Conditions: Neovascular Age-related Macular Degeneration (nAMD)
Keywords: Open label study, intravitreal injection, biosimilar, aflibercept, PFS
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This was an open-label, single arm, multicenter, Phase IIIb study in subjects with (wet) nAMD, eligible for IVT aflibercept treatment.

Detailed description:
This was an open-label, single arm, multicenter, Phase IIIb study in subjects with nAMD, eligible for Intravitreal (IVT) aflibercept treatment.

Screening and Baseline could be performed on the same day.

Subjects with nAMD received a single dose of study treatment (2 mg SOK583 in 0.05 mL) in line with the Eylea US PI, which recommends a dose of 2 mg aflibercept (0.05 mL) administered by IVT injection. Only subjects already under IVT Eylea treatment and hence familiar with the IVT procedure were eligible for the study. Administration of the study treatment was embedded into their individual dosing schedule.

Demonstration of the safe use of the PFS containing SOK583A1 was based on the performance of at least 3 different ophthalmologist teams.

Follow-up visits were performed on-site on Day 8 (±2 days) and on Day 31 (+4 days - end of study visit). Subjects participated for 30 to 34 days in the study including Baseline and treatment on Day 1 (Screening and Baseline could be performed on the same day) and the last safety follow-up on Day 31 (a time window of plus 4 days was allowed for the last safety follow-up).

Arms:
arm 1: participants received a single dose of 2 mg SOK583 in 0.05 mL (40 mg/mL) and completed the study

Interventions: intervention 1: SOK583A1 (40 mg/mL) intervention 2: Prefilled Syringe (PFS)
Intervention descriptions: intervention 1: SOK583A1 provided in a Prefilled Syringe (PFS), which includes 2 mg aflibercept in 0.05 mL for IVT administration intervention 2: Prefilled Syringe (PFS)

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................4
List of figures.......................................................................................................................4
List of abbreviations ............................................................................................................5
Glossary of terms.................................................................................................................6
Protocol summary................................................................................................................9
1
Introduction........................................................................................................................12
1.1
Background............................................................................................................12
1.2
Purpose...................................................................................................................14
2
Objectives and endpoints...................................................................................................14
3
Study design.......................................................................................................................14
4
Rationale ............................................................................................................................15
4.1
Rationale for study design......................................................................................15
4.2
Rationale for dose/regimen and duration of treatment...........................................15
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................15
4.4
Purpose and timing of interim analyses/design adaptations ..................................16
4.5
Risks and benefits ..................................................................................................16
4.6
Rationale for Public Health Emergency mitigation procedures.............................17
5
Study population................................................................................................................17
5.1
Inclusion criteria ....................................................................................................17
5.2
Exclusion criteria ...................................................................................................17
6
Treatment...........................................................................................................................19
6.1
Study treatment ......................................................................................................19
6.1.1
Investigational and control drugs ..........................................................19
6.1.2
Additional study treatments...................................................................19
6.1.3
Treatment arms/group ...........................................................................19
6.1.4
Treatment duration ................................................................................20
6.2
Other treatment(s) ..................................................................................................20
6.2.1
Concomitant therapy .............................................................................20
6.2.2
Prohibited medication............................................................................20
6.3
Preparation and dispensation .................................................................................20
6.3.1
Handling of study treatment and other treatment..................................21
6.3.2
Instruction for prescribing and taking study treatment..........................21
6.4
Participant numbering, treatment assignment, randomization...............................22
6.4.1
Participant numbering ...........................................................................22


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6.5
Dose escalation and dose modification..................................................................22
6.6
Additional treatment guidance...............................................................................22
6.6.1
Treatment compliance ...........................................................................22
6.6.2
Recommended treatment of adverse events ..........................................22
7
Informed consent procedures.............................................................................................22
8
Visit schedule and assessments..........................................................................................23
8.1
Screening................................................................................................................25
8.1.1
Information to be collected on screening failures .................................25
8.2
Participant demographics/other baseline characteristics........................................25
8.3
Safety .....................................................................................................................25
8.3.1
Pregnancy and assessments of fertility..................................................25
8.4
Additional assessments ..........................................................................................26
9
Discontinuation and completion ........................................................................................26
9.1
Discontinuation from study treatment and from study ..........................................26
9.1.1
Discontinuation from study treatment...................................................26
9.1.2
Discontinuation from study...................................................................26
9.1.3
Lost to follow-up...................................................................................27
9.2
Withdrawal of informed consent/Opposition to use data.......................................27
9.3
Study completion and post-study treatment...........................................................27
9.4
Early study termination by the Sponsor.................................................................27
10 Safety monitoring, reporting and committees....................................................................28
10.1
Definition of adverse events and reporting requirements......................................28
10.1.1
Adverse events.......................................................................................28
10.1.2
Serious adverse events...........................................................................29
10.1.3
SAE reporting........................................................................................30
10.1.4
Pregnancy reporting...............................................................................31
10.1.5
Reporting of study treatment errors including misuse/abuse ................31
10.2
Additional safety monitoring .................................................................................31
11 Data collection and database management ........................................................................32
11.1
Data collection .......................................................................................................32
11.2
Database management and quality control ............................................................32
11.3
Site monitoring.......................................................................................................32
12 Data analysis and statistical methods.................................................................................33
12.1
Analysis sets...........................................................................................................33
12.2
Participant demographics and other baseline characteristics.................................33
12.3
Treatments..............................................................................................................33


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12.4
Analysis supporting primary objectives.................................................................33
12.4.1
Definition of primary endpoint(s) .........................................................33
12.4.2
Statistical model, hypothesis, and method of analysis ..........................34
12.5
Sample size ............................................................................................................34
Primary endpoint(s)................................................................................................34
13 Ethical considerations and administrative procedures.......................................................34
13.1
Regulatory and ethical compliance........................................................................34
13.2
Responsibilities of the investigator and IRB/IEC..................................................35
13.3
Publication of study protocol and results...............................................................35
13.4
Quality Control and Quality Assurance.................................................................35
14 Protocol adherence.............................................................................................................35
14.1
Protocol amendments.............................................................................................36
15 References..........................................................................................................................37
List of tables
Table 2-1
Objectives and related endpoints...........................................................14
Table 6-1
Investigational and control drug............................................................19
Table 6-2
Prohibited medication............................................................................20
Table 8-1
Assessment schedule .............................................................................24
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................31
List of figures
Figure 1-1
Studies conducted in the SOK583A1 in-use program...........................14
Figure 3-1
Study design ..........................................................................................15


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List of abbreviations
AE
Adverse event
eCRF
Electronic case report form
EDC
Electronic data capture
FAS
Full analysis set
FDA
Food and Drug Administration
IFU
Instructions for Use
IMP
Investigational medicinal product
IOP
Intraocular pressure
IVT
Intravitreal(ly)
PFS
Prefilled syringe
SAE
Serious adverse event
SOK583A1
Product code of Sandoz’ proposed aflibercept containing biosimilar product
US PI
US Prescribing information
VEGF
Vascular endothelial growth factor


