Conditions: Neovascular Age-related Macular Degeneration
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 449
Healthy volunteers: no

Brief summary:
This is a randomised, double-masked, parallel group, multicentre study to evaluate the efficacy, safety, Pharmacokinetics (PK), and immunogenicity of SB15 compared to Eylea® in subjects with neovascular AMD.

Detailed description:
Subjects will be randomised in a 1:1 ratio to receive either SB15 or Eylea® (administered via intravitreal \[IVT\] injection 2 mg \[0.05 mL\] every 4 weeks for the first 3 months (i.e., at Weeks 0, 4, and 8), followed by 2 mg \[0.05 mL\] once every 8 weeks). At Week 32, subjects in Eylea® treatment group will be randomised again in a 1:1 ratio to either continue on Eylea® treatment or be transitioned to SB15 treatment. In the 8-week treatment cycle, IPs (SB15 or Eylea®) will be administered up to Week 48, and the last assessment will be done at Week 56, corresponding to the end of follow-up for all subjects.

Arms:
arm 1: Subjects randomized into SB15 group will receive SB15 2 mg (0.05 mL) via intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg (0.05 mL) once every 8 weeks until Week 48. arm 2: Subjects randomized into Eylea group will receive Eylea 2 mg (0.05 mL) via intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg (0.05 mL) once every 8 weeks until Week 48.

At Week 32, subjects in Eylea group will re-randomized into SB15 or Eylea group. After re-randomization, subjects transited to SB15 group will receive SB15 2 mg (0.05 mL) once every 8 weeks until Week 48 and subjects remaining in Eylea group will continue to receive Eylea 2 mg (0.05 mL) once every 8 weeks until Week 48.

Interventions: intervention 1: SB15 (Proposed aflibercept biosimilar) intervention 2: Eylea (Aflibercept)
Intervention descriptions: intervention 1: Subjects randomized into SB15 group will receive SB15 2 mg (0.05 mL) via intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg (0.05 mL) once every 8 weeks until Week 48. Starting at Week 32, subjects transited from Eylea to SB15 will receive SB15 2 mg (0.05 mL) via intravitreal injection every 8 weeks. intervention 2: Subjects randomized into Eylea group will receive Eylea 2 mg (0.05 mL) via intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg (0.05 mL) once every 8 weeks until Week 48.

Protocol document:
Prot_000.pdf: 
SB15 (proposed aflibercept biosimilar) 
SB15-3001 
Version 1.0, Oct 30, 2019 
 
Samsung Bioepis – Confidential and Proprietary Information 
 
 
Page 1 of 94 
 
. 
 
Clinical Study Protocol 
 
A Phase III Randomised, Double-masked, Parallel Group, Multicentre 
Study to Compare the Efficacy, Safety, Pharmacokinetics, and 
Immunogenicity between SB15 (proposed aflibercept biosimilar) and 
Eylea® in Subjects with Neovascular Age-related Macular Degeneration 
 
 
 
Product 
SB15 (proposed aflibercept biosimilar) 
EudraCT Number 
2019-003883-28 
US IND Number (if applicable) 
N/A 
Protocol Number 
SB15-3001 
Study Phase 
Phase III 
Version and Effective Date 
Version 1.0 
Oct 30, 2019 
 
 
 
 
 
 
 
Sponsor 
Samsung Bioepis Co., Ltd.  
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
 
This document contains confidential information belonging to Samsung Bioepis Co., Ltd. Your acceptance or 
review of this document constitutes agreement that you will not copy or disclose the information contained 
herein to others or use it for unauthorised purposes without written authorisation from the Sponsor. 
 
 


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SYNOPSIS 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB15 (proposed aflibercept biosimilar) 
Name of Active Ingredient: 
Aflibercept 
Title of Study: 
A Phase III randomised, double-masked, parallel group, multicentre study to compare the efficacy, safety, 
pharmacokinetics, and immunogenicity between SB15 (proposed aflibercept biosimilar) and Eylea® in subjects 
with neovascular age-related macular degeneration 
Protocol No: 
SB15-3001 
Phase: III 
Investigator sites: 
Approximately 60 Investigator sites globally 
Planned Study Period: Approximately 59 weeks per subject 
Screening period will be 3 weeks. Investigational product (IP; SB15 or Eylea®) will be given for 48 weeks and 
the last assessment will be done at Week 56. 
Objectives: 
Primary objective 
The primary objective of this study is to demonstrate the equivalence in efficacy of SB15 compared to Eylea® 
in subjects with neovascular age-related macular degeneration (AMD). 
Secondary objective(s) 
The secondary objectives are: 
• 
To evaluate the safety of SB15 compared to Eylea® 
• 
To evaluate the systemic exposure of SB15 compared to Eylea® in subjects participating in 
pharmacokinetics (PK) evaluation 
• 
To evaluate the immunogenicity of SB15 compared to Eylea® 
Study Design: 
This is a randomised, double-masked, parallel group, multicentre study to evaluate the efficacy, safety, PK, and 
immunogenicity of SB15 compared to Eylea® in subjects with neovascular AMD. Subjects will be randomised 
in a 1:1 ratio to receive either SB15 or Eylea® (administered via intravitreal [IVT] injection 2 mg [0.05 mL] 
every 4 weeks for the first 3 months (i.e., at Weeks 0, 4, and 8), followed by 2 mg [0.05 mL] once every 8 
weeks). At Week 32, subjects in Eylea® treatment group will be randomised again in a 1:1 ratio to either 
continue on Eylea® treatment or be transitioned to SB15 treatment. In the 8-week treatment cycle, IPs (SB15 
or Eylea®) will be administered up to Week 48, and the last assessment will be done at Week 56, corresponding 
to the end of follow-up for all subjects. 
Number of Subjects: 
Approximately a total of 446 subjects will be randomised in this study. 
Target Population: Subjects with neovascular AMD 
Eligibility Criteria: 
Only one eye will be designated as the study eye. For subjects who meet eligibility criteria in both eyes, the 
eye with the worse visual acuity will be selected as the study eye. If both eyes have equal visual acuity, the eye 


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SB15-3001 
Version 1.0, Oct 30, 2019 
 
Samsung Bioepis – Confidential and Proprietary Information 
 
 
Page 3 of 94 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB15 (proposed aflibercept biosimilar) 
Name of Active Ingredient: 
Aflibercept 
with clearer lens and ocular media will be selected at the Investigator’s discretion. If there is no objective basis 
for selecting the study eye, factor such as ocular dominance, other ocular pathology, and subject preference 
should be considered by the Investigator in making the selection. Subject with only one functional eye (defined 
as Best Corrected Visual Acuity (BCVA) of counting finger or less on the eye with worse vision) cannot be 
enrolled, even if otherwise eligible for the study. 
Inclusion criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Age ≥ 50 years at Screening 
2. Treatment naïve, *active subfoveal choroidal neovascularisation (CNV) lesion secondary to AMD in 
the study eye 
 
* Active CNV indicates presence of leakage and intra- or sub-retinal fluid which should be confirmed 
by the central reading centre during Screening. 
3. The area of CNV must occupy at least 50% of total lesion in the study eye (confirmed by the central 
reading centre during Screening) 
4. Total lesion area ≤ 9.0 Disc Areas (DA) in size (including blood, scars, and neovascularisation) in the 
study eye (confirmed by the central reading centre during Screening) 
5. BCVA of 20/40 to 20/200 (letter score of 73 to 34, inclusive) using original series Early Treatment 
Diabetic Retinopathy Study (ETDRS) charts or 2702 series Number charts in the study eye at 
Screening and at Week 0 (Day 1) prior to randomisation 
6. Non-childbearing potential female (e.g., permanently sterilized, postmenopausal [defined as 12 
months with no menses without an alternative medical cause prior to Screening]), OR childbearing 
potential female subjects or male subjects with their (respectively male or female) partners who agree 
to use at least two forms of appropriate contraception method that can achieve a failure rate of less 
than 1% per year (e.g., established use of oral, injected, intravaginal, transdermal, or implanted 
hormonal contraceptive, placement of an intrauterine device or intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomised partner, physical barrier, sexual abstinence) from 
Screening until 3 months after the last IVT injection of IP 
7. Written informed consent form (ICF) must be obtained from the subject prior to any study related 
procedure (if the subject is legal blindness or illiterate, an impartial witness should be present during 
the entire informed consent discussion) 
8. Willingness and ability to undertake all scheduled visits and assessments 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for the study: 
1. Study eye: Sub- or intra-retinal haemorrhage that comprises more than 50% of the entire lesion or 
presence of blood with the size of 1 DA or more involving the centre of fovea (confirmed by the 
central reading centre during Screening) 
2. Study eye: Scar, fibrosis, or atrophy involving the centre of the fovea (confirmed by the central reading 
centre during Screening) 
3. Study eye: Presence of CNV due to other causes, such as ocular histoplasmosis, trauma, multifocal 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB15 (proposed aflibercept biosimilar) 
Name of Active Ingredient: 
Aflibercept 
choroiditis, angioid streaks, history of choroidal rupture, or pathologic myopia (confirmed by the 
central reading centre during Screening) 
4. Study eye: Presence of retinal pigment epithelial tears or rips involving the macula (confirmed by the 
central reading centre during Screening) 
5. Study eye: Presence of macular hole at any stage (confirmed by the central reading centre during 
Screening) 
6. Study eye: Any concurrent macular abnormality other than AMD which could affect central vision or 
the efficacy of IP including but not limited to epiretinal membrane, vitreomacular traction, macular 
telangiectasia, retinal vascular abnormality, etc. (confirmed by the central reading centre during 
Screening) 
7. Study eye: Any concurrent ocular condition which, in the opinion of the Investigator, could either 
confound the interpretation of efficacy and safety of IP (e.g., ocular media opacities such as significant 
cataract, optic neuropathy etc.) or require medical or surgical intervention during the study period 
8. Either eye: History or clinical evidence of diabetic retinopathy (except for mild non-proliferative 
diabetic retinopathy) or diabetic macular oedema (DME) 
9. Study eye: Current vitreous haemorrhage 
10. Either eye: Any previous IVT anti-vascular endothelial growth factor (VEGF) treatment (e.g., 
bevacizumab, ranibizumab, aflibercept, pegaptanib, etc.) 
11. Any previous systemic anti-VEGF treatment 
12. Study eye: History of treatment involving macula such as macular laser photocoagulation, 
photodynamic therapy (PDT), transpupillary thermotherapy (TTT), radiation therapy, or any ocular 
treatment for neovascular AMD 
13. Any systemic treatment or therapy (including prescribed herbal medication) to treat neovascular AMD 
within 30 days prior to randomisation, and such treatment or therapy will not be allowed during the 
study period. However, dietary supplements, vitamins, or minerals will be allowed. 
14. Study eye: History of vitrectomy, scleral bucking (encircling), glaucoma filtration surgery, corneal 
transplantation, or pan-retinal photocoagulation 
15. Study eye: Previous ocular (intraocular and peribulbar) corticosteroids injection/implant within 1 year 
prior to randomisation 
16. Study eye: Topical ocular corticosteroids administered for ≥ 30 consecutive days or for ≥ 60 non-
consecutive days within 90 days prior to randomisation 
17. Use of systemic corticosteroids for 30 or more consecutive days within 90 days prior to randomisation 
(inhaled steroid is permitted). 
18. Study eye: Any other intraocular surgery (including cataract surgery or Yttrium Aluminium Garnet 
[YAG] laser posterior capsulotomy in association with prior posterior chamber intraocular lens [IOL] 
implantation) or periocular surgery within 90 days prior to randomisation, except for lid surgery, 
which may not have taken place within 30 days prior to randomisation. 
19. Current use of medications known to be toxic to the lens, retina, or optic nerve, including 
deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines, vigabatrin, ethambutol, 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB15 (proposed aflibercept biosimilar) 
Name of Active Ingredient: 
Aflibercept 
at Screening and such medications will not be allowed during the study period. 
20. Study eye: Previous radiation therapy near the region of the study eye 
21. Previous participation in clinical studies with IP to treat neovascular AMD in either eye.  
22. Previous participation in clinical studies with IP to treat disease other than neovascular AMD within 
90 days prior to randomisation (excluding dietary supplementary, vitamins, and minerals). Such 
participation will not be allowed during the study period even if the IP is dietary supplementary, 
vitamins, or minerals. 
23. Subject with only one functional eye (defined as BCVA of counting finger or less on the eye with 
worse vision) 
24. Study eye: Spherical equivalent of the refractive error demonstrating more than 6 diopters of myopia. 
For subjects who have undergone previous refractive or cataract surgery in the study eye, the 
preoperative refractive error in the study eye cannot exceed 6 diopters of myopia. 
25. Study eye: Aphakia or absence of the posterior capsule (unless it occurred as a result of a YAG laser 
posterior capsulotomy in association with prior posterior chamber IOL implantation) 
26. Either eye: Active or suspected ocular and periocular infection at Screening or at randomisation (e.g., 
infectious blepharitis, infectious conjunctivitis, infection in eyelid) 
27. Either eye: Active intraocular inflammation including scleritis at Screening or at randomisation 
28. Either eye: History of idiopathic or autoimmune-associated uveitis 
29. Study eye: Uncontrolled ocular hypertension (defined as intraocular pressure [IOP] ≥ 25 mmHg 
despite treatment with anti-glaucoma medication) at Screening  
30. Known allergic reactions and/or hypersensitivity to any component of Eylea® or SB15 
31. History of allergy to the fluorescein sodium for injection in angiography 
32. History of a medical condition that would preclude scheduled study visits or safe use of IP in the 
opinion of the Investigator (e.g., history of organ transplant, immunocompromised subject, etc.) 
33. Uncontrolled systemic disease including but not limited to uncontrolled diabetes mellitus (in the 
opinion of the Investigator), uncontrolled systemic hypertension (systolic blood pressure ≥ 180 mmHg 
and/or diastolic blood pressure ≥ 100 mmHg on optimal medical regimen), or uncontrolled atrial 
fibrillation (resting heart rate ≥ 110 beats per minutes) at Screening 
34. Stroke, transient ischaemic attacks, or myocardial infarction within 180 days prior to randomisation 
35. History of recurrent significant infections and/or current treatment for systemic infection  
36. Severe renal impairment with dialysis or a history of renal transplant 
37. Malignancy (other than non-melanoma skin cancer) under treatment or with history of metastatic 
disease  
38. Women of childbearing potential who are pregnant, planning to become pregnant, lactating, or not 
using adequate birth control, as specified in protocol. For women of childbearing potential, a serum 
pregnancy test must result negative at Screening. 
39. Employees of investigational sites, individuals directly involved with the conduct of the study, 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB15 (proposed aflibercept biosimilar) 
Name of Active Ingredient: 
Aflibercept 
prisoners, and persons who are legally institutionalized 
Investigational Products: 
• 
Test IP: SB15 (proposed aflibercept biosimilar) 
• 
Reference IP: Eylea® (aflibercept) 
• 
Formulation: Solution for injection 
• 
Route of administration: IVT injection 
• 
Dose regimen: 2 mg (0.05 mL) every 4 weeks for the first 3 months, followed by 2 mg (0.05 mL) 
once every 8 weeks 
Study Endpoints 
Primary efficacy endpoint 
• 
Change from baseline in BCVA at Week 8 
Secondary efficacy endpoints 
The secondary efficacy endpoints are: 
• 
Change from baseline in BCVA over time up to Week 32 and up to Week 56 
• 
Proportion of subjects who lost fewer than 15 letters in BCVA compared to baseline at Week 32 and 
Week 56 (proportion of subjects who maintained BCVA) 
• 
Proportion of subjects who gained 15 letters or more in BCVA compared to baseline at Week 32 and 
Week 56 
• 
Change from baseline in central subfield thickness (CST) and total retinal thickness (TRT) at Week 
4, and over time up to Week 32 and up to Week 56 (based on assessment by the central reading centre) 
- 
CST measured from internal limiting membrane (ILM) to retinal pigment epithelium (RPE) in 
1-mm central subfield 
- 
TRT measured from ILM to Bruch’s membrane (BM) in 1-mm central subfield 
• 
Proportion of subjects with intra- or sub-retinal fluid on optical coherence tomography (OCT) at 
Week 32 and Week 56 (based on assessment by the central reading centre) 
• 
Change from baseline in CNV area at Week 32 and Week 56 (based on assessment by the central 
reading centre) 
• 
Proportion of subjects with active CNV leakage at Week 32 and Week 56 (based on assessment by 
the central reading centre) 
Safety endpoints 
• 
Incidence of ocular adverse events (AEs) or serious ocular AEs 
• 
Incidence of non-ocular AEs and serious non-ocular AEs 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB15 (proposed aflibercept biosimilar) 
Name of Active Ingredient: 
Aflibercept 
• 
Incidence of intraocular inflammation and IOP increase 
• 
Changes in vital signs and clinical laboratory parameters  
PK endpoints 
Blood samples for PK assessment will be collected in approximately 40 subjects participating in PK evaluation 
(20 subjects per treatment group in initial randomisation at Week 0 [Day 1]). 
• 
Pre-dose (trough serum concentration [Ctrough]) 
- 
Systemic exposure measured pre-dose at Week 0 (Day 1), Week 4, Week 8, Week 24, Week 32, 
and Week 40 
• 
Post-dose (close to maximum serum concentration [Cmax]) 
- 
Systemic exposure measured once between 24 hours and 72 hours after IVT injection of IP at 
Week 0 (Day 1) 
- 
Systemic exposure measured on 1 day, 2 days, and 3 days after the date of IVT injection of IP 
at Week 24 (total 3 times of PK sample collection for 3 consecutive days) 
• 
Systemic exposure measured during the visit at Week 56 (end of study [EOS] visit) 
Immunogenicity endpoints 
Blood samples for immunogenicity assessment will be collected pre-dose at Week 0 (Day 1), Week 4, Week 8, 
Week 24, Week 32, and Week 40. Blood samples for immunogenicity assessment will also be collected during 
the visit at Week 56 (EOS visit) or early termination (ET) visit 
• 
Incidence of anti-drug antibodies (ADAs) to aflibercept 
• 
Incidence of neutralising antibodies (NAbs) to aflibercept 
Exploratory endpoint 
• 
Proportion of subjects with sub-RPE fluid on OCT at Week 32 and Week 56 (based on assessment 
by the central reading centre) 
The quality of life (QOL) is assessed using National Eye Institute 25-Item Visual Function Questionnaire (NEI 
VFQ-25). 
• 
Change from baseline in subscale scores and composite scores of NEI VFQ-25 at Week 32 and 
Week 56 
Statistical Methods  
Analysis sets for efficacy analyses 
The Full Analysis Set (FAS) consists of all randomised subjects. Following the intent-to-treat principle, 
subjects will be analysed according to the treatment group they are assigned to at randomisation. However, 
subjects who do not have any efficacy assessment result after randomisation and do not receive IP during 
the study period will be excluded from FAS. 
Per-Protocol Set (PPS) consists of all FAS subjects who have BCVA assessment result at baseline and at 
Week 8 without any major protocol deviations (PDs) that have impact on the BCVA assessment. Major PDs 
that will lead to exclusion from this set will be pre-defined prior to unmasking the treatment group 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB15 (proposed aflibercept biosimilar) 
Name of Active Ingredient: 
Aflibercept 
assignment for analyses. 
Efficacy analyses 
The primary efficacy analysis will aim to demonstrate equivalence in terms of change from baseline in BCVA 
at Week 8 between SB15 and Eylea®.  
The equivalence between the two treatment groups will be declared if the 90% confidence interval (CI) of 
the difference is entirely contained within the pre-defined equivalence margin of [−3 letters, 3 letters]. The 
90% CI of the difference between the two treatment groups in relation to the change from baseline in BCVA 
at Week 8 will be estimated for the FAS. The same analysis will be performed for the PPS as a sensitivity 
analysis.  
For the European Medicines Agency (EMA) submission, equivalence between the two treatment groups will 
be declared if the 95% CI of the difference is entirely contained within the pre-defined equivalence margin 
of [−3 letters, 3 letters]. The 95% CI of the difference between the two treatment groups in relation to the 
change from baseline in BCVA at Week 8 will be estimated for the FAS. The same analysis will be performed 
for the PPS as a sensitivity analysis. For those subjects who drop out of the study prematurely, a multiple 
imputation will be used under the missing at random assumption. The 95% CI of the difference between the 
two treatment groups will also be estimated for the FAS as supportive analysis. 
As the secondary efficacy endpoints, change from baseline in BCVA, CST, TRT, and CNV area will be 
summarised descriptively by treatment group and visit.  
Proportion of subjects who lost fewer than 15 letters and gained 15 letters or more in BCVA compared to 
baseline, subjects with intra- or sub-retinal fluid, and subjects with active CNV leakage will be summarised 
descriptively by treatment group and visit. 
The two-sided 95% CI of the Least Square mean (LSMean) difference of change from baseline in secondary 
efficacy endpoints between the two treatment groups will be estimated. 
Safety analyses 
All reported terms for AEs (ocular or non-ocular) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®). AEs including ocular AEs in the study eye and/or fellow eye as well as non-ocular 
AEs will be summarised descriptively by treatment group.  
Changes in vital signs and clinical laboratory parameters will be summarised descriptively by treatment 
group and visit. All other safety variables will be summarised descriptively by treatment group and visit 
unless specified otherwise.  
PK analyses 
Blood samples for PK assessment will be collected in approximately 40 subjects participating in PK 
evaluation (20 subjects per treatment group in initial randomisation at Week 0 [Day 1]). The systemic 
exposure will be summarised descriptively by treatment group and visit. 
Immunogenicity analyses 
The number and proportion of subjects with ADA and NAb results (e.g., ‘positive’ or ‘negative’) will be 
summarised descriptively by treatment group and visit. 
Exploratory analyses 
Proportion of subjects with sub-RPE fluid on OCT at Week 32 and Week 56 will be summarised descriptively 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB15 (proposed aflibercept biosimilar) 
Name of Active Ingredient: 
Aflibercept 
by treatment group and visit. 
For NEI VFQ-25 as a measurement of QOL, subscale scores (general health, general vision, ocular pain, 
near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-
specific role difficulties, vision-specific dependency, driving, colour vision, and peripheral vision) and the 
composite score, which represent overall visual function, will be calculated, and the change from baseline 
will be summarised descriptively by treatment group and visit. 
Sample size calculation 
For the calculation of the equivalence margin for BCVA, the mean changes in BCVA were referred from 
VIEW1 study of Eylea® in subjects with neovascular AMD.  
In the VIEW1 study, as reported in the Summary of Product Characteristics (SmPC) of Eylea®, the mean 
change of BCVA at Month 12 (standard deviation [SD]) was 10.9 (13.8) letters for the dosing of 2 mg every 
4 weeks in the Eylea® treatment group and the LSMean difference between Eylea® and Lucentis® 
(ranibizumab) with its 95% CI was 3.15 (0.92, 5.37) letters. 
The United States of America (US) Food and Drug Administration (FDA) Guidance describes that if the 
active control (Eylea® in this study) has shown superiority to other active treatments (Lucentis® in VIEW1) 
in the past, the difference demonstrated (3.15 letters) represents a conservative estimate of historical evidence 
of sensitivity to drug-effects, one that could serve as a basis for choosing M1. Therefore, the equivalence 
margin of 3 letters was chosen as it would be less than the LSMean difference in VIEW1 study, which proved 
statistical superiority to ranibizumab. 
The ETDRS chart has 5 letters in one line (that is the minimum limit, in terms of number of letters, for 
detecting a visual acuity change); thus, the difference of more than 5 letters in BCVA could be considered as 
a minimal clinically important difference. In addition, most of the anti-VEGF non-inferiority clinical trials 
on AMD also used a non-inferiority margin of 5 letters. Therefore, the equivalence margin of [−3 letters, 3 
letters] is considered to be a conservative margin to test the clinical equivalence between SB15 and Eylea®. 
With the equivalence limit of [−3 letters, 3 letters], a sample size of 216 subjects per treatment group was 
calculated with the assumptions of the mean difference of 0.5 letters and SD of 9.0 at the overall 5% 
significance level, providing 80% power to reject the null hypothesis. Overall 446 subjects (223 per treatment 
group) will be randomised into the study, allowing 3% loss from the randomised subjects, if any. 


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GRAPHICAL STUDY DESIGN AND SCHEDULE OF ACTIVITIES 
 
Figure 1. Graphical Study Design 
ICF = informed consent form; ® = randomisation; IVT = intravitreal; OCT = optical coherence tomography; BCVA = best corrected visual acuity; PK = pharmacokinetics; W = week 
 


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Table 1. Schedule of Activities 
Procedures 
Study Period 
W: Week 
Screening25 
W0 
W4 
W8 
W16 
W24 
W32 
W40 
W48 
EOT26 
W56 
EOS27/ET28 
D: Day 
 (± Visit Window)  
D-21 to D-1 
D1 
D29 
(± 7) 
D57 
(± 7) 
D113 
(± 7) 
D169 
(± 7) 
D225 
(± 7) 
D281 
(± 7) 
D337 
(± 7) 
D393 
(± 7) 
V: Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Written informed consent1 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographic data2 
X 
 
 
 
 
 
 
 
 
 
Medical/ophthalmic history 
X 
 
 
 
 
 
 
 
 
 
Physical examination3 
X 
 
 
 
 
 
 
 
 
X 
Randomisation4 
 
X 
 
 
 
 
X5 
 
 
 
Vital signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA examination7 
X 
X8 
X 
X9 
(Primary) 
X 
X 
X 
X 
X 
X 
OCT10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FP/FA11 
X 
 
 
 
 
 
X 
 
 
X 
Indirect ophthalmoscopy12 (pre- and post-dose) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp examination13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intraocular pressure14 (pre- and post-dose) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NEI VFQ-2515 
 
X 
 
 
 
 
X 
 
 
X 
Clinical laboratory test16 
X 
 
 
X 
 
 
X 
X 
 
X 
Blood sampling for immunogenicity17 
 
X 
X 
X 
 
X 
X 
X 
 
X 
Blood sampling for PK18 
 
X 
X 
X 
 
X  
X 
X 
 
X19 
Pregnancy test20 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IP injection21 
 
X22 
X 
X 
X 
X 
X 
X 
X 
 


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Procedures 
Study Period 
W: Week 
Screening25 
W0 
W4 
W8 
W16 
W24 
W32 
W40 
W48 
EOT26 
W56 
EOS27/ET28 
D: Day 
 (± Visit Window)  
D-21 to D-1 
D1 
D29 
(± 7) 
D57 
(± 7) 
D113 
(± 7) 
D169 
(± 7) 
D225 
(± 7) 
D281 
(± 7) 
D337 
(± 7) 
D393 
(± 7) 
V: Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
AE monitoring23 
Continuously 
Prior or concomitant medication or therapy24 
Continuously 
AE = adverse event; BCVA = best corrected visual acuity; EOS = end of study; EOT = end of treatment; ET = early termination; FA = fluorescein angiography; FP = fundus photography; IP = 
investigational product; NEI VFQ-25 = National Eye Institute 25-item Visual Function Questionnaire; OCT = optical coherence tomography; PK = pharmacokinetics. 
 
