of its occurrence. The 


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pregnancy must be followed up to determine outcome (including spontaneous miscarriage, 
elective termination, normal birth, or congenital abnormality) and status of mother and child, 
even if the participant was discontinued from the study. Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE. Spontaneous miscarriages 
must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the Investigator’s attention after 
the participant has completed the study, and considered by the Investigator as possibly related to 
the study treatment, must be promptly reported to the Sponsor. 
Pregnancy is considered a criterion for discontinuation from the study; 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 in the Study Eye with sight-threatening potential, meeting one or more of the following 
criteria: 
o Causes a decrease ≥30 letter 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 
Appendix 4 for grading scales). 
o Requires surgical intervention to prevent permanent loss of sight. 
• Cases of potential liver injury (Appendix 7) 
As with all AEs occurring in a study participant, a decision will be made by the Investigator 
concerning additional exposure to study treatment and further participation in the study. 


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8.4 
Pharmacokinetics 
To understand the systemic pharmacokinetic (PK) of the study intervention following intravitreal 
injection, plasma concentration of KSI-301 will be measured. For exploratory purposes, 
 
Blood samples of approximately 4 mL will be collected from participants for measurement of 
plasma concentrations of KSI-301 or aflibercept, 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 the anti-drug antibodies as 
specified in the SoA (Section 1.3). Additionally, plasma samples should also be collected and 
evaluated at the final visit from participants who discontinued study intervention or were 
withdrawn from the study as per the SoA.  
The detection and characterization of ADAs to KSI-301 will be performed using a validated 
assay method. Plasma samples will be screened for antibodies binding to KSI-301 and the titer of 
confirmed positive samples will be reported. Specificity analyses may be performed to further 
characterize the immunogenicity of KSI-301. Anti-KSI-301 antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study 
intervention(s) (neutralizing antibodies or 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.  


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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 
Statistical Hypothesis 
The study hypothesis is that the proportion of eyes improving ≥2 steps on DRSS from baseline at 
Week 48 among participants treated with KSI-301 5 mg Q24W will be superior to the 
participants in the sham group.  
9.2 
Sample Size Determination 
A sample size of approximately 240 participants with a target enrollment of approximately 120 
participants in each treatment group (1:1 ratio) was calculated using the following assumptions:  
• Anticipated 
 of participants with a ≥2-step improvement from baseline in DRSS 
score in the KSI-301 5 mg Q24W group versus 
 in the sham group.  
• Statistical power of ≥90%. 
• Overall Type I error rate of 0.05. 
• The statistical method used to compare the proportion with a ≥2-step improvement from 
baseline in DRSS score for the KSI-301 treatment group at Week 48 compared with sham 
will be the Cochran-Manzel Haenszel (CMH) method, stratified 
 
. 
• Loss to follow-up/drop-out rate of approximately 
. 
 
 
 
 
 
 
Note: “enrolled” means a participant's agreement to participate in a clinical study following 
completion of the informed consent process, 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 
Population 
Description 
Randomized/ Intent to Treat 
(ITT) Set 
The ITT set will consist of all participants who were randomized into one of 
the study arms. 
For analyses based on this population, participants will be grouped 
according to the study intervention assigned at randomization. 
Evaluable/Per Protocol (PP) Set 
The PP set will consist of all ITT participants who fulfill all 
inclusion/exclusion criteria and have no significant protocol deviations that 
are expected to have a significant impact on the assessment of efficacy, 
including lack of compliance with study treatment, missing data, and having 
taken any prohibited medication. All analyses using the PPS will group 
participants according to the study intervention they received. 
Safety Set 
All participants randomly assigned to study intervention and who receive at 
least one dose of study intervention. Participants will be analyzed according 
to the intervention they received. 
Pharmacokinetic/Biomarker/ADA 
Evaluable Set 
The PK/biomarker evaluable data set will consist of all participants in the 
ITT Population with at least one post-Day 1 evaluable sample. The ADA 
evaluable data set will consist of all participants in the ITT Population with 
at least one evaluable sample. 
 
9.4 
Statistical Analyses 
The study SAP will fully specify the statistical methodology and reporting for all aspects of the 
planned analyses. The SAP will be finalized prior to database lock and executed thereafter, and it 
will include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints.  
Additional unplanned analyses may be required after all planned analyses have been completed, 
and additional analyses of key efficacy metrics may be performed between the primary and final 
analyses to support marketing applications for various jurisdictions. Any unplanned analyses will 
be clearly identified in the clinical study report. 
Results of the Week 48 analyses may be reported to the public and to health authorities before 
the completion 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 100 analyses are completed.  
9.4.1 
General Considerations 
At Day 1, participants will be randomized 1:1 into one of two treatment arms: 
• Group A: KSI-301 5 mg via intravitreal injection at  
Day 1, Week 8, Week 20, and every 24 weeks thereafter through Week 92.  
• Group B: Sham injections at  
Day 1, Week 8, Week 20, and every 24 weeks thereafter through Week 92. 


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This study is divided into two efficacy and safety assessment periods (Section 1.2), as follows: 
• Year 1: from baseline to Week 48; and 
• Year 2: from Week 52 to Week 100. 
At Week 48, the primary endpoint (the proportion of eyes improving ≥2 steps on DRSS from 
baseline at Week 48) will be compared between the KSI-301 5 mg treatment group and sham 
using the CMH method 
 
 Missing values post-baseline will be imputed using 
the last observation carried forward (LOCF) procedure. If a participant develops a sight-
threatening complication due to DR (DME, PDR, or ASNV), a color fundus photograph for 
DRSS grading will be obtained and submitted to the reading center at the time of diagnosis, and 
DRSS scores collected subsequently will be censored. Baseline will be carried forward if all 
post-baseline observations are missing. 
Analysis of data for the first period of the study will be performed when all participants have 
either completed the Week 48 visit or have discontinued from the study, all data have been 
entered into the database, cleaned, and verified as appropriate, and the database has been locked. 
Likewise, analysis of data for the second period of the study will be performed when all 
participants have either completed the Week 100 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 alternative 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) 
Unless stated otherwise, all analyses described will be performed on the ITT population.  
The primary endpoint is defined as the proportion of eyes improving ≥2 steps on DRSS from 
baseline at Week 48. The primary assessment of efficacy will be based on a pairwise comparison 
of the proportion of eyes improving ≥2 steps on DRSS between the KSI-301 5 mg treatment 
group compared with the sham group. 
Analysis of the primary endpoint data will be performed when the following occur: 
• all participants have either completed the Week 48 visit or have discontinued from 
the study prior to the Week 48 visit, whichever comes later; and 
• all data up to and including the Week 48 visit have been entered into the database, 
and have been cleaned, and verified as appropriate; and  


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• the database for the primary analysis locked. 
If there are no imbalances on important prognostic factors at baseline, the CMH method and 
corresponding confidence intervals will be used for evaluation of treatment differences. An alpha 
level of 0.05 will be used for hypothesis testing and confidence intervals will be (1-α) or 95% 
confidence intervals.  
Full details on the statistical testing procedures along with supplementary and sensitivity 
analyses will be provided in the SAP. 
9.4.3 
Secondary Endpoint(s) 
Key secondary endpoints will be assessed at Week 48, Week 96 and, if applicable, over time:  
• Proportion of eyes developing any of the following from baseline: 
- 
PDR or ASNV; 
- 
Vitreous hemorrhage or tractional retinal detachment believe to be due to PDR; or 
- 
DME. 
• Proportion of eyes developing PDR or ASNV from baseline. 
• Proportion of eyes developing vitreous hemorrhage or tractional retinal detachment, believed 
to be due to PDR, from baseline. 
• Proportion of eyes developing DME from baseline. 
• Proportion of eyes with a ≥2-step improvement from baseline on DRSS from baseline. 
• Proportion of eyes with a ≥2-step worsening from baseline on DRSS from baseline. 
• Proportion of eyes with a ≥3-step improvement from baseline on DRSS from baseline. 
• Proportion of eyes with a ≥3-step worsening from baseline on DRSS from baseline. 
• Time to first development of either PDR, ASNV, or DME. 
• Time to first development of PDR or ASNV. 
• Time to first development of vitreous hemorrhage or tractional retinal detachment, believed 
to be due to PDR. 
• Time to first development of DME. 
• Time to first development of a ≥2-step improvement on the DRSS. 
• Time to first development of a ≥2-step worsening on the DRSS. 
• Time to first development of a ≥3-step improvement on the DRSS. 
• Time to first development of a ≥3-step worsening on the DRSS. 
• Mean change in SD-OCT central subfield thickness (CST) from baseline. 


