A 52-week Multicenter, Randomized, Double-masked, 2-arm Parallel Study to Compare Efficacy, Safety and Immunogenicity of SOK583A1 to Eylea®, Administered Intravitreally, in Patients With Neovascular Age-related Macular Degeneration
Phase: PHASE3
Conditions: Neovascular Age-related Macular Degeneration
Sponsor: Sandoz

Sandoz Biopharmaceuticals Clinical Development
SOK583A1 (INN: aflibercept)
Clinical Trial Protocol CSOK583A12301 / NCT04864834
A 52-week multicenter, randomized, double-masked, 2-arm 
parallel study to compare efficacy, safety and 
immunogenicity of SOK583A1 to Eylea®, administered 
intravitreally, in patients with neovascular age-related 
macular degeneration
Document type:
Amended Protocol Version
EUDRACT number:
2019-004838-41
Version number:
4.0 Clean (incorporating amendment 3)
Clinical Trial Phase:
III
Release date:
28-Jun-2022 (content final)
Property of Hexal AG and Sandoz Inc.
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Hexal AG and Sandoz Inc.
Clinical Trial Protocol Template Version 4.0 (15-Feb-2021)

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Clinical Trial Protocol (Version No. 4.0 Clean)
Protocol No. CSOK583A12301
Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................5
List of figures.......................................................................................................................5
List of abbreviations ............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 3.....................................................................................................................11
Amendment 2.....................................................................................................................13
Amendment 1.....................................................................................................................15
Protocol summary..............................................................................................................17
1
Introduction........................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose...................................................................................................................21
2
Objectives and endpoints...................................................................................................22
2.1
Primary estimands..................................................................................................22
2.2
Secondary estimands..............................................................................................23
3
Study design.......................................................................................................................23
4
Rationale ............................................................................................................................25
4.1
Rationale for study design......................................................................................25
4.2
Rationale for dose/regimen and duration of treatment...........................................26
4.3
Rationale for choice of control drugs (comparator)...............................................26
4.4
Purpose and timing of interim analyses.................................................................26
4.5
Risks and benefits ..................................................................................................27
4.5.1
Blood sample volume............................................................................28
5
Study population................................................................................................................28
5.1
Inclusion criteria ....................................................................................................29
5.2
Exclusion criteria ...................................................................................................29
6
Treatment...........................................................................................................................32
6.1
Study treatment ......................................................................................................32
6.1.1
Investigational and control drugs ..........................................................32
6.1.2
Additional study treatments...................................................................32
6.1.3
Treatment arms/group ...........................................................................33
6.1.4
Treatment duration ................................................................................33
6.2
Other treatment(s) ..................................................................................................33
6.2.1
Concomitant therapy .............................................................................33
6.2.2
Prohibited medication............................................................................34

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Protocol No. CSOK583A12301
6.2.3
Rescue medication for the study eye.....................................................34
6.3
Participant numbering, treatment assignment, randomization...............................34
6.3.1
Participant numbering ...........................................................................34
6.3.2
Treatment assignment, randomization...................................................35
6.4
Treatment masking.................................................................................................35
6.5
Dose escalation and dose modification..................................................................38
6.6
Additional treatment guidance...............................................................................38
6.6.1
Treatment compliance ...........................................................................38
6.6.2
Recommended treatment of adverse events ..........................................38
6.6.3
Emergency breaking of assigned treatment code ..................................38
6.7
Preparation and dispensation .................................................................................39
6.7.1
Handling of study treatment and additional treatment ..........................39
6.7.2
Instruction for prescribing and taking study treatment..........................40
7
Informed consent procedures.............................................................................................41
8
Visit schedule and assessments..........................................................................................42
8.1
Screening................................................................................................................47
8.1.1
Information to be collected on screening failures .................................49
8.2
Participant demographics/other baseline characteristics........................................49
8.3
Efficacy..................................................................................................................49
8.3.1
Visual acuity..........................................................................................50
8.3.2
Spectral-domain optical coherence tomography (SD-OCT) .................50
8.3.3
Color fundus (CF) photography and fluorescein angiography (FA).....50
8.3.4
Appropriateness of efficacy assessments ..............................................51
8.4
Safety .....................................................................................................................51
8.4.1
Laboratory evaluations..........................................................................52
8.4.2
Immunogenicity.....................................................................................53
8.4.3
Complete ophthalmic examination........................................................54
8.4.4
Pregnancy and assessments of fertility..................................................55
8.4.5
Post-injection assessment......................................................................55
8.4.6
Appropriateness of safety measurements ..............................................56
8.5
Additional assessments ..........................................................................................56
8.5.1
Pharmacokinetics...................................................................................56
8.5.2
Imaging..................................................................................................57
8.5.3
Systemic VEGF concentrations.............................................................57
9
Discontinuation and completion ........................................................................................57
9.1
Discontinuation of study treatment and from study...............................................57

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Protocol No. CSOK583A12301
9.1.1
Discontinuation of study treatment .......................................................57
9.1.2
Discontinuation from study...................................................................58
9.1.3
Lost to follow up ...................................................................................58
9.2
Withdrawal of informed consent/Opposition to use data/biological samples........59
9.3
Study completion and post-study treatment...........................................................59
9.4
Early study termination by the Sponsor.................................................................60
10 Safety monitoring, reporting, and committees...................................................................60
10.1
Definition of adverse events and reporting requirements......................................60
10.1.1
Adverse events.......................................................................................60
10.1.2
Serious adverse events...........................................................................62
10.1.3
SAE reporting........................................................................................63
10.1.4
Pregnancy reporting...............................................................................64
10.1.5
Reporting of study treatment errors.......................................................64
10.2
Additional Safety Monitoring................................................................................64
10.3
Committees ............................................................................................................65
11 Data Collection and Database management ......................................................................65
11.1
Data collection .......................................................................................................65
11.2
Database management and quality control ............................................................65
11.3
Site monitoring.......................................................................................................66
12 Data analysis and statistical methods.................................................................................67
12.1
Analysis sets...........................................................................................................67
12.2
Participant demographics and other baseline characteristics.................................68
12.3
Treatments..............................................................................................................68
12.4
Analysis of the primary estimand ..........................................................................68
12.4.1
Definition of primary endpoint(s) .........................................................68
12.4.2
Statistical model, hypothesis, and method of analysis ..........................68
12.4.3
Handling of remaining intercurrent events of primary estimand ..........69
12.4.4
Handling of missing values not related with intercurrent events ..........69
12.4.5
Sensitivity analyses for primary estimand.............................................69
12.4.6
Supplementary analysis.........................................................................70
12.5
Analysis of secondary endpoints............................................................................70
12.5.1
Efficacy endpoint(s) ..............................................................................70
12.5.2
Safety endpoints ....................................................................................70
12.5.3
Pharmacokinetics...................................................................................72
12.6
Analysis of exploratory endpoints .........................................................................72
12.6.1
Evaluation of systemic VEGF concentrations.......................................72

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Protocol No. CSOK583A12301
12.7
Interim analyses .....................................................................................................72
12.8
Sample size calculation..........................................................................................73
12.8.1
Primary endpoint(s)...............................................................................73
12.8.2
Secondary endpoint(s)...........................................................................75
13 Ethical considerations and administrative procedures.......................................................75
13.1
Regulatory and ethical compliance........................................................................75
13.2
Responsibilities of the investigator and IRB/IEC..................................................75
13.3
Publication of study protocol and results...............................................................75
13.4
Quality Control and Quality Assurance.................................................................75
14 Protocol adherence.............................................................................................................76
14.1
Protocol amendments.............................................................................................76
15 References..........................................................................................................................76
16 Appendices.........................................................................................................................79
List of tables
Table 2-1
Objectives and related endpoints...........................................................22
Table 6-1
Investigational and control drug............................................................32
Table 6-2
Prohibited medication............................................................................34
Table 6-3
Masking and unmasking plan................................................................37
Table 8-1
Assessment schedule .............................................................................44
Table 8-2
Assessments and specifications.............................................................51
Table 8-3
Laboratory assessments.........................................................................52
Table 10-1
Guidance for capturing the study treatment errors................................64
Table 12-1
Treatment Least Square Means at Week 8............................................73
Table 12-2
Differences of Treatment Least Square Means at Week 8....................73
Table 12-3
Assumptions for sample size calculations based on FDA and EMA 
requirements ..........................................................................................74
List of figures
Figure 3-1
Study design ..........................................................................................25

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Protocol No. CSOK583A12301
List of abbreviations
ADA
Anti-drug antibody
AE
Adverse event
AMD
Age-related macular degeneration
ANCOVA
Analysis of covariance
ATC
Anatomical Therapeutic Chemical
BCVA
Best-Corrected Visual Acuity
CF
Color fundus photography
CI
Confidence interval
CMO&PS
Chief Medical Office and Patient Safety
CNV
Choroidal neovascularization
COVID-19
Coronavirus disease of 2019
CRC
Central Reading Center
CRO
Contract Research Organization
CSR
Clinical study report
CSFT
Central Subfield Thickness
DBL
Database lock
eCRF
Electronic Case Report/Record Form 
EOS
End of Study visit
ETDRS
Early Treatment Diabetic Retinopathy Study
EqM
Equivalence margin
Eylea EU
Europe-authorized Eylea®; the registered trademark sign “®” will be omitted for 
Eylea in this document
FA
Fluorescein Angiography
FAS
Full Analysis Set
FCS
Fully conditional specification
FSH
Follicle-stimulating hormone
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GCS
Global Clinical Supply
IAS
Immunogenicity Analysis Set
ICF
Informed Consent Form
ICH
International Council on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IOP
Intraocular pressure
IRB
Institutional Review Board
IRT
Interactive Response Technology
IVT
Intravitreal
LDH
Lactate dehydrogenase
LLOQ
Lower limit of quantification

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Protocol No. CSOK583A12301
MedDRA
Medical dictionary for regulatory activities 
MMRM
Mixed-model repeated measures
nAMD
Neovascular age-related macular degeneration
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
PK Analysis Set
PMDA
Pharmaceuticals and Medical Devices Agency (Japan)
PP
Per-Protocol
PPS
Per Protocol Set
q4w
Every 4 weeks
q8w
Every 8 weeks
RAS
Randomized Analysis Set
RPE
Retinal Pigment Epithelium
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome - Corona Virus - 2
SD
Standard deviation
SD-OCT
Spectral-Domain Optical Coherence Tomography
SmPC
Summary of Product Characteristics
SOK583A1
Product code of Sandoz’ proposed aflibercept containing biosimilar product
US PI
United States Prescribing Information
VEGF
Vascular Endothelium Growth Factor

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Central subfield 
thickness
Average thickness of circular area within 1 mm diameter around the foveal 
center from retinal pigment epithelium (RPE) to internal limiting membrane, 
inclusively 
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve masking of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Discontinuation 
from study
Point/time when the participant permanently stops receiving the study 
treatment (SOK583A1 or Eylea EU) and further protocol required 
assessments or follow-up, for any reason. No specific request is made to stop 
the use of their samples or data.
Discontinuation of 
study treatment
Point/time when the participant permanently stops receiving the study 
treatment (SOK583A1 or Eylea EU) for any reason (prior to the planned 
completion of study drug administration, if any). Participant agrees to the other 
protocol required assessments including follow-up. No specific request is 
made to stop the use of their samples or data.
Dosage
Dose of the study treatment given to the study participant in a time unit 
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from source documents used at the point of care
End of the clinical 
study
The end of the clinical study is defined as the last visit of the last participant 
Enrollment
Point/time of participant entry into the study at which informed consent must 
be obtained 
Estimand
A precise description of the treatment effect reflecting the clinical question 
posed by the study objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable.
Fellow eye
The participant’s contralateral eye not treated with study treatment
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest.
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Masked/evaluating 
Investigator
For the entire study duration and all study participants, the masked/evaluating 
Investigator is responsible for all aspects of the study (the conduct/supervision 
of all assessments and treatment decisions except the injection procedures 
and the safety assessment following the injections)
Medication 
number
A unique identifier on the label of medication kits in studies that dispense 
study drug using an IRT system.

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Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization, but have been inadvertently randomized into the study
Other treatments
Treatment that may be needed or allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Participant
A patient with the condition of interest for the study, i.e. neovascular age-
related macular degeneration, and who is willing to participate in the study and 
signed the ICF 
Participant 
Number
A unique number assigned to each participant upon signing the ICF. This 
number is the definitive, unique identifier for the participant and should be 
used to identify the participant throughout the study for all data collected, 
sample labels, etc.
Period
The subdivisions of the study design (e.g. Screening, Treatment, Follow up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical study database setup and eventually in analysis
Personal data
Participant information (participant identifier information, study information and 
biological samples) collected by the Investigator that is transferred to Sponsor 
for the purpose of the clinical study
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Randomization 
number
A unique identifier assigned to each randomized participant
Rescreening
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment 
and as specified by the protocol
Retesting
Safety laboratory tests and vital signs can be repeated once to confirm clinical 
significance or to exclude technical errors, as specified by the protocol. If the 
repeat test evaluation or result remains outside of the specified range for 
laboratory or vital signs, the participant must be considered as a Screen 
Failure
Screen Failure
A participant who did not meet 1 or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical 
study
The start of the clinical study is defined as the signature of the informed 
consent by the first participant
Study eye
The participant’s eye which complies with all eligibility criteria and is selected 
to be treated with study treatment
Study treatment
Any drug or combination of drugs or intervention administered to the study 
participant as part of the required study procedures
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 

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Protocol No. CSOK583A12301
the related clinical question of interest, which might or might not be the same 
as the study treatment.
Unmasked treating 
Investigator
For the entire study duration and all study participants, the unmasked treating 
Investigator only performs the injection and assesses participant safety 
following the injection 
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.
Visual acuity 
assessor
The visual acuity assessor (which could be a masked/evaluating Investigator) 
performs the BCVA assessments and is masked to the assigned treatment
Withdrawal of 
study consent
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data 

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Clinical Trial Protocol (Version No. 4.0 Clean)
Protocol No. CSOK583A12301
Amendment 3
Amendment rationale
This amendment to version 3.0 of the protocol of Study CSOK583A12301 includes the 
evaluation of systemic VEGF concentrations at Week 48 (pre-dose) and Week 52. The aim of 
this assessment is to evaluate the concentrations of systemic VEGF in the 2 treatment groups at 
Week 52, i.e. 4 weeks after IVA treatment with aflibercept. VEGF concentration at Week 48 
(pre-dose) will be used as baseline value to calculate the relative change in VEGF between 
Week 48 and Week 52. The VEGF evaluation was recommended by EMA in a scientific advice.
This amendment applies to those participants who agree to additional blood collection for the 
evaluation of systemic VEGF concentrations. They will document their agreement by signing 
the corresponding ICF. 
Study status
The study is ongoing. First participant first visit was on 11-May-2021, and recruitment was 
completed on 22-May-2022. The Sponsor will make all efforts to recruit as many participants 
as possible for the VEGF assessment.
Changes to the protocol
Section 2
•
The evaluation of systemic VEGF concentrations was added as an exploratory objective
Section 4.5.1
•
The evaluations of systemic VEGF concentration were added (including the required 
blood volume)
Section 7
•
Details of the updated ICF on evaluation of systemic VEGF concentrations were added
Section 8
•
The collection of additional blood samples was included in Table 8-1
Section 8.5.3 (new section)
•
The evaluation of systemic VEGF concentration was added
Section 12.1
•
The analysis set for the evaluation of systemic VEGF concentrations was added
Section 12.5.3
•
Additional assessment for the PK substudy was added 
Section 12.6.1 (new section)
•
The analysis of systemic VEGF concentrations was added
Other minor changes to wording were made. This includes a correction of the wording of the 
secondary endpoint CNV lesion size. Mean changes of CNV lesion size using FA from 
Screening to Week 8 and 52 will be evaluated.

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Changes to specific sections of the protocol are shown in the track changes version using strike 
through red font for deletions and red underlined font for insertions.
This amended protocol will be sent to the IEC/IRBs and HAs for approval or notification as 
required according to local regulations. 
The inclusion of additional time points for blood collection is a substantial change to the 
protocol.
An additional ICF will be composed and the eCRF will be updated in accordance with this 
amendment.