1.  Written informed consent must be obtained from the subject prior to any study related procedures. 
2.  Demographic data includes the date of birth (year of birth is required), gender, race, and ethnicity. 
3.  Physical examination will be performed at Screening and Week 56 (EOS visit) or ET visit. Body weight will be measured and recorded at Screening and Week 56 (EOS visit) or ET visit, 
whereas height will be measured and recorded only at Screening. 
4.  All subjects’ eligibility should be confirmed by the central reading centre and the Investigator prior to randomisation. 
5.  At Week 32, subjects in Eylea® treatment group will be randomised in a 1:1 ratio to either continue on Eylea® treatment or be transitioned to SB15 treatment. Subjects receiving SB15 will 
continue to receive SB15 up to Week 48, but they will also follow the randomisation procedure in order to maintain masking. 
6.  Vital signs include blood pressure, pulse rate, and body temperature. Vital signs will be assessed at Screening and prior to intravitreal (IVT) injection of IP at each visit until Week 48. Vital 
signs will also be assessed at Week 56 (EOS visit) or ET visit. 
7.  Visual acuity will be assessed in both the study eye and fellow (non-study) eye at Screening and prior to IVT injection of IP at each visit until Week 48. Visual acuity will also be assessed 
during the final visit at Week 56 (EOS visit) or ET visit. Subject must use either original series Early Treatment Diabetic Retinopathy Study (ETDRS) chart or 2702 series Number chart (at a 
starting distance of 4 meters) consistently from Screening to Week 56 (EOS visit) or ET visit. Visual acuity testing must be performed before dilation of pupils and other ophthalmic procedures 
including FA/FP and OCT assessment. A decrease in visual acuity of ≥ 15 letters from the last assessment of VA should be reported as AEs/serious AEs (SAEs) as appropriate. If there is a 
decrease in visual acuity of ≥ 30 letters from the last assessment of visual acuity or if there is a decrease in visual acuity to the level of light perception or worse, it should be reported as SAE. 
8.  The Investigator must confirm that the subject can read between 73 letters and 34 letters, inclusive, in the study eye using original series ETDRS chart or 2702 series Number chart at Week 0 
(Day1) prior to randomisation.  
9.  Visit at Week 8 is the most critical as this is the visit scheduled for the primary endpoint assessment. Thus, every effort should be made to adhere to the visit schedule for the subjects. 
10.  OCT will be performed on both eyes at Screening and those images taken from both eyes will be sent to the central reading centre. OCT will be performed on the study eye prior to IVT 
injection of IP at each visit until Week 48. OCT will also be performed on the study eye at Week 56 (EOS visit) or ET visit. OCT images taken from the study eye will be sent to the central 
reading centre. Only OCT devices certified by the central reading centre are allowed to be used in this study. If one or more OCT devices are certified in an investigational site, a subject must 
use the same OCT system from the same manufacture consistently from Screening to Week 56 (EOS visit) or ET visit.  
11.  FP/FA will be performed on both eyes at Screening and those images taken from both eyes will be sent to the central reading centre. FP/FA will also be performed on the study eye prior to 
IVT injection of IP at Week 32 and at Week 56 (EOS visit) or ET visit. Those images taken from the study eye at Week 32 and Week 56 (EOS visit) or ET visit will be sent to the central 


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reading centre. Only FP/FA devices certified by the central reading centre are allowed to be used in this study. If one or more FP/FA devices are certified in an investigational site, a subject 
must use the same FP/FA system from the same manufacture consistently from Screening to Week 56 (EOS visit) or ET visit.  
12.  Indirect ophthalmoscopy using a standard way (i.e., usually using a head-mounted light source and a 20-30 lens) will be performed on the study eye at Screening and prior to IVT injection of 
IP and 0-15 minutes after IVT injection of IP at each visit until Week 48. Indirect ophthalmoscopy will also be performed at Week 56 (EOS visit) or ET visit. 
13.  Slit lamp examination will be performed on both the study eye and fellow eye (non-study eye) at Screening and prior to IVT injection of IP at each visit until Week 48. Slit lamp examination 
will also be performed at Week 56 (EOS visit) or ET visit.  
14.  Intraocular pressure (IOP) should be measured using Goldmann applanation tonometry. The same method of IOP measurement must be used in each subject from Screening to Week 56 (EOS 
visit) or ET visit. IOP will be measured on the study eye at Screening as well as prior to each IVT injection of IP and 30-60 minutes after IVT injection of IP at each visit until Week 48. IOP 
will also be measured at Week 56 (EOS visit) or ET visit. If IOP is measured prior to OCT and FP/FA, IOP should be carefully measured not to cause corneal erosion, which might affect the 
quality of OCT/FP/FA images. 
15.  NEI VFQ-25 will be performed at Week 0 (Day1) after randomisation. Subsequently, NEI VFQ-25 should be performed before dilation of pupils at Week 32 and at Week 56 (EOS visit) or ET 
visit. 
16.  Blood and urine samples for clinical laboratory test will be collected at Screening and prior to IVT injection of IP at Week 8, Week 32, and Week 40. Blood and urine samples will also be 
collected at Week 56 (EOS visit) or ET visit. Urine samples must be collected before performing FA to avoid interference with fluorescein in urinalysis. 
• Haematology: Haemoglobin, haematocrit, platelet count, and white blood cell count (total and differential) 
• Chemistry: Sodium, potassium, creatinine, glucose, calcium, phosphorus, total bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate 
dehydrogenase 
• Urinalysis (dipstick): Protein, blood, leucocytes, nitrite, glucose, ketone, pH, specific gravity, bilirubin, and urobilinogen 
17.  Blood samples for immunogenicity assessment will be collected prior to IVT injection of IP at Week 0 (Day 1), Week 4, Week 8, Week 24, Week 32, and Week 40. Blood samples for 
immunogenicity assessment will also be collected at Week 56 (EOS visit) or ET visit. 
18.  Blood samples for PK assessment will be collected only in approximately 40 subjects participating in PK evaluation (20 subjects per treatment group in initial randomisation at Week 0 [Day 
1]). Blood samples for pre-dose PK assessment will be collected prior to IVT injection of IP at Week 0 (Day 1), Week 4, Week 8, Week 24, Week 32, and Week 40. Blood samples for post-
dose PK assessment will be collected once between 24 hours and 72 hours after IVT injection of IP at Week 0 (Day 1) and on 1 day, 2 days, and 3 days after the date of IVT injection of IP at 
Week 24 (total 3 times of PK sample collection for 3 consecutive days). Blood samples for PK assessment will also be collected at Week 56 (EOS visit). 
19.  Blood samples for PK assessment should not be collected at ET visit. 
20.  Only for women of childbearing potential, a serum pregnancy test must be performed at Screening. A pregnancy test (on serum or urine at the Investigator’s discretion) must be repeated and 
a negative result shall be obtained prior to each IVT injection of IP after randomisation. 
21.  Subjects will be administered SB15 or Eylea® 2 mg (0.05 mL) via IVT injection into the study eye every 4 weeks for the first 3 months, followed by 2 mg (0.05 mL) once every 8 weeks up 
to Week 48. Dosing visits will be allowed within ± 7 days of the scheduled dosing visit date (except Week 0 [Day 1], visit window not allowed). 
22.  The first IVT injection of IP should be performed at the same day of randomisation.  
23.  Ocular AEs in the study eye and/or fellow eye as well as non-ocular AEs will be recorded after the written informed consent is obtained from the subject until Week 56 (EOS visit) or ET visit 
(including a follow-up visit or telephone interview). 
24.  Any medications, including prescription drugs, non-prescription drugs, or any therapy received locally (in the study eye and/or fellow eye) or systemically within 180 days prior to Screening 
will be recorded until Week 56 (EOS visit) or ET visit (including a follow-up visit or telephone interview). 
25.  If the subject is not randomised within 21 days after signing the informed consent form, the subject will be screen failed. Once a subject is screen failed for one eye, he or she should not be 
re-screened for the same eye. Screening for the other eye is allowed within the screening period. 
26.  EOT visit is defined as the visit for the last scheduled IVT injection of SB15 or Eylea®. The Sponsor will not provide IP (SB15 or Eylea®) to subjects after they complete the EOT visit. 
27.  EOS visit is defined as Week 56, corresponding to 8 weeks (± 7 days) after the last scheduled IVT injection of SB15 or Eylea®. 
28.  ET visit is recommended to be performed at 8 weeks (± 7 days) after the last IVT injection of SB15 or Eylea®. When this schedule is not available (e.g., due to subject not available), the ET 
visit should still be performed as soon as available and no later than Week 56 from the first IVT injection of IP. If ET visit occurs before 7 weeks after the last IVT injection of IP, a follow-up 


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visit or telephone interview will be conducted at 8 weeks (± 7 days) after the last IVT injection of IP to collect adverse events and related concomitant medications. 
 
 


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Table 2. Blood Sampling Schedule for PK, Immunogenicity, and Clinical Laboratory Test 
Visit 
Week  
(± Visit Window) 
Sampling Time 
PK Sampling 
(Only in Subjects 
Participating PK 
Evaluation) 
Immunogenicity Sampling 
(in All Randomised 
Subjects) 
Clinical Laboratory Test 
(in All Randomised 
Subjects) 
V1 
Screening 
D-21 to D-1 
- 
- 
O* 
V2 
Week 0 
Prior to IVT injection 
O 
O 
- 
24-72 hr after IVT injection 
O 
- 
- 
V3 
Week 4 (± 7 days) 
Prior to IVT injection 
O 
O 
- 
V4 
Week 8 (± 7 days) 
Prior to IVT injection 
O 
O 
O 
V6 
Week 24 (± 7 days) 
Prior to IVT injection 
O 
O 
- 
1 day after IVT injection 
O 
- 
- 
2 days after IVT injection 
O 
- 
- 
3 days after IVT injection 
O 
- 
- 
V7 
Week 32 (± 7 days) 
Prior to IVT injection 
O 
O 
O 
V8 
Week 40 (± 7 days) 
Prior to IVT injection 
O 
O 
O 
V10 
Week 56 (EOS 
visit) 
 (± 7 days) 
Samples to be collected during the visit 
O 
O 
O 
- 
ET visit 
Samples to be collected during the visit 
- 
O 
O 
D = day; EOS = end of study; ET = early termination; hr = hour; IVT = intravitreal; PK = pharmacokinetics; V = visit 
* In all subjects who signed written informed consent 


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LIST OF ABBREVIATIONS 
 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
AEs of special interests 
AMD 
Age-related macular degeneration 
ATE 
Arterial thromboembolic event 
AUC 
Area under the plasma drug concentration-time curve 
BCVA 
Best Corrected Visual Acuity 
BM 
Bruch’s membrane 
CHO 
Chinese Hamster Ovary 
CI 
Confidence interval 
Cmax 
Maximum serum concentration 
CNV 
Choroidal neovascularisation 
CRO 
Contract Research Organisation 
CRT 
Central retinal thickness 
CSR 
Clinical study report 
CST 
Central subfield thickness 
Ctrough 
Trough serum concentration 
DA 
Disc Areas 
DME 
Diabetic macular oedema 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EOS 
End of study 
ET 
Early termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FP 
Fundus photography 


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GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
ILM 
Internal limiting membrane 
IOL 
Intraocular lens 
IOP 
Intraocular pressure 
IP 
Investigational product 
IRB 
Institutional Review Board 
IVT 
Intravitreal 
IWRS 
Interactive Web Response System 
LSMean 
Least Square mean 
MedDRA® 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralising antibody 
NEI VFQ-25 
National Eye Institute 25-Item Visual Function Questionnaire 
NOAEL 
No observed adverse effect level 
OCT 
Optical coherence tomography 
PD 
Protocol deviation 
PDT 
Photodynamic therapy 
PI 
Prescribing Information 
PlGF 
Placental growth factor 
PK 
Pharmacokinetic(s) 
PKS 
PK Analysis Set 
PPS 
Per-Protocol Set 
QOL 
Quality of life 
RAN 
Randomised Set 
RPE 
Retinal pigment epithelium 
RSI 
Reference safety information 
RVO 
Retinal vein occlusion 
SAE 
Serious AE 
SAF 
Safety set 


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SAP 
Statistical analysis plan 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard operation procedures 
TRT 
Total retinal thickness 
TTT 
Transpupillary thermotherapy 
US 
The United States of America 
VEGF 
Vascular endothelial growth factor 
WHO-DDE 
World Health Organisation-Drug Dictionary Enhanced 
YAG 
Yttrium Aluminium Garnet 
 
 
 


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TABLE OF CONTENTS 
SYNOPSIS............................................................................................................................................................. 2 
GRAPHICAL STUDY DESIGN AND SCHEDULE OF ACTIVITIES ........................................................ 10 
LIST OF ABBREVIATIONS .......................................................................................................................... 16 
TABLE OF CONTENTS ................................................................................................................................. 19 
LIST OF TABLES ............................................................................................................................................ 24 
LIST OF FIGURES .......................................................................................................................................... 24 
LIST OF STUDY STAFF ............................................................................................................................... 25 
1. INTRODUCTION .......................................................................................................................................... 26 
 Background ................................................................................................................................................ 26 
 Overview of SB15 ..................................................................................................................................... 26 
1.2.1. Non-Clinical Studies of SB15 ............................................................................................................. 27 
 Comparator Investigational Product: Eylea® ............................................................................................. 27 
1.3.1. Non-clinical Data of Reference Product ............................................................................................. 27 
1.3.2. Clinical Data of reference product in neovascular AMD .................................................................... 28 
 Study Rationale .......................................................................................................................................... 28 
 Risk and Benefit Assessment ..................................................................................................................... 29 
1.5.1. Known Potential Risks ....................................................................................................................... 29 
1.5.2. Known Potential Benefits ................................................................................................................... 29 
1.5.3. Assessment of Potential Risks and Benefits ....................................................................................... 30 
2. STUDY OBJECTIVES AND ENDPOINTS ................................................................................................. 30 
 Study Objectives ........................................................................................................................................ 30 
2.1.1. Primary Objective ............................................................................................................................... 30 
2.1.2. Secondary Objectives ......................................................................................................................... 30 
 Study Endpoint .......................................................................................................................................... 30 
2.2.1. Primary Efficacy Endpoint ................................................................................................................. 30 
2.2.2. Secondary Endpoints .......................................................................................................................... 31 
3. STUDY DESIGN ............................................................................................................................................ 32 
 Overview of Study Design ......................................................................................................................... 32 
 Rationale for Study Design ........................................................................................................................ 32 
3.2.1. Scientific Rationale for Study Design ................................................................................................. 32 
3.2.2. Rationale for Dose Selection .............................................................................................................. 33 
3.2.3. Rationale for Pharmacokinetic Assessments....................................................................................... 33 
3.2.4. Rationale for Immunogenicity Assessments ....................................................................................... 34 


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 Duration of Study Participation ................................................................................................................. 34 
 Number of Subjects ................................................................................................................................... 34 
 End of Study Definition ............................................................................................................................. 34 
4. STUDY POPULATION.................................................................................................................................. 34 
 Overview ................................................................................................................................................... 34 
 Inclusion Criteria ....................................................................................................................................... 34 
 Exclusion Criteria ...................................................................................................................................... 35 
 Screen Failures and Re-screening .............................................................................................................. 37 
 Replacement .............................................................................................................................................. 38 
5. TREATMENT AND INVESTIGATIONAL PRODUCT ............................................................................ 38 
 Treatment of the Subjects .......................................................................................................................... 38 
5.1.1. Dosing and Treatment Schedule ......................................................................................................... 38 
5.1.2. Assignment of Subjects to Treatment Group ...................................................................................... 38 
5.1.3. Withholding Investigational Products ................................................................................................. 38 
5.1.4. Masking .............................................................................................................................................. 39 
5.1.5. Unmasking .......................................................................................................................................... 39 
 Investigational Product .............................................................................................................................. 39 
5.2.1. Identity of Investigational Product...................................................................................................... 39 
5.2.2. Preparation and administration of Investigational Product ................................................................. 40 
5.2.3. Formulation, Packaging, and Labelling .............................................................................................. 40 
5.2.4. Product Storage and Stability ............................................................................................................. 40 
5.2.5. Treatment Compliance and Investigational Product Accountability ................................................... 41 
 Prohibited Medication or Therapy ............................................................................................................. 41 
 Fellow Eye Treatment ................................................................................................................................ 43 
6. STUDY ASSESSMENT .................................................................................................................................. 43 
 Efficacy Assessment .................................................................................................................................. 43 
6.1.1. Best Corrected Visual Acuity (BCVA) ................................................................................................ 43 
6.1.2. Anatomical Parameters ....................................................................................................................... 44 
 Safety Assessment ..................................................................................................................................... 44 
6.2.1. Adverse Events ................................................................................................................................... 44 
6.2.2. Clinical Laboratory Evaluations ......................................................................................................... 44 
6.2.3. Physical Examination ......................................................................................................................... 45 
6.2.4. Vital Signs ........................................................................................................................................... 45 


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 Pregnancy Test ........................................................................................................................................... 46 
 Ophthalmic Assessments ........................................................................................................................... 46 
6.4.1. Full Ophthalmic Examinations ........................................................................................................... 46 
6.4.2. Optical Coherence Tomography (OCT) .............................................................................................. 47 
6.4.3. Fundus Photography (FP) and Fluorescein Angiography (FA) ........................................................... 48 
 NEI VFQ-25 .............................................................................................................................................. 48 
 Other Assessments ..................................................................................................................................... 48 
6.6.1. Pharmacokinetic (PK) Assessment ..................................................................................................... 48 
6.6.2. Immunogenicity Assessment .............................................................................................................. 49 
7. STUDY PROCEDURES ................................................................................................................................ 49 
 Study Flow and Visit Schedule .................................................................................................................. 49 
7.1.1. Screening Visit (Visit 1, D-21 to D-1) ................................................................................................ 49 
7.1.2. Treatment Period ................................................................................................................................. 51 
7.1.3. End of Study (EOS) Visit (Visit 10, Week 56 ± 7 days) ................................................................... 58 
7.1.4. Early Termination (ET) Visit .............................................................................................................. 59 
7.1.5. Unscheduled visit................................................................................................................................ 60 
 Discontinuation .......................................................................................................................................... 60 
7.2.1. Subject Discontinuation from Study Treatment .................................................................................. 60 
7.2.2. Discontinuation of Study Sites ........................................................................................................... 61 
7.2.3. Discontinuation of the Study .............................................................................................................. 62 
8. SAFETY MONITORING AND REPORTING ............................................................................................ 62 
 Adverse Events (AEs) ................................................................................................................................ 62 
8.1.1. Definition of Adverse Event ............................................................................................................... 62 
8.1.2. Clinically Significant Abnormality ..................................................................................................... 63 
8.1.3. Period of Observation for Adverse Events .......................................................................................... 63 
8.1.4. Reporting Adverse Events .................................................................................................................. 63 
8.1.5. Severity Assessment ........................................................................................................................... 64 
8.1.6. Causality Assessment .......................................................................................................................... 64 
8.1.7. Emergency Unmasking for Safety Reasons and Accidental Unmasking ............................................ 64 
8.1.8. Expectedness Assessment ................................................................................................................... 65 
8.1.9. Withdrawal due to Adverse Events ..................................................................................................... 65 
 Serious Adverse Events ............................................................................................................................. 65 
8.2.1. Definition of Serious Adverse Event .................................................................................................. 65 


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8.2.2. Reporting Serious Adverse Events...................................................................................................... 67 
 Adverse Events of Special Interest (AESI) ................................................................................................ 67 
 Reporting Visual Acuity-related Adverse Event ........................................................................................ 68 
 Pregnancy .................................................................................................................................................. 68 
 Independent Data and Safety Monitoring Board ....................................................................................... 68 
9. STATISTICAL METHODS AND DATA ANALYSIS .................................................................................. 68 
 Statistical Hypotheses ................................................................................................................................ 69 
 Analysis Sets .............................................................................................................................................. 69 
 Subject Demographic and Baseline Characteristics ................................................................................... 70 
 Analysis of the Primary Objective ............................................................................................................. 70 
 Analysis of the Secondary Objectives ........................................................................................................ 70 
9.5.1. Efficacy Variable Analyses ................................................................................................................. 70 
9.5.2. Safety Analyses ................................................................................................................................... 71 
9.5.3. Pharmacokinetic Analyses .................................................................................................................. 71 
9.5.4. Immunogenicity Analyses................................................................................................................... 71 
 Exploratory analyses .................................................................................................................................. 71 
 Sample Size Calculations .......................................................................................................................... 71 
10. DATA COLLECTION AND MANAGEMENT ......................................................................................... 72 
 Data Confidentiality ................................................................................................................................. 72 
 Monitoring ............................................................................................................................................... 73 
 Data Handling and Record Keeping ........................................................................................................ 73 
 Future Use of Stored Specimens and Data............................................................................................... 73 
 Database Management and Coding ......................................................................................................... 73 
 Quality Control and Quality Assurance ................................................................................................... 74 
 Protocol Deviation (PD) .......................................................................................................................... 74 
11. ETHICS CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES .......................................... 75 
 Institutional Review Boards (IRB) and Independent Ethics Committees (IEC) ...................................... 75 
 Ethical Conduct of the Study ................................................................................................................... 75 
 Written Informed Consent ........................................................................................................................ 75 
 Investigator Information .......................................................................................................................... 76 
11.4.1. Investigator Obligations .................................................................................................................... 76 
11.4.2. Training of Investigator Site Personnel ............................................................................................. 76 
11.4.3. Protocol Signatures ........................................................................................................................... 76 


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11.4.4. Financing and Insurance ................................................................................................................... 76 
12. PUBLICATION POLICY ............................................................................................................................ 76 
13. REFERENCES ............................................................................................................................................. 78 
APPENDIX A: GRADING SCALE FOR ANTERIOR CHAMBER FLARE ....................................... 79 
APPENDIX B: GRADING SCALE FOR ANTERIOR CHAMBER CELLS ........................................ 80 
APPENDIX C: GRADING SCALE FOR VITREOUS HAZE ................................................................. 81 
APPENDIX D: NATIONAL EYE INSTITUTE 25-ITEM VISUAL FUNCTION QUESTIONNAIRE 
(NEI VFQ-25 QUESTIONNAIRE) ................................................................................................................. 82 
 
 


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LIST OF TABLES 
Table 1. Schedule of Activities ............................................................................................................................. 11 
Table 2. Blood Sampling Schedule for PK, Immunogenicity, and Clinical Laboratory Test ................................ 15 
Table 3. Investigational Products .......................................................................................................................... 40 
Table 4. Prohibited Medication and Therapy ........................................................................................................ 41 
Table 5. Parameters for Clinical Laboratory Tests ................................................................................................ 45 
 
LIST OF FIGURES 
Figure 1. Graphical Study Design......................................................................................................................... 10 
 
 
 


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LIST OF STUDY STAFF 
 
SPONSOR: 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
Tel: +82 (32) 455 6114 
 
Clinical Project Manager  
Clinical Research Physician  
Clinical 
Development
Assistant 
Statistician  
Safety Physician 
Project Safety Lead 
 
 
PPD


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1. Introduction 
 Background 
Age-related macular degeneration (AMD) is a disease that affects the macular region of the retina, 
causing progressive loss of central vision. AMD is the major cause of severe visual loss in older adults 
if left untreated. Choroidal neovascularisation (CNV) due to neovascular AMD is responsible for most 
AMD-related severe vision loss. Visual impairment leads to reduced quality of life (QOL), poorer 
general health, and increased mortality. In the developed world, AMD is known as the most frequent 
cause of uncorrectable severe vision loss in people older than 55 years of age. As many as 30% of adults 
aged 75 years or older develop signs of senile retinal degeneration, and the prevalence of AMD is 
increasing in an aging population. 
Pathogenesis of AMD includes drusen genesis, lipofuscin genesis, local inflammatory state genesis, as 
well as angiogenesis. Angiogenesis is the development of new blood vessels from pre-existing vessels 
and whilst being a crucial process in normal physiology, it is an important pathogenic process in both 
benign and malignant disease. Vascular endothelial growth factor (VEGF) is one of the activators of 
angiogenesis and abnormal angiogenesis is a hallmark of neovascular AMD. CNV represents the growth 
of new blood vessels from the choroid into the subretinal pigment epithelium. Several proangiogenic 
factors are consistently upregulated during CNV formation, particularly two members of the VEGF 
family, VEGF-A and placental growth factor (PlGF). These factors activate quiescent endothelial cells 
and promote cell proliferation, migration, and vascular permeability. Retinal pigment epithelium (RPE) 
produces VEGF-A via two major pathways; complement activation and oxidative stress. 
Overproduction of VEGF-A leads to the breakdown of the blood-retinal barrier and formation of new 
blood vessels into the retina. Leakage of blood from these abnormal vessels results in oedema and loss 
of vision if left untreated [1]. 
Early treatments for CNV including laser ablation or photodynamic therapy (PDT) with verteporfin 
decreased severe vision loss rather than truly stabilizing vision or resulting in clinically significant 
improvements in visual acuity. Currently, the most common and effective clinical treatment for 
neovascular AMD is anti-VEGF therapy. Effective treatment for neovascular AMD is based on 
inhibition of the angiogenic protein VEGF. The first anti-VEGF drug to be used in trials for neovascular 
AMD was pegaptanib sodium which is an aptamer that selectively binds to and neutralizes VEGF-A165, 
but not VEGF-A121. Ranibizumab is a monoclonal humanized antibody fragment that binds all VEGF-
A isoforms. In the two pivotal studies, ranibizumab showed gains in vision of patients affected by 
neovascular AMD that led to widespread use of ranibizumab for treatment of neovascular AMD. 
Another drug that showed efficacy initially when used systemically and then intravitreally was 
bevacizumab which is a whole monoclonal antibody and binds all isoforms of VEGF-A. Although 
bevacizumab is not approved for this specific indication, it was used as an off-label treatment for 
neovascular AMD. Aflibercept is a recombinant protein that includes binding domains of VEGF 
receptors 1 and 2 and it blocks all VEGF-A isoforms and VEGF-B, and blocks PlGF. The VIEW 1 and 
2 trials demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen 
after loading dose offering the potential to reduce the risk from monthly intravitreal (IVT) injections 
and the burden of monthly monitoring. Aflibercept is the most recent major new molecule to be used 
clinically worldwide [1]. 
 Overview of SB15 
SB15 has been developed as a similar biological medicinal product to Eylea® having aflibercept as the 
active substance. Eylea® is currently indicated for the treatment of patients with neovascular AMD, 
macular oedema secondary to retinal vein occlusion (RVO; branch RVO or central RVO), and diabetic 