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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described 
in the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Clinical Trial Team
A group of people responsible for the planning, execution and reporting of 
all clinical study activities. Examples of team members include the Study 
Lead, Medical Monitor, Trial Statistician etc.
Discontinuation from 
study
Point/time when the participant permanently stops receiving the study 
treatment 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 from 
study treatment
Point/time when the participant permanently stops receiving the study 
treatment 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 participant in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
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 data/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. The action of enrolling 1 or more participants
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
combines source documents and case report forms (eCRFs) into one 
application, allowing for the real time collection of clinical study information 
to sponsors and other oversight authorities, as appropriate
Investigational drug/ 
treatment
The drug whose properties are being tested in the study
Investigational Medical 
Device
Medical Device being assessed for safety or performance in a clinical 
investigation. This includes devices already on the market and being 
evaluated for new intended uses, new populations, new materials, or 
design changes
Medication number
A unique identifier on the label of medication kits
Off-site
Describes study activities that are performed at remote location by an off-
site healthcare professional, such as procedures performed at the 
participant's home.
Off-site healthcare 
Professional (OHP)
A qualified healthcare professional, such as include those used in the 
study e.g. Nurse, Phlebotomist, Physician, who performs certain protocol 
procedures for the participant in an off-site location such as a participant's 
home.
Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy)


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Participant
A study participant (can be a healthy volunteer or a patient). “Participant” 
terminology is used in the protocol whereas term “Subject” is used in data 
collection.
In this study, a participant is a patient with (wet) neovascular age-related 
macular degeneration, requiring IVT administration of 2 mg aflibercept due 
to nAMD, 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 informed 
consent. 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 collected by the investigator that is coded and 
transferred to the Sponsor for the purpose of the clinical study. This data 
includes participant identifier information and study information.
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
Testing of vital signs can be repeated once to confirm clinical significance 
or to exclude technical errors. If the repeat test evaluation or result 
remains outside of the specified range for vital signs, the participant must 
be considered as a Screen Failure
Remote
Describes any study activities performed at a location that is not the 
investigative site where the investigator will conduct the study, but is for 
example a home or another appropriate location
Screen Failure
A participant who did not meet one 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 treatment
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy
Tele-visit
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the participant is not at the 
investigative site where the investigator will conduct the study.
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 the related clinical question of interest, which might or might 
not be the same as the study treatment.


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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.
Withdrawal of study 
consent (WoC) / 
Opposition to use of 
data 
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data (opposition to use data) AND no longer 
wishes to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation.
Opposition to use data occurs in the countries where collection and 
processing of personal data is justified by a different legal reason than 
consent.


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Protocol summary
Protocol number
CSOK583A12304
Full Title
An open-label, single-arm, multicenter study in patients with 
neovascular age-related macular degeneration to evaluate the safety 
of SOK583A1 (40 mg/mL), a proposed aflibercept biosimilar product, 
provided in a prefilled syringe
Brief title
Study of the safety of use of intravitreal SOK583A1 provided in a 
prefilled syringe
Sponsor and Clinical 
Phase
Sandoz Inc., 100 College Road West, Princeton, NJ 08540, USA
Phase IIIb
Investigation type
Drug (Biosimilar) 
Study type
Interventional
Purpose and rationale
This is a multicenter, open label Phase IIIb study to evaluate the safety 
of use of a PFS containing SOK583A1 (40 mg/mL) and to support the 
collection of observations of the PFS use for intravitreal injection, when 
utilized by qualified ophthalmologists, who follow the IFU appropriately 
to prepare and administer IVT injections to patients, suffering from 
nAMD.
Primary Objective(s) 
The primary objective of the study is to evaluate the safety of use of a 
PFS containing SOK583A1 (40 mg/mL) in patients requiring IVT 
aflibercept treatment (capturing the AEs), when utilized by qualified 
ophthalmologists, supported by trained assistants, who follow the IFU 
appropriately, to prepare and administer IVT injections to patients, 
suffering from nAMD. 
Study design
This is an open-label, single arm, multicenter, Phase IIIb study in 
patients with (wet) neovascular age-related macular degeneration, 
eligible for IVT aflibercept treatment.
Screening and Baseline (Day 1) may be performed on the same day. 
A follow-up visit on-site will be performed on Day 8 (±2 days) and on 
Day 31 (+4 days - end of study visit). 
Demonstration of the safety use of the PFS containing SOK583A1 will 
be based on the performance of at least 3 different ophthalmologist 
teams. 
Participants will receive study medication once. Only patients already 
under IVT Eylea treatment and hence are familiar with the IVT 
procedure are eligible for the study. Administration of the study 
medication will be embedded into the routine treatment scheme. In 
compliance with the US label the recommended dose for aflibercept is 
2 mg (0.05 mL) administered by IVT injection every 4 weeks 
(approximately every 28 days, monthly) for the first 3 months, followed 
by 2 mg (0.05 mL) via IVT injection once every 8 weeks (2 months). A 
narrow window of flexibility for the drug administration (in accordance 
with the biosimilar safety and efficacy study CSOK583A12301) is 
possible: ± 3 days during the initial phase (first 3 months) and ± 7 days 
during the maintenance phase (thereafter).
The participants of this study will be also part of an observational study, 
in which the ability of Health Care Professionals (HCPs), including 


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qualified ophthalmologists and assistants who may perform the 
preparation steps, will be assessed to prepare and administer to 
patients intravitreal (IVT) injection using SOK583A1 2 mg Device and 
to follow the Instructions for Use (IFU). 
Study population
Male and female patients ≥ 50 years of age treated with Eylea 
(intravitreally) due to nAMD and have received at least two injections 
during the induction phase already; 38 participants will be included into 
this clinical study.
Key Inclusion criteria

Patients ≥ 50 years of age at baseline

Patients diagnosed with nAMD (uni- or bilateral)

Patients already under IVT Eylea treatment (last injection of the 
induction period or maintenance phase)

Willing and able to comply with all study procedures, and be likely 
to complete the study

Signed informed consent must be obtained before any 
assessment is performed
Key Exclusion criteria

Active, suspected or recent (within 4 weeks) intraocular 
inflammation (grade trace or above) in the study eye at baseline, 
which is of clinical significance according to the investigator’s 
judgment, such as active infections of the anterior segment; this 
includes conjunctivitis (except mild blepharitis), keratitis, scleritis, 
idiopathic or autoimmune associated uveitis or endophthalmitis

Any uncontrolled ocular hypertension or glaucoma in the study 
eye (defined as IOP ≥ 26 mmHg, despite treatment with anti-
glaucomatous medication)

History of a medical, ocular or non-ocular condition, that in the 
judgment of the investigator, would preclude a safe administration 
of investigational product

Visual Acuity Score (VAS) worse than 20/200 on a Snellen chart, 
the generally accepted level of legal blindness

Topical ocular corticosteroids administered for at least 30 
consecutive days within 3 months prior to screening

Systemic treatment with long-acting corticosteroids (more than 
10 mg prednisolone equivalent) within 3 months prior to screening 
Current or planned use of systemic medications known to be toxic 
to the lens, retina or optic nerve, including deferoxamine, 
chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and 
ethambutol

Any invasive intraocular surgery, prior long-acting therapeutic 
agent, or ocular drug release device implantation (approved or 
investigational) in the study eye any time during the past 3 
months

Receipt of any systemic anti-VEGF within the last 6 months prior 
to enrollment

Uncontrolled hypertension (defined as a systolic value ≥ 160 
mmHg or diastolic value ≥ 100 mmHg at Screening) 

Participants who do not comply with the local COVID-19 
regulations of the study site
Study treatment
SOK583A1 provided in a PFS, which includes 2 mg aflibercept in 
0.05 mL for IVT administration.