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Protocol No. CSOK583A12301
Amendment 2
Amendment rationale
The amendment to the version 2.0 of the protocol of Study CSOK583A12301 includes 
recommendations on SAE reporting provided by BfArM (SAEs need to be reported 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
learning of its occurrence).
Additionally, definition criteria for pathologic myopia (exclusion criterion #3) were modified 
and corresponding diagnostic methods were adapted. The combination of determining the 
spherical equivalent and analyzing the images assessed at screening are considered to be 
sufficient to exclude patients adequately from the study. 
The analyses of the primary estimand were updated and clarified. The study protocol language 
was additionally updated in line with the updated Sandoz protocol template, e.g. by clarifying 
discontinuation of study treatment and from study and related ICF handling.
Study status
The study is ongoing. First participant first visit was on 11-May-2021, and, as of 30-Nov-2021, 
161 participants have received study treatment.
Changes to the protocol
Section 2.1
•
The justification and attributes for primary estimands were revised
Section 4.5
•
Results from the safety review of the first 20 participants treated in the study was included 
in the benefit-risk assessment
Section 5.2
•
Definition criteria of pathologic myopia was modified in exclusion criterion #3 
Section 6.6.3
•
Breaking the masking code of a participant for further treatment after disease progression 
was removed (related to the updated Sandoz protocol template)
Section 9.1
•
Wording on withdrawal of study treatment was revised (new Section 9.1.1) (related to the 
updated Sandoz protocol template)
•
Wording on discontinuation from study was added (new Section 9.1.2) (related to the 
updated Sandoz protocol template)
Section 9.2
•
A participant’s opposition to use data/biological samples was added (related to the 
updated Sandoz protocol template)
Section 9.4
•
Reasons for early study termination by the Sponsor were updated (related to the updated 
Sandoz protocol template)

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Protocol No. CSOK583A12301
Section 10.1.3
•
Instructions for SAE reporting were updated based on recommendations by the BfArM 
and the updated Sandoz protocol template 
Section 10.1.4
•
Pregnancy reporting was updated (related to the updated Sandoz protocol template)
Section 12.1
•
Wording for analysis sets was revised 
Section 12.4.3
•
Wording for handling of remaining intercurrent events was revised 
Section 12.4.4
•
Handling of missing values not related to intercurrent events for primary estimands was 
revised
Section 12.4.5
•
Sensitive analyses for primary estimands was updated
Section 12.5.1
•
Subgroup analysis for secondary efficacy endpoint by ADA status was removed
Other minor changes to wording were made. Changes to specific sections of the protocol are 
shown in the track changes version using strike through red font for deletions and red underlined 
for insertions.
This amended protocol will be sent to the IEC/IRBs and HA for approval or notification as 
required according to local regulations. 
The change of exclusion criterion #3 described in this amended protocol is a substantial change 
to the protocol.
The ICF and eCRF were updated in accordance with this amendment.

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Clinical Trial Protocol (Version No. 4.0 Clean)
Protocol No. CSOK583A12301
Amendment 1
Amendment rationale
Amendment to the version 1.0 of the protocol of Study CSOK583A12301 includes 
recommendations provided by IRBs/IECs and ANSM. Additionally, the study protocol 
language were modified to improve clarity, accuracy and ensure better adherence to the protocol.
Study status
Screening enrolment has not yet started. The first participant first visit is planned for Apr-2021. 
Protocol version 1.0 has been submitted to Health Authorities, IECs and IRBs. 
Changes to the protocol
Protocol summary
•
The study title was corrected (‘administered intravitreally’ had been missing) 
•
The exclusion criterion related to infection or inflammation in either eye was aligned with 
Exclusion Criterion #4 without changing the meaning
Section 4.5.1
•
The blood sample volume was corrected
Section 5.2
•
Minor changes and clarification on the inclusion criterion #4 without changing the 
meaning
•
Minor changes and clarification on the exclusion criteria #3, 4 (in line with the Eylea 
SmPC), 9, 13, 14 18, 19, 28 without changing the meaning
Section 6.1
•
Investigational and control drugs will be supplied by the local Sponsor. This was corrected 
in Table 6-1
Section 6.2
•
Clarification added on Table 6-2 Prohibited medication about the use of bevacizumab
Section 6.4
•
Correction on the drug supply open label kit description
•
Correction on Sponsor staff or delegate information
Section 6.7.2
•
Clarification on the intravitreal procedure which should follow the Site Investigational 
Product (IP) Administration and Handling Manual, local practice and local guidelines
•
Clarification and alignment with exclusion criterion #4
Section 8
•
The assessments performed on Day 2 and Day 58 (PK sub-study participants only) were 
clarified in Table 8-1
•
Coagulation tests were included in Table 8-1
•
FSH testing at screening were included in the Table 8-1

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•
BCVA assessment and study eye and fellow eye documentation during Screening and 
Baseline visits were clarified in Table 8-1
Section 8.2
•
The need of documentation of Year of Birth data on the medical source was added
Section 8.3.1
•
Clarification on the selection of the study eye in case of both eyes are eligible during 
screening
Section 8.3.2
•
Clarification about OCT technology validation and certification provided by CRC
Section 8.4
•
The requirement for equipment calibration and maintenance was added
•
The information that CF and FA images will be stored at CRC was added 
Section 8.4.3
•
Tonometer specifications were removed  in order to allow sites to use their standard of 
care equipment
•
The reference to a manual of procedures was removed because sufficient information and 
further instructions are provided at this section
Section 8.4.5
•
Post-injection procedures were clarified
Section 10.1.4
•
A newborn follow-up period in case of pregnancy was included
Section 15
•
The list of references was updated by removing references not cited in the protocol
Other minor clarifications were made where applicable. Changes to specific sections of the 
protocol are shown in the track changes version using strike through red font for deletions and 
red underlined for insertions.
This amended protocol will be sent to the IEC/IRBs and HA for approval or notification as 
required according to local regulations. 
The changes described in this amended protocol are not substantial.
The ICF was updated in accordance with this amendment. No changes on the eCRF are needed.

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Protocol No. CSOK583A12301
Protocol summary
Protocol number
CSOK583A12301
Full Title
A 52-week, multicenter, randomized, double-masked, 2-arm parallel study 
to compare efficacy, safety and immunogenicity of SOK583A1 to Eylea®, 
administered intravitreally, in patients with neovascular age-related macular 
degeneration
Brief Title
Phase III study assessing the efficacy, safety and immunogenicity of 
SOK583A1 versus Eylea® in patients with neovascular age-related macular 
degeneration
Sponsor and 
Clinical Phase
Phase III
Hexal AG, Industriestr. 25, 83607 Holzkirchen, Germany 
and
Sandoz Inc., 100 College Road West, Princeton, NJ 08540, USA
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
To demonstrate similar efficacy, safety and immunogenicity of SOK583A1 
and Eylea EU as per Eylea approved treatment regimen in patients with 
nAMD
Primary 
Objective(s) 
To demonstrate similar efficacy of SOK583A1 and Eylea EU in terms of 
BCVA. The endpoint for primary objective is the mean change from 
Baseline in BCVA score using ETDRS testing charts at Week 8.
The primary clinical question of interest is: Does SOK583A1 have similar 
efficacy as Eylea EU in terms of mean change in BCVA score in 
participants with nAMD who are anti-VEGF naive, without important 
protocol deviations and adherent to the treatment and completed the 
treatment to Week 8? 
Secondary 
Objectives
To evaluate if the anatomical outcome of SOK583A1 is similar to Eylea EU 
•
Mean change in CSFT using SD-OCT from Baseline to Week 1, 4, 
8, 24 and 52
•
Mean change of CNV lesion size using FA from Screening to 
Week 8 and 52
To evaluate if the efficacy of SOK583A1 is similar to Eylea EU in terms of 
BCVA 
•
Mean change from Baseline in BCVA score using ETDRS testing 
charts at Week 24 and 52
To evaluate if SOK583A1 is similar to Eylea EU in terms of safety
•
Incidence of ocular and non-ocular AEs over 52 weeks
To evaluate if SOK583A1 is similar to Eylea EU in terms of immunogenicity 
•
Development of binding and neutralizing ADAs up to Week 52
To evaluate the systemic exposure of SOK583A1 and Eylea EU in 
participants of the PK assessment 
•
Aflibercept concentration assessments at Baseline and 24 hours 
after the first and third injections

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Exploratory 
objective
To evaluate systemic VEGF concentrations in participants treated with 
SOK583A1 or Eylea EU
•
VEGF concentration assessment at Week 48 (pre-dose) and 
Week 52
Study design
This is an international, multicenter, randomized, double-masked, 2-arm 
parallel study, in patients with nAMD, with a total duration of 52 weeks. The 
study participants will be randomized at Baseline in a 1:1 ratio into 2 
treatment groups:
SOK583A1: IVT administration of 2 mg of SOK583A1 in the study eye, 
every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 
8 weeks (q8w) at Weeks 16, 24, 32, 40 and 48.
Eylea EU: IVT administration of 2 mg of Eylea EU in the study eye, every 
4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 
8 weeks (q8w) at Weeks 16, 24, 32, 40 and 48.
Population
The study will randomize 460 male and female patients that are 50 years of 
age or older, anti-VEGF treatment naive for both eyes, with active CNV 
secondary to AMD in the study eye 
Key Inclusion 
criteria
•
Signed informed consent must be obtained prior to participation in 
the study.
•
Participants must be 50 years of age or older at Screening
•
Anti-VEGF treatment-naive for both eyes with active CNV lesions 
secondary to AMD that affect the central subfield in the study eye
•
Total area of CNV (including both classic and occult components) 
must comprise > 50% of the total lesion area in the study eye
•
Intra- and/or subretinal fluid affecting the central subfield of the 
study eye
•
BCVA between 73 and 38 letters, inclusive, in the study eye at 
Screening and Baseline using ETDRS testing charts
Key Exclusion 
criteria
•
Concomitant conditions or ocular disorders in the study eye, 
including cataract and diabetic macular edema, at Screening or 
Baseline which could, in the opinion of the Investigator, prevent 
response to study treatment or may confound interpretation of 
study results, compromise visual acuity or require medical or 
surgical intervention during the course of the study
•
Any active or suspected intraocular or periocular infection or 
inflammation in either eye
•
Uncontrolled glaucoma defined as IOP > 25 mmHg on medication, 
or according to Investigator’s judgement, at Screening or Baseline, 
in the study eye
•
Presence of amblyopia, amaurosis or ocular disorders in the fellow 
eye with BCVA < 38 letters using ETDRS testing charts at 
Screening
•
Previous ocular treatments with any anti-VEGF or investigational 
drugs in either eye
Study treatment
SOK583A1 2 mg/0.05 mL
Eylea EU 2 mg/0.05 mL

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Treatment of 
interest
The randomized treatment (the investigational treatment SOK583A1 or the 
control treatment Eylea EU)
Efficacy 
assessments
•
BCVA using ETDRS testing charts
•
Spectral Domain Optical Coherence Tomography (SD-OCT)
•
Color fundus photography and fluorescein angiography
Pharmacokinetic 
assessments 
Aflibercept concentration assessments before the first injection (Baseline, 
pre-dose) and 24 hours after the first and third injections
Pharmacodynamic 
assessment
Systemic VEGF concentration assessment at Week 48 (pre-dose) and 
Week 52
Key safety 
assessments
•
AE monitoring
•
Ophthalmic examination
•
Vital signs
•
Laboratory assessments
•
Anti-drug antibodies
•
Pregnancy testing
Data analysis
To evaluate the primary objective, ANCOVA will be performed for change in 
BCVA score from baseline to Week 8; the model will include treatment as a 
factor, and Baseline BCVA and age as continuous covariates.
The primary objective, for which analysis will be conducted in the Per 
Protocol Set (PPS), is considered met if:
1.
For EMA requirement: the 95% CI for the difference in change in 
BCVA score from baseline to Week 8 is completely contained 
within the equivalence interval of [-3.5, 3.5].
2.
For FDA requirement: the 90% CI for the difference in change in 
BCVA score from baseline to Week 8 is completely contained 
within the equivalence interval of [-3.0, 3.0].
Summary statistics for continuous variables will include the number of 
nonmissing observations, mean, SD, minimum, median, and maximum. 
Summary statistics for discrete variables will be presented in contingency 
tables and will include absolute (n) and relative frequencies (%).
Key words
Age-related macular degeneration, anti-VEGF, biosimilar

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1
Introduction
1.1
Background
AMD is the leading cause of severe vision loss affecting 10%-13% of individuals over the age 
of 65 years in North America, Europe, and Australia (Kawasaki et al 2010; Rein et al 2009; 
Smith et al 2001). Genetic, environmental and health factors play an important role in the 
pathogenesis of the disease.
AMD is classified into 2 clinical subtypes: the non-neovascular or dry form and the neovascular 
(exudative) or wet form (Ferris et al 1984; Lim et al 2012; Miller et al 2013). Neovascular AMD 
is characterized by the growth of abnormal new blood vessels (neovascularization) under the 
retinal pigment epithelium (RPE) or subretinal space from the subjacent choroid, termed 
choroidal neovascularization (CNV) (Ferris et al 1984). These newly formed vessels have an 
increased likelihood to leak blood and serum, damaging the retina by stimulating inflammation 
and scar tissue formation. This damage to the retina results in progressive, severe, and 
irreversible vision loss (Shah et al 2007; Shah et al 2009). Without treatment, most affected 
eyes will have poor central vision (20/200) within 12 months (Blinder et al 2003). Although the 
neovascular form of the disease is only present in about 10% of all AMD cases, it accounted 
for approximately 90% of the severe vision loss from AMD prior to the introduction of 
antivascular endothelial growth factor (anti-VEGF) treatments (Ferris et al 1983; Sommer et al 
1991; Wong et al 2008).
VEGF has been shown to be elevated in patients with nAMD, and is thought to play a key role 
in the neovascularization process (Spilsbury et al 2000). The use of IVT pharmacotherapy 
targeting VEGF has significantly improved visual outcomes in patients with nAMD (Bloch et 
al 2012; Campbell et al 2012). Anti-VEGF treatments, such as ranibizumab (Lucentis®), 
aflibercept (Eylea®) and brolicuzumab (Beovu®), inhibit VEGF signaling pathways and have 
been shown to halt the growth of neovascular lesions and resolve retinal edema.
SOK583A1 (INN: aflibercept) is being developed by Sandoz as a proposed biosimilar to the 
aflibercept product Eylea® (hereafter referred to as Eylea) licensed for ophthalmological 
indications in the EU to Bayer Pharma AG and in the US to Regeneron Pharmaceuticals Inc. 
(Eylea EU SmPC; Eylea US PI). The development of SOK583A1 aims for the treatment of all 
indications currently approved for Eylea (since the receptor and mechanism of action of 
aflibercept are the same in the different ophthalmological indications). Biosimilarity will be 
supported by the totality of evidence from analytical, clinical PK, efficacy, safety and 
immunogenicity data.
Development of biosimilars
A biosimilar is a biological medicinal product that contains a version of the active substance of 
an already authorized biological medicinal product with demonstrated similarity in physico-
chemical characteristics, biological activity, efficacy and safety, based on a comprehensive 
comparability exercise (Weise et al 2011; Schneider et al 2012). It is intended to be used at the 
same dose(s) and dosing regimen(s) to treat the same disease(s) as the reference product. The 
development and commercialization of biosimilars can help address unmet medical needs by 

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improving access to well-established therapeutic interventions while improving healthcare 
affordability (McCamish and Woollett 2012).
Biological medicinal products are derived from living cells or organisms and consist of 
relatively large and complex molecular entities. Due to the inherent variability of the biological 
system as well as potential manufacturing process changes introduced over time, any resulting 
biological will display a certain range of variability, even between different batches of the same 
originator product (Weise et al 2011). Manufacturers and Health Authorities are managing this 
variability based on the principle that changes in quality attributes can be accepted as long as 
they do not alter the safety and efficacy of the biologic product (Schiestl et al 2011).
Development of SOK583A1
SOK583A1 contains the same active ingredient, aflibercept, as Eylea. Aflibercept is a fusion 
protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to 
the Fc portion of human IgG1 by recombinant DNA technology. Aflibercept functions as a 
decoy receptor (“VEGF trap”), binding to VEGF A and B and placental growth factor (PIGF), 
thus blocking the binding and activation of cognate VEGF receptors (Eylea EU SmPC; Eylea 
US PI).
Study CSOK583A12301 (hereinafter referred to as ‘Study A12301’) is the first clinical study 
in which SOK583A1 is being administered in humans. Aflibercept is administered via IVT, 
directly at the site of action, and the systemic exposure is low and variable following IVT 
injection. The efficacy of aflibercept for neovascular retinopathy is not associated with the 
systemic PK. Hence, study A12301 includes only a descriptive PK substudy to confirm that the 
low systemic exposure of SOK583A1 is within the same range observed following Eylea EU 
after IVT administration (Eylea EU SmPC; Eylea US PI).
The study aims, by using a sensitive indication and endpoints, to detect any clinically 
meaningful differences in comparison to Eylea. Accordingly, nAMD has been selected as the 
indication for this study for the following reasons:
•
the pivotal studies of Eylea have been conducted in this indication
•
nAMD is considered as a sensitive indication based on the magnitude of aflibercept’s 
efficacy demonstrated in previous phase III anti-VEGF trials and the absence of 
concomitant medication for underlying disease, and therefore, representative indication for 
a biosimilar study.
1.2
Purpose
The purpose of the study is to demonstrate similar efficacy, safety and immunogenicity of 
SOK583A1 and Eylea EU as per Eylea approved treatment regimen in patients with nAMD. 
This study is part of the clinical development program of SOK583A1, and has been set up to 
support worldwide registration of SOK583A1 as a proposed biosimilar product to Eylea.