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macular oedema (DME) by both European Medicines Agency (EMA) and the United States of America 
(US) Food and Drug Administration (FDA). In addition, EMA approved Eylea® for the treatment of 
myopic CNV and the US FDA approved Eylea® for the treatment of diabetic retinopathy [2; 3].  
SB15 is produced by recombinant deoxyribonucleic acid (DNA) technology in a Chinese Hamster 
Ovary (CHO) mammalian cell expression system and purified by various affinity and ion exchange 
chromatography steps that include specific viral inactivation and removal procedures. 
According to the guideline International Conference on Harmonisation Q6B, characterisation of a 
biological therapeutic must involve its physicochemical properties, biological activities, purity, 
impurities, and quantity. The characterisation study will employ the ‘state-of-the-art’ analytical methods 
in order to investigate the primary, secondary, higher-order structures, and the post-translational 
modifications associated the structural heterogeneity, the charge variants, the purity, and the biological 
activities. 
1.2.1. Non-Clinical Studies of SB15 
As outlined in the “Guideline on similar biological medicinal products containing biotechnology-
derived proteins as active substance: non-clinical and clinical issues” [4], a risk-based approach was 
taken to the non-clinical evaluation of SB15. A series of in vitro biologic activity studies is to be 
performed in order to demonstrate non-clinical similarity between SB15 and Eylea®. In line with the 
guideline, if similarity is to be demonstrated in quality and in vitro comparisons to provide non-clinical 
evidence of similarity between SB15 and Eylea®, in vivo studies will not be performed. Moreover, in 
vitro studies are considered to be the more sensitive measurement than with in vivo studies. Also, non-
clinical safety pharmacology, reproductive and developmental toxicity, and carcinogenicity studies 
were not performed, as they are not required for non-clinical testing of biosimilars as outlined in the 
guideline [4]. 
 Comparator Investigational Product: Eylea® 
1.3.1. Non-clinical Data of Reference Product 
Effects in non-clinical studies on repeated dose toxicity were observed only at systemic exposures 
considered substantially in excess of the maximum human exposure after IVT administration at the 
intended clinical dose indicating little relevance to clinical use. Erosions and ulcerations of the 
respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were 
observed at systemic exposures in excess of the maximum human exposure. The systemic exposure 
based on maximum serum concentration (Cmax) and area under the plasma drug concentration-time 
curve (AUC) for free aflibercept were approximately 200- and 700-fold higher, respectively, when 
compared to corresponding values observed in humans after an IVT dose of 2 mg. At the No observed 
adverse effect level (NOAEL) of 0.5 mg/eye in monkeys the systemic exposure was 42- and 56-fold 
higher based on Cmax and AUC, respectively. No studies have been conducted on the mutagenic or 
carcinogenic potential of aflibercept. An effect of aflibercept on intrauterine development was shown 
in embryo-foetal development studies in pregnant rabbits with intravenous (3 to 60 mg/kg) as well as 
subcutaneous (0.1 to 1 mg/kg) administration. The maternal NOAEL was at the dose of 3 mg/kg or 1 
mg/kg, respectively. A developmental NOAEL was not identified. At the 0.1 mg/kg dose, the systemic 
exposures based on Cmax and cumulative AUC for free aflibercept were approximately 17- and 10-fold 
higher, respectively, when compared to corresponding values observed in humans after an IVT dose of 
2 mg. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with 
intravenous administration of aflibercept at doses ranging from 3 to 30 mg/kg. Absent or irregular 
menses associated with alterations in female reproductive hormone levels and changes in sperm 


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morphology and motility were observed at all dose levels. Based on Cmax and AUC for free aflibercept 
observed at the 3 mg/kg intravenous dose, the systemic exposures were approximately 4,900-fold and 
1,500-fold higher, respectively, than the exposure observed in humans after an IVT dose of 2 mg. All 
changes were reversible [2; 3]. 
1.3.2. Clinical Data of reference product in neovascular AMD 
In patients treated with Eylea® (one injection per month for three consecutive months, followed by one 
injection every 2 months), central retinal thickness (CRT) decreased soon after treatment initiation, and 
the mean CNV lesion size was reduced, consistent with the results seen with ranibizumab 0.5 mg every 
month. 
In the VIEW1 study there were mean decreases in CRT on optical coherence tomography (OCT) (–130 
and –129 microns at week 52 for the Eylea® 2 mg every two months and ranibizumab 0.5 mg every 
month study groups, respectively). Also, at the 52-week time point, in the VIEW2 study there were 
mean decreases in CRT on OCT (–149 and –139 microns for the Eylea® 2 mg every two months and 
ranibizumab 0.5 mg every month study groups, respectively). The reduction of CNV size and reduction 
in CRT were generally maintained in the second year of the studies. 
The ALTAIR study was conducted in Japanese patients with treatment naïve neovascular AMD, 
showing similar outcomes to the VIEW studies using 3 initial monthly Eylea® 2 mg injections, followed 
by one injection after a further 2 months, and then continued with a treat-and-extend regimen with 
variable treatment intervals (2- or 4-week adjustments) up to a maximum 16-week interval according 
to pre-specified criteria. At Week 52, there were mean decreases in CRT on OCT of –134.4 and –126.1 
microns for the 2-week adjustment group and the 4-week adjustment group, respectively. The 
proportion of patients without fluid on OCT at Week 52 was 68.3% and 69.1% in the 2- and 4-week 
adjustment groups, respectively. 
In a pharmacokinetic (PK) sub-study in 6 neovascular AMD patients with frequent sampling, maximum 
plasma concentrations of free aflibercept (systemic Cmax) were low, with a mean of approximately 0.02 
μg/ml (range 0 to 0.054) within 1 to 3 days after a 2 mg intravitreal injection, and were undetectable 2 
weeks following dosage in almost all patients. Aflibercept does not accumulate in the plasma when 
administered intravitreally every 4 weeks [2]. 
The safety and efficacy of Eylea® were assessed in two randomised, multi-centre, double-masked, 
active-controlled studies in patients with neovascular AMD (VIEW1 and VIEW2) with a total of 2,412 
patients treated and evaluable for efficacy (1,817 with Eylea®). Patient ages ranged from 49 to 99 years 
with a mean of 76 years. In these clinical studies, approximately 89% (1,616/1,817) of the patients 
randomised to treatment with Eylea® were 65 years of age or older, and approximately 63% 
(1,139/1,817) were 75 years of age or older [2; 3]. 
 Study Rationale 
A biosimilar is a biological medicinal product that is highly similar to an already authorised original 
biological medicinal product (reference medicinal product) in terms of quality, tolerability, and efficacy 
based on a comprehensive comparability exercise [4; 5]. The EMA and the US FDA have developed 
specific guidelines for a biologic drug to be approved as a biosimilar [5; 6]. These guidelines 
recommend a stepwise approach in developing a biosimilar starting with extensive physicochemical 
and biological characterisation before initiating clinical studies for the comparison of the efficacy, 
tolerability, PK properties, and immunogenicity of the biosimilar. The purpose of this study is to 
demonstrate the equivalence in efficacy of SB15 compared to Eylea® and to evaluate the safety and 
immunogenicity in subjects with neovascular AMD. In addition, systemic exposure of SB15 to Eylea® 


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will also be evaluated in subjects participating in PK evaluation. 
 Risk and Benefit Assessment 
1.5.1. Known Potential Risks 
According to Eylea® Prescribing Information (PI) and Summary of Product Characteristics (SmPC), 
there are IVT injection related risks such as endophthalmitis, intraocular inflammation, retinal break, 
retinal detachment, iatrogenic traumatic cataract. There is a risk of intraocular pressure (IOP) elevation 
within 60 minutes of IVT injection. Sustained increased of IOP was also reported. As this is a therapeutic 
protein, there is a potential for immunogenicity with investigational products (IPs; SB15 or Eylea®). 
There is a potential risk of non-ocular haemorrhage and arterial thromboembolic events (ATEs) 
following IVT use of VEGF inhibitors, including Eylea®. There is a risk of retinal pigment epithelial 
tear after anti-VEGF therapy for neovascular AMD [2; 3]. 
In order to ensure the safety of subjects who participate in the study, the followings will be performed 
during the study. Proper aseptic injection techniques must always be used when administering Eylea®. 
The patient should be instructed to report their symptoms related to these adverse events (AEs) without 
delay and should be managed appropriately. Special precaution is needed in patients with poorly 
controlled glaucoma and Eylea® should not be injected while the IOP is ≥ 30 mmHg. In all cases, both 
the IOP and the perfusion of the optic nerve head must therefore be monitored and managed 
appropriately. Patients should be instructed to report any signs or symptoms of intraocular inflammation, 
e.g., pain, photophobia, or redness, which may be a clinical sign attributable to hypersensitivity. There 
are limited data on safety in the treatment of patients with central RVO, branch RVO, DME, or myopic 
CNV with a history of stroke or transient ischaemic attacks or myocardial infarction within the last 6 
months and caution should be exercised when treating such patients. Caution also should be used in 
patients with a large and/or high pigment epithelial retinal detachment. 
This study will take place at multicentre with accessible medical facilities which will allow immediate 
treatment of medical emergencies. All study related procedures will be conducted by medical staffs with 
appropriate level of training and expertise and an understanding of the IPs, its target, and mechanism 
of action. Subjects will have a safety follow-up at the end of study (EOS) visit, 8 weeks after the last 
IVT injection of IP. An independent Data and Safety Monitoring Board (DSMB) will convene at pre-
specified intervals to conduct interim monitoring of accumulating safety data. Following each data 
review, the DSMB will make recommendations regarding the conduct of the study, including 
continuation of the study without modifications, modification of the protocol, pausing of subject 
enrolment until the resolution of an issue, or termination of the study for safety reasons. 
1.5.2. Known Potential Benefits 
Neovascular AMD is characterized by growth of abnormal vessel from choroid and retina and vascular 
leakage from abnormal vessels, leading to eventual damage to tissue in macula. VEGF-A is in excess 
in the eye of subjects with neovascular AMD and thought to contribute to pathophysiology of 
neovascular AMD. VEGF acts via two receptor tyrosine kinases; VEGFR-1 and VEGFR-2, present on 
the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of 
leucocytes. Excessive activation of these receptors by VEGF-A can result in pathological 
neovascularisation and excessive vascular permeability. Eylea® acts as a soluble decoy receptor that 
binds VEGF-A and PlGF with higher affinity than their natural receptors, and thereby can inhibit the 
binding and activation of these cognate VEGF receptors. 
Eylea® reduce abnormal growth of new vessels and vascular leakage in retinal diseases. In pooled 
analysis of two VIEW studies in neovascular AMD, subject treated with 2 mg every 8 weeks after 3 


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monthly loading doses showed Best Corrected Visual Acuity (BCVA) improvement of 8.4 letters and 
7.6 letters at Week 52 and Week 96, respectively. The proportion of patients maintaining visual acuity 
was 95.3% and 92.4%, and the proportion of patients who gained 15 letters or more was 30.9% and 
33.4% at Week 52 and Week 96, respectively. Visual gain was accompanied by decreases in CRTby –
139 microns and –133 microns at Week 52 and Week 96, respectively [7; 8]. 
Although clinical data is currently unavailable, SB15 is expected to have similar clinical outcome to 
Eylea® based on the physicochemical and biological similarity. 
1.5.3. Assessment of Potential Risks and Benefits 
If left untreated, neovascular AMD progress overtime resulting in permanent visual loss. Treatment with 
anti-VEGF agents prevent disease progression and allow maintenance and improvement of vision. 
Although there have been alternative treatments such as PDT with verteprofin, macular 
photocoagulation, and transpupillary thermotherapy (TTT), these treatments failed to improve visual 
acuity and function as shown in anti-VEGF treatments. Benefit of Eylea® treatment including 
preservation of reading and driving vision, and ability to recognize face outweigh the potential risks of 
endophthalmitis, intraocular inflammation, retinal tear, retinal detachment, iatrogenic traumatic cataract, 
development of immunogenicity, and ATEs. 
The available data demonstrate a high degree of physicochemical and biological similarity of SB15 
with the reference medicinal product (Eylea®). The suitability of the methodology employed to evaluate 
the similarity of SB15 and Eylea® in a pharmaceutical setting were confirmed by EMA and the US FDA. 
The known and potential risks of receiving SB15 are expected to be similar to those seen with Eylea®. 
In conclusion, sufficient evidence exists for the justification of the administration of SB15, as a similar 
biological medicinal product of Eylea®, to subjects with neovascular AMD. 
The study protocol provides adequate instructions for the detection and treatment of AEs arising 
following the administration of the IP. 
2. Study Objectives and Endpoints 
 Study Objectives 
2.1.1. Primary Objective 
The primary objective of this study is to demonstrate the equivalence in efficacy of SB15 compared to 
Eylea® in subjects with neovascular AMD. 
2.1.2. Secondary Objectives 
The secondary objectives are: 
• 
To evaluate the safety of SB15 compared to Eylea® 
• 
To evaluate the systemic exposure of SB15 compared to Eylea® in subjects participating in PK 
evaluation 
• 
To evaluate the immunogenicity of SB15 compared to Eylea® 
 Study Endpoint 
2.2.1. Primary Efficacy Endpoint 
• 
Change from baseline in BCVA at Week 8 


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2.2.2. Secondary Endpoints 
Secondary efficacy endpoints 
• 
Change from baseline in BCVA over time up to Week 32 and up to Week 56 
• 
Proportion of subjects who lost fewer than 15 letters in BCVA compared to baseline at Week 
32 and Week 56 (proportion of subjects who maintained BCVA) 
• 
Proportion of subjects who gained 15 letters or more in BCVA compared to baseline at Week 
32 and Week 56 
• 
Change from baseline in central subfield thickness (CST) and total retinal thickness (TRT) at 
Week 4, and over time up to Week 32 and up to Week 56 (based on assessment by the central 
reading centre) 
- 
CST measured from internal limiting membrane (ILM) to RPE in 1-mm central 
subfield 
- 
TRT measured from ILM to Bruch’s membrane (BM) in 1-mm central subfield 
• 
Proportion of subjects with intra- or sub-retinal fluid on OCT at Week 32 and Week 56 (based 
on assessment by the central reading centre) 
• 
Change from baseline in CNV area at Week 32 and Week 56 (based on assessment by the 
central reading centre) 
• 
Proportion of subjects with active CNV leakage at Week 32 and Week 56 (based on assessment 
by the central reading centre) 
Safety endpoints 
• 
Incidence of ocular AEs or serious ocular AEs 
• 
Incidence of non-ocular AEs and serious non-ocular AEs 
• 
Incidence of intraocular inflammation and IOP increase 
• 
Changes in vital signs and clinical laboratory parameters 
PK endpoints 
Blood samples for PK assessment will be collected in approximately 40 subjects participating in PK 
evaluation (20 subjects per treatment group in initial randomisation at Week 0 [Day 1]). 
• 
Pre-dose (trough serum concentration [Ctrough]) 
- 
Systemic exposure measured pre-dose at Week 0 (Day 1), Week 4, Week 8, Week 24, 
Week 32, and Week 40 
• 
Post-dose (close to Cmax) 
- 
Systemic exposure measured once between 24 hours and 72 hours after IVT injection 
of IP at Week 0 (Day 1) 


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- 
Systemic exposure measured on 1 day, 2 days, and 3 days after the date of IVT 
injection of IP at Week 24 (total 3 times of PK sample collection for 3 consecutive 
days) 
• 
Systemic exposure measured during the visit at Week 56 (EOS visit) 
Immunogenicity endpoints 
Blood samples for immunogenicity assessment will be collected pre-dose at Week 0 (Day 1), Week 4, 
Week 8, Week 24, Week 32, and Week 40. Immunogenicity sampling will also be collected during the 
visit at Week 56 (EOS visit) or early termination (ET) visit. 
• 
Incidence of anti-drug antibodies (ADAs) to aflibercept 
• 
Incidence of neutralising antibodies (NAbs) to aflibercept 
Exploratory endpoint 
• 
Proportion of subjects with sub-RPE fluid on OCT at Week 32 and Week 56 (based on 
assessment by the central reading centre) 
The QOL is assessed using National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-
25). 
• 
Change from baseline in subscale scores and composite scores of NEI VFQ-25 at Week 32 and 
Week 56 
3. Study Design 
 Overview of Study Design 
This is a randomised, double-masked, parallel group, multicentre study to evaluate the efficacy, safety, 
PK, and immunogenicity of SB15 compared to Eylea® in subjects with neovascular AMD. Subjects will 
be randomised in a 1:1 ratio to receive either SB15 or Eylea® (administered via IVT injection 2 mg 
[0.05 mL] every 4 weeks for the first 3 months, followed by 2 mg [0.05 mL] once every 8 weeks). 
At Week 32, subjects in Eylea® treatment group will be randomised again in a 1:1 ratio to either continue 
on Eylea® treatment or be transitioned to SB15 treatment. IPs (SB15 or Eylea®) will be administered 
up to Week 48. Subjects receiving SB15 will continue to receive SB15 up to Week 48 but they will also 
follow the randomisation procedure to maintain masking. 
The screening period is 21 days. IP (SB15 or Eylea®) will be given until 48 weeks and the last 
assessment will be done at Week 56, corresponding to the end of follow-up for all subjects. 
 Rationale for Study Design 
3.2.1. Scientific Rationale for Study Design 
The purpose of this study is to demonstrate the equivalence in clinical efficacy of Eylea® and SB15 in 
subjects with neovascular AMD. 
Neovascular AMD is an indication approved by both EMA and the US FDA. In addition, neovascular 
AMD typically demonstrates homogeneous disease progressions with fewer compounding factors than 
DME or RVO. Though DME is one of the major causes of visual impairment in patients with diabetic 
retinopathy and thus a successful management of glycemia reduces the risk of developing progression 


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of DME, the disease progression of DME is influenced by numerous factors such as glycemia, 
hypertension, and lipid level [9]. RVO, involving a central retinal vein or a branch retinal vein, results 
in various vision loss of visual acuity (moderate to severe) [10]. For example, nonischaemic central 
RVO may resolve fully with good visual outcomes or may progress to the ischaemic type, while 
ischaemic central RVO usually presents with a severe visual loss [11]. 
Left untreated, neovascular AMD shows a common disease progression. For instance, it results in severe 
visual impairment with an average loss of around 4 lines of visual acuity within 2 years of disease onset 
[12]. Although this neovascular form accounts for only approximately 10% to 20% of the AMD cases, 
it is responsible for 80% to 90% of AMD-associated vision loss [13]. Therefore, neovascular AMD 
subjects with potential serious clinical outcome without an appropriate treatment are the most 
appropriate population to evaluate the similarity between SB15 and Eylea®. 
In the pivotal studies for the treatment of neovascular AMD with Eylea®, the primary efficacy endpoints 
were the proportion of the subjects losing < 15 letters from baseline in visual acuity. The treatment of 
ranibizumab or aflibercept prevents the loss of visual acuity in approximately 90% of patients and 
improves visual acuity over time in terms of gaining letters. 
The proportion of subjects losing < 15 letters in the visual acuity indicates the preventive effect of the 
loss of visual acuity. Thus, the proportion of subjects losing < 15 letters in the visual acuity would not 
be a sensitive primary endpoint to detect product-specific effect between the proposed biosimilar 
product and the reference product. 
On the other hand, change from baseline in visual acuity could reflect any change (improvement or 
deterioration) in the disease status and is more sensitive in detecting product-specific effects between 
the two treatments. Thus, the mean change from baseline in BCVA is an appropriate primary endpoint 
for the proposed study. 
Visual acuity was assessed monthly in neovascular AMD patients during the study period in pivotal 
studies with Eylea®. The efficacy plateau was reached approximately at Week 12 or Week 16. The most 
sensitive timing to detect any potential differences between the proposed biosimilar product and the 
reference product could be the visit before the efficacy plateau is reached. 
Thus, to increase sensitivity, the evaluation of equivalence between SB15 and Eylea® is to be conducted 
at Week 8 before the efficacy plateau is reached. 
Transition will be performed at Week 32 to investigate the clinical impact of switching from Eylea® to 
SB15. 
3.2.2. Rationale for Dose Selection 
The selection of the aflibercept dose and dosing interval is based on safety and efficacy data obtained 
from 2 pivotal clinical trials (VIEW 1 and VIEW 2) in neovascular AMD. Aflibercept administration in 
this study is 2 mg (0.05 mL or 50 microliters) administered by IVT injection every 4 weeks 
(approximately every 28 days, monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) 
via IVT injection once every 8 weeks (2 months). 
3.2.3. Rationale for Pharmacokinetic Assessments 
Although a Phase I comparative PK study comparing the proposed biosimilar product to reference 
product is a fundamental component in supporting a demonstration of biosimilarity, a Phase I 
comparative PK study has not been necessary to support a demonstration of biosimilarity due to 
negligible systemic exposure following IVT injection of aflibercept. However, for supporting the 


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assessment of overall systemic safety of SB15 relative to Eylea®, systemic exposures will be collected 
and compared in the subgroup population (approximately 40 subjects, 20 subjects per treatment group 
in initial randomisation at Week 0 [Day 1]) in Phase III comparative efficacy study. 
3.2.4. Rationale for Immunogenicity Assessments 
Biological/biotechnology-derived proteins can induce an unwanted immune response that is triggered 
by more than a single factor and the consequence of immunogenicity may vary considerably, ranging 
from irrelevant to therapy to serious and life-threatening. Immune responses may affect both safety and 
effectiveness such as altering PK, inducing anaphylaxis, or promoting development of NAbs that 
neutralise the product as well as its endogenous protein counterpart. 
In pivotal clinical studies of Eylea®, the frequency of ADAs has been reported as 1% to 4%. Observed 
levels of immunogenicity were relatively low and there were no differences in efficacy or safety 
between patients with or without immunoreactivity. 
For subject safety and for demonstrating biosimilarity, immunogenicity will be assessed in this study 
according to the recommended guideline. 
 Duration of Study Participation 
After Screening, the duration of study participation will be 56 weeks per subject including 48-week 
treatment period and 8-week post-treatment follow-up period. 
 Number of Subjects 
Approximately 446 subjects are planned to be randomised from approximately 60 sites for study 
duration. 
 End of Study Definition 
A subject is considered to have completed the study if he or she has completed the last visit or the last 
scheduled procedure shown in Table 1. The EOS is defined as completion of the last scheduled visit 
(Week 56) shown in Table 1. The end of this clinical study is defined as completion of the last subject’s 
EOS visit. 
4. Study Population 
 Overview 
Eligibility for participation in this study will be based on the inclusion/exclusion criteria. Only one eye 
will be designated as the study eye. For subjects who meet eligibility criteria in both eyes, the eye with 
the worse visual acuity will be selected as the study eye. If both eyes have equal visual acuity, the eye 
with clearer lens and ocular media will be selected at the Investigator’s discretion. If there is no 
objective basis for selecting the study eye, factor such as ocular dominance, other ocular pathology, and 
subject preference should be considered by the Investigator in making the selection. Subject with only 
one functional eye (defined as BCVA of counting finger or less on the eye with worse vision) cannot be 
enrolled, even if otherwise eligible for the study. 
 Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Age ≥ 50 years at Screening 


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2. Treatment naïve, *active subfoveal CNV lesion secondary to AMD in the study eye 
 
* Active CNV indicates presence of leakage and intra- or sub-retinal fluid which should be 
confirmed by the central reading centre during Screening. 
3. The area of CNV must occupy at least 50% of total lesion in the study eye (confirmed by the 
central reading centre during Screening) 
4. Total lesion area ≤ 9.0 Disc Areas (DA) in size (including blood, scars, and neovascularisation) 
in the study eye (confirmed by the central reading centre during Screening) 
5. BCVA of 20/40 to 20/200 (letter score of 73 to 34, inclusive) using original series Early 
Treatment Diabetic Retinopathy Study (ETDRS) charts or 2702 series Number charts in the 
study eye at Screening and at Week 0 (Day 1) prior to randomisation 
6. Non-childbearing potential female (e.g., permanently sterilized, postmenopausal [defined as 
12 months with no menses without an alternative medical cause prior to Screening]), OR 
childbearing potential female subjects or male subjects with their (respectively male or female) 
partners who agree to use at least two forms of appropriate contraception method that can 
achieve a failure rate of less than 1% per year (e.g., established use of oral, injected, 
intravaginal, transdermal, or implanted hormonal contraceptive, placement of an intrauterine 
device or intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised 
partner, physical barrier, sexual abstinence) from Screening until 3 months after the last IVT 
injection of IP 
7. Written informed consent form (ICF) must be obtained from the subject prior to any study 
related procedure (if the subject is legal blindness or illiterate, an impartial witness should be 
present during the entire informed consent discussion) 
8. Willingness and ability to undertake all scheduled visits and assessments 
 Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for the study: 
1. Study eye: Sub- or intra-retinal haemorrhage that comprises more than 50% of the entire lesion 
or presence of blood with the size of 1 DA or more involving the centre of fovea (confirmed 
by the central reading centre during Screening) 
2. Study eye: Scar, fibrosis, or atrophy involving the centre of the fovea (confirmed by the central 
reading centre during Screening) 
3. Study eye: Presence of CNV due to other causes, such as ocular histoplasmosis, trauma, 
multifocal choroiditis, angioid streaks, history of choroidal rupture, or pathologic myopia 
(confirmed by the central reading centre during Screening) 
4. Study eye: Presence of retinal pigment epithelial tears or rips involving the macula (confirmed 
by the central reading centre during Screening) 
5. Study eye: Presence of macular hole at any stage (confirmed by the central reading centre 
during Screening) 
6. Study eye: Any concurrent macular abnormality other than AMD which could affect central 
vision or the efficacy of IP including but not limited to epiretinal membrane, vitreomacular 


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traction, macular telangiectasia, retinal vascular abnormality, etc. (confirmed by the central 
reading centre during Screening) 
7. Study eye: Any concurrent ocular condition which, in the opinion of the Investigator, could 
either confound the interpretation of efficacy and safety of IP (e.g., ocular media opacities such 
as significant cataract, optic neuropathy etc.) or require medical or surgical intervention during 
the study period 
8. Either eye: History or clinical evidence of diabetic retinopathy (except for mild non-
proliferative diabetic retinopathy) or DME 
9. Study eye: Current vitreous haemorrhage 
10. Either eye: Any previous IVT anti-VEGF treatment (e.g., bevacizumab, ranibizumab, 
aflibercept, pegaptanib, etc.) 
11. Any previous systemic anti-VEGF treatment 
12. Study eye: History of treatment involving macula such as macular laser photocoagulation, PDT, 
TTT, radiation therapy, or any ocular treatment for neovascular AMD 
13. Any systemic treatment or therapy (including prescribed herbal medication) to treat 
neovascular AMD within 30 days prior to randomisation, and such treatment or therapy will 
not be allowed during the study period. However, dietary supplements, vitamins, or minerals 
will be allowed. 
14. Study eye: History of vitrectomy, scleral bucking (encircling), glaucoma filtration surgery, 
corneal transplantation, or pan-retinal photocoagulation 
15. Study eye: Previous ocular (intraocular and peribulbar) corticosteroids injection/implant 
within 1 year prior to randomisation 
16. Study eye: Topical ocular corticosteroids administered for ≥ 30 consecutive days or for ≥ 60 
non-consecutive days within 90 days prior to randomisation 
17. Use of systemic corticosteroids for 30 or more consecutive days within 90 days prior to 
randomisation (inhaled steroid is permitted). 
18. Study eye: Any other intraocular surgery (including cataract surgery or Yttrium Aluminium 
Garnet [YAG] laser posterior capsulotomy in association with prior posterior chamber 
intraocular lens [IOL] implantation) or periocular surgery within 90 days prior to 
randomisation, except for lid surgery, which may not have taken place within 30 days prior to 
randomisation. 
19. Current use of medications known to be toxic to the lens, retina, or optic nerve, including 
deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines, vigabatrin, 
ethambutol, at Screening and such medications will not be allowed during the study period. 
20. Study eye: Previous radiation therapy near the region of the study eye 
21. Previous participation in clinical studies with IP to treat neovascular AMD in either eye.  
22. Previous participation in clinical studies with IP to treat disease other than neovascular AMD 
within 90 days prior to randomisation (excluding dietary supplementary, vitamins, and 
minerals). Such participation will not be allowed during the study period even if the IP is 
dietary supplementary, vitamins, or minerals. 