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• Mean change in BCVA from baseline. 
• Proportion of eyes who lose ≥5, ≥10, or ≥15 letters in BCVA from baseline. 
• Proportion of eyes with a BCVA score of ≥69 letters (20/40 approximate Snellen equivalent). 
• Proportion of eyes with prolonged vision loss. 
• Incidence of ocular and systemic adverse events up to Week 48 and Week 100. 
• Systemic anti-drug antibody status over time (in the ADA-evaluable population). 
• Systemic pharmacokinetic profile (i.e. systemic exposure) over time (in the PK-evaluable 
population). 
Unless stated otherwise, all analyses described will be performed on the ITT population.  
For continuous key secondary efficacy endpoints, the between-group changes from baseline in 
BCVA at each time point will be computed and compared using t-tests, generalized linear 
models, mixed effects models, or other approaches as documented in the SAP. In addition, 
comparisons between groups determined by fixed effects of interest will be performed by 
analysis of covariance (ANCOVA) in which the dependent variable is the continuous variable of 
interest at the specified time point, the covariate is the baseline value of the variable of interest. 
Treatment group as well as stratification variables will be entered as fixed effects. Results of the 
t-test will be reported as 95% confidence intervals for within group mean change from baseline. 
Results of ANCOVA will be reported as 95% confidence interval for the difference in adjusted 
means for the grouping determined by the fixed effects of interest. 
Time to first development of DME, PDR, and/or ASNV, in combination and individually will be 
analyzed using Kaplan-Meier estimates. Log-rank tests will be performed, comparing the two 
treatment groups, as well as 95% confidence intervals for the time to the first ‘complication’ for 
the difference of each treatment group. Time to first development of a ≥2-step and ≥3-step 
worsening on the DRSS will be analyzed similarly. 
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.  
Similar to the analysis of the primary endpoint, missing efficacy values post-baseline will be 
imputed using the last observation carried forward (LOCF) procedure. If a participant develops a 
vision-threatening complication due to DR (DME, PDR, and/or ASNV), DRSS scores collected 
after the development of the vision-threatening complication will be censored. Baseline will be 
carried forward if all post-baseline observations are missing.  
Additional endpoints and full details on statistical considerations will be provided in the SAP. 


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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 population 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. 
9.4.6 
Pharmacokinetic and Biomarker Analysis 
PK analyses will be outlined in the PK Analysis Plan; potential exploratory biomarker analyses 
will be outlined in a biomarker analysis plan. 
9.5 
Interim Analysis 
There is no interim analysis planned for this study.  


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


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10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This study will be conducted in OECD (Organisation for Economic Co-operation and 
Development) countries 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 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 
and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
If required by the IRB/EC, participants must be re-consented to the most current version of the 
ICF(s) during their participation in the study. 
A copy of the ICF(s) must be provided to the participant. 
Participants who are re-screened are required to sign a new ICF if it has been more than 30 days 
from the initial consent date. 
The ICF will contain a separate section that addresses the use of remaining samples for optional 
exploratory research. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to participate 
in this optional research will not provide this separate signature. 
10.1.4 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.  
Participant medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. All laboratory specimens, evaluation forms, 
reports, and other records will be identified in a manner designed to maintain participant 
confidentiality. All records will be kept in a secure storage area with limited access. Upon the 


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participant’s permission, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
All information provided by the Sponsor, verbally and in writing, is confidential. The 
Investigator agrees not to disclose any such information without prior written permission of the 
Sponsor. This document may be disclosed to study personnel under the Principal Investigator’s 
supervision and to the IRB/IEC 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 electronic CRF 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., Contract 
Research Organizations). 
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 the following: 
• 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; and 
- 
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 
multicenter 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 6 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 6:  
Protocol KS301P106: Required Safety Laboratory Tests 
Laboratory 
Tests 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
White blood cell (WBC) 
count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) 
Count 
Hemoglobin 
Glycated hemoglobin 
(HbA1c) 
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 
 
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 (to verify non-childbearing potential as required in 
Section 10.6.1) and estradiol (only if determined to be additionally required by the 
Investigator to verify non-childbearing potential). 
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  
 
 
 


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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/associated procedures) 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 
• 
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 one of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 


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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. 
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. 
 
 
 


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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. 
 
 
 
 
 
 
 
 
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. 
• 
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. 
 
 
 
 
 
 
 
 


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10.4 
Appendix 4: Grading Scale for Assessment of Anterior Chamber Flare or Cells, 
Vitreous Cells or Haze.  
10.4.1 
Grading Scales for Anterior Chamber Cells or Flare 
The SUN Working Group Grading Scale for Anterior Chamber Cells 
Grade 
Cells in Field1 
0 
<1 
0.5+ 
1-5 
1+ 
6-15 
2+ 
16-25 
3+ 
26-50 
4+ 
>50 
Abbreviations: SUN = Standardization of uveitis nomenclature. 
14 
Field size is a 1 mm by 1 mm slit beam. 
Source: (Jabs 2005) 
 
The SUN Working Group Grading Scale for Anterior Chamber Flare 
Grade 
Cells in Field1 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens details clear) 
3+ 
Marked (iris and lens details hazy) 
4+ 
Intense (fibrin or plastic aqueous)  
Abbreviations: SUN = Standardization of uveitis nomenclature. 
15 
Field size is a 1 mm by 1 mm slit beam. 
Source: (Jabs 2005) 
 
 


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


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


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


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during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
10.6.2 
Contraception Guidance 
Participants who use oral contraceptives, 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 
 
  
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 post-ovulation 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 
 
 
 Men must refrain from donating sperm during this 
same time period. 
10.6.3 
Collection of Pregnancy Information 
Female participants who become pregnant: 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a participant's pregnancy.  


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• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or 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 
The amendment history for Protocol KS301P106 is provided in Table 7. 
Table 7: 
Protocol KS301P106: Amendment History 
Version 
Version Date 
Description 
1.1 
17 May 2021 
Changes from Version 1.0 include the following: 
• 
Minor editorial and administrative revisions. 
1.0 
20 April 2021 
Original protocol; used for pre-submission activities. This version was not 
submitted to any health authorities or IRBs/ECs, nor was it implemented. 
 


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11.0 
REFERENCES 
1. 
Aiello, L. P., Avery, R. L., Arrigg, P. G., et al. (1994). Vascular endothelial growth factor 
in ocular fluid of patients with diabetic retinopathy and other retinal disorders. New 
England Journal of Medicine, 331(22), 1480-1487. 
2. 
Bressler, S. B., Liu, D., Glassman, A. R., et al. (2017). Change in diabetic retinopathy 
through 2 years: secondary analysis of a randomized clinical trial comparing aflibercept, 
bevacizumab, and ranibizumab. JAMA ophthalmology, 135(6), 558-568. 
3. 
Campochiaro, P. A., Clark, W. L., Boyer, D. S., et al. (2015). Intravitreal Aflibercept for 
Macular Edema Following Branch Retinal Vein Occlusion. Ophthalmology, 122(3), 538-
544. 
4. 
Cheloni, R., Gandolfi, S. A., Signorelli, C., et al. (2019). Global prevalence of diabetic 
retinopathy: protocol for a systematic review and meta-analysis. BMJ open, 9(3), 
e022188. 
5. 
Durham, J. T., & Herman, I. M. (2011). Microvascular modifications in diabetic 
retinopathy. Current diabetes reports, 11(4), 253-264. 
6. 
Flaxel, C. J., Adelman, R. A., Bailey, S. T., et al. (2020). Diabetic Retinopathy Preferred 
Practice Pattern®. Ophthalmology, 127(1), P66-P145. 
7. 
Foster, C. S., & Vitale, A. T. (2013). Diagnosis & Treatment of Uveitis: JP Medical Ltd. 
8. 
Gragoudas, E. S., Adamis, A. P., Cunningham Jr, E. T., et al. (2004). Pegaptanib for 
neovascular age-related macular degeneration. New England Journal of Medicine, 
351(27), 2805-2816. 
9. 
ACCORD Study Group and ACCORD Eye Study Group (2010). Effects of medical 
therapies on retinopathy progression in type 2 diabetes. New England Journal of 
Medicine, 363(3), 233-244. 
10. 
Holz, F. G., Sadda, S. R., Busbee, B., et al. (2018). Efficacy and safety of lampalizumab 
for geographic atrophy due to age-related macular degeneration: Chroma and Spectri 
phase 3 randomized clinical trials. JAMA ophthalmology, 136(6), 666-677. 
11. 
Homayouni, M. (2009). Vascular endothelial growth factors and their inhibitors in ocular 
neovascular disorders. Journal of ophthalmic & vision research, 4(2), 105. 
12. 
Ip, M. S., Domalpally, A., Hopkins, J. J., et al. (2012). Long-term effects of ranibizumab 
on diabetic retinopathy severity and progression. Archives of Ophthalmology, 130(9), 
1145-1152. 
13. 
Jabs, D., Nussenblatt, R., & Rosenbaum, J. (2005). Standardization of uveitis 
nomenclature for reporting clinical data. Results of the First International Workshop. 
American Journal of Ophthalmology, 140(3), 509-516. 


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14. 
Leasher, J. L., Bourne, R. R., Flaxman, S. R., et al. (2016). Global estimates on the 
number of people blind or visually impaired by diabetic retinopathy: a meta-analysis 
from 1990 to 2010. Diabetes Care, 39(9), 1643-1649. 
15. 
Lim, J. I. (2020). Intravitreal Aflibercept Injection for Nonproliferative Diabetic 
Retinopathy: Year 2 Results from the PANORAMA Study. Investigative ophthalmology 
& visual science, 61(7), 1381-1381. 
16. 
Lu, M., Amano, S., Miyamoto, K., et al. (1999). Insulin-induced vascular endothelial 
growth factor expression in retina. Investigative ophthalmology & visual science, 40(13), 
3281-3286. 
17. 
Nussenblatt, R. B., Palestine, A. G., Chan, C.-C., et al. (1985). Standardization of Vitreal 
inflammatory Activity in Intermediate and Posterior Uveitis. Ophthalmology, 92(4), 467-
471. 
18. 
Stewart, M. W. (2017). A review of ranibizumab for the treatment of diabetic 
retinopathy. Ophthalmology and therapy, 6(1), 33-47. 
19. 
Tolentino, M. J., Mcleod, D. S., Taomoto, M., et al. (2002). Pathologic features of 
vascular endothelial growth factor-induced retinopathy in the nonhuman primate. 
American Journal of Ophthalmology, 133(3), 373-385. 
20. 
Wells, J. A., Glassman, A., Ayala, A., et al. (2015). Diabetic Retinopathy Clinical 
Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular 
edema. N Engl J Med, 372(13), 1193-1203. 
21. 
Wells, J. A., Glassman, A. R., Ayala, A. R., et al. (2016). Aflibercept, bevacizumab, or 
ranibizumab for diabetic macular edema: two-year results from a comparative 
effectiveness randomized clinical trial. Ophthalmology, 123(6), 1351-1359. 
22. 
Wu, L., Fernandez-Loaiza, P., Sauma, J., et al. (2013). Classification of diabetic 
retinopathy and diabetic macular edema. World journal of diabetes, 4(6), 290. 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
A Prospective, Randomized, Double-masked, Sham-controlled, Multi-center, Two-arm, 
Phase 3 Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 in Participants 
with Moderately Severe to Severe Non-proliferative Diabetic Retinopathy (NPDR) 
(GLOW) 
 
 
Sponsor: 
Kodiak Sciences Inc. 
1200 Page Mill Road 
Palo Alto, CA 94304 USA 
Sponsor Contact  
& Medical Monitor: 
  
 
Kodiak Sciences Inc. 
IND Number: 
136167 
Protocol Number: 
KS301P106 
EUDRACT Number: 
2020-001064-29 
Test Product: 
KSI-301 (tarcocimab tedromer) 
Statistical Analysis Plan Version: 
1.0 
Statistical Analysis Plan Version 
Date:  
September 26, 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, Sham-
controlled, Multi-center, Two-arm, Phase 3 Study to 
Evaluate the Efficacy and Safety of Intravitreal KSI-
301 in Participants with Moderately Severe to Severe 
Non-proliferative Diabetic Retinopathy (NPDR) 
(GLOW) 
Protocol Code: 
KS301P106 
Statistical Analysis Plan Version: 
1.0 
Statistical Analysis Plan Version 
Date: 
September 26, 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 
Study Interventions ................................................................................................11 
3.3 
Randomization and Stratification ..........................................................................11 
4.0 
TYPES OF PLANNED ANALYSES .............................................................................11 
4.1 
Data Monitoring Committee Analyses ..................................................................11 
4.2 
Interim Analyses ....................................................................................................12 
4.3 
Primary Analysis (Week 48) ..................................................................................12 
4.3.1 
Timing of the Primary Analysis ............................................................12 
4.3.2 
Data to be Analyzed for the Primary Analysis Period ..........................12 
5.0 
GENERAL STATISTICAL METHODS ......................................................................12 
5.1 
Reporting Conventions ..........................................................................................13 
5.2 
Standard Calculations ............................................................................................14 
5.3 
Study Definitions and Derived Variables ..............................................................15 
5.4 
Analysis Sets ..........................................................................................................15 
5.4.1 
Full Analysis Set ...................................................................................15 
5.4.2 
Safety Analysis Set ...............................................................................15 
5.5 
Examination of Subgroups .....................................................................................15 
5.6 
Multiple Comparisons/Multiplicity .......................................................................16 
5.7 
Multicenter Studies ................................................................................................16 
5.8 
Analysis Visit .........................................................................................................16 
6.0 
BASELINE ANALYSES .................................................................................................17 
6.1 
Disposition of Subjects ..........................................................................................17 
6.2 
Demographic and Other Baseline Characteristics .................................................18 
6.2.1 
Demographics and Baseline Characteristics .........................................18 


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6.2.2 
Ocular and Other Medical History ........................................................19 
6.2.3 
Prior and Concomitant Medications/Procedures ...................................19 
6.3 
Protocol Deviations ................................................................................................20 
7.0 
EFFICACY ANALYSES ................................................................................................21 
7.1 
Primary Efficacy Analysis .....................................................................................21 
7.1.1 
Primary Estimand ..................................................................................21 
7.1.2 
Analysis of Primary Efficacy Endpoint ................................................22 
7.1.3 
Sensitivity Analysis 1 ............................................................................23 
7.1.4 
Sensitivity Analysis 2 ............................................................................23 
7.2 
Key Secondary Efficacy Analyses .........................................................................23 
7.2.1 
Proportion of Eyes Developing Any Sight-Threatening 
Complication .........................................................................................24 
7.2.2 
Proportion of Eyes Improving ≥3 Steps on DRSS ................................24 
7.2.3 
Proportion of Eyes Developing PDR ....................................................24 
7.3 
Additional Secondary Efficacy Analyses ..............................................................25 
7.4 
Exploratory Analyses .............................................................................................28 
7.5 
Subgroup Analyses ................................................................................................29 
8.0 
SAFETY EVALUATION ................................................................................................29 
8.1 
Exposure to Study Medication ...............................................................................29 
8.2 
Adverse Events ......................................................................................................29 
8.3 
Deaths, Serious Adverse Events, and other Significant Adverse Events ..............31 
8.4 
Pregnancies ............................................................................................................31 
8.5 
Intraocular Pressure ...............................................................................................31 
8.6 
Clinical Laboratory Evaluations ............................................................................31 
8.7 
Vital Signs ..............................................................................................................32 
9.0 
SAMPLE SIZE CONSIDERATIONS ...........................................................................32 
10.0 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ..................................................................................................32 
11.0 
REFERENCES .................................................................................................................34 
12.0 
APPENDICES ..................................................................................................................34 
Appendix 1: Schedules of Activities..................................................................................35 
SoA-A 35 
SoA-B 37 
Appendix 2: Sample SAS Code .........................................................................................39 
Cochran–Mantel–Haenszel (CMH) Test Adjusting Randomization Strata ...........39 


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Kaplan-Meier Estimates and Log-rank Test ..........................................................39 
Mixed Model for Repeated Measures ....................................................................39 
Reference for Weighted Percentages Based on Weighted Average of 
Observed Estimates Across Strata Using CMH Weights .....................41 
 
LIST OF TABLES 
Table 1: Objectives and Endpoints ..................................................................................................9 
Table 2: Subgroups 
15 
Table 3: Windows for Unscheduled Visit ......................................................................................17 
Table 4: Additional Secondary Efficacy Endpoints and Analysis Methods ..................................26 
Table 5: Exploratory Efficacy Endpoints and Analysis Methods ..................................................28 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
APTC 
ASNV 
Alanine aminotransferase 
Antiplatelet Trialists Collaboration 1994 
Anterior segment neovascularization 
AST 
ATC 
Aspartate aminotransferase 
Anatomical Therapeutic Chemical 
ATE 
Arterial thromboembolic events 
BCVA 
BMI 
Best-corrected visual acuity 
Body mass index 
BP 
Blood pressure 
CMH 
Cochran-Mantel-Haenszel  
CNV 
Choroidal Neovascularization 
CSR 
Clinical Study Report 
CST 
Central Subfield Thickness 
DME 
DR 
DRSS 
Diabetic Macular Edema 
Diabetic retinopathy 
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 
ICE 
Intercurrent event 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug (application) 
IOI 
Intraocular inflammation 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT 
LOCF 
Interactive Response Technology 
Last observation carried forward 
LOQ 
Level of Quantification 
MAR 
Missing at Random 
MNAR 
Missing not at Random 
MedDRA 
The Medical Dictionary for Regulatory Activities 
MMRM 
NPDR 
Mixed Model for Repeated Measures 
Non proliferative diabetic retinopathy 


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Abbreviation 
Definition 
OCT 
PDR 
PRP 
PT 
Optical Coherence Tomography 
Proliferative Diabetic Retinopathy 
Panretinal photocoagulation 
Preferred term 
Q12W 
Every twelve weeks 
Q24W 
Every twenty-four weeks 
SAE 
Serious Adverse Event 
SAP 
SMQ 
SoA-A 
SoA-B 
SOC 
TEAE 
TESAE 
Statistical Analysis Plan 
Standardized MedDRA Queries 
Schedule of Activities-A 
Schedule of Activities-B 
System Organ Class 
Treatment-emergent adverse event 
Treatment-emergent serious adverse event 
ULN 
Upper Limits of Normal 
VA 
VRC 
Visual acuity 
Vienna Reading Center 
VEGF 
WHO 
Vascular Endothelial Growth Factor 
World Health Organization 
 
 
 


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1.0 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide a comprehensive and detailed 
description of the methods and presentation of data analyses for Study KS301P106 (Protocol 
Amendment 1.1, dated 17 May 2021), entitled A Prospective, Randomized, Double-masked, 
Sham-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate the Efficacy and Safety of 
Intravitreal KSI-301 in Participants with Moderately Severe to Severe Non-proliferative 
Diabetic Retinopathy (NPDR). This study is conducted in accordance with the protocol, 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.  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. 
 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
Table 1 lists the primary, key secondary and additional 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 superior to 
sham treatment, with respect to proportion of eyes 
improving ≥2 steps on Diabetic Retinopathy 
Severity Scale (DRSS) from baseline at Week 48. 
• The proportion of eyes improving ≥2 steps on DRSS from baseline at 
Week 48. 
Key Secondary  
To demonstrate that KSI-301 5 mg is superior to 
sham treatment, with respect to proportion of eyes 
with vision-threatening complications of diabetes, 
and proportion of eyes improving ≥3 steps on 
Diabetic Retinopathy Severity Scale (DRSS).  
 
• Proportion of eyes developing any of the following from baseline 
through Week 48:  
     - PDR or ASNV;  
     - Vitreous hemorrhage or tractional retinal detachment believed to be 
       due to PDR; or 
     - DME. 
 
• Proportion of eyes improving ≥3 steps on DRSS from baseline at Week 
48. 
 
• Proportion of eyes developing PDR through Week 48. 
Additional Secondary 
To evaluate the efficacy of KSI-301 5 mg 
compared to sham treatment. 
• Proportion of eyes developing PDR or ASNV from baseline through 
Week 48.  
 
• Proportion of eyes developing vitreous hemorrhage or tractional retinal 
detachment, believed to be due to PDR, from baseline through Week 48.  
 
• Proportion of eyes developing DME from baseline through Week 48.  
 
• Proportion of eyes with a ≥2-step worsening from baseline on DRSS 
from baseline at Week 48.  
 
• Proportion of eyes with a ≥3-step worsening from baseline on DRSS 
from baseline at Week 48. 
 
• Time to first development of PDR, ASNV, or DME through Week 48. 
 
• Time to first development of PDR or ASNV through Week 48. 
 
• Time to first development of vitreous hemorrhage or tractional retinal 
detachment, believed to be due to PDR through Week 48.  
 
• Time to first development of DME through Week 48.  
 
• Mean change in SD-OCT central subfield thickness (CST) from 
baseline by visit over time. 
 
• Mean change in BCVA from baseline by visit over time.  
 
• Proportion of eyes who lose ≥5, ≥10, or ≥15 letters in BCVA from 
baseline by visit over time.  
 


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Objectives 
Corresponding Endpoints 
To evaluate the safety and tolerability of KSI-301 
5 mg compared to sham treatment. 
Incidence of ocular and systemic adverse events up to Week 48. 
 
3.0 
INVESTIGATIONAL PLAN 
3.1 
Study Design  
This is a Phase 3, prospective, randomized, double-masked, two-arm, multi-center study 
evaluating the efficacy and safety of repeated dosing of KSI-301 5 mg administered by 
intravitreal injections in participants with treatment-naïve NPDR.  A brief description of the 
study design and study treatment regimen appears below; additional details can be found in the 
study protocol. 
The schedules of activities are provided in Appendix 1 (SoA-A and SoA-B).   
The overall duration of the study was intended to be approximately 2 years (100 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 100; thus, 
the maximum participant duration is approximately 103 weeks and includes a screening period 
of up to 21 days (Days -21 to -1), a treatment period of approximately 92 weeks (Day 1 to Week 
92), a safety/efficacy assessment at Week 96, and a final follow-up for safety assessments at 
Week 100 
. The primary endpoint will be assessed at Week 48; 
although secondary endpoints for efficacy were intended to be assessed at Weeks 48 and 96, the 
Sponsor has made a decision as of late July 2023 to discontinue further development of KSI-301, 
and therefore data collected after Week 48 will be incomplete. 
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 and/or worse DR severity at Screening will be 
selected as the Study Eye. If both eyes are eligible and have the same BCVA and/or DR severity 
or one eye has worse BCVA and the fellow eye has worse DR, 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 via intravitreal injection at Day 1, Week 8, Week 20, and every 24 
weeks thereafter through Week 92. 
• Group B: Sham injection at Day 1, Week 8, Week 20, and every 24 weeks thereafter through 
Week 92. 
Participants who develop sight-threatening complications of DR in the Study Eye will be treated 
with open-label KSI-301 5 mg, irrespective of the treatment group that they were originally 
randomized into (KSI-301 5 mg or sham). The original treatment group randomization will 
remain masked throughout the study. Sight-threatening complications of DR in the Study Eye 
include DME, PDR, and/or ASNV. The diagnosis of DME, PDR, and/or ASNV will be made by 
the masked Investigator. See protocol Table 3 for definition of each sight-threatening 
complication. 


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At the visit that a sight-threatening complication of DR is diagnosed (i.e., the “Dx Visit”), 
treatment with open-label KSI-301 5 mg will be initiated. Starting at the Dx Visit, participants 
will no longer follow the study visits and assessments outlined in SoA-A of Appendix 1, nor 
receive further masked treatments. Instead, they will follow the study visits and assessments 
outlined in SoA-B of Appendix 1, which is specific to the participants who develop DME, PDR, 
and/or ASNV. 
Treatment of DME, PDR, and/or ASNV will consist of the following: 
• Two doses of KSI-301 5 mg, given four weeks apart (+/- 7 days), followed by KSI-301 5 mg 
once every 12 weeks (Q12W; +/-14 days). Thus, the first dose shall occur during the study 
visit in which DME, PDR, and/or ASNV was diagnosed, and the second dose shall occur 4 
weeks (+/- 7 days) later. Thereafter, subsequent doses shall occur Q12W (+/-14 days). 
More frequent visits and more frequent treatments with KSI-301 5 mg and/or pan-retinal 
photocoagulation (PRP) are at the discretion of the Investigator if the sight-threatening 
complication(s) are still present. Treatment with KSI-301 5 mg may not be given more often than 
monthly (28 ± 7 days). 
 
3.2 
Study Interventions 
Study interventions are summarized in the Protocol Table 4. 
 
3.3 
Randomization and Stratification 
Patients who meet all inclusion criteria and none of the exclusion criteria will be centrally 
assigned to a randomized study intervention using an Interactive Response Technology (IRT) 
system. Randomization will be stratified by 
 
  
 
4.0 
TYPES OF PLANNED ANALYSES 
4.1 
Data Monitoring Committee Analyses  
An Independent Data Monitoring Committee (IDMC) will monitor study conduct and safety on 
an ongoing basis.  Members of the IDMC will be external to the Sponsor and will follow a 
charter that outlines the IDMC membership and responsibilities, the timing of IDMC meetings, 
the content of the analysis report for the IDMC meetings, and the communication with the 
Sponsor. The IDMC can recommend changes to the conduct of the study based on the evaluated 
data and may recommend stopping the study early for safety reasons only as detailed in the 
charter.  
 


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4.2 
Interim Analyses 
No interim analyses were planned or performed.  
 
4.3 
Primary Analysis (Week 48) 
4.3.1 
Timing of the Primary Analysis 
The primary analysis will be performed when all patients have either completed the Week 48 
visit or have discontinued from the study prior to the Week 48 visit, whichever comes later, the 
data up to and including the Week 48 visit have been entered, cleaned and verified as 
appropriate, and the database for the primary analysis is frozen.  
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 48) will be included in the primary analyses: 
o Demographics and Baseline Ocular and Non-Ocular Characteristics  
o Subject Disposition at Week 48 
o Efficacy Analyses 
o Sensitivity and Subgroup Analyses for the Primary Efficacy Endpoint  
o Secondary Efficacy Analyses up to Week 48 
o Interventions 
o Study Treatment and Exposure 
o Safety  
o AEs (including SAEs and AESIs), by Event Type (i.e., Study Eye, Fellow-Eye, 
Non-Ocular) 
o Clinical laboratory 
o Vital signs 
o 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. 
 


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5.1 
Reporting Conventions 
Tables and figures will be summarized by treatment group. Tables summarizing demographics 
and other baseline characteristics will also include a column for all patients combined. In 
general, all data collected and any derived data will be presented in subject data listings, for all 
randomized patients. Listings will be ordered by treatment group, subject number, and 
assessment or event date. The treatment groups will be displayed in the same order as the 
summary tables. The treatment groups presented in listings will be based on the planned 
assignment, unless otherwise noted. 
In general, continuous variables will be summarized to indicate the study population sample size 
(N), number of subjects with available data (n), mean, SD, median, 25th (Q1) and 75th (Q3) 
quartiles, minimum, and maximum values.  Categorical variables will be summarized by the 
population size (N), number of subjects with available data (n), number of subjects in each 
category, and the percentage of subjects in each category. Unless otherwise noted, the 
denominator to determine the percentage of subjects in each category will be based on the 
number of subjects with available data. The denominator for percentages for incidence data (such 
as adverse events) will be based on the number of subjects in the analysis population “at risk.” 
Select ordinal data may be summarized using both descriptive statistics and counts and 
percentages of subjects in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Percentages that round down to 0 or 
up to 100% will be displayed as “<0.1%” and “>99.9%”, respectively. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form e.g., on the electronic case report form 
(eCRF) and are outlined as follows: 
o The mean and median will be rounded to an additional decimal place than the 
precision of the variable of summarization;  
o Measures of variability (e.g., SD, SE) will be rounded to two additional decimal 
places than the precision of the variable of summarization; and 
o Minimum and maximum values will be presented using the same precision as the 
variable of summarization. 
Other statistics (e.g., CIs) will be presented using the same general rules outlined above or 
assessed for the most appropriate presentation based on the underlying data. 
Unless noted otherwise, statistical significance testing will be two-sided and performed using 
α=0.05. Confidence intervals (CIs) will be calculated at the 95% level, reflecting a type I error 
rate of 0.05. P-values will be reported for all statistical tests, rounded to four decimal places. P-
values less than 0.0001 will be displayed as “<0.0001”; p-values greater than 0.9999 will be 
displayed as “>0.9999”.  
 


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5.2 
Standard Calculations 
Where appropriate, the calculated study day will be presented with the assessment or event date 
on subject data listings. Study day will be determined as: 
o The assessment/event date minus the date of first dose of study drug, if the 
assessment/event date is prior to the date of first dose; and 
o The assessment/event date minus the date of first dose of study drug, plus one, if 
the assessment/event date is on or after the date of first dose. 
Start and stop dates will be imputed when partial dates are present as needed, to determine 
treatment emergent events and concomitant medications/procedures. No imputations will be 
done for a completely missing start/stop date or for subjects who did not receive study treatment. 
Start dates with a missing day but with month and year available will be imputed such that: 
o If the provided month and year match the month and year for that subject’s first 
dose date, then the Day 1 date will be used. 
o In all other cases the 1st of the month will be used with the provided month and 
year. 
Start dates with a missing day and month but with available year will be imputed such that: 
o If the provided year matches the year for that subject’s first dose date, then the 
first dose date will be used. 
o In all other cases the 1st of January will be used with the provided year. 
Stop dates will be imputed as follows: 
o Missing day with a provided year and month will use the last day of the month. 
o Missing day and month with provided year will use December 31. 
If the imputed stop date is greater than the last study date for the subject, then the imputed date 
will be replaced with the last available event date for the subject in the study. 
Other variables requiring calculations will be derived using the following formulas: 
o Days: A duration between two dates expressed in days will be calculated using 
the following conventions: 
- 
Later date – earlier date + 1. 
o Months: A duration expressed in months will be calculated by dividing the 
duration in days by (365.25 /12). 
o Years: A duration expressed in years will be calculated by dividing the duration in 
days by 365.25. 
 


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5.3 
Study Definitions and Derived Variables 
Unless otherwise specified, the duration of Week 48 analysis is defined as Study Day 1 until 
Week 48, as it is meant to be inclusive both of study treatments leading to the primary efficacy 
outcome at Week 48 and of safety assessments in that period.  
Baseline values are defined as the most recent values prior to the first dose of study treatment.  
 
5.4 
Analysis Sets 
The efficacy and safety analyses that are specified in Sections 7.0 and 8.0 will utilize the analysis 
sets as specified in this section.   
 
5.4.1 
Full Analysis Set  
The Full Analysis Set (FAS) includes all patients who received any study treatment (KSI-301 or 
sham) and have gradable DRSS value at baseline. 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  
The Safety Analysis Set includes all patients who received any study treatment (KSI-301 or 
sham). Patients will be analyzed according to the study treatment they actually received.  
 
5.5 
Examination of Subgroups 
The primary efficacy endpoints will be summarized in the following subgroups of baseline 
characteristics. 
Table 2: Subgroups 
 
Characteristics 
Subgroup 
Age 
18-64 years of age 
65-74 years of age 
75-84 years of age 
≥ 85 years of age 
< 65 years of age 
≥ 65 years of age 
< 75 years of age 
≥ 75 years of age 
Sex 
Female 
Male 
Ethnicity 
Hispanic or Latino 
Not Hispanic or Latino 
DRSS* 
Level ≤47 


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Characteristics 
Subgroup 
Level ≥53 
HbA1c level* 
≤8.5% 
>8.5% 
Investigational site* 
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 
Aphakic 
Pseudophakic 
Phakic  
 
 
 
Other subgroup analyses may be explored. 
 
5.6 
Multiple Comparisons/Multiplicity 
 
 
 
 
 
 
5.7 
Multicenter Studies 
This is a multicenter, international study. Efficacy data collected from all study sites will be 
pooled for data analysis. The effect of study site on the efficacy analysis results may be explored, 
as needed.  
 
5.8 
Analysis Visit  
For efficacy analyses, unscheduled or early termination visits will be assigned a study day and 
then mapped to the appropriate analysis window as detailed in Table 3. In the event where more 
than one record falls in the same analysis window, the following rules will be used in sequential 
order to determine the record that will be used for data analysis: 


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o If there is a scheduled visit (including scheduled visits from SoA-B in Appendix 
1) in the analysis window, then the scheduled visit’s data will be used. 
o If there is no scheduled visit in the analysis visit window, the record (including 
records from SoA-B in Appendix 1) that is the closest to the scheduled study day 
at a given visit will be used. 
o 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 8 
56 
2 
98 
Week 20  
140 
99 
182 
Week 32 
224 
183 
266 
Week 44 
308 
267 
322 
Week 48 
336 
323 
364 
Week 56  
392 
365 
434 
Week 68 
476 
435 
518 
Week 80 
560 
519 
602 
Week 92 
644 
603 
658 
Week 96 
672 
659 
686 
Note: Nominal visits for efficacy assessments are at Day 1, Week 8, every 12 weeks from Week 20 – Week 44, Week 48, 
every 12 weeks from Week 56 – Week 92, and Week 96. 
 
6.0 
BASELINE ANALYSES 
6.1 
Disposition of Subjects 
Subject disposition will be summarized by treatment group and overall.  The following will be 
summarized: 


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o The number of patients screened 
o The number of patients randomized 
o The number of patients (%) in the Full Analysis set  
o The number (%) in the Safety Analysis set   
o The number (%) completing the study treatment  
o The number (%) discontinuing the study treatment and the reasons for 
discontinuation of study treatment by Week 48 and by end of study 
o The number (%) discontinuing the study and the reasons for discontinuation of 
study by Week 48 and by end 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: 
• BCVA: continuous  
• Intraocular pressure in the study eye, continuous and by category (≤21, 22-29, >29 
mmHg) 
• Lens status (aphakic, pseudophakic, phakic) 


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Ocular Imaging, OCT:  
• Center Subfield Thickness (CST) 
 
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: 
o Prior medications are those taken prior to the start of the first dose of study 
treatment 
o Concomitant medications are those with  
o a start date on or before the last dose of study treatment and  
o a stop date after the first dose of study treatment or are ongoing at the end of the 
study 
 
See Section 5.2 for imputation of missing or partial dates.   
 
Prior and concomitant medications will be separately summarized by ocular and non-ocular for 
the Safety Analysis Set as follows: 
• The number and percentage of patients with at least one prior / concomitant medication / 
procedure will be presented. 
• The number and percentage of patients with at least one prior / concomitant medication / 
procedure within each ATC Level 4, and preferred name will be presented.   


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• Patients reporting use of more than one medication / procedure at each level of 
summarization (any medication received, ATC class, and generic drug name) will be 
counted only once. 
• The summary will be sorted using numerical counts by descending order of Therapeutic 
Subgroup, then descending order of preferred name in the KSI-301 group.  Where groups 
or terms tie will be sorted by descending order in the sham group, then alphabetically. 
 
Prior medications and concomitant medications (ocular and non-ocular) will be listed separately 
for the Safety Analysis Set.  
The following will be summarized and listed for concomitant medications and procedures: 
o Ocular (study eye and fellow eye separately) and non-ocular concomitant 
medications that were initiated before start of treatment.  
o Ocular (study eye and fellow eye separately) and non-ocular concomitant 
medications that were initiated after the start of treatment. 
o Medications prescribed after study treatment discontinuation for patients who 
remain in the study will be listed separately.  
o Concomitant ocular procedures (study eye and fellow eye separately) 
administered while patients were on study treatment will be summarized and 
listed.  
o Concomitant study eye procedures administered after study treatment 
discontinuation for patients who remain in the study will be listed separately. 
 
In the listings the relative start and stop day of prior / concomitant medication (ocular and non-
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): 
o From start of the study to the data freeze for the Week 48 Primary 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 major protocol deviations will also be summarized by site. Protocol 
deviations will be listed in a subject data listing.  


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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 moderately 
severe or severe NPDR. 
The most relevant aspects of the study eligibility criteria for defining this population include the 
following key inclusion and exclusion criteria: 
Inclusion criteria 
1. Participants with moderately severe to severe NPDR in the Study Eye (DRSS levels 47 and 
53 as determined by the reading center based on color fundus photographs), who have not 
previously received intravitreal medications for DR or DME, and in whom pan-retinal 
photocoagulation (PRP) can be safely deferred for at least 6 months per the Investigator.  
2. BCVA ETDRS letter score in the Study Eye of ≥69 letters (approximate Snellen equivalent 
of 20/40 or better) in the Study Eye at Screening and confirmed at Day 1. 
Exclusion criteria 
1. Presence of center-involved DME in the study eye, defined for this purpose as CST of 
≥320 microns on SD-OCT (Heidelberg Spectralis or equivalent value on other OCT 
instruments).  
2. Prior PRP in the Study Eye. 
3. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional 
retinal detachment in the Study Eye. 
 
7.1.1.2 
Primary Efficacy Endpoint/Variable of Interest 
The primary efficacy variable of interest is DRSS, a categorical variable measured at each study 
visit by the reading center based on color fundus photographs.  The primary efficacy endpoint is 
the proportion of eyes improving ≥2 steps on DRSS from baseline at Week 48.  
 
7.1.1.3 
Hypotheses and Test 
The following hypothesis for the primary efficacy variable regarding the proportion of patients 
with a ≥2-step improvement from baseline in DRSS score in the study eye at week 48 will be 
conducted to demonstrate the superiority of the KSI-301 group compared to the sham group. 


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The hypothesis to be tested is:  
H0: pk - ps = 0 
vs 
H1: pk - ps ≠ 0 
Where pk and ps are the true proportions of patients with a ≥2-step improvement from baseline in 
DRSS score in the study eye at week 48 in the KSI-301 and sham groups, respectively. The 
primary efficacy endpoint will be tested at the significance level of α = 0.0498. 
 
7.1.1.4 
Intercurrent Events 
The following intercurrent events (ICEs) may impact the assessment of the primary efficacy 
endpoint: 
1. Treatment misallocation at 1 or more study visits. 
2. Use of prohibited medications in the study eye. 
3. Development of sight-threatening complication(s) and initiation of open-label KSI-301 5 
mg treatment, panretinal photocoagulation, or other treatment for DME, ASNV, and/or 
PDR. 
4. Premature discontinuation from study treatment due to study eye adverse events or due to 
lack of efficacy. 
5. Premature discontinuation from study treatment due to events unrelated to study 
treatment such as malignancies, systemic infections, trauma, or other systemic adverse 
events that are not treatment-related, including discontinuations due to COVID-19. 
Intercurrent events will be classified by the Sponsor prior to treatment code unmasking to 
prevent potential bias. Intercurrent events and the time to intercurrent events will be tabulated 
and listed 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 have gradable DRSS value at baseline.  
The statistical analysis will be performed using the Cochran-Mantel-Haenszel (CMH) method, 
 
A ‘Hypothetical’ strategy will be applied for all intercurrent events where measurements after 
occurrence of intercurrent event will be imputed using the last observation carry forward (LOCF) 
procedure. For patients who develop sight-threatening complication(s) and have non-gradable 
value at their first visit where open-label treatment is administered, the non-gradable values will 
be imputed as no change from baseline. For patients without intercurrent event, missing and non-
gradable values at Week 48 will be imputed using LOCF. Baseline will be carried forward if all 
post-baseline observations are missing or non-gradable. Non-gradable values are observations 
where DRSS level is 90.  


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The p-value will be reported for comparison between KSI-301 and sham groups. In addition, the 
weighted percentages difference between the KSI-301 and sham (i.e., KSI-301 – sham) and 
95.02% 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 CMH method as described for the primary efficacy analysis will be used for all sensitivity 
analyses below. 
7.1.3 
Sensitivity Analysis 1  
In this analysis, a ‘Composite’ strategy will be applied for all intercurrent events where patients 
with occurrence of intercurrent event by Week 48 will be considered as non-responders. For 
patients without intercurrent event, missing and non-gradable values at Week 48 will be imputed 
using LOCF, and baseline will be carried forward if all post-baseline observations are missing or 
non-gradable as in the primary analysis. 
 
7.1.4 
Sensitivity Analysis 2  
This analysis will follow the same ‘Hypothetical’ strategy for handling of intercurrent events and 
analysis method as the primary analysis, with the exception that patients with the following 
significant protocol deviations will be excluded from the analysis: deviation from key 
inclusion/exclusion criteria as defined in Section 7.1.1.1, treatment misallocation at 1 or more 
study visits by Week 48, and use of prohibited medications in study eye at any point by Week 
48.   
 
7.1.5 
Sensitivity Analysis 3 
This analysis will follow the same ‘Hypothetical’ strategy for handling of intercurrent events and 
analysis method as the primary analysis, with the exception that patients with baseline DRSS 
level outside of levels 47 and 53 will be excluded from the analysis. 
 
7.2 
Key Secondary Efficacy Analyses 
The key secondary endpoints will be estimated based on the FAS, defined as in Section 5.4.1.   
Together with the primary endpoint and the key secondary endpoints, this family of tests will be 
conducted hierarchically to maintain a familywise Type I error rate of 4.98%.  Each test within 
this family will be conducted at the 4.98% level if the preceding test was significant at the 4.98% 
level. 
 


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7.2.1 
Proportion of Eyes Developing Any Sight-Threatening 
Complication 
The first key secondary efficacy endpoint of interest is the proportion of eyes developing any of 
the following from baseline through Week 48: 
- PDR or ASNV;  
- Vitreous hemorrhage or tractional retinal detachment believed to be due to PDR; or  
- DME.  
The development of the above sight-threatening complications is tabulated from adverse events, 
procedures and eCRFs.  
The following intercurrent events will be evaluated in this key secondary endpoint: 
- Treatment misallocation at 1 or more study visits. 
- Use of prohibited medications in the study eye. 
-Premature discontinuation from study treatment due to study eye adverse events or due 
to lack of efficacy. 
-Premature discontinuation from study treatment due to events unrelated to study 
treatment such as malignancies, systemic infections, trauma, or other systemic adverse 
events that are not treatment-related, including discontinuations due to COVID-19. 
The same analysis method from the primary efficacy endpoint will be used for the first key 
secondary efficacy endpoint. See Section 7.1.2. 
 
7.2.2 
Proportion of Eyes Improving ≥3 Steps on DRSS 
The second key secondary efficacy endpoint of interest is proportion of eyes improving ≥3 steps 
on DRSS from baseline at Week 48. The same intercurrent events and analysis method from the 
primary efficacy endpoint will be used. See Sections 7.1.1.4 and 7.1.2. 
A sensitivity analysis for this key secondary efficacy endpoint will be performed where patients 
with baseline DRSS level outside of levels 47 and 53 will be excluded from the analysis. 
 
7.2.3 
Proportion of Eyes Developing PDR 
The third key secondary efficacy endpoint of interest is the proportion of eyes developing PDR 
from baseline through Week 48. The same intercurrent events and analysis method from the first 
key secondary efficacy endpoint will be used. See Section 7.2.1. 
 


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7.3 
Additional Secondary Efficacy Analyses 
As specified in Section 4.0, the Primary Analysis will evaluate the efficacy of KSI-301 compared 
to sham from Day 1 up to Week 48.   
Table 4 lists the additional secondary efficacy endpoints, efficacy variable derivations, reporting 
statistics and analysis methods for the Primary Analysis and until the end of study. 
Binary secondary efficacy endpoints will utilize the Cochran-Mantel-Haenszel (CMH) method 
stratified by the randomization stratification factors (i.e. baseline DRSS level and HbA1c level).  
Time to event endpoints will be analyzed using the Kaplan-Meier estimates. The number of 
observations censored will be provided for each treatment group. The 50th percentile of 
Kaplan-Meier estimates will be used to estimate the median time to first event in each treatment 
group.  A 2-sided 95% CI will be provided for the estimates. A log-rank test stratified by the 
randomization stratification factors (i.e. baseline DRSS level and HbA1c level) will be 
performed to compare the survival distributions between the treatments. The hazard ratio and its 
95% CI will be reported from a Cox regression model stratified by the same randomization 
stratification factors with treatment as the covariate. For patients not known to have had an event 
at the time of the analysis data cutoff, the time will be censored at the date of the last scheduled 
study visit at analysis data cutoff. 
Continuous endpoints (e.g. mean change from baseline in BCVA) will utilize a Mixed Model for 
Repeated Measures (MMRM).  The model assumes missing at random (MAR). The model will 
include the change from baseline value as the dependent variable; categorical covariates of 
treatment group, protocol scheduled visit, treatment × visit interaction, and the randomization 
stratification factors (i.e. baseline DRSS level and HbA1c level) as well as continuous covariate 
of baseline BCVA, as fixed effects; and then subject as a random effect.  Within-subject 
correlations will be assumed to follow an unstructured covariance matrix. If the model assuming 
an unstructured covariance matrix does not converge, a heterogeneous compound symmetry 
structure or an AR(1) covariance structure will be fitted. 
For all additional secondary efficacy endpoints, data after the occurrence of intercurrent event 
will be censored, and missing and non-gradable data will not be imputed. Only observed, 
gradable and non-censored data will be used for analysis. 


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Table 4: Additional Secondary Efficacy Endpoints and Analysis Methods 
Additional Secondary 
Efficacy Endpoint 
Variable Derivation  
[Source] 
Summary Statistics  
[Analysis Set] 
Method of Analysis 
Proportion of eyes developing 
PDR or ASNV from baseline 
through Week 48  
Binary endpoint: 
patients developed PDR or ASNV (yes/no) 
[Sight-threatening Complication/EDC] 
Difference in proportions (%) 
and 95% CI at each time point  
[FAS], up to Week 48 
 
CMH method adjusting for 
randomization stratification factors 
(similar to Section 7.1.2) 
Proportion of eyes developing 
vitreous hemorrhage or 
tractional retinal detachment, 
believed to be due to PDR, 
from baseline through Week 48  
Binary endpoint: 
patients developed vitreous hemorrhage or 
tractional retinal detachment believed to be due 
to PDR (yes/no) 
[Sight-threatening Complication/EDC/Review 
of AEs] 
Proportion of eyes developing 
DME from baseline through 
Week 48  
Binary endpoint: 
patients developed DME (yes/no) 
[Sight-threatening Complication/EDC] 
Proportion of eyes with a ≥2-
step or a ≥3-step worsening on 
DRSS from baseline at Week 
48 
Binary endpoints:  
patients with a ≥2-step worsening in DRSS 
(yes/no); patients with a ≥3-step worsening in 
DRSS (yes/no); 
 
Proportion of eyes who lose ≥5, 
≥10, or ≥15 letters in BCVA 
from baseline by visit 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] 
Time to first development of 
PDR, ASNV, or DME through 
Week 48 
Time to event endpoint: 
Time from first treatment to development of 
PDR, ASNV, or DME (in months) 
[Sight-threatening Complication/EDC] 
 
 
 
 
 
 


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Additional Secondary 
Efficacy Endpoint 
Variable Derivation  
[Source] 
Summary Statistics  
[Analysis Set] 
Method of Analysis 
Time to first development of 
PDR or ASNV through Week 
48  
Time to event endpoint: 
Time from first treatment to development of 
PDR or ASNV (in months) 
[Sight-threatening Complication/EDC] 
 
 
 
 
 
 
 
Hazard ratio and 95% CI 
[FAS], up to Week 48 
 
 
 
 
 
 
 
 
Kaplan-Meier and Cox regression model 
stratified by randomization stratification 
factors (Section 7.3) 
Time to first development of 
vitreous hemorrhage or 
tractional retinal detachment, 
believed to be due to PDR 
through Week 48  
Time to event endpoint: 
Time from first treatment to development of 
vitreous hemorrhage or tractional retinal 
detachment, believed to be due to PDR (in 
months) 
[Sight-threatening Complication/EDC/Review 
of AEs] 
Time to first development of 
DME through Week 48  
Time to event endpoint: 
Time from first treatment to development of 
DME (in months) 
[Sight-threatening Complication/EDC] 
Mean change in SD-OCT 
central subfield thickness 
(CST) from baseline by visit 
over time 
Continuous Endpoint: 
Change from baseline to each time point  
  
 
LS Mean difference in change 
from baseline to each time 
point and 95% CI 
[FAS], up to Week 48 
[FAS], up to end of study 
MMRM (Section 7.3) adjusting for 
baseline CST, with time, treatment, and 
time*treatment interaction and 
randomization stratification as factors 
Unstructured covariance matrix 
Mean change in BCVA from 
baseline by visit over time 
Continuous Endpoint: 
Change from baseline to each time point  
[Visual Acuity Score/EDC] 
LS Mean difference in change 
from baseline to each time 
point and 95% CI 
[FAS], up to Week 48 
[FAS], up to end of study 
MMRM (Section 7.3) adjusting for 
baseline BCVA, with time, treatment, 
and time*treatment interaction and 
randomization stratification as factors 
Unstructured covariance matrix 
 
 


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7.4 
Exploratory Analyses 
Analysis of the following exploratory endpoints may be undertaken as deemed appropriate. 
Table 5: Exploratory Efficacy Endpoints and Analysis Methods 
Exploratory Efficacy 
Endpoint 
Variable Derivation  
[Source] 
Summary Statistics  
[Analysis Set] 
Method of Analysis 
Mean change in SD-OCT 
central subfield thickness 
(CST) from baseline until 
switch to Schedule B by visit 
over time 
Continuous Endpoint: 
Change from baseline to each time point  
  
 
Mean/Median 
[Patients who switch to 
Schedule B], until switch to 
Schedule B 
Descriptive 
Mean change in BCVA from 
baseline until switch to 
Schedule B by visit over time 
Continuous Endpoint: 
Change from baseline to each time point  
[Visual Acuity Score/EDC] 
Mean/Median 
[Patients who switch to 
Schedule B], until switch to 
Schedule B 
Descriptive 
Mean change in SD-OCT 
central subfield thickness 
(CST) from time moved to 
Schedule B until end of follow-
up by visit over time 
Continuous Endpoint: 
Change from time moved to Schedule B to 
each time point  
[EDC]  
 
Mean/Median 
[Patients who switch to 
Schedule B], until end of 
follow-up 
Descriptive 
Mean change in BCVA from 
time moved to Schedule B until 
end of follow-up by visit over 
time 
Continuous Endpoint: 
Change from time moved to Schedule B to 
each time point  
[Visual Acuity Score/EDC]  
 
Mean/Median 
[Patients who switch to 
Schedule B], until end of 
follow-up 
Descriptive 


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7.5 
Subgroup Analyses 
For each of the subgroups listed in Table 2, the primary efficacy endpoint (i.e., proportion of 
eyes improving ≥2 steps on DRSS from baseline at Week 48) will be analyzed using the CMH 
method 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 stratified CMH test. 
A forest plot will be provided to present the treatment effect of these subgroups. 
 
8.0 
SAFETY EVALUATION 
Safety analyses will be performed for the Safety Analysis Set. In the Primary Analysis, safety 
data from Day 1 to Week 48 will be summarized by treatment group.  
 
8.1 
Exposure to Study Medication 
Study eye exposure to study medication will be summarized (open-label KSI-301 5mg treatment 
will not be included here).  Summaries will include: 
o Mean (SD) and median number of injections, and number of patients receiving ≥1 
injection, 1, 2, 3, 4, 5, etc. of KSI-301 or sham injections from Day 1 to Week 48 
and from Day 1 to the end of study.   
o Duration of study drug exposure (mean [SD] and median, in months) for subjects 
receiving KSI-301 5 mg or sham. 
o Listings will include treatment (KSI-301, sham) and date of injection. 
For patients who develop sight-threatening complication(s), exposure to open-label KSI-301 
5mg treatment will be summarized and listed similarly as above. 
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. A 
separate listing will list patients who receive open-label KSI-301 5mg treatment with the same 
variables. 
 
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. 
Treatment emergent AEs (TEAEs) are events with onset date on or after the initiation of study 
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VEGF in study eye on or after last dose date, or start date of open-label KSI-301 treatment due to 
development of sight-threatening complication, whichever occurs first.  
If the severity score of an adverse event is missing, the severity score will be imputed as severe. 
If the relatedness of an adverse event is missing, the adverse event will be considered related. 
At each level of summarization (e.g., any AE, system organ class, and preferred term), subjects 
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 48 for the 
following: 
o Ocular TEAEs and treatment-emergent serious AEs (TESAEs) (study eye and 
fellow eye separately) 
o Non-ocular TEAEs and TESAEs  
o Ocular TEAEs leading to study treatment discontinuation (study eye and fellow 
eye separately) 
o Ocular TEAEs by severity (study eye and fellow eye separately) 
o Non-ocular TEAEs by severity  
o Related ocular TEAEs (study eye and fellow eye separately) by severity 
o Related non-ocular TEAEs by severity  
o Intraocular inflammation TEAEs and TESAEs not associated with infection, 
autoimmunity, drug toxicity, or traumatic etiologies (study and fellow eye 
separately).   
o IOI TEAEs and TESAEs associated with infection (study and fellow eye 
separately).   
o IOI TEAEs and TESAEs associated with autoimmune, drug toxicity, or trauma 
(study and fellow eye separately).   
o Arteriothromboembolic (ATE) Adverse Events. ATEs will be tabulated as those 
events meeting the Anti-Platelet Trialists’ Collaboration criteria (i.e., nonfatal 


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myocardial infarction, nonfatal stroke, and vascular death, including deaths of 
unknown cause) 
o Adverse events of special interest [AESI] (study eye, fellow eye and non-ocular 
combined), as defined in the protocol Section 8.3.6 
o Injection procedure related TEAEs and TESAEs in study eye 
o Non-serious TEAEs and TESAEs (study eye, fellow eye and non-ocular 
combined) 
All AEs and serious AEs will be presented separately in data listings by treatment group, subject 
ID, and event date.  Adverse events from patients who remain in the study after study treatment 
discontinuation will be listed.  
For subjects who receive open-label KSI-301 5mg treatment due to development of sight-
threatening complications, ocular TEAEs and TESAEs for study eye starting from when subjects 
switch to open-label KSI-301 treatment will be summarized until the end of study. All AEs 
(study eye, fellow eye and non-ocular) will be presented in a data listing by subject ID, and event 
date. 
 
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.  
 
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 
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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 at Week 48 and Week 96 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 
A sample size of approximately 240 participants with a target enrollment of approximately 120 
participants in each treatment group (1:1 ratio) was calculated using the following assumptions: 
• Anticipated 
of participants with a ≥2-step improvement from baseline 
in DRSS score in the KSI-301 5 mg Q24W group versus 
 in the sham 
group. 
• Statistical power of ≥90%. 
• Overall Type I error rate of 0.05. 
• The statistical method used to compare the proportion with a ≥2-step 
improvement from baseline in DRSS score for the KSI-301 treatment group at 
Week 48 compared with sham will be the Cochran-Manzel Haenszel (CMH) 
method,
 
 
• Lost to follow-up/dropout rate of approximately
 
 
10.0 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES 
The Week 100 analyses will not be performed per protocol, since the study was discontinued 
early by the Sponsor.  


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In this SAP, the Sponsor has defined the primary estimand, analysis populations, and strategies 
for addressing intercurrent events, missing data, and a set of sensitivity analyses for the primary 
efficacy outcome.  Where relevant, these definitions take precedence over those defined in the 
study protocol. 
 


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11.0 
REFERENCES 
US Food and Drug Administration Guidance Document - E9(R1) Statistical Principles for 
Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials (May 2021). 
Available at https://www.fda.gov/media/148473/download.  
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.  
 
12.0 
APPENDICES 
Appendix 1: Schedules of Activities (SoA-A and SoA-B) 
Appendix 2: Sample SAS Code 
 


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Appendix 1: Schedules of Activities 
 
SoA-A   
The following schedule of activities, SoA-A, shall be followed for all visits unless a participant 
is diagnosed with sight-threatening complication(s) of DR in their Study Eye. Upon diagnosis of 
sight-threatening complication(s) of DR in their Study Eye, participants shall then follow SoA-B 
instead of SoA-A. 
 


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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 SAEs caused by a 
protocol-mandated assessment should be reported. After initiation of study intervention (Day 1), all AEs will be 
reported until the final study visit or the ET visit if applicable. See protocol section 8.3.1.  
3. Height and weight will be recorded at the screening visit only. 
4. Clinical laboratory test as described in protocol Appendix 2 and Table 5. 
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 48 and Week 96, and only in the 
Study Eye at all other timepoints. 
7. Perform BCVA before any other ophthalmic assessments and prior to dilation. 
8. Method used to measure IOP must remain consistent throughout study.  
9. It is mandatory that the same model of device is used for the entire duration of the study. 
10. Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional 
details are provided in protocol Section 7.1. 
11. Post injection assessments include vision check for counting fingers and tonometry. The post-injection 
assessments should be performed by unmasked assessors. 
12. Week 100 is a final safety assessment that will be done via telephone call for all participants, except in 
WOCBP, in which case a site visit is required for the safety assessment that includes a pregnancy test. 
 
 
 


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SoA-B   
The following schedule of activities, SoA-B, shall be followed once a participant is diagnosed 
with sight-threatening complication(s) of DR in their Study Eye. Upon diagnosis of sight-
threatening complication(s) of DR in their Study Eye, participants will be treated with open-label 
KSI-301 5 mg, regardless of the treatment group that they were originally randomized into, and 
SoA-B will be followed instead of SoA-A. Additional details are provided in protocol Section 
4.1.3.1.  
  


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 Abbreviations: ADA = anti-drug antibody; AE = adverse event; ASNV = anterior segment neovascularization; 
BCVA = best corrected visual acuity; Dx Visit = the first study visit where a sight-threatening complication of 
diabetic retinopathy (DME, PDR, and/or ASNV) is diagnosed; DME = diabetic macular edema; ET=Early 
Termination; ETDRS = early treatment diabetic retinopathy study; IOP = intraocular pressure; NAB = neutralizing 
antibody; PK = pharmacokinetics; PDR = proliferative diabetic retinopathy; Q12W = once every 12 weeks; SAE = 
serious adverse event; SD-OCT = spectral domain optical coherence tomography; WOCBP = women of 
childbearing potential.  
1 Dx Visit is the first study visit where a sight-threatening complication of diabetic retinopathy (DME, PDR, and/or 
ASNV, as defined in protocol Section 4.1.3.1) is diagnosed in the Study Eye; open-label KSI-301 treatment will be 
initiated at this visit.  
2 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.  
3 Height and weight will be recorded at the screening visit only.  
4 Clinical laboratory tests as described in protocol Appendix 2 and Table 5.  
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 Week 96, and only in the Study Eye at all other 
timepoints.  
7 Perform BCVA before any other ophthalmic assessments and prior to dilation.  
8 Method used to measure IOP must remain consistent throughout study.  
9 It is mandatory that the same model of device is used for the entire duration of the study.  
10 Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional 
details are provided in protocol Section 7.1.  
11 Post injection assessments include vision check for counting fingers and tonometry. The post-injection 
assessments should be performed by unmasked assessors.  
12 Continue visits Q12W until Week 92.  
13 Week 100 is a final safety assessment that will be done via telephone call for all participants, except in WOCBP, 
in which case a site visit is required for the safety assessment that includes a pregnancy test. 
 


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Appendix 2: Sample SAS Code 
 
 
 
       
  
 
 
 
  
 
 
 
 
 
 
 
 
   
 
   
 
       
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 


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