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2
Objectives and endpoints
The study design, objectives and endpoints have been discussed and agreed with FDA, EMA 
and PMDA. For the detailed description of the primary endpoint and its statistical analysis, see 
Section 12.4 Analysis of the primary estimand.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 
•
To demonstrate similar efficacy of 
SOK583A1 and Eylea EU in terms of 
BCVA
•
Mean change from baseline in BCVA score 
using ETDRS testing charts at Week 8
Secondary Objective(s)
Endpoint(s) for secondary objective(s)
•
To evaluate if the anatomical outcome of 
SOK583A1 is similar to Eylea EU
•
Mean change in CSFT using SD-OCT from 
Baseline to Week 1, 4, 8, 24 and 52
•
Mean change of CNV lesion size using FA 
from Screening to Week 8 and 52 
•
To evaluate if the efficacy of SOK583A1 is 
similar to Eylea EU in terms of BCVA
•
Mean change from Baseline in BCVA score 
using EDTRS testing charts at Week 24 and 
52 
•
To evaluate if SOK583A1 is similar to 
Eylea EU in terms of safety
•
Incidence of ocular and non-ocular AEs over 
52 weeks 
•
To evaluate if SOK583A1 is similar to 
Eylea EU in terms of immunogenicity
•
Development of binding and neutralizing 
ADAs up to Week 52 
•
To evaluate the systemic exposure of 
SOK583A1 and Eylea EU in participants of 
the PK assessment
•
Aflibercept concentration assessments at 
Baseline (pre-dose) and 24 hours after the 
first and third injections 
Exploratory Objective
Endpoint(s) for exploratory objective
•
To evaluate systemic VEGF concentration 
in participants treated with SOK583A1 or 
Eylea EU
•
Systemic VEGF concentration assessments at 
Week 48 (pre-dose) and Week 52
2.1
Primary estimands
The primary clinical question of interest is: Does SOK583A1 have similar efficacy as Eylea-
EU in terms of mean change in BCVA score in participants with nAMD who are anti-VEGF 
naive, without important protocol deviations and adherent to the treatment and completed the 
treatment to Week 8?
The justification for using observed per-protocol (PP) estimand (Lou et al 2019) as the primary 
estimand is that given the sequential approach of biosimilar development, similarity between 
test and reference product on an analytical and nonclinical level will have already demonstrated 
before the initiation of the clinical studies. This provides a rationale to assume that the ideal-
exact equality condition is satisfied. The observed PP estimand will also prioritize sensitivity 
to detect differences between treatments if any exists by assessing the treatment effect for 
participants who follow the intention of the protocol as closely as possible. 
The primary estimand is described by the following attributes:

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1. Population: anti-VEGF treatment-naïve patients with nAMD without important protocol 
deviations and adherent to the treatment and completed the treatment (2 IVT injections) to 
Week 8). Further details on the population are provided in Section 5 Population
2. Endpoint: change from baseline in mean BCVA score at Week 8
3. Treatment of interest: the randomized treatment (SOK583A1 or Eylea EU). Further details 
on the treatment are provided in Section 6 Treatment
4. Since the primary analysis is only on those participants who adhere to and complete 
treatment and do not have important protocol deviations, there will be no intercurrent 
events for the observed PP estimand. 
5. The summary measure: difference in mean change from baseline to Week 8 in BCVA 
scores between SOK583A1 and Eylea EU.
2.2
Secondary estimands
Not applicable
3
Study design
This is an international, multicenter, randomized, double-masked, 2-arm parallel study, in 
patients with nAMD, with a total duration of 52 weeks. A total of 460 study participants will 
be randomized at Baseline in a 1:1 ratio into 2 treatment groups. The randomization will be 
stratified by region (US, Rest of the World, Japan), age (< 75 years and ≥ 75 years) and Baseline 
BCVA categories (< 64 letters and ≥ 64letters).
The study consists of 3 periods: a Screening Period of up to 2 weeks (+ 1 week in case of 
technical errors, e.g, laboratory results could not be obtained, samples were lost, destroyed, 
hemolized, or images were of insufficient quality) to assess participant’s eligibility, the 
Treatment Period (Baseline to Week 48) and a Follow-up Period (Week 48 to Week 52). An 
outline of the study periods is presented in Figure 3-1 Study design, and a detailed visit and 
assessment schedule is provided in Table 8-1 Assessment schedule.
Screening Period (screening to randomization, Day -14 to Baseline)
The Screening Period begins with the first screening procedure once the participant has 
provided written informed consent to participate in the study and ends at randomization visit 
(Baseline) of the study. The Screening Period of up to 2 (+ 1) weeks will be used to assess 
eligibility of the participants. As participants with nAMD require rapid therapeutic intervention, 
the screening period must be kept as short as possible.  
Retesting BCVA or imaging assessments with the purpose of capturing new BCVA or imaging 
assessments that previously failed to qualify the participant is not allowed. Imaging can be 
retested only in case of technical errors. 
Rescreening is allowed once. For rescreening and retesting details, see Section 8.1 Screening.
Participants must have the diagnosis of nAMD in the study eye confirmed at Screening by the 
CRC.

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Treatment Period (Baseline to Week 48)
Only 1 eye will be selected as study eye and treated with study treatment (SOK583A1 or Eylea 
EU). The Treatment Period begins with randomization (Baseline) and ends with the completion 
of Week 48 treatment and assessments. After confirmation of eligibility, participants will be 
randomized in a 1:1 ratio into either the SOK583A1 or the Eylea EU treatment group. During 
the Treatment Period, participants will receive a single IVT injection of fixed 2 mg of 
SOK583A1 or Eylea EU in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 
8, and thereafter every 8 weeks (q8w) at Weeks 16, 24, 32, 40 and 48.
A study visit schedule will be established at the time of randomization for all participants. All 
efforts should be made to adhere to all scheduled visits and assessments as outlined in the 
assessment schedule or as close to the designated day/time as possible, according to the allowed 
visit window (Table 8-1 Assessment schedule). All efforts should be made to revert back to the 
planned visit schedule taking into consideration the restrictions on the minimum treatment 
interval for the study treatment, i.e. 2 consecutive injections should be spaced by at least 21 days. 
For more details, please refer to Section 8 Visit schedule and assessments.
Week 48 corresponds to the last treatment visit.
For ADA assessment, serum samples will be collected before drug administration at Baseline 
and at Weeks 1, 4, 8, 16, 24 and 40, and at EOS. Samples to determine aflibercept serum 
concentrations will be obtained at the same time as immunogenicity samples.
For PK assessment, serum and plasma samples will be collected from 20 participants per 
treatment group (total of 40 participants) before the first study drug injection and 24 (±1) hours 
after the first (Visit 2) and third study drug injections (Visit 5). For the 40 participants in the 
PK substudy, extra visits will be necessary 24 hours after the first (Visit 2) and third study drug 
injections (Visit 5). See Section 8 Visit schedules and assessment and Table 8-1 Assessment 
schedule.
For the evaluation of systemic VEGF concentrations, plasma will be collected at Week 48 (pre-
dose) and Week 52 in participants who agree to the additional blood collection.
Follow-up Period (Week 48 to Week 52)
The Follow-up Period consists of 4 weeks for the safety follow-up after the last injection 
administered at Week 48. The last study assessments will be performed at the EOS visit, at 
Week 52, 4 weeks (± 7 days), after the last study drug administration (Table 8-1).
Participants who withdraw from the study prior to study completion or participants who 
discontinue the study treatment for any reason, will be asked to return for an early 
discontinuation (EOS) visit, 4 weeks (± 7 days) after their last study drug administration.

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Figure 3-1
Study design
The Screening Period should be completed up to 2 weeks. It can be extended to up to 3 weeks 
in total in case of technical errors when retesting is needed (laboratory results could not be 
obtained, samples were lost, destroyed or hemolyzed or images with insufficient quality).
4
Rationale
4.1
Rationale for study design
This study is part of the clinical development program for SOK583A1 and aims to support 
worldwide registration of SOK583A1 as a proposed biosimilar product to Eylea. The concept 
study design has been discussed and agreed with FDA, EMA, and PMDA.
The main indication of Eylea is the treatment of nAMD which was supported by the results of 
2 parallel Phase III studies of aflibercept VIEW 1 and VIEW 2 (0.5 and 2.0 mg IVT doses; 2 
regimens, every 4 weeks and every 8 weeks) compared with the control arm (ranibizumab 
0.5 mg IVT, every 4 weeks). At 52 weeks, all aflibercept groups were non-inferior to the 
ranibizumab group with equal stabilization of vision in 95% of eyes (Heier et al 2012). 
Aflibercept 2 mg q8w IVT, after the loading phase of 3 injections q4w, is an established 
standard of care option for patients with nAMD with consistency of the approved dose and 
posology across the countries.
The study has a parallel-group design with a total duration of 52 weeks. The overall study design 
closely resembles the Eylea or similar studies investigating non-inferiority of other anti-VEGF 
drugs with the aflibercept. The proposed treatment scheme and dosing is in line with the 
authorized label and standard of care. The primary endpoint analysis is based on BCVA data 
collected up to 8 weeks. Further evaluation of efficacy, PK, safety and immunogenicity is based 
on data up to Week 52.
The primary efficacy endpoint based on BCVA (ETDRS testing charts letters, measured at 
starting distance of 4 meters) will be assessed by masked personnel. Historically, the change 
from Baseline in BCVA at a selected time point is considered appropriate as the primary 
efficacy endpoint in confirmatory nAMD studies. In Eylea’s pivotal studies, VIEW 1 and VIEW 
2 (Heier et al 2012), the mean BCVA change from Baseline reached a plateau starting at Week 

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12 (upon maintenance treatment q8w), and therefore at an earlier time point (Week 8), the 
BCVA is still ascending before the maximal treatment effect is reached. BCVA change from 
baseline at Week 8 is considered a sensitive endpoint to detect a potential clinically meaningful 
efficacy difference between SOK583A1 and Eylea.
The study will recruit anti-VEGF naive nAMD participants with BCVA at Screening and 
Baseline between 73 to 38 letters, both inclusive, in the study eye. By limiting the upper BCVA 
to 73 letters, the study will include participants that have a potential for at least 10 letters gain 
in visual acuity, thereby avoiding a ceiling effect. In the same way, since it would be difficult 
to evaluate decreases in visual acuity at a level worse than legal blindness, BCVA of 38 letters 
was established as the lower limit for eligibility. 
The participants must have CNV lesions secondary to AMD, defined by the presence of leakage 
evidenced by fluorescein angiography and intra- or subretinal fluid, as evidenced by optical 
coherence tomography.
Equivalence testing related to the primary efficacy parameter BCVA will be based on a margin 
of 3.5 letters for EMA analysis and 3.0 letters for FDA analysis. A change in BCVA > 5 letters 
is considered relevant in the clinical practice regardless of the underlying disease. Therefore, 
this equivalence margin provides assurance that any proof of equivalence only occurs if the 
observed treatment differences are of no clinical relevance.
Randomization will be stratified by region (US, Rest of the World, Japan), age (<75 years and 
≥ 75 years) and Baseline BCVA categories (< 64 letters and ≥ 64 letters) in order to ensure a 
balanced and homogeneous allocation of participants in each arm.
Masked treatment for 48 weeks followed by a safety follow-up of 4 weeks allows for a 1 year 
safety evaluation of SOK583A1 compared with Eylea EU. 4 weeks for safety follow up are 
considered acceptable period based on the site of study drug administration and the fact that the 
majority of AEs being local.
4.2
Rationale for dose/regimen and duration of treatment
SOK583A1 is being developed as a similar biological medicinal product to Eylea. Therefore, 
the dose, frequency and route of administration of the study medication are chosen according 
to Eylea pivotal trials and the current Eylea US PI and in line with Eylea EU SmPC for the 
treatment of nAMD.
4.3
Rationale for choice of control drugs (comparator)
SOK583A1 is being developed as a similar biological medicinal product to Eylea. EU-
authorized Eylea has been chosen as the comparator in this study to confirm similarity in terms 
of efficacy, safety and immunogenicity.
4.4
Purpose and timing of interim analyses
An interim analysis will be performed after randomized patients completed Week 40 or 
discontinued prior to Week 40. The purpose of interim analysis is to allow for initial dossier 
submission of the primary endpoint results evaluated at Week 8, including all safety and 

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efficacy data collected up to the data cutoff point, which is considered sufficient by FDA, EMA, 
and PMDA for initial dossier submission.
Participants will remain in the study and will continue to receive masked treatment through the 
planned treatment duration of 48 weeks, to allow further evaluation of efficacy and safety. 
Treatment masking of individual participants and data will remain intact for all participants, 
masked Investigators and staff and selected staff from the Sponsor until the final DBL has 
occurred; see Table 6-3 Masking and unmasking plan. Additional information is presented in 
Section 12.7 Interim analyses.
4.5
Risks and benefits
The risk to participants in this study may be minimized by compliance with the eligibility 
criteria and the study procedures, as well as close clinical monitoring for any safety signals.
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlines in the 
exclusion criteria. If there is any questions that the participant will not reliably comply, they 
should not be entered or continue in the study.
Eylea has been licensed and commercialized world-wide since 2011. Clinical studies provided 
evidence of efficacy and safety in all approved indications, including nAMD. Since approval 
of Eylea, an extensive post-marketing experience has been gathered which confirms Eylea’s 
established safety and efficacy profile and demonstrates its favorable risk-benefit ratio (Eylea 
EU SmPC; Eylea US PI).
In terms of safety profile, IVT aflibercept is well tolerated across all indications. The most 
common AEs for Eylea (≥ 5%) are conjunctival hemorrhage, eye pain, cataract, vitreous 
detachment, vitreous floaters, and intraocular pressure increased (Eylea US PI). SAEs are also 
reported in a low incidence: hypersensitivity, endophthalmitis and retinal detachments, and a 
potential risk of thromboembolic events.
One of the potential risks associated with any biopharmaceutical product is the induction of an 
immunogenic response, and therefore assessment of ADA development is planned throughout 
study. 
From the currently available analytical data, it is concluded that SOK583A1 and Eylea are 
similar at the physicochemical and functional level. SOK583A1 is therefore expected to have 
similar efficacy, safety and immunogenicity profile. All participants of the study will therefore 
be receiving active therapy with a similar expectation of benefit. The contraindications, 
precautions and warnings of Eylea will also apply to SOK583A1.
A safety review of the first 20 participants in Study A12301 showed that IVT injections of 
SOK583A1 or Eylea EU were safe and well tolerated in patients with nAMD. No treatment-
emergent AEs were recorded. No new safety signal was detected.
Further details of the known and potential risks and benefits associated with aflibercept are 
presented in the Investigator’s Brochure and Eylea EU SmPC and Eylea US PI.

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COVID-19 (SARS-Cov-2 virus) Pandemic considerations
During the global pandemic, the safety of clinical study participants remains paramount at all 
times. The responsibility of the investigator is to continually and carefully assess the benefit-
risk ratio for each patient as the pandemic develops and needs to take all necessary measures to 
maintain patient safety at all times.
Study treatment IVT injection of Eylea/SOK583A1 does not put patients at increased risk of 
COVID-19 infection, as aflibercept has no immunomodulatory or immunosuppressant effects. 
However, given their age, patients with nAMD are at higher risk for developing a more severe 
COVID-19 course of disease. As patients with nAMD are at risk for complete and permanent 
loss of vision, according to the American Academy of Ophthalmology, IVT injections for 
nAMD fall under the category of essential care and the treatment should not be stopped due to 
the risk of permanent vision loss (American Academy of Ophthalmology). The Royal College 
of Ophthalmologists Medical Retinal Management Plan during COVID-19 recommends for 
new patients with nAMD to be treated with a loading phase of 3 injections of anti-VEGF and 
then continued on q8w, which is in line with the study’s treatment schedule (Royal College of 
Ophthalmology). Maintaining a regular schedule of eye injections is important in retaining the 
vision and missing even one appointment can have a negative effect since nAMD progresses 
rapidly and can produce sudden and severe central vision loss if not treated (Blinder et al 2003).
The Investigator is responsible to assure that patients with infections at screening are excluded 
from study participation, and study participants are not exposed to increased risk through 
participation in the study. If required to assure patient safety, the Investigator may conduct 
unscheduled laboratory assessments at any time during the study. This includes but is not 
limited to e.g. SARS-Cov-2 testing taking into consideration local government policy and site’s 
own procedures. Testing result and any AEs associated with disease should be managed and 
documented as described in Section 10 Safety monitoring and reporting.
4.5.1
Blood sample volume
A volume of approximately 140 mL is planned to be collected over a period of 52 weeks, from 
each participant as part of the study. Additional samples may be required for safety monitoring.
In case of participation in the PK substudy, approximately 31 mL of blood will be additionally 
collected. 
For those participants who agree to blood collection for the evaluation of systemic VEGF 
concentrations, approximately 12 mL of blood will be additionally collected.
Timing of blood sample collection is outlined in Table 8-1 Assessment schedule. A summary 
blood log is provided in the Laboratory Manual. Instructions for all sample collection, blood 
sample volume, processing, storage, and shipment information is also available in the 
Laboratory Manual.
5
Study population
The study will enroll male and female patients who are 50 years of age or older, anti-VEGF 
treatment naive for both eyes, and diagnosed with active CNV secondary to AMD in the study 