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23. Subject with only one functional eye (defined as BCVA of counting finger or less on the eye 
with worse vision) 
24. Study eye: Spherical equivalent of the refractive error demonstrating more than 6 diopters of 
myopia. For subjects who have undergone previous refractive or cataract surgery in the study 
eye, the preoperative refractive error in the study eye cannot exceed 6 diopters of myopia. 
25. Study eye: Aphakia or absence of the posterior capsule (unless it occurred as a result of a YAG 
laser posterior capsulotomy in association with prior posterior chamber IOL implantation) 
26. Either eye: Active or suspected ocular and periocular infection at Screening or at 
randomisation (e.g., infectious blepharitis, infectious conjunctivitis, infection in eyelid) 
27. Either eye: Active intraocular inflammation including scleritis at Screening or at 
randomisation 
28. Either eye: History of idiopathic or autoimmune-associated uveitis 
29. Study eye: Uncontrolled ocular hypertension (defined as IOP ≥ 25 mmHg despite treatment 
with anti-glaucoma medication) at Screening 
30. Known allergic reactions and/or hypersensitivity to any component of Eylea® or SB15 
31. History of allergy to the fluorescein sodium for injection in angiography 
32. History of a medical condition that would preclude scheduled study visits or safe use of IP in 
the opinion of the Investigator (e.g., history of organ transplant, immunocompromised subject, 
etc.) 
33. Uncontrolled systemic disease including but not limited to uncontrolled diabetes mellitus (in 
the opinion of the Investigator), uncontrolled systemic hypertension (systolic blood pressure 
≥ 180 mmHg and/or diastolic blood pressure ≥ 100 mmHg on optimal medical regimen), or 
uncontrolled atrial fibrillation (resting heart rate ≥ 110 beats per minutes) at Screening 
34. Stroke, transient ischaemic attacks, or myocardial infarction within 180 days prior to 
randomisation 
35. History of recurrent significant infections and/or current treatment for systemic infection  
36. Severe renal impairment with dialysis or a history of renal transplant 
37. Malignancy (other than non-melanoma skin cancer) under treatment or with history of 
metastatic disease  
38. Women of childbearing potential who are pregnant, planning to become pregnant, lactating, or 
not using adequate birth control, as specified in protocol. For women of childbearing potential, 
a serum pregnancy test must result negative at Screening. 
39. Employees of investigational sites, individuals directly involved with the conduct of the study, 
prisoners, and persons who are legally institutionalized 
 Screen Failures and Re-screening 
Screen failures are defined as subjects who consent to participate in the clinical trial but do not meet 
one or more criteria required for participation in the trial during the screening procedures. A minimal 
set of screen failure information is required. If the subject is not randomised within 21 days after signing 


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the ICF, the subject should be screen failed. 
Once a subject is screen failed for one eye, he or she should not be re-screened for the same eye. 
Screening for the other eye is allowed within the screening period and the subject will use the same 
screening number. 
 Replacement 
Subjects who are discontinued from IP after randomisation will not be replaced. 
5. Treatment and Investigational Product 
 Treatment of the Subjects 
5.1.1. Dosing and Treatment Schedule 
Subjects will be administered SB15 or Eylea® 2 mg via IVT injection into the study eye every 4 weeks 
for the first 3 months, followed by 2 mg once every 8 weeks up to Week 48 (a total of 8 administrations 
of IP) unless they are early discontinued from IP.  
IP injection will be performed by the Investigator according to delegation of study personnel for this 
study. 
Dosing visits will be allowed within ± 7 days of the scheduled dosing date (except Week 0 [Day 1], 
visit window not allowed). Dosing skip is defined when a subject does not receive the IP within 20 days 
after scheduled dosing date for Week 0 and/or Week 4 visits and 48 days after scheduled dosing date 
for the subsequent visits. Next scheduled dosing date and visit window should not be altered even 
though previous dosing is not performed on the scheduled dosing date or previous dosing is skipped. 
5.1.2. Assignment of Subjects to Treatment Group 
A unique subject number will be assigned to subjects at Screening. The subject number will be used to 
register the subject using the Interactive Web Response System (IWRS) and the subject will then be 
randomised (in a ratio of 1:1) to either SB15 or Eylea®. At Week 32, subjects receiving Eylea® will be 
randomised again in a 1:1 ratio to either continue on Eylea® treatment or be transitioned to SB15 
treatment. Subjects receiving SB15 will continue to receive SB15 but they will also follow the 
randomisation procedure to maintain masking. 
These randomisations will occur according to a computer-generated randomisation scheme which will 
randomise subjects at a centre-level. If a subject is withdrawn, the randomisation number(s) will not be 
re-used. At each study visit the Investigator or designee should contact the IWRS and an appropriate 
number of codes will be provided. These codes will indicate which vials should be dispensed to the 
subject. Further details on using the IWRS system are presented in the IWRS Manual. 
5.1.3. Withholding Investigational Products 
If a subject experiences an AE or the subject’s safety or well-being could be compromised by IVT 
injection of IP at the Investigator’s discretion, IPs should be withheld until the event has resolved or 
adequately repaired. 
In case of following events in the study eye, IP must be withheld. 
• 
≥ 30 mmHg in pre-injection IOP measurement 
• 
A retinal break 


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• 
Active or suspected ocular and periocular infection 
• 
Active severe intraocular inflammation (e.g., 4+ anterior chamber cell/flare or 4+ vitritis) 
• 
Performed or planned intraocular surgery within the previous or next 28 days 
For the following events in the study eye, IP withholding should be considered by the Investigator. 
• 
A decrease in BCVA of ≥ 30 letters compared with the last assessment of visual acuity 
• 
A subretinal haemorrhage involving the centre of the fovea equal to or more than one DA in 
size or, if the size of the haemorrhage is ≥ 50%, of the total lesion area 
In case of following events, IP must be permanently discontinued 
• 
Rhegmatogenous retinal detachment or full-thickness macular hole in the study eye 
• 
A subject misses any of first two doses or two consecutive doses during the study period after 
randomisation 
NOTE: Please refer to the permanent IP discontinuation criteria in Section 7.2.1. 
5.1.4. Masking 
This study is double-masked. Subjects, Investigators, and other study personnel will remain masked to 
the treatment group assignment throughout the study period after randomisation. 
To ensure the masking of the treatment group assignment, one carton will contain only one IP vial (SB15 
or Eylea®). The carton and IP vial will be packed and labelled in identical appearance. 
5.1.5. Unmasking 
After all subjects complete the procedures at Week 24, or its corresponding visit, a limited number of 
identified individuals of the Sponsor and/or Contract Research Organisation (CRO) will be unmasked 
only for the reporting purpose to regulatory agency. Available efficacy and safety data, PK, and 
immunogenicity data will be analysed and reported in the main clinical study report (CSR). However, 
subjects, Investigators, and other study personnel will remain masked throughout the whole study 
period 
After the last subject completes the procedures at Week 56 (EOS visit) or the corresponding visit and 
database is locked, the treatment group assignment will be unmasked and all study data will be analysed 
and reported in the final CSR. 
Emergency and accidental unmasking are referred to in Section 8.1.7. 
 Investigational Product 
5.2.1. Identity of Investigational Product 
The IPs will be supplied to investigational site in one carton containing a single vial. 
Details of the IPs are provided in Table 3. 


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Table 3. Investigational Products 
Active Pharmaceutical Ingredient: Aflibercept 
SB15 
Formulation 
Solution for intravitreal injection 
Contents 
One vial of 0.05 mL contains 2 mg aflibercept 
Storage conditions 
Stored in refrigerator (2-8°C), Do not freeze 
US sourced Eylea® 
Formulation 
Solution for intravitreal injection 
Contents 
One vial of 0.05 mL contains 2 mg aflibercept 
Storage conditions 
Stored in refrigerator (2-8°C), Do not freeze 
 
5.2.2. Preparation and administration of Investigational Product 
IPs should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are 
visible, the vial must not be used. 
Using aseptic technique, all of the SB15 and Eylea® vial contents are withdrawn through a filter needle 
attached to a 1-mL syringe. The filter needle should be discarded after withdrawal of the vial contents 
and should not be used for IVT injection. The filter needle should be replaced with a sterile 30-gauge x 
1/2-inch needle for the IVT injection of IP. The contents should be expelled until the plunger tip is 
aligned with the line that marks 0.05 mL on the syringe. 
The IVT injection procedure should be carried out under controlled aseptic technique in accordance 
with local practice. 
Each vial should only be used for the treatment of a single eye. 
5.2.3. Formulation, Packaging, and Labelling 
Aflibercept (SB15 or Eylea®) will be supplied for use as an iso-osmotic solution for IVT injection (2 
mg per vial for SB15 or US sourced Eylea®). 
These IP vials will be packed and labelled in a double-masked manner for clinical use. The labels for 
carton and vial will contain the protocol number, unique identifier, Sponsor company name, expiry or 
retest date, storage condition, and all other details according to the Good Manufacturing Practice (GMP) 
and other relevant local laws and/or regulations. 
The temperature will be monitored properly during the study period. The IP should be stored in a secure 
area and clearly labelled and stored away from other IP or medication to prevent confusion (for example 
in a clearly marked box on a separate shelf of the refrigerator). 
A detailed guideline for IP preparation, administration, storage, and destruction will be provided in the 
Pharmacy Manual. 
5.2.4. Product Storage and Stability 
SB15 and Eylea® should be stored at 2°C to 8°C (36°F to 46°F) in the original carton until time of use 
to protect from light. The temperature will be monitored properly during the study period. If continuous 
monitoring is not available then manual temperature logs should be generated and recorded to ensure 
proper storage conditions. If a temperature deviation occurred, responsible person should contact the 
Sponsor to determine if the drug is still appropriate for use. 
Do not freeze SB15 or Eylea® vials. The IPs must not be used beyond the expiration date. 


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5.2.5. Treatment Compliance and Investigational Product Accountability 
All IP injections will be given by the Investigator or designee to ensure compliance. The exact date and 
time of IP injection must be recorded in the source documentation and the electronic case report form 
(eCRF). 
The Investigator or designee should maintain the documents of IP accountability and record the IP kit 
number administered to subjects. IP accountability and dispensing records must be kept and contain the 
following information: 
• 
The identification of the subjects to whom the drug was dispensed. 
• 
The date(s) and quantity of the drug dispensed and exact package to the subject. 
• 
The dispensing and inventory logs must be available for inspection by the monitor. 
The used IP will be destructed at the investigational site according to local regulation after drug 
accountability done. All unused IPs should be returned to the Sponsor or designated vendor unless local 
destruction at site is approved by the Sponsor. If destruction is authorised at the investigational site, the 
Investigator must ensure that the materials are destroyed in compliance with all applicable 
environmental regulations, institutional policies, and any instructions provided by the Sponsor. 
Destruction of the IP must be adequately documented. 
 Prohibited Medication or Therapy 
Prohibited medication and therapy during the study period are presented in Table 4. 
Any other medications that are considered necessary for the subject’s welfare, and that are not expected 
to interfere with the evaluation of the IP may be given at the Investigator’s discretion. 
Details of any medications including prescription drugs, non-prescription drugs, or any therapy (except 
dietary supplements, vitamins, or minerals) received locally (in the study eye and/or fellow eye) or 
systemically within 180 days prior to Screening will be collected until Week 56 (EOS visit) or early 
termination (ET) visit (including a follow-up visit or telephone interview). Details to be recorded 
include name (generic name preferred), dose number and unit, frequency of administration, route of 
administration, start and stop dates, and the AE it relates to (if applicable). 
Table 4. Prohibited Medication and Therapy 
Medication or Therapy 
Time to be prohibited 
Eye to be prohibited 
IVT anti-VEGF treatment (e.g., bevacizumab, 
aflibercept, ranibizumab, pegaptanib, etc.) to 
treat neovascular AMD 
• Prior to randomisation 
• Study eye 
• Fellow eye 
IVT anti-VEGF treatment except IP (SB15 or 
Eylea®) 
• From randomisation to 
EOS/ET visit 
• Study eye 
IVT anti-VEGF treatment (e.g., bevacizumab, 
ranibizumab, pegaptanib, etc.) except 
aflibercept 
• From randomisation to 
EOS/ET visit 
• Fellow eye 
NOTE: If a subject has 
AMD in the fellow eye 
during the study period 
after randomisation, 
ONLY Eylea® 
(aflibercept) will be 
allowed to treat AMD. 


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Medication or Therapy 
Time to be prohibited 
Eye to be prohibited 
Systemic anti-VEGF agents (e.g., bevacizumab, 
ziv-aflibercept, etc.) 
• Prior to randomisation 
• From randomisation to 
EOS/ET visit 
Not applicable 
History of treatment involving macula such as 
macular laser photocoagulation, PDT, TTT, 
radiation therapy, or any ocular treatment for 
neovascular AMD  
• Prior to randomisation 
• From randomisation to 
EOS/ET visit 
• Study eye 
Systemic treatment or therapy (including 
prescribed herbal medication) to treat 
neovascular AMD. However, dietary 
supplements, vitamins, and minerals are 
allowed. 
• Within 30 days prior to 
randomisation 
• From randomisation to 
EOS/ET visit 
Not applicable 
Vitrectomy, scleral bucking (encircling), 
glaucoma filtration surgery, corneal 
transplantation, or pan-retinal photocoagulation 
• Prior to randomisation 
• Study eye 
Intraocular or peribulbar corticosteroid 
injection/implant 
• Within 1 year prior to 
randomisation  
• From randomisation to 
EOS/ET visit 
• Study eye 
Topical ocular corticosteroids 
• ≥ 30 consecutive days or ≥ 
60 non-consecutive days 
within 90 days prior to 
randomisation 
• Study eye 
Use of systemic corticosteroids 
(inhaled steroid is permitted) 
• ≥ 30 consecutive days 
within 90 days prior to 
randomisation 
Not applicable  
Any other intraocular surgery (including 
cataract surgery or YAG laser posterior 
capsulotomy). 
• Within 90 days prior to 
randomisation 
• Within the previous 28 
days before IP injection or 
next 28 days after IP 
injection during the study 
period 
• Study eye 
Peribulbar surgery 
• Within 90 days prior to 
randomisation 
• Study eye 
Lid surgery 
• Within 30 days prior to 
randomisation 
• Cosmetic lid surgery is not 
allowed from randomisation 
to EOS/ET visit 
• Study eye 
Medications known to be toxic to the lens, 
retina, or optic nerve including deferoxamine, 
chloroquine/hydroxychloroquine, tamoxifen, 
phenothiazines, vigabatrin, and ethambutol 
• From Screening to 
EOS/ET visit 
Not applicable 


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Medication or Therapy 
Time to be prohibited 
Eye to be prohibited 
Radiation therapy near the region of the study 
eye 
• Prior to randomisation 
• From randomisation to 
EOS/ET visit 
• Study eye 
Ocular IPs to treat neovascular AMD  
• Prior to randomisation 
• From randomisation to 
EOS/ET visit 
• Study eye 
• Fellow eye 
Systemic IPs to treat neovascular AMD 
• Prior to randomisation 
• From randomisation to 
EOS/ET visit 
Not applicable 
Ocular IPs to treat diseases other than 
neovascular AMD 
• Within 90 days prior to 
randomisation 
• From randomisation to 
EOS/ET visit 
• Study eye 
• Fellow eye 
Non-ocular IPs (excluding dietary supplements, 
vitamins, and minerals) to treat diseases other 
than neovascular AMD 
• Within 90 days prior to 
randomisation 
• From randomisation to 
EOS/ET visit 
NOTE: During the study 
period, IPs such as dietary 
supplements, vitamins and 
minerals will be prohibited. 
Not applicable 
AMD = age-related macular degeneration; EOS = end of study; ET = early termination; IP = investigational product; IVT = 
intravitreal; PDT = photodynamic therapy; TTT = transpupillary thermotherapy; VEGF = vascular endothelial growth factor; 
YAG = Yttrium Aluminium Garnet 
 Fellow Eye Treatment 
The fellow eye (non-study eye) will not be considered as an additional study eye. If a subject has AMD 
in the fellow eye, the subject could receive ONLY Eylea® during the study period and should remain in 
the study. Eylea® for AMD treatment in the fellow eye will be reimbursed or provided by the Sponsor 
during the study period after randomisation. 
Fellow eye injection will be performed by the Investigator for this study. However, visits for fellow eye 
injection are not part of study, thus it will be scheduled in accordance with local practice. If a subject 
has both eyes injected on the same day, fellow eye should be injected after completion of IVT injection 
of IP on the study eye. Ocular AEs for the fellow eye and non-ocular AEs will be monitored and recorded 
after the written informed consent is obtained from the subject until Week 56 (EOS visit) or ET visit. 
6. Study Assessment 
 Efficacy Assessment 
6.1.1. Best Corrected Visual Acuity (BCVA) 
Visual acuity will be assessed in both the study eye and fellow eye (non-study eye) at Screening and 
prior to IVT injection of IP at each visit until Week 48. Visual acuity will also be assessed in both the 
study eye and fellow eye (non-study eye) at Week 56 (EOS visit) or ET visit.  


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Visual acuity will be assessed using original series ETDRS charts or 2702 series Number charts at a 
starting distance of 4 meters, and then continue at a distance of 1 meter, if required by ETDRS protocol. 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS visit) or ET visit. 
Visual acuity testing must be performed before dilation of pupils and other ophthalmic procedures 
including FP (fundus photography)/FA (fluorescein angiography) and OCT assessment. 
Visual acuity examiners and visual acuity lanes at investigational sites must be certified to ensure 
consistent measurement of BCVA prior to BCVA test to subjects. 
A detailed instruction for conducting visual acuity testing and refraction will be provided in the Visual 
Acuity Testing Manual. 
NOTE (refer to Section 8.4) 
• 
A decrease in visual acuity of ≥ 15 letters from the last assessment of visual acuity should be 
reported as AE/serious AE (SAE) as appropriate. 
• 
A decrease in visual acuity of ≥ 30 letters from the last assessment of visual acuity should be 
reported as SAE. 
• 
A decrease in visual acuity to the level of light perception or worse should be reported as SAE. 
6.1.2. Anatomical Parameters 
The average retinal thickness in the central 1-mm area in the ETDRS grid (CST and TRT), the presence 
of intra- or sub-retinal fluid and sub-RPE fluid will be evaluated using OCT at Screening and prior to 
IVT injection of IP until Week 48. OCT will also be performed at Week 56 (EOS visit) or ET visit.  
The CNV area and the presence of CNV leakage will also be evaluated using FP/FA at Screening and 
prior to IVT injection of IP at Week 32. FP/FA will also be performed at Week 56 (EOS visit) or ET 
visit. 
 Safety Assessment 
6.2.1. Adverse Events 
All AEs including ocular AEs in the study eye and/or fellow eye as well as non-ocular AEs will be 
recorded from the time when the written informed consent is obtained from the subject to Week 56 
(EOS visit) or ET visit (including a follow-up visit or telephone interview). AEs should be elicited from 
subjects using non-leading questions such as ‘How are you feeling?’. Further information on AE 
monitoring and reporting is presented in Section 8. 
6.2.2. Clinical Laboratory Evaluations 
Blood and urine samples for clinical laboratory test will be collected at Screening and prior to IVT 
injection of IP at Week 8, Week 32, and Week 40. Blood and urine samples for clinical laboratory test 
will be also collected at Week 56 (EOS visit) or ET visit. Urine samples must be collected before 
performing FA to avoid interference with fluorescein in urinalysis. 
Blood samples will be analysed in central laboratory and urine samples will be tested in each 
investigational site by using a dipstick which will be provided by the Sponsor. A detailed process for 
clinical laboratory sampling, handling, storage, and shipping will be provided in the Central Laboratory 
Manual for safety lab testing. 


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The parameters for clinical laboratory tests are listed in Table 5. 
Table 5. Parameters for Clinical Laboratory Tests 
Haematology 
Chemistry 
Urinalysis1 
 
Haemoglobin 
 
Haematocrit 
 
Platelet count 
 
White blood cell count (total 
and differential; neutrophils, 
lymphocytes, 
monocytes, 
eosinophils, and basophils) 
 
Sodium 
 
Potassium 
 
Creatinine 
 
Glucose 
 
Calcium 
 
Phosphorus 
 
Total bilirubin 
 
Albumin 
 
Alanine aminotransferase 
 
Aspartate aminotransferase 
 
Alkaline phosphatase 
 
Lactate dehydrogenase 
 
Protein 
 
Blood 
 
Leucocytes 
 
Nitrite 
 
Glucose 
 
Ketone 
 
pH 
 
Specific gravity 
 
Bilirubin 
 
Urobilinogen 
1 Urinalysis will be tested using a dipstick which will be provided by the Sponsor. 
 
The Investigator will check any laboratory values which have potential significance in subject’s safety 
during the study period. The Investigator will also evaluate any change in laboratory values. Each out 
of range result should be assessed as not clinically significant or clinically significant by the Investigator 
and reported as AE if relevant. All laboratory abnormalities that require intervention (e.g., IP 
withholding, IP discontinuation, concomitant medication) must be assessed as clinically significant and 
the clinically significant abnormalities should be recorded as AEs.  
Clinical laboratory test including haematology, clinical chemistry, and urinalysis may be repeated 
during the study period at the Investigator’s discretion. 
When a scheduled laboratory test result would not be available due to the subject missing the visit or to 
technical issues (e.g., sampling error, handling error, tube breakage), it is recommended to perform or 
repeat the test as soon as available (e.g., at the next scheduled visit) at discretion of the Investigator. 
For laboratory tests required at Screening, any missing result should be repeated within the screening 
period.  
6.2.3. Physical Examination 
Physical examination will be performed at Screening and Week 56 (EOS visit) or ET visit. The physical 
examination may include an assessment of the subject’s general appearance, skin, head, neck, throat, 
lymph nodes, cardiovascular, neurological, thyroid, musculoskeletal/extremities, respiratory systems, 
and the subject’s abdomen. Abnormal findings will be documented on the source document, and any 
clinically significant abnormality or worsening of a previously noted abnormality should be recorded 
as an AE. 
Body weight will be measured and recorded at Screening and Week 56 (EOS visit) or ET visit, whereas 
height will be measured and recorded only at Screening. 
6.2.4. Vital Signs 
Vital signs include blood pressure, pulse rate, and body temperature. Vital signs will be assessed at 
Screening and prior to IVT injection of IP at each visit until Week 48. Vital signs will also be assessed 


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at Week 56 (EOS visit) or ET visit.  
The Investigator should assess all vital signs and any clinically significant abnormalities should be 
reported as AE. 
 Pregnancy Test 
For women of childbearing potential, a serum pregnancy test must be performed at Screening. The 
serum samples taken at Screening will be analysed in central laboratory.  
At each visit during the study, women of childbearing potential must repeat a pregnancy test and a 
negative result shall be obtained before each IVT injection of IP. After randomisation, pregnancy tests 
will be performed either on serum or urine at the Investigator’s discretion. 
Additional unscheduled (serum or urine) pregnancy tests may be performed during the study period 
when any suspicion of pregnancy arises at the Investigator’s discretion. 
When a pregnancy test result at Screening would not be available due to technical issues (e.g., handling 
error, sampling error, tube breakage), the test shall be repeated in all circumstances (missing results at 
Screening would be considered as screening failure). 
 Ophthalmic Assessments 
6.4.1. Full Ophthalmic Examinations 
The full ophthalmic examination will consist of macroscopic examination of the eye and adnexa 
(including but not limited to abnormal pupil reaction to light and afferent pupillary defect, etc.), slit 
lamp biomicroscopy, IOP measurements, and indirect ophthalmoscopy. Abnormal finding should be 
assessed as not clinically significant or clinically significant by the Investigator and reported as AE if 
relevant. 
During study period, fellow eye will be evaluated according to local practice to determine whether or 
not AMD develops. If the AMD is diagnosed in the fellow eye during the study period, this event should 
be also reported as an AE. 
Slit lamp biomicroscopy 
The slit lamp examination of anterior segment (conjunctiva, cornea, lens, iris, aqueous reaction [flare 
and cells]) will be performed on both the study eye and fellow eye at Screening and prior to IVT 
injection of IP at each visit until Week 48. Slit lamp examination will also be performed at Week 56 
(EOS visit) or ET visit.  
Grading scales for anterior chamber flare and cells are provided in APPENDIX A and APPENDIX B. 
NOTE 
The following events should be reported as AE of special interest (AESI) (Section 8.3): 
• 
Any case of intraocular infection (suspected infection) such as endophthalmitis 
• 
Any case of non-infectious intraocular inflammation such as iritis, vitritis, and iridocyclitis 
• 
Iatrogenic traumatic cataract 
IOP measurement 


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IOP will be measured on the study eye at Screening as well as prior to IVT injection of IP and 30-60 
minutes after IVT injection of IP at each visit until Week 48. IOP will also be measured at Week 56 
(EOS visit) or ET visit. In case of any abnormalities, relevant immediate intervention and follow up per 
standard of care should be taken to ensure subjects safety. AEs/SAEs should be reported as appropriate 
(Section 8). 
IOP should be measured using Goldmann applanation tonometry. The same method of IOP 
measurement must be used in each subject from Screening to Week 56 (EOS visit) or ET visit. In case 
IOP is measured prior to OCT and FP/FA, IOP should be carefully measured not to cause corneal erosion, 
which might affect the quality of OCT/FP/FA images.  
NOTE 
The following events should be reported as AESI (Section 8.3): 
• 
New onset pre-injection IOP of ≥ 25 mmHg 
• 
Post-injection IOP of ≥ 35 mmHg 
Indirect ophthalmoscopy 
Indirect ophthalmoscopy using a standard way (i.e., usually using a head-mounted light source and a 
20-30 lens) will be performed on the study eye to evaluate posterior segment including vitreous, optic 
nerve, macula, peripheral retina, or retinal vasculature at Screening and prior to IVT injection of IP and 
0-15 min after IVT injection of IP at each visit until Week 48. Indirect ophthalmoscopy will also be 
performed at Week 56 (EOS visit) or ET visit. 
Vitreous will be assessed for inflammatory response and the grading scale for vitreous haze is provided 
in APPENDIX C. 
NOTE 
The events should be reported as AESI (Section 8.3): 
• 
Retinal pigment epithelial tear 
• 
Subretinal haemorrhage with the size of 1 DA or more involving the centre of the fovea, or if 
the size of the haemorrhage is ≥ 50% of the total lesion area 
6.4.2. Optical Coherence Tomography (OCT) 
OCT will be performed on both eyes at Screening and those images taken from both eyes will be sent 
to the central reading centre. 
OCT will be performed on the study eye prior to IVT injection of IP at each study visit until Week 48. 
OCT will also be performed on the study eye at Week 56 (EOS visit) or ET visit. OCT images taken 
from the study eye will be sent to the central reading centre. Retinal thickness (CST and TRT), the 
presence of intra- or sub-retinal fluid, and sub-RPE fluid will be evaluated in the central reading centre. 
The Investigator will evaluate the OCT images sent to the central reading centre in terms of safety 
assessment. 
Site staffs who will perform OCT scans in this study must be certified by the central reading centre 
before performing study procedure. Only OCT devices certified by the central reading centre are 
allowed to be used in this study. If one or more OCT devices are certified in an investigational site, a 
subject must use the same OCT system from the same manufacture consistently from Screening to Week 