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Key safety assessments
AEs that occur during the study period will be monitored and reported.
Other assessments 
Observation of the preparation and the injection using the PFS. This is 
described in a separate study protocol.
Data analysis
All safety analyses will be performed descriptively.
Key words
Open label study, intravitreal injection, biosimilar, aflibercept, PFS


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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®; hereafter referred to as 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 licensed for ophthalmological indications in the EU to Bayer Pharma 
AG and in the US to Regeneron Pharmaceuticals Inc. (Eylea US PI). The development of 
SOK583A1 aims for the treatment of all indications currently approved for Eylea. Biosimilarity 
will be supported by the totality of evidence from analytical, efficacy, safety, and 
immunogenicity data of an ongoing Phase III study.
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 US PI).
Study CSOK583A12301 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 


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neovascular retinopathy is not associated with the systemic PK. Hence, study CSOK583A12301 
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.
In the pivotal study, SOK583A1 will be available in a vial only and not in a PFS (intended for 
commercial use). During the FDA BPD Type 2 meeting held in 06/2019, it was confirmed that 
a clinical in-use study for the PFS is required. This study will evaluate the ability of 
ophthalmologists and their assistants to perform the preparation and administration of 
SOK583A1 following the IFU for the PFS (described in the observational protocol). 
Therefore, the current study will be performed for safety purposes (capturing AEs to follow 
Good Clinical Practice guidelines - described in this clinical protocol) and will support the 
observational study for collection of observations on PFS use for IVT injection. There will be 
2 separate protocols as follows:

The clinical study protocol is designed to collect safety data obtained from the IVT 
injections conducted with the use of the PFS (described within this document).

The observational study protocol (provided separately, with protocol number “PRT-
SOK583_02_HFSP_Observational Study Protocol_PFS_vs1.0 (
, 8566 
0012a)-0003951390” is designed to evaluate the ability of observational study 
participants, including qualified ophthalmologists and assistants who may perform the 
preparation steps, to prepare and administer IVT injections to patients using SOK583A1 2 
mg PFS and to follow the IFU. The study will be considered successful if all Healthcare 
Professionals demonstrate success on all safety critical tasks and essential tasks. In case of 
unsuccessful task completion, the root cause analysis will evaluate whether the IFU was 
the cause of unsuccessful task completion. Furthermore, it also includes to evaluate if a 
potential (technical) issues of the presentation lead to this result.
Figure 1-1 illustrates the proposed studies for the SOK583A1 in-use program. This protocol 
will cover the clinical (safety) study of this program only.


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Figure 1-1
Studies conducted in the SOK583A1 in-use program
1.2
Purpose
The clinical protocol describes a multicenter, open label Phase IIIb study, intended to evaluate 
the safety of use of a PFS containing SOK583A1 (40 mg/mL), when utilized by qualified 
ophthalmologists, who follow the IFU appropriately to prepare and administer IVT injections 
to patients, suffering from nAMD. Safety aspects will be assessed for the application as well as 
for the IMP.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

Evaluate the safety of use of PFS containing 
SOK583A1 (40 mg/mL) in patients requiring 
IVT aflibercept treatment (capturing the AEs)
Endpoint(s) for primary objective(s)

Occurrence of ocular or non-ocular AEs 
during the study-reporting period
3
Study design
This is an open-label, single arm, multicenter, Phase IIIb study in patients with (wet) 
neovascular age-related macular degeneration, eligible for IVT aflibercept treatment.
Screening and Baseline may be performed on the same day. A follow-up visit will be performed 
on-site on Day 8 (±2 days) and on Day 31 (+4 days - end of study visit). 
Demonstration the safety of using of the PFS containing SOK583A1 will be based on the 
performance of at least 3 different ophthalmologist teams. 
The use of the PFS will be analyzed and rated by external observers. The details of the 
observational study will be described in detail in a separate study protocol. 
Participating nAMD patients will receive study medication once. Only patients already under 
IVT Eylea treatment and hence are familiar with the IVT procedure are eligible for the study. 
Administration of the study medication will be embedded into the routine treatment scheme. In 
compliance with the US label the recommended dose for aflibercept is 2 mg (0.05 mL) 
administered by IVT injection every 4 weeks (approximately every 28 days, monthly) for the 
first 3 months, followed by 2 mg (0.05 mL) via IVT injection once every 8 weeks (2 months). 
A narrow window of flexibility for the drug administration (in accordance with the biosimilar 


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safety and efficacy study CSOK583A12301) is possible: ± 3 days during the initial phase (first 
3 months) and ± 7 days during the maintenance phase (after 3 months).
Figure 3-1
Study design
4
Rationale
4.1
Rationale for study design
The study will evaluate the safety of use of SOK583A1 (40 mg/mL) provided in a PFS (also 
including safety of the IMP) where in addition under a separate study protocol, the ability to 
follow the IFU and giving the IVT SOK583A1 injection to patients requiring IVT aflibercept 
treatment due to nAMD is observed. To support registration of the PFS containing SOK583A1 
in the US, the FDA has requested a human factor/clinical in-use study, which will evaluate the 
ability of the Health Care Professional professionals to follow the IFU to prepare the injection 
and administer the product to the vitreous (Meeting Type: Biosimilar, Meeting Category: FDA 
BPD Type 2 meeting, FDA Meeting Minutes of 12-Jun-2019). The results of the human factor 
evaluations and the results from the safety observations will be described in a separate report.
4.2
Rationale for dose/regimen and duration of treatment
Each participant who enters the study will be given a single injection of SOK583A1 (40 mg/mL) 
provided in a PFS embedded into their routine treatment scheme. SOK583A1 is being 
developed as a biosimilar product to Eylea. Therefore, the dose of the study medication was 
chosen according to the current Eylea US PI for IVT aflibercept injection.
One injection will be given to support the observation of use of the PFS based on the IFU. 
Participants will be considered to have completed the study after the evaluations on Day 31 
(+4 days). Afterwards, the participant will receive Eylea again (after the appropriate time 
interval).
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Control drugs (comparator/placebo) or combination drugs are not planned in this study.


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4.4
Purpose and timing of interim analyses/design adaptations
An interim analysis is not planned for this study.
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.
Eylea has been licensed and commercialized world-wide since 2011. Clinical studies provided 
evidence of efficacy and safety in all approved indications. 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 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 increase in intraocular pressure (Eylea US PI). SAEs are also 
reported in a low incidence: hypersensitivity, endophthalmitis and retinal detachments, and a 
potential risk of thromboembolic events.
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, to 
participate in the study, they must adhere to the contraception requirements outlines in the 
exclusion criteria. If there are any questions that the participant will not reliably comply, they 
should not be entered or continue in the 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. Since no data are available so far, we 
cannot exclude that a switch from Eylea to SOK583A1 may result in the development of anti-
drug antibodies.
Further details of the known and potential risks and benefits associated with aflibercept are 
presented in the Investigator Brochure and Eylea US PI.
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 aflibercept 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 


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patients with nAMD to be treated with a loading phase of 3 injections of anti-VEGF and then 
continued on q8w (Royal College of Ophthalmology). 
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.
Based on the available data and the current literature, no specific dispositions need to be done 
due to COVID-19 vaccination.
4.6
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities, i.e. pandemic, 
epidemic, or natural disaster, mitigation procedures to ensure participant safety and study 
integrity are listed in relevant sections. Notification of the public health emergency should be 
discussed with Sandoz prior to implementation of mitigation procedures, and 
permitted/approved by Local or Regional Health Authorities and Ethics Committees as 
appropriate.
5
Study population
The study population will be male and female patients ≥ 50 years old who are diagnosed with 
nAMD and requiring IVT treatment with Eylea and have received at least 2 injections during 
the induction phase already. Thirty-eight participants are expected to be injected at 
approximately 3 sites in the US.
5.1
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Patients ≥ 50 years of age at baseline
2. Patients diagnosed with nAMD (uni- or bilateral)
3. Patients already under IVT Eylea treatment (last injection of the induction period or 
maintenance phase)
4. Willing and able to comply with all study procedures, and be likely to complete the study
5. Signed informed consent must be obtained before any assessment is performed
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. Active or recent (within 4 weeks) intraocular inflammation (grade trace or above) in the 
study eye at baseline, which is of clinical significance according to the investigator’s 
judgment, such as active infections of the anterior segment; this includes conjunctivitis 
(except mild blepharitis), keratitis, scleritis, idiopathic or autoimmune associated uveitis or 
endophthalmitis


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2. Any uncontrolled ocular hypertension or glaucoma in the study eye (defined as IOP 
≥ 26 mmHg, despite treatment with anti-glaucomatous medication)
3. History of a medical, ocular or non-ocular condition, that in the judgment of the 
investigator, would preclude a safe administration of investigational product
4. Visual Acuity Score (VAS) worse than 20/200 on a Snellen chart, the generally accepted 
level of legal blindness
5. Topical ocular corticosteroids administered for at least 30 consecutive days within 3 
months prior to screening
6. Systemic treatment with long-acting corticosteroids (more than 10 mg prednisolone 
equivalent) within 3 months prior to screening 
7. Current or planned use of systemic medications known to be toxic to the lens, retina or 
optic nerve, including deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, 
phenothiazines and ethambutol
8. Any invasive intraocular surgery, prior long-acting therapeutic agent, or ocular drug 
release device implantation (approved or investigational) in the study eye any time during 
the past 3 months
9. Receipt of any systemic anti-VEGF within the last 6 months prior to enrollment
10. Pregnant or nursing (lactating) women or women of child-bearing potential (WOCBP) is 
defined as all women less than 1 year postmenopausal or less than 6 weeks since 
sterilization at Baseline, unless they are using highly effective methods of contraception 
during dosing of study treatment.
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. Highly effective contraception methods include: 

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. 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 
study treatment. 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 patients on the 
study, the vasectomized male partner should be the sole partner for that patients.

Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example, hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment No additional exclusions may be 


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applied by the investigator, to ensure that the study population will be representative of all 
eligible patients.
Women are considered post-menopausal and not of childbearing 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 childbearing 
potential.
11. Uncontrolled hypertension (defined as a systolic value ≥ 160 mmHg or diastolic value ≥ 
100 mmHg at Screening) 
12. Participants who do not comply with the local COVID-19 regulations of the study site
6
Treatment
6.1
Study treatment
SOK583A1 is formulated as a sterile solution aseptically filled in a PFS for single use. The 
study medication SOK583A1 will be provided in a PFS, with 40 mg/mL of aflibercept solution 
for IVT injection (2 mg/0.05 mL).
The Sponsor will ensure sufficient supplies of SOK583A1 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 
Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Presentation
Sponsor (global 
or local)
SOK583A1 
(40 mg/mL)
Solution for 
injection
IVT 
PFS
(2 mg/0.05 mL)
Sponsor (local)
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this study.
6.1.3
Treatment arms/group
This is a single-arm, open-label study where all patients will receive a single injection of 
SOK583A1 (40 mg/mL) provided in a PFS at Baseline.


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6.1.4
Treatment duration
The total study duration for the individual participant is approximately 31 days. Screening and 
IVT injection of SOK583A1 may be done on the same day. A follow-up visit will be performed 
on Day 8 (±2 days) and on Day 31 (+4 days - end of study visit). 
6.2
Other treatment(s)
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 Case Report Forms.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Sponsor medical monitor or qualified 
delegate before enrolling a participant or allowing a new medication to be started. If the 
participant is already enrolled, contact the Sponsor or qualified delegate to determine if the 
participant should continue participation in the study.
6.2.2
Prohibited medication
Prohibited medications after the start of 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 the study. Any medication which may be required to treat ocular or systemic 
AEs and permitted oral or injectable contraceptives for female participants are allowed and 
must be recorded in the appropriate eCRF page.
The standard of care or other approved treatment according to the investigator choice 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 (except if for 
treatment of AE)
Study eye: Laser treatment for AMD
Discontinue study
Systemic: Systemic corticosteroids for 15 or more consecutive 
days1
Discontinue study
Systemic: anti-VEGF therapy
Discontinue study
Study eye, fellow eye and systemic: Patients under any 
investigational drug, biologic or device (not authorized for use)
Discontinue study
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
6.3
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.


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A unique medication number is printed on the study medication label.
The study medication has a 2-part label (base plus tear-off label), immediately before dispensing 
the package to the participant, site personnel will detach the outer part of the label from the 
package and affix it to the participant’'s source document.
6.3.1
Handling of study treatment and other treatment
6.3.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Sponsor Quality Assurance.
Medication labels will be in the local language and comply with the local legal requirements. 
They will include storage conditions for the study treatment but no information about the 
participant except for the medication number.
The investigator 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 
field monitors during site or remote monitoring visits, and at the completion of the study.
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation and guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Sponsor 
monitor or to the Sponsor address provided in the investigator folder at each site.
The study treatment and all required clinical study supplies will be distributed direct to the 
participant utilizing an extension of the IND for compliance purposes.
6.3.1.2
Handling of other treatment
6.3.2
Instruction for prescribing and taking study treatment
The IVT injection will be carried out under controlled, aseptic conditions per local clinical practice. 
The study eye will be assessed before and after IVT injection to ensure that the procedure and/or 
the study treatment had not endangered the health of the eye. An IVT injection is contraindicated in 
patients with active or suspected ocular or periocular infections and in patients with active or 
suspected intraocular inflammation; therefore, the investigator should verify that these conditions 
are not present in either eye (study and fellow eyes) prior to every injection. 
Used study treatment will be recorded/databased. Date and time of the injection to the patient will 
be recorded in the eCRF. 
The conduct of IVT injections will be observed by an external study team member to ensure 
compliance with the proposed commercial instruction for use.


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6.4
Participant numbering, treatment assignment, randomization
6.4.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled, i.e. signed the ICF, for screening and is retained for 
the participant throughout his/her participation in the study. The Participant No. consists of the 
Center Number (Center No.) (as assigned by the Sponsor to the investigative site) with a 
sequential Participant No. suffixed to it, so that each participant’s participation is numbered 
uniquely across the entire database. Upon signing the informed consent form, the participant is 
assigned to the next sequential Participant No. available.
6.5
Dose escalation and dose modification
Investigational study treatment dose adjustments or modifications are not possible.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
This is not in scope, since each patient receives only a single injection of aflibercept 2 mg provided 
in a PFS.
6.6.2
Recommended treatment of adverse events
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.
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) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. 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). Since videotaping is necessary for the observational 
study and the patient might be seen on this video as well, patients must also specifically agree 
to this procedure. 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 


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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 for aflibercept can be found in the Eylea 
US PI. 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 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. 
Women of childbearing 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 to 
participate in the study, they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to the Sponsor after 
IRB/IEC approval.
8
Visit schedule and assessments 
Table 8.1 Assessment schedule lists all assessments and indicates with an “X” the visits when 
they are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation.
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation.
Screening and Baseline may be performed on the same day. A follow-up visit will be performed 
on Day 8 (±2 days) and on Day 31 (+4 days - end of study visit). The safety assessment will 
include ocular and non-ocular assessments according to clinical practice (e.g. blood pressure, 
IOP, slitlamp, ophthalmoscopy). Any occurred events on this period should be collected in the 
source, and SAEs must be reported to the Sponsor safety according instructions in Section 
10.1.3.
The conduct of the IVT injection and preparation will be observed and videotaped by an 
external 
member 
and 
will 
follow 
observational 
study 
protocol 
(PRT-
SOK583_02_HFSP_Observational Study Protocol_PFS_vs1.0 (
, 8566 
0012a)-0003951390), to ensure compliance with IFU.


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Table 8-1
Assessment schedule
Open Label Treatment
Safety Follow-Up
Safety Follow-Up (EOS)
 
Baseline
Follow-Up
Follow-Up
 
Day 1
Day 8±2
Day 31+4
Informed consent
X
Inclusion / Exclusion criteria
X
Demography
X
Medical history
X
Prior/Concomitant medication
X
X
X
Study drug administration
X
Observation of IFU and the use of the PFS1
X
Adverse Events
X
X
X
Pregnancy Test
S
Vital signs
X
X
X
Intraocular Pressure (IOP)
X
X
X
Ocular Assessments (slit lamp, ophthalmoscopy)
S
S
S
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 The conduct of IVT injections will be observed by an external study team member to ensure compliance with the IFU; this will be described in a 
separate observational study protocol


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8.1
Screening
Screening
Participants 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). 
Rescreening is not allowed in this study.
Retesting
Measurement of vital signs can be repeated once to confirm clinical significance or to exclude 
technical errors. If the repeat test evaluation or result remains outside of the specified range for 
vital signs, the participant must be considered as a Screen Failure.
8.1.1
Information to be collected on screening failures
There is no separate screening period planned for this study. Patient’s Eligibility will be 
assessed at Screening Visit. 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). Afterwards, patient’s eligibility 
will be assessed.
Patients who sign an informed consent but do not receive the IVT injection will be considered 
a screen failure and the reason for the screen failure will be also documented. The demographic 
information, informed consent, and Inclusion/Exclusion data must be completed in the eCRF 
and also be kept in the source documents for screen failure subjects. No data will be entered 
into the clinical database for patients who are screen failures, unless the patient experienced a 
SAE (see SAE section for reporting details).
8.2
Participant demographics/other baseline characteristics
The following data will be collected: age, sex, race, ethnicity, vital signs, study eye, IOP, prior 
concomitant medications, medical history, and current medical conditions.
8.3
Safety
The investigator will perform safety assessments according to clinical practice (e.g. slitlamp, 
IOP measurement, ophthalmoscopy). IOP ≥ 26 mmHg should be reported as AE and any 
clinically significant changes by the discretion of the Investigator should be also reported as 
AEs. The safety assessments selected are standard for this indication and patient population.
The assessment schedule is provided in Table 8-1.
For details on AE collection and reporting, refer to Section 10.1.
8.3.1
Pregnancy and assessments of fertility
A urine pregnancy test will be conducted for all women of childbearing potential to assess 
pregnancy before inclusion in the study.


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Additional pregnancy testing might be performed if requested by local requirements.
8.4
Additional assessments
Additional assessments include the following and will be specified in the observational study 
protocol 
(PRT-SOK583_02_HFSP_Observational 
Study 
Protocol_PFS_vs1.0 
(
 
, 8566 0012a)-0003951390).
9
Discontinuation and completion
9.1
Discontinuation from study treatment and from study
9.1.1
Discontinuation from study treatment
This is a single dose study, therefore discontinuation of study treatment is not applicable.
Patients who decide they do not wish to participate in the study further should NOT be 
considered withdrawn from the study UNLESS they withdraw their consent (see withdrawal of 
informed consent in Section 9.1.2). Where possible, they should return for the safety 
assessments indicated in the assessment schedule. If they fail to return for these assessments 
for unknown reasons, every effort (e.g. telephone, e-mail, and letter) should be made to contact 
the patients/pre-designated contact as specified in the lost to follow-up section. This contact 
should preferably be done according to the study visit schedule.
If the patients cannot or is unwilling to attend a follow up visit during the study period, the site 
staff should maintain regular telephone contact with the patient, or with a person pre-designated 
by the patient. This telephone contact should preferably be done according to the study visit 
schedule.
9.1.2
Discontinuation from study
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. If the 
participant agrees, a final evaluation at the time of the patient’s study withdrawal should be 
made as detailed in the assessment table.
The Sponsor will continue to keep and use collected study information (including any data 
resulting from analysis of a patient’s samples until the time of withdrawal) according to the 
applicable law.


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9.1.3
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.2
Withdrawal of informed consent/Opposition to use data
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore, and

Does not allow further visits or assessments, and

Does not want any further study related contacts
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 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.
In this situation, it is not allowed to conduct further assessments and the data that would have 
been collected at subsequent visits will be considered missing. Further attempts to contact the 
participant are also not permitted 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 should be made as detailed in the assessment table (refer to 
Section 8).
Further details on withdrawal of consent or the exercise of participants’ data privacy rights are 
included in the corresponding informed consent form.
9.3
Study completion and post-study treatment
Study completion is defined as when the last patient finishes the End of Study Visit, 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. 
9.4
Early study termination by the Sponsor
The study can be terminated by the Sponsor at any time for any reason. This may include 
reasons related to the benefit/risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. In taking the decision to 
terminate, the Sponsor will always consider the patient welfare and safety. Should early 
termination be necessary, patients must be seen as soon as possible (provide instruction for 


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contacting the patients, when the patient should come for a final visit) and treated as a 
prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed to ensure that adequate consideration is given to the protection of the patient’s 
interests. The investigator or Sponsor depending on the local regulation will be responsible for 
informing IRBs / IECs of the early termination of the trial.
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 patient 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.
The investigator has the responsibility for managing the safety of individual patient and 
identifying AEs.
The qualified medical personnel of the sponsor will be readily available to advise on trial related 
medical questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. AEs also may be detected when they are volunteered by the patient during or 
between visits or through physical examination findings, laboratory test findings, or other 
assessments.
AEs must be recorded in the Adverse Events eCRF 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):
1. The severity grade includes the following: 
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. 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 trial drug, they 
happen 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 patient.
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.


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All AEs must be treated appropriately. Treatment may include one or more of the following:

no action taken (further observation only)

Concomitant medication or non-drug therapy given.
6. Its outcome 
a. not recovered/not resolved
b. recovered/resolved
c. recovering/resolving
d. recovered/resolved with sequelae
e. fatal
f.
unknown
Conditions that were already present at the time of informed consent should be recorded in 
medical history source document of the patient.
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 30 days, following the injection. 
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) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure.
10.1.2
Serious adverse events
A 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 patient 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 (please 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

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition


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
treatment on an emergency outpatient 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 patient 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 patient 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 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.
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred.
10.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to the Sponsor safety within 24 hours of learning of its occurrence. 
SAEs will be reported in paper form. Detailed instructions regarding the submission process 
and requirements are to be found in the investigator folder provided to each site.
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 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered 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 Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a chief medical officer & 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 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 European Union 
(EU) Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries.


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Safety events occurring during the study will be reported as AEs in the eCRF. Device 
malfunction observations are to be reported to the respective Sponsor Country Organization 
Quality Assurance.
10.1.4
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to the 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 Sponsors 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 and any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
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).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
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 only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
eCRF (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, please see the 
respective sections.
10.2
Additional safety monitoring
No additional safety monitoring is planned in this study.


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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 database lock, the investigator will receive copies of the patient 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
The Sponsor’s personnel or designated Contract Research Organization (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 
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 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history/current medical conditions 
and AEs will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked 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 Sponsor 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
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 


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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 and 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, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form 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 
checks of the consistency of the source data with the eCRFs 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
12.1
Analysis sets
The FAS includes all enrolled patients who receive a dose of study treatment. 
12.2
Participant demographics and other baseline characteristics
Demographic data will be listed and summarized descriptively for the FAS. Categorical data 
will be presented as frequencies and percentages. For continuous data, mean, standard deviation, 
median, minimum, and maximum will be presented. Relevant medical histories and current 
medical conditions at baseline will be summarized by system organ class and preferred term for 
all patients.
12.3
Treatments
Descriptive summary statistics for exposure to study treatment will be provided for the FAS. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system for all patients.
12.4
Analysis supporting primary objectives
12.4.1
Definition of primary endpoint(s)
Occurrence of ocular or non-ocular AEs during the study-reporting period.


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12.4.2
Statistical model, hypothesis, and method of analysis
No formal hypothesis tests will be performed in this study. All safety analyses will be performed 
descriptively using the FAS.
Adverse events
The number (and percentage) of patients with treatment-emergent AEs (events started after the 
single dose of study treatment or events present prior to start of study treatment but which 
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 summaries will be provided for study treatment related AEs, SAEs, other significant 
AEs leading to discontinuation of the study. Separate presentations will be provided related to 
ocular events in the study eye and fellow eye and systemic events. Patient listings of all AEs 
will be provided. Other serious or clinically significant non-fatal AEs will be listed separately.
A patient with multiple AEs within a primary system organ class is only counted once towards 
the total of the primary system organ class.
Ophthalmic examinations
Pre-injection and post-injection IOP measurements will be listed. In addition, the IOP during 
follow-up visit will also be listed.
Vital signs
Vital signs data will be collected and listed.
12.5
Sample size
The sample size has been discussed during a FDA BPD Type 2 meeting in June 2019. A sample 
size of at least 30 patients has been agreed by FDA. To avoid unexpected issues in terms of 
withdraws, missing or incomplete data, 38 patients will be included per study (30 minimum 
required plus a buffer).
Primary endpoint(s)
No formal statistical power calculations to determine sample size were performed for this study.
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.


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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 informed consent form, 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 a 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 the 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 
the 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 trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT, 
etc.).
For details on the Sponsor publication policy including authorship criteria, please refer to the 
Sponsor publication policy training materials that were provided to you at the initiation visit.
13.4
Quality Control and Quality Assurance
The 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.
Audits of investigator sites, vendors, and the Sponsor’s 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 the 


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Sponsor and not use it for any purpose other than the study, except for the appropriate 
monitoring on 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.


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15
References
References are available upon request
American Academy of Ophthalmology; COVID-19 resources; available from 
https://www.aao.org/coronavirus (accessed on 06-May-2020).
Blinder KJ, Bradley S, Bressler NM, et al (2003) TAP and VIP Therapy Study Groups. Effect 
of lesion size, visual acuity and lesion composition on visual acuity change with or without 
verteporfin therapy for choroidal neovascularization secondary to age-related macular 
degeneration: TAP and VIP Report No. 1. Am J Ophthalmol; 136: 407-18.
Bloch SB, Larsen M, Munch IC (2012) Incidence of legal blindness from age-related macular 
degeneration in Denmark: Year 2000 to 2010. Am J Ophthalmol; 153: 209-13.
Campbell JP, Bressler SB, Michels M, et al (2009) Ranibizumab versus verteporfin for 
neovascular age-related macular degeneration. N Engl J Med; 355: 1432-44.
EU Guidance 2011/C 172/01: Detailed guidance on the collection, verification and 
presentation of adverse event/reaction reports arising from clinical trials on medicinal 
products for human use. Available from: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/2011_c172_01/2011_c172_01_en.pdf (accessed on 17-Feb-2020).
Eylea US Prescribing Information (updated 30-Mar-2021). Available from: 
https://www.accessdata.fda.gov/scripts/cder/daf/ (accessed on 08-Jun-2021).
Ferris FL (1983) Senile degeneration. Review of epidemiologic features. Am J Ophthalmol; 
118: 132-51.
Ferris FL, Fine SL, Hyman L (1984) Age-related macular degeneration and blindness due to 
neovascular maculopathy. Arch Ophthalmol; 102: 1640-2.
Kawasaki R, Yasuda M, Song S, et al (2010) The prevalence of age-related macular 
degeneration in Asians: A systematic review and meta-analysis. Ophthalmology; 177: 921-7.
Lim LS, Mitchell P, Seddon JM, et al (2012) Age-related macular degeneration. Lancet; 379: 
1728-38.
McCamish M, Woollett G (2012) The state of the art in the development of biosimilars. Clin 
Pharmacol Ther; 91: 405-17.
Miller JW (2013) Age-Related Macular Degeneration Revisited – Piercing the puzzle: The 
LXIX Edward Jackson Memorial Lecture. Am J Ophthalmol; 155: 1-35.
Rein DB, Wittenborn BS, Zhang X, et al (2009) Vision Health Cost-Effectiveness Study 
Group. Forecasting age-related macular degeneration through the year 2050. Arch 
Ophthalmol; 127: 533-40.
Royal College of Ophthalmologists; COVID-19 Response; available from 
https://www.rcophth.ac.uk/about/rcophth-covid-19-response/ (accessed on 06-May-20).
Schiestl M (2011) A biosimilar industry view on the implementation of the WHO guidelines 
on evaluating similar biotherapeutic products. Biologicals; 30: 1179-85.


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Schneider CK, Vleminckx C, Gravanis I, et al (2012) Setting the stage for biosimilar 
monoclonal antibodies. Nat Biotechnol; 30: 1179-85.
Shah AR, Del Priore LV (2007) Progressive visual loss in subfoveal exudation in age-related 
macular degeneration: a meta-analysis using Lineweaver-Burke plots. Am J Ophthalmol; 143: 
83-9.
Shah AR, Del Priore LV (2009) Natural history of predominantly classic, minimally classic 
and occult subgroups in age-related macular degeneration. Am J Ophthalmol; 116: 1901-7.
Smith W, Assink J, Klein R, et al (2001) Risk factors for age-related macular degeneration: 
Pooled findings from three continents. Ophthalmology; 108: 697-704.
Sommer A, Tielsch JM, Katz J, et al (1991) Racial differences in the cause-specific 
prevalence of blindness in East Baltimore. N Engl J Med; 14: 1412-17.
Spilsbury K, Garrett KL, Shen WY, et al (2000) Over expression of vascular endothelial 
growth factor (VEGF) in the retinal pigment epithelial leads to the development of choroidal 
neovascularization. Am J Pathol; 157: 135-44.
Weise M, Bielsky MC, De Smet K, et al (2011) Biosimilars – why terminology matters. Nat 
Biotechnol; 29: 690-3.
Wong TY, Chakravarthy U, Klein R, et al (2008) The natural history and prognosis of 
neovascular age-related macular degeneration: a systemic review of the literature and meta-
analysis. Ophthalmology; 115: 116-26.

SAP_001.pdf: 
Sandoz Biopharmaceuticals Clinical Development
SOK583A1 (INN: aflibercept)
CSOK583A12304 / NCT05161806
An open-label, single-arm, multicenter study in patients with 
neovascular age-related macular degeneration to evaluate the 
safety of SOK583A1 (40 mg/mL), a proposed aflibercept biosimilar 
product, provided in a prefilled syringe 
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation
Document status:
Final 
Release date:
14-Dec-2021
Number of pages:
13
Property of Sandoz Inc.
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Sandoz Inc.
Template Version 4.0, Effective from 23-Apr-2021


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SAP Final 1.0
Study No. CSOK583A12304
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
14-
Dec-
2021
Prior 
to 
DB 
lock
Creation of 
final version
N/A - First version
NA


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SAP Final 1.0
Study No. CSOK583A12304
Table of contents
Table of contents..................................................................................................................3
List of tables.........................................................................................................................4
List of figures.......................................................................................................................4
List of abbreviations ............................................................................................................5
1
Introduction..........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives, endpoints and estimands..............................................................6
2
Statistical methods ...............................................................................................................7
2.1
Data analysis general information............................................................................7
2.1.1
General definitions ..................................................................................7
2.2
Analysis sets.............................................................................................................7
2.3
Subject disposition, demographics and other baseline characteristics.....................8
2.3.1
Subject disposition...................................................................................8
2.3.2
Demographics and other baseline characteristics....................................8
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)..............................................................................................................8
2.4.1
Study treatment / compliance..................................................................8
2.4.2
Prior, concomitant and post therapies .....................................................8
2.5
Analysis supporting primary objective(s)................................................................8
2.5.1
Primary endpoint(s).................................................................................8
2.5.2
Statistical hypothesis, model, and method of analysis ............................8
2.5.3
Handling of missing values .....................................................................9
2.5.4
Sensitivity analyses .................................................................................9
2.5.5
Supplementary analyses ..........................................................................9
2.6
Analysis supporting secondary objectives...............................................................9
2.7
Safety analyses.........................................................................................................9
2.7.1
Adverse events (AEs)..............................................................................9
2.7.2
Deaths....................................................................................................10
2.7.3
Laboratory data......................................................................................10
2.7.4
Other safety data....................................................................................10
2.8
Interim analysis......................................................................................................11
3
Sample size calculation......................................................................................................11
4
Change to protocol specified analyses...............................................................................11
5
Appendix............................................................................................................................11
5.1
Imputation rules .....................................................................................................11


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5.1.1
Study treatment......................................................................................11
5.1.2
AE date imputation................................................................................12
5.1.3
Concomitant medication date imputation..............................................13
5.2
AEs coding/grading................................................................................................13
5.3
Statistical models ...................................................................................................13
5.4
Rule of exclusion criteria of analysis sets..............................................................13
6
Reference ...........................................................................................................................13
List of tables
Table 1-1
Objectives and related endpoints.............................................................7
Table 2-1
Clinically notable criteria for vital signs ...............................................10
List of figures
Figure 1-1
Study design ............................................................................................6


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List of abbreviations
AE
Adverse Event
ATC
Anatomical Therapeutic Classification
CRF
Case Report Form
CSR
Clinical Study report
DBL
Database Lock
eCRS
Electronic Case Retrieval Sheet
FAS
Full Analysis Set
IOP
Intraocular pressure
MedDRA
Medical Dictionary for Drug Regulatory Affairs
nAMD
Neovascular age-related macular degeneration
PT
Preferred Term
RAP
Reporting & Analysis Process
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SOC
System organ class
SOK583A1
Product code of Sandoz’ proposed aflibercept containing biosimilar product
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
The purpose of the SAP is to describe the implementation of the statistical analyses planned in 
the protocol. The analyses described are based on the Clinical Study Protocol (CSP) Version 
1.0 dated 14-Sep-2021. 
A detailed description of the planned TFLs to be presented in the CSRs will be provided in 
accompanying TFL Shells document.
Any deviations from this SAP with rationale will be described in the CSR.
1.1
Study design
This is an open-label, single arm, multicenter, Phase IIIb study in subjects with (wet) 
neovascular age-related macular degeneration, eligible for IVT aflibercept treatment. Screening 
and Baseline may be performed on the same day. A follow-up visit will be performed on-site 
on Day 8 (±2 days) and on Day 31 (+4 days - end of study visit).  
Subjects who consent will undergo all screening activities to evaluate their eligibility based on 
the inclusion and exclusion criteria. Subjects who meet all inclusion criteria and none of the 
exclusion criteria will receive 1 injection of SOK583A1 (2 mg/0.05 mL) provided in a prefilled 
syringe.
The study population will be male and female subjects ≥ 50 years old who are treated with 
Eylea (intravitreally) due to nAMD and have received at least 2 injections during the induction 
phase already. Thirty-eight subjects are expected to be injected at approximately 3 sites in the 
United States of America.
Randomization is not applicable for this open-label study.
The primary analysis will be conducted after DBL.
No interim analyses are planned.
Figure 1-1
Study design
1.2
Study objectives, endpoints and estimands 
The primary objective and endpoint is given in Table 1-1 below.


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Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

Evaluate the safety of use of a prefilled 
syringe containing SOK583A1 (40 mg/mL) in 
subjects requiring IVT aflibercept treatment 
Endpoint(s) for primary objective(s)

Occurrence of ocular or non-ocular AEs 
during the study-reporting period
Secondary objectives and endpoints are not defined for this study.
2
Statistical methods
2.1
Data analysis general information
Data will be analyzed by the CRO Biostatistics and Statistical Programming group according 
to the data analysis Section 12 of the study protocol and analyses planned in this document 
unless otherwise specified. 
All statistical analyses will be performed using SAS® (SAS Institute, Cary NC, USA, version 
9.4 or higher).
Medical coding will be conducted for AEs and Medical History using MedDRA version 24.1 
or higher. Coding for medication and procedures will be performed using WHODrug Global 
B3 September 2021 or later. 
2.1.1
General definitions 
Study treatment refers to SOK583A1 (2 mg/0.05 mL) provided in a prefilled syringe.
Baseline is defined as the last available assessment collected prior to study treatment. 
The date of study treatment administration is defined as Study Day 1. All other study days will 
be labeled relative to Day 1.  
All data collected after study treatment are defined as post-baseline. 
The study day for a scheduled or unscheduled visit after Day 1 is defined as:
Study day = (date of visit) – (date of study treatment) + 1
The study day for a scheduled or unscheduled visit before Day 1 is defined as:
Study day = (date of visit) – (date of study treatment) 
2.2
Analysis sets 
The only analysis set defined is the Full Analysis Set (FAS) which will include all enrolled 
subjects who receive an injection of study treatment. 
The FAS will be used for the analysis of all variables.


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2.3
Subject disposition, demographics and other baseline 
characteristics
2.3.1
Subject disposition
The number of subjects screened and treated will be summarized.
The number and percentage of subjects who complete or discontinue from the study will be 
summarized including the reasons for discontinuation.
The number and percentage of subjects with important protocol deviations will be summarized 
by deviation category. A listing of important protocol deviations will be provided.
2.3.2
Demographics and other baseline characteristics
Demographic and other baseline data at screening (age at study entry, gender, race, ethnicity, 
body height, body weight and BMI) will be summarized descriptively.
Baseline ocular characteristics including primary diagnosis and date of diagnosis will be listed 
for the study eye.
Medical histories and current medical conditions will be coded with the MedDRA version 24.1 
or higher. All medical histories and current medical conditions will be listed.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The total number of subjects who received an injection of study treatment will be presented. 
2.4.2
Prior, concomitant and post therapies
Medications will be coded according to the ATC classification system.
Non-drug therapies and procedures will be coded using MedDRA version 24.1 or higher. 
Prior and concomitant medications and non-drug therapies and procedures will be listed.
2.5
Analysis supporting primary objective(s)
Data analysis will be performed when all subjects have completed the study.
2.5.1
Primary endpoint(s)
The incidence of ocular and non-ocular AEs are the primary endpoints. The primary endpoints 
will be analyzed for the FAS.
2.5.2
Statistical hypothesis, model, and method of analysis 
No formal hypothesis testing will be performed in this study. 
See Section 2.7.1 for details of the analyses to be performed for AEs.


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2.5.3
Handling of missing values 
This is a single dose, open-label study with 3 scheduled visits over the period of 1 month. 
Therefore, missing data will not be imputed.
2.5.4
Sensitivity analyses 
Not applicable.
2.5.5
Supplementary analyses
Not applicable.
2.6
Analysis supporting secondary objectives 
No secondary objectives are defined for this study.
2.7
Safety analyses
All safety analyses will be performed for the FAS.
2.7.1
Adverse events (AEs)
AEs will be coded using MedDRA version 24.1 or higher. 
All AEs will be listed. SAEs will be listed separately.
Summaries will include all TEAEs which are defined as AEs that develop after start of study 
treatment or any events already present that worsens following exposure to study treatment until 
the subject discontinues or completes the study.
An overview table will summarize the number and percentage of subjects with at least 1 of the 
following TEAEs: any TEAE, TEAE suspected to be treatment-related, SAE, SAE suspected 
to be treatment-related, AESI, TEAE leading to discontinuation and TEAE leading to death. 
Subjects with more than 1 TEAE in a particular category will be counted only once in that 
category. 
The number and percentage of subjects who reported TEAEs will be summarized by primary 
SOC and PT for:

all TEAEs 

all TEAEs by maximum severity
Separate summaries will be provided for study treatment related TEAEs, SAEs, and TEAEs 
leading to discontinuation of the study. Analyses will be performed for ocular AEs for the study 
eye only and non-ocular AEs. Ocular AEs for the fellow eye will be listed only.
Listing of all AEs will be provided. SAEs will be listed separately.
If a subject reports more than one AE with the same PT, the AE will be counted only once for 
that PT. If a subject reports more than one AE within the same primary SOC, the subject will 
be counted only once for that SOC.


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2.7.1.1
Adverse events of special interest / grouping of AEs
AESI is defined in the latest version of eCRS core safety topics, using the safety profiling plan 
flag at the time of analysis implementation (i.e. study database lock). Listing will be provided 
for AESI.
2.7.1.2
Adverse event reporting for clinicaltrials.gov
For the legal requirements of clinicaltrials.gov, two required tables on TEAEs which are not 
SAEs with an incidence greater than or equal to x% (default is 5% but a lower cut off may be 
applied and this will be determined based on the final data) and on treatment emergent SAEs 
will be provided by SOC and PT for the FAS. 
If for the same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
 a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
 more than one occurrence will be counted if there is > 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE/non SAE has to be checked in a block e.g. 
among AE's in a ≤ 1 day gap block, if at least one SAE is occurring, then one occurrence is 
calculated for that SAE.
2.7.2
Deaths
All deaths recorded during the study will be listed.
2.7.3
Laboratory data
Laboratory data is not collected in this study.
2.7.4
Other safety data
2.7.4.1
Intraocular pressure (IOP)
All IOP measurements will be listed for subjects who fulfil at least one of the following criteria:

IOP ≥ 26 mmHg

Increase ≥ 10 mmHg from pre-injection IOP to post-injection IOP within a visit
2.7.4.2
Vital signs
All vital signs measurements will be listed for subjects who fulfil at least one of the following 
clinically notable criteria:
Table 2-1
Clinically notable criteria for vital signs
Variable
Category
Critical Values
Systolic blood 
High
Either >180 with an increase from baseline >30 or >200 absolute


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Variable
Category
Critical Values
pressure (mmHg)
Low
Either <90 with a decrease from baseline >30 or <75 absolute
High
Either >105 with an increase from baseline >20 or >115 absolute
Diastolic blood 
pressure (mmHg)
Low
Either <50 with a decrease from baseline > 20 or <40 absolute
High
Either >120 with an increase from baseline of >25 or >130 
absolute
Pulse rate (bpm)
Low
Either <50 with a decrease from baseline >30 or <40 absolute
2.8
Interim analysis
No interim analysis is planned for this study.
3
Sample size calculation
No formal statistical power calculations to determine sample size were performed for this study. 
4
Change to protocol specified analyses
Protocol section 12.2 states that relevant medical histories and current medical conditions at 
baseline will be summarized. Given the small sample size, these data will be listed only.
Protocol section 12.3 states that concomitant medications and significant non-drug therapies 
prior to and after the start of the study treatment will be summarized. Given the small sample 
size, these data will be listed only.
Protocol section 12.4.2 states that AE presentations will be presented for the fellow eye. AEs 
reported for the fellow eye will be listed only.  
Protocol section 12.4.2 states that pre-injection and post-injection IOP measurements will be 
listed. Instead, IOP measurements will only be listed for subjects who have at least IOP 
measurement meeting the criteria defined in Section 2.7.4.1.
Protocol section 12.4.2 states that all vital signs data will be listed. Instead, vital signs 
measurements will only be listed for subjects who have at least 1 vital signs measurement 
meeting the criteria defined in Section 2.7.4.2.
5
Appendix
5.1
Imputation rules
5.1.1
Study treatment
Missing or partial dates are not allowed in completing the study treatment administration eCRF 
page. 


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5.1.2
AE date imputation
5.1.2.1
Adverse event end date imputation
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed.
If the imputed AE end date is less than the existing AE start date then use AE start date as AE 
end date.
5.1.2.2
Adverse event start date imputation
Completely missing AE start dates will not be imputed.
Before imputing AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min(informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
Imputations rules using the AE start reference date:
1. If the AE start date ‘year’ value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL. 
2. If the AE start date ‘year’ value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
a. If AE ‘month’ is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if AE ‘month’ is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the treatment start month, the imputed AE start date 
is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month start 
point (01MONYYYY), AE start reference date + 1 day). 


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If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date.  
5.1.3
Concomitant medication date imputation
No imputation for concomitant medication as data will be listed only.
5.1.3.1
Prior therapies date imputation
No imputation for prior therapies as data will be listed only.
5.2
AEs coding/grading
AEs will be coded using the MedDRA terminology. No grading system for AEs will be used. 
Medical history and prior/concomitant non drug therapies/procedures will be coded using the 
MedDRA terminology. 
Prior/concomitant medications will be coded using the WHODRUG Global B3 terminology. 
The MedDRA version 24.1 or higher and WHODRUG Global B3 September 2021 or later will 
be used and will be described in the footnote of relevant outputs.
5.3
Statistical models
No hypothesis testing will be performed for this study.
5.4
Rule of exclusion criteria of analysis sets 
Only one analysis set is defined, the FAS. No protocol deviations are defined which lead to 
exclusion from the FAS. 
6
Reference
Not applicable.