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eye. A total of 460 participants will be randomized. Participants who drop out after they have 
been randomized will not be replaced.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Participants must be 50 years of age or older at Screening
3. Anti-VEGF treatment-naive patients for either eye and systemically
4. Study eye diagnosed with active CNV lesions (type 1 and/ or type 2) secondary to AMD 
and/or Retinal Angiomatous Proliferation lesions (type 3), affecting the central subfield. 
Active CNV lesion is defined by the presence of leakage as evidenced by fluorescein 
angiography, and intra- or subretinal fluid as evidenced by optical coherence tomography, 
both confirmed by the CRC at Screening
5. Total area of CNV (including both classic and occult components) must comprise > 50% 
of the total lesion area in the study eye, confirmed by the CRC at Screening
6. BCVA between 73 and 38 letters, both inclusive, in the study eye at Screening and 
Baseline using ETDRS testing charts
7. Willing and able to comply with all study procedures, and be likely to complete the study
8. Clear ocular media and adequate pupil dilatation in both eyes to permit good quality 
photographic imaging
In cases where both eyes are eligible, the eye with the worse BCVA at Baseline will be selected 
as the study eye. If both eyes have the same BCVA, it is recommended to select the right eye 
as the study eye. However, the Investigator may select the eye with better visual acuity based 
on medical reasons or local ethical requirements, which must be justified.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
Ocular conditions and treatments:
1. Previous treatment with any anti-VEGF therapy in either eye or investigational drugs in 
study eye or fellow eye, at any time prior to Baseline
2. Participant has received any approved treatment for nAMD (other than vitamin and 
dietary supplements) in the study eye and at any time prior the Baseline
3. Presence of other causes of CNV, including pathologic myopia (spherical equivalent of –
8 diopters or more negative), ocular histoplasmosis syndrome, angioid streaks,choroidal 
rupture, or multifocal choroiditis in the study eye, assessed by imaging at screening by 
CRC and appropriately stated in the multi-modal eligibility confirmation report
4. Any active or suspected intraocular or periocular infection or active or suspected 
intraocular inflammation (e.g. infectious conjunctivitis, keratitis, scleritis, 
endophthalmitis, infectious blepharitis, uveitis) in either eye at Screening or Baseline

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5. Subfoveal fibrosis, atrophy, or scarring extending > 50% of total lesion area in the study 
eye as assessed by the Investigator at Screening and confirmed by the CRC prior to 
randomization
6. Subretinal hemorrhage that is ≥ 50% of the total lesion area in the study eye, or if the 
subretinal hemorrhage involving the fovea is 1 or more disc areas (≥ 2.54 mm2) in size in 
the study eye, as assessed by FA and confirmed by the CRC
7. Retinal pigment epithelium (RPE) rip/tear in the study eye at Screening or Baseline
8. Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 
weeks prior to Baseline
9. History or evidence of the following, in the study eye:
•
Intraocular (including cataract surgery) or refractive surgery within the 90 day period 
prior to Baseline. The yttrium aluminum garnet (YAG) posterior capsulotomy is 
allowed no later than 4 weeks prior to Baseline
•
Previous penetrating keratoplasty or vitrectomy
•
Previous panretinal photocoagulation
•
Previous photodynamic therapy
•
Previous submacular surgery or other surgical intervention for AMD
•
Retinal detachment or treatment or surgery for retinal detachment
•
Any history of macular hole of stage 2 and above
•
Prior trabeculectomy or other filtration surgery
•
Ocular trauma within 6 months prior to Baseline
10. History of hypersensitivity to any of the study treatments or its excipients, or clinically 
relevant sensitivity to fluorescein dye, as assessed by the Investigator
11. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg 
on medication or according to Investigator’s judgment at Screening or Baseline
12. Aphakia and/or absence of the posterior capsule in the study eye at Screening or Baseline, 
unless it occurred as a result of a YAG posterior capsulotomy in association with prior 
posterior chamber intraocular lens implantation
13. Intra or periocular use of corticosteroids in the study eye within a 6 month period prior to 
Baseline
14. Use of topical ocular corticosteroids in the study eye for 30 or more consecutive days 
within the 90 days period prior to Baseline 
15. Previous therapeutic radiation near the region of the study eye
16. Concomitant conditions or ocular disorders in the study eye, including media opacities, 
cataract and diabetic macular edema, at Screening or Baseline which could, in the opinion 
of the Investigator, prevent response to study treatment or may confound interpretation of 
study results (efficacy and safety), compromise visual acuity or require medical or surgical 
intervention during the course of the study
17. Presence of amblyopia, amaurosis or ocular disorders with BCVA <38 letters (ETDRS 
testing charts) in the fellow eye at Screening (except when due to conditions whose 
surgery may improve VA, e.g. cataract)
18. Presence of Scleromalacia in either eye

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19. Participants requiring anti-VEGF treatment of the fellow eye at Baseline will not be 
eligible for the PK substudy
Systemic conditions and treatments:
20. Previous systemic treatment with any anti-VEGF therapy
21. Use of systemic corticosteroids for 30 or more consecutive days within the 90 days prior 
to Baseline, with the exception of low stable doses of corticosteroids (defined as ≤ 10 mg 
prednisolone or equivalent dose used for 90 days or more prior to Baseline). 
22. Uncontrolled blood pressure defined as a systolic value ≥ 160 mmHg or diastolic value 
≥ 100 mmHg at Screening 
23. Stroke or myocardial infarction during the 6-month period prior to Baseline
24. Participation in an investigational systemic drug, biologic, or device study within 30 days 
or duration of 5 half-lives of the investigational product (whichever is longer) prior to 
Baseline. Note: observational clinical studies solely involving over-the-counter vitamins, 
supplements, or diets are not exclusionary
25. Presence of infection at Screening or active infection within 2 weeks before Screening
26. Underlying advanced, severe and uncontrolled concomitant condition (including, but not 
limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, 
cardiac, inflammatory, infectious or gastrointestinal), physical examination finding, or 
clinical laboratory finding which in the opinion of the Investigator place the participant at 
unacceptable risk from participation in the study
27. History of a medical condition (including, but not limited to chronic disease, 
immunosuppression, metabolic dysfunction, prior exposure to other drugs that may pose 
risk of infection or allergic reactions) that, in the judgment of the Investigator, would 
preclude scheduled study visits, completion of the study, or a safe administration of 
investigational product, or that might affect participant safety or interpretation of the study 
results.
28. Pregnant or nursing (lactating) women and women of child-bearing potential, defined as 
all women physiologically capable of becoming pregnant, unless they are using highly 
effective methods of contraception while taking study treatment and for 3 months after 
stopping the medication. Highly effective contraception methods include:
•
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.
•
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment.
•
Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant.
•
Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 

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contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS).
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks ago. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment she is considered not of child-bearing potential. If 
natural (spontaneous) amenorrhea with an appropriate clinical profile has been reported for a 
female participant for 12 months, in the absence of the above medical documentation, FSH 
testing is required for this female participant regardless of reported reproductive/menopausal 
status at Screening (Section 8.4.4 Pregnancy and assessments of fertility).
In case local regulations deviate from the contraception methods listed above, local regulations 
apply and will be described in the ICF.
6
Treatment
6.1
Study treatment
SOK583A1 is formulated as a sterile solution aseptically filled in a sterile glass vial for single 
use and the content of the vial must not be split.
The study medications SOK583A1 and Eylea EU will be supplied in study kits, each kit 
containing one sterile glass vial for single use, with 40 mg/ml of aflibercept solution for IVT 
injection (2 mg/50 µL).
The Sponsor will ensure sufficient supplies of SOK583A1 and Eylea EU for treatment use to 
allow for the completion of the study.
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/Control 
Drug
(Name and Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor 
(global or 
local)
SOK583A1 (40 mg/mL)
Solution for 
injection
Intravitreal (IVT) 
Glass Vial
(2 mg/0.05 mL)
Sponsor 
(local and 
global)
Eylea EU (40 mg/mL)
Solution for 
injection
Intravitreal (IVT) 
Glass Vial
(2 mg/0.05 mL)
Sponsor 
(local and 
global)
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.

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6.1.3
Treatment arms/group
Participants, including the 40 participants in the PK substudy, will be assigned at Baseline visit 
to 1 of the following 2 treatment arms/groups with approximately 230 participants in each arm 
in a ratio of 1:1.
•
SOK583A1: IVT administration of 2 mg of SOK583A1 in the study eye, every 4 weeks 
(q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 
24, 32, 40 and 48.
•
Eylea: IVT administration of 2 mg of Eylea in the study eye, every 4 weeks (q4w) at 
Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 24, 32, 40 
and 48.
6.1.4
Treatment duration
The planned duration of treatment is 48 weeks as discussed in Section 3 Study design.
Discontinuation of study treatment for a participant occurs when study drug is stopped earlier 
than the protocol planned duration, and can be initiated by either the participant or the 
Investigator.
Participants who prematurely discontinue study treatment for any reason except withdrawal of 
consent should have the EOS visit scheduled 4 weeks after the last study treatment 
administration.
For discontinuation details, see Section 9 Study discontinuation and completion.
6.2
Other treatment(s)
In the study eye, no other treatments for nAMD other than the study treatment, are permitted 
throughout the course of the study.
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate eCRF. Additionally, the eCRF will also capture data on medications 
(used within the past 90 days) and procedures administered prior to study start.
During the study, if the fellow eye develops nAMD or other condition, it may also be treated 
with standard of care approved in the respective country at the discretion of the Investigator. 
Fellow eye treatment will be captured in the eCRF. The fellow eye should be treated and 
monitored according to the routine practice and AEs captured in the eCRF. It is recommended 
that the fellow eye and study eye are not treated on the same day if the site routine permits.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact the Sponsor/delegated CRO medical 
monitor before randomizing a participant or allowing a new medication to be started. If the 
participant is already enrolled, contact Sponsor/delegated CRO to determine if the participant 
should continue to take study treatment or should discontinue the study treatment.

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6.2.2
Prohibited medication
Prohibited medications after the start if the study (i.e. ICF signature) are displayed in Table 6-
2 Prohibited medication. Any participant who receives one of these treatments will be 
discontinued from study treatment. Any medication which may be required to treat ocular or 
systemic AEs and permitted oral or injectable contraceptives for female participants are 
permitted and must be recorded in the appropriate eCRF page. 
The standard of care or other approved treatment according to the Investigator practice for 
nAMD and other diseases in the fellow eye are permitted and must be recorded in the 
appropriate eCRF page.
Table 6-2
Prohibited medication
Medication
Action taken
Study eye: Intra-or periocular corticosteroids
Discontinue study treatment 
(except if for treatment of AE)
Study eye: Laser treatment for AMD
Discontinue study treatment
Study eye: Anti-VEGF therapy other than study treatment
Discontinue study treatment
Systemic: Systemic corticosteroids for 15 or more consecutive 
days1 
Discontinue study treatment
Systemic: anti-VEGF therapy
Discontinue study treatment
Study eye, fellow eye and systemic: Any investigational drug, 
biologic or device (with the exception of over-the-counter 
vitamins, supplements or diets). Bevacizumab for the fellow 
eye is not allowed if not approved for nAMD in the respective 
country
Discontinue study treatment
1 Permitted: low stable doses of corticosteroids (≤10 mg prednisolone or equivalent dose used for 
90 days or more prior to Baseline), inhaled, nasal, intra-articular and short term (< 14 consecutive 
days) oral corticosteroids or dermal steroids
6.2.3
Rescue medication for the study eye
Rescue treatment is not permitted in the study eye.
Per the Investigator’s discretion, at any time, if the study eye nAMD gets worse resulting in a 
≥ 10 letters loss in BCVA at 2 consecutive visits or a ≥15 letters loss in BCVA at 1 visit 
compared with the best previous measurement, and the study eye BCVA value is not better than 
the baseline value, the participant may require rescue treatment. In this case, the study treatment 
should be discontinued.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number, which is assigned when the 
participant is enrolled for screening and is retained for the participant throughout his/her 
participation in the study. A new Participant Number consists of the Center Number (Center 
Number) (as assigned by Sponsor to the investigative site) with a sequential Participant Number 
suffixed to it, so that each participant's participation is numbered uniquely across the entire 

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database. Upon signing the ICF, the participant is assigned to the next sequential Participant 
Number available.
In case of participant is rescreened, the participant will need to sign a new ICF and a new 
Participant Number will be assigned by the EDC system. The date of the new Informed Consent 
signature must be entered on the appropriate eCRF under the new Participant Number. Informed 
Consent for a rescreened participant must be obtained prior to performing any study-related 
assessments.
6.3.2
Treatment assignment, randomization
At Baseline visit all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms in a 1:1 ratio. Approximately 460 participants 
will be randomized. The Investigator or his/her delegate will contact the IRT after confirming 
that the participant fulfills all the inclusion/exclusion criteria (confirmed by CRC). The IRT 
will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and Investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment.
Randomization will be stratified by PK data collection, region (US, Rest of the World, Japan), 
age (< 75 years and ≥ 75 years) and Baseline BCVA categories (< 64 letters and ≥ 64 letters) in 
order to ensure a balanced and homogeneous allocation of participants in each arm. For 
participants of the PK substudy (those who sign both the main ICF and the PK ICF), 
randomization will be stratified by age and Baseline BCVA categories, and a list of 
randomization numbers will be generated by IRT with a 1:1 randomization ratio to SOK583A1 
or Eylea EU. For all other participants (those who sign only the main ICF), randomization will 
be stratified by region, age and Baseline BCVA categories and a list of randomization numbers 
will be generated by IRT with a 1:1 randomization ratio to SOK583A1 or Eylea EU.
The randomization scheme for participants will be reviewed and approved by a member of the 
Sponsor Randomization Office.
6.4
Treatment masking
This is a participant, Investigator, and Sponsor-masked study. Participants, Investigators, and 
the Sponsor will remain masked to study treatment throughout the study, except where indicated 
below.
The identity of the study treatments cannot be concealed since the appearance of the vials differs. 
To maintain the double-masked design of the study it is necessary to involve unmasked staff at 
the study site for handling the study medication.

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Treatment masking of individual participants will remain intact until the final DBL has occurred 
by ensuring: randomization data are kept strictly confidential until the time of unmasking and 
will not be accessible by anyone else involved in the study except the unmasked injecting 
physician. The masked personnel and participants will remain masked to the treatment 
assignment until the final DBL. Following final DBL all roles may be considered unmasked.
An independent masked review of fundus photography, fluorescein angiography and optical 
coherence tomography (SD-OCT) images will be performed at a CRC.
Site staff
With the exception of any unmasked site staff identified below, all site staff (including study 
Investigator and study nurse) will be masked to study treatment throughout the study.
Unmasking a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site.
Drug product will be supplied in open label kits, so an unmasked pharmacist/unmasked study 
personnel who is independent of the study team will be required in order to maintain the mask. 
This unmasked pharmacist/unmasked study personnel will receive treatment allocation/kit 
numbers from the IRT with the appropriate treatment allocation numbers. Appropriate measures 
must be taken by the unmasked pharmacist/unmasked study personnel to ensure that the 
treatment assignments are concealed from the rest of the site staff.
Unmasked site staff must not perform any clinical assessments (BCVA, disease activity 
assessments, or complete ophthalmic examination). To ensure that the treatment will be masked 
to the participant and the Investigator, receipt, handling and administration of the IVT injection 
will be performed by unmasked study site personnel not involved with study assessments. Also, 
the unmasked site personnel and unmasked injecting physician must not perform assessment of 
any ocular or non-ocular safety parameters, or assess causality of AEs for participants during 
the course of the study except an event reported immediately following IVT injection. All 
unmasked study documentation will be kept strictly confidential and will not be accessible by 
the masked site staff. The unmasked Investigator/site personnel should, however, assess 
participant safety immediately following injection.
Once the designated roles are determined, the roles should not be switched at any time after 
randomization. Every effort must be made to limit the number of unmasked study personnel to 
ensure integrity of the masked study.
Sponsor staff or delegate
The following unmasked Sponsor or delegate roles are required for this study:
•
Unmasked CRO field monitor(s), unmasked CRO Clinical Operations Lead and unmasked 
CRO Project Manager
•
Unmasked clinical staff managing drug re-supply to site or interacting with unmasked 
field monitors/unmasked clinical lead, e.g. unmasked Sponsor clinical manager
•
Unmasked designated study team members for primary endpoint analysis during the 
interim analysis 
•
Unmasked quality assurance staff and unmasked compliance manager