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56 (EOS visit) or ET visit.  
All original OCT images will be kept in the investigational site and copies will be sent to the central 
reading centre for analysis and archiving 
A detailed instruction for OCT image acquisition and transmission will be provided in the Image 
Handbook.  
6.4.3. Fundus Photography (FP) and Fluorescein Angiography (FA) 
FP/FA will be performed on both eyes at Screening and those images taken from both eyes will be sent 
to the central reading centre. 
FP/FA will also be performed on the study eye prior to IVT injection of IP at Week 32 and at Week 56 
(EOS visit) or ET visit. FP/FA images taken from the study eye will be sent to the central reading centre. 
Lesion type, total lesion area, CNV area, haemorrhage, and the presence of CNV leakage will be 
evaluated in the central reading centre. The Investigator will evaluate the FP/FA images sent to the 
central reading centre in terms of safety assessment. 
Site staffs who will perform FA/FP in this study must be certified by the central reading centre before 
performing study procedure. Only FP/FA device certified by the central reading centre is allowed to be 
used in this study. If one or more FP/FA devices are certified in an investigational site, a subject must 
use the same FP/FA system from the same manufacture consistently from Screening to Week 56 (EOS 
visit) or ET visit.  
All original FP/FA images will be kept in the investigational site and copies will be sent to the central 
reading centre for analysis and archiving. If any significant change in the posterior pole (e.g., subretinal 
haemorrhage, macular hole, vitreous haemorrhage or opacity, retinal detachment, etc.) is detected with 
fundus examination, additional FP and/or FA can be performed at the Investigator’s discretion, but the 
images will not be sent to the central reading centre. 
A detailed instruction for FP/FA image acquisition and transmission will be provided in the Image 
Handbook. 
 NEI VFQ-25 
Vision-related QOL will be assessed using the NEI VFQ-25 with interviewer administered format 
(APPENDIX D). NEI VFQ-25 will be performed at Week 0 (Day 1) after randomisation. Then, NEI 
VFQ-25 should be performed before dilation of pupils at Week 32 and at Week 56 (EOS visit) or ET 
visit. 
All questionnaires will be administered in the local language. The Investigator or delegated site staff 
will conduct a questionnaire survey with the subject in a quiet room. The responses collected from the 
subject will be recorded on a paper questionnaire and entered successively into the eCRF. 
 Other Assessments 
6.6.1. Pharmacokinetic (PK) Assessment 
Blood samples for PK assessment will be collected in approximately 40 subjects (20 subjects per 
treatment group in initial randomisation at Week 0 [Day 1]) participating in PK evaluation. 
The investigational sites which are interested in taking part in PK sub-study and are also fully equipped 
as per study requirement will be selected before the study starts. The selected investigational sites will 


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be defined as PK investigational sites which are registered in the IWRS. 
Subjects screened at PK investigational sites will be asked to participate in the PK sub-study. Only 
subjects who consent to the PK blood sampling will be enrolled in this sub-study. Once the threshold 
of PK subjects is reached, the following subjects enrolled at the PK investigational sites will be ‘non-
PK subjects’ for whom blood sampling for PK assessment will not be performed. 
Blood samples for pre-dose PK assessment will be collected prior to IVT injection of IP at Week 0 (Day 
1), Week 4, Week 8, Week 24, Week 32, and Week 40. Blood samples for post-dose PK assessment will 
be collected once between 24 and 72 hours after IVT injection of IP at Week 0 (Day 1) and on 1 
day, 2 days, and 3 days after the date of IVT injection of IP at Week 24 (total 3 times of PK sample 
collection for 3 consecutive days). Blood samples for PK assessment will also be collected during the 
final visit at Week 56 (EOS visit). Blood samples for PK assessment should not be collected at ET visit. 
Subjects’ samples may be used for method validation and/or investigation, only for this study. 
A detailed process for PK sampling, handling, storage, and shipping will be provided in the Central 
Laboratory Manual for PK and Immunogenicity. 
6.6.2. Immunogenicity Assessment 
Blood samples for immunogenicity assessment will be collected in all randomised subjects.  
Blood samples for immunogenicity assessment will be collected prior to IVT injection of IP at Week 0 
(Day 1), Week 4, Week 8, Week 24, Week 32, and Week 40. Blood samples for immunogenicity 
assessment will also be collected at Week 56 (EOS visit) or ET visit. Subjects’ samples may be used for 
method validation and/or investigation, only for this study. 
A detailed process for immunogenicity sampling, handling, storage, and shipping will be provided in 
the Central Laboratory Manual for PK and Immunogenicity. 
7. Study Procedures 
During this study, efficacy, safety, PK, and immunogenicity assessments will be performed. All results 
shall be recorded in the source documents along with the date and time the procedures were performed. 
Such assessments must be performed at the times outlined in Table 1. 
 Study Flow and Visit Schedule 
NOTE: The most critical assessment will be at Week 8 as this is the visit for primary endpoint 
assessment. Thus, every effort should be made to adhere to the visit schedule for the subjects. 
7.1.1. Screening Visit (Visit 1, D-21 to D-1)  
Screening shall be performed within 21 days before randomisation (i.e., excluding the day of 
randomisation).  
• 
Written informed consent 
The Investigator must discuss the study with the subject and obtain written informed consent from the 
subject prior to any study related procedures. If the subject is not randomised within 21 days after 
signing the ICF, the subject will be screen failed. Once a subject is screen failed for one eye, he or she 
shall not be re-screened for the same eye. Screening for the other eye is allowed within the screening 
period (Section 4.4). 
The following procedures should be performed: 


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• 
Evaluate subject compliance with all inclusion and exclusion criteria 
• 
Demographic data 
• 
Medical & ophthalmic history 
• 
Physical examination (including body weight and height) 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Pregnancy test for women of childbearing potential (serum) 
• 
Blood and urine sampling for clinical laboratory tests  
- Urine samples must be collected before performing FA to avoid interference with 
fluorescein in urinalysis. 
• 
Ocular assessments: 
- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including FP/FA and OCT 
assessment) 
 
The Investigator must confirm that the subject can read between 73 letters and 34 letters, 
inclusive, in the study eye (Please see inclusion criteria #5). If the subject is not eligible 
at this point, no further study assessment should be performed, and the subject should 
be screen failed. 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit.  
- Slit lamp biomicroscopy 
- Indirect ophthalmoscopy 
- OCT in both eyes (images should be sent to central reading centre) 
- FP & FA in both eyes (images should be sent to central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant and previous medication or therapy 
Investigators are advised to send for review OCT and FP/FA images to the central reading centre as 
soon as possible as this could take more time than the other procedures and Investigators should avoid 
exceeding the allowed 21 days for completing Screening. If the subject is screen failed due to any 
reasons before the Investigator send OCT and/or FP/FA images to the central reading centre, the 
Investigator does not have to send the subject’s OCT and/or FP/FA images to the central reading centre. 
The central reading centre will send central review results confirming the subject’s eligibility to the 
investigational site. If a subject is confirmed as ineligible from the central reading centre due to poor 


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quality of images, but the investigator still considers the subject eligible for the study, the Investigator 
may be allowed to send a second set of images to the central reading centre. In this case, only FP/FA or 
OCT (and not all other screening procedures) will be repeated and the result should be confirmed within 
the screening period of 21 days. Only in this case, the subject will retain the subject number initially 
assigned. 
Once the subject is confirmed eligible for the study, the subject will be reminded in particular of the 
study restrictions such as contraception, prohibited medications, and other study requirements. The 
Investigator shall pay attention to each subject’s particular needs in order to provide the necessary 
training and advice and foster protocol compliance. 
7.1.2. Treatment Period 
7.1.2.1. Visit 2 (Week 0 [Day 1]) 
The following procedures should be performed 
• 
Evaluate subject compliance with all inclusion and exclusion criteria 
• 
BCVA examination 
- The Investigator must confirm that the subject can read between 73 letters and 34 letters, 
inclusive, in the study eye using original series ETDRS charts or 2702 series Number 
charts (before dilation of the pupils and other ophthalmic procedures including OCT 
assessment) prior to randomisation (Please see inclusion criteria #5). 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit. 
• 
After a subject’s eligibility is confirmed by the central reading centre and the Investigator, 
subject should be randomised to either SB15 or Eylea® treatment group. 
• 
The first IVT injection of IP and all other study procedures (except blood sampling for post-
dose PK assessment) should be performed at the same day of randomisation. 
 Before IVT injection of IP 
• 
NEI VFQ-25 (prior to dilation of pupil after randomisation) 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Blood sampling for immunogenicity 
• 
Blood sampling for PK for subjects participating in PK evaluation 
• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 
potential 
• 
Ocular assessments: 
- Slit lamp biomicroscopy 
- Indirect ophthalmoscopy 


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- OCT (images should be sent to the central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring  
• 
Review of concomitant and previous medication or therapy 
 IVT injection of IP 
• 
IP (SB15 or Eylea®) will be given in the study eye. 
 After IVT injection of IP 
• 
Ocular assessments: 
- Indirect ophthalmoscopy (0-15 min post-dose) 
- IOP using Goldmann applanation tonometry (30-60 min post-dose) 
• 
Blood sampling for PK for subjects participating in PK evaluation (once between 24 hours and 
72 hours post-dose) 
• 
AE monitoring 
7.1.2.2. Visit 3 (Week 4 ± 7 days) 
 Before IVT injection of IP 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Blood sampling for immunogenicity 
• 
Blood sampling for PK for subjects participating in PK evaluation 
• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 
potential 
• 
Ocular assessments: 
- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including OCT assessment) 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit 
- Slit lamp biomicroscopy  
- Indirect ophthalmoscopy  
- OCT (images should be sent to the central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant medication or therapy 


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 IVT injection of IP 
• 
IP (SB15 or Eylea®) will be given in the study eye. 
 After IVT injection of IP 
• 
Ocular assessments: 
- Indirect ophthalmoscopy (0-15 min post-dose) 
- IOP using Goldmann applanation tonometry (30-60 min post-dose) 
• 
AE monitoring  
7.1.2.3. Visit 4 (Week 8 ± 7 days) 
 Before IVT injection of IP 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Blood and urine sampling for clinical laboratory tests 
• 
Blood sampling for immunogenicity 
• 
Blood sampling for PK for subjects participating in PK evaluation 
• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 
potential 
• 
Ocular assessments: 
- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including OCT assessment) 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit 
- Slit lamp biomicroscopy  
- Indirect ophthalmoscopy  
- OCT (images should be sent to central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant medication or therapy 
 IVT injection of IP 
• 
IP (SB15 or Eylea®) will be given in the study eye. 
 After IVT injection of IP 
• 
Ocular assessments: 
- Indirect ophthalmoscopy (0-15 min post-dose) 


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- IOP using Goldmann applanation tonometry (30-60 min post-dose) 
• 
AE monitoring 
7.1.2.4. Visit 5 (Week 16 ± 7 days) 
 Before IVT injection of IP 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 
potential. 
• 
Ocular assessments: 
- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including OCT assessment) 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit 
- Slit lamp biomicroscopy  
- Indirect ophthalmoscopy  
- OCT (images should be sent to the central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant medication or therapy 
 IVT injection of IP 
• 
IP (SB15 or Eylea®) will be given in the study eye. 
 After IVT injection of IP 
• 
Ocular assessments: 
- Indirect ophthalmoscopy (0-15 min post-dose) 
- IOP using Goldmann applanation tonometry (30-60 min post-dose) 
• 
AE monitoring 
7.1.2.5. Visit 6 (Week 24 ± 7 days) 
 Before IVT injection of IP 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Blood sampling for immunogenicity 
• 
Blood sampling for PK for subjects participating in PK evaluation 
• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 


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potential 
• 
Ocular assessments: 
- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including OCT assessment) 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit 
- Slit lamp biomicroscopy  
- Indirect ophthalmoscopy  
- OCT (images should be sent to the central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant medication or therapy 
 IVT injection of IP 
• 
IP (SB15 or Eylea®) will be given in the study eye. 
 After IVT injection of IP 
• 
Ocular assessments: 
- Indirect ophthalmoscopy (0-15 min post-dose) 
- IOP using Goldmann applanation tonometry (30-60 min post-dose) 
• 
Blood sampling for PK for subjects participating in PK evaluation (on 1 day, 2 days, and 3 
days after the date of IVT injection of IP; total 3 times of PK sample collection for 3 
consecutive days) 
• 
AE monitoring 
7.1.2.6. Visit 7 (Week 32 ± 7 days) – Re-randomisation 
 Before IVT injection of IP 
• 
NEI VFQ-25 (prior to dilation of pupil) 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Blood and urine sampling for clinical laboratory tests 
- Urine samples must be collected before performing FA to avoid interference with 
fluorescein in urinalysis. 
• 
Blood sampling for immunogenicity 
• 
Blood sampling for PK for subjects participating in PK evaluation 


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• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 
potential 
• 
Ocular assessments: 
- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including FP/FA or OCT 
assessment) 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit 
- Slit lamp biomicroscopy  
- Indirect ophthalmoscopy  
- OCT (images should be sent to the central reading centre) 
- FP & FA (images should be sent to the central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant medication or therapy 
 IVT injection of IP 
• 
IP (SB15 or Eylea®) will be given in the study eye. 
 After IVT injection of IP 
• 
Ocular assessments: 
- Indirect ophthalmoscopy (0-15 min post-dose) 
- IOP using Goldmann applanation tonometry (30-60 min post-dose) 
• 
AE monitoring 
7.1.2.7. Visit 8 (Week 40 ± 7 days) 
 Before IVT injection of IP 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Blood and urine sampling for clinical laboratory tests 
• 
Blood sampling for immunogenicity 
• 
Blood sampling for PK for subjects participating in PK evaluation 
• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 
potential 
• 
Ocular assessments: 


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- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including OCT assessment) 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit 
- Slit lamp biomicroscopy  
- Indirect ophthalmoscopy  
- OCT (images should be sent to the central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant medication or therapy 
 IVT injection of IP 
• 
IP (SB15 or Eylea®) will be given in the study eye. 
 After IVT injection of IP 
• 
Ocular assessments: 
- Indirect ophthalmoscopy (0-15 min post-dose) 
- IOP using Goldmann applanation tonometry (30-60 min post-dose) 
• 
AE monitoring 
7.1.2.8. End of Treatment Visit (Visit 9, Week 48 ± 7 days) 
End of treatment (EOT) visit is defined as the visit for the last scheduled IVT injection of SB15 or 
Eylea®. The Sponsor will not provide IP (SB15 or Eylea®) to subjects after they complete the EOT visit. 
 Before IVT injection of IP 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 
potential 
• 
Ocular assessments: 
- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including OCT assessment) 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit 
- Slit lamp biomicroscopy 
- Indirect ophthalmoscopy 


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- OCT (images should be sent to the central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant medication or therapy 
 IVT injection of IP 
• 
IP (SB15 or Eylea®) will be given in the study eye. 
 After IVT injection of IP 
• 
Ocular assessments: 
- Indirect ophthalmoscopy (0-15 min post-dose) 
- IOP using Goldmann applanation tonometry (30-60 min post-dose) 
• 
AE monitoring 
7.1.3. End of Study (EOS) Visit (Visit 10, Week 56 ± 7 days) 
EOS visit is defined as 8 weeks (± 7 days) after the last scheduled IVT injection (i.e., Week 48) of IP. 
All subjects who complete the last scheduled IVT injection at Week 48 will conduct EOS visit. 
• 
NEI VFQ-25 (prior to dilation of pupil) 
• 
Physical examination (including body weight) 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Blood and urine sampling for clinical laboratory tests 
- Urine samples must be collected before performing FA to avoid interference with 
fluorescein in urinalysis. 
• 
Blood sampling for immunogenicity 
• 
Blood sampling for PK for subjects participating in PK evaluation 
• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 
potential 
• 
Ocular assessments: 
- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including FP/FA or OCT 
assessment) 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit 
- Slit lamp biomicroscopy 


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- Indirect ophthalmoscopy 
- OCT (images should be sent to the central reading centre) 
- FP & FA (images should be sent to the central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant medication or therapy 
7.1.4. Early Termination (ET) Visit 
Subjects who discontinue from the study at any time before study termination will be required to attend 
an ET visit. 
The ET visit is recommended to be performed at 8 weeks (± 7 days) after the last IVT injection of IP. 
When this schedule is not available (e.g., due to subject not available), the ET visit should still be 
performed as soon as available and no later than Week 56 from the first IVT injection of IP. 
In particular, for safety monitoring, if ET visit occurs before 7 weeks after the last IVT injection of IP, 
a follow-up visit or telephone interview will be pursued at 8 weeks (± 7 days) after the last IVT injection 
of IP in order to collect AEs and related concomitant medications. If a subject is not available, a follow-
up visit or telephone interview will be performed as soon as possible, but no later than Week 56 from 
the first IVT injection of IP. Every attempt shall be made to contact the subject for safety monitoring 
unless the subject has withdrawn his/her consent to collect safety-related information (Section 7.2.1). 
The following procedures will be performed: 
• 
NEI VFQ-25 (prior to dilation of pupil) 
• 
Physical examination (including body weight) 
• 
Vital signs (temperature, blood pressure, and pulse rate) 
• 
Blood and urine sampling for clinical laboratory tests 
- Urine samples must be collected before performing FA to avoid interference with 
fluorescein in urinalysis. 
• 
Blood sampling for immunogenicity 
• 
Pregnancy test (serum or urine at the Investigator’s discretion) for all women of childbearing 
potential 
• 
Ocular assessments: 
- BCVA examination using original series ETDRS charts or 2702 series Number charts 
(before dilation of the pupils and other ophthalmic procedures including FP/FA or OCT 
assessment) 
 
Subject must use the same type of chart consistently from Screening to Week 56 (EOS 
visit) or ET visit 


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- Slit lamp biomicroscopy 
- Indirect ophthalmoscopy  
- OCT (images should be sent to the central reading centre) 
- FP & FA (images should be sent to the central reading centre) 
- IOP using Goldmann applanation tonometry 
• 
AE monitoring 
• 
Review of concomitant medication or therapy 
If a subject discontinues the study treatment to receive other alternate treatment, ET visit should be 
performed prior to starting the alternate treatment (Section 7.2.1). 
7.1.5. Unscheduled visit 
Unscheduled visit is allowed during study period at the discretion of the Investigator, if deemed 
clinically necessary. Any tests, procedures, or assessments performed at the unscheduled visits will be 
recorded in the source documents and be entered in the eCRF if entry is available. 
 Discontinuation 
7.2.1. Subject Discontinuation from Study Treatment 
The subject must be permanently discontinued from IPs in the event of any of the following: 
• 
Consent withdrawal by subject 
- 
If the subject withdraws his/her consent, the Investigator must inquire the reasons for 
consent withdrawal as to whether it is related to the study (e.g., documented lack of 
efficacy, AE, or pregnancy); however, the subject could refuse to provide such reason. 
- 
If the main reason for consent withdrawal is considered related to the study, the 
Investigator may select the appropriate reason for withdrawal (other than just consent 
withdrawal) from a pre-defined list as below. 
• 
Any newly developed or aggravated ophthalmic abnormality other than AMD in the study eye 
which could interfere with evaluation of efficacy or safety of IP (e.g., retinal vascular 
abnormality, glaucoma, etc.) 
• 
Rhegmatogenous retinal detachment or full-thickness macular hole in the study eye 
• 
AEs in the study eye which in the opinion of the Investigator and/or subject would require IP 
discontinuation (e.g., intraocular inflammation, subretinal haemorrhage, vitreous haemorrhage, 
local infection, etc.)  
• 
Decision by the Investigator that the subject requires alternate treatment to treat neovascular 
AMD (e.g., other anti-VEGF agents, PDT, intravitreal gas injection, vitrectomy, or other 
surgical intervention) in the study eye 
Note: ET visit should be performed prior to starting the alternate treatment. 
• 
Development of DME in either eye 


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• 
Any other AEs and/or interventions considered intolerable as expose the subject to a risk that 
outweighs the benefits of participating in the study in the opinion of the Investigator and/or 
subject 
• 
Decision by the Sponsor that IP discontinuation is in the subject’s best medical interest 
• 
Protocol deviations which may adversely affect the subject’s safety and/or integrity of data as 
agreed by the Investigator and/or upon request from the Sponsor 
• 
IP non-compliance 
- 
A subject misses any of first two doses (IVT injection of IP at Week 0 [Day 1] and Week 4) 
after randomisation 
- 
A subject misses two consecutive doses during the study period after randomisation 
• 
Administrative decision by the Investigator and/or the Sponsor for a reason (e.g., a suspicion 
of fraud, the subject enrolling in multiple clinical studies, lack of compliance, etc.) other than 
that of an AE 
• 
Lost to follow-up 
Note: Before a subject is deemed lost to follow-up, the Investigator or designee will make 
every effort to regain contact with the subject. 
• 
Unmasking (except unmasking for the purpose of regulatory reporting) 
• 
Pregnancy of study subject 
• 
Death of any cause 
If a subject is prematurely discontinued from IP due to any of the above described reasons excluding 
death, the subject will complete the ET procedures (Section 7.1.4) and will be requested if he/she agrees 
to provide written consent for continuing the follow-up and further data collection subsequent to his or 
her ET visit. 
If a subject who is permanently discontinued from IP agrees to continue follow-up for associated clinical 
outcome information until Week 56, the consent form for ET subject shall be requested to be signed by 
the subject for this limited participation in the study, and the subject will continue to be assessed for all 
study endpoints per protocol until the subject withdraws consent or receives other non-protocol defined 
treatment, whichever occurs earlier. 
If a subject does not agree to continue follow-up of associated clinical outcome information, the subject 
will be terminated from the study accordingly. The data and blood samples collected on the subject up 
to ET visit remains in the study database and no further data will be collected. 
In all cases, the reason for IP discontinuation must be recorded in the eCRF and in the subject’s medical 
record. 
7.2.2. Discontinuation of Study Sites 
Investigational site participation may be discontinued if the Sponsor, the Investigator, or the Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) of the investigational site judge it necessary 
for any reason. Health authorities and IRB/IEC will be informed about the discontinuation of the study 
sites in accordance with applicable regulations. 


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7.2.3. Discontinuation of the Study 
The Sponsor may terminate this study prematurely for reasonable cause provided that written notice is 
submitted to the Investigator, IRB/IEC, and relevant authorities in advance of the intended termination:  
• 
Unsatisfactory enrolment with respect to quantity or quality 
• 
Discontinuation of development of the study drug 
• 
The decision by the Sponsor to terminate the study based on medical/ethical, business 
decision/strategic, or study conduct-related reasons 
If the study is terminated or discontinued prematurely, the Sponsor will promptly notify to the 
Investigator. The Investigator may be informed of additional procedures to be followed in order to 
assure that adequate consideration is given to the protection of the subject’s welfare and best interests. 
Health authorities and IRB/IEC will be informed about the discontinuation of the study in accordance 
with applicable regulations. 
8. Safety Monitoring and Reporting 
 Adverse Events (AEs) 
8.1.1. Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject, clinical investigation subject administered the 
medicinal (investigational) product or other protocol-imposed intervention and which does not 
necessarily have to have a causal relationship with this treatment or intervention. An AE can therefore 
be an unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of any dose of a medicinal (investigational) product or other 
protocol-imposed intervention regardless of attribution. 
All AEs including ocular AEs in the study eye and/or fellow eye as well as non-ocular AEs will be 
collected from the time when the written informed consent is obtained from the subject until Week 56 
(EOS visit) or ET visit (including a follow-up visit or telephone interview). 
In particular, if the AMD is diagnosed in the fellow eye during the study period, this event should be 
also reported as an AE. 
Pre-existing conditions and any abnormal findings from assessments at the time of Screening which are 
not related to protocol-imposed intervention (i.e., before the first IP administration) should not be 
reported as AEs, but reported among the medical history of the subject. However, pre-existing 
conditions which worsen (i.e., change in severity) that meet the definition of an AE during the study 
period are to be reported as AEs. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs assuming that the medical condition for which the procedure was performed is known. 
The underlying medical condition should be reported as AE accordingly. For example, an acute 
appendicitis that begins during the AE reporting period should be reported as an AE and the resulting 
appendectomy should be recorded as treatment of the AE. 
By definition, any event that emerges during IP treatment having been absent pre-treatment, or worsens 
relative to the pre-treatment state will be considered as a Treatment-emergent Adverse Event (TEAE). 
For the purposes of safety analysis, TEAEs will be collected and analysed. 


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8.1.2. Clinically Significant Abnormality 
If there are any abnormalities discovered during the laboratory test, physical examination, vital signs, 
and/or other safety assessments and the abnormality is assessed clinically significant by the Investigator, 
it should be reported as an AE. This does not apply to pre-existing conditions which have been 
documented at Screening or if the abnormality is consistent with a current diagnosis (underlying disease 
or other AEs). If it is not specified or defined elsewhere in the protocol, clinically significant 
abnormalities may include the events that led to a clinically significant intervention, including 
withdrawal of the IP treatment, significant additional concomitant medication, and others, upon medical 
judgement by the Investigator. 
If a clinically significant laboratory finding, or any other abnormality emerging from safety assessments, 
is not associated with a diagnosis of a disease or syndrome, the abnormality itself should be reported as 
an AE in the eCRF. If the abnormality can be characterised by a precise clinical term, the clinical term 
should be reported as the AE. For example, an elevated serum potassium concentration of 7.0 mEq/L 
should be reported as ‘hyperkalemia’. Observations of the same clinically significant abnormality from 
visit to visit should not be repeatedly reported as AEs in the eCRF, unless their severity grade, 
seriousness, or etiology changes. 
8.1.3. Period of Observation for Adverse Events 
All AEs (ocular or non-ocular), including SAEs, will be collected from the time of signing the written 
informed consent until Week 56 (EOS visit). However, if a subject would withdraw from the study prior 
to Week 56 (EOS visit), AEs and SAEs shall be collected as follows: 
• 
If the subject would withdraw after receiving the first dose of IP, AEs and SAEs should be 
actively collected up until the latter, either ET visit or a follow-up visit/telephone interview 
(Section 7.1.4). In addition, if the subject agrees to continue the follow-up of clinical-
associated outcomes until Week 56 (Section 7.2.1), data collected until week 56 will be also 
recorded. 
• 
If the subject would withdraw during the screening period, before enrolment, and/or before 
receiving the first dose of IP, AEs and SAEs should be collected up until the time the subject 
withdraws. 
Unresolved AEs should be followed up until Week 56 (EOS visit) or ET visit (including a follow-up 
visit or telephone interview), as available and consented to by the subject, and the collected follow-
up information will be recorded in the eCRF. The Investigator should observe the AEs for appropriate 
medical care of the subject until AE resolution or stabilisation up to Week 56 (EOS visit) or ET visit 
(including a follow-up visit or telephone interview). 
8.1.4. Reporting Adverse Events 
AEs are to be reported in the eCRF and reviewed by the Investigator. When reporting an AE, a 
diagnosis (when possible and appropriate), rather than each individual sign and symptom, should be 
reported. 
Each AE is to be assessed to determine if it meets the criteria of an SAE (Section 8.2.1 for SAE 
definition). If an AE is classified as an SAE, it must be reported to the Sponsor, or its designated 
representative, promptly according to the timeline specified in Section 8.2.2. For an SAE, a diagnosis 
corroborated with a description of signs and symptoms as well as other supporting information (e.g., 
results of exams) that led to the diagnosis should be described in the SAE report form and reported 
to the Sponsor, or its designated representative, according to the procedures described in Section 


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8.2.2. 
8.1.5. Severity Assessment 
The Investigator is responsible for assessing and reporting the severity of AEs. 
Following classifications should be used to classify AEs: 
• 
Mild events are usually transient and do not interfere with the subject’s daily activities, 
• 
Moderate events introduce a low level of inconvenience or concern to the subject and may 
interfere with daily activities, 
• 
Severe events interrupt the subject’s usual daily activities. 
8.1.6. Causality Assessment 
The Investigator is responsible for assigning a causal relationship to each AE. The causal relationship 
between the IP and the AE should be defined as not related (no) or related (yes). 
Events should be classified as ‘related’ if there is a reasonable possibility that the IP caused the AE. 
This means that there are facts (evidence) or arguments to suggest a causal relationship. 
Events should be classified as ‘not related’ if there is no reasonable possibility that the IP caused the 
AE. 
8.1.7. Emergency Unmasking for Safety Reasons and Accidental Unmasking 
During the study period after randomisation, emergency unmasking should be considered only when 
knowledge of the treatment group assigned to the subject is deemed essential for the subject’s safety 
by the Investigator. In such situations, emergency unmasking may be performed by the Investigator 
(or designee) through the IWRS system. In case failure of unmasking through IWRS system, the 
Investigator will follow the manual unmaking process described in IWRS manual. 
Overall, the Investigator (or designee) is responsible for 1) identifying clinical courses or situations 
where the emergency medical care of a study subject requires knowledge of their masked treatment 
assignment, 2) implementing the emergency unmasking procedures with associated communication 
pathways, 3) documenting the reasons for unmasking and which parties were unmasked as 
appropriate, and 4) informing their local IRB/IEC and the Sponsor of all subjects whose assignment 
was unmasked. 
Similarly, in case of accidental unmasking (i.e., accidental in that it occurred but it was not deliberated 
by the Investigator), as soon as the Investigator becomes aware that the treatment group assigned to 
a subject is unmasked, the Investigator should promptly document the accidental unmasking and 
inform the Sponsor and the CRO (within 24 hours) of the unmasking occurrence as well as of possible 
route causes, if information is available. 
In general, pertinent information regarding the circumstances of unmasking of a subject’s treatment 
group must be documented in the subject’s source documents. This includes who performed the 
unmasking, the subject(s) affected, the reason for the unmasking, the date of the unmasking, and the 
relevant IP information.  
Important note: Emergency or accidental unmasking is one of the reasons for subject’s 
discontinuation from study treatment (Section 7.2.1). 


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8.1.8. Expectedness Assessment 
Expectedness of AEs will be assessed by reference safety information (RSI) in the Investigator’s 
Brochure (IB). The latest SmPC of Eylea®, Annex I of EPAR Product Information posted on the EMA 
website (https://www.ema.europa.eu/en) will be used as reference when assessing the expectedness 
of AEs for the reference product after database lock and planned unblinding or emergency unblinding. 
8.1.9. Withdrawal due to Adverse Events 
Subject’s withdrawal from the IP due to an AE should be distinguished from withdrawal due to 
personal reasons. Subjects withdrawn due to an AE are those who are discontinued from IP because, 
in the opinion of the Investigator, the risks related with the AE may outweigh the potential benefits 
of continuing the participation in the study. Thus, the decision of withdrawal due to an AE shall be 
taken by the Investigator in the subject’s best interest due to safety reasons. Subjects withdrawn due 
to an AE should be followed up for safety until the time point specified in Section 8.1.3. If subjects 
cannot be followed, the reason(s) will be documented by the Investigator (e.g., lost to follow-up, 
withdrawal of subject’s consent to be followed up). When a subject withdraws from the IP due to a 
SAE, the SAE must be reported and followed in accordance with the requirements outlined in Section 
8.2.2. 
 Serious Adverse Events 
8.2.1. Definition of Serious Adverse Event 
An SAE is any untoward medical occurrence at any dose that: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability/incapacity 
• 
Results in congenital anomaly/birth defects 
• 
Is medically important 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalisation. However, if it is determined that the event may 
jeopardise the subject and may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious. 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 hospitalisation or development of drug dependency or drug abuse. 
The term ‘severe’ is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as ‘serious’, which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to a subject’s 
life or functioning. 
In addition, sight-threatening ocular adverse event will be reported as SAE if it meets one or more of 
the following criteria: 


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• 
A decrease in visual acuity of ≥ 30 letters from the last assessment of visual acuity 
• 
A decrease in visual acuity to the level of light perception or worse 
• 
Severe intraocular inflammation (e.g., 4+ anterior chamber cell/flare or 4+ vitritis) 
• 
Requirement of surgical intervention to prevent permanent loss of vision (e.g., vitrectomy, 
vitreous tap or biopsy with IVT injection of antibiotics, laser treatment, IVT gas injection, or 
retinal cryopexy) 
• 
In the investigator’s opinion, medical intervention may be required to prevent permanent loss 
of vision 
8.2.1.1. Life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
8.2.1.2. Hospitalisation 
AEs reported from clinical studies associated with inpatient hospitalisation or prolongations of 
hospitalisation are considered serious. 
Any admission to a healthcare facility more than 24 hours meets these criteria. Admission also 
includes transfer within the hospital to an acute/intensive care unit (e.g., from the medical floor to a 
coronary care unit, neurological floor to a tuberculosis unit). Staying at the observation unit in the 
emergency room for more than 24 hours qualifies for hospitalisation. 
Any events leading to a subsequent emergency room visit or inpatient hospitalisation for less than 24 
hours may be regarded as medically important for its seriousness criteria, at the discretion of the 
Investigator based on medical judgement. 
Hospitalisation or prolongation of hospitalisation in the absence of a precipitating clinical AE is not 
in itself an SAE. Examples include: 
• 
Admission for treatment of a pre-existing (prior to ICF signed) condition not associated with 
the development of a new AE or with a worsening of the pre-existing condition 
• 
Diagnostic admission (e.g., for work-up of persistent pre-treatment laboratory abnormality) 
• 
Social admission (e.g., study subject has no place to sleep) 
• 
Administrative admission (e.g., for a regular check-up) 
• 
Protocol-specified admission during a clinical study (e.g., for a procedure required by the study 
protocol) 
• 
Elective admission not associated with an AE (e.g., for elective cosmetic surgery) 
• 
Pre-planned treatments or surgical procedures 
: Pre-planned treatments or surgical procedures should be noted in the relevant source 
document for the individual subject. 


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8.2.2. Reporting Serious Adverse Events 
SAEs will be collected as generally specified in Section 8.1.3 and, in case of ET visit, as detailed in 
Section 7.1.4. All SAEs must be reported to the Sponsor or its designated representative via eCRF 
SAE report form at least within 24 hours of the Investigator becoming aware of the event. A paper 
SAE form can be used as backup in every case when the electronic form would not be available. 
Date and time (wherever possible) of the Investigator becoming aware of the SAE will be recorded 
in the SAE form and source document as appropriate. 
In particular, if the SAE is fatal or life-threatening, the Sponsor must be notified immediately (within 
24 hours), irrespective of the extent of available AE information. This timeframe also applies to 
additional (follow-up) information that becomes available on previously forwarded SAE reports. The 
Sponsor will then apply expedited reporting procedures according to local and international 
regulations as appropriate. 
The Investigator is obligated to pursue and provide information to the Sponsor on all SAEs in 
accordance with the required reporting timeframe of 24 hours from the Investigator’s awareness. In 
addition, the Investigator may be requested by the Sponsor to obtain specific additional follow-up 
information in an expedited fashion. In general, this will include a description of the SAE, which 
should be provided in sufficient detail so as to allow for a complete medical assessment of the case 
and independent determination of possible causality. Information on other possible causes of the 
event, such as concomitant medications and illnesses must be provided. In the case of a subject death, 
if an autopsy is performed upon consent from responsible parties, a summary of available autopsy 
findings must be submitted as soon as possible to the Sponsor or its designated representative. 
Follow-up information for the SAE should be actively sought and submitted by the Investigator as 
the information becomes available. 
 Adverse Events of Special Interest (AESI) 
The following AEs in the study eye will be classified as AESIs in this study: 
• 
Intraocular pressure increase 
- 
New onset pre-injection IOP of ≥ 25 mmHg 
- 
Post-injection IOP ≥ 35 mmHg 
• 
Any case of intraocular infection (suspected infection) such as endophthalmitis 
• 
Any case of non-infectious intraocular inflammation such as iritis, vitritis, and iridocyclitis 
• 
Iatrogenic traumatic cataract 
• 
Retinal pigment epithelial tear 
• 
Subretinal haemorrhage with the size of 1 DA or more involving the centre of the fovea, or if 
the size of the haemorrhage is ≥ 50% of the total lesion area 
Other, non-ocular, AESIs include the following: 
• 
Arterial thromboembolic events including non-myocardial infarction ATEs and cardiovascular 
ischaemic events 
• 
Non-ocular haemorrhage 


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 Reporting Visual Acuity-related Adverse Event 
• 
A decrease in visual acuity of ≥ 15 letters from the last assessment of visual acuity should be 
reported as AE/SAE as appropriate 
• 
A decrease in visual acuity of ≥ 30 letters from the last assessment of visual acuity should be 
reported as SAE. 
• 
A decrease in visual acuity to the level of light perception or worse should be reported as SAE 
 Pregnancy 
Any pregnancy, including those of female partners of male subjects treated with the IP, should be 
reported to the Sponsor. If the female partner of a male subject becomes pregnant, a written consent 
must be obtained from the female partner before collecting any pregnancy-related information. All 
pregnancies associated with the subject, from the time the subject receives the first IVT injection of 
IP until either Week 56 (EOS visit) or ET visit, should be reported to the Sponsor. Pregnancy reports 
should be submitted to the Sponsor within 24 hours from when the Investigator became aware of the 
pregnancy, using the pregnancy report form. 
Although pregnancy is not an AE, all pregnancies must be followed up every 2 months until 6-8 
weeks after the outcome of the pregnancy becomes available, unless the subject is lost to follow-up. 
The pregnancy outcome should be notified to the Sponsor by submitting a follow-up pregnancy report 
form. If the outcome of the pregnancy meets SAE criteria then the Investigator should report this case 
according to the SAE reporting process (Section 8.2.2). 
 Independent Data and Safety Monitoring Board 
An independent DSMB will be assigned for this study. The DSMB will consist of external experts 
(e.g., physician, clinical pharmacologists, or biostatisticians) and will review the safety and 
tolerability data from the study at pre-specified intervals. The details of the safety data and time points 
for review will be described in the DSMB Charter and in the DSMB statistical analysis plan (SAP). 
In addition, an ongoing masked review of AEs, including clinical laboratory data will be continuously 
undertaken by the Sponsor medical monitor and pharmacovigilance team. 
9. Statistical Methods and Data Analysis 
Further information on the statistical methods to be used in this study will be provided in the SAP, 
which will be finalised prior to the database lock for reporting the main CSR. 
Statistical analysis and reporting will be performed as follows: 
• 
Interim safety analysis for independent DSMB meeting: 
A DSMB SAP, describing the methodology and presentation of results and access to results 
will be prepared as a separate document. The safety reports for the DSMB data review 
meetings will be prepared according to the DSMB SAP.  
The statistical analysis will be performed by an independent statistical reporting team and 
the results will be communicated to the DSMB directly by an independent unmasked 
statistician. 
• 
Main CSR: 


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The main analysis will take place once all subjects complete the procedures at Week 24, or 
its corresponding visit. Available efficacy and safety data, PK, and immunogenicity data will 
be analysed and reported. 
At the time of this reporting, a limited number of identified individuals of the Sponsor or 
CRO will be unmasked for reporting purpose. However, subjects, Investigators, and other 
study personnel will remain masked throughout the entire study period. 
• 
Final CSR: 
The final analysis will take place after the last subject completes the procedures at Week 56 
or the corresponding visit. All study data will be analysed and reported for final CSR. 
 Statistical Hypotheses 
This is a study to demonstrate equivalence in change from baseline in BCVA at Week 8 between SB15 
and Eylea®. The null hypothesis tested for the primary efficacy analysis is that either (1) SB15 is inferior 
to Eylea® or (2) SB15 is superior Eylea® based on a pre-specified equivalence margin. 
The equivalence between the two treatment groups will be declared if the 90% confidence interval (CI) 
of the difference is entirely contained within the pre-defined margin of [-3 letters, 3 letters]. The 90% 
CI of the difference between the changes from baseline in BCVA at Week 8 of the two treatment groups 
will be estimated for the Full Analysis Set (FAS). 
For the EMA submission, equivalence between the two treatment groups will be declared if the 95% CI 
of the difference is entirely contained within the pre-defined equivalence margin of [−3 letters, 3 letters]. 
The 95% CI of the difference between the two treatment groups in relation to the change from baseline 
in BCVA at Week 8 will be estimated for the FAS. 
 Analysis Sets 
The following sets will be used for the analyses performed in the study: 
• 
Randomised Set (RAN) consists of all subjects who receive a randomisation number at the 
randomisation visit. 
• 
FAS consists of all randomised subjects. Following the intent-to-treat principle, subjects will 
be analysed according to the treatment group they are assigned to at randomisation. However, 
subjects who do not have any efficacy assessment result after randomisation and do not receive 
IP during the study period will be excluded from FAS. 
• 
Per-Protocol Set (PPS) consists of all FAS subjects who have BCVA assessment result at 
baseline and Week 8 without any major protocol deviations (PDs) that have impact on the 
BCVA assessment. Major PDs that will lead to exclusion from this set will be pre-defined prior 
to unmasking the treatment group assignment for analyses. 
• 
Safety Set 1 (SAF1) consists of all subjects who receive at least one IP during the study period. 
Subjects will be analysed according to the IP received. 
• 
Safety Set 2 (SAF2) consists of all subjects in the SAF1 who receive at least one IP after 
re-randomisation at Week 32. Subjects will be analysed according to the IP received. 
• 
PK Analysis Set (PKS) consists of all subjects in the SAF1 who participate in PK evaluation 
at PK investigational sites (PK subjects) and have at least one serum concentration data. 


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 Subject Demographic and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarised by treatment group for the RAN 
and PKS. Continuous variables (e.g., age, weight, height) will be summarised with descriptive statistics 
(n, mean, standard deviation [SD], median, minimum, maximum) and categorical variables (e.g., gender, 
race, ethnicity) will be summarised with frequency and percentage. 
Comparison between treatment groups in baseline characteristics will be performed using the chi-square 
test or F-test as appropriate. The results of these tests will be provided including the p-value only for 
descriptive purposes and will not be used as a formal basis to determine the factors to be included in 
primary or secondary efficacy analysis models. If baseline imbalances are detected for any of the factors, 
additional analyses may be performed to adjust for these baseline differences. 
Relevant medical and ophthalmic history will be summarised by treatment group for the RAN. 
Duration of exposure to IP and number of injections will be summarised descriptively by treatment 
group for the SAF1. Prior and concomitant medications will be summarised by treatment group with 
frequency and percentage. 
 Analysis of the Primary Objective 
The primary efficacy analysis will aim to demonstrate equivalence in terms of change from baseline in 
BCVA at Week 8 between SB15 and Eylea®.  
The primary efficacy analysis will be performed for the FAS with the change from baseline in BCVA at 
Week 8 using an analysis of covariance model with the baseline BCVA as a covariate and region (or 
pooled centres) and treatment group as factors. The equivalence between the two treatment groups will 
be declared if the two-sided 90% CI of the difference of Least Squares mean (LSMean) of change from 
baseline in BCVA at Week 8 is entirely contained within the pre-defined equivalence margin of [−3 
letters, 3 letters]. The same analysis will be performed for the PPS as a sensitivity analysis. 
For the EMA submission, the primary efficacy analysis will be performed for the FAS with the change 
from baseline in BCVA at Week 8 using an analysis of covariance model with the baseline BCVA as a 
covariate and region (or pooled centres) and treatment group as factors. The equivalence between the 
two treatment groups will be declared if the two-sided 95% CI of the difference of LSMean of change 
from baseline in BCVA at Week 8 is entirely contained within the pre-defined equivalence margin of 
[−3 letters, 3 letters]. The same analysis will be performed for the PPS as a sensitivity analysis. For 
those subjects who drop out of the study prematurely, a multiple imputation will be used under the 
missing at random assumption. The 95% CI of the difference between the two treatment groups will 
also be estimated for the FAS as supportive analysis. 
 Analysis of the Secondary Objectives 
9.5.1. Efficacy Variable Analyses 
As the secondary efficacy endpoints, change from baseline in BCVA, CST, TRT, and CNV area will be 
summarised descriptively by treatment group and visit.  
Proportion of subjects who lost fewer than 15 letters and gained 15 letters or more in BCVA compared 
to baseline, subjects with intra- or sub-retinal fluid, and subjects with active CNV leakage will be 
summarised descriptively by treatment group and visit. 
The two-sided 95% CI of the LSMean difference of change from baseline in secondary efficacy 
endpoints between the two treatment groups will be estimated. 


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9.5.2. Safety Analyses 
Safety analyses will be performed for main period, transition period, and overall study period unless 
specified otherwise. Analyses for main and transition period will be performed in the SAF1 and SAF2 
respectively and analyses for the overall study period will be performed in the SAF1. 
All reported terms for AEs (ocular or non-ocular) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®). AEs including ocular AEs in the study eye and/or fellow eye as well 
as non-ocular AEs will be summarised descriptively by treatment group. Intraocular inflammation will 
also be summarised similarly. 
Change in intraocular pressure, vital signs, and clinical laboratory parameters will be summarised 
descriptively by treatment group and visit. All other safety variables will be summarised descriptively 
by treatment group and visit unless specified otherwise. 
9.5.3. Pharmacokinetic Analyses 
Blood samples for PK assessment will be collected in approximately 40 subjects participating in PK 
evaluation (20 subjects per treatment group in initial randomisation at Week 0 [Day 1]). The systemic 
exposure will be summarised descriptively by treatment group and visit. If fellow eye received Eylea® 
during the study period after randomisation, the concentration measured after treatment for the fellow 
eye will be listed, but excluded from the summary statistics. 
9.5.4. Immunogenicity Analyses 
The number and proportion of subjects with ADA and NAb results (e.g., ‘positive’ or ‘negative’) will 
be summarised by treatment group and visit. If fellow eye received Eylea® during the study period after 
randomisation, the ADA and NAb results obtained after treatment for the fellow eye will be listed, but 
excluded from the summary statistics. 
 Exploratory analyses 
Proportion of subjects with sub-RPE fluid on OCT at Week 32 and Week 56 will be summarised 
descriptively by treatment group and visit. 
For NEI VFQ-25 as a measurement of QOL, subscale scores (general health, general vision, ocular pain, 
near activities, distance activities, vision-specific social functioning, vision-specific mental health, 
vision-specific role difficulties, vision-specific dependency, driving, colour vision, and peripheral 
vision) and the composite score, which represent overall visual function, will be calculated, and the 
change from baseline will be summarised by treatment group and visit. 
 Sample Size Calculations 
For the calculation of the equivalence margin for BCVA, the mean changes in BCVA were referred from 
VIEW1 study of Eylea® in subjects with neovascular AMD.  
In the VIEW1 study of SmPC of Eylea®, the mean change of BCVA at Month 12 (SD) was 10.9 (13.8) 
letters for the dosing of 2 mg every 4 weeks Eylea® treatment group and the LSMean difference between 
Eylea® and Lucentis® (ranibizumab) with its 95% CI was 3.15 (0.92, 5.37) letters. 
The US FDA Guidance describes that if the active control (Eylea® in this study) has shown superiority 
to other active treatments (Lucentis® in VIEW1) in the past, the difference demonstrated (3.15 letters) 
represents a conservative estimate of historical evidence of sensitivity to drug-effects, one that could 
serve as a basis for choosing M1. Therefore, the equivalence margin of 3 letters, which would be less 


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than the LSMean difference in VIEW1 study, which proved statistical superiority to ranibizumab. 
The ETDRS chart has 5 letters in one line (that is the minimum limit for visual acuity change) and thus 
the difference more than 5 letters in BCVA could be considered as a minimal clinically important 
difference. In addition, most of the anti-VEGF non-inferiority clinical trials on AMD also used a non-
inferiority margin of 5 letters. Therefore, the equivalence margin of [−3 letters, 3 letters] is considered 
to be a conservative margin to test the clinical equivalence between SB15 and Eylea®. 
With the equivalence limit of [−3 letters, 3 letters], 216 subjects per treatment group was calculated 
with the assumptions of the mean difference of 0.5 letters and SD of 9.0 at the overall 5% significance 
level, providing 80% power to reject the null hypothesis. Overall 446 subjects (223 per treatment group) 
will give 216 completers per treatment group assuming a 3% loss from the randomised subjects. 
The nQuery Advisor® option two one-sided equivalence tests (TOST) for two-group design gives the 
following statement to estimate the n per group to show the equivalence: “When the sample size in each 
group is 216, a two group design will have 80% power to reject both the null hypothesis that the test 
mean minus the standard mean is below -3 and the null hypothesis that the test mean minus the standard 
mean is above 3 i.e., that the test and standard are not equivalent, in favor of the alternative hypothesis 
that the means of the two groups are equivalent, assuming that the expected difference in means is 0.5, 
the common standard deviation is 9 and that each test is made at the 2.5% level.” 
With the equivalence limit of [−3 letters, 3 letters] for the US FDA submission, 173 subjects per 
treatment group (overall sample size of 346) was calculated with the assumptions of the mean difference 
of 0.5 letters and SD of 9.0 at the overall 10% significance level, providing 80% power to reject the 
null hypothesis. 
The nQuery Advisor® option two one-sided equivalence tests for two-group design gives the following 
statement to estimate the n per group to show the equivalence: “When the sample size in each group is 
173, a two group design will have 80% power to reject both the null hypothesis that the test mean minus 
the standard mean is below -3 and the null hypothesis that the test mean minus the standard mean is 
above 3 i.e., that the test and standard are not equivalent, in favor of the alternative hypothesis that the 
means of the two groups are equivalent, assuming that the expected difference in means is 0.5, the 
common standard deviation is 9 and that each test is made at the 5% level.” 
Therefore, the sample size of 446 allows enough power to detect the equivalence in both situations. 
10. Data Collection and Management 
 Data Confidentiality 
Information about study subjects will be kept confidential. Subject identification information will be 
labelled with a code number, and will not include the subject’s name or other information that could 
identify them. A list linking the code and the subject’s name will be kept in the investigational site files 
as required by International Council for Harmonisation (ICH) E6 (R2) Good Clinical Practice (GCP) to 
protect the subject’s confidentiality. 
The coded information will be sent to the Sponsor (or designee) who will analyse it and report the study 
results both to regulatory and ethical authorities. The Sponsor may also place data on public websites 
or publish journal articles based upon these results. Subject names or other directly identifiable 
information will not appear on any reports, publications, or other disclosures of clinical study outcomes. 
Care will be taken to prevent subjects being identified through these publications. In addition, data may 
be shared with other companies or researchers to aid further research into AMD. Such data sharing 
practices will be covered by confidentiality agreements. No-one outside the investigational site will 


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have access to subject-identifiable information. 
 Monitoring 
The Sponsor has engaged the services of a CRO to perform all monitoring functions within this clinical 
study. The monitors will work in accordance with the CRO standard operation procedures (SOPs) and 
have the same rights and responsibilities as monitors from the Sponsor organisation. Monitors will 
establish and maintain regular contact between the Investigator and the Sponsor. 
Monitors will evaluate the competence of each investigational site and inform the Sponsor about any 
problems relating to facilities, technical equipment, or medical staff. During the study period, monitors 
will check that written informed consent has been obtained correctly from all subjects and that data are 
recorded correctly and completely. Monitors will also perform source data verification by comparing 
entries in the eCRF with corresponding source data and informing the Investigator of any errors or 
omissions. Monitors will verify adherence to the protocol at the investigational site. All protocol 
deviations will be reported to the Sponsor via the Monitoring Visit Reports. Monitors will arrange for 
the supply of IP and ensure appropriate storage conditions are maintained. 
Monitoring visits will be conducted at regular intervals according to ICH E6 (R2) GCP. The monitor 
will provide written reports to the Sponsor on each occasion they make contacts with the Investigator 
regardless of whether it is by phone or in person. 
Further details on the monitoring processes and the level of source data verification to be performed 
will be outlined in the monitoring plan. 
 Data Handling and Record Keeping 
The Investigator must maintain essential study documents including protocol and protocol amendments, 
completed eCRFs, signed written ICFs and its revisions/updates, completed eCRFs, other relevant 
correspondence according to ICH E6 (R2) GCP, and other relevant study requirements (if applicable) 
until at least 2 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 2 years after the 
formal termination of clinical development of the IP or 15 years from completion of the study, or 
whichever longer according to the relevant local laws and/or regulations. These documents should be 
retained for a longer period if required by the applicable regulatory requirements or the investigational 
site, institution or private practice in which the study is being conducted. Subject identification codes 
(subject names and corresponding study numbers) will be retained for the same period of time. These 
documents may be transferred to another responsible party, deemed acceptable by the Sponsor, and who 
agrees to abide by the retention policies. Written notification of transfer must be submitted to the 
Sponsor. The Investigator must contact the Sponsor prior to disposing of any study records and obtain 
written permission to do so. 
 Future Use of Stored Specimens and Data 
The Sponsor or designated representative can store PK and/or immunogenicity samples for maximum 
7 years after the end of the clinical study. The Sponsor or designated representative should operate under 
the same regulations related to and take the same responsibility to save personal data. The sample may 
be used for additional assay to be performed if considered scientific relevant or requested by regulatory 
authorities in order to have the possibility to perform the assay. 
 Database Management and Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the data 


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management of the Sponsor (or an appropriate company designated by the Sponsor to perform these 
activities). The study eCRF is the primary data collection instrument for the study. Subject data will be 
captured in an eCRF and reviewed by the monitor in order to check adherence to the protocol and to 
detect any data inconsistency or discrepancy from source document. 
The Investigator must ensure that the clinical data required by the study protocol are carefully reported 
in the eCRF. He/she must also check that the data reported in the eCRF correspond to those in the 
medical records. The investigator will sign all collected data in eCRF. 
Data must be entered into eCRFs in English by the designated investigational site staffs in a timely 
manner. Source documents should be available during periodic visits by study monitors to enable review 
for completeness and acceptability. Any correction to the data entered into the eCRF must be carried 
out by the Investigator or a designated member of staff. These changes may be made either on the 
initiative of the investigational site staff or in response to monitoring or data queries. Any changes to 
written data must be made using ICH E6 (R2) GCP corrections and any change to electronic data should 
be made in a system which can provide an audit trail. Monitors and clinical data managers will review 
the eCRF for accuracy and can generate queries to the investigational staff for resolution. Corrections 
will be recorded in an audit trail that records the old information, the new information, and identification 
of the person making the changes, date of correction made and reason for change. The Investigator must 
sign and date the eCRF pages as indicated. 
Medical/surgical history and underlying diseases and AEs will be coded using MedDRA®. Concomitant 
medications will be coded using the World Health Organisation-Drug Dictionary Enhanced (WHO-
DDE). The versions of coding dictionaries used will be stated in the clinical study report. 
 Quality Control and Quality Assurance 
During the conduct of the study, the Sponsor or its agent will conduct periodic monitoring visits to 
ensure that the protocol and ICH E6 (R2) GCP are being followed. The monitors may review source 
documents to confirm that the data recorded on the eCRFs are accurate. The Investigator and institution 
will allow the domestic and foreign regulatory authorities, sponsor’s monitors and auditors’ direct 
access to source documents to perform this verification. The investigational site may be subject to 
review by the IRB/IEC, and/or to quality assurance audits performed by the Sponsor, and/or to 
inspection by appropriate regulatory authorities. It is important that Investigators and their relevant 
personnel are available during the monitoring visits and possible audits or inspections and that sufficient 
time is devoted to the process. 
 Protocol Deviation (PD) 
PDs will be pre-defined prior to subject enrolment and documented separately named as ‘protocol 
deviation definition list’ which includes category (e.g., violation of inclusion/exclusion criteria, use of 
prohibited medication, non-compliance with treatment), deviation description, severity (major or 
minor), time point for protocol deviations. Major PDs are defined as those deviations from the protocol 
likely to have an impact on the perceived efficacy and/or safety of study treatments. 
PDs will be reviewed and confirmed prior to database lock to decide which subjects and/or subject data 
will be excluded from certain analyses. Decisions regarding the exclusion of subjects and/or subject 
data from analyses will be documented and approved prior to database lock. 


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11. Ethics Considerations and Administrative procedures 
 Institutional Review Boards (IRB) and Independent Ethics Committees (IEC) 
The Investigator and the Sponsor will follow all local laws and regulations relating to contact with and 
approvals from IRB/IEC. 
The Investigator must provide the Sponsor with documentation of IRB/IEC approval of the protocol 
and written informed consent before the study may begin at the investigational site. The Investigator 
will supply documentation to the Sponsor relating to the annual renewal of the protocol from the 
IRB/IEC and any approvals of revisions to the ICF or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC any new information that may adversely affect 
the safety of subjects or the conduct of the study. Similarly, the Investigator will submit written 
summaries of the study status to the IRB/IEC on a regular basis and in accordance with the timelines 
required locally. Upon completion of the study, the Investigator will provide the ethics committee with 
a report on the outcome of the study if required by local regulations. 
 Ethical Conduct of the Study 
This study will be conducted and informed consent will be obtained from each subject according to the 
ethical principles stated in the Declaration of Helsinki (2013), the applicable guidelines for ICH E6 (R2) 
GCP, and the applicable drug and data protection laws and regulations of the countries where the study 
will be conducted. 
 Written Informed Consent 
The written informed consent will be used to explain the risks and benefits of study participation to the 
subject in simple terms prior to any study related procedures. The written informed consent contains a 
statement that the consent is freely given, that the subject is aware of the risks and benefits of entering 
the study, and that the subject is free to withdraw from the study at any time. Written consent must be 
given by the subject after the receipt of detailed information on the study. 
The Investigator is responsible for ensuring that informed consent is obtained from each subject and for 
obtaining the appropriate signatures and dates on the written informed consent prior to the performance 
of any protocol procedures and prior to the first IVT injection of IP. The Investigator will provide each 
subject with a copy of the signed and dated written informed consent and this will be documented in 
the subject’s source notes. Depending on local regulation, authorized site staff can obtain the ICF 
subjects as well. Before informed consent may be obtained, the Investigator, or a person designated by 
the Investigator, should provide the subject or the subject’s legally acceptable representative ample time 
and opportunity to inquire about details of the trial and to decide whether or not to participate in the 
study. Prior to a subject’s participation in the study, the written ICF should be signed and personally 
dated by the subject or by the subject’s legally acceptable representative, and by the person who 
conducted the informed consent discussion. 
If the subject is legal blindness or illiterate, an impartial witness should be present during the entire 
informed consent discussion. After the written informed consent and any other written information to 
be provided to subjects is read and explained to the subject/impartial witness, and after the 
subject/impartial witness has orally consented to the subject’s participation in the study. The subject (if 
capable of doing so) and/or the impartial witness will personally sign and date the written informed 
consent. In case both subject and impartial witness will sign the ICF, the subject will sign first. In 
particular, by signing the written informed consent, the impartial witness attests that the information in 


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the written informed consent and any other written information was accurately explained to the subject 
and apparently understood by the subject, and that written informed consent was freely given by the 
subject. 
 Investigator Information 
11.4.1. Investigator Obligations 
This study will be conducted in accordance with the ICH E6 (R2) GCP, the ethical principles that have 
their origin in the Declaration of Helsinki (2013), and other local laws and/or regulations. 
The Investigator is the qualified physician who is responsible for ensuring that the study is conducted 
according to the signed the Investigator statement, the study protocol and applicable regulations; for 
protecting the rights, safety and welfare of subjects under the Investigator’s care; and for the control of 
drugs under investigation. The Investigator must obtain the written informed consent of each subject to 
whom IP will be administered. The Investigator is also responsible for supervising any individual or 
party who conducts study-related duties at investigational site to ensure the integrity. 
11.4.2. Training of Investigator Site Personnel 
Before the first subject is enrolled into the study, a Sponsor representative will review and discuss the 
requirements of the Clinical Study Protocol and related documents with the investigational staff and 
will also train them in any study-specific procedures. 
The Investigator will ensure that appropriate training relevant to the study is given to all investigational 
site staff and that any new information relevant to the performance of this study is forwarded to the 
investigational site staff involved. 
The Investigator will maintain a record of all individuals involved in the study (medical, nursing, and 
other investigational site staff). 
11.4.3. Protocol Signatures 
The Investigator must sign the Investigator Signature Page of this protocol prior to enrolling subjects 
in the study. By signing the protocol signature page, the Investigator attests in writing that he or she has 
read, understood, and will conduct the study in accordance with the study protocol, ICH E6 (R2) GCP, 
and other relevant local laws and/or regulations. 
11.4.4. Financing and Insurance 
Samsung Bioepis Co., Ltd. is the Sponsor of this study and will support the financial aspects for the 
study conduct at the investigational site. 
Details of financial agreements are provided in the Clinical Study Agreements with the investigational 
sites. The Sponsor has obtained suitable insurance for this study. The insurance details may be provided 
to the investigational sites and/or Investigators who are responsible for providing the IRB/IEC with 
these details according to local requirements if any. 
12. Publication Policy 
The Sponsor supports the efforts of health authorities to increase the transparency of medical research 
conducted in human subjects. The Sponsor will register and maintain the information of clinical studies 
on a public registry program. The Sponsor is committed to the public disclosure of the results from 
clinical studies through posting on public clinical study data banks. The Sponsor will comply with the 


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guidelines of regulatory authorities with regards to public registration and disclosure of clinical study 
data. 
The clinical study data collected during the study are confidential and proprietary to the Sponsor. 
Sponsor shall have the right to delete any confidential or proprietary information contained in any 
proposed abstract or presentation. 
Any publications from this study should be approved by the Sponsor prior to publication or presentation. 
The rights of the Investigator with regard to publication of this study are described in the Clinical Study 
Agreement. 
 
 


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13. References 
[1] Age related macular degeneration – challenge for future: Pathogenesis and new perspectives for the 
treatment. 
European 
Geriatric 
Medicine. 
(Feb 
2015). 
Retrieved 
Jul 
16, 
2019 
from 
https://www.sciencedirect.com/science/article/pii/S1878764914001995?via%3Dihub 
[2] Eylea® EPAR – Product Information. EMA (Jul 09, 2019). Retrieved Jul 16, 2019 from 
https://www.ema.europa.eu/en/documents/product-information/eylea-epar-product-
information_en.pdf 
[3] Eylea® Prescribing Information. FDA (Aug 12, 2019). Retrieved Sep 26, 2019 from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125387s060lbl.pdf 
[4] Guideline on similar biological medicinal products containing biotechnology-derived proteins as 
active 
substance: 
non-clinical 
and 
clinical 
issues. 
EMA. 
(Dec 
18, 
2014). 
EMEA/CHMP/BMWP/42832/2005. 
Rev1. 
Retrieved 
Jul 
16, 
2019 
from 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-
products-containing-biotechnology-derived-proteins-active_en-2.pdf 
[5] Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference 
product. FDA. (Apr 2015). Retrieved Jul 16, 2019 from https://www.fda.gov/media/82647/download 
[6] Guideline on similar biological medicinal products containing biotechnology-derived proteins as 
active substance: quality issues (revision 1). EMA. (May 22, 2014). EMA/CHMP/BWP/247713/2012. 
Retrieved Jul 16, 2019 from https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active_en-0.pdf 
[7] Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related 
macular degeneration. Ophthalmology. 2012 Dec; 119 (12): 2537-48. 
[8] Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular 
age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014 
Jan; 121 (1): 193-201. 
[9] Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010; 376: 124-36. 
[10] Coscas G, Loewenstein A, Augustin A, et al. Management of retinal vein occlusion-consensus 
document. Ophthalmologica. 2011; 226: 4-28. 
[11] Hayreh SS, Podhajsky PA, Zimmerman MB. Natural history of visual outcome in central retinal 
vein. Ophthalmology. 2011; 118(1): 119- 33. 
[12] Chakravarthy U, Wong TY, Fletcher A, et al. Clinical risk factors for age-related macular 
degeneration: a systematic review and meta-analysis. BMC Ophthalmol. 2010; 10 (31): 1-13. 
[13] Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to 
neovascular maculopathy. Arch Ophthalmol. 1984; 102 (11): 1640-2. 
 
 


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APPENDIX A: Grading Scale for Anterior Chamber Flare 
Grading Scale for Anterior Chamber Flare 
Grade 
Description 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens details clear) 
3+ 
Marked (iris and lens details hazy) 
4+ 
Intense (fibrin or plastic aqueous) 
Reference: The Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for 
reporting clinical data: Results of the first international workshop. Am J Ophthalmol. 2005; 140 (3): 509-16. 


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APPENDIX B: Grading Scale for Anterior Chamber Cells 
Grading Scale for Anterior Chamber Cells 
Field size is 1 × 1 mm slit beam 
Grade 
Cells in Field 
0 
< 1 cell 
0.5+ 
1-5 cells 
1+ 
6-15 cells 
2+ 
16-25 cells 
3+ 
26-50 cells 
4+ 
> 50 cells 
Reference: The Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for 
reporting clinical data. Results of the first international workshop. Am J Ophthalmol. 2005; 140 (3): 509-16. 


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APPENDIX C: Grading Scale for Vitreous Haze 
Grading Scale for Vitreous Haze 
Grade 
Description 
0 
No evident vitreous haze at all 
0.5+ 
Trace inflammation, normal striations and reflex of nerve fiber layer not visible 
1+ 
Mild blurring of optic nerve head and retinal vessels 
2+ 
Moderate blurring of optic nerve head and retinal vessels  
3+ 
Optic nerve head visible, but the borders are quite blurry. 
4+ 
Optic nerve head obscured 
Reference: Nussenblatt RB, Palestine AG, Chan CC, et al. Standardization of vitreal inflammatory activity in intermediate and 
posterior uveitis. Ophthalmology. 1985 Apr; 92 (4): 467-71. 


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APPENDIX D: National Eye Institute 25-Item Visual Function Questionnaire (NEI 
VFQ-25 questionnaire) 
 
National Eye Institute  
Visual Functioning Questionnaire - 25 
(VFQ-25) 
 
Version 2000 
 
 
(INTERVIEWER ADMINISTERED FORMAT) 
 
 
 
January 2000 
 
 
RAND hereby grants permission to use the "National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25) July 1996, in accordance 
with the following conditions which shall be assumed by all to have been agreed to as a consequence of accepting and using this document: 
 
1.  Changes to the NEI VFQ-25 - July 1996 may be made without the written permission of RAND. However, all such changes shall be 
clearly identified as having been made by the recipient. 
2.  The user of this NEI VFQ-25 - July 1996 accepts full responsibility, and agrees to hold RAND harmless, for the accuracy of any 
translations of the NEI VFQ-25 Test Version - July 1996 into another language and for any errors, omissions, misinterpretations, or 
consequences thereof. 
3.  The user of this NEI VFQ-25 - July 1996 accepts full responsibility, and agrees to hold RAND harmless, for any consequences resulting 
from the use of the NEI VFQ-25. 
4.  The user of the NEI VFQ-25 - July 1996 will provide a credit line when printing and distributing this document or in publications of 
results or analyses based on this instrument acknowledging that it was developed at RAND under the sponsorship of the National Eye Institute. 
5.  No further written permission is needed for use of this NEI VFQ-25 - July 1996.  
 
7/29/96 
 


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Instructions: 
I’m going to read you some statements about problems which involve your vision or feelings that you 
have about your vision condition. After each question I will read you a list of possible answers. Please 
choose the response that best describes your situation. 
Please answer all the questions as if you were wearing your glasses or contact lenses (if any). 
Please take as much time as you need to answer each question. All your answers are confidential. In 
order for this survey to improve our knowledge about vision problems and how they affect your quality 
of life, your answers must be as accurate as possible. Remember, if you wear glasses or contact lenses 
for a particular activity, please answer all of the following questions as though you were wearing them. 
 
 


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Visual Functioning Questionnaire - 25 
 
 
PART 1 - GENERAL HEALTH AND VISION 
 
1. 
In general, would you say your overall health is*:  
 
 
(Circle One) 
READ CATEGORIES: 
Excellent ..........................................   1 
 
Very Good ........................................   2 
 
Good ................................................   3 
 
Fair ...................................................   4 
 
Poor .................................................   5 
 
2. 
At the present time, would you say your eyesight using both eyes (with glasses or contact lenses, if you 
wear them) is excellent, good, fair, poor, or very poor or are you completely blind? 
 
 
(Circle One) 
READ CATEGORIES: 
Excellent ..........................................   1 
 
Good ................................................   2 
 
Fair ...................................................   3 
 
Poor .................................................   4 
 
Very Poor .........................................   5 
 
Completely Blind .............................   6 
 
__________________________________________________________________________ 
* Skip Question 1 when the VFQ-25 is administered at the same time as the SF-36 or RAND 36-Item Health 
Survey 1.0 
 
 


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3. How much of the time do you worry about your eyesight? 
 
(Circle One) 
READ CATEGORIES: 
None of the time ............................................   1 
 
A little of the time ..........................................   2 
 
Some of the time ............................................   3 
 
Most of the time .............................................   4 
 
All of the time? ..............................................   5 
 
 
 
4. 
How much pain or discomfort have you had in and around your eyes (for example, burning, itching, or 
aching)? Would you say it is: 
 
(Circle One) 
READ CATEGORIES: 
None ................................................   1 
 
Mild .................................................   2 
 
Moderate ..........................................   3 
 
Severe, or .........................................   4 
 
Very severe? .....................................   5 
 
 
 
 


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PART 2 - DIFFICULTY WITH ACTIVITIES 
 
The next questions are about how much difficulty, if any, you have doing certain activities wearing your glasses 
or contact lenses if you use them for that activity. 
 
5. 
How much difficulty do you have reading ordinary print in newspapers?  Would you say you have:  
 
(READ CATEGORIES AS NEEDED) 
 
(Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 
 
6. 
How much difficulty do you have doing work or hobbies that require you to see well up close, such as 
cooking, sewing, fixing things around the house, or using hand tools? Would you say: 
 
(READ CATEGORIES AS NEEDED) 
 
 (Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 
 


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7. 
Because of your eyesight, how much difficulty do you have finding something on a crowded shelf? 
 
(READ CATEGORIES AS NEEDED) 
 
(Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 
8. 
How much difficulty do you have reading street signs or the names of stores?    
 
(READ CATEGORIES AS NEEDED) 
 
(Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 


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9. 
Because of your eyesight, how much difficulty do you have going down steps, stairs, or curbs in dim light 
or at night?  
 
(READ CATEGORIES AS NEEDED) 
 
(Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 
10. 
Because of your eyesight, how much difficulty do you have noticing objects off to the side while you are 
walking along? 
 
(READ CATEGORIES AS NEEDED) 
 
(Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 
 


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11. 
Because of your eyesight, how much difficulty do you have seeing how people react to things you say? 
(READ CATEGORIES AS NEEDED) 
 
(Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 
 
 
12. 
Because of your eyesight, how much difficulty do you have picking out and matching your own clothes? 
 
(READ CATEGORIES AS NEEDED) 
 
(Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 
 


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13. 
Because of your eyesight, how much difficulty do you have visiting with people in their homes, at parties, 
or in restaurants? 
(READ CATEGORIES AS NEEDED) 
 
(Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 
 
14. 
Because of your eyesight, how much difficulty do you have going out to see movies, plays, or sports events? 
 
(READ CATEGORIES AS NEEDED) 
 
(Circle One) 
 
No difficulty at all ..............................................................................   1 
 
A little difficulty .................................................................................   2 
 
Moderate difficulty ............................................................................   3 
 
Extreme difficulty ..............................................................................   4 
 
Stopped doing this because of your eyesight .....................................   5 
 
Stopped doing this for other reasons or not  
interested in doing this........................................................................   6 
 
 
 
 
 
 
 


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15. 
Now, I’d like to ask about driving a car. Are you currently driving, at least once in a while? 
 
(Circle One) 
 
 
Yes ..................................... 1 Skip To Q 15c 
 
No ...................................... 2 
 
15a. 
IF NO, ASK: Have you never driven a car or have you given up driving? 
 
(Circle One) 
 
Never drove………… 1       Skip To Part 3, Q 17 
 
Gave up………………2 
 
15b. 
IF GAVE UP DRIVING: Was that mainly because of your eyesight, mainly for some other reason, 
or because of both your eyesight and other reasons? 
 
(Circle One) 
 
Mainly eyesight ……………………..1              Skip To Part 3, Q 17 
 
Mainly other reasons………………...2              Skip To Part 3, Q 17 
 
Both eyesight and other reasons……..3              Skip To Part 3, Q 17 
 
15c. 
IF CURRENTLY DRIVING: How much difficulty do you have driving during the daytime in 
familiar places? Would you say you have: 
 
(Circle One) 
 
 
No difficulty at all ..................................................  1 
 
A little difficulty ....................................................  2 
 
Moderate difficulty ................................................  3 
 
Extreme difficulty ..................................................  4 
 
 
 
 
 
 


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16.     How much difficulty do you have driving at night? Would you say you have:  
(READ CATEGORIES AS NEEDED) 
 
 
(Circle One) 
 
No difficulty at all ........................................................   1 
 
A little difficulty ...........................................................   2 
 
Moderate difficulty .......................................................   3 
 
Extreme difficulty ........................................................   4 
 
Have you stopped doing this because 
of your eyesight ...........................................................   5 
 
Have you stopped doing this for other  
reasons or are you not interested in  
doing this.......................................................................  6 
 
 
 
16a. 
How much difficulty do you have driving in difficult conditions, such as in bad weather, during 
rush hour, on the freeway, or in city traffic? Would you say you have:  
(READ CATEGORIES AS NEEDED) 
 
 
(Circle One) 
 
No difficulty at all ........................................................   1 
 
A little difficulty ...........................................................   2 
 
Moderate difficulty .......................................................   3 
 
Extreme difficulty ........................................................   4 
 
Have you stopped doing this because 
of your eyesight ...........................................................   5 
 
Have you stopped doing this for other  
reasons or are you not interested in  
doing this......................................................................   6 
 
 


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PART 3: RESPONSES TO VISION PROBLEMS 
 
The next questions are about how things you do may be affected by your vision. For each one, I’d like you to tell 
me if this is true for you all, most, some, a little, or none of the time. 
 
 
(Circle One On Each Line) 
 
READ CATEGORIES: 
All of the 
time 
 
Most of 
the time 
 
Some of 
the time 
 
A little of 
the time 
 
None of 
the time 
 
17. Do you accomplish  
less than you would  
like because of your vision? ..........  
1 
2 
3 
4 
5 
 
18. Are you limited in how long you can 
work or do other activities because  
of your vision? ...............................  
1 
2 
3 
4 
5 
 
19. How much does pain or discomfort 
in or around your eyes, for example, 
burning, itching, or aching, keep you 
from doing what you’d like to be 
doing? Would you say: ..................  
1 
2 
3 
4 
5 
 
 
 


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For each of the following statements, please tell me if it is definitely true, mostly true, mostly false, or definitely 
false for you or you are not sure. 
 
 
(Circle One On Each Line) 
 
Definitely 
True 
Mostly True 
Not  
Sure 
Mostly 
False 
Definitely 
False 
20. 
I stay home most of the time because of
my eyesight ................................................. 
1 
2 
3 
4 
5 
 
 
 
 
 
21. 
I feel frustrated a lot of the time because
of my eyesight .......................................  
1 
2 
3 
4 
5 
 
 
 
 
 
22. 
I have much less control over what I do,
because of my eyesight .........................  
1 
2 
3 
4 
5 
 
 
 
 
 
23. 
Because of my eyesight, I have to rely
too much on what other people tell me .  
1 
2 
3 
4 
5 
 
 
 
 
 
24. 
I need a lot of help from others because
of my eyesight .......................................  
1 
2 
3 
4 
5 
 
 
 
 
 
25. 
I worry about doing things that will 
embarrass myself or others, because of
my eyesight ...........................................  
1 
2 
3 
4 
5 
 
 
That’s the end of the interview. Thank you very much for your time and your help.  
 
 
 


PPD
PPD


SB15 (proposed aflibercept biosimilar) 
SB15-3001 
Version 1.0, Oct 30, 2019 
 
Samsung Bioepis – Confidential and Proprietary Information 
 
 
 
SIGNATURE PAGE 
Declaration of the Principal/Coordinating Investigator 
Protocol Title: A Phase III randomised, double-masked, parallel group, multicentre study to compare 
the efficacy, safety, pharmacokinetics, and immunogenicity between SB15 (proposed aflibercept 
biosimilar) and Eylea® in subjects with neovascular age-related macular degeneration 
This clinical study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational medicinal product, as well as 
with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration 
of Helsinki, 2013 and the guidelines on Good Clinical Practice applicable to this clinical study. 
 
Principal/Coordinating Investigator 
Name: 
 
Institution: 
 
Signature: 
 
Date: 
 
 
 
 
(MMM DD, YYYY) 
 
 
 
 

SAP_001.pdf: 
SB15 (proposed aflibercept biosimilar)  
SB15-3001 CSR SAP 
Amendment 1, May 10, 2022 
 
Samsung Bioepis – Confidential 
Page 1 of 47 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
A Phase III Randomised, Double-masked, Parallel Group, Multicentre 
Study to Compare the Efficacy, Safety, Pharmacokinetics, and 
Immunogenicity between SB15 (proposed aflibercept biosimilar) and 
Eylea® in Subjects with Neovascular Age-related Macular Degeneration 
 
 
 
 
 
 
 
 
 
Protocol Number 
SB15-3001 
Study Phase 
Phase III 
Type of analyses  
Clinical Study Report (CSR) 
Authors 
 
 
 
 
 
Version and Effective Date 
Amendment 1 
  May 10, 2022 
 
 
This document contains confidential information belonging to Samsung Bioepis Co., Ltd. 
Your acceptance or review of this document constitutes agreement that you will not copy 
or disclose the information contained herein to others or use it for unauthorised purposes 
without written authorization from the Sponsor. 
 
 
PPD


SB15 (proposed aflibercept biosimilar)  
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Amendment 1, May 10, 2022 
 
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MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorised Version 
Draft 0.1 
Aug 05, 2020 
 
Not applicable – First version 
Pre-final 
Jan 27, 2021 
 
 
Pre-final 0.2 
Mar 31, 2021 
 
1. “Region (Centre)” is replaced by 
“Centre”, “Region (Country)” is 
replaced by “Country” 
2. “Summary of TEAE for COVID-19” 
is added to section 9 
Pre-final 0.3 
May 20, 2021 
 
Add “Iris color in study eye” in section 5 
and subgroup analysis in section 4.5 
Pre-final 0.4 
Aug 27, 2021 
 
Update time point for IA in section 1 
Pre-final 0.5 
Sep 23, 2021 
 
Update section 6, PT is sorted by 
descending order of subject frequency 
based on total treatment group in shell 
and dry run, but SAP is inconsistently 
mentioned SB15 treatment group, so 
SAP is updated to use total treatment 
group instead. 
Pre-final 0.6 
Oct 28, 2021 
 
Update section 5 to add fisher’s exact 
test 
 
 
 
Update appendix 1 to use date of last 
participation instead of date of last visit 
for CM 
 
 
 
Update section 9 to add AE definition 
for transition period analysis 
Pre-final 0.7 
Nov 15, 2021 
 
Update section 7.1.3 to impute 
components of BCVA instead of BCVA 
total score 
 
 
 
Update section 7.2.2 to remove tipping 
point 
 
 
 
Update section 9 to excluding  'Related 
to COVID-19' VACCINE or  
VACCINATION from TEAE for 
COVID-19 
 
 
 
“South Korea” is replaced by “Korea” 
everywhere 
Pre-final 0.8 
Nov 22, 2021 
 
Replace “date of last visit” by “date of 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorised Version 
last participation” in appendix 1 
algorithm for concomitant 
1.0 
Dec 14, 2021 
 
Finalization 
Amendment 1 
May 10, 2022 
 
1. The treatment groups for the summary 
and analysis were elaborated for the 
clarification in the section 3 
2. Tipping point analysis was removed 
and more details about the missing data 
imputation methods of handling missing 
secondary efficacy variables were added 
for the clarification in section 7.2.3 
 
 
 
PPD
PPD


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Amendment 1, May 10, 2022 
 
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TABLE OF CONTENTS 
MODIFICATION HISTORY ............................................................................................................ 2 
LIST OF ABBREVIATIONS ............................................................................................................. 6 
1. Introduction............................................................................................................................. 8 
2. Study Objectives ..................................................................................................................... 8 
2.1. 
Primary Objective ........................................................................................................ 8 
2.2. 
Secondary Objectives ................................................................................................... 8 
2.3. 
Sample Size Calculation .............................................................................................. 9 
3. General Considerations ......................................................................................................... 10 
3.1. 
Analyses Sets ............................................................................................................. 11 
3.2. 
Protocol Deviations .................................................................................................... 12 
3.3. 
Disposition and Withdrawals ..................................................................................... 13 
3.4. 
Study Day................................................................................................................... 14 
3.5. 
Baseline ...................................................................................................................... 14 
3.6. 
Retests, Unscheduled Visits and Early Termination Data and Visit Mapping ........... 14 
3.7. 
Common Calculations ................................................................................................ 15 
3.8. 
Software Version ........................................................................................................ 15 
4. Statistical Considerations ...................................................................................................... 15 
4.1. 
Multicentre Studies .................................................................................................... 15 
4.2. 
Missing Data .............................................................................................................. 15 
4.3. 
Multiple Comparisons/Multiplicity ............................................................................ 15 
4.4. 
Active-Control Studies Intended to Show Equivalence ............................................. 15 
4.5. 
Examination of Subgroups ......................................................................................... 16 
5. Demographic and Other Baseline Characteristics ................................................................ 17 
6. OCULAR and NON-OCULAR Surgical and Medical History ............................................ 19 
7. Efficacy and Pharmacokinetic Analyses ............................................................................... 19 
7.1. 
Primary Efficacy Analysis ......................................................................................... 19 
 
Analysis of Primary Efficacy Endpoint ..................................................................... 19 
 
Missing Data Methods of Primary Efficacy Endpoint ............................................... 20 
 
Sensitive Analysis of Primary Efficacy Endpoint ...................................................... 21 
 
Supportive Analysis of Primary Efficacy Endpoint ................................................... 21 
7.2. 
Secondary Efficacy Analysis ..................................................................................... 22 
 
Secondary Efficacy Variables and Derivations .......................................................... 22 
 
Analysis of Secondary Efficacy Endpoints ................................................................ 23 
 
Missing Data Methods for Secondary Efficacy Variables.......................................... 24 
7.3. 
Exploratory Efficacy Analysis ................................................................................... 25 
 
Proportion of subjects with sub-
RPE fluid on OCT at Week 32 and Week 56 (based on assessment by the central reading centr
e) 
25 
 
Change from baseline in subscale scores and composite scores of NEI VFQ-
25 at Week 32 and Week 56 ...................................................................................................... 25 
7.4. 
Pharmacokinetic Analysis .......................................................................................... 25 
8. Safety Analyses .................................................................................................................... 26 
8.1. 
Study Medication Exposure ....................................................................................... 26 
8.2. 
Prior/Concomitant Medications ................................................................................. 28 
8.3. 
Prohibited Medications .............................................................................................. 28 


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8.4. 
Laboratory Evaluations .............................................................................................. 29 
8.5. 
Vital Signs .................................................................................................................. 30 
8.6. 
Immunogenicity Analysis .......................................................................................... 30 
8.7. 
Other observations related to Safety Analyses ........................................................... 32 
9. Adverse Events ..................................................................................................................... 33 
10. References............................................................................................................................. 39 
APPENDIX 1. PARTIAL DATE CONVENTIONS ....................................................................... 40 
APPENDIX 2. CODE FOR PROHIBITIVE MEDICATION ......................................................... 42 
APPENDIX 3. LABORATORY TEST PARAMETERS ................................................................ 42 
APPENDIX 4. VISIT LABEL FOR STDUY PERIOD ................................................................... 43 
APPENDIX 5. SAMPLE CODES FOR PRIMARY ANALYSIS ................................................... 43 
APPENDIX 6. SAS CODE OF ADJUSTED RISK DIFFERENCE................................................ 44 
APPENDIX 7. CODE FOR COVID-19 RELATED TERMS ......................................................... 44 
APPENDIX 8. SCORING METHODOLOGY FOR VFQ-25: ....................................................... 44 
STATISTICAL ANALYSES PLAN SIGNATURE PAGES ............................................................. 47 
 
 


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LIST OF ABBREVIATIONS 
ADA 
Anti-drug Antibodies 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AMD 
Age-related Macular Degeneration 
ANCOVA 
Analyses of Covariance 
ATC 
Anatomical Therapeutic Chemistry 
BCVA 
Best Corrected Visual Acuity 
BLQ 
Below Limit of Quantitation 
BM 
Bruch’s Membrane 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CNV 
Choroidal Neovascularisation 
COVID-19 
Coronavirus Disease 2019 
CRO 
Clinical Research Organisation 
CSR 
Clinical Study Report 
CST 
Central Subfield Thickness 
CV 
Coefficient Variation 
DA 
Disc Area 
DBP 
Diastolic Blood Pressure 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
ENR 
Enrolled Set 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analyses Set 
FDA 
Food and Drug Administration 
ILM 
Internal Limiting Membrane 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IVT 
Intravitreal 
LSMean 
Least Squares Mean 
MAR 
Missing-at-Random 
MCMC 
Markov-Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MI 
Multiple Imputation 
MNAR 
Missing-not-at-Random 
NAb 
Neutralizing Antibody 
NEI VFQ-25 
National Eye Institute 25-Item Visual Function Questionnaire 
OCT 
Optical Coherence Tomography 
RPE 
Retinal Pigment Epithelium 
PD 
Protocol Deviation 
PK 
Pharmacokinetic  
PKS 
Pharmacokinetic Analysis Set 
PPS 
Per-Protocol Set 
Pre-AEs 
Pre-treatment Adverse Events 
PT 
Preferred Term 
QOL 
Quality of Life 
RAN 
Randomised Set 
SAE 
Serious Adverse Events 
SAF 
Safety Set  
SAP 
Statistical Analyses Plan 
 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDRG 
Study Data Reviewer’s Guide 
SDTM 
Study Data Tabulation Model 
SI 
International System of Units 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TOST 
Two One-sided Equivalence Tests 
TRT 
Total Retinal Thickness 
US 
United States of America 
VEGF 
Vascular Endothelial Growth Factor 
 
 
 


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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy, safety, pharmacokinetics (PK), and immunogenicity data for SB15-3001. It describes the 
data to be summarised and analysed, including specifics of the statistical analyses to be performed. 
This Statistical Analyses Plan (SAP) is based on the Protocol version 1.0, dated Oct 30, 2019. The 
following analyses will be performed for this study. 
 
For main Clinical Study Report (CSR) the safety, efficacy, PK, and immunogenicity analyses will be 
performed on available data when all subjects complete the procedures at Week 32, or its 
corresponding visit. The detail data cut-off rule used for main CSR reporting will be implemented 
for Study Data Tabulation Model (SDTM) datasets and described in SDTM specification and Study 
Data Reviewer’s Guide (SDRG). 
 
At the time of this reporting, a limited number of identified individuals of the Sponsor or clinical 
research organisation (CRO) will be unmasked for reporting purpose. However, subjects, 
Investigators, and other study personnel will remain masked throughout the entire study period. 
 
For final CSR the safety, efficacy, PK and immunogenicity analyses will be performed after the last 
subject completes the procedures at Week 56 or the corresponding visit. All study data will be 
analysed and reported for the final CSR.  
 
All study data collected until End of Study (EOS) or Early Termination (ET) of the study including 
Safety follow-up (If done) will be used for reporting of the summary and analysis results. Data 
collected in Follow-up period upon data collection agreement will just be provided in study listings 
in the CSR. 
2. STUDY OBJECTIVES 
2.1. Primary Objective 
The primary objective is to demonstrate the equivalence in efficacy of SB15 compared to Eylea® in 
subjects with neovascular age-related macular degeneration (AMD).  
2.2. Secondary Objectives 
The secondary objectives are: 
- 
To evaluate the safety of SB15 compared to Eylea®. 
- 
To evaluate the systemic exposure of SB15 compared to Eylea® in subjects participating in  
PK evaluation. 


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- 
To evaluate the immunogenicity of SB15 compared to Eylea®. 
2.3. Sample Size Calculation 
For the calculation of the equivalence margin for Best Corrected Visual Acuity (BCVA), the mean 
changes in BCVA were referred from VIEW1 study of Eylea® in subjects with neovascular AMD. 
In the VIEW1 study of SmPC of Eylea®, the mean change of BCVA at Month 12 (standard deviation 
[SD]) was 10.9 (13.8) letters for the dosing of 2 mg every 4 weeks Eylea® treatment group and the 
Least Squares Mean (LSMean) difference between Eylea® and Lucentis® (ranibizumab) with its 95% 
confidence interval (CI) was 3.15 (0.92, 5.37) letters. 
The United States of America (US) Food and Drug Administration (FDA) Guidance describes that if 
the active control (Eylea® in this study) has shown superiority to other active treatments (Lucentis® 
in VIEW1) in the past, the difference demonstrated (3.15 letters) represents a conservative estimate 
of historical evidence of sensitivity to drug-effects, one that could serve as a basis for choosing M1. 
Therefore, the equivalence margin of 3 letters, which would be less than the LSMean difference in 
VIEW1 study, which proved statistical superiority to ranibizumab. 
The Early Treatment Diabetic Retinopathy Study (ETDRS) chart has 5 letters in one line (that is the 
minimum limit for visual acuity change) and thus the difference more than 5 letters in BCVA could 
be considered as a minimal clinically important difference. In addition, most of the anti-Vascular 
Endothelial Growth Factor (VEGF) non-inferiority clinical trials on AMD also used a non-inferiority 
margin of 5 letters. Therefore, the equivalence margin of [−3 letters, 3 letters] is considered to be a 
conservative margin to test the clinical equivalence between SB15 and Eylea®. 
With the equivalence limit of [−3 letters, 3 letters], 216 subjects per treatment group was calculated 
with the assumptions of the mean difference of 0.5 letters and SD of 9.0 at the overall 5% 
significance level, providing 80% power to reject the null hypothesis. Overall 446 subjects (223 per 
treatment group) will give 216 completers per treatment group assuming a 3% loss from the 
randomised subjects. 
The nQuery Advisor® option two one-sided equivalence tests (TOST) for two-group design gives the 
following statement to estimate the n per group to show the equivalence: “When the sample size in 
each group is 216, a two group design will have 80% power to reject both the null hypothesis that the 
test mean minus the standard mean is below -3 and the null hypothesis that the test mean minus the 
standard mean is above 3 i.e., that the test and standard are not equivalent, in favor of the alternative 
hypothesis that the means of the two groups are equivalent, assuming that the expected difference in 
means is 0.5, the common standard deviation is 9 and that each test is made at the 2.5% level.” 
With the equivalence limit of [−3 letters, 3 letters] for the US FDA submission, 173 subjects per 
treatment group (overall sample size of 346) was calculated with the assumptions of the mean 


SB15 (proposed aflibercept biosimilar)  
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difference of 0.5 letters and SD of 9.0 at the overall 10% significance level, providing 80% power to 
reject the null hypothesis. 
The nQuery Advisor® option two one-sided equivalence tests for two-group design gives the 
following statement to estimate the n per group to show the equivalence: “When the sample size in 
each group is 173, a two group design will have 80% power to reject both the null hypothesis that the 
test mean minus the standard mean is below -3 and the null hypothesis that the test mean minus the 
standard mean is above 3 i.e., that the test and standard are not equivalent, in favor of the alternative 
hypothesis that the means of the two groups are equivalent, assuming that the expected difference in 
means is 0.5, the common standard deviation is 9 and that each test is made at the 5% level.” 
Therefore, the sample size of 446 allows enough power to detect the equivalence in both situations. 
3. GENERAL CONSIDERATIONS 
 
The analysis study period consists of screening, main period and transition period (Figure 1), each 
period is defined as below:  
Screening period is defined as study period from informed consent date prior to randomisation at Week 
0 (Day 1). 
Main period is defined as study period on or after randomisation at Week 0 (Day 1) and before re-
randomisation at Week 32, or until last study participation date if patients withdrew/discontinued 
before Week 32.  


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Transition period is defined as study period from the re-randomisation at Week 32 until end of study 
(Week 56) or until last study participation date if patients withdrew/discontinued after Week 32.  
Overall period is defined as study period consisting of screening period, main period and transition 
period.  
According to study design, descriptive statistics and results of efficacy analysis of main period will 
be provided by following main treatment groups in general: 
• 
SB15 
• 
Eylea® 
Treatment effect comparison will be performed between SB15 and Eylea®. 
For the summary of transition period, the results will be provided by following transition treatment 
groups in general: 
• 
SB15+SB15 
• 
Eylea® Overall (Eylea®+SB15 / Eylea®+Eylea®) 
• 
Eylea®+SB15 
• 
Eylea®+Eylea® 
Treatment effect comparison in efficacy analysis will be performed between following treatment 
groups: 
• 
SB15 (SB15* / SB15+SB15) vs. Eylea® (Eylea®* / Eylea®+Eylea®) 
• 
Eylea®+SB15 vs. Eylea®+Eylea® 
• 
SB15 vs. Eylea® overall 
 
SB15* or Eylea®* refers to subjects who is randomised to SB15 or Eylea® respectively and 
discontinued from IP before transition at Week 32. 
Summary of overall study period will be provided by following overall treatment groups in general: 
• 
SB15 (SB15* / SB15+SB15) 
• 
Eylea® Overall (Eylea®* / Eylea®+Eylea® / Eylea®+SB15) 
• 
Eylea®+SB15 
• 
Eylea®+Eylea® 
Treatment groups for the listing will be presented as below: 
• 
SB15 
• 
SB15+SB15 
• 
Eylea® 
• 
Eylea®+Eylea® 
• 
Eylea®+SB15 
3.1. Analyses Sets 
The following sets will be used for the analyses performed in the study: 


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•  Enrolled Set (ENR) consists of all subjects who provide informed consent for this study. 
• 
Randomised Set (RAN) consists of all subjects who receive a randomisation number at the 
randomisation visit.  
• 
Full Analyses Set (FAS) consists of all randomised subjects. Following the intent-to-treat 
principle, subjects will be analysed according to the treatment group they are assigned to at 
randomisation. However, subjects who do not have any efficacy assessment result after 
randomisation and do not receive Investigational Product (IP) during the study period will 
be excluded from FAS. 
• 
Per-Protocol Set (PPS) consists of all FAS subjects who have BCVA assessment result at 
baseline and Week 8 without any major protocol deviations (PDs) that have impact on the 
primary BCVA assessment. Major PDs that will lead to exclusion from this set will be pre-
defined prior to unmasking the treatment group assignment for analyses. Subjects meeting 
any of following criteria will be excluded from PPS as well even if it’s not captured as a 
PD: 
a. Subjects missed any of IP injection at Week 0 or Week 4 
b. IP injection (+/- 7 days) at Week 4 is out of visit window 
• 
Safety Set 1 (SAF1) consists of all subjects who receive at least one IP during the study 
period. Subjects will be analysed according to the IP received. 
• 
Safety Set 2 (SAF2) consists of all subjects in the SAF1 who receive at least one IP after re-
randomisation at Week 32. Subjects will be analysed according to the IP received. 
• 
Pharmacokinetic Analysis Set (PKS) consists of all subjects in the SAF1 who participate in 
PK evaluation at PK investigational sites (PK subjects) and have at least one serum 
concentration data.  
The number of subjects in the analysis sets will be summarised by overall treatment group for the 
RAN. A by-subject listing of analyses population details will be provided for the RAN by treatment 
group and will include country, centre, subject identifier, inclusion/exclusion flag for each analysis 
set and reason for exclusion from PPS. 
3.2. Protocol Deviations 
PDs will be pre-defined prior to subject enrolment and documented separately named as Protocol 
Deviation Definition List which includes category (e.g., violation of inclusion/exclusion criteria, use 
of prohibited medication, non-compliance with treatment), deviation description, severity (major or 
minor), time point for each PD. Major PDs are defined as those deviations from the protocol likely to 


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have an impact on the perceived efficacy and/or safety of study treatments. PDs that are a result of 
COVID-19 will be identified in the DV domain through PD categories of COVID-19. This will allow 
the reporting of the PDs related to COVID-19 in the SDTM datasets. 
PDs and analysis sets will be reviewed and confirmed prior to database lock to decide which subjects 
and/or subject data will be excluded from certain analyses. Decisions regarding the exclusion of 
subjects and/or subject data from analyses will be documented and approved prior to database lock. 
A summary of the number and percentage of subjects with PD by severity (major and minor) and 
category will be presented for the RAN by main treatment group. Percentages will be based on the 
number of subjects in RAN by main treatment group. The summary of PD will be also provided by 
centre and main treatment group.   
A by-subject listing of major and minor PDs will be provided including subject identifier, category, 
PD description, severity, PDs related to COVID-19 and exclusion from analyses set (Yes/No) for the 
RAN. 
3.3. Disposition and Withdrawals 
Subject Disposition 
A clear accounting of the disposition of all subjects who enter the study will be provided for the ENR, 
from enrolment to study completion. The subject disposition summaries include the following: 
• 
The number of subjects enrolled, the number and percentage of screen failures and reasons for 
screen failure will be summarised by treatment group. 
• 
Subjects completed IP at Week 8, subjects discontinued from IP before Week 8, the reasons of 
discontinuation of treatment, subjects discontinued from IP before Week 8 related to COVID-19 
will be summarised by treatment group.  
• 
Subjects completed at Week 32, subjects discontinued from IP of main treatment period before re-
randomisation at Week 32, the reasons of discontinuation of treatment, subjects discontinued from 
IP before Week 32 related to COVID-19 will be summarised by treatment group.  
• 
Subjects completed IP after transition at Week 32 up to Week 48, subjects discontinued from IP 
of transition treatment period after re-randomisation at Week 32, the reasons of discontinuation of 
treatment, subjects discontinued from IP after transition at Week 32 related to COVID-19 will be 
summarised by treatment group.  
• 
Subjects with EOS visit completed, subjects with EOS visit not performed, the reasons for EOS 
visit not done will be summarised by treatment group.  
The summary of subject disposition above will be also provided by centre and treatment group.  


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• 
A by-subject listing of subject disposition will be generated using the ENR, including start/end 
date of treatment period, primary reasons of withdrawal or screening failure, and reasons for EOS 
visit not done. 
Visit not performed/ window deviation (including relatedness to COVID-19) 
• 
Subjects with planned visit not performed, visit window deviation, reason for visit not performed 
and visit window deviation including relatedness to COVID-19 will be summarised using the RAN 
by visit and treatment group.  
• 
A by-subject listing of planned visits not performed, visit window deviation will be generated 
using the RAN, including reasons not performed, reasons for visit window deviation, and 
relatedness to COVID-19. 
3.4. Study Day 
Study Day will be calculated from the first IP dosing date and will be used to show start/end day of 
assessments and events. Study day of the first IP dosing date will be Day 1. 
• 
If the date of the event is on or after the first IP dosing date, then: 
Study Day = (date of event – first IP dosing date) + 1 
• 
If the date of the event is prior to the first IP dosing date, then: 
Study Day = (date of event – first IP dosing date) 
 
When the event date is partial or missing, study day will be calculated after proper imputation as 
described in APPENDIX 1, and the event date will appear as it is along with the calculated study day 
in the listing. 
3.5. Baseline 
The baseline value will be defined as the last available measurement value prior to the first IP 
administration.  
3.6. Retests, Unscheduled Visits and Early Termination Data and Visit Mapping 
In general, the data recorded at the scheduled visit will be presented in the by visit summaries.  
Early termination data will be mapped to the next scheduled visit for by visit summaries. By-subject 
listings will display original early termination visit. 
Unscheduled/repeated measurements will not be included in the by visit summaries. However, 
unscheduled/repeated measurements (except for the baseline value) will contribute to the worst-case 
value for shift tables and incidence of significant abnormality tables. 


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Listings will include scheduled, unscheduled, repeated, and early termination visit. And visit label of 
Week X (R) to indicate the measurement if it is retested or unscheduled.  
3.7. Common Calculations 
For the purpose of converting days to years or months, 1 year will be equal to 365.25 days, 1 month 
will be equal to 30.44 days and 1 week will be equal to 7 days. 
For quantitative measurements, change from baseline at Visit X will be calculated as follows: 
Change at Visit X = Test Value at Visit X (Value) – Baseline Value (Base) 
3.8. Software Version 
All report outputs will be conducted using SAS® version 9.4 or a higher version. 
4. STATISTICAL CONSIDERATIONS 
4.1. Multicentre Studies 
This study will be conducted by multiple investigators at multiple centres internationally. The 
participating countries in the study are Czech Republic, Hungary, Poland, Estonia, Russia, Latvia, 
Korea, Japan, United States, and Croatia. Multicentre will be pooled by country, for the primary 
efficacy variable, the statistical model to be used for the estimation of treatment effects will adjust 
for country, by including country as a main effects term in the model. Adjustment for country will 
also be performed, wherever possible, in the analysis of the secondary efficacy variables.  
4.2. Missing Data 
Missing safety data will not be imputed generally unless otherwise specified. Handling method of 
partial or missing dates is described in APPENDIX 1; Missing efficacy data will be handled as 
described in Section 7 of this analysis plan. 
4.3. Multiple Comparisons/Multiplicity 
No multiple comparison adjustments for type I error will be used. 
4.4. Active-Control Studies Intended to Show Equivalence 
This is an active-control study to demonstrate the equivalence of efficacy of SB15 to Eylea® in subjects 
with neovascular AMD. The null hypothesis tested for the primary efficacy analysis is that either (1) 


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SB15 is inferior to Eylea® or (2) SB15 is superior to Eylea® based on a pre-specified equivalence 
margin. 
 
For FDA submission, the equivalence between the main treatment groups will be declared if the 90% 
CI of the difference is entirely contained within the pre-defined equivalence margin of [−3 letters, 3 
letters].  
 
For European Medicines Agency (EMA) submission, equivalence between the main treatment groups 
will be declared if the 95% CI of the difference is entirely contained within the pre-defined equivalence 
margin of [−3 letters, 3 letters].  
4.5. Examination of Subgroups 
Best Correct Visual Acuity (BCVA) 
The primary efficacy variable BCVA will be summarised and analysed by the following prognostic 
factors at baseline or immunogenicity (8-week anti-drug antibodies (ADA) result was defined as an 
overall ADA result up to Week 8, refer to Section 8.6) results for exploratory purpose: 
 
- 
Summary of change from baseline in BCVA by overall ADA result up to Week 8 for FAS 
- 
Subgroup analysis of change from baseline in BCVA at Week 8 by overall ADA result up to 
Week 8 for FAS  
- 
Subgroup analysis of change from baseline in BCVA at Week 8 by lesion type (Occult, 
Predominantly Classic, and Minimally Classic) at baseline for FAS 
- 
Subgroup analysis of change from baseline in BCVA at Week 8 by total lesion area (≤4DA vs. 
＞4DA) at baseline for FAS 
- 
Subgroup analysis of change from baseline in BCVA at Week 8 by country for FAS 
- 
Subgroup analysis of change from baseline in BCVA at Week 8 by BCVA baseline (<50 letter 
score vs. ≥ 50 letter score) for FAS 
- 
Subgroup analysis of change from baseline in BCVA at Week 8 by Age group (<75 years vs. ≥ 
75 years) for FAS 
- 
Subgroup analysis of change from baseline in BCVA at Week 8 by Iris Color Group in Study 
Eye (Light Color and Dark Color) for FAS 
In addition, forest plot will be used to display the difference of LSMean of change from baseline in 
BCVA at Week 8 between main treatment groups, with 95% CI and 90% CI respectively by pre-
defined subgroups above, for each subgroup level, a covariance model with baseline BCVA as a 
covariate (except for subgroup factor BCVA baseline analyses), country and treatment as fixed 
factors will be used to construct the difference of LSMean and CI.  


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Treatment-Emergent Adverse Event (TEAE) 
All TEAEs based on categories of overall ADA result (Positive, Negative, Inconclusive) will be 
summarised by System Organ Class (SOC), Preferred Term (PT), including the number and percentage 
of subjects experiencing events. 
 
- 
Ocular TEAEs in the study eye, fellow eye, and non-ocular TEAEs by overall ADA result up to 
Week 56, overall treatment group, system organ class and preferred term for SAF1 and overall 
period 
- 
Ocular TEAEs in the study eye, fellow eye, and non-ocular TEAEs by overall ADA result up to 
Week 32, main treatment group, system organ class and preferred term for SAF1 and main 
period 
- 
Ocular TEAEs in the study eye, fellow eye, and non-ocular TEAEs by overall ADA result after 
transition up to Week 56, transition treatment group, system organ class and preferred term for 
SAF2 and transition period 
5. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Subject demographics and baseline characteristics will be summarised by overall treatment group for 
the RAN and main treatment group for the PKS. Continuous variables (e.g., age, weight, height, 
Body mass index (BMI)) will be summarised by treatment group with descriptive statistics (n, mean, 
SD, median, minimum, and maximum). Qualitative variables (e.g., gender, race, and ethnicity) will 
be summarised by treatment group with frequency and percentages. The summary of subject 
demographics and baseline characteristics will be also provided by country and treatment group.   
By-subject listings of demographic and other baseline characteristics will be provided. 
Demographics Characteristics 
• 
Age (years) – calculated at the time of signing the Informed Consent form as follows. 
Age = Year of Informed Consent - Year of Birth 
• 
Age Group (years) – < 75, ≥ 75 
• 
Gender – Female, Male 
• 
Childbearing potential – Yes, No, Not applicable (Male) 
• 
Race – White, American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, Other 
• 
Ethnicity – Hispanic or Latino, Chinese, Indian (Indian subcontinent), Japanese, Mixed ethnicity, 
Other 
• 
Weight (kg) and Height (cm) at Screening 


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• 
BMI (kg/m2) – derived as weight (kg)/[height(m)]2 
• 
Country – Czech Republic, Hungary, Poland, Estonia, Latvia, Croatia, United States, Korea, Japan 
and Russia.   
• 
Region – EU (Czech Republic, Hungary, Poland, Estonia, Latvia and Croatia), United States, and 
Others (Korea, Japan and Russia)  
• 
Iris Color in Study Eye – Blue, blue/grey, grey, Green, Hazel, Brown or dark brown, Unknown 
• 
Iris Color Group in Study Eye– Light Color (Blue, blue/grey, grey, Green, Hazel), Dark Color 
(Brown or dark brown). 
Other Baseline Characteristics 
• 
BCVA (Total letter score) 
• 
BCVA Group – < 50 letter score, ≥ 50 letter score 
• 
Central subfield thickness (CST) (μm) 
• 
Total retinal thickness (TRT) (μm) 
• 
Presence of intra- or sub-retinal fluid 
• 
Presence of sub-Retinal pigment epithelium (RPE) fluid 
• 
Total lesion area (mm2) 
• 
Area of Choroidal Neovascularisation (CNV) (mm2) 
• 
Lesion type (Predominantly Classic, Minimally Classic, Occult, Not Available) 
• 
Presence of CNV leakage 
• 
Years since first diagnosis of neovascular AMD in study eye (year) 
• 
Years since first diagnosis of neovascular AMD in fellow eye (year) 
• 
Intraocular Pressure (mmHg)  
• 
Lens status in study eye (No cataract, Cataract, Pseudophakia, Pseudophakia with Open Posterior 
Capsule) 
• 
Composite scores of National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) 
 


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Statistical Tests for Demographic and Other Baseline Characteristics 
Comparison between main treatment groups in baseline characteristics will be performed using the 
chi-square test, F-test, or Fisher’s exact test as appropriate. The results of these tests will be provided 
including the p-value only for descriptive purposes and will not be used as a formal basis to determine 
the factors to be included in primary or secondary efficacy analysis models. If baseline imbalances are 
detected for any of the factors, additional analyses may be performed to adjust for these baseline 
differences. 
6.  OCULAR AND NON-OCULAR SURGICAL AND MEDICAL 
HISTORY 
Medical and surgical histories will be coded using Medical Dictionary for Regulatory Activities central 
coding dictionary (MedDRA version 23.0). 
Ocular medical/surgical histories and Non-ocular medical/ surgical histories will be summarised 
separately by SOC and PT by main treatment group. Percentages will be based on the number of 
subjects in the RAN. Primary system organ classes were presented alphabetically; within a SOC, PTs 
were sorted by descending order of subject frequency based on the total treatment group. If the 
frequency of the preferred terms were tied, the preferred terms were ordered alphabetically. Also, if a 
subject had multiple conditions with the same preferred term and primary system organ class, the 
subject was counted only once. 
 
 
By-subject listings will be provided separately for ocular and non-ocular medical or surgical history 
for the RAN.  
7. EFFICACY AND PHARMACOKINETIