Clinical trial NCT04049266
Conditions: Wet Macular Degeneration
Keywords: AMD Wet AMD choroidal neovascularization secondary to age-related macular degeneration KSI-301 Aflibercept Vascular endothelial growth factor VEGF Anti-VEGF Antibody biopolymer conjugate Macular Degeneration Wet Macular Degeneration Retinal Degeneration Retinal Diseases Eye Diseases Vision Disorders Vision, low Kodiak
Sponsor: Kodiak Sciences Inc
Start date: 2019-10-08; Completion date: 2022-04-26
Enrollment: 559 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, durability, and pharmacokinetics of KSI-301 administered at 12, 16 and 20 weeks intervals as specified in the protocol, compared with aflibercept once every 8 weeks (Q8W), in participants with treatment-naïve neovascular (wet) age-related macular degeneration (nAMD).

Detailed description:
This study is divided into a 3-week screening period, a 92-week treatment period, and a final 4-week follow-up period. At baseline patients will be randomized 1:1 into two treatment arms: KSI-301 5 mg and aflibercept 2 mg.

Arms: arm 1: Drug: KSI-301 5 mg. KSI-301 5 mg will be administered by intravitreal injection into the study eye at 12, 16, and 20 weeks intervals as specified in the study protocol.

Drug: Sham Procedure. The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking. arm 2: Drug: Aflibercept 2 mg. Aflibercept 2 mg will be administered by intravitreal injection into the study eye once every 4 weeks for 3 consecutive months, followed by once every 8 weeks.

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

Protocol documents:
Prot_000.pdf: 
Official title:  
A Phase 2b/3, Prospective, Randomized, Double-masked,   
 
 
Active Comparator-controlled, Multi-center Study to Investigate the Efficacy 
and Safety of Repeated Intravitreal Administration of KSI-301 in Subjects with 
Neovascular (Wet) Age-related Macular Degeneration (DAZZLE) 
NCT Number:  
NCT04049266
Document Date: 
Protocol Version 3.0, 02 June 2021 




CONFIDENTIAL 
Protocol KSI-CL-102 Version 3.0 
 
 
KSI-301 – Kodiak Sciences Inc. 
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Protocol Approval – Sponsor Signatory 
 
Study Title: 
A Phase 2b/3, Prospective, Randomized, Double-masked, Active 
Comparator-controlled, Multi-center Study to Investigate the Efficacy and 
Safety of Repeated Intravitreal Administration of KSI-301 in Subjects 
with Neovascular (Wet) Age-related Macular Degeneration (DAZZLE) 
Protocol Number: 
KSI-CL-102 Version 3.0 
Protocol Date: 
02 June 2021 
 
Protocol accepted and approved by: 
 
Kodiak Sciences Inc. 
2631 Hanover Street 
Palo Alto, CA 94304 
 
 
 
 
Signature 
 
Date 
 
 
 


CONFIDENTIAL 
Protocol KSI-CL-102 Version 3.0 
 
 
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Principal Investigator Signature  
 
Study Title: 
A Phase 2b/3, Prospective, Randomized, Double-masked, Active 
Comparator-controlled, Multi-center Study to Investigate the Efficacy and 
Safety of Repeated Intravitreal Administration of KSI-301 in Subjects 
with Neovascular (Wet) Age-related Macular Degeneration (DAZZLE) 
Protocol Number: 
KSI-CL-102 Version 3.0 
Protocol Date: 
02 June 2021 
 
I have read the protocol described above. I agree to conduct the study as described in the protocol. I also 
agree to conduct this study in compliance with Good Clinical Practice (GCP) and all applicable national 
and local laws and regulations, as well as with the requirements of the appropriate Institutional Review 
Board or independent Ethics Committee (IRB/IEC) and any other institutional requirements. These are 
stated in “Guidance for Good Clinical Practice” International Council for Harmonisation (ICH) guideline 
E6(R1) of Technical Requirements for Registration of Pharmaceuticals for Human Use, the Declaration 
of Helsinki, and any other applicable regulatory requirements. No changes will be made to the study 
protocol without prior written approval of the Sponsor and the IRB/IEC. 
 
Principal Investigator 
 
 
Print Name of Investigator 
 
 
 
 
Signature 
 
Date 
 
 
 


CONFIDENTIAL 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
PROTOCOL APPROVAL – SPONSOR SIGNATORY ...........................................................2 
PRINCIPAL INVESTIGATOR SIGNATURE ..........................................................................3 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES .........................................................................................................................7 
LIST OF FIGURES .......................................................................................................................7 
LIST OF ABBREVIATIONS .......................................................................................................8 
PROTOCOL SYNOPSIS ............................................................................................................11 
1.0 
INTRODUCTION............................................................................................................20 
1.1 
Study Rationale ......................................................................................................20 
1.1.1 
Research Hypothesis .............................................................................20 
1.2 
Background ............................................................................................................20 
1.2.1 
Wet Age-Related Macular Degeneration ..............................................20 
1.2.2 
Vascular Endothelial Growth Factor .....................................................21 
1.2.3 
Description of KSI-301 .........................................................................21 
1.2.4 
Dose Rationale ......................................................................................22 
1.3 
Benefit/Risk Assessment .......................................................................................23 
1.3.1 
Known Potential Benefits .....................................................................23 
1.3.2 
Known Potential Risks ..........................................................................23 
1.3.3 
Overall Benefit/Risk Conclusion ..........................................................26 
2.0 
STUDY OBJECTIVES ....................................................................................................26 
2.1 
Primary Objective ..................................................................................................26 
2.2 
Secondary Objectives.............................................................................................26 
3.0 
SUBJECT SELECTION .................................................................................................27 
3.1.1 
Inclusion Criteria ...................................................................................27 
3.1.2 
Exclusion Criteria..................................................................................28 
4.0 
INVESTIGATIONAL PLAN .........................................................................................30 
4.1 
Study Design ..........................................................................................................30 
4.2 
Screening Period ....................................................................................................31 
4.3 
Screening Failure ...................................................................................................31 
4.4 
Treatment Period ....................................................................................................31 
4.4.1 
Administration of Study Drug ...............................................................31 
4.5 
Missed Visits ..........................................................................................................38 
4.6 
Rescue Treatment...................................................................................................38 
4.6.1 
Masking and Unmasking ......................................................................38 


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4.7 
Treatment Compliance ...........................................................................................39 
4.8 
End of Treatment ...................................................................................................39 
4.8.1 
Reasons for Withdrawal/Discontinuation .............................................40 
4.8.2 
Treatment Interruption and/or Discontinuation due to Adverse 
Events or Concomitant Procedures .......................................................40 
4.8.3 
Handling of Study Treatment Discontinuation and Withdrawals .........41 
4.8.4 
Replacements ........................................................................................42 
4.9 
End of Study ..........................................................................................................42 
4.10 
Treatment After End of Study................................................................................42 
4.11 
Non-protocol-specified Treatments .......................................................................42 
4.11.1 
Concomitant Therapy ............................................................................42 
4.11.2 
Prohibited Therapy ................................................................................43 
5.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUG ................................................43 
5.1 
KSI-301 ..................................................................................................................43 
5.1.1 
Drug Description and Formulation .......................................................43 
5.1.2 
Drug Packaging and Labeling ...............................................................44 
5.1.3 
Drug Reconstitution and Handling........................................................44 
5.1.4 
Drug Storage .........................................................................................44 
5.2 
Aflibercept .............................................................................................................44 
5.3 
Sham Formulation ..................................................................................................44 
5.4 
Study Drug Accountability and Reconciliation .....................................................44 
6.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................45 
6.1 
Study Assessments .................................................................................................45 
6.1.1 
Medical History and Demographic Data...............................................45 
6.1.2 
Ophthalmic Exams ................................................................................46 
6.1.3 
Injection Procedure ...............................................................................46 
6.1.4 
Post-injection Assessments in the Study Eye .......................................47 
6.1.5 
Best Corrected Visual Acuity (BCVA) and Low Luminance BCVA...47 
6.1.6 
Fundus Photography (FP) .....................................................................47 
6.1.7 
Spectral Domain Optical Coherence Tomography (SD-OCT) .............47 
6.1.8 
Fluorescein Angiography (FA) .............................................................48 
6.1.9 
Disease Activity Assessments ...............................................................48 
6.1.10 
Vital Signs .............................................................................................48 
6.1.11 
Adverse Events......................................................................................48 
6.2 
Safety Monitoring Committee ...............................................................................58 
6.3 
Pregnancy ...............................................................................................................58 


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6.4 
Laboratory Analyses ..............................................................................................58 
6.4.1 
Abnormal Laboratory Values ................................................................59 
6.4.2 
Abnormal Liver Function Tests ............................................................60 
6.5 
Pharmacokinetic, Biomarker, and Immunogenicity Assessments .........................60 
7.0 
STATISTICAL AND ANALYTICAL PLAN ...............................................................60 
7.1 
Primary Efficacy Endpoint ....................................................................................61 
7.2 
Secondary Efficacy Endpoints ...............................................................................61 
7.3 
Sample Size Calculations .......................................................................................63 
7.4 
Analysis Sets ..........................................................................................................63 
7.5 
Statistical Analysis Methodology ..........................................................................64 
7.5.1 
Analysis of Primary Efficacy Endpoint ................................................64 
7.5.2 
Analysis of Key Secondary Efficacy Endpoints ...................................65 
7.5.3 
Analyses of Additional Secondary Efficacy Endpoints ........................65 
7.5.4 
Pharmacokinetic Analyses ....................................................................65 
7.5.5 
Safety Analyses .....................................................................................65 
7.5.6 
Interim Analyses ...................................................................................66 
8.0 
DATA QUALITY ASSURANCE ...................................................................................66 
8.1 
Data Management ..................................................................................................66 
9.0 
ETHICS ............................................................................................................................67 
9.1 
Independent Ethics Committee or Institutional Review Board .............................67 
9.2 
Ethical Conduct of the Study .................................................................................67 
9.3 
Subject Information and Consent...........................................................................68 
10.0 
INVESTIGATOR’S OBLIGATIONS ...........................................................................68 
10.1 
Study Monitoring Requirements ............................................................................68 
10.2 
Confidentiality .......................................................................................................69 
10.3 
Financial Disclosure and Obligations ....................................................................70 
10.4 
Study Conduct ........................................................................................................70 
10.5 
Adverse Events and Study Report Requirements ..................................................71 
10.6 
Investigator’s Final Report ....................................................................................71 
10.7 
Records Retention ..................................................................................................71 
10.8 
Publications ............................................................................................................72 
11.0 
STUDY MANAGEMENT ...............................................................................................72 
11.1 
Study Termination .................................................................................................72 
11.2 
Protocol Amendments ............................................................................................73 
11.3 
Final Report ...........................................................................................................73 
12.0 
APPENDICES ..................................................................................................................74 


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12.1 
Appendix 1: Unscheduled Safety Assessment Visits ............................................75 
12.2 
Appendix 2: Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreous Hemorrhage Density, and Vitreous Haze .....................................76 
12.2.1 
Grading Scales for Anterior Chamber Cells or Flare ............................76 
12.2.2 
Grading Scale for Vitreous Cells ..........................................................77 
12.2.3 
Grading Scale for Vitreous Haze ..........................................................77 
12.3 
Appendix 3: Protocol Amendment History ...........................................................78 
13.0 
REFERENCE LIST .........................................................................................................79 
 
LIST OF TABLES 
Table 1. 
Protocol KSI-CL-102: Schedule of Activities (SoA) – First Year ............16 
Table 2. 
Protocol KSI-CL-102: Schedule of Activities (SoA) – Second Year ........18 
Table 3.  
Protocol KSI-CL-102: Risk Assessment ...................................................24 
Table 4. 
Protocol KSI-CL-102: Year 1 Dosing Schedules in the KSI-301 and 
Aflibercept Treatment Groups ...................................................................36 
Table 5. 
Protocol KSI-CL-102: Year 2 Dosing Schedules in the KSI-301 and 
Aflibercept Treatment Groups ...................................................................37 
Table 6.  
Protocol KSI-CL-102: Study Treatment Interruption/Subject 
Discontinuation Criteria .............................................................................41 
Table 7: 
Protocol KSI-CL-102: Amendment History ..............................................78 
LIST OF FIGURES 
Figure 1. 
Protocol KSI-CL-102: Study Schematic ....................................................15 
 
 
 


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


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Abbreviation 
Definition 
GGT 
Gamma-glutamyl-transferase 
GLP 
Good laboratory practice 
IB 
Investigator’s Brochure  
ICF 
Informed consent form 
ICH 
International conference on harmonization  
ICMJE 
International committee of medical journal editors 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational medicinal product 
IND 
Investigational new drug (application) 
IOP 
Intraocular pressure 
IP 
Investigational product  
IRB 
Institutional review board 
IEC 
Independent or institutional ethics committee 
IRC 
Intraretinal cysts 
IRF 
Intraretinal fluid 
ITT 
Intent to treat 
IRT 
IUD 
Interactive Response Technology 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IVT 
Intravitreal 
LLBCVA 
Low luminance best corrected visual acuity 
LPLO 
Last subject last observation 
ME 
Macular edema 
MedDRA 
The medical dictionary for regulatory activities 
NAB 
Neutralizing antibody 
NOAEL 
No observed adverse effect level 
OCT 
Optical coherence tomography 
OU 
Both eyes 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
Q8W 
Every eight weeks 
Q12W 
Every twelve weeks 
Q16W 
Q20W 
Every sixteen weeks 
Every twenty weeks 
RPE 
Retinal pigment epithelium 
RVO 
Retinal vein occlusion  
SAE 
Serious adverse event 


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Abbreviation 
Definition 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction  
SAR-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD-OCT 
Spectral domain optical coherence tomography 
SDV 
Source data verification  
SE 
Study Eye 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SoA 
Schedule of activities 
SRF 
Subretinal fluid 
SUN 
Standardization of uveitis nomenclature 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAEs 
Treatment emergent adverse events 
ULN 
Upper limits of normal 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 
wAMD 
Wet (neovascular) age-related macular degeneration 
WBC 
White blood cell 
WHODrug 
World health organization drug dictionary 
WMA 
World medical association  
WOCBP 
Women of childbearing potential 


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PROTOCOL SYNOPSIS 
Protocol Number: 
KSI-CL-102 
Version: 
3.0 
IND Number: 
136167 
Eudra CT Number: 
2018-003428-35 
Title: 
A Phase 2b/3, Prospective, Randomized, Double-masked, Active Comparator-
controlled, Multi-center Study to Investigate the Efficacy and Safety of Repeated 
Intravitreal Administration of KSI-301 in Subjects with Neovascular (Wet) Age-
related Macular Degeneration (DAZZLE) 
Sponsor: 
Kodiak Sciences Inc 
2631 Hanover Street 
Palo Alto, CA 94304 USA 
Phase of Development: 
2b/3 
Study Rationale: 
KSI-301 is an antibody biopolymer conjugate that inhibits vascular endothelial 
growth factor (VEGF). It is designed to provide similar (non-inferior) 
improvements in visual acuity with an extended intraocular half-life and longer 
treatment intervals compared to aflibercept. 
Number of Sites/Facilities 
Enrolling Subjects:  
Approximately 110-125 sites in 10-15 countries globally. 
Test Product (Dosage and 
Route of Administration): 
KSI-301 5 mg 
 administered via intravitreal injection 
Comparator Product 
(Dosage and Route of 
Administration): 
Aflibercept 2 mg (50 µL) administered via intravitreal injection 
Non-Investigational 
Medicinal Products: 
Sham intravitreal injection procedure, to preserve masking.  
Study Objectives: 
Primary:  
To demonstrate that KSI-301 5 mg is non-inferior to aflibercept 2 mg with 
respect to mean change in best corrected visual acuity (BCVA) from Day 1 to 
Year 1. Year 1 is defined as the mean of the Week 48 and 52 measurements.  
Secondary:  
• 
To evaluate the efficacy of KSI-301 5 mg compared to aflibercept 2 mg 
from Day 1 to Week 96 by assessing visual and anatomical parameters. 
• 
To evaluate the proportion of subjects maintained on a Q12W, Q16W, 
or Q20W dosing regimen of KSI-301 over the duration of the first 52 
weeks. 
• 
To evaluate the safety and tolerability of KSI-301 5 mg compared to 
aflibercept 2 mg. 
• 
To assess the systemic pharmacokinetics and immunogenicity of 
KSI-301. 


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Study Population: 
Male and female subjects ≥ 50 years with treatment-naïve wet (neovascular) age-
related macular degeneration (wAMD). 
Number of Subjects 
(Planned): 
Approximately 550 subjects (275 per arm).  
Study Design: 
This is a prospective, randomized, double-masked, active comparator controlled, 
multi-center Phase 2b/3 study that will evaluate the efficacy and safety of 
KSI-301 compared with aflibercept in subjects with wAMD. 
• This study is divided into a 3-week screening period, a 92-week treatment 
period, and a final 4-week follow-up period (Figure 1, Study Schematic).  
First Year (Day 1 Visit through Week 52 Visit): 
At baseline subjects will be randomized 1:1 into two treatment arms: KSI-301 
5 mg and aflibercept 2 mg. All subjects will receive 3 monthly loading doses of 
their assigned treatment. Thereafter the dosing regimen of subjects in the KSI-
301 treatment arm will be based on Year 1 Disease Activity Assessments. The 
dosing regimen of subjects in the aflibercept treatment arm following the three 
initial injections will be fixed at Q8W. 
Second Year (Week 52 Visit through Week 96 Visit): 
The dosing regimen of subjects in the KSI-301 treatment arm will be based on 
Year 2 Disease Activity Assessments. 
 
 
 
Treatment assignment and dose frequency adjustments will be provided by the 
interactive response technology (IRT) system.  
Study Duration: 
Approximately 3 years 
Treatment Duration: 
92 weeks 
Participant Duration: 
Up to approximately 99 weeks. 
Efficacy Assessments: 
• 
Changes in BCVA using Early Treatment Diabetic Retinopathy Study 
(ETDRS) visual acuity testing; 
• 
Optical coherence tomography (OCT); and 
• 
Fluorescein angiography (FA) 
Efficacy evaluations will be conducted according to the Schedule of Activities 
(SoA) provided in Table 1 (Year 1) and Table 2 (Year 2). 
Systemic Pharmacokinetic 
or Biomarker Assessments: 
• 
Pharmacokinetic (PK): plasma concentration of study drug; 
• 
Biomarker: systemic biomarker levels may be evaluated for exploratory 
purposes; 
• 
Immunogenicity: detection of anti-drug antibodies (ADA) in subject plasma 
samples. Additional immunogenicity testing of samples may be performed 
to further characterize the ADA response for specificity and/or neutralizing 
antibodies (NAB); 


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Safety Assessments: 
• 
Incidence of adverse events (AEs), including serious AEs (SAEs) and AEs 
of special interest (AESIs); 
• 
Ophthalmic examination with slit-lamp biomicroscopy and indirect 
ophthalmoscopy; 
• 
Intraocular pressure measurement (IOP); and 
• 
BCVA by the ETDRS acuity test. 
Assessments performed in the event of an unscheduled safety visit are at the 
discretion of the Investigator. 
Key Ocular Eligibility 
Criteria: 
Key Ocular Inclusion Criteria:  
1. Active, treatment-naïve choroidal neovascularization (CNV) secondary to 
AMD, including subfoveal, juxtafoveal and extrafoveal lesions or retinal 
angiomatous proliferation (RAP) lesions with a CNV component that affect 
the central subfield as evidenced by FA or OCT in the Study Eye at 
Screening. 
2. The CNV area in the Study Eye must be at least 50% of total lesion size at 
Screening. 
3. A lesion area <30 mm2 (12 disc areas) of any CNV lesion subtype in the 
Study Eye. 
4. Intra and/or subretinal fluid and/or SHRM (subretinal hyperreflective 
material) affecting the central subfield of the Study Eye on OCT at 
Screening. 
5. BCVA ETDRS score between 80 and 25 letters (20/25 to 20/320 Snellen 
equivalent), inclusive, in the Study Eye at Screening and reconfirmed at Day 
1. 
6. Decrease in vision in the Study Eye determined by the Investigator to be 
primarily the result of wAMD. 
Only one eye per subject is eligible to participate in the study.  
Key Ocular Exclusion Criteria:  
1. BCVA of hand motion or worse in the non-Study Eye or non-physical 
presence of a non-Study Eye (i.e., monocular). 
2. Active or suspected ocular or periocular infection or inflammation in either 
eye at Day 1. 
3. CNV secondary to other causes in the Study Eye, including pathologic 
myopia, angioid streaks, prior trauma, ocular histoplasmosis, or others. 
4. Any history of macular pathology unrelated to AMD but affecting vision or 
contributing to subretinal or intraretinal fluid, such as central serous 
chorioretinopathy.  
5. Fibrosis or atrophy of >50% of the lesion size and/or involving the foveal 
center of the Study Eye at Screening. 
6. Subretinal blood affecting the foveal center of the Study Eye and/or more 
than 50% of the lesion size at Screening. 
7. Any approved or investigational treatment for neovascular AMD (other than 
oral vitamin supplements) in the Study Eye at any time. 


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8. Prior macular laser (e.g., thermal laser or photodynamic therapy laser) in the 
Study Eye.   
Statistical Methods: 
General Considerations: In general, continuous data will be summarized by 
descriptive statistics, including number of subjects (N), mean, standard deviation 
or standard error of the mean, median, maximum, and minimum. Categorical 
data will be summarized by frequency and percentage of subjects. The following 
assumptions were made to calculate the sample size of 550 subjects (275 per 
treatment group): 
• 
Overall Type I error rate of 0.025. Testing at the 0.025 level corresponds 
to setting 95% confidence intervals. 
• 
Statistical power of ≥90%. 
• 
Standard deviation of the distribution of change in visual acuity from 
baseline 
 (averaged over Weeks 48 and 52). 
• 
The maximum clinically acceptable true difference for KSI-301 to be 
considered non-inferior, or the “non-inferiority margin,” 
.  
• 
The anticipated true difference in mean change from baseline in BCVA 
between treatment groups is 0. That is, both treatment arms are expected 
to have the same efficacy. 
• 
The statistical test used to compare the two treatment groups at Week 52 
is an independent t-test on the mean change in visual acuity from 
baseline. 
• 
Lost to follow-up rate 
 
Efficacy: Unless stated otherwise, all analyses described will be performed on 
the ITT population. The primary endpoint is defined as the mean change in 
ETDRS BCVA from Day 1 to Year 1. The primary assessment of efficacy will 
be based on a non-inferiority comparison in mean change in BCVA between the 
two treatment groups. Confidence intervals will be 100(1-2 α) or 95% confidence 
intervals. If the null hypothesis of inferiority is rejected, testing for superiority 
will be performed.  
Safety: All safety data will be summarized for the Safety Population using 
descriptive statistics by treatment arm. 
Interim Analyses: 
 
 
 
. 
Independent Data 
Monitoring Committee 
(IDMC): 
An IDMC will monitor the study conduct and subject safety on an ongoing basis. 
Date of Protocol/ 
Amendment 
02 June 2021/Amendment 3.0 






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1 
Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in Section 4.8. 
2 
Ophthalmic assessments will be performed in both eyes at Screening, Week 52 and Week 96, and in the Study Eye only at all other timepoints. 
3 
Perform before any other ophthalmic assessments and prior to dilation. 
4 
Post-injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
5 
Blood draws for ADA, plasma PK, and biomarker samples are to be taken pre-injection.  
6 
Urine pregnancy test will be performed locally for women of childbearing potential, prior to fluorescein angiogram and study treatment (if applicable). If 
urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. Local urine testing will be standard for the protocol unless serum testing 
is required by local regulation or IRB/IEC. 
 
 




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Abbreviations: ADA = anti-drug antibody; AE = adverse event; BCVA = best corrected visual acuity; ET = early termination; ETDRS = early treatment diabetic 
retinopathy study; IRT = interactive response technology; PK = pharmacokinetics; SAE = serious adverse event; SD-OCT = spectral domain optical 
coherence tomography; WOCBP = women of childbearing potential. 
1 
Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in Section 4.8. 
2 
Ophthalmic assessments will be performed in both eyes at Screening, Week 52 and Week 96, and in the Study Eye only at all other timepoints. 
3 
Perform before any other ophthalmic assessments and prior to dilation. 
4 
Post injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
5 
Blood draws for ADA, plasma PK, and biomarker samples are to be taken pre-injection.  
6 
Urine pregnancy test will be performed locally for women of childbearing potential, prior to fluorescein angiogram and study treatment (if applicable). If 
urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. Local urine testing will be standard for the protocol unless serum testing 
is required by local regulation or IRB/IEC. 


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1.0 
INTRODUCTION 
1.1 
Study Rationale 
KSI-301 is an anti-VEGF biopharmaceutical with an extended ocular half-life. KSI-301 offers a 
potential for subjects to experience a longer interval between consecutive intravitreal injections. 
Furthermore, KSI-301 may improve real-world outcomes of anti-VEGF therapy which are 
currently restricted by both the high treatment burden and insufficient durability of existing anti-
VEGF agents. KSI-301 may offer a particularly important and clinically relevant benefit over 
existing therapies for patients with wAMD. 
1.1.1 
Research Hypothesis 
Treatment with KSI-301 will provide non-inferior mean change in BCVA with a less frequent 
dosing schedule than aflibercept in subjects with previously untreated wAMD. 
1.2 
Background 
1.2.1 
Wet Age-Related Macular Degeneration 
Age-related macular degeneration (AMD) is a common eye condition affecting people 50 years 
of age and older throughout the world. Population-based studies have shown that AMD accounts 
for 8.7% of all blindness worldwide and it is the most common cause of blindness in developed 
countries. As the world’s population continues to both grow and age, more individuals will be 
afflicted with AMD, and it is estimated that 196 million people will have AMD in the year 2020  
(Wong 2014). AMD is a progressive disease affecting the central portion of the retina, known as 
the macula, which is the region of the eye responsible for sharp, central vision and color 
perception. The likelihood of AMD progression and associated vision loss increases with age. 
Wet AMD (wAMD, also known as neovascular AMD) is an advanced form of AMD 
characterized by choroidal neovascularization and fluid leakage within and under the retina. Wet 
AMD is the leading cause of severe vision loss in people over the age of 50 in the United States 
and the European Union (EU), with a reported prevalence of approximately 1.25 million and an 
annual incidence of approximately 148,000 new cases each year in the United States 
(Wong 2014). The likelihood of disease progression increases with age, and both the prevalence 
and incidence of wAMD are projected to accelerate worldwide. It has additionally been observed 
that approximately 50% of patients presenting with wAMD in one eye will develop wAMD in 
the other eye within five years, leading to a substantial number of subjects requiring treatment in 
both eyes (Chew 2014). In many eyes with wAMD, the disease can progress quickly with rapid 
loss of central vision needed for activities such as reading and driving. Untreated or undertreated 
wAMD can result in subretinal scarring with irreversible photoreceptor damage and loss and can 
lead to permanent vision impairment or even blindness. 




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Thus, similar to other anti-VEGF biologics such as aflibercept and ranibizumab, intravitreal 
KSI-301 is expected to act as an anti-angiogenic and anti-permeability agent with clinical benefit 
in VEGF-A mediated disorders such as wAMD, but with improved ocular durability. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of KSI-301 is 
provided in the Investigator’s Brochure. 
1.2.4 
Dose Rationale 
1.2.4.1 
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 dose of 5 mg is approximately 
fold the equivalent molar 
dose of anti-VEGF binding capacity, at the time of injection, relative to 2 mg aflibercept (the 
marketed aflibercept dose for the treatment of wAMD). Given this and the improved ocular 
pharmacokinetics of KSI-301 relative to unconjugated antibodies or biologics, preclinical 
modeling suggests that the 5 mg dose of KSI-301 results in 
-fold the equivalent ocular 
concentration of aflibercept at 3 months after dosing. Because both the 2.5 mg (
 µL) and 5 mg 
(
 µL) doses under study in the ongoing Phase 1b study have been well-tolerated, the higher 
5 mg dose of KSI-301 is a desirable target dose for the treatment of wAMD subjects because it is 
expected to further extend the durability of the pharmacological anti-VEGF effect compared to 
aflibercept.  
The
 µL injection volume used to deliver a 5 mg dose has been well-tolerated in previous 
KSI-301 studies (additional information can be found in the IB) as well as in other studies for of 
 
As shown in the IB, there were no KSI-301 dose limiting toxicities up through the maximum 
feasible dose of 
 bilaterally dosed monthly for seven doses up to 40 weeks of 
observations and histopathological analysis for the recovery group. Thus, dosing at longer 
intervals (i.e., Q8W and Q12W) are supported with a greater safety margin. Based on the volume 
of the vitreous, the nonclinical NOAEL 
 safety margin for the 
starting to highest dose, respectively, for the Phase 1 study. 
This current Phase 2b/3 study is designed to test whether KSI-301 5 mg dosed Q12W to Q20 is 
non-inferior to aflibercept dosed Q8W. 
 
 
 
 
 
 
 


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1.2.4.2 
Aflibercept Dose Rationale 
A variety of dosing regimens are approved for aflibercept. In this global study, aflibercept 2 mg 
(0.05 mL) is administered via intravitreal injection every 4 weeks (approximately every 28 days) 
for the first 3 doses, followed by an injection once every 8 weeks. This regimen is approved and 
well-accepted globally and is considered a standard of care regimen for which an appropriate 
non-inferiority margin for the present study can be derived. 
1.3 
Benefit/Risk Assessment 
1.3.1 
Known Potential Benefits 
KSI-301, an intravitreal VEGF inhibitor developed to treat wAMD, 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 
KSI-301 should be at least comparable to standard of care. 
Long-term and real-world outcomes of approved anti-VEGF therapies are currently limited by 
the high treatment burden caused by their insufficient durability. Emerging efficacy data from 
the ongoing Phase 1b portion of Study KSI-CL-101 support KSI-301’s extended ocular half-life 
and less frequent dose regimen compared to aflibercept. Thus, KSI-301 may provide clinically 
relevant benefits over existing therapies for wAMD. 
1.3.2 
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 subjects are also carefully considered. A summary of known 
potential risks associated with KSI-301 is provided in Table 3. Risks associated with exposure to 
the virus SARS-CoV-2 are discussed below in Section 1.3.2.1. 
 
 


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Table 3.  
Protocol KSI-CL-102: 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 subjects treated with KSI-301. 
Clinical experience with commercially 
available intravitreal VEGF inhibitors 
has shown that SAEs related to 
inflammatory reactions can occur.  
Additional details are provided in 
IB Section 5.4.2.1. 
Subjects 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 6.1.11.2). 
Subjects with known hypersensitivity to intravitreal 
agents such as aflibercept or any ingredient of KSI-301 
are excluded from this study (Section 3.1.2.2). 
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. 
Subjects with recent history (6 months) of myocardial 
infarction or stroke are excluded from this study 
(Section 3.1.2.2). 
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. 
Subjects 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 6.1.11.9). Subjects 
with active or suspected ocular infection or 
inflammation in either eye (e.g., blepharitis, infectious 
conjunctivitis, keratitis, scleritis, endophthalmitis) are 
excluded from this study (Section 3.1.2.1). During the 
study, subjects with active intraocular inflammation will 
have study treatment interrupted (Section 4.8.2) 
 
 
 


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Table 3.  
Protocol KSI-CL-102: Risk Assessment (Cont’d) 
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. 
Subjects with known hypersensitivity to intravitreal 
agents such as aflibercept or any ingredient of KSI-301 
are excluded from this study (Section 3.1.2.2). 
Study Procedures 
Risks associated 
with the method of 
administration 
These risks include endophthalmitis, 
increases in intraocular pressure, 
retinal detachment, retinal tear, 
traumatic cataract, and intraocular 
hemorrhage. 
Additional details are provided in 
IB Section 5.4.2.5. 
Proper and aseptic injection technique when 
administering intravitreal injections will be used 
(Section 6.1.3). Subjects will be monitored following the 
injection and instructed to report any symptoms 
suggestive of severe intraocular inflammation without 
delay to facilitate early diagnosis and treatment 
(Section 6.1.11.9). Intraocular pressure and the 
perfusion of the optic nerve head will also be monitored 
and managed (Section 6.1.4). Subjects with active ocular 
infection or inflammation in either eye (e.g., blepharitis, 
infectious conjunctivitis, keratitis, scleritis, 
endophthalmitis) are excluded from this study 
(Section 3.1.2.1). 
Abbreviations: ATE = arterial thromboembolic event; IB = Investigator’s Brochure; SAE = serious adverse event; 
VEGF = vascular endothelial growth factor. 
 
1.3.2.1 
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 subjects 
are carefully considered and will be documented on an ongoing basis. In wAMD, both earlier 
diagnosis and earlier initiation of treatment with intravitreal anti-VEGF therapy are associated 
with better functional outcomes (Chew 2014). Moreover, intravitreal anti-VEGF treatment is 
recognized as an essential healthcare service during the pandemic by ophthalmology physician 
societies worldwide. This trial affords all subjects the opportunity to receive anti-VEGF therapy 
for their wAMD. Measures that prioritize trial subject safety and data integrity have been 
developed in consideration of local guidelines.  
In order to minimize any added risk of exposure associated with trial participation beyond that 
associated with standard of care treatment, the schedule of activities has been optimized to allow 
for an adequate follow-up and assessment of the safety and efficacy of KSI-301 without 
unnecessarily increasing subject exposure beyond that which may already exist from their 
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As the pandemic situation develops, the Sponsor will reassess risks, which will be documented 
as part of the Sponsor’s trial master file. In the event of escalation of the pandemic during the 
course of this trial and local circumstances lead to a local change in risk assessment, additional 
measures may be implemented. In this case, an Investigator-driven risk assessment will be 
conducted and documented in the Investigator’s site master file and communicated to the 
Sponsor. 
1.3.3 
Overall Benefit/Risk Conclusion 
The potential benefits of treatment of wAMD with KSI-301 (longer treatment intervals) have 
been considered against both the risks associated with KSI-301 treatment and the COVID-19 
pandemic. Subjects in this study will be carefully monitored with special attention to known and 
potential risks and managed as appropriate. Exclusion criteria restrict enrollment of subjects at 
higher risk, and routine monitoring and follow-up evaluations will be conducted for early 
detection of any AEs, as noted in Section 6.1.11. Reassessment of the risks will continue as the 
COVID-19 situation develops and any changes to this approach will be documented accordingly. 
In wAMD, both earlier diagnosis and earlier initiation of treatment with intravitreal anti-VEGF 
therapy are associated with better functional outcomes (Chew 2014). Moreover, intravitreal anti-
VEGF treatment is recognized as an essential healthcare service during the pandemic by the 
World Health Organization and physician groups worldwide. Therefore, based upon the well-
known, clinically demonstrated mechanism of action (Homayouni 2009); favorable nonclinical 
and Phase 1/1b 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.  
 
2.0 
STUDY OBJECTIVES  
2.1 
Primary Objective 
The primary objective of this study is to demonstrate that KSI-301 5 mg is non-inferior to 
aflibercept 2 mg with respect to mean change in BCVA from Day 1 to Year 1. Year 1 is defined 
as the mean of the Week 48 and 52 measurements.  
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the efficacy of KSI-301 5 mg compared to aflibercept 2 mg from Day 1 to 
Week 96 by assessing visual and anatomical parameters. 
• To evaluate the proportion of subjects maintained on a Q12W, Q16W, or Q20W dosing 
regimen of KSI-301 over the duration of the first 52 weeks. 


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• To evaluate the safety and tolerability of KSI-301 5 mg compared to aflibercept 2 mg. 
• To assess the systemic pharmacokinetics and immunogenicity of KSI-301. 
 
3.0 
SUBJECT SELECTION 
Approximately 550 subjects will be enrolled (275 per treatment group). Subjects will be assigned 
to study treatment 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 subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
3.1.1 
Inclusion Criteria 
Each subject must meet all the criteria outlined below to be enrolled in this study.  
3.1.1.1 
Ocular Inclusion Criteria 
Where applicable inclusion criteria will be confirmed or assessed by the independent, masked 
image Reading Center.  
1. Active, treatment-naïve choroidal neovascularization (CNV) secondary to AMD, including 
subfoveal, juxtafoveal and extrafoveal lesions or retinal angiomatous proliferations (RAP) 
lesions with a CNV component that affect the central subfield as evidenced by FA or OCT in 
the Study Eye at Screening. 
2. The CNV area in the Study Eye must be at least 50% of total lesion size at Screening. 
3. A lesion area <30 mm2 (12-disc areas) of any CNV lesion subtype in the Study Eye. 
4. Intra and/or subretinal fluid and/or SHRM (subretinal hyperreflective material) affecting the 
central subfield of the Study Eye on OCT at Screening. 
5. BCVA ETDRS score between 80 and 25 letters (20/25 to 20/320 Snellen equivalent), 
inclusive, in the Study Eye at screening and reconfirmed at Day 1. 
6. Decrease in vision in the Study Eye determined by the Investigator to be primarily the result 
of wAMD. 
In cases where both eyes are eligible, the eye with the worse BCVA at the Screening Visit will 
be selected as the Study Eye. If both eyes have the same BCVA, the decision of which eye to 
select as the Study Eye will be made by the Investigator. Only one eye per subject can participate 
in the study.  


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3.1.1.2 
General Inclusion Criteria 
7. Capable of understanding the informed consent, provides signed and dated informed consent, 
and agrees to comply with protocol requirements. 
8. Male or female ≥50 years of age. 
9. For women of childbearing potential: agreement to remain as abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per 
year during the treatment period 
.  
 A woman is considered of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (≥ 12 months of amenorrhea with no identified cause 
other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus). The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements. 
 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. 
 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. 
 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 subject. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
10. For men: agreement to remain abstinent or use contraceptive measures and agreement to 
refrain from donating sperm, as defined below: 
 With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate 
of < 1% per year during the treatment period 
 
 after the last dose of study drug. Men must refrain from 
donating sperm during this same time period. 
11. Ability and willingness to undertake all the scheduled visits and assessments. 
3.1.2 
Exclusion Criteria 
Subjects meeting any of the criteria outlined below will be excluded from the study.  
3.1.2.1 
Ocular Exclusion Criteria 
Where applicable exclusion criteria will be confirmed or assessed by the independent, masked 
image Reading Center.  


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1. BCVA of hand motion or worse in the non-Study Eye or non-physical presence of a non-
Study Eye (i.e., monocular). 
2. Active or suspected ocular or periocular infection or inflammation in either eye at Day 1. 
3. CNV secondary to other causes in the Study Eye, including pathologic myopia, angioid 
streaks, prior trauma, ocular histoplasmosis, or others. 
4. Any history of macular pathology unrelated to AMD but affecting vision or contributing to 
subretinal or intraretinal fluid, such as central serous chorioretinopathy.  
5. Fibrosis or atrophy of >50% of the lesion size and/or involving the foveal center of the Study 
Eye at Screening. 
6. Subretinal blood affecting the foveal center of the Study Eye and/or more than 50% of the 
lesion size at Screening. 
7. Retinal pigment epithelium tear or rip in the Study Eye at Screening. 
8. Any approved or investigational treatment for neovascular AMD (other than oral vitamin 
supplements) in the Study Eye at any time. 
9. Prior macular laser (e.g., thermal laser or photodynamic therapy laser) in the Study Eye. 
10. Any history or evidence of a concurrent intraocular condition in the Study Eye that, in the 
judgment of the Investigator, could require either medical or surgical intervention during the 
study to prevent or treat visual loss. 
11. Prior intraocular or periocular steroids in the Study Eye. 
12. Current vitreous hemorrhage or history of vitreous hemorrhage in the Study Eye within 3 
months of Screening. 
13. Prior vitrectomy surgery in the Study Eye. 
14. Intraocular surgery other than uncomplicated cataract surgery (i.e., retinal detachment 
surgery) within 3 months of Day 1, or uncomplicated cataract surgery within 1 month of Day 
1 in the Study Eye. 
15. Uncontrolled glaucoma in the Study Eye defined as IOP >25 mmHg on medication at 
Screening or Day 1. 
16. History of glaucoma-filtering surgery in the Study Eye. 
17. History of corneal transplant in the Study Eye. 
18. History of autoimmune or idiopathic uveitis in either eye. 
19. Aphakia in the Study Eye. 
 


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3.1.2.2 
General Exclusion Criteria 
20. 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. 
21. 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. 
22. History of hypersensitivity to any component of KSI-301, aflibercept, ophthalmic dye 
(fluorescein), dilating drops, or any of the anesthetic or antimicrobial preparations used 
during the study, as assessed by the Investigator. 
23. Women who are pregnant or lactating or intending to become pregnant during the study. 
24. Women of childbearing potential must have a negative urine pregnancy test result within 28 
days prior to Day 1. If the urine pregnancy test is positive, it must be confirmed with a serum 
pregnancy test. 
25. Participation in an investigational study within 30 days prior to the screening visit that 
involved treatment with any drug (excluding vitamins and minerals) or device. 
26. Treatment with systemic anti-VEGF therapeutics within 90 days prior to Screening. 
27. Stroke or myocardial infarction in the 6-month period prior to Day 1. 
28. Uncontrolled blood pressure defined as a systolic value > 180 mmHg or diastolic value ≥100 
mmHg while at rest at Screening or on Day 1. 
• 
If a subject’s initial blood pressure measurement exceeds these values, a second 
reading may be taken later on the same day or a different day during the screening 
period. If the subject’s blood pressure is controlled by antihypertensive 
medications, the subject should be on a stable medication regimen continuously 
for 30 days prior to Day 1. 
 
4.0 
INVESTIGATIONAL PLAN 
4.1 
Study Design 
This is a Phase 2b/3, prospective, randomized, double-masked, active comparator controlled, 
multi-center study evaluating the efficacy and safety of repeated dosing of 5 mg KSI-301 
administered by intravitreal injections in treatment-naïve subjects with wAMD. 
The overall duration of the study is approximately 2 years after the last subject is randomized to 
the study. The study will consist of a screening period of up to 21 days (-21 to -1) and a 
treatment period of approximately 2 years (Day 1 to Week 92), followed by the final study visit 
at Week 96. The duration of the study is defined for each subject as the date a signed written 


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informed consent is provided through the last follow-up visit at Week 96. A single eye per 
subject will be designated as the Study Eye. If both eyes are eligible to become the Study Eye, 
the eye with worse visual BCVA at Screening will be selected as the Study Eye. If both eyes 
have the same BCVA, the decision of which eye to select as the Study Eye will be made by the 
Investigator. Only one eye per subject can participate in the study.  
Subjects will be randomized 1:1 into one of the following dose groups:  
• KSI-301 5 mg; or 
• Aflibercept 2 mg. 
Randomization will be stratified by
 
 
Additional details of the randomization methods 
are described in the statistical analysis plan (SAP). 
4.2 
Screening Period 
Subjects 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 subject’s standard 
care. After providing informed consent, subjects will be evaluated for entry criteria during the 
screening period within 21 days before administration of study drug(s). Re-screening after screen 
failure will be allowed.  
4.3 
Screening Failure 
Screen failures are defined as subjects who consent to participate in this study and are not 
randomized. To ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, the IRT system will collect 
information on screen failures, including the date of consent and reason(s) for screen failure. 
This study permits the re-enrollment of a subject that has discontinued the study as a pre-
treatment failure (i.e. re-screening is allowed during the screening period). When re-screening, 
the subject must be re-consented if more than 30 days have elapsed since the date of the last 
informed consent and meet all eligibility criteria. 
4.4 
Treatment Period 
Subjects in this study will be treated until Week 92, 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 4.8.1 are met. 
4.4.1 
Administration of Study Drug 
Study Year 1 (Day 1 Visit through Week 52 Visit): 


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As shown in Table 4, all subjects will receive 3 initial injections of either KSI-301 or aflibercept, 
at Day 1, Week 4, and Week 8. The minimum interval between doses is 21 days. 
KSI-301 Arm:  
Following the 3 initial injections, the dosing regimen will be based on Disease Activity 
Assessments and may vary between Q12W to Q20W.  
Year 1 Disease Activity Assessments: 
• At Week 20 (12 weeks after the Week 8 dose), subjects that meet the Disease Activity 
Criteria will be dosed with KSI-301 and assigned to a Q12W dosing regimen through the 
remaining duration of the first year.  
• Subjects that do not meet the Disease Activity criteria at Week 20 will not be dosed with 
KSI-301 at Week 20 and will be reassessed at Week 24. 
• At Week 24 (16 weeks after the Week 8 dose), subjects that meet the Disease Activity 
criteria will be dosed with KSI-301 and assigned to a Q16W dosing regimen.  
• Subjects that do not meet the Disease Activity criteria at Week 24 will not be dosed with 
KSI-301, will be assigned to a Q20W dosing regimen and dosed with KSI-301 at Week 
28. 
• At Week 36 (12 weeks after the Week 24 dose), subjects in the Q16W dosing regimen 
that meet the Disease Activity criteria will be adjusted to the Q12W dosing regimen, 
dosed with KSI-301 and maintained on this dosing interval through the remaining 
duration of the first year. 
• Subjects who do not meet the Disease Activity criteria at Week 36 will continue their 
designated Q16W dosing regimen, with the next KSI-301 dosing at Week 40. 
• At Week 40 (12 weeks after the Week 28 dose), subjects in the Q20W dosing regimen 
that meet the Disease Activity criteria will be adjusted to the Q12W dosing regimen and 
dosed with KSI-301. 
• Subjects that do not meet the Disease Activity criteria at Week 40 will not be dosed with 
KSI-301 at Week 40 and will be reassessed at Week 44.  
• At Week 44 (16 weeks after the Week 28 dose), subjects in the Q20W dosing regimen 
that meet the Disease Activity criteria will be adjusted to the Q16W dosing regimen and 
dosed with KSI-301. 
• Subjects who do not meet the Disease Activity criteria at Week 44 will continue their 
designated Q20W dosing regimen through the remainder of the first year. 
Year 1 Disease Activity Criteria: 






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Masking: To maintain masking, all subjects will be treated with randomized study treatment or 
sham injections at all planned monthly study visits except for the Week 12 visit as the study 
dosing schedules of KSI-301 and aflibercept do not require dosing at that timepoint.  


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Table 4. 
Protocol KSI-CL-102: Year 1 Dosing Schedules in the KSI-301 and Aflibercept Treatment Groups 
 


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Table 5. 
Protocol KSI-CL-102: Year 2 Dosing Schedules in the KSI-301 and Aflibercept Treatment Groups 


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4.5 
Missed Visits 
Every attempt should be made to avoid missed visits.  
The IRT will adjust the dosing schedule in consideration of missed visits, out of window visits 
and missing data during a visit. 
4.6 
Rescue Treatment 
Subjects with active wAMD who experience severe visual acuity loss as defined below shall be 
eligible to be treated with standard of care if they meet this criterion at any time during the study:  
• Loss of ≥ 15 BCVA ETDRS letters compared to Day 1. 
Institution of rescue therapy for subjects who meet this criterion is at the discretion of the 
Investigator. Subjects who discontinue study drug to receive rescue treatment should NOT be 
considered withdrawn from the study. Unless they withdraw consent or there is additional risk to 
the subject, subjects 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, Week 
52 and Week 96 (primary and secondary endpoint) visits. The Sponsor will not provide rescue 
treatment. All procedures in the Early Termination visit should be completed prior to 
administration of the rescue treatment. 
4.6.1 
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. At least one investigator will be designated as the 
evaluating physician who will be masked to subjects’ treatment assignments and will evaluate all 
ocular assessments. At least one other investigator (and designated unmasked assistants, as 
needed) will be designated as the treating (injecting) physician who will be unmasked to 
subjects’ treatment assignments and will administer injections (KSI-301, aflibercept and sham) 
as well as the immediate post-injection assessments and tonometry. The post-injection tonometry 
exams can also be performed by an unmasked assistant. The unmasked treating physician and 
unmasked staff must not divulge treatment assignment to anyone. 
Subjects, study site personnel (except for the treating physician(s), unmasked 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, and low luminance 
examinations) will be masked to the subject treatment assignment. The BCVA examiner will 
have no access to the VA scores of a subject’s previous visits and may have access only to a 
subject’s refraction data from previous visits. 


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A subject’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the subject depends on knowing the study treatment the subject received. 
Emergency code break is available to the Investigator on-line in the IRT. If unmasking is 
necessary for subject management (for example, in the case of a serious adverse event (SAE) for 
which subject management might be affected by knowledge of the treatment assignment), the 
Investigator will be able to break the treatment code by accessing the IRT. Treatment codes must 
not be broken except in emergency situations. If the Investigator wishes to know a subject’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, CRO pharmacovigilance personnel) will break the treatment code for all serious, 
unexpected suspected adverse reactions that are considered by the Investigator or Sponsor to be 
related to study drug. The subject may continue to receive treatment, and the Investigator, 
subject, and Sponsor or CRO personnel, except for the pharmacovigilance personnel who must 
have access to subject treatment assignments to fulfill their roles, will remain masked to 
treatment assignments. 
Additional information regarding masking and unmasking will be outlined in the study Masking 
Manual. 
4.7 
Treatment Compliance 
Only subjects enrolled in the study may receive study treatment and only ophthalmologists who 
have experience administering intravitreal injections may administer study treatment. 
The unmasked Investigator is responsible for administering the correct dose of KSI-301 and 
aflibercept and for administering sham, according to the study protocol.  
4.8 
End of Treatment  
Subjects 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 
subjects in the study. The end-of-treatment visit should occur 28 +/- 7 days after study treatment 
is discontinued or before a new treatment regimen begins.  
Subjects who discontinue study drug should NOT be considered withdrawn from the study. 
Unless they withdraw consent or there is additional risk to the subject, subjects 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, Week 52 and Week 96 (primary and 
secondary endpoint) visits. 
The reasons for study treatment discontinuation and/or withdrawal from the study (study 
discontinuation) will be recorded on the appropriate eCRF.    


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4.8.1 
Reasons for Withdrawal/Discontinuation 
The reasons for study treatment discontinuation and/or withdrawal from the study (study 
discontinuation) will be recorded on the appropriate eCRF. A subject may be withdrawn from 
the study for any of the following reasons: 
1. The subject does not meet the protocol inclusion or exclusion criteria. 
2. The subject is noncompliant with the protocol. 
3. The subject has a serious or intolerable adverse event(s) (AE(s)) that in the Investigator’s 
opinion requires withdrawal from the study. 
4. The subject has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal. 
5. The subject is lost to follow-up. 
6. Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subjects’ safety if they remain in the study. 
7. The subject withdraws consent, or the Investigator or Sponsor decides to discontinue the 
subject’s participation in the study. 
8. Pregnancy. 
The Investigator will also withdraw a subject if the Sponsor terminates the study. Upon 
occurrence of a serious or intolerable AE, the Investigator will confer with the Sponsor. If a 
subject 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 subject may withdraw his or her consent at any time. 
4.8.2 
Treatment Interruption and/or Discontinuation due to Adverse Events or 
Concomitant Procedures 
Study treatment interruption and/or subject discontinuation from the study treatment due to 
certain AEs or concomitant procedures in the Study Eye will be determined using the criteria 
provided in Table 6. If any of these are met, treatment will be interrupted (or discontinued if 
applicable). Treatment may be resumed after resolution of the AE(s) and upon agreement with 
both the Investigator and Medical Monitor. The reason for study treatment interruption or 
discontinuation should be recorded on the appropriate eCRF and, if applicable, on the Adverse 
Event eCRF. 


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Table 6.  
Protocol KSI-CL-102: Study Treatment Interruption/Subject 
Discontinuation Criteria 
Event 
(MedDRA Preferred Term) 
Criteria 
Vision loss 
Interrupt study treatment for treatment-related decrease of ≥30 letters 
in BCVA in the Study Eye compared with the most recent prior visit.  
Intraocular inflammation  
Interrupt study treatment if any active intraocular inflammation is 
present in the Study Eye.  
Intraocular surgery 
Interrupt study treatment for intraocular surgery in the Study Eye, for 
example cataract surgery. 
Treatment may resume no earlier than 10 days after uncomplicated 
cataract surgery, provided there is no evidence of post-operative 
intraocular inflammation. For complicated cataract surgery or 
following other intraocular surgery, study treatment may be resumed as 
determined by the Investigator following discussion with the Medical 
Monitor. 
Elevated intraocular pressure 
Interrupt study treatment if the pre-injection IOP is >30 mmHg in the 
Study Eye.  
Retinal tear or break 
Interrupt study treatment if a retinal tear or break is present in the 
Study Eye.  
Treatment may be resumed no earlier than 14 days after successful 
laser retinopexy, as determined by the Investigator. 
Retinal detachment or macular 
hole 
Interrupt study treatment if rhegmatogenous retinal detachment or 
Stage 3 or Stage 4 macular hole occurs in the Study Eye. 
Treatment may be resumed no earlier than 14 days after successful 
treatment, as determined by the Investigator, following discussion with 
the Medical Monitor. 
Active infection 
Interrupt study treatment if infectious cellulitis, conjunctivitis, keratitis, 
scleritis, or endophthalmitis occurs in or around either eye. 
Infections should be treated as per the local standard of care. 
 
4.8.3 
Handling of Study Treatment Discontinuation and Withdrawals 
Subjects should be strongly encouraged to stay in the study and undergo as many scheduled 
visits as possible, with emphasis on the Week 48, Week 52, and Week 96 visits. However, 
subjects are free to withdraw from the study or study treatment at any time upon request. Subject 
participation in the study may be stopped at any time at the discretion of the Investigator or at the 
request of the Sponsor. 
Subjects who discontinue study treatment or active participation in the study will no longer 
receive study drug. When a subject discontinues from study treatment or active participation in 


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the study, the reason(s) for study treatment discontinuation or withdrawal shall be recorded by 
the Investigator on the relevant page of the electronic case report form (eCRF). Whenever 
possible, all subjects who discontinue study treatment or withdraw from the study prematurely 
will undergo an Early Termination visit. Subjects who fail to return for final assessments must be 
contacted by the site by phone and in writing to obtain follow-up. 
If a subject exits early from the study between visits, the Investigator must attempt to contact the 
subject and advise the subject to return for a final visit to complete the exit procedures. If the 
subject is unable or unwilling to return for the Early Termination visit, the ‘date of exit’ will be 
the date that the subject was last seen at the site or contacted by other communication.  
It is vital to obtain follow-up data on any subject withdrawn because of an AE or serious AE 
(SAE). In every case, efforts must be made to undertake protocol-specified, safety follow-up 
procedures. 
4.8.4 
Replacements 
Subjects who discontinue study drug treatment will not be replaced or allowed to re-start the 
study treatment.  
4.9 
End of Study 
The end of the study according to the protocol is defined as the last follow-up visit of the last 
subject enrolled or a Sponsor decision to terminate the study, whichever comes first.  
Study data may be collected beyond the end of the study. 
4.10 
Treatment After End of Study 
After subjects complete their final follow-up visit or discontinue from the study prematurely, all 
subjects 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 subject’s study treatment period. 
4.11 
Non-protocol-specified Treatments  
4.11.1 
Concomitant Therapy 
Use of all concomitant medications will be recorded in the subject’s eCRF. This will include all 
prescription drugs, herbal products, vitamins, minerals, and over the counter (OTC) medications. 
Any changes in concomitant medications also will be recorded in the subject’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the subject during the study 
may be given at the discretion of the Investigator. However, it is the responsibility of the 
Investigator to ensure that details regarding the medication are recorded in full in the eCRF. 


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Subjects who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. 
In case the non-Study Eye requires anti-VEGF treatment during the conduct of the study for the 
treatment of wAMD, the subject may be treated at the discretion of the Investigator and 
according to the standard of care in the respective country. The treatment of the non-Study Eye 
may be implemented at any time once the Day 1 injection has been administered. Non-Study Eye 
anti-VEGF treatment must be documented on the appropriate eCRF. If the non-Study Eye 
requires treatment at the same visit as the Study Eye, all Study Eye assessments and Study Eye 
treatment administration should be completed before treating the non-Study Eye, and the non-
Study Eye should be treated by the unmasked physician to preserve masking.  
4.11.2 
Prohibited Therapy 
At the discretion of the Investigator, subjects 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 aflibercept or KSI-301 in the 
Study Eye, 
• Systemic anti-VEGF therapy, 
• Concurrent use of intravitreal or periocular steroids or steroid implants in the Study Eye, 
• Concurrent use of macular photocoagulation or photodynamic therapy with verteporfin in 
the Study Eye, and 
• Investigational treatment with any drug (other than vitamins and minerals) or device. 
Subjects whose medical care requires use of a prohibited therapy must have study treatment 
interrupted in order to receive that therapy. After discussion with the Sponsor’s Medical 
Monitor, subjects whose study treatment has been interrupted but no longer need a prohibited 
therapy may resume study treatment. 
 
5.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUG 
5.1 
KSI-301 
5.1.1 
Drug Description and Formulation 
KSI-301 is an antibody biopolymer conjugate consisting of a recombinant, mammalian cell 
expressed full-length humanized anti-VEGF monoclonal antibody that is covalently conjugated 
to a branched high molecular weight phosphorylcholine-based biopolymer. 


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KSI-301 will be supplied by the Sponsor as a sterile liquid aqueous solution at 
 mg/ml (based 
on antibody mass) and filled into single-use vials.  
5.1.2 
Drug Packaging and Labeling 
KSI-301 will be packaged and labeled according to current good manufacturing practices. Each 
vial will be labeled with the study drug number/name, strength, name of the Sponsor, lot number 
and the required cautionary statement(s). 
5.1.3 
Drug Reconstitution and Handling 
KSI-301 drug product is an aqueous solution that is that is provided in vials and filled into 
syringes by unmasked site personnel without reconstitution or dilution. 
The instructions for administration of KSI-301 drug product are described in the Pharmacy 
Manual. 
5.1.4 
Drug Storage 
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 Pharmacy Manual for additional instructions.  
5.2 
Aflibercept 
Aflibercept will be supplied by the Sponsor as a sterile liquid for intravitreal injection in single-
use glass vials. Refer to the Pharmacy Manual for additional details. For information regarding 
the administration of aflibercept, refer to the country-specific approved prescribing information 
for aflibercept, such as the Summary of Product Characteristics (SmPC). 
5.3 
Sham Formulation 
The sham vial is an empty glass vial which will remain empty throughout the sham treatment 
procedure (full details of the sham procedure are in the Pharmacy Manual). A sham injection is 
used for masking purposes and mimics an intravitreal injection. It involves pressing the blunt end 
of an empty syringe, without a needle, against an anesthetized eye. A sham vial is provided to 
help maintain masking of the study. 
5.4 
Study Drug Accountability and Reconciliation 
Study drug packaging will be overseen by Kodiak Sciences Inc. or their CRO partner 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. 


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The investigational site will acknowledge receipt of the study drug, to confirm the shipment 
condition and content. Any damaged shipments will be replaced. Upon arrival of the study drug 
at the site, site personnel will complete the following: 
• Check the drug shipment for damage. 
• Verify proper identity, quantity, integrity of seals and temperature conditions. 
• Report any deviations or product complaints to the Sponsor or their delegate upon 
discovery. 
The Investigator or delegate 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. 
The Investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation and final disposition records). 
Remaining study drug will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site must obtain written authorization from the Sponsor before any study 
drug is destroyed, and study drug destruction must be documented on the appropriate form. 
 
6.0 
STUDY ASSESSMENTS AND PROCEDURES 
Before undertaking any study procedures, all potential subjects will sign an informed consent 
form (ICF). Subjects will have the opportunity to have any questions answered before signing 
the ICF. The Investigator must address all questions raised by the subject. The Investigator or 
designee will also sign the ICF. 
Study procedures and their timing are summarized in the Schedule of Activities (SoA) for Year 1 
(Table 1) and Year 2 (Table 2). Assessments performed in the event of an unscheduled safety 
visit (Section 13.1) 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. 
6.1 
Study Assessments 
6.1.1 
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 medications, herbal or 
homeopathic remedies, nutritional supplements) used by the subject regularly or within 30 days 
preceding Day 1 must be recorded. A full ocular history including prior ocular treatments will be 
noted. Demographic data will include age, sex, and self-reported race, ethnicity and smoking 
status.  


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6.1.2 
Ophthalmic Exams 
Unless otherwise noted, ophthalmic assessments are for the Study Eye only. 
Slit-lamp examination which will include:  
• Inspection of the eyelids, 
• Inspection of the cornea, 
• Examination of the anterior chamber,  
• Examination of the pupil, 
• Examination of the iris, 
• Inspection of the lens, 
• Inspection of the vitreous body, and 
• Inspection of the retina and optic disc. 
Dilated indirect ophthalmoscopy will include examination of the peripheral retina. 
Tonometry shall be conducted as part of the ophthalmic exam. The method of IOP measurement 
(such as Goldmann tonometry or Tonopen) must remain the same throughout the study for each 
subject. Pre-injection tonometry should be performed prior to pupil dilation.  
Subjects will be instructed to report any signs or symptoms of intraocular inflammation (uveitis) 
or endophthalmitis that may be a clinical sign and include symptoms such as pain, photophobia, 
redness, or reduced vision. 
6.1.3 
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 IVT injections. Aseptic technique must be observed by clinic staff 
involved in the assembly of the injection tray, study drug preparation, anesthetic preparation, and 
study treatment administration. To minimize the risk of infection the periocular skin and eyelid 
of the Study Eye must be disinfected with 10% povidone iodine swabs and 5% povidone iodine 
must be applied to the bulbar conjunctiva directly over and surrounding the injection site.  
The unmasked injecting Investigator will choose one of the acceptable methods of ocular 
anesthesia on a per subject basis. Subconjunctival anesthesia is recommended (but not required) 
to maximize subject comfort. In order to maintain masking the selected method of anesthesia for 
an individual subject must remain constant for the duration of the trial and at all visits 
irrespective of the study treatment assigned during the study visit (KSI-301, Aflibercept or 
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Additional specifications and instructions regarding acceptable equipment and imaging 
techniques will be provided by the Reading Center. 
6.1.8 
Fluorescein Angiography (FA) 
Two-field FA will be performed at all the study sites by qualified personnel. It is mandatory that 
the same model of device is used for the entire duration of the study.  
Additional specifications and instructions regarding acceptable equipment imaging and imaging 
techniques will be provided by the Reading Center. 
6.1.9 
Disease Activity Assessments 
The IRT will make the necessary adjustments to the dosing schedule based on disease activity 
data from the study site. Details of the Disease Activity Assessments are described in  
Section 4.4.1. 
6.1.10 
Vital Signs 
The following vital signs will be assessed taken with the subject in a seated position after resting 
for 5 minutes: blood pressure, pulse rate, and body temperature, in addition to height and weight 
at Screening. 
6.1.11 
Adverse Events 
The following definitions, based on the International Conference on Harmonization (ICH) 
Clinical Safety Data Management Guidance for Industry, E2A, will be used for the purpose of 
identifying AEs in this clinical trial.  
6.1.11.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject enrolled in the study, regardless of 
treatment assignment that does not necessarily have a causal relationship with the study drug. An 
AE can therefore be any unfavorable and unintended sign (including, for example, an abnormal 
laboratory finding), symptom, syndrome, disease, or increase in severity of a pre-existing 
abnormality, whether or not considered related to the study drug.  
Examples of AEs include the following: 
• Any treatment-emergent signs and symptoms (events that are a change from the subject’s 
baseline conditions, including an increase in frequency or severity). 
• Clinically significant laboratory findings as judged by the Investigator. 
• Disease-related (indication) signs and symptoms not present at baseline. 
• Reactions from the investigational treatment, including method of administration. 


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• Injury or accidents. 
• Any other event or finding that the Investigator feels is clinically significant. 
Disease-related signs and symptoms present at Screening should not be recorded as AEs.  
Adverse events will be recorded starting after the first dose of trial drug [treatment emergent AEs 
(TEAEs)] and continuing until 4 weeks after the last dose or until the last follow-up visit 
required by the protocol, whichever comes later. 
Events that are not considered AEs include the following: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’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 subject’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. 
 
6.1.11.2 
Monitoring Adverse Events 
Adverse events will be assessed starting after the first dose of trial drug (TEAEs) and up to 4 
weeks after the last dose of study drug.  Serious AEs that occur more than 4 weeks after the last 
dose of study drug need not be reported unless the Investigator considers them related to study 
drug. 
At every study visit, subjects will be asked a standard nonleading question to elicit any medically 
related changes in their well-being. They will also be asked if they have been hospitalized, had 
any accidents, used any new medications, or changed concomitant medication regimens (both 
prescription and OTC medications). 
In addition to subject 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 subject safety will be documented on the AE page in the eCRF. 


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6.1.11.3 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s daily 
activities. The intensity of the AE will be rated as mild, moderate, or severe using the following 
criteria: 
Mild: 
These events require minimal or no treatment and do not interfere with the 
subject’s daily activities in a significant manner – it may be an annoyance. 
Moderate: 
These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
normal functioning, but it is not hazardous to the subject’s health. 
Severe: 
These events produce significant impairment of functioning or incapacitation 
and is a definite hazard to the subject’s health. 
 
The evaluation of severity is distinguished from “seriousness.” A severe event might not meet 
the criteria for seriousness and a serious event might be evaluated as mild or moderate in 
intensity. For example, a subject might have a severe headache that does not require 
hospitalization and is consequently not serious; or a subject might have a mild myocardial 
infarction that requires hospitalization and is, therefore, serious. 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. AEs characterized as intermittent do not 
require documentation of onset and duration of each episode. 
6.1.11.4 
Assessment of Causality 
The causality of each AE must be assessed by the masked Investigator. The masked 
Investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. For the 
purposes of IND safety reporting, “reasonable possibility” means there is evidence to suggest a 
causal relationship between the IP and the AE. 
The following considerations should be assessed by the Investigator to guide determination of 
causality: 
• Temporal association between the study treatments (injection procedure and study drug) 
and the event; 
• Cessation or re-challenge (e.g., of a suspected concomitant medication); 
• Compatibility with known effects of the study treatments; 
• Known effects of concomitant medications; 


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• Pre-existing risk factors; and/ or 
• A plausible mechanism. 
The relationship to the intravitreal injection procedure or to study drug 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 drug. 
• Related - There is a reasonable possibility that the AE is related to the injection 
procedure or to the study drug. 
6.1.11.5 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Investigators should use correct medical terminology/concepts when recording AEs on the 
Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
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) 
Active inflammation in the vitreous should be clinically differentiated from cellular debris from 
prior episodes of inflammation, hemorrhage, or other causes. 
• Endophthalmitis: diffuse intraocular inflammation predominantly involving the vitreous 
cavity but also involving the anterior chamber, implying a suspected underlying 
infectious cause 
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”. 


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• 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.  
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported. All AEs will be followed to 
adequate resolution. The Medical Dictionary for Regulatory Activities (MedDRA) will be used 
to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE.  
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
6.1.11.6 
Definition of Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life-threatening (at the time of the event); 
• Requires in-patient hospitalization or prolongation of existing hospitalization; 
o In general, hospitalization signifies that the subject 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. 
o Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• Results in persistent or significant disability/ incapacity; 
o The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
o This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 


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influenza, and accidental trauma (e.g., sprained ankle) which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect (in an offspring); and/or 
• Is an important medical event. 
o Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment by the Investigator or Sponsor, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  
For this study, scheduled hospitalizations for administration of the IP, elective surgery, or for 
scheduled study procedures, are not to be reported as SAEs. 
6.1.11.7 
Reporting Serious Adverse Events 
Any AE that meets SAE criteria (Section 6.1.10.6) must be reported to the Sponsor or its 
designee immediately (i.e., within 24 hours) after the time site personnel first learn about the 
event. SAE reporting instructions are outlined in the Site Binder.  
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. 
6.1.11.8 
Definition of Adverse Events of Special Interest (AESI) 
An AE of special interest (AESI) is one of scientific and medical concern specific to the 
Sponsor’s product or program where ongoing monitoring and rapid communication by the 
Investigator to the Sponsor may be appropriate. These AEs may be serious or non-serious. 
Applicable AEs may require additional investigation in order to characterize and understand, and 
depending upon the nature of the event, rapid communication by the Sponsor to other parties 
may also be required. 
6.1.11.9 
Reporting Adverse Events of Special Interest (AESI) 
These AESIs must be reported by the Investigator using the same mechanism (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: 
• Cases of potential liver injury (see Section 6.4.2). 
• AEs resulting from medication error, including overdose, incorrect dose, incorrect drug, 
incorrect administration or incorrect kit. 
• AEs with sight-threatening potential, meeting one or more of the following criteria: 


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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 
Section 13.2 for grading scales). 
o Requires surgical intervention to prevent permanent loss of sight. 
As with all AEs occurring in a study subject, a decision will be made by the Investigator 
concerning additional exposure to study treatment and further participation in the study. 
6.1.11.10 Immediate Reporting Requirements from Investigator to Sponsor 
The Investigator must report certain events to the Sponsor or its CRO partner to allow for 
appropriate measures to be taken to manage potential new risks in a clinical study. These events 
should be reported immediately to the Sponsor, and in all cases within 24 hours of learning from 
the event. The following events should be immediately reported, regardless of relationship to 
study drug: 
• SAEs 
• Non-serious AESIs 
• Pregnancies 
In addition, the Investigator must report new significant follow-up information for these events 
immediately (within 24 hours). New significant information includes: 
• New signs or symptoms of a change in the diagnosis 
• Significant new diagnostic test results 
• Change in causality based on new information 
• Change in the outcome of the event, including recovery 
• Additional narrative information on the clinical course of the event 
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and the IRB/IEC. 
6.1.11.11 Expedited Reporting to Regulatory Authorities, Investigators, Institutional 
Review Boards and Ethics Committees 
The Sponsor will promptly evaluate all suspected unexpected serious adverse reactions 
(SUSARs) and serious and non-serious AESIs against cumulative product experience to identify 
possible new safety findings. Expectedness of these events will be assessed using the following 
reference documents: 


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• KSI-301 Investigator's Brochure; and 
• Aflibercept (Eylea®) European Medicines Agency (EMA) Summary of Product 
Characteristics. 
The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
Reporting requirements will also be based on the Investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
All cases will be reported to the IRB/IEC in accordance with the standard operating procedures 
(SOPs) and policies of the IRB/IEC and reported to regulatory authorities, per local regulations 
such that: 
• All fatal or life-threatening AEs will be reported immediately after the Sponsor receives 
the initial report from the Investigator; and 
• All nonfatal or non-life-threatening cases will be reported within a maximum of 15 days 
after the initial Investigator’s report. 
6.1.11.12 Diagnosis Versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF. If a diagnosis is subsequently 
established, all previously reported AEs based on signs and symptoms should be nullified and 
replaced by one AE report based on the single diagnosis, with a starting date that corresponds to 
the starting date of the first symptom of the eventual diagnosis. 
6.1.11.13 Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious secondary 
events. However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the Adverse Event eCRF. For 
example: 
• If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• If vomiting results in severe dehydration, both events should be reported separately on 
the eCRF. 


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• If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• If dizziness leads to a fall and subsequent fracture, all three events should be reported 
separately on the eCRF. 
• If vitreous hemorrhage results in VA decrease only the vitreous hemorrhage should be 
reported. 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to whether 
the events are associated. 
6.1.11.14 Persistent or Recurrent Adverse Events  
A persistent AE is one that extends continuously, without resolution, between subject evaluation 
timepoints. Such events should only be recorded once on the Adverse Event eCRF. The initial 
severity of the event should be recorded, and the severity should be updated to reflect the most 
extreme severity any time the event worsens. If the event becomes serious, the Adverse Event 
eCRF should be updated to reflect this. 
A recurrent AE is one that resolves between subject evaluation timepoints and subsequently 
recurs. Each recurrence of an AE should be recorded separately on the Adverse Event eCRF. 
6.1.11.15 Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported as an 
AE if it meets any of the following criteria: 
• Accompanied by clinical symptoms. 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation). 
• Results in a medical intervention or a change in concomitant therapy. 
• Clinically significant in the Investigator’s judgment. 
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event 
eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF, unless the etiology changes. The initial 


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severity of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens. 
6.1.11.16 Deaths 
All deaths that occur during the protocol-specified AE reporting period regardless of relationship 
to study treatment, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor. 
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the Adverse Event eCRF. Generally, only one such event should be reported. If the cause of 
death is unknown and cannot be ascertained at the time of reporting, “unexplained death” should 
be recorded on the Adverse Event eCRF. If the cause of death later becomes available (e.g., after 
autopsy), “unexplained death” should be replaced by the established cause of death. The term 
"sudden death" should not be used unless combined with the presumed cause of death (e.g., 
"sudden cardiac death"). 
6.1.11.17 Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the Screening visit for this study. Such 
conditions should be recorded on the Medical History eCRF. 
A pre-existing medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study. When recording such events on the eCRF, it 
is important to clearly inform the concept that the pre-existing condition has changed by 
including the characteristics of the change. 
6.1.11.18 Adverse Events Associated with an Overdose 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied. An overdose or incorrect administration of study treatments is not itself an AE, 
but it may result in an AE. All AEs associated with an overdose or incorrect administration of 
study drug should be recorded on the eCRF and should be reported to the Sponsor immediately 
(no more than 24 hours after the event is recognized). 
6.1.11.19 Follow-Up of Subjects Reporting Adverse Events 
The Investigator is responsible for adequate and safe medical care of subjects during the trial and 
for ensuring that appropriate medical care and relevant follow-up procedures are maintained after 
the trial. All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the Investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered stable. 


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6.2 
Safety 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. 
6.3 
Pregnancy 
Samples for pregnancy testing will be taken at the Screening and Day 1 visits and then monthly, 
as specified in the SoA for Year 1 (Table 1) and Year 2 (Table 2). 
Prior to enrollment in the study, female subjects of childbearing potential and male subjects must 
be advised of the importance of avoiding pregnancy or partner pregnancy, respectively, during 
the trial and the potential risks associated with an unintentional pregnancy.  
During the study, female and male subjects are to be instructed to contact the Investigator 
immediately if they suspect they might be pregnant or if their partner becomes pregnant, 
respectively. 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 in a 
Sponsor prepared form. To ensure subject safety, each pregnancy must be reported to the 
Sponsor or its designee immediately (within 24 hours) after learning of its occurrence. The 
pregnancy must be followed-up to determine outcome (including spontaneous miscarriage, 
elective termination, normal birth, or congenital abnormality) and status of mother and child, 
even if the subject 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 subject has completed the study, and considered by the Investigator as possibly related to the 
study treatment, must be promptly reported to the Sponsor. 
6.4 
Laboratory Analyses 
Blood samples for the following laboratory assessments will be at taken as specified in the SoA 
for Year 1 (Table 1) and Year 2 (Table 2): 
• Hematology: hemoglobin, platelet count, white blood cell (WBC) and differential; 


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• Renal function: serum creatinine and blood urea nitrogen (BUN); 
• Hepatic function: serum bilirubin, alkaline phosphatase, gamma-glutamyl-transferase 
(GGT), serum glutamic oxaloacetic transaminase (SGOT)/ aspartate aminotransferase 
(AST) and serum glutamic pyruvic transaminase (SGPT)/ alanine aminotransferase 
(ALT); and 
• Electrolytes: sodium, potassium, chloride, bicarbonate, calcium and phosphate. 
If the Investigator judges a laboratory value outside of the normal range as clinically significant, 
the Investigator may at their discretion repeat the laboratory determination as judged appropriate 
to ensure the validity of the abnormal result.  
6.4.1 
Abnormal Laboratory Values 
Any abnormal laboratory test results (hematology or clinical chemistry) or other abnormal 
diagnostic findings (e.g., ECGs, radiological scans, vital sign measurements), including those 
that worsen from baseline, felt to be clinically significant in the medical and scientific judgment 
of the Investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs. 
Not every laboratory abnormal value qualifies as an AE. An abnormal laboratory test result must 
be reported as an AE if it meets any of the following criteria:  
• Accompanied by clinical symptoms. 
• Results in a change in study treatment (e.g., treatment discontinuation or interruption). 
• Results in a medical intervention. 
• Clinically significant in the Investigator’s judgment. 
It is the responsibility of the Investigator to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated abnormal laboratory result should 
be classified as an AE. 
If a clinically significant laboratory value abnormality is a sign of a disease or syndrome, only 
the diagnosis should be recorded on as an AE in the eCRF. If it is not a sign of a disease or 
syndrome, the abnormality itself should be recorded as an AE in the eCRF, describing if the 
value is above or below the normal range (e.g., “elevated sodium”, instead of “abnormal 
sodium”).  
In case the same clinically significant laboratory abnormality is observed in subsequent visits it 
should not be recorded repeatedly as an AE in the eCRF, unless the etiology changes. The initial 
severity of the event should be recorded and updated in case the event worsens. 


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6.4.2 
Abnormal Liver Function Tests 
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); and 
• 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. 
6.5 
Pharmacokinetic, Biomarker, and Immunogenicity Assessments 
Blood samples (4 mL) for systemic pharmacokinetic, systemic biomarker, and systemic 
immunogenicity testing will be taken at the timepoints specified in the SoA for Year 1 (Table 1) 
and Year 2 (Table 2). Supplementary testing of samples may be used for exploratory evaluation 
of the bioanalytical method. 
To understand the systemic PK of the study drug following intravitreal injection, plasma 
concentration of KSI-301 will be measured. For exploratory purposes, plasma VEGF levels or 
other blood factors may be evaluated as systemic biomarkers. Plasma samples of comparator 
may also be analyzed for systemic PK and systemic biomarkers. 
As with all therapeutic proteins, there is the potential for an immune response in subjects treated 
with KSI-301. The detection of anti-drug antibodies (ADAs), or anti-KSI-301 antibodies in 
subject plasma samples will be assessed. Additional immunogenicity testing of samples may be 
performed to further characterize the ADA response for specificity and/or neutralizing antibodies 
(NAB).  
Details on sampling procedures, sample storage and shipment will be provided by the central 
laboratory. 
 
7.0 
STATISTICAL AND ANALYTICAL PLAN 
Analysis of the primary (Year 1) data will be performed when all subjects have either completed 
the Week 52 visit or have discontinued from the study prior to the Week 52 visit, whichever 
comes later, and all data up to and including the Week 52 visit have been entered into the 
database, cleaned and verified as appropriate, and the database for the primary analysis locked. 
Analysis of data for Year 2 of the study will be performed when all subjects have either 
completed the Week 96 visit or have discontinued from the study, and all data have been entered 
into the database, cleaned and verified as appropriate, and the database locked.  


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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. 
Additional unplanned analyses may be required after all planned analyses have been completed, 
and additional analyses of key efficacy metrics may be performed between the primary and final 
analyses to support marketing applications for various jurisdictions. Any unplanned analyses will 
be clearly identified in the clinical study report. 
Results of the Year 1 analyses may be reported to the public and to health authorities before the 
completion of the two-year portion of the study. Subjects, masked study site staff, and the 
Reading Center will remain masked to treatment assignments until the entire two-year study is 
completed, the database is locked, and the two-year analyses are completed.  
7.1 
Primary Efficacy Endpoint 
The primary endpoint of this study will be the mean change in BCVA from Day 1 to Year 1, 
comparing subjects receiving KSI-301 to aflibercept at a non-inferiority margin of 4 letters. Year 
1 is defined as the mean BCVA at Weeks 48 and 52.  
7.2 
Secondary Efficacy Endpoints 
At Year 1: 
• Proportion of subjects on a Q12W, Q16W or Q20W dosing regimen of KSI-301 at Week 
52 
• Proportion of subjects who gain ≥ 5, ≥10 and ≥15 letters from baseline over time 
• Proportion of subjects who lose ≥ 5, ≥10 and ≥15 letters from baseline over time 
• Mean change from baseline in BCVA from baseline to Week 12, Week 16, and over time 
• Proportion of subjects with BCVA Snellen equivalent of 20/40 or better from baseline 
over time  
• Proportion of subjects with BCVA Snellen equivalent of 20/200 or worse from baseline 
over time 
• Mean change in OCT CST from baseline to Week 12, Week 16, and over time 
• Mean change in OCT intraretinal fluid volume from baseline to Week 12, Week 16, and 
over time 
• Mean change in OCT subretinal fluid volume from baseline to Week 12, Week 16, and 
over time 
• Proportion of subjects without intraretinal fluid on OCT from baseline to Week 12, Week 
16 and over time 
• Proportion of subjects without subretinal fluid on OCT from baseline to Week 12, Week 
16 and over time 


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• Proportion of subjects without pigment epithelial detachments on OCT from baseline 
over time 
• Mean change in CNV total lesion area on FA from baseline at Year 1 
• Mean chance in area of leakage on FA from baseline at Year 1 
• Number of study drug injections received in the KSI-301 and aflibercept groups through 
Year 1 
• For the KSI-301 group, the predictability of being on Q12W, Q16W, or Q20W dosing at 
the end of Year 1 on the basis of the first set of Disease Activity Assessments (at Weeks 
20 and 24).  
At Year 2: 
• Proportion of subjects who gain ≥ 5, ≥10 and ≥15 letters from baseline over time 
• Proportion of subjects who lose ≥ 5, ≥10 and ≥15 letters from baseline over time 
• Mean change from baseline in BCVA from baseline over time 
• Proportion of subjects with BCVA Snellen equivalent of 20/40 or better from baseline 
over time  
• Proportion of subjects with BCVA Snellen equivalent of 20/200 or worse from baseline 
over time  
• Mean change in OCT CST from baseline over time  
• Mean change in OCT intraretinal fluid volume from baseline to Week 12, Week 16, and 
over time 
• Mean change in OCT subretinal fluid volume from baseline to Week 12, Week 16, and 
over time 
• Proportion of subjects without intraretinal fluid on OCT from baseline over time 
• Proportion of subjects without subretinal fluid on OCT from baseline over time 
• Proportion of subjects without pigment epithelial detachments on OCT from baseline 
over time 
• Mean change in CNV total lesion area on FA from baseline at Year 2 
• Mean chance in area of leakage on FA from baseline at Year 2 
For BCVA and OCT, Year 1 is defined as the average measurement at Weeks 48 and 52 and 
Year 2 is defined as the average measurement at Weeks 92 and 96. 
A full list of secondary endpoints, including the delineation of key versus additional secondary 
endpoints, will be outlined in the SAP. 


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7.3 
Sample Size Calculations 
Subjects will be randomized in a 1:1 ratio to KSI-301 or the active comparator, aflibercept. The 
sample size for the comparison between the KSI-301 and aflibercept groups at Year 1 is based on 
a non-inferiority approach. The following assumptions were made to calculate the sample size: 
• Overall Type I error rate of 0.025. Testing at the 0.025 level corresponds to setting 95% 
confidence intervals. 
• Statistical power of ≥90%. 
• Standard deviation of the distribution of change in visual acuity from baseline of 
 
letters (averaged over Weeks 48 and 52). 
• The maximum clinically-acceptable true difference for KSI-301 to be considered non-
inferior, or the “non-inferiority margin,” 
  
• The anticipated true difference in mean change from baseline in BCVA between 
treatment groups is 0. That is, both treatment arms are expected to have the same 
efficacy. 
• The statistical test used to compare the two treatment groups at Week 52 is an 
independent t-test on the mean change in visual acuity from baseline. 
• Lost to follow-up rate 
 
The sample size calculated using the above assumptions is 550 subjects (275 per treatment 
group). 
Confidence intervals will be 100(1-2 α) or 95% confidence intervals. If the null hypothesis of 
inferiority is rejected, testing for superiority will be performed. That is, if the lower confidence 
limit for the difference in mean BCVA lies within (-4, ∞), the null hypothesis of inferiority will 
be rejected, and the non-inferiority will be established. Furthermore, if the lower confidence limit 
lies within (0, ∞), superiority will be established. 
 
 
 
 
 
 
 
7.4 
Analysis Sets 
Full details and definitions of analysis sets will be provided in the SAP. The following analysis 
sets will be used in the statistical analyses: 


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• Intent to treat set (ITT) will be comprised of all subjects who were randomized in the study. 
For analyses based on this population, subjects will be grouped according to the treatment 
assigned at randomization. 
• Per-protocol set (PPS): The PPS will consist of all ITT subjects 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 subjects according to treatment actually received. 
• Safety set: The safety set will consist of all subjects who received any study drug. All 
analyses using the safety set will group subjects according to treatment actually received. 
• Systemic pharmacokinetic (PK)/biomarker/ADA set: The PK/biomarker data set will consist 
of all subjects with at least one post Day 1 data point. The ADA data set will consist of all 
subjects with pre-dose sample on Day 1 and at least one post Day 1 data point. 
7.5 
Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.4 or later.  
Results from this study will be reported using descriptive statistics-number of subjects (N), 
mean, standard deviation or standard error of the mean, median, maximum and minimum for 
continuous outcomes and frequency and percentage for categorical variables. Data will be listed 
in data listings.   
Details of all analyses, including imputation approaches for handling of missing data, will be 
included in the SAP. The results of all analyses detailed in the SAP will appear in the final 
clinical study report. 
7.5.1 
Analysis of Primary Efficacy Endpoint 
Unless stated otherwise, all analyses described will be performed on the ITT population.  
The primary endpoint is defined as the mean change in ETDRS BCVA from Day 1 to Year 1. 
Year 1 is defined as the mean BCVA at Weeks 48 and 52. The primary assessment of efficacy 
will be based on a pairwise comparison in mean change in BCVA between the two treatment 
groups. If there are no imbalances on important prognostic factors at baseline, a simple 
independent t-test and corresponding confidence intervals will be used for evaluation of 
treatment differences. If there are imbalances in key prognostic factors at baseline (e.g., BCVA) 
generalized linear models or other statistical models (such as mixed effects models) will be used 
to estimate the difference in mean change in VA between treatment groups and confidence 
intervals derived from the corresponding standard error of the estimate. These models will also 
include indicator variables for stratification variables. An alpha level of 0.025 will be used for 
hypothesis testing and confidence intervals will be 100(1-2α) or 95% confidence intervals. If the 
null hypothesis of inferiority is rejected, testing for superiority will be performed.  


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Full details on the statistical testing procedures along with supplementary and sensitivity 
analyses will be provided in the SAP. 
7.5.2 
Analysis of Key Secondary Efficacy Endpoints 
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 timepoint 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 
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. 
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.  
Full details will be provided in the SAP. 
7.5.3 
Analyses of Additional Secondary Efficacy Endpoints 
Continuous and categorical secondary efficacy endpoints will be analyzed as described in the 
SAP. 
7.5.4 
Pharmacokinetic Analyses 
PK Analyses will be outlined in the PK Analysis Plan. 
7.5.5 
Safety Analyses 
The safety analysis (using the safety set as described in Section 7.4) will use outcomes of all 
subjects who were exposed to study treatment regardless of adherence to the protocol or 
treatment outcome. Safety analyses will be conducted concurrently with efficacy analyses.  
In addition to analyses of ocular safety events, all reported AEs will be listed by MedDRA term, 
frequency, severity, association to the study therapy, and treatment group. By-treatment incidence 
rates will also be calculated for the treatment groups. For certain AEs, per-injection rates will 
also be described. 


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7.5.6 
Interim Analyses 
 
 
 
 
   
 
 
Full details regarding interim analyses will be provided in the SAP. 
8.0 
DATA QUALITY ASSURANCE 
This study will be conducted according to the ICH E6 guideline for GCP for all risk and quality 
processes described in the applicable procedural documents. The quality management approach 
to be implemented in this study will be documented and will comply with the current ICH 
guidance on quality and risk management. 
8.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The Investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories. These source documents may include ophthalmic clinical images, 
laboratory reports, among others. 
The Sponsor or a designated CRO will be responsible for data management of this study, 
including quality checking of the data. Sites will be responsible for data entry into the eCRF via 
the EDC system. Data entered manually will be collected via EDC using eCRFs. The analysis 
data sets will be a combination of these data and data from other sources (e.g., laboratory data). 
In the event of discrepancies in the data, the Sponsor will request data clarification from the sites, 
which the sites will resolve electronically in the EDC system. The audit trail of the EDC system 


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will keep records of the eCRFs and the correction documents. The Sponsor will supply eCRF 
specifications for this study. 
Clinical data management will be performed in accordance with all applicable standards and data 
cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies 
in the data. AE terms will be coded using the MedDRA, an internal validated medical dictionary, 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODRUG). 
 
9.0 
ETHICS 
9.1 
Independent Ethics Committee or Institutional Review Board 
Federal regulations and the International Council for Harmonisation (ICH) guidelines require 
that approval be obtained from an IRB/IEC before participation of human subjects in research 
studies. Before study onset, the protocol, informed consent, advertisements to be used for the 
recruitment of study subjects, and any other written information regarding this study to be 
provided to the subject or the subject’s legal guardian must be approved by the IRB/IEC. 
Documentation of all IRB/IEC approvals and of the IRB/IEC compliance with ICH harmonised 
tripartite guideline E6 Good Clinical Practice (GCP) will be maintained by the site and will be 
available for review by the Sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the 
date approval or a favorable opinion was granted.  
Any changes to the protocol, ICF, advertisements (if applicable), and any other written 
information provided to the subjects can only be made by the Sponsor and must be reviewed and 
approved by the IRB/IEC. 
The Investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The Investigator 
must promptly supply the Sponsor or its designee, the IRB/IEC, and, where applicable, the 
institution, with written reports on any changes significantly affecting the conduct of the study or 
increasing the risk to subjects. 
9.2 
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, ICH and GCP guidelines, and in 
accordance with the ethical principles for medical research involving human subjects as stated in 
the Declaration of Helsinki. 


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9.3 
Subject Information and Consent 
A written informed consent in compliance with all applicable regulatory authority regulations 
shall be obtained from each subject before entering the study or performing any unusual or 
nonroutine procedure that involves risk to the subject.  
The Principal Investigator (PI) will ensure that the nature, purpose, procedures, duration, 
potential risks and potential benefits of participation in the study are explained to each subject. 
The subject will be provided with the IRB approved ICF, written in a language in which they 
understand, and given sufficient time to ask questions and to consider all information provided 
and the risks associated with participation. Subjects will be explained about the voluntary nature 
of participation in the study and will be provided with contact information for the appropriate 
individuals should questions or concerns arise during the study. The subject will be informed that 
they have the right to withdraw from the study at any time without any disadvantage.  
Once the Investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give consent to participate 
in the study by signing the ICF.  
The Investigator shall retain the signed original ICF and give a copy of the signed original form 
to the subject or legal guardian. 
 
10.0 INVESTIGATOR’S OBLIGATIONS 
The following administrative items are meant to guide the Investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB/IEC 
but will not result in protocol amendments. 
10.1 
 Study Monitoring Requirements 
The PI/institution(s) will permit trial-related monitoring, audits, IRB review and regulatory 
inspections, and will provide direct access to source data/documentation. 
Site visits will be conducted in accordance with the monitoring plan to evaluate study data, 
subject’s medical records, source document worksheets, and eCRFs in accordance with current 
ICH-GCP guidelines. During these site visits, source documents will be reviewed to confirm the 
study is being conducted according to the protocol and that subject safety is being maintained. 
Additionally, source data verification (SDV) will be conducted for accuracy of data entered into 
the EDC system. 
Regularly scheduled site visits to monitor proper conduct of the study will be conducted by 
Sponsor and/or contract research organization (CRO) representatives. During these visits, 


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essential study documents, subject medical records, trial-related activities and protocol 
adherence, completed source document worksheets, eCRFs, and any data pertinent to the study 
will be reviewed with the site personnel. If necessary, the site monitor will conduct re-training of 
study site personnel to ensure compliance with the protocol and applicable regulation. 
The monitor is responsible for inspecting the eCRFs throughout the study to verify adherence to 
the protocol as well as completeness, accuracy, and consistency of the data. The monitor will 
also ensure adherence to local regulations on the conduct of clinical research. The monitor 
should have direct access to subject medical records and other study related records needed to 
verify the accuracy of the entries on the eCRFs.  
The PI agrees to cooperate with the monitor to ensure that any problems detected in the course of 
these monitoring visits are resolved. 
In accordance with the International Conference on Harmonization Guidance on GCP and the 
Sponsor’s audit plans, study sites may be selected for audit. Inspection of site facilities (e.g., 
pharmacy, medication storage areas, laboratories) and review of study related records will occur 
to evaluate the study conduct and compliance with the protocol, International Conference on 
Harmonization, GCP and applicable regulatory requirements. 
The PI will also permit the local regulatory authorities to inspect facilities and records relevant to 
this study. The PI is to ensure that the Sponsor is notified immediately of any notice or conduct 
of such inspection. 
10.2 
 Confidentiality 
The confidentiality of the subjects will be maintained by coding each subject enrolled in the 
study through assignment of a unique identification number. Subject identifiers including names 
are not included in any data set provided to the Sponsor. 
All information provided by the Sponsor, verbally and in writing, is confidential. The 
Investigator agrees not to disclose any such information without prior written permission of the 
Sponsor. This document may be disclosed to study personnel under the PI’s supervision and to 
the IRB under the condition that they also agree to maintain its confidentiality. Any 
supplemental information (e.g., protocol amendment) that may be added to this document is 
confidential and must also be handled accordingly. The information obtained from the Sponsor 
may be disclosed to obtain informed consent from subjects who wish to participate in the study. 
Study documents provided by the Sponsor (protocols, Investigator’s Brochure (IB), etc.) will be 
stored appropriately to ensure their confidentiality.  
Subject 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 subject confidentiality. All 
records will be kept in a secure storage area with limited access. Clinical information will not be 


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released without the written permission of the subject (or the subject’s legal guardian), except as 
necessary for monitoring and auditing by the Sponsor, its designee, the US Food and Drug 
Administration (FDA) or other governmental health authorities, or the IRB/IEC. 
The PI must ensure that any subject data or records that are transmitted are de-identified. 
Subjects will be identified by an anonymized subject number on the eCRFs or other study related 
documents. Other study related documents (e.g., signed ICFs) should be kept in strict confidence 
by the PI. 
Upon the subject’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection upon request by representatives of 
the regulatory authority, national and local health authorities, the Sponsor, and the investigative 
site’s IRB. 
The Investigator and all employees and coworkers 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. 
10.3 
 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements required under 21 CFR 
54. In addition, the Investigator 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 subject’s disease. 
10.4 
 Study Conduct 
The Investigator agrees that the study will be conducted as outlined in this protocol and 
according to the principles of ICH E6. The Investigator will conduct all aspects of this study in 
accordance with all national, state, and local laws or regulations. Study information from this 
protocol will be posted on publicly available clinical trial registers. 


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10.5 
 Adverse Events and Study Report Requirements 
By participating in this study, the Investigator agrees to submit reports of SAEs to the Sponsor 
and/or IRB/IEC according to the timeline and method outlined in the protocol. In addition, the 
Investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 
10.6 
 Investigator’s Final Report 
Upon completion of the study, the Investigator, where applicable, should inform the institution; 
the Investigator/institution should provide the IRB/IEC with a summary of the study’s outcome 
and the Sponsor and regulatory authority(ies) with any reports required. 
10.7 
 Records Retention 
The PI must ensure that adequate records are maintained for the study including the protocol, 
protocol amendments, source document worksheets and DVDs of electronic case record books, 
source documents, signed ICFs, drug accountability records, AE reports, screening logs, records 
of drug accountability, subject charts and records, laboratory reports, IRB approvals, 
correspondence with IRB, correspondence with Sponsor, all documents submitted to Sponsor, all 
documents submitted to regulatory and government authorities, other source documents, other 
pertinent data and all study communications, whether written, telephonic, or electronic. 
These files must be available for audit or inspection at any time by the Sponsor, monitor, and/or 
applicable regulatory authorities. 
None of the required documents may be destroyed or transferred to the control of another party 
without the written approval of the Sponsor. Subject medical records may be archived in 
accordance with the archiving regulations or facilities of the investigational sites. 
As required by 21CFR 312.62, Investigators must retain essential documents for a period of 2 
years following approval to market of the product in the same indication or for a period of 2 
years from the time the FDA is notified that development in the same indication has been 
discontinued. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. It is the responsibility of the 
Sponsor to inform the Investigator/institution as to when these documents no longer need to be 
retained. 
The Sponsor will inform the PI/institution in writing of the need for record retention and will 
notify the PI/institution in writing when the trial related records no longer need to be retained. 


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10.8 
 Publications 
After completion of the study, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, the Sponsor will be responsible for these 
activities and will work with the Investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The Sponsor has final approval authority over all such issues. 
Data are the property of the Sponsor and cannot be published without prior authorization from 
the Sponsor, but data and publication thereof will not be unduly withheld.  
Authorship will be determined by mutual agreement and in line with the International Committee 
of Medical Journal Editors (ICMJE) authorship requirements. Any formal publication of the 
study in which contribution of Sponsor personnel exceeded that of conventional monitoring will 
be considered as a joint publication by the Investigator and the appropriate Sponsor personnel, 
following the same ICMJE guidelines and requirements. 
Any inventions and resulting patents or improvements originating from the use of data from this 
study will become and remain exclusive and unburdened property of the Sponsor. 
 
11.0 STUDY MANAGEMENT 
11.1 
 Study Termination 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the right 
to discontinue the study at any time for clinical or administrative reasons. 
If the clinical study is prematurely terminated or suspended, the Sponsor will inform the 
Investigator and the regulatory authorities of the termination/ suspension and the reason(s) for 
the termination/suspension. The Investigator should promptly notify the IEC/IRB of the 
termination or suspension and of the reasons. The Sponsor reserves the right to close the 
investigational site or terminate the study in its entirety at any time, for reasonable cause. 
Reasons for the closure of an investigational site or termination of a study may include: 
• Unsatisfactory subject enrollment; 
• The Investigator fails to comply with the protocol or GCP guidelines; 
• Incidence or severity of AEs indicate a potential safety concern; and/or 
• Sufficient data suggesting lack of efficacy. 
If the Sponsor terminates the study for safety reasons, it will immediately notify the 
Investigator(s) by telephone and subsequently will provide written confirmation of and 
instructions for study termination. The Investigator may be informed of additional procedures to 


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be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The Investigator will be responsible for informing the IRBs/IECs of the early 
termination of the trial. 
11.2 
 Protocol Amendments 
Modification of the protocol, except as necessary to remove an apparent, immediate hazard to the 
subject, is prohibited without prior written agreement in the form of a protocol amendment. All 
amendments will be created by the Sponsor and must be approved by the IEC/IRB and 
regulatory authorities prior to implementation except when required to mitigate immediate safety 
risks or when the changes involve only logistical or administrative revisions. 
11.3 
 Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by the 
applicable regulatory requirement(s). The Sponsor will also ensure that the clinical study reports 
in marketing applications meet the standards of the ICH Guideline E3: Structure and Content of 
Clinical Study Reports.  
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study report. The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the opportunity 
to review the complete study results. 
Upon completion of the clinical study report, the Sponsor will provide the Investigator with the 
full summary of the study results. The Investigator is encouraged to share the summary results 
with the study subjects, as appropriate. The study results will be posted on publicly available 
clinical trial registries. 
 
 


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12.0 
APPENDICES 
Appendix 1:  Unscheduled Safety Assessment Visits 
Appendix 2:  Grading Scale for Assessment of Anterior Chamber Flare or Cells, Vitreous 
Hemorrhage Density, and Vitreous Haze 
Appendix 3:  Protocol Amendment History 
 
 


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12.1 
Appendix 1: Unscheduled Safety Assessment Visits 
Assessments performed at unscheduled safety visits are at the discretion of the Investigator. The 
following safety assessments are recommended: 
• Vital signs (blood pressure, respiration rate, pulse, temperature); 
• Hematology, serum chemistry panel, and coagulation panel; 
• Best corrected visual acuity; 
• Slit-lamp examination (both eyes); 
• Tonometry (both eyes); 
• Indirect ophthalmoscopy (both eyes); 
• Adverse events*; 
• Concurrent ocular procedures; and 
• Concomitant medications. 
*The causality of adverse events is to be evaluated by a masked physician. 
 
 


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12.2 
Appendix 2: Grading Scale for Assessment of Anterior Chamber Flare or Cells, 
Vitreous Hemorrhage Density, and Vitreous Haze 
12.2.1 
Grading Scales for Anterior Chamber Cells or Flare 
 
The SUN Working Group Grading Scale for Anterior Chamber Cells 
Grade 
Cells in Field1 
0 
< 1 
0.5+ 
1-5 
1+ 
6-15 
2+ 
16-25 
3+ 
26-50 
4+ 
>50 
Abbreviations: SUN = Standardization of uveitis nomenclature. 
1 
Field size is a 1 mm by 1 mm slit beam 
Source: Jabs 2005 
The SUN Working Group Grading Scale for Anterior Chamber Flare 
Grade 
Cells in Field1 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens details clear) 
3+ 
Marked (iris and lens details hazy) 
4+ 
Intense (fibrin or plastic aqueous)  
Abbreviations: SUN = Standardization of uveitis nomenclature. 
2 
Field size is a 1 mm by 1 mm slit beam 
Source: Jabs 2005 
 
 
 


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12.2.2 
Grading Scale for Vitreous Cells 
Grade 
Description 
0 
No Cells 
½+  
1-10 
1 + 
11-20 
2 + 
21- 30 
3 + 
31 - 100 
4+ 
Greater than 100 
Source: Foster 2002 
 
12.2.3 
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 
 
 




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13.0 REFERENCE LIST 
1. 
Brown DM, Kaiser PK, Michels M, et al., (2006). ANCHOR Study Group. Ranibizumab 
versus verteporfin for neovascular age-related macular degeneration N Engl J 
Med.;355(14):1432-44. 
2. 
Campochiaro PA at al, (2015). Molecular pathogenesis of retinal and choroidal vascular 
diseases. Prog Retin Eye Res;49:67-81. 
3. 
Cheung N, Mitchell P, Wong TY et al., (2010) Diabetic retinopathy. Lancet; 
376(9735):124-36 
4. 
Chew EY, Clemons TE, Agron E, et al., (2014). Ten-year follow-up of age-related 
macular degeneration in the age-related eye disease study. AREDS Report No. 36. JAMA 
Ophthalmol132(3):272-277. 
5. 
Chew EY, Clemons TE, Bressler SB, et al. (2014). Randomized trial of a home 
monitoring system for early detection of choroidal neovascularization home monitoring 
of the Eye (HOME) study. Ophthalmology, 121: 535-44. 
6. 
Chong V. (2016) Ranibizumab for the treatment of wet AMD: a summary of real-world 
studies. Eye (Lond);30(2):270-86.  
7. 
Flaxel CJ, Adelman RA, Bailey ST, et al. (2020). Diabetic Retinopathy Preferred 
Practice Pattern®. Ophthalmology, 127: P66-P145. 
8. 
Foster CS, Vitale AT. (2002) Diagnosis and Treatment of Uveitis, JP Medical Ltd. 
9. 
Gragoudas ES, Adamis AP, Cunningham Jr ET, et al. 2004. Pegaptanib for neovascular 
age-related macular degeneration. New England Journal of Medicine, 351: 2805-16. 
10. 
Heier JS, Brown DM, Chong V, et al., (2012). VIEW 1 and VIEW 2 Study Groups. 
Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. 
Ophthalmology. 2012 Dec;119(12):2537-48. 
11. 
Holz FG, Sadda SR, Busbee B, et al. (2018). Efficacy and safety of lampalizumab for 
geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 
randomized clinical trials. JAMA ophthalmology, 136: 666-77. 
12. 
Homayouni M. (2009). Vascular endothelial growth factors and their inhibitors in ocular 
neovascular disorders. Journal of ophthalmic & vision research, 4: 105. 
13. 
Jabs DA, Nussenblatt RB, Rosenbaum JT (2005). Standardization of Uveitis 
Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for 
reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 
140(3):509-16. 
14. 
Nguyen QD, Tatlipinar S, Shah SM, et al., (2006). Vascular endothelial growth factor is a 
critical stimulus for diabetic macula edema. Am J Ophthalmol;142(6):961-9. 


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15. 
Nguyen QN, Brown DM, Marcus DM, et al., (2012) RISE and RIDE Research Group. 
Ranibizumab for diabetic macular edema: results from 2 Phase III randomized trials: 
RISE and RIDE. Ophthalmology;119(4):789–801 
16. 
Nussenblatt RB, Palestine AG, Chan CC, Roberge F. (1985) Standardization of vitreal 
inflammatory activity in intermediate and posterior uveitis. Ophthalmology. 92(4):467-
71. 
17. 
Rosenfeld PJ, Brown DM, Heier JS, et al., (2006). MARINA Study Group. Ranibizumab 
for neovascular age-related macular degeneration. N Engl J Med;355(14):1419-31 
18. 
Rubio RG, Adamis AP et al., (2016). Ocular Angiogenesis: Vascular Endothelial Growth 
Factor and Other Factors. Dev Ophthalmol.;55:28-37 
19. 
Souied EH, Dugel PU, Ferreira A, et al. (2016). Severe Ocular Inflammation Following 
Ranibizumab or Aflibercept Injections for Age-Related Macular Degeneration: A 
Retrospective Claims Database Analysis. Ophthalmic Epidemiol, 23: 71-9. 
20. 
Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group. 
(2014). The neovascular age-related macular degeneration database: multicenter study of 
92 976 ranibizumab injections: report 1: visual acuity. Ophthalmology;121(5):1092-101. 
21. 
Wong WL, Su X, Li X, , et al., (2014). Global prevalence of age-related macular 
degeneration and disease burden projection for 2020 and 2040: a systematic review and 
meta-analysis. Lancet Glob Health.;2(2):e106-16. 
 
 

SAP_001.pdf: 
Official title: 
A Phase 2b/3, Prospective, Randomized, Double-masked,
Active Comparator-controlled, Multi-center Study to Investigate the Efficacy 
and Safety of Repeated Intravitreal Administration of KSI-301 in Subjects with 
Neovascular (Wet) Age-related Macular Degeneration (DAZZLE)
NCT Number:  
NCT04049266
Document Date:  
Statistical Analysis Plan Version 1.0, 03 February 2022






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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .............................................................................................1 
SPONSOR SIGNATORY .............................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF TABLES .........................................................................................................................4 
LIST OF ABBREVIATIONS .......................................................................................................5 
1.0 
INTRODUCTION..............................................................................................................7 
2.0 
STUDY OBJECTIVES ......................................................................................................7 
2.1 
Primary Objective ....................................................................................................7 
2.2 
Secondary Objectives ...............................................................................................7 
3.0 
INVESTIGATIONAL PLAN ...........................................................................................8 
3.1 
Study Design ............................................................................................................8 
3.2 
Treatments Administered .........................................................................................8 
3.3 
Method of Assigning Participants to Treatment Groups .........................................9 
3.4 
Selection and Timing of Dose for Each Participant .................................................9 
4.0 
TYPES OF PLANNED ANALYSES .............................................................................10 
4.1 
Data Monitoring Committee Analyses ..................................................................10 
4.2 
Interim Analyses ....................................................................................................10 
4.3 
Final Analyses ........................................................................................................10 
5.0 
GENERAL STATISTICAL METHODS ......................................................................11 
5.1 
Statistical Computing Software .............................................................................11 
5.2 
Reporting Conventions ..........................................................................................11 
5.3 
Standard Calculations ............................................................................................12 
5.4 
Study Definitions and Derived Variables ..............................................................13 
5.5 
Analysis Sets ..........................................................................................................13 
5.5.1 
Randomized Set Year 1 (RSY1) ...........................................................13 
5.5.2 
Randomized Set Year 2 (RSY2) ...........................................................13 
5.5.3 
Full Analysis Set Year 1 (FASY1) .......................................................13 
5.5.4 
Full Analysis Set Year 2 (FASY2) .......................................................13 
5.5.5 
Safety Set Year 1 (SSY1) ......................................................................14 
5.5.6 
Safety Set Year 2 (SSY2) ......................................................................14 
5.6 
Examination of Subgroups .....................................................................................14 
5.7 
Multiple Comparisons/Multiplicity .......................................................................15 
5.8 
Multicenter Studies ................................................................................................15 
5.9 
Analysis Visit .........................................................................................................15 
5.10 
Disposition of Subjects ..........................................................................................16 
IND No. 136167, SN 0036


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5.11 
Baseline Data .........................................................................................................16 
5.11.1 
Demographics and Other Baseline Characteristics (including Ocular 
Baseline Characteristics) .......................................................................16 
5.11.2 
Ocular and Other Medical History ........................................................18 
5.11.3 
Prior Medications ..................................................................................18 
5.12 
Protocol Deviations ................................................................................................18 
6.0 
EFFICACY ANALYSES ................................................................................................19 
6.1 
Primary Estimand ...................................................................................................19 
6.1.1 
Population targeted by the scientific question ......................................19 
6.1.2 
Primary Endpoint/Variable of Interest ..................................................19 
6.1.3 
Hypothesis to be Tested ........................................................................20 
6.1.4 
Intercurrent Events (ICE) ......................................................................20 
6.2 
Analysis of the Primary Endpoint ..........................................................................21 
6.2.1 
Sensitivity Analysis – Hypothetical Policy ...........................................21 
6.2.2 
Tipping Point Sensitivity Analyses of the Primary Endpoint ...............21 
6.3 
Secondary Efficacy Endpoints Year 1 ...................................................................23 
6.4 
Exploratory Efficacy Endpoints Year 1 .................................................................24 
6.5 
Year 2 Efficacy Endpoints .....................................................................................26 
6.6 
Subgroup Analyses ................................................................................................26 
7.0 
SAFETY EVALUATION ................................................................................................26 
7.1 
Exposure to Study Medication ...............................................................................26 
7.2 
Adverse Events ......................................................................................................27 
7.3 
Deaths, Serious Adverse Events, and other Significant Adverse Events ..............28 
7.4 
Pregnancies ............................................................................................................28 
7.5 
Clinical Laboratory Evaluations ............................................................................28 
7.6 
Vital Signs ..............................................................................................................28 
7.7 
Concomitant Medications and Procedures .............................................................29 
8.0 
SAMPLE SIZE CONSIDERATIONS ...........................................................................29 
9.0 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ..................................................................................................29 
10.0 
REFERENCES .................................................................................................................31 
11.0 
APPENDICES ..................................................................................................................31 
 
LIST OF TABLES 
Table 1: Windows for Unscheduled Visit ......................................................................................15 
IND No. 136167, SN 0036


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
 
ANCOVA 
Analysis of Covariance 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AMD 
Age-related Macular Degeneration 
AST 
Aspartate aminotransferase 
ATE 
Arterial Thromboembolic Events 
BCVA 
Best-Corrected Visual Acuity 
BP 
Blood Pressure 
CMH 
Cochran-Mantel-Haenszel  
CNV 
Choroidal Neovascularization 
CSR 
Clinical Study Report 
CST 
Central Subfield Thickness 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ET 
Early Termination 
ETDRS 
Early treatment diabetic retinopathy study 
FA 
Fluorescein Angiogram 
FASY1 
FASY2 
Full-Analysis Set Year 1 
Full-Analysis Set Year 2 
FDA 
Food and Drug Administration 
FP 
Fundus photography 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl-transferase 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug (application) 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LOQ 
Level of Quantification 
MAR 
Missing at Random 
MNAR 
Missing Not at Random 
MedDRA 
The Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
OCT 
Optical Coherence Tomography 
Q8W 
Every eight weeks 
IND No. 136167, SN 0036


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Q12W 
Every twelve weeks 
Q16W 
Every sixteen weeks 
Q20W 
Every twenty weeks 
RSY1 
Randomized Set Year 1 
RSY2 
Randomized Set Year 2 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSY1 
Safety Set Year 1 
SSY2 
Safety Set Year 2 
ULN 
Upper Limits of Normal 
VEGF 
Vascular Endothelial Growth Factor 
wAMD 
Wet (neovascular) Age-related Macular Degeneration 
WHODrug 
World Health Organization Drug Dictionary 
 
 
 
IND No. 136167, SN 0036


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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 KSI-CL-102 (Protocol 
Version 3.0, dated 02 June 2021), A Phase 2b/3, Prospective, Randomized, Double-masked, 
Active Comparator-controlled, Multi-center Study to Investigate the Efficacy and Safety of 
Repeated Intravitreal Administration of KSI-301 in Subjects with Neovascular (Wet) Age-related 
Macular Degeneration (DAZZLE). This study is conducted in accordance with the protocol, 
Good Clinical Practice (GCP), the Declaration of Helsinki, and any other applicable regulatory 
requirements.  
Descriptions of planned analyses are provided to avoid post hoc decisions that may affect the 
interpretation of the statistical analysis. 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 results to be presented in the clinical study report (CSR). 
Details about the unmasking plan, including the procedures and guidelines that Kodiak, study 
sites, and vendors will follow to ensure that masking of the study is appropriately maintained in 
the second year 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 herein; any changes or deviations from 
this SAP relative to the final analyses will be fully documented in the CSR. Minor changes or 
deviations from the templates for tables, figures, and listings need not be documented in the 
CSR. 
2.0 
STUDY OBJECTIVES  
2.1 
Primary Objective  
The primary objective of this study is to demonstrate that KSI-301 5 mg is non-inferior to 
aflibercept 2 mg with respect to mean change in BCVA from Day 1 to Year 1. Year 1 is defined 
as the mean of the Week 48 and 52 measurements. 
2.2 
Secondary Objectives  
The secondary objectives of this study are: 
• To evaluate the efficacy of KSI-301 5 mg compared to aflibercept 2 mg by assessing visual 
and anatomical parameters. 
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• To evaluate the durability of KSI-301 5 mg as measured by the proportion of subjects on 
Q12W, Q16W or Q20W dosing regimens.  
• To evaluate the safety and tolerability of KSI-301 5 mg compared to aflibercept 2 mg. 
• To assess the systemic pharmacokinetics and immunogenicity of KSI-301. 
3.0 
INVESTIGATIONAL PLAN 
3.1 
Study Design  
This is a prospective, randomized, double-masked, active comparator controlled, multi-center 
Phase 2b/3 study that will evaluate the efficacy and safety of KSI 301 compared with aflibercept 
in subjects with treatment-naive wAMD. 
The schedule of activities is provided in Appendix 1.  
The study is divided into a 3-week screening period, a 92-week treatment period, and a final 
4-week follow-up period.  
First Year (Day 1 through Week 52): 
At baseline subjects will be randomized 1:1 into two treatment arms: KSI-301 5 mg and 
aflibercept 2 mg. All subjects will receive 3 monthly loading doses of their assigned treatment. 
Thereafter the dosing regimen of subjects in the KSI-301 treatment arm will be Q12W to Q20W 
based on Year 1 disease activity assessments. The dosing regimen of subjects in the aflibercept 
treatment arm following the three initial injections will be fixed at Q8W. 
Second Year (Week 52 through Week 96): 
Beginning at Week 52, the dosing regimen of subjects in the KSI-301 treatment arm will be 
based on Year 2 Disease Activity Assessments.
 
End of Study Treatment and End of Study Participation 
Subjects who discontinue study drug should not be considered withdrawn from the study unless 
they withdraw consent or there is additional risk to the subject. Subjects 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, Week 52 and Week 96 visits. 
3.2 
 Treatments Administered 
KSI-301 investigational product will be provided by the Sponsor as a sterile solution for 
intravitreal injection. KSI-301 Drug Product is an aqueous solution that is provided in single-use 
vials and filled into syringes by unmasked site personnel without reconstitution or dilution. 
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The aflibercept active comparator product will be supplied by the Sponsor as a sterile liquid for 
intravitreal injection. Aflibercept is an aqueous solution that is provided in single-use vials and 
filled into syringes by unmasked site personnel without reconstitution or dilution. 
The sham vial is an empty glass vial which will remain empty throughout the sham treatment 
procedure. A sham injection is used for masking purposes and mimics an intravitreal injection. It 
involves pressing the blunt end of an empty syringe, without a needle, against an anesthetized 
eye. A sham vial is provided to help maintain masking of the study. Sham injections are given at 
every monthly visit in which an active KSI-301 or aflibercept injection is not administered. 
3.3 
Method of Assigning Participants to Treatment Groups  
Subjects who meet all inclusion criteria and none of the exclusion criteria are randomized using 
the Interactive Response Technology (IRT) system. Treatment assignments are based on a 
predetermined randomization schedule developed by The Emmes Company, LLC, Rockville, 
MD.  
Randomization is stratified by baseline
 
 
 
 
  
3.4 
Selection and Timing of Dose for Each Participant 
At each visit in which treatment is scheduled to be administered, each participant will receive 
intravitreal injections of study treatment or a sham injection to maintain masking.  
Year 1 (Day 1 through Week 52 [Pre-Treatment]):  
KSI-301 Arm:  
Following the 3 initial injections, the dosing regimen will be based on disease activity 
assessments and may vary from Q12W to Q20W.  
Aflibercept Arm:  
Following the 3 initial monthly injections, subjects randomized to aflibercept will be dosed at a 
fixed Q8W dosing regimen for the duration of the first year. 
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Year 2 (Week 52 through Week 96):  
KSI-301 Arm:  
Beginning at Week 52, dosing regimen adjustments in the KSI-301 group will also be based on 
disease activity assessments, but the dosing regimens can be adjusted to both reduce or extend 
the treatment interval in increments of Q4W per dosing cycle, although the adjustment of Q20W 
to Q12W is also allowed when needed. The minimum dosing interval is Q12W and the 
maximum dosing interval is Q20W.  
  
 
  
4.0 
TYPES OF PLANNED ANALYSES 
4.1 
Data Monitoring Committee Analyses  
An Independent Data Monitoring Committee (IDMC) will monitor study conduct and safety on 
an ongoing basis. Members of the IDMC will be external to the Sponsor and will follow a charter 
that outlines the IDMC membership and responsibilities, the timing of IDMC meetings, the 
content of the analysis report for the IDMC meetings, and the communication with the Sponsor. 
The IDMC can recommend changes to the conduct of the study based on the evaluated data and 
may recommend stopping the study early for safety reasons only as detailed in the charter.  
4.2 
Interim Analyses 
 
 it was not performed.  
4.3 
Final Analyses 
The analysis of the primary (Year 1) data will be performed when all subjects have either 
completed the Week 52 visit or have discontinued from the study prior to the Week 52 visit, 
whichever comes later, and the Year 1 data are cleaned and verified as appropriate, frozen, and 
unmasked. Safeguards will be put in place to ensure that the unmasking does not introduce 
operational biases in the conduct of the ongoing study. Details of the unmasking plan are 
described in a separate document.  
Analysis of data for Year 2 of the study will be performed when all subjects have either 
completed the Week 96 visit or have discontinued from the study, and all data have been entered 
into the database, cleaned and verified as appropriate, and the database locked. 
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5.0 
GENERAL STATISTICAL METHODS 
5.1 
Statistical Computing Software 
SAS Version 9.4 or higher (SAS Institute Inc., Cary NC, USA) will be used for the study 
analyses described in this SAP. 
5.2 
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 subjects combined. In 
general, all data collected and any derived data will be presented in subject data listings, for all 
randomized subjects. Listings will be ordered by treatment group, subject number, and 
assessment or event date. The treatment groups will be displayed in the same order as the 
summary tables. The treatment groups presented in listings will be based on the planned 
assignment, unless otherwise noted. 
In general, continuous variables will be summarized to indicate the study population sample size 
(N), number of subjects with available data (n), mean, SD, median, 25th (Q1) and 75th (Q3) 
quartiles, minimum, and maximum values. Categorical variables will be summarized by the 
population size (N), number of subjects with available data (n), number of subjects in each 
category, and the percentage of subjects in each category. Unless otherwise noted, the 
denominator to determine the percentage of subjects in each category will be based on the 
number of subjects with available data. The denominator for percentages for incidence data (such 
as adverse events) will be based on the number of subjects in the analysis population “at risk.” 
Select ordinal data may be summarized using both descriptive statistics and counts and 
percentages of subjects in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Percentages that round down to 0 or 
up to 100% will be displayed as “<0.1%” and “>99.9%”, respectively. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form e.g., on the electronic case report form 
(eCRF) and are outlined as follows: 
• The mean and median will be rounded to an additional decimal place than the precision 
of the variable of summarization;  
• Measures of variability (e.g., SD, SE) will be rounded to two additional decimal places 
than the precision of the variable of summarization; and 
• Minimum and maximum values will be presented using the same precision as the 
variable of summarization. 
Other statistics (e.g., CIs) will be presented using the same general rules outlined above or 
assessed for the most appropriate presentation based on the underlying data. 
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Unless stated otherwise, statistical significance testing will be two-sided and performed using 
α=0.05. Confidence intervals (CIs) will be calculated at the 95% level, reflecting a type I error 
rate of 0.05. P-values will be reported for all statistical tests, rounded to four decimal places. P-
values less than 0.0001 will be displayed as “<0.0001”; p-values greater than 0.9999 will be 
displayed as “>0.9999”.  
5.3 
Standard Calculations 
Where appropriate, the calculated study day will be presented with the assessment or event date 
on subject data listings. Study day will be determined as: 
• The assessment/event date minus the date of first dose of study drug, if the 
assessment/event date is prior to the date of first dose; and 
• The assessment/event date minus the date of first dose of study drug, plus one, if the 
assessment/event date is on or after the date of first dose. 
Start and stop dates will be imputed when partial dates are present as needed, to determine 
treatment emergent events and concomitant medications/procedures. No imputations will be 
done for a completely missing start/stop date or for subjects who did not receive study treatment. 
Start dates with a missing day but with month and year available will be imputed such that: 
• If the provided month and year match the month and year for that subject’s first dose 
date, then the Day 1 date will be used. 
• In all other cases the 1st of the month will be used with the provided month and year. 
Start dates with a missing day and month but with available year will be imputed such that: 
• If the provided year matches the year for that subject’s first dose date, then the first dose 
date will be used. 
• In all other cases the 1st of January will be used with the provided year. 
Stop dates will be imputed as follows: 
• Missing day with a provided year and month will use the last day of the month. 
• Missing day and month with provided year will use December 31. 
If the imputed stop date is greater than the last study date for the subject, then the imputed date 
will be replaced with the last available event date for the subject in the study. 
Other variables requiring calculations will be derived using the following formulas: 
• Days: A duration between two dates expressed in days will be calculated using the 
following conventions: 
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- 
Later date – earlier date + 1. 
• Months: A duration expressed in months will be calculated by dividing the duration in 
days by (365.25 /12). 
• Years: A duration expressed in years will be calculated by dividing the duration in days 
by 365.25. 
 
5.4 
Study Definitions and Derived Variables 
• Unless otherwise specified, the duration of Study Year 1 is defined as Study Day 1 until 
Week 52 (pre-treatment), as it is meant to be inclusive both of study treatments leading to 
the primary efficacy outcome at Year 1 and of safety assessments in that period.  
• Similarly, the duration of Study Year 2 is defined as being from Week 52 (post-
treatment) onwards until week 96, unless otherwise specified.  
• Year 1 baseline values are defined as the most recent values prior to the first dose of 
study treatment. That is, for values collected at the Day 1 visit pre-treatment, those values 
will be considered baseline. For data collected only at the screening visit but not at Day 1, 
the screening visit values will be considered the baseline.  
• Baseline for Year 2 for the re-randomized aflibercept group is defined as the last value 
prior to the re-randomization. 
 
5.5 
Analysis Sets 
5.5.1 
Randomized Set Year 1 (RSY1) 
The set will include all randomized subjects in Year 1.  
5.5.2 
Randomized Set Year 2 (RSY2) 
The set will include all subjects who were re-randomized to aflibercept 2 mg or KSI-301 5 mg 
Q8W. Subjects will be analyzed according to their assigned treatment at re-randomization. 
5.5.3 
Full Analysis Set Year 1 (FASY1) 
The set includes all randomized subjects who received at least one active study treatment (KSI-
301 or aflibercept) in Year 1. Subjects will be analyzed according to their randomized treatment. 
5.5.4 
Full Analysis Set Year 2 (FASY2) 
The set includes all randomized subjects who received at least one active study treatment 
(KSI-301 or aflibercept) in Year 2. Subjects will be analyzed according to their randomized 
treatment. 
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5.5.5 
Safety Set Year 1 (SSY1) 
The set includes all subjects who received any study treatment in Year 1.  
5.5.6 
Safety Set Year 2 (SSY2) 
The set includes all subjects who received any study treatment in Year 2. Subjects will be 
analyzed according to treatment they actually received. 
5.6 
Examination of Subgroups 
The primary efficacy endpoint will be summarized in the following subgroups of baseline 
characteristics: 
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 
BCVA 
• 
BCVA: ≥70 letters 
• 
BCVA: 69-50 letters 
• 
BCVA: ≤ 49 letters 
 
 
 
 
 
Geographic location 
• 
North America 
• 
Rest of World 
Race 
• 
White 
• 
Black or African American 
• 
Asian 
• 
American Indian or Alaska Native 
• 
Native Hawaiian or other Pacific Islander 
• 
Other 
Lens status 
• 
Phakic  
• 
Pseudophakic 
• 
Aphakic 
CNV lesion type 
• 
Classic or Predominantly Classic 
• 
Minimally Classic or Occult 
• 
Other: RAP or PCV Lesion 
• 
Ungradable 
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Other subgroups analyses may be explored. 
5.7 
Multiple Comparisons/Multiplicity 
A nominal type I error penalty of 0.0001 will be applied for each of the three unmasked safety 
reviews undertaken by the independent data monitoring committee prior to the primary analysis.  
Thus, the primary efficacy endpoint will be tested using a two-sided significance level of 0.0497. 
Multiplicity adjustments are not planned for any other endpoints. 
5.8 
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. 
5.9 
Analysis Visit  
For efficacy analyses, unscheduled or early termination visits will be assigned a visit day and 
then mapped to the appropriate analysis window as detailed in Table 1. In the event where more 
than one visit falls in the same analysis window, the following rules will be used in sequence to 
determine the record that will be analyzed: 
• If there is a scheduled visit in the analysis window, then the scheduled visit’s data will be 
used. 
• If there is no scheduled visit in the analysis visit window, the data closest to the 
scheduled day/time visit will be used. 
• If there is no scheduled visit in the analysis visit window and there is a tie between the 
visits with regards to the number of days/hours before and after the scheduled day, the 
later data will be used. 
Visit windows will not apply to listings. 
Windowing will be applied to the data prior to any missing data imputations or analysis. 
Table 1: Windows for Unscheduled Visit 
 
Nominal Visit 
Scheduled Study 
Day 
Starting Day for 
Nominal Visit 
Ending Day for 
Nominal Visit 
Day 1 
1 
1 
1 
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Week 1 
7 
4 
14 
Week 4 
28 
15 
42 
Week 8 – Week 96 
Week*7 
(Week*7)-13 
(Week*7)+14 
 
5.10 
Disposition of Subjects 
Subject disposition will be summarized for all subjects by treatment group and for all subjects 
combined in Year 1. Summaries will include the number of subjects screened and randomized, 
and number of subjects (%) in the FASY1 and SSY1 populations, completing the treatment in 
Year 1, and discontinuing Year 1 study treatment early by the reason for discontinuation. Subject 
disposition will also be summarized separately for each study site. 
Summaries for Year 2 will be produced. They will include the number and percentage of subjects 
, subjects completing the study, and subjects discontinuing study treatment early 
by the reason for study discontinuation. 
Subject completion status, date of study completion/discontinuation, study day of 
discontinuation, and reason for discontinuation will be listed.  
Inclusion and exclusion eligibility will be listed. 
5.11 
Baseline Data 
5.11.1 
Demographics and Other Baseline Characteristics (including Ocular Baseline 
Characteristics) 
Summaries of demographics and baseline characteristics will include 
• Sex 
• Age continuous  
• Age categorical <65, ≥ 65, < 75, ≥75, 65-74, 75-84, >85 years of age  
• Ethnicity  
• Race 
• Geographical region (North America, Rest of World) 
• Smoking status 
• Systolic and diastolic blood pressure  
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• Intraocular pressure in the study eye 
• Intraocular pressure in the study eye, categorical (≤21, 22-29, >29 mmHg) 
• Lens status (phakic, pseudophakic, aphakic) 
• BCVA: by stratification categories and continuous 
• 
  
• LLVA: continuous 
• Ocular Imaging:  
• OCT: 
• Central Subfield Thickness (CST; 
 
• Intraretinal fluid: Presence/Absence, presence/absence within the central 1mm 
• Subretinal fluid: Presence/Absence, presence/absence within the central 1mm, 
height of SRF at center point 
• Subretinal hyperreflective material (SHRM): presence/absence, presence/absence 
within the central 1mm, height of SHRM at the center point 
• Pigment epithelial detachment (PED): presence/absence, presence/absence in the 
central 1mm 
• Outer retinal tubulation: presence/absence, presence/absence within the central 
1mm 
• FA: 
• Presence/absence of leakage; presence/absence of leakage at the foveal center; 
area of leakage associated with CNV 
• Total area of CNV 
• Total lesion area 
• Type of lesion (e.g., classic, predominantly classic, minimally classic, occult, 
RAP lesion, PCV lesion, ungradable) 
• CNV location (e.g., subfoveal, juxtafoveal, extrafoveal) 
• Presence/absence of RPE atrophy 
• Presence/absence of subretinal hemorrhage 
• Presence/absence of fibrosis 
• FP: 
• Hemorrhage: presence/absence, presence/absence inside the central millimeter, 
involvement of foveal center 
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• Fibrosis: presence/absence, presence/absence inside the central millimeter, 
involvement of foveal center 
• Drusen: visible/not visible 
Results will be presented by treatment group overall and by site for the Year 1 full analysis set 
population (FASY1), and for Year 2 re-randomized aflibercept subjects (FASY2).  
 
Individual participants’ demographics and baseline characteristics used for stratification will be 
listed. 
5.11.2 
Ocular and Other Medical History 
Medical history including non-ocular events and ocular events for the study and fellow (non-
study) eyes will be tabulated by system organ class and preferred term of the MedDRA 
dictionary. Two listings will be provided: one listing for all non-ocular medical history and an 
additional one for ocular history by treatment, subject, and study/non-study eye. 
5.11.3 
Prior Medications 
Prior medications (ocular and non-ocular) will be summarized by Anatomical Therapeutic 
Chemical (ATC4) class and preferred name according to the WHODrug Global medications 
dictionary. Prior medications are those that have a start date prior to the first study treatment. 
Ocular medications will be presented separately for the study eye and fellow eye. Prior 
medications will also be classified as to whether they were still being taken by the patient on Day 
1. A listing of all prior medications will be provided. 
5.12 
Protocol Deviations 
All major protocol violations will be determined and categorized prior to Year 1 unmasking and 
at the end of the study, prior to final database lock and unmasking. The number and percentage 
of subjects with any major protocol deviation as well as the number and percentage of subjects 
with deviations within each category of major deviation will be presented.  
Major protocol deviations will be summarized by treatment group and all treatment groups 
combined for the FASY1 and FASY2 populations. The summaries will also be presented by site.  
Major protocol deviations will also be listed by subject.  
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6.0 
EFFICACY ANALYSES 
6.1 
Primary Estimand 
6.1.1 
Population targeted by the scientific question 
The population targeted by the scientific question is patients with active, treatment-naïve 
choroidal neovascularization (CNV) due to age-related macular degeneration, a condition also 
called “wet AMD” or “neovascular AMD.”  
The most relevant aspects of the study eligibility criteria for defining this population include the 
following key inclusion and exclusion criteria: 
Inclusion criteria 
(1) Active, treatment-naïve choroidal neovascularization (CNV) secondary to AMD, 
including subfoveal, juxtafoveal and extrafoveal lesions or retinal angiomatous 
proliferations (RAP) lesions with a CNV component that affect the central 
subfield as evidenced by FA or OCT in the study eye at screening. 
(2) A lesion area <30 mm2 (12 disc areas) of any CNV lesion subtype in the study 
eye. 
(3) Intra and/or subretinal fluid and/or SHRM (subretinal hyperreflective material) 
affecting the central subfield of the study eye on OCT at screening. 
(4) BCVA ETDRS score between 80 and 25 letters (20/25 to 20/320 Snellen 
equivalent), inclusive, in the study eye at screening and reconfirmed at Day 1. 
Exclusion criteria 
(1) Any approved or investigational treatment for neovascular AMD (other than oral 
vitamin supplements) in the study eye at any time. 
(5) CNV secondary to other causes in the study eye, including pathologic myopia, 
angioid streaks, prior trauma, ocular histoplasmosis, or other. 
(6) Any history of macular pathology unrelated to AMD but affecting vision or 
contributing to subretinal or intraretinal fluid, such as central serous 
chorioretinopathy. 
 
6.1.2 
Primary Endpoint/Variable of Interest 
The variable of interest is visual acuity, a continuous variable measured at each study visit using 
the ETDRS BCVA approach. The primary efficacy endpoint is the mean change in BCVA from 
Day 1 to Year 1, with Year 1 is defined as the mean of the Week 48 and 52 measurements. 
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If the Week 48 or Week 52 assessment is missing, the available value will be used in the 
analysis. 
6.1.3 
Hypothesis to be Tested 
 
H0: μK - μA ≤ 
 letters  
vs 
HA: μK - μA > 
 letters 
Where μK and μA are the mean changes from baseline to the Weeks 48 and 52 average BCVA in 
the KSI-301 and aflibercept groups respectively. 
Non-inferiority will be demonstrated if the lower limit of the two-sided 95.03% confidence 
interval for the treatment difference (KSI-301 – aflibercept) is greater than the prespecified NI 
margin 
 ETDRS letters. Furthermore, superiority will be established if the lower limit of the 
two-sided 95.03% confidence interval for the treatment difference (KSI-301 – aflibercept) is 
greater than zero. 
6.1.4 
Intercurrent Events (ICE) 
The following intercurrent events (ICEs) may impact the assessment of the primary efficacy 
endpoint: 
1. Deviations from key inclusion/exclusion criteria as defined above. 
2. Treatment misallocation (including sham or active treatment) of more than 1 study 
treatment. 
3. Use of prohibited wAMD therapies in the study eye. 
4. Premature discontinuation from study treatment due to a) study eye adverse events or b) 
due to lack of efficacy. 
5. Premature discontinuation from study treatment due to events unrelated to study 
treatment such as malignancies, systemic infections, trauma, or other systemic adverse 
events that are not treatment-related, including discontinuations due to COVID-19. 
 
Intercurrent events will be classified by the Sponsor prior to treatment code unmasking to 
prevent potential bias. 
Intercurrent events will be tabulated by treatment group. 
Strategies for addressing the potential impact of these intercurrent events are described below. 
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6.2 
Analysis of the Primary Endpoint 
The primary efficacy endpoint will be estimated based on the FASY1, i.e., all randomized 
subjects who received at least one treatment injection in Year 1 and using all available post-
baseline measurements up to Week 52 or until the subject discontinues study treatment. The 
‘While on-Treatment’ policy will be applied for the primary endpoint. 
A Mixed Model for Repeated Measurements (MMRM) will be used. MMRM assumes Missing 
at Random and uses all available data in the prediction model. MMRM balances the benefits of 
preserving unbiased estimates because of randomization with the desire to obtain estimates for a 
comparison of true biological treatment effects. 
The model will include the categorical covariates of treatment group, visit, visit-by-treatment 
group interaction and randomization stratification factors as fixed effects. An unstructured 
subject covariance matrix will be assumed. The change from baseline in BCVA score averaged 
over Weeks 48 and 52 will be compared between treatment groups. The comparisons will be 
performed using a contrast over Weeks 48 and 52. 
If the model assuming an unstructured covariance matrix does not converge, a heterogenous 
compound symmetry structure or an AR(1) covariance structure will be fitted. 
6.2.1 
Sensitivity Analysis – Hypothetical Policy 
A sensitivity analysis will be conducted using all subjects who do not have any of the following 
intercurrent events: deviations from key inclusion/exclusion criteria as defined above, treatment 
misallocations as defined above, and use of prohibited wAMD therapies in the study eye during 
the study treatment period. 
The sensitivity analysis based on this set is a type of ‘Hypothetical Policy’ strategy. The same 
type of MMRM as described for the primary analysis will be used.  
6.2.2 
Tipping Point Sensitivity Analyses of the Primary Endpoint 
Tipping point analyses will be conducted where an offset (‘delta based imputation’ penalty) is 
applied to the MAR imputation distribution applying a range of BCVA letters penalties ranging 
from 0 letter (MAR) 
 letters decrease 
 the non-inferiority threshold) in 0.5 letter 
decrements. The delta-based multiple imputations method will pertain to the following 2 groups 
of subjects: 
1. Tipping Point Analysis 1: Subjects randomized to the KSI-301 arm with missing data 
considered missing not at random (MNAR), i.e. subjects who prematurely discontinue 
from study treatment due to study eye adverse events or due to lack of efficacy  
2. Tipping Point Analysis 2: Subjects randomized to the KSI-301 who discontinue 
prematurely for any reason 
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The following steps will be undertaken (see Appendix 4 for SAS syntax):  
Step 1a: A fully conditional imputation model (FCS) with predictive mean matching will be 
applied to all subjects’ missing change from baseline BCVA values  
Step 1b: A penalty will be applied to the imputed primary efficacy endpoint for the Weeks 48 
and 52 in step 1a  
Fifteen complete data sets will be generated. The proposed number of imputed datasets will 
ensure an efficiency of at least 99% assuming a maximum of 12% rate of missing primary 
efficacy endpoint data using Rubin’s approximation (Rubin 1987). 
Step 2: a mixed model identical to the one used for the primary analysis will be run for each of 
the 15 imputed data sets 
Step 3: the estimated mean treatment differences from the 15 datasets for all imputations will be 
combined and Rubin’s method will be applied to derive an estimate of the 1-year treatment 
difference 
Steps 1-3 are repeated for each of the two data sets with scenario groups identified above in the 
KSI-301 treatment arm and for the range of penalties in the BCVA change from baseline. The 
tipping point in each will be the penalty value that will render the lower bound of the confidence 
interval for mean treatment differences to be greater than 4 letters decrease. After the tipping 
point is identified, clinical judgment will determine the plausibility of the assumptions 
underlying this tipping point.  
 
 
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6.3 
Secondary Efficacy Endpoints Year 1  
Secondary Efficacy 
Endpoint 
Variable Derivation/Source  
Summary Statistics 
 
Population 
Method of Analysis 
Proportion of subjects on the 
KSI-301 Q12W, Q16W or 
Q20W dosing regimen at 
Year 1 
For each subject in the KSI-301 arm, the 
duration (12, 16 or 20 weeks) from the last 
active treatment prior to Week 48 until the next 
active treatment at or after Week 48 is 
identified / IRT 
Proportion (%) 
 
FASY1  
 
 
Descriptive 
 
 
Number of study medication 
injections received in the 
KSI-301 and aflibercept 
groups during the first year 
of treatment 
 
For each subject the number of active (non-
sham) injections received from Day 1 to Week 
48 (inclusive) will be summed / IRT 
Median, Quartiles, Mean, 
Distribution 
 
FASY1 
Descriptive 
 
Mean change from baseline 
in BCVA over Weeks 36 to 
52 and over Weeks 36 to 40 
Continuous endpoint. Change from Day 1 to 
each timepoint. 
Visual Acuity Score/EDC 
Least Squares Mean difference 
in change from baseline at 
each time point 
 
FASY1 
Contrast for average of Weeks 36 to 
Week 52 and Weeks 36 to 40 using 
the MMRM model used for deriving 
the primary endpoint estimate 
Proportion of subjects who 
gain ≥ 5, ≥10 and ≥15 letters 
from baseline over time in 
Year 1 
 
Binary endpoints: subject has a BCVA gain ≥ 5 
(yes/no); subject has a BCVA gain ≥ 10 
(yes/no); subject has a BCVA gain ≥ 15 
(yes/no).  
Visual Acuity Score/EDC                                      
Difference in proportions (%) 
and 95% CI at each time point  
 
FASY1 
Stratified analysis of the binary 
endpoint using CMH adjusting for 
baseline randomization stratification 
factors 
Proportion of subjects who 
lose ≥ 5, ≥10 and ≥15 letters 
from baseline over time in 
Year 1 
 
Binary endpoints: subject has a BCVA loss ≥ 5 
(yes/no); subject has a BCVA loss ≥ 10 
(yes/no); subject has a BCVA loss ≥ 15 
(yes/no).  
Visual Acuity Score/EDC 
Difference in proportions (%) 
and 95% CI at each time point  
 
FASY1 
Stratified analysis of the binary 
endpoint using CMH adjusting for 
baseline randomization stratification 
factors 
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Secondary Efficacy 
Endpoint 
Variable Derivation/Source  
Summary Statistics 
 
Population 
Method of Analysis 
Mean change from baseline 
in BCVA over time in Year 1  
 
Continuous endpoint. Change from Day 1 to 
each timepoint. 
Visual Acuity Score/EDC 
Least Squares Mean difference 
in change from baseline at 
each time point 
 
FASY1 
MMRM model used for deriving the 
primary endpoint estimate 
Proportion of subjects with 
BCVA Snellen equivalent of 
20/40 or better (69 or more 
ETDRS letters) from baseline 
over time 
Binary endpoint: subject has a BCVA Snellen 
equivalent of 20/40 or better (yes/no) at the 
timepoint. 
Visual Acuity Score/EDC 
Difference in proportions (%) 
and 95% CI at each time point  
 
FASY1 
Stratified analysis of the binary 
endpoint using CMH adjusting for 
baseline randomization stratification 
factors 
Proportion of subjects with 
BCVA Snellen equivalent of 
20/200 or worse (38 or fewer 
ETDRS letters) from baseline 
over time 
Binary endpoint: subject has a BCVA Snellen 
equivalent of 20/200 or worse (yes/no) at the 
timepoint. 
Visual Acuity Score/EDC 
Difference in proportions (%) 
and 95% CI at each time point  
 
FASY1 
Stratified analysis of the binary 
endpoint using CMH adjusting for 
baseline randomization stratification 
factors 
Mean change in OCT central 
subfield retinal thickness 
(CST) from baseline over 
time and at Year 1 averaged 
over Weeks 48 and 52 
Continuous Endpoint. Change from Day 1 to 
each timepoint 
  
 
Least Squares Mean difference 
in change from baseline to 
each timepoint 
FASY1 
MMRM adjusting for baseline CST, 
with time, treatment, and 
time*treatment interaction and 
randomization stratification as 
factors 
Unstructured covariance matrix 
 
 
6.4 
Exploratory Efficacy Endpoints Year 1  
Analysis of the following exploratory endpoints may be undertaken as deemed appropriate. 
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Exploratory Endpoint 
Variable/Source  
Summary Statistics 
 
Population 
Method of Analysis 
Mean change in CNV total lesion area 
on FA from baseline at Year 1 
 
Continuous endpoint. Change from 
Day 1 to Year 1 
 
Least Squares Mean difference in 
change from baseline at Year 1 
FASY1 
ANCOVA adjusting for baseline total 
CNV lesion area, with treatment and 
randomization stratification as factors 
 
Mean change in area of leakage on FA 
from baseline at Year 1 
 
Continuous endpoint. Change from 
Day 1 to Year 1 
  
Least Squares Mean difference in 
change from baseline at Year 1 
 
FASY1 
ANCOVA adjusting for baseline total 
CNV lesion area, with treatment and 
randomization stratification as factors. 
 
Proportion of subjects without 
intraretinal fluid on OCT from 
baseline to Year 1 over time 
Binary endpoint. Subject has no 
intraretinal fluid (yes/no) at the 
timepoint 
 
Difference in proportions (%) and 
95% CI at each time point  
 
FASY1 
Stratified analysis of the binary 
endpoint using CMH adjusting for 
baseline randomization stratification 
factors 
Proportion of subjects without 
subretinal fluid on OCT from baseline 
to Year 1 over time 
Binary endpoint. Subject has no 
subretinal fluid (yes/no) at the 
timepoint 
 
Difference in proportions (%) and 
95% CI at each time point  
 
FASY1 
Stratified analysis of the binary 
endpoint using CMH adjusting for 
baseline randomization stratification 
factors 
Proportion of subjects without 
pigment epithelial detachments on 
OCT from baseline to Year 1 
over time 
Binary endpoint. Subject has no 
pigment epithelial detachments 
(yes/no) at the timepoint 
 
Difference in proportions (%) and 
95% CI at each time point  
 
FASY1 
Stratified analysis of the binary 
endpoint using CMH adjusting for 
baseline randomization stratification 
factors 
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6.5 
Year 2 Efficacy Endpoints 
The same efficacy endpoints as described above for the Year 1 data set will be subsequently 
analyzed for the Year 2 data set.  
The Year 2 endpoints analyses will use the methodologies as described above for the 
corresponding Year 1 analyses as appropriate. The analysis population will be the FASY2 set.  
 
 
 
 
2). 
6.6 
Subgroup Analyses 
For the subgroups described in Section 5.5, the change in BCVA from Day 1 to Year 1 (with 
Year 1 defined as the mean of the Week 48 and 52 measurements) will be analyzed using an 
MMRM. The model will include the categorical covariates of treatment group, visit, visit-by-
treatment group interaction factors as fixed effects and Day 1 as a covariate. An unstructured 
covariance matrix will be assumed.  
7.0 
SAFETY EVALUATION 
7.1 
Exposure to Study Medication 
Study eye exposure to study medication will be summarized. Summaries will include: 
• Mean (SD) and median number of injections, and number of subjects receiving ≥1 
injection, 1, 2, 3, 4, 5, etc. of KSI-301 or aflibercept injections from Day 1 to Week 48 
inclusive (SSY1), from Week 52 to Week 96 (SSY2), and from Day 1 to Week 96 
(SSY2).   
• Duration of study drug exposure (mean [SD] and median, in months) for subjects 
receiving KSI-301 5 mg or aflibercept 2 mg, for the SSY1 and SSY2 populations. 
Listings will include treatment (KSI-301, aflibercept, sham) and date of injection. 
A listing of subjects who received study treatment other than the one assigned at randomization 
will include the randomized treatment, the actual administered treatment, Visit, and study Day.  
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7.2 
Adverse Events 
Adverse events will be coded to a Medical Dictionary for Regulatory Activities Terminology 
(MedDRA) version 23.1 or later. AEs (Adverse Events) and SAEs (Serious Adverse Events) will 
be summarized and listed by ocular events for the treated eye, ocular events for the non-treated 
eye, and non-ocular (systemic) events. 
Adverse events starting after the first study injection and continuing until 4 weeks (28 days) after 
the last study injection will be considered treatment emergent AEs (TEAE).  
If the severity score of an adverse event is missing, the severity score will be imputed as severe. 
If the relatedness of an adverse event is missing, the adverse event will be considered related. 
At each level of summarization (e.g., any AE, system organ class, and preferred term), subjects 
experiencing more than one TEAE will be counted only once. In the summary of TEAEs by 
severity grade, subjects will be counted once at the highest severity reported at each level of 
summarization.  
Frequency tables including subjects’ incidence rates will be provided through Year 1 and 
separately from Year 1 to Year 2 for the following: 
• Ocular TEAEs and treatment-emergent serious AEs [TESAEs] (study eye and fellow eye 
separately) 
• Non-ocular TEAEs and TESAEs  
• Ocular TEAEs leading to study treatment discontinuation (study eye and fellow eye 
separately) 
• Per-injection rates of select ocular TESAEs including traumatic cataract, 
endophthalmitis, intraocular inflammation, and retinal detachment. The rate per injection 
is calculated as the number of serious events/total number of non-sham study treatment 
injections. 
• Ocular TEAEs by severity (study eye and fellow eye separately) 
• Non-ocular TEAEs by severity  
• Related ocular TEAEs (study eye and fellow eye separately) by severity 
• Related non-ocular TEAEs by severity  
• Intraocular Inflammation TEAEs (study and fellow eye separately). See Appendix 3 for 
preferred terms used to identify events of IOI 
• Intraocular Inflammation TESAEs (study and fellow eye separately) 
• Intraocular Pressure: mean and mean change from baseline in pre-injection and post-
injection IOP, and mean and mean change from pre-injection to post-injection IOP, over 
time in the study eye. Baseline is defined as the pre-injection value at Day 1.  
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• Arteriothromboembolic Adverse Events. See Appendix 2 for preferred terms used to 
identify ATEs.  
• Adverse events of special interest [AESI], as defined in the protocol 
Adverse event data will be presented in data listings by treatment group, subject, and event date. 
Serious AEs, AEs leading to discontinuation of the study drug, intraocular inflammation adverse 
events, and arteriothromboembolic adverse events will be presented in separate data listings. 
Adverse events for subjects who remain in the study after study treatment discontinuation will be 
listed.  
7.3 
Deaths, Serious Adverse Events, and other Significant Adverse Events 
All deaths during the study will be listed by treatment group and subject and will include the 
primary cause of death. Serious AEs and other significant AEs, including those that led to 
interruption or withdrawal of the study drug, will be provided in separate subject data listings. 
7.4 
Pregnancies 
Listings of pregnancies, if any, and outcomes will be presented.  
7.5 
Clinical Laboratory Evaluations 
Continuous laboratory parameters will be summarized, using mean, standard deviation, median, 
and range for each visit assessed. Laboratory parameters as well as change from baseline for 
each parameter will be presented at Year 1 and at Year 2 in the safety populations. 
Subjects with ALT or AST more than 3 times the Upper Limits of Normal (ULN) in combination 
with an elevated total bilirubin (more than 2 times the ULN); or ALT or AST more than 3 times 
the ULN in combination with clinical jaundice will be listed. 
Other clinical laboratory results through Year 1 and from Year 1 to Year 2 will be listed and 
values outside the normal ranges will be flagged along with the clinical significance. 
For summary of continuous laboratory parameters, values that are lower than the LOQ will be 
assigned a value that is 1 unit less than the LOQ. Values that are above the LOQ will be assigned 
a value that is 1 unit higher than the LOQ. 
7.6 
Vital Signs  
Vital signs including pulse, systolic/diastolic blood pressure, body temperature, height, weight, 
and BMI will be summarized by treatment group. Descriptive statistics will be presented for 
results and change from baseline at each visit where parameters were scheduled to be collected. 
Results will be presented by Year 1 and Year 2 in the safety populations. Vital signs will be 
listed by treatment group, subject, and visit date.  
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Vital signs will be summarized by visit and treatment group for the parameters collected. Vital 
sign parameters will also be listed. 
7.7 
Concomitant Medications and Procedures 
Concomitant medications during study treatment for Year 1 and Year 2 will be summarized. 
The number and percentage receiving any medication by ATC drug class (level 4) and generic 
drug name will be presented. Subjects reporting use of more than one medication at each level of 
summarization (any medication received, ATC class, and generic drug name) will be counted 
only once. ATC class terms will be displayed by descending order of incidence, as will generic 
drug names within each ATC class. 
The following will be summarized and listed: 
• Ocular (study eye and fellow eye separately) and non-ocular concomitant medications 
that were initiated before start of treatment.  
• Ocular (study eye and fellow eye separately) and non-ocular concomitant medications 
that were initiated after the start of treatment. 
• Medications prescribed after study treatment discontinuation for subjects who remain in 
the study will be listed separately.  
• Concomitant ocular procedures (study eye and fellow eye separately) administered while 
subjects were on study treatment will be summarized and listed.  
• Concomitant study eye procedures administered after study treatment discontinuation for 
subjects who remain in the study will be listed separately. 
8.0 
SAMPLE SIZE CONSIDERATIONS 
The sample size for this study has been determined based on a two-group evaluation of non-
inferiority using a t-distribution (one-sided significance level of 0.025) with a non-inferiority 
margin 
 BCVA letters difference in the change from baseline between treatment groups 
A sample size of 550 participants (275 per treatment arm) provides 91% percent power for the 
evaluation of non-inferiority assuming an expected treatment difference of 0 BCVA letters and a 
standard deviation of 
 letters, and an assumed dropout rate of 
 in each treatment arm. 
 
 No data were unmasked for the determination of the final study sample size.  
9.0 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES 
No changes in the conduct of the study have occurred relative to the latest version of the protocol 
at this time.  
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The study protocol was finalized prior to the FDA’s adoption of the ICH E9(R1) guidance on 
estimands and sensitivity analysis in clinical trials. In this SAP, the Sponsor has defined the 
primary estimand including the primary efficacy analysis and strategies for addressing 
intercurrent events, missing data, and a set of sensitivity analyses for the primary efficacy 
outcome. This overrides the definitions of the study populations and proposed analyses of the 
primary endpoint in the study protocol which predate the adoption of the ICH E9(R1) guidance. 
Other clarifications or changes in planned analyses in this SAP relative to those described in 
Version 3.0 of the Protocol include the following: 
• The definitions of Year 1 and Year 2 as applied to different endpoints were clarified 
• The secondary objective for evaluating the durability of KSI-301 was clarified 
• The Year 2 efficacy endpoints description was simplified   
• Several anatomic OCT endpoints originally described in the protocol as secondary endpoints 
were reclassified as exploratory endpoints  
• The endpoint related to predictability of subjects being maintained over time on a particular 
dosing regimen was removed because it is not informative given the flexibility of the KSI-
301 dosing regimen being evaluated in the study 
• Endpoints related to volumetric measurements of fluid parameters on OCT were removed 
due to data availability 
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10.0 
REFERENCES 
Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, 
myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of 
patients. Antiplatelet Trialists' Collaboration [published correction appears in BMJ 1994 Jun 
11;308(6943):1540]. BMJ. 1994;308(6921):81-106. 
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. Accessed November 13, 2021. 
US Food and Drug Administration Guidance Document – Non-Inferiority Clinical Trials to 
Establish Effectiveness (November 2016). Available at 
https://www.fda.gov/media/78504/download. Accessed November 13, 2021. 
Rubin, D.B. (1987) Multiple Imputation for Nonresponse in Surveys, New York, John Wiley 
and Sons. 
Littell, Ramon C., George Milliken, Walter W. Stroup, Russell D. Wolfinger, and Oliver 
Schabenberger (2006) SAS(R) for Mixed Models, 2nd Edition (2006), SAS Institute, Cary NC. 
Little, R.J.A. and Rubin, D.B. (2002). Statistical Analysis with Missing Data, 2nd edition, New 
York: John Wiley. SAS/STAT® 14.1 User’s Guide The MIANALYZE Procedure, SAS institute, 
Cary, NC, available online at 
https://support.sas.com/documentation/onlinedoc/stat/141/mianalyze.pdf (accessed Feb 1, 2022). 
SAS/STAT® 14.1 User’s Guide The MI Procedure, SAS institute, Cary, NC, available online at 
https://support.sas.com/documentation/onlinedoc/stat/141/mi.pdf (accessed Feb 1, 2022).  
van Buuren, Stef Flexible Imputation of Missing Data, 2nd Edition (2018) available online at 
https://stefvanbuuren.name/fimd/ (accessed Feb 1, 2022). 
 
11.0 
APPENDICES 
Appendix 1: Schedule of Activities 
 
 
  
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Appendix 1: Schedule of Activities  
 
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1 
Participants who discontinue study treatment should NOT be considered withdrawn from the study. Additional details are provided in Section 4.8 of the 
study protocol. 
2 
Ophthalmic assessments will be performed in both eyes at Screening, Week 52 and Week 96, and in the study eye only at all other timepoints. 
3 
Perform before any other ophthalmic assessments and prior to dilation. 
4 
Post-injection assessments include vision check for counting fingers and tonometry. The post-injection assessments should be performed by unmasked 
assessors. 
5 
Blood draws for ADA, plasma PK, and biomarker samples are to be taken pre-injection.  
6 
Urine pregnancy test will be performed locally for women of childbearing potential, prior to fluorescein angiogram and study treatment (if applicable). If 
urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. Local urine testing will be standard for the protocol unless serum testing 
is required by local regulation or IRB/IEC. 
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5 
Blood draws for ADA, plasma PK, and biomarker samples are to be taken pre-injection.  
6 
Urine pregnancy test will be performed locally for women of childbearing potential, prior to fluorescein angiogram and study treatment (if applicable). If 
urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. Local urine testing will be standard for the protocol unless serum testing 
is required by local regulation or IRB/IEC. 
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