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The unmasked field monitors are required to review drug accountability and allocation at site. 
The unmasked monitors are not provided with a randomization list directly but will be 
unmasked through review of source documentation compiled by the unmasked 
pharmacist/unmasked site personnel, which details treatment allocation to individual 
participants. The unmasked monitors will also be able to review the treatment allocation 
cards/randomization list provided to the unmasked pharmacist/unmasked site personnel
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug products. These individuals are not provided with randomization lists directly, but may be 
unmasked through communication of drug re-supply needs via the unmasked site 
pharmacists/unmasked site personnel.
An independent masked review of color fundus photography, fluorescein angiography and 
optical coherence tomography images for participants in the study will be performed at a CRC.
After all participants have completed Week 40 assessment and after the database has been 
partially locked for the interim analysis designated study team members will be unmasked to 
the study medication assignment. Participant, investigators and the rest of the study team will 
remain masked until after the final DBL. Details will be provided in a blinding charter.
All unmasked personnel will keep randomization lists and data or information that could 
unmask other study team members confidential and secure until final clinical DBL. Following 
final DBL all roles may be considered unmasked. See Table 6-3 for an overview of the masking 
and unmasking plan.
Table 6-3
Masking and unmasking plan 
Time or Event
Role
Randomization 
list generated
Treatment 
allocation 
and dosing
Safety event 
(single 
participant 
unmasked)
Interim 
analysis
Participants
M
M
UI
M
Site staff
M
M
UI
M
Central Laboratory, CRC
M
M
M
M
Unmasked site staff e.g. 
pharmacy staff, medication 
administrating Investigator 
and staff
NA
U
U
NA
Global Clinical Supply and 
Randomization Office
U
U
U
NA
Unmasked 
Sponsor/delegate staff e.g. 
for study treatment re-
supply GCS), unmasked 
monitor(s), unmasked CRO 
Clinical Operations Lead 
and unmasked CRO 
Project Manager
NA
U
U
NA

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Time or Event
Role
Randomization 
list generated
Treatment 
allocation 
and dosing
Safety event 
(single 
participant 
unmasked)
Interim 
analysis
Pharmacovigilance 
Sponsor staff
NA
NA
UI
NA
Sponsor/delegate staff 
involved in primary 
endpoint analysis
M
M
M
U
All other Sponsor staff not 
identified above (study 
team, project team, 
management and decision 
boards, support functions)
M
M
M
M
M=remains masked; NA=not applicable in this study; U=unmasked; UI=allowed to be unmasked on 
individual participant level
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments are not permitted. Study treatment 
can be interrupted if warranted due to an AE.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
IRT needs to be accessed by unmasked study personnel at every visit, even if the study treatment 
is not needed at that visit as per the assessment of the Investigator. Registration of all visits in 
the IRT system is necessary and when treatment is warranted, IRT will provide a medication 
(kit) number to administer the assigned investigational product to the participant. The date and 
time of all study treatment injections administered during the study and any deviations from the 
protocol treatment schedule will be captured by the unmasked study personnel or by unmasked 
field monitor on the appropriate study treatment dispensing form.
Exposure to the study treatment will be based on the number of injections administered. 
Compliance with the study treatment will be assessed by the unmasked field monitor at each 
visit using vial counts and information provided by the pharmacist or by the unmasked study 
personnel.
6.6.2
Recommended treatment of adverse events
The Investigators will follow local guidelines and their best medical practice and judgement to 
treat AEs accordingly. Medication used to treat AEs must be recorded in the appropriate eCRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely.

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Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the Investigator contacts 
the system to break a treatment code for a participant, he/she must provide the requested 
participant identifying information and confirm the necessity to break the treatment code for 
the participant. The Investigator will then receive details of the investigational drug treatment 
for the specified participant and a fax or email confirming this information. The system will 
automatically inform the Sponsor monitor for the site and the study team that the code has been 
broken.
It is the masked or unmasked Investigator’s responsibility to ensure that there is a dependable 
procedure in place to allow access to the IRT/code break cards at any time in case of emergency. 
The Investigator will provide:
•
protocol number
•
participant number
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unmasking 
can be performed at any time.
6.7
Preparation and dispensation
Each study site must have masked and unmasked study personnel. Sites will be supplied with 
study drug in packaging as described under investigational and control drugs (Section 6.1.1 
Investigational and control drugs). No vials, kits or study treatment will be handed out to the 
participants.
A unique medication number is printed on the study medication label.
Unmasked study personnel will identify the study medication kits to dispense to the participant 
by contacting the IRT and obtaining the medication number(s). The study medication has a 2-
part label (base plus tear-off label). Immediately before dispensing the medication kit to the 
participant, unmasked study personnel will detach the outer part of the label from the packaging 
and affix it to the source document.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated unmasked person at the study site, handled 
and stored safely and properly and kept in a secured location to which only the unmasked 
Investigator and designated unmasked site personnel have access. Upon receipt, all study 
treatment must be stored according to the instructions specified on the labels and in the 
Investigator’s Brochure.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Sponsor Quality Assurance.

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Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
The unmasked study personnel must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by unmasked monitors during site visits or remotely and at the completion of the 
study.
At the conclusion of the study, and as appropriate during the course of the study, the site 
pharmacist or designee, after approval from the unmasked study personnel will return all unused 
study treatment, and a copy of the completed drug accountability log to the unmasked Sponsor 
address or unmasked CRO monitor provided in the Investigator folder at each site.
6.7.1.2
Handling of additional treatment
See Section 6.2.1 Concomitant therapy for fellow eye treatment documentation.
6.7.2
Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
The treatment period will be divided into 2 periods for the IVT injections of SOK583A1 and 
Eylea EU, with different intervals, as per approved regimen:
•
In the loading period, treatment with SOK583A1 or Eylea EU will occur every 4 weeks 
for 3 injections, 1 injection per visit (Baseline, Week 4, Week 8)
•
Maintenance period: Participants will receive one injection of SOK583A1 or Eylea EU 2 
mg every 8 weeks for 5 injections, 1 injection per visit (Week 16, Week 24, Week 32, 
Week 40 and Week 48)
Study treatment should be administered in the study eye on the day of the study visit, or if not 
possible, within +3 days after the study visit, except for the Baseline, in which study treatment 
administration should occur within the next 24 hours, as described in Section 8 Visit schedule 
and assessments. If the assessments and treatments take place on the same day, treatment must 
occur after completion of the efficacy assessments described in Section 8.3 Efficacy and pre-
injection safety measures (tonometry, slit lamp and fundus examinations) described in Section 
8.4.3 Complete ophthalmic examination. If study visit assessments and the corresponding 
treatment occur on separate days, a repeat safety check-up should be performed prior to 
treatment of the eye and results documented in the source documents. If any safety concern 
arises related to the study eye that, in opinion of the Investigator, may be impacted by the study 
treatment or injection procedure, treatment needs to be cancelled. Any adverse events must be 
recorded in the eCRF.
The IVT injection procedures, including aseptic and antimicrobial requirements, should follow 
the Site Investigational Product (IP) administration and Handling Manual, and local clinical 
practice guidelines. The IVT injection will be performed by the unmasked Investigator. The 
unmasked study personnel and injecting physician must not perform assessment of any ocular 
or non-ocular safety parameters, or assess causality of AEs for participants during the course of 
the study.

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IVT injection is contra-indicated in participants with active or suspected ocular or periocular 
infections and in participants with active or suspected intraocular inflammation. Therefore, 
Investigators should verify that these conditions are not present in either eye prior to every 
injection.
Treatment dose adjustments and/or interruptions are not permitted unless interruptions are 
warranted by an AE.
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the participant’s representative(s) or participant’s legal 
representative(s) gives consent (if allowed according to local requirements), the participant 
must be informed about the study to the extent possible given his/her understanding. If the legal 
representative gives consent, an impartial witness should also sign the ICF reassuring that 
participant was explained with the ICF content. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document.
Participant must be able to read, understand and willing to sign the informed consent. If unable 
to read due to visual impairment, informed consent must be read to verbatim by an impartial 
witness or a family member.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The participant or representative/ legal representative 
will receive a copy of the fully signed and dated ICF. The signed ICF should remain in the 
Investigator site file or, if locally required, in the subject’s note/file of the medical institution. 
The process of obtaining informed consent must be documented in the participant source 
documents.
The Sponsor or delegate will provide to Investigators in a separate document a proposed ICF 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed ICF suggested by the Investigator must 
be agreed by Sponsor before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s Brochure. This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between Investigator’s Brochure updates will be communicated as appropriate, for example, 
via an Investigator notification or an aggregate safety finding. New information might require 
an update to the informed consent and then must be discussed with the participant.
The following ICFs are included in this study:
•
Main study consent
•
An optional PK descriptive analysis for 40 participants in total, which requires a separate 
consent form signature. The consent form will describe the additional blood samples and 

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study visits required. It is required as part of this protocol that the Investigator from 
selected sites presents this option to the participants, as permitted by local governing 
regulations. The process for obtaining consent should be exactly the same as described 
above for the main ICF.
•
An optional evaluation of systemic VEGF concentration at Week 48 (pre-dose) and 
Week 52. The ICF describes the additional blood samples required at the specific time 
points. The Investigator at selected sites presents this option to the participants, as 
permitted by local governing regulations. The process for obtaining consent should be 
exactly the same as for the main ICF.
•
As applicable, Pregnancy Outcomes Reporting Consent for female participants
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements.
Declining to participate in these optional assessments (PK descriptive analysis or VEGF 
evaluation) will in no way affect the participant’s ability to participate in the main research 
study.
A copy of the approved version of all consent forms must be provided to Sponsor after IRB/IEC 
approval.
8
Visit schedule and assessments
The assessment schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation.
A planned study visit schedule will be established at Baseline for all participants. All post-
Baseline and/ or subsequent scheduled visits will be calculated based on the Baseline visit date. 
All efforts should be made to adhere to all scheduled visits and assessments as outlined in the 
assessment schedule or as close to the designated day/time as possible, according to the visit 
window (Table 8-1). All efforts should be made to revert back to the planned visit schedule 
taking into consideration the restrictions on the minimum treatment interval for the study 
treatment, i.e. 2 consecutive injections should be spaced by at least 21 days. Treatment is 
intended to be administered on the day of study visit, or if not possible, within 3 days after the 
study visit when the per-protocol assessments took place, except Baseline, in which study 
treatment administration should occur within the next 24 hours. For a given protocol visit 
(except for Baseline), assessments can be performed on two consecutive days in which both 
days must occur within the visit window
For all visits, efficacy and safety assessments should be performed prior to any administration 
of study treatment.
Missed or rescheduled visits should not lead to automatic discontinuation. Participants who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the EOS visit will be performed, except 
the color fundus photography and fluorescein angiography if there was color fundus 
photography and fluorescein angiography within the previous 12 weeks. At this final visit, all 

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dispensed investigational product should be reconciled, and the AE and concomitant 
medications recorded on the eCRF.

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Table 8-1
Assessment schedule
Period
Treatment
Follow-up
Visit Name
Screening
Baseline
Treatment Period
Safety (EOS)
Week
1
4
8
16
24
32
40
48
52
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Day
-14 to -1
1 
25
8
29
57
585
113
169
225
281
337
365
Visit window
+ 7
± 3
± 3
± 3
± 7
± 7
± 7
± 7
± 7
± 7
Obtain informed consent
X
PK informed consent (only 
for 20 participants per arm)1
X
Randomization
X
Demography
X
Inclusion/exclusion criteria
X
X
Medical history/current 
medical conditions 
X
Prior/Concomitant 
Medications
X
X
X5
X
X
X
X5
X
X
X
X
X
X
Physical Examination
S
S
Vital Signs
X
X
X5
X
X
X
X5
X
X
X
X
X
X
Pregnancy serum test2 
X2
X2
Pregnancy urine test2
S2
S2
S2
S2
S2
S2
S2
S2
S2
FSH3
X3
Laboratory Assessments 
(hematology, biochemistry, 
urinalysis, coagulation)4
X4
X4
X4
X4
Blood (serum) sampling ADA 
(all participants, pre-dose)
X
X
X
X
X
X
X
X

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Period
Treatment
Follow-up
Visit Name
Screening
Baseline
Treatment Period
Safety (EOS)
Week
1
4
8
16
24
32
40
48
52
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Day
-14 to -1
1 
25
8
29
57
585
113
169
225
281
337
365
Visit window
+ 7
± 3
± 3
± 3
± 7
± 7
± 7
± 7
± 7
± 7
Blood (serum) sampling for 
total drug concentration, pre-
dose
 
X
X5
X
X
X
X5
X
X
X
X
Blood (plasma) sampling for 
systemic VEGF 
concentrations
X9,10
X9
Blood (plasma) sampling for 
PK (only for 20 participants 
per arm)5
X5
X5
X5
BCVA6
X
X
X
X
X
X
X
X
X
X
X
Complete Ophthalmic Exam7
X
X
X
X
X
X
X
X
X
X
X
SD-OCT 6
X
X
X
X
X
X
X
X
X
X
X
Color Fundus Photography6
X
X
X
Fluorescein Angiography6
X
X
X
SOK583A1/ Eylea EU IVT 
administration
X
 
X
X
X
X
X
X
X
Post-injection assessment8
X
 
X
X
X
X
X
X
X
Adverse Events
X
X
X5
X
X
X
X5
X
X
X
X
X
X
X=assessment to be recorded in the clinical database or received electronically from a vendor
S=assessment to be recorded in the source documentation only
1 PK analysis Informed Consent must be obtained from 20 participants per arm, from selected sites.

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2 Only in women with childbearing potential; during the study, urine pregnancy testing should be done at monthly intervals. When a visit is not planned for 
a month (during the maintenance period), site team should schedule clinic visits monthly for urine pregnancy tests. The positive urine test needs to be 
confirmed with serum test.
3 Only in the absence of medical documentation to confirm the women is not of child-bearing potential in cases of surgical bilateral oophorectomy without 
a hysterectomy, and reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
4 All blood draws should be performed prior to fluorescein administration and prior to receiving the IVT injection; urinalysis should be done locally at site, 
using dipstick
5 PK substudy participants only; PK assessment will be done in 20 participants per arm only, at selected sites. Samples should be collected pre-dose at 
V2; 24 (±1) h post-dose at V2 and 24 (±1) h post-dose at V5. The collection of blood for total drug concentration on Day 2 and Day 58 must be done only 
for participants participating in the PK study. 
6 Assessments must be done prior to the IVT injections; BCVA must be performed in the study eye in all visits and in both eyes at Screening; at Baseline, 
only study eye BCVA needs to be tested and documented at eCRF; in cases where both eyes are eligible per Screening data, BCVA has to be 
performed for both eyes at Baseline in order to select the Study eye.
SD-OCT will be performed in the study eye in all visits and in the fellow eye at Screening only. FA and Color fundus photography will be done in the 
study eye at Screening, Week 8 and Week 52, and in the fellow eye at Screening only. With the exception of Screening, if the fellow eye is examined in 
accordance with clinical practice and the Investigator’s discretion, the data should be documented in the eCRF only in case of an AE. Details on study 
eye selection are provided in Section 5.1.
7 Includes slit-lamp exam, IOP measurement, and fundus exam. Dilation for the fundus exam is at the discretion of the Investigator. Ophthalmic exam will 
be performed in both eyes at Screening. All other evaluations are study eye only or also in the fellow eye at discretion of investigator.
8 The study eye will be evaluated 0-5 minutes and 30-60 minutes post-injection to ensure that the injection procedure and/or the investigational product 
have not endangered the health of the eye. It includes an evaluation of central retinal artery perfusion via gross assessment of vision and measurement 
of IOP. Direct visualization to assess the central retinal artery, presence of retinal detachment, presence of new intraocular hemorrhage(s) might be 
appropriate at the discretion of the Investigator and/or based on the results of gross assessment of vision and IOP measurement). Participants should be 
instructed to contact the Investigator immediately to report symptoms as e.g. eye pain, redness of the eye, photophobia, blurring of vision.
9 Only in participants who agree to the evaluation of systemic VEGF concentrations (Week 48 and 52). Plasma samples will be taken from subjects 
receiving anti-VEGF treatment for the study eye only. Subjects receiving anti-VEGF treatment for both eyes are excluded from participation in the 
evaluation of systemic VEGF concentrations at Week 48 and Week 52.
10 Blood sample needs to be taken pre-dose.

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8.1
Screening
Screening
The participant must have signed and dated the ICF before any study procedures, including 
screening procedures, are performed. The Screening Period starts with the first screening 
procedure (other than signing the ICF). Screening procedures may be performed on multiple 
days but must be completed within 14 days, up to 2 (+1) weeks, prior to randomization. The 
screening procedures are:
•
Informed consent (in addition to the main study Informed consent, the 40 participants of 
the PK substudy must sign also the PK Informed consent)
•
Demographic and medical history information, including prior/concomitant medications 
used within 90 days
•
Physical examination
•
Vital signs (blood pressure, pulse, respiratory rate and body temperature)
•
Serum pregnancy test if the participant is female and of childbearing potential
•
Serum FSH fertility test in case of absence of medical documentation to confirm the 
female participant is not of child-bearing potential (surgical bilateral oophorectomy 
without a hysterectomy, and/or reported 12 months of natural (spontaneous) amenorrhea 
with an appropriate clinical profile)
•
Blood samples for blood chemistry/hematology (blood draws should be performed prior to 
injection of fluorescein dye)
•
Local dipstick urinalysis
•
BCVA on both eyes
•
Complete ophthalmic examination of both eyes, including slit-lamp exam, IOP 
measurement and fundus exam
•
SD-OCT on both eyes (the images should be submitted within 24 hours to the CRC for 
eligibility determination)
•
FA on both eyes (the images should be submitted within 24 hours to the CRC for 
eligibility determination). FA images from a previous routine evaluation may be used as 
long as FA was performed within 3 days of the screening visit.
•
3-field color fundus photography on both eyes (the images should be submitted within 24 
hours to the CRC for eligibility determination)
•
Participant registration, including screen failures, in the EDC system for obtaining the 
participant ID number
•
Contact IRT to enter participant ID number
•
Monitor/reporting AEs
•
Schedule Baseline Visit

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Retesting
Only retesting of safety laboratory tests and vital signs is permitted and only under the 
following circumstances:
•
Safety laboratory tests and vital signs can be repeated ONCE in order to confirm the 
clinical significance, if the participant has completed Screening events but failed 1 or 
more eligibility criterion related to safety laboratory and vital signs
and
•
the repeat test can be completed within 14 days (if repeated within 14 days, the other 
screening assessments do not need to be repeated).
•
The Investigator may perform retesting also to rule out any technical or measurement 
error(s) or in case of loss or sample damage prior to analysis.
If a repeat test evaluation or result remains outside of the specified range for laboratory or vital 
signs, the participant must be considered as a screening failure. The participant may however 
be rescreened (see below).
Retesting will NOT be permitted for the purpose of capturing new BCVA or imaging 
assessments that previously failed to qualify the participant. 
Medical judgment should be exercised to ensure that treatment is not withheld in order for a 
participant to participate in the study.
Rescreening
Participants may be invited for a new Screening visit (rescreening) only under the following 
circumstances. Prior to rescreening, each case must be discussed and agreed with the Sponsor 
on a case-by-case basis.
•
Participants who do not meet the eligibility criteria may be invited once for a new 
Screening visit (rescreening).
•
Participants who were retested for confirming the clinical significance of 1 or more safety 
labs or vital signs parameter during the initial screening (see above) and failed the related 
eligibility criterion or criteria can be rescreened once at an appropriate time-point based on 
the medical judgement.
•
Participants who present with a temporary medical condition precluding participation may 
be rescreened once. In this case, retesting is not permitted during rescreening for any 
reason.
•
A participant can also be rescreened once in case of sample loss or damage.
For rescreening, the following conditions will be required:
•
Participant must sign a new ICF before any study-specific assessment.
•
Participant must be logged as a screen failure into the IRT and entered as a rescreen. A 
participant not entered into IRT as a rescreen will not be eligible for randomization.
•
A new screening window of up to 2 weeks must commence from the time of re-consent.
•
All screening procedures must be repeated if rescreening is to occur beyond 14 days from 
the original Screening visit date

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Rescreening is NOT permitted if, based on medical judgment, any signs or symptoms assessed 
on Day -1 are suggestive of any significant illness and/or acute infection.
Participants who are randomized and fail to start study treatment, e.g. participants randomized 
in error, must be considered early terminators. The reason for early termination must be 
recorded on the disposition eCRF. In this case, rescreening of the participant is not permitted.
8.1.1
Information to be collected on screening failures
Participants who sign an ICF and subsequently found to be ineligible prior to randomization 
will be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate eCRF. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screening failure participants. No other data will be entered 
into the clinical database for participants who are screening failures, unless the participant 
experienced a SAE during the screening phase (see Section 10.1.3 for SAE reporting details). 
If the participant fails to be randomized, the IRT must be notified within 2 days of the screening 
failure that the participant was not randomized.
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered early terminators. The reason for early termination should be recorded on 
the appropriate eCRF as well as on the screening and enrollment log.
8.2
Participant demographics/other baseline characteristics
Participants demographic and Baseline characteristics data to be collected include: age at 
screening, gender, race/ethnicity, relevant medical history/current medical condition present 
before signing ICF, prior/current medications, primary diagnosis of nAMD, time since 
diagnosis of nAMD (in days), whether nAMD is unilateral or bilateral, iris color, definition of 
the study eye, intraocular pressure, BCVA (both as a continuous variable and using categories 
(< 64 letters and ≥ 64 letters), ophthalmic examinations, retinal imaging, lesion type 
(predominately classic, minimally classic, occult), foveal involvement (subfoveal, extrafoveal, 
undeterminable), CNV lesion size, presence of subretinal fluid, presence of intraretinal 
fluid/cyst, presence of sub RPE fluid, (CSFT), vital signs, laboratory lab results, pregnancy test, 
and adverse events. 
Year of birth should be collected and documented at source document only on-site.
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF page whenever, in their judgment, the test abnormality occurred prior to the informed 
consent signature.
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. Participant race and ethnicity are collected and 
analyzed to identify variations in safety or efficacy due to these factors as well as to assess the 
diversity of the study population as required by Health Authorities.
8.3
Efficacy
The following parameters will be assessed to demonstrate similar efficacy of SOK583A1 and 
Eylea EU:

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•
BCVA score using ETDRS testing charts starting at 4 meters
•
CSFT using SD-OCT
•
Choroidal neovascularization lesion size by FA and Color Fundus Photography
All efficacy assessments should be performed prior to any administration of study treatment.
8.3.1
Visual acuity
ETDRS visual acuity testing should precede any examination requiring administration of eye 
drops to dilate the eye or any examination requiring contact with the eye. Visual acuity of the 
study eye will be assessed at each study visit and the fellow eye will be assessed at Screening 
only, using BCVA (best correction determined from protocol refraction). In cases where both 
eyes are eligible for the study during the Screening Period, the definition of study eye will be 
based upon the Baseline Visit evaluations. BCVA results from the eye selected by the 
investigator as the study eye must be documented in the eCRF. The fellow eye BCVA and the 
rationale for selection of study eye should be documented at source document only. BCVA 
measurements will be taken in a sitting position using ETDRS-like visual acuity testing charts. 
The details of the procedure and training materials will be provided in the applicable manual. 
Certifications of the assessment procedures and assessors will occur prior to any evaluation of 
study participants.
Participants at sites in some Asian countries will undergo BCVA testing using numerical charts 
instead of letters charts.
8.3.2
Spectral-domain optical coherence tomography (SD-OCT)
SD-OCT will be assessed in the study eye at every visit and in fellow eye at Screening only. 
Although SD-OCT is the preferred method and is referred to throughout the protocol, other 
types of OCT can be used, if agreed to and validated by the Central Reading Centre as specified 
in the applicable manual. These assessments will be performed by a trained technician or 
Investigator at the sites and should be performed after BCVA assessment and prior to any study 
drug administration. The SD-OCT machine used for an individual participants should not 
change for the duration of the study. CSFT and central foveal thickness will be measured by 
SD-OCT. The CSFT represents the average retinal thickness of the circular area within 1 mm 
diameter around the foveal center.
A CRC will be used in this study. The CRC will provide sites with a Study Manual and trainings 
materials for the specified study ocular images. Before any study images are obtained, site 
personnel, test images, systems and software will be certified and validated by the CRC, as 
specified at the Manual. All SD-OCT images will be obtained by trained and study-certified 
site personnel at the study site and forwarded to the CRC for independent standardized analysis 
and storage. At the Screening Visit, SD-OCT images will be submitted to the CRC for eligibility 
determination. Feedback from the CRC will be provided to the sites via email or fax. For further 
procedural details, refer to applicable manual provided by the CRC.
8.3.3
Color fundus (CF) photography and fluorescein angiography (FA)
Three-field CF photography and fluorescein angiography will be performed in the study eye at 
Screening, Week 8 and EOS visits and in the fellow eye at the Screening only. In case of 

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premature termination there is no need to repeat the color fundus photography and fluorescein 
angiography if there was CF photography and FA within the previous 12 weeks.
A standardized procedure for the collection of FA and 3-field CF images is provided by the 
CRC in a separate manual. Certification of the equipment and examiners at each site will occur 
prior to evaluation of study participants. All CF and FA images will be obtained by trained and 
study-certified site personnel at the study sites and forwarded to the CRC for independent 
standardized analysis and storage. At the Screening Visit, retinal images will be sent to CRC 
for eligibility determination. Feedback from the CRC will be provided to the sites via email or 
fax. 
FA images from previous routine evaluations may be used as long as they were performed 
within 3 days of the Screening visit using CRC-certified equipment and examiners.
8.3.4
Appropriateness of efficacy assessments
All study procedures related to the assessment of efficacy are standard for this indication and 
patient population and are well established in the field of ophthalmologic clinical practice and 
clinical research. In particular, the imaging assessments, SD-OCT and FA, are standard 
diagnostic tools used in registration studies of Eylea and other anti-VEGF therapies. The 
assessment of BCVA, as a measure of retinal function, will be performed using standard 
procedures extensively used in clinical studies.
8.4
Safety
Safety assessments will include physical examination, vital signs, ophthalmic examinations, 
laboratory evaluation as well as monitoring and recording type, frequency, and severity for all 
AEs. Safety assessments are specified below with Table 8-1 Assessment schedule detailing 
when each assessment is to be performed.
All equipment including applications/software must be calibrated, validated and/or maintained 
according to the applicable regulations/guidelines, manufacturer’s recommendations and local 
practices prior to performing any study specific activities.
For details on AE collection and reporting, see Section 10.1.1 Adverse events.
Table 8-2
Assessments and specifications
Assessment
Specification
Physical 
examination
Physical examination will be performed at Screening and at the EOS visit, as a 
general health check according to local clinical practice.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior 
to signing informed consent must be recorded on the appropriate eCRF page that 
captures medical history. Clinical significant findings identified after signing 
informed consent which meet the definition of an AE must be recorded as an 
adverse event on the Adverse Event section of the eCRF.
Vital signs
Vital signs include assessment of sitting blood pressure (systolic and diastolic 
pressure in mmHg), body temperature, respiratory rate (in breaths per minute) and 
pulse rates (in beats per minute) and will be collected in all visits before treatment 
and blood collection. Body temperature should be collected according to the 
standard local practice.

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Assessment
Specification
After the participant has been sitting for 5 minutes, with back supported and both 
feet placed on the floor, systolic and diastolic blood pressure will be measured 
using a validated device with an appropriately sized cuff.
If the blood pressure measurement is elevated as specified in the exclusion 
criteria, at the Screening visit, the blood pressure measurement must be repeated 
after 20 minutes. If the repeated measurement is elevated, then the participant is 
not eligible to be enrolled into the study. The results will be recorded in the eCRF.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected at applicable visits 
(Screening, Week 8, Week 24 and EOS visit), except the urine, which will be analyzed at each 
site. Samples for Bioanalytical testing (aflibercept concentrations, immunogenicity testing) will 
be performed at the Sponsor laboratory or a qualified contract laboratory. 
 
 
 
Details on the collection, shipment of the samples and reporting of the results by the central 
laboratory are provided in the applicable manual.
All blood samples will be obtained by venipuncture, at the time points outlined in Table 8-1 
Assessment schedule. The date and time of blood collection will be recorded in the participant’s 
medical record.
Unscheduled laboratory assessments may be obtained at any time during the study to assess any 
perceived safety concerns.
No specific action is pre-defined within the protocol to respond to specific abnormal laboratory 
values, as it will be decided by the Investigator, taking into account the overall status of the 
participant.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. Clinically notable laboratory findings are defined 
in the Laboratory Manual.
Table 8-3
Laboratory assessments
Test 
category
Test name
Hematology
Hematocrit, hemoglobin, red blood cells count (RBC), white blood cells count (WBC) 
with differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils), and 
quantitative platelet count
Chemistry
Serum electrolytes (sodium, potassium, chloride, phosphorus, calcium, magnesium), 
uric acid, urea nitrogen, creatinine, albumin, glucose, total protein, total bilirubin and 
direct bilirubin, serum glutamic oxaloacetic transaminase (SGOT)/aspartate 
aminotransferase (AST), serum glutamic pyruvic transaminase (SGPT)/alanine 
CCI
CCI

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Test 
category
Test name
aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase 
(ALP) and lactate dehydrogenase (LDH)
Urinalysis
Dipsticks will be provided by the central laboratory to the sites for local urinalysis 
assessment. Dipstick measurements for specific gravity, pH, protein, glucose, 
ketones, bilirubin, nitrite, leucocyte and urine occult blood
Coagulation
International normalized ratio (INR), Activated partial thromboplastin time (APTT)
Pregnancy 
Test
Serum/urine pregnancy test (see Section 8.4.4 Pregnancy and assessments of 
fertility)
Additional 
Test
FSH (see Section 8.4.4 Pregnancy and assessments of fertility)
8.4.2
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity and the emergence of 
antibodies to human recombinant proteins is well documented. Antibodies directed against a 
therapeutic agent may have neutralizing activity and interfere with the efficacy of the treatment. 
For safety reasons, evaluation for ADA has been included in this study.
8.4.2.1
Immunogenicity blood sample collection and handling
Immunogenicity will be assessed by measuring ADA levels in serum of all participants. Blood 
samples for ADA assessment will be collected from all participants randomized and treated at 
the time points defined in the assessment schedule in Table 8-1. Additional sampling and 
evaluation for ADAs will be collected (unscheduled samples) in case of signals of an 
unexpected ocular inflammation.
Sample collection, labeling, processing of serum, shipment and storage should be performed as 
per instructions provided in the laboratory manual.
The actual exact sample collection date and time must be recorded on the appropriate CRF. 
Communication of immunogenicity results to Investigators occurs after DBL and finalization 
of the Clinical Study Report.
8.4.2.2
Analytical methods for ADA
Immunogenicity of SOK583A1 as determined by the formation of antibodies against the drug 
will be evaluated by using validated immunoassays. The validation procedure and serum sample 
analysis will follow international guidelines.
All samples will first be analyzed in a screening assay. Study samples with a result below the 
validated screening cut-point are negative for binding ADA and will be reported accordingly. 
In the event of a positive result (result above the screening cut-point) the sample will be 
additionally analyzed in a secondary confirmatory assay (specificity assay). In case the assay 
signal can be reduced after addition of excess of SOK583A1 beyond the validated confirmatory 
cut-point, a sample will be reported as confirmed positive. In contrast, samples with a result 
above the screening cut-point in the screening assay but which are negative in the confirmatory 
assay will be reported as negative.

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The titer of confirmed positive results will be reported. In addition, confirmed positive ADA 
samples will be analyzed for their neutralization potential in a neutralizing antibody assay.
Serum samples to determine total drug concentrations will be obtained at the same time as 
immunogenicity samples to support result interpretation. For details on the drug concentration 
determinations, see also Section 8.5.1 Pharmacokinetics.
All immunogenicity assays will be performed at the Sponsor’s bioanalytical laboratory or a 
qualified contract laboratory.
8.4.3
Complete ophthalmic examination
Pupil dilatation for slit lamp examination and ophthalmoscopy can be performed as optional 
according to local practice. The ophthalmic exam will consist of the following:
•
Slit-lamp examination – included evaluation of the lids/lashes, conjunctiva, cornea, iris, 
lens, and aqueous reaction (cells and flare). This test should be completed at every 
scheduled visit to examine the study eye. The fellow eye will be examined at Screening 
and on the discretion of the masked Investigator. The test results will be recorded in the 
source documents only. Any clinically significant abnormalities (as judged by the masked 
Investigator) should be recorded on the AE page of the eCRF.
•
IOP measurement – The tonometry method must remain consistent throughout the study 
for each participant. The IOP should be assessed by the masked Investigator/masked staff 
in the study eye, pre-dose and post-dose at every scheduled visit with the exception of the 
assessment 0-5 minutes after the IVT injection, which may be conducted, if needed, by the 
unmasked Investigator at his/her discretion. The study eye IOP values (mmHg) must be 
entered into the eCRF. 
In the fellow eye, IOP will be assessed at Screening and the value (mmHg) must be entered 
into the eCRF. In the other visits, fellow eye IOP assessment is done on the discretion of 
the Investigator and the values will be documented at medical source only.
Treatment and close monitoring of IOP should be performed by the Investigator according 
to local clinical practice for any non-transient elevation in the IOP (≥ 25 mmHg). Intravitreal 
procedure is not recommended unless normalization of IOP has been achieved. Post-dose 
IOP should be assessed after every IVT injection, between 30-60 minutes after injection and 
if IOP ≥ 25 mmHg, assessment should be repeated until back to normal. 
Any clinically relevant abnormalities in either eye should be recorded on the AE page of 
the eCRF.
•
Fundus exam/Ophthalmoscopy – includes evaluation of the vitreous, retina, macula, 
choroid, and optic nerve. Dilatation for the fundus exam is at the discretion of the masked 
Investigator. This test should be conducted by the Investigator at the Screening visit and at 
all other visits, in the study eye. The fellow eye will be examined at Screening and on the 
discretion of the Investigator. An examination of the peripheral retina must also be 
conducted to ensure that the IVT injection can safely be performed. The test results will be 
recorded in the source documents only. Any clinically significant abnormalities (as judged 
by the masked Investigator) should be recorded on the AE page of the eCRF.

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8.4.4
Pregnancy and assessments of fertility
For women 50 years or older in the study, pregnancy is not expected. However, to avoid 
exceptional rare occurrences, all pre-menopausal women who are not surgically sterile will have 
pregnancy testing. Additional pregnancy testing might be performed if requested by local 
requirements.
Highly effective contraception is required for women of child-bearing potential during the study 
drug administration and for 3 months after stopping the study drug.
A serum pregnancy test will be conducted for all women of child-bearing potential to assess 
pregnancy before inclusion into the study at Screening visit and then, at EOS. During the study, 
urine pregnancy testing should be done at monthly intervals. When a visit is not planned for a 
month (during the maintenance period), the clinical site team should schedule clinic visits 
monthly for urine pregnancy tests. The positive urine test needs to be confirmed with serum 
test. If positive, the participant must be discontinued from study treatment. Refer to Table 8-1 
Assessment schedule. Results of all pregnancy testing must be available as source 
documentation.
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening
8.4.5
Post-injection assessment
The study eye will be assessed before, immediately after 0-5 minutes and after 30-60 minutes 
after each IVT injection. The unmasked Investigator is responsible to conduct the assessment 
occurring immediately after the injection (0-5 minutes post-injection assessment). All other 
post-injection assessments must be performed by the masked Investigator. These assessments 
include gross assessments of:
•
vision (e.g. count fingers, hand motion, light perception, no light perception), 
•
the status of the central retina artery, by direct visualization, at the discretion of the 
investigator, 
•
presence of retinal detachment, by direct observation of the retina, at the discretion of the 
Investigator,
•
presence of new intraocular hemorrhage, at the discretion of the Investigator,
•
measurement of IOP immediately after 0-5 minutes of IVT injection, at the discretion of 
the Investigator.

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IOP measurement is mandatory after 30-60 minutes after each IVT injection. In case of 
abnormal findings, assessments will continue on intervals at the discretion of the Investigator, 
until the central retinal artery is adequately perfused and the IOP is back to normal.
Any participant who develops significantly raised IOP (≥ 25mmHg) or a non-adequately 
perfused central retinal artery at any time during the study should be monitored according to 
the Investigator’s clinical judgment and may undergo additional procedures and measurements 
of IOP beyond those specified in the protocol. If, at the conclusion of the required evaluation 
period following an injection there are no safety concerns, the participant will leave the site. If 
any concern or immediate toxicity is noted, the participant will remain at the site and will be 
treated according to the designated evaluating physician’s clinical judgment. If any issues 
regarding IOP are noted during the post-injection assessment, then the participant should be 
scheduled for a follow up visit (Unscheduled Visit) the day following injection, if required in 
the opinion of the Investigator. 
Clinically relevant changes that are observed during the post-injection assessment should be 
reported as AEs. Participants should be instructed to contact the Investigator immediately to 
report symptoms as e.g. eye pain, redness of the eye, photophobia, blurring of vision.
8.4.6
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population and also 
aligned with the safety assessments as per Eylea’s safety profile (Eylea EU SmPC; Eylea US 
PI).
8.5
Additional assessments
8.5.1
Pharmacokinetics
Free aflibercept and total aflibercept will be quantified in plasma and serum, respectively, using 
validated assays detecting both Eylea and SOK583A1. Concentrations will be expressed in 
mass per volume units.
Concentrations below the LLOQ and missing data will be labeled as such in the Bioanalytical 
Report and respective data transfers. The concentrations will be summarized by treatment and 
time point for which the concentrations below LLOQ will be treated as zero.
8.5.1.1
Pharmacokinetics blood sample collection and handling
PK samples for determination of free and total aflibercept will be collected from 20 participants 
per arm at Visit 2 (pre-dose and 24 (±1) hours after the first dose) and Visit 5 (approximately 
24 (±1) hours post-dose), as defined in the assessment schedule.
Additionally, blood samples for determination of total drug concentration will be collected from 
all participants at the same time points as ADA sample collection is performed (see assessment 
schedule indicated in Table 8-1 Assessment schedule), to support result interpretation of 
immunogenicity analysis. Total drug blood samples will also be taken at unscheduled time 
points, in case of additional sampling and ADA evaluation (unscheduled samples) as indicated 
in Section 8.4.2.2 Analytical methods for ADA.

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Sample collection, labeling, processing to serum or plasma, shipment and storage should be 
performed as per instructions provided in the laboratory manual.
8.5.1.2
Analytical methods for pharmacokinetics
Two bioanalytical methods will be used to determine free and total aflibercept concentrations 
in plasma or serum samples, respectively, obtained for nAMD participants in this study. Briefly, 
the concentration of free or total aflibercept will be determined in validated immunoassays. The 
concentration of aflibercept in the study samples will be determined by interpolation using a 
standard curve with known concentrations of aflibercept. Concentrations will be expressed in 
mass per volume unites (ng/mL). All assessments will be performed at the Sponsor’s 
bioanalytical laboratory or a qualified contract laboratory.
8.5.2
Imaging
The methods for assessment and recording of SD-OCT, color fundus photography and FA are 
specified in the Central Reading Center Imaging Manual.
8.5.3
Systemic VEGF concentrations
Only patients receiving anti-VEGF treatment for the study eye are eligible for evaluation of 
systemic VEGF concentrations. Subjects receiving anti-VEGF treatment for both eyes are 
excluded from participation in the evaluation of systemic VEGF concentrations. 
Blood (plasma) samples will be collected from those participants who agree to additional blood 
collection for evaluation of systemic VEGF concentrations at Visit 10 (Week 48, pre-dose) and 
Visit 11 (Week 52). 
Sample collection, labeling, processing to plasma, shipment and storage should be performed 
as per instructions provided in the laboratory manual.
Free VEGF will be quantified in plasma using a validated assay. The concentration of free 
VEGF in the study samples will be determined by interpolation using a standard curve with 
known concentrations of VEGF. Concentrations will be expressed in mass per volume units 
(pg/mL).
All assessments will be performed at the Sponsor’s bioanalytical laboratory or a qualified 
contract laboratory.
9
Discontinuation and completion
9.1
Discontinuation of study treatment and from study
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration, if any), 
and can be initiated by either the participant or the Investigator.
The Investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant’s well-being. 

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The Investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all participants who are prematurely withdrawn from the study.
Participants who started study treatment but prematurely discontinued treatment and/or study 
will not be replaced.
Discontinuation of study treatment is required under the following circumstances:
•
Participant/guardian decision
•
Pregnancy
•
Use of rescue treatment in the study eye or prohibited treatment as per recommendations 
in Section 6.2.2 Prohibited medication
•
Any situation in which continued study participation might result in a safety risk to the 
participant
•
Following emergency unmasking as per Section 6.6.3 Emergency breaking of assigned 
treatment code
If discontinuation of study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants who discontinue from study treatment agree to return for the EOS assessments 
indicated in the assessment schedule (refer to Section 8 Visit schedule and assessments).
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact:
•
new/concomitant treatments
•
Adverse events/Serious Adverse Events
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment and inform the date and primary reason for stopping the study treatment
If discontinuation occurs because the treatment code has been broken, see Section 6.6.3 
Emergency breaking of assigned treatment code.
9.1.2
Discontinuation from study
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8 Visit schedule and 
assessments).
9.1.3
Lost to follow up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 

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consent/oppose to the use of their data/biological samples, the Investigator must show “due 
diligence” by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed.
9.2
Withdrawal of informed consent/Opposition to use 
data/biological samples
Withdrawal of consent/opposition to use data/biological samples occurs when a participant:
•
Explicitly requests to stop use of their data (opposition to use participant’s data and 
biological samples)
and
•
No longer wishes to receive study treatment
and
•
Does not want further visits or assessments (including further study-related contacts)
This request should be documented in written (depending on local regulations) and recorded in 
the source documentation.
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information.
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8 Visit schedule and assessments).
Sponsor will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition.
9.3
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their EOS and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by 
the Investigator or, in the event of an early study termination decision, the date of that decision.
All randomized and/or treated participants should have a safety follow-up visit (EOS) 
conducted 4 weeks after last administration of study treatment. The information collected must 

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be included at eCRF and is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3 SAE reporting. Documentation of 
attempts to contact the participant should be recorded in the source documentation.
The Investigator is advised to provide appropriate follow-up nAMD treatment for all 
participants completing the study or prematurely withdrawn from the study.
9.4
Early study termination by the Sponsor
The study can be terminated by Sponsor at any time. The Sponsor may terminate this study 
prematurely, either in its entirety or at any study site.
Reasons for early termination, but not limited to:
•
Failure by the participant and/or the study site to comply with the protocol (e.g. 
noncompliance), the requirements of the IEC/IRB or local health authorities, the 
Sponsor’s procedures, or GCP guidelines
•
Inadequate recruitment of participants by the Investigator/failure of the Investigator to 
enter study participants at an acceptable rate
•
Recommendations from applicable board(s) after review of safety data based on the 
number and/or severity of suspected unexpected serious adverse reactions 
(SUSARs)/SAEs/AEs in the study, or new data becoming available, which raise concern 
about the safety profile of the study treatment.
•
High frequency of adverse events
•
Recommendations from applicable board(s) after review of safety and efficacy data
•
Discontinuation of further study drug development
In taking the decision to terminate, Sponsor will always consider the participant welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible for 
a final visit and treated as a participant who discontinued from study treatment. The Investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the participant’s interests. The Investigator or 
Sponsor/delegated depending on the local regulation will be responsible for informing 
IRBs/IECs of the early termination of the study.
10
Safety monitoring, reporting, and committees
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom or disease) in a clinical investigation 
participant after providing written informed consent for participation in the study. Therefore, 
an AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product.

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The Investigator has the responsibility for managing the safety of individual participant and 
identifying AEs.
Sponsor qualified medical personnel will be readily available to advise on study related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. Adverse events also may be detected when they are volunteered by the 
participant during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information as far as possible. If the event is serious, see Section 
10.1.2 Serious adverse events:
1. The severity grade:
•
mild: usually transient in nature and generally not interfering with normal activities
•
moderate: sufficiently discomforting to interfere with normal activities
•
severe: prevents normal activities
2. Its relationship to the study treatment or the ocular injection procedure. If the event is due 
to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected.’ The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the study drug, but they occur in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single participant
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
All AEs must be treated appropriately. Treatment may include 1 or more of the following:
•
no action taken (e.g. further observation only)
•
study drug interrupted/withdrawn
•
concomitant medication or non-drug therapy given
•
participant hospitalized/participant’s hospitalization prolonged (Section 10.1.2)
6. Its outcome:
•
not recovered/not resolved
•
recovered/resolved
•
recovering/resolving
•
recovered/resolved with sequelae
•
fatal
•
unknown

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Conditions that were already present at the time of informed consent should be recorded in the 
medical history of the participant.
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms.
AE monitoring should be continued for at least 4 weeks following the last dose of study 
treatment. For participants that have withdrawn consent or discontinued treatment; see Section 
9.1 Discontinuation.
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) regarding any changes in severity, suspected relationship to 
the study drug, interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator’s Brochure.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
•
they induce clinical signs or symptoms
•
they are considered clinically significant
•
they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with the underlying disease. Alert ranges for laboratory are included in the Laboratory Manual.
10.1.2
Serious adverse events
An SAE is defined as any AE (appearance of (or worsening of any pre-existing)) undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria:
•
fatal
•
life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (refer to the ICH-E2D Guidelines).
•
results in persistent or significant disability/incapacity
•
constitutes a congenital anomaly/birth defect
•
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
•
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
•
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

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•
social reasons and respite care in the absence of any deterioration in the participant’s 
general condition
•
treatment on an emergency out-patient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
•
is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 4 weeks after the last administration of study treatment 
must be reported to Sponsor safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the Investigator folder 
provided to each site. Information about all SAEs is collected and recorded on the Serious 
Adverse Event Report Form; all applicable sections of the form must be completed in order to 
provide a clinically thorough report.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information. An SAE occurring at a different time interval 
or otherwise considered as completely unrelated to a previously reported one must be reported 
separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
Patient Safety (CMO&PS) Department associate may urgently require further information from 
the Investigator for Health Authority reporting. The sponsor may need to issue an Investigator 
Notification (IN) to inform all Investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 

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2011/C 172/01 or as per national regulatory requirements in participating countries. The 
incidence of key AEs, such as intraocular inflammation or endophthalmitis, will be followed 
closely by the sponsor during the study duration.
Any SAEs experienced after the last visit (EOS) should only be reported to Sponsor Safety if 
the Investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
If a female study participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the study participant. The participant must be 
given adequate time to read, review and sign pregnancy consent form. This consent form is 
necessary to allow Investigator to collect and report information regarding the pregnancy. To 
ensure participant safety, each pregnancy occurring after signing the informed consent must be 
reported to Sponsor within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the Investigator to the Sponsor CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. The newborn should 
be followed up for 12 months after the date of delivery.
Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition).
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety CMO&PS only if associated with an SAE.
Table 10-1
Guidance for capturing the study treatment errors
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
For more information on AE and SAE definition and reporting requirements, see the 
corresponding sections above.
10.2
Additional Safety Monitoring
Not applicable

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10.3
Committees
A Data Monitoring Committee is considered not required for the study A12301 based on 
following reasons: 
•
the study is performed in patients with nAMD, which is a non-critical (i.e. not life-
threatening) indication in a non-special (e.g. pediatrics or mentally disabled) population
•
analytical data demonstrate a high degree of structural and functional similarity between 
SOK583A1 and Eylea
•
the safety of excipients used for SOK583A1 formulation has been shown with other 
medications available in the market for treatment of nAMD 
•
the safety profile of aflibercept is established and well known
•
the Sponsor will closely review all adverse events, specially, post-injection 
endophthalmitis, intraocular infections/inflammations, and will conduct clinical and 
product safety assessments; selective unmasking may be considered in case of a 
significant concern is identified during the study conduct
No interim analyses for early stopping or design modification are planned.
11
Data Collection and Database management
11.1
Data collection
Designated Investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the Investigator staff.
The Investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate
After final DBL, the Investigator will receive copies of the participant data for archiving at the 
investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Sponsor personnel (or designated CRO) will review the data entered by investigational staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated masked Investigator site staff are required 
to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
(WHO) Drug Reference List, which employs the Anatomical Therapeutic Chemical 

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classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to the 
Sponsor. Color fundus photography, fluorescein angiograms, and OCT images will be 
processed centrally by the CRC and the results will be sent electronically to Sponsor. The data 
manager staff will perform a reconciliation of the data entered on the eCRF versus what is 
received from the CRC and central labs.
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
study treatment changes will be tracked using an Interactive Response Technology (IRT). The 
system will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Sponsor (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the designated clinical team and 
monitor. The code break functionality will remain available until study shut down or upon 
request of Sponsor.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unmasked and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Sponsor development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a delegated 
Sponsor/CRO representative will review the protocol and data capture requirements (i.e. eCRFs) 
with the Investigators and their staff. During the study, Sponsor employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. The field 
monitor will visit the site to check the completeness of participant records, the accuracy of data 
capture/data entry, the adherence to the protocol and to Good Clinical Practice, the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized CRA organization. Additionally, a central analytics organization may analyze data, 
identify risks and trends for site operational parameters, and provide reports to Sponsor clinical 
teams to assist with study oversight.
The Investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, retinal images and the results of any other tests or assessments. 
All information on CRFs must be traceable to these source documents in the participant’s file. 
The Investigator must also keep the original ICF signed by the participant (a signed copy is 
given to the participant).
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Sponsor monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 

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checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.
12
Data analysis and statistical methods
Data analysis will be performed at 2 time points: an interim analysis after all subjects completed 
Week 40 or discontinued before Week 40 and a final analysis after all subjects completed the 
study. Analysis of the primary endpoint (mean change from Baseline in BCVA at Week 8) will 
be conducted on all participants in the Per-Protocol Set (PPS) at the interim analysis. Any 
efficacy and safety data of participants collected during the study will also be analyzed for the 
final analysis
Any data analysis carried out independently by the Investigator should be submitted to the 
Sponsor before publication or presentation.
12.1
Analysis sets
The Randomized Analysis Set (RAS) consists of all randomized participants. The RAS will 
include all participants who were randomized including those that were not treated.
The Full Analysis Set (FAS) comprises all randomized participants to whom study treatment 
has been assigned by randomization, to whom at least one treatment was administered and for 
which at least one post-baseline BCVA value is available. According to the intent to treat 
principle, participants will be analyzed according to the treatment they have been assigned to 
during the randomization procedure.
The Safety Set includes all randomized participants who received at least 1 dose of study 
treatment. Participants will be analyzed according to the study treatment received.
The PPS is a subset of participants of the FAS and is characterized by the following criteria:
•
The primary BCVA assessments at baseline and Week 8 are available
•
The participants received treatment according to the protocol at Day 1 and Week 4
•
The participants have not experienced any important protocol deviations up to Week 8
The criteria to qualify a protocol deviation as important regarding the evaluation of the study’s 
primary objective will be provided in the SAP.
The PK Analysis Set (PKS) will be the analysis set used for analyzing free and total drug 
concentration in a subset of participants. The PKS comprises participants with at least one 
evaluable post-baseline drug concentration assessment. Participants requiring both eyes 
treatment at baseline are not eligible for the PK substudy. Participants who start with uni-lateral 
nAMD at baseline but convert to bi-lateral nAMD during PK assessment period and get 
aflibercept treatment will be excluded from PK analysis.
The VEGF Analysis Set will be the analysis set used for evaluating systemic VEGF 
concentrations in a subset of participants. The VEGF Analysis Set comprises those participants 
who received study treatment at Week 48 and have a VEGF concentration assessment at 
Week 52. Participants requiring treatment of both eyes are not eligible for the evaluation of 
systemic VEGF concentrations. 

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The Immunogenicity Analysis Set (IAS) consists of all randomized patients who received at 
least one dose of the investigational treatment (SOK583A1 or Eylea EU) and have 
immunogenicity blood samples collected and analyzed at Baseline and at least 1 time point 
post-baseline. Patients with positive immunogenicity at Baseline will be excluded from IAS.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS, PPS and Safety Set. Descriptive 
statistics will be produced for age as a continuous variable, but age will also be included as age 
categories (< 75 years and ≥ 75 years), and BCVA as a continuous variable and BCVA 
categories (< 64 letters and ≥ 64 letters).
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
SD, median, minimum, and maximum will be presented. For selected parameters, 25th and 75th 
percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, for all participants in the FAS by treatment group.
12.3
Treatments
Study medication administration will be summarized for all participants in the Safety Set by 
treatment. All treatment-related information will also be listed by treatment. Categorical data 
will be summarized as frequencies and percentages. For continuous data, mean, standard 
deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.
The extent of treatment exposure will be presented based on the overall number of injections 
and the number of participants injected per visit using the Safety set.
Prior medications (any medication taken up to 90 days prior to Screening) and concomitant 
medications (ocular and non-ocular) will be listed and summarized according to the Anatomical 
Therapeutic Chemical (ATC) classification system, by treatment group. Additionally, the 
number and percentage of participants who had procedures performed during the study will be 
summarized by SOC and PT according to MedDRA terminology.
12.4
Analysis of the primary estimand
12.4.1
Definition of primary endpoint(s)
BCVA will be assessed using the ETDRS testing charts at an initial distance of 4 meters. The 
change from Baseline in BCVA in letters is defined as difference between BCVA score between 
Week 8 and Baseline.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary aim of the study is to demonstrate equivalence of change in BCVA score from 
Baseline at Week 8 between participants with nAMD treated with SOK583A1 and participants 
treated with Eylea EU. The primary analysis will be performed on the PPS, which is the most 

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appropriate analysis set to use when testing for equivalence. The justification of the 
corresponding primary estimand is detailed in Section 2.1 Primary estimands.
FDA and EMA have different requirements on the equivalence testing for the primary 
endpoint :
•
EMA equivalence testing requirements: To demonstrate the equivalence of the difference 
in change from baseline at Week 8 in BCVA, the resulting 95% CI of the difference must 
lie within the equivalence interval of [-3.5, 3.5].
•
FDA equivalence testing requirements: To demonstrate the equivalence of the difference 
in change from baseline at Week 8 in BCVA, the resulting 90% CI of the difference must 
lie within the equivalence interval of [-3.0, 3.0].
The following statistical hypotheses will be tested to assess equivalence between SOK583A1 
and Eylea EU in terms of change from baseline in BCVA score at Week 8.
H0: |SOK583A1 – Eylea| ≥ Δ versus H1: |SOK583A1 – Eylea| < Δ
Therapeutic equivalence in terms of change from Baseline in BCVA for EMA requirement will 
be concluded if the 95% CI for the difference in mean changes is contained within the interval 
[−3.5, 3.5]. This is statistically equivalent to calculating 2 independent one-sided tests at 2.5%-
alpha level (one in each direction), of which both have to be successful.
Therapeutic equivalence in terms of change from baseline in BCVA for FDA requirement will 
be concluded if the 90% CI for the difference in mean changes is contained within the interval 
[−3.0; 3.0]. This is statistically equivalent to calculating 2 independent one-sided tests at a 5%-
alpha level, of which both have to be successful.
Analysis of covariance (ANCOVA) will be performed and the model will include treatment as 
a factor, and Baseline BCVA and age as continuous covariates. The least-squares means for the 
treatments will be calculated and the CIs for the difference in the 2 products will be obtained 
from the ANCOVA model. Consistent with the two one-sided tests for bioequivalence at the 
2.5% significance level (Schuirmann 1987), 95% CIs for change from Baseline in BCVA will 
be derived. Similarly, 90% CIs for change from Baseline in BCVA will be obtained.
12.4.3
Handling of remaining intercurrent events of primary estimand
Since the primary analysis is only on those participants who adhere to and complete treatment 
and do not have important protocol deviations, there will be no intercurrent events for the 
observed PP estimand.
12.4.4
Handling of missing values not related with intercurrent events
As primary analysis will be performed on PPS as defined in section 12.1, there will be no or 
minimum missing data for primary endpoint, the change from baseline at Week 8 in BCVA 
scores. Therefore, no imputation for missing data will be performed for primary analysis. 
12.4.5
Sensitivity analyses for primary estimand
A sensitivity analysis will be conducted to impute missing data using last observation carried 
forward (LOCF) method if missing data of primary endpoint is observed in PPS. Observed 

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values from both scheduled and unscheduled visits will be used for the LOCF imputation. For 
participants with no post-baseline value, no imputation will be performed. 
In addition, sensitivity analysis to compare the results from the ANCOVA model for the 
primary estimand with a MMRM model will be performed. The MMRM model will include 
treatment, visit and interaction between time and treatment as categorical variables, and age and 
baseline BCVA as continuous variables. As the model can handle partial data from a participant 
when estimating the variance-covariance matrix, participants with both baseline BCVA value 
and at least one available value at Week 4 or Week 8 will be included in the analysis. This 
sensitivity MMRM analysis will be conducted using the PPS.
12.4.6
Supplementary analysis
To explore the robustness of inferences from the primary observed PP estimand, a 
supplementary analysis on FAS using the same statistical model of ANCOVA as for the primary 
analysis will be performed. Missing data will be imputed using LOCF imputation. Observed 
values from both scheduled and unscheduled visits will be used for the LOCF imputation. For 
participants with no post-baseline value, no imputation will be performed.  
Sensitivity analysis to compare the results from the ANCOVA model for supplementary 
analysis with a MMRM model will be performed. The MMRM model will include treatment, 
visit and interaction between time and treatment as categorical variables, and age and baseline 
BCVA as continuous variables. As the model can handle partial data from a participant when 
estimating the variance-covariance matrix, participants with both baseline BCVA value and at 
least one available value at Week 4 or Week 8 will be included in the analysis. This sensitivity 
MMRM analysis will be conducted using the FAS.
12.5
Analysis of secondary endpoints
12.5.1
Efficacy endpoint(s)
•
Mean change in BCVA score from Baseline to Week 24 and Week 52 will be summarized 
descriptively by treatment. 
•
Mean change in CSFT (as determined by SD-OCT from CRC) from baseline to Weeks 1, 
4, 8, 24 and 52 will be summarized descriptively by treatment
•
Mean change of CNV lesion size using FA from Screening to Weeks 8 and 52 will be 
summarized descriptively by treatment
12.5.2
Safety endpoints
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
Baseline summaries). Summary tables for adverse events (AEs) will summarize only on-
treatment events, with a start date during the on-treatment period (treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 4 weeks 
after the date of the last actual administration of any study treatment.

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There are no formal safety hypotheses in this study. All safety analyses will be performed using 
the Safety Set. The safety endpoints are based on the variables from the safety assessments 
which include:
•
Ocular and non-ocular and systemic treatment-emergent AEs and SAEs
•
Ophthalmic examinations
•
Vital signs
•
Laboratory results
•
Post-injection assessments
•
ADA (development of binding and neutralizing ADA up to Week 52)
Adverse events
A treatment-emergent AE is defined as any AE that develops after initiation of the study 
treatments or any event already present that worsens following exposure to the study treatment. 
All information obtained on adverse events will be displayed by treatment group and participant
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-masked 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways:
•
by treatment, primary system organ class and preferred term
•
by treatment, primary system organ class, preferred term and maximum severity
Separate presentations will be provided related to ocular events in the study eye and fellow eye 
and systemic events. Sensitivity safety analyses excluding participants requiring treatment of a 
fellow eye during study will be performed. Separate summaries will be provided for study 
medication related adverse events, death, serious adverse events, other significant adverse 
events leading to discontinuation.
Additional subgroup analyses by ADA status (positive, negative) will be performed.
A participant with multiple AEs within a primary system organ class is only counted once 
towards the total of the primary system organ class.
There is no planned statistical testing in the safety analyses. Listings of death, SAEs, AEs 
leading to study treatment discontinuation, AE leading to study withdrawal and study treatment 
related AEs will be provided.
Vital signs
All vital signs data (blood pressure, pulse, respiratory rate and body temperature) will be listed 
by treatment group, participant, and visit/time. Summary statistics will be provided by treatment 
and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 

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treatment and visit/time. Shift tables using the low/normal/high/(low and high) classification 
will be used to compare baseline value to post baseline value by treatment and visit.
Values outside the extended normal range will be listed by participant and treatment arm and 
flagged in data listings.
Ophthalmic examinations
Pre-injection IOP measurements will be presented descriptively (absolute values and change 
from baseline). Post-injection IOP measurements will be listed.
Immunogenicity
For all immunogenicity analyses, the IAS will be used. All immunogenicity results will be listed 
by treatment group, participant, and visit. The incidence of participants who develop binding 
ADAs and neutralizing antibodies (NAbs) by visit and overall will be compared between 
treatment, descriptively. In addition, summary of the immunogenicity results of the participants 
that received aflibercept treatment in the fellow eye will be presented.
12.5.3
Pharmacokinetics
Free (plasma) and total (serum) aflibercept concentration data of participants included in the 
PKS will be listed by treatment, participant, and sampling time point. Descriptive summary 
statistics for free and total drug concentrations will be provided by treatment and sampling time 
point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero.
Summary statistics will include arithmetic mean, SD, coefficient of variation, median, 
minimum and maximum. Concentrations below LLOQ will be treated as zero in summary 
statistics.
Additionally, success criteria (assessment of non-similarity between the SOK583A1 and Eylea) 
will be specified in the SAP before DBL as per EMA recommendation. 
12.6
Analysis of exploratory endpoints
12.6.1
Evaluation of systemic VEGF concentrations
Free plasma VEGF concentration data of participants included in the VEGF Analysis Set will 
be listed by treatment, participant, and sampling time point. Descriptive summary statistics for 
free VEGF concentrations will be provided by treatment and sampling time point, including the 
frequency (n, %) of concentrations below the LLOQ. Percentage change in VEGF 
concentrations from Week 48 to Week 52 will also be summarized.
Summary statistics will include arithmetic mean, SD, coefficient of variation, median, 
minimum, and maximum.
12.7
Interim analyses
An Interim analysis will be performed after all participants have completed Week 40 or 
discontinued prior to Week 40. Formal testing of the primary endpoint with full level alpha will 
be performed at the primary analysis time point. A final analysis will be performed after all 

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participants have completed Week 52 (or discontinued prior to Week 52). The Clinical Study 
Report post final analysis at Week 52 will be cumulative and will also include the analyses from 
Week 40 cut-off primary Clinical Study Report.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Margin justification
The equivalence margin for the mean difference in the primary endpoint was discussed and 
have been agreed with FDA, EMA and PMDA.
The meta-analysis for justification of the equivalence margin is based on data from eight studies 
of anti-VEGF therapies in nAMD patients: ANCHOR (Brown et al 2009); MARINA 
(Rosenfeld et al 2006); HARBOR (Ho et al 2014); PIER 1 (Regillo et al 2008); VIEW 1 and 
VIEW 2 (Heier et al 2012); and HAWK and HARRIER (Dugel et al 2020). All studies included 
in the analysis are randomized controlled trials (RCTs) with a total of 3562 patients treated with 
aflibercept 2 mg, ranibizumab 0.5 mg, or having received a sham injection. BCVA in letters at 
two months (8 weeks) was assessed in all of the studies. A meta-analysis was performed with 
the available data from these studies to support the proposed EQ margin. The mean change in 
BCVA at two months (8 weeks) and the standard error were extrapolated from the respective 
publication. A fixed effect model with study (1=studies comparing ranibizumab vs. non VEGF-
based treatments, or different dosing regimen of ranibizumab; and 2=studies comparing anti-
VEGF treatments) and treatment (aflibercept, ranibizumab, sham injection) as 2 fixed factors 
were fitted for the data. The inverse value of the variance was used as the exponential family 
dispersion parameter weight for each observation. The results from the meta-analysis are 
presented in Table 12-1 and Table 12-2.
Table 12-1
Treatment Least Square Means at Week 8
95% CI
Treatment
Estimate
Standard Error
Lower
Upper
Aflibercept 2 mg
6.1626
0.4210
5.3374
6.9878
Ranibizumab 0.5 mg
6.7229
0.2931
6.1485
7.2973
Sham Injection
-2.6135
0.6813
-3.9488
-1.2782
Table 12-2
Differences of Treatment Least Square Means at Week 8
95% CI
Treatment 
Comparisons 
Estimate
Standard Error
Lower
Upper
Aflibercept 2 mg vs 
Sham Injection
8.7761
0.9018
7.0087
10.5436
Ranibizumab 0.5 mg 
vs Sham Injection
9.3364
0.7269
7.9118
10.7610
Aflibercept 2 mg vs 
Ranibizumab 0.5 mg 
-0.5602
0.5337
-1.6063
0.4858

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The point estimate of the mean difference for change from baseline in BCVA at 8 weeks 
between aflibercept and sham injection is +8.8 letters with a 95% CI of (+7.00, +10.54).
The lower bound of the 95% CI is used to justify an appropriate margin.
EMA and PMDA considered the proposed margin of ± 3.5 letters as acceptable as it retains at 
least 50% of the treatment effect and is well away from the 5 letters (a 5 letters loss in BCVA 
has been used as a retreatment criterion in several studies).
FDA considered a margin of ± 3.0 letters as acceptable.
Based on EMA and PMDA requirements:
The sample size is based on considering EqM (equivalence margin) of ± 3.5 letters, using a 95% 
CI and SD of 10 letters for the change from Baseline in BCVA at Week 8. Assuming no 
difference between SOK583A1 and Eylea, at least 214 participants per treatment group (428 
evaluable participants in total) will be required for the study with 90% power to show 
equivalence of SOK583A1 to Eylea. The limits of a two-sided 95% CI will exclude a difference 
in means of more than 3.5 letters in the change from Baseline in BCVA.
Based on FDA requirements:
The sample size is based on considering EqM (equivalence margin) of ± 3.0 letters, using a 90% 
CI and SD of 9.5 letters for the change from Baseline in BCVA at Week 8. Assuming no 
difference between SOK583A1 and Eylea, at least 218 participants per treatment group 
(436 evaluable participants in total) will be required for the study with 90% power to show 
equivalence of SOK583A1 to Eylea. The limits of a two-sided 90% CI will exclude a difference 
in means of more than 3.0 letters in the change from Baseline in BCVA.
Combined sample size:
The sample size of 460 participants planned to be randomized in the study will cover both FDA 
and EMA requirements, including the expected drop-out rate of 5%. As COVID-19 pandemic 
situation may evolve during the study conduct, leading to higher overall proportion of missing 
data, an assessment to change the assumption for the drop-out rate will be performed and the 
sample size increased accordingly.
Table 12-3
Assumptions for sample size calculations based on FDA and EMA 
requirements
EMA
FDA
Confidence level
95%
90%
Power
90%
90%
EqM
3.5 letters
3.0 letters
Treatment difference
0
0
SD
10 letters
9.5 letters
N per treatment arm
214
218
Drop-out rate
5%
5%
Sample size
452
460

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12.8.2
Secondary endpoint(s)
None of the secondary endpoints are considered as key secondary endpoints and therefore no 
sample size calculation was performed for these.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a study, the Investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the study 
protocol, written ICF, consent form updates, participant recruitment procedures (e.g. 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the Investigator is required to sign the protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Sponsor monitors, auditors, Sponsor Quality Assurance representatives, designated agents of 
Sponsor, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the Investigator must inform Sponsor immediately that 
this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this study will be submitted for publication 
and posted in a publicly accessible database of clinical study results, such as the Novartis 
clinical study results website and all required Health Authority websites (e.g. Clinicaltrials.gov, 
EudraCT etc.).
Details of the Sponsor publication policy including authorship criteria based on the Sponsor 
publication policy will be provided as training materials at the study Investigator Meetings and 
included into the Site File.
Any data analysis conducted independently by the Investigators should be submitted to the 
Sponsor before publication or presentation.
13.4
Quality Control and Quality Assurance
Sponsor maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.

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Audits of Investigator sites, vendors, and Sponsor systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical study. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Sponsor processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it to 
Sponsor and not use it for any purpose other than the study, except for the appropriate 
monitoring of study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by the 
Sponsor and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the Sponsor, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the Health Authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, the Sponsor 
should be notified of this action and the IRB/IEC at the study site should be informed according 
to local regulations.
15
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16
Appendices
Not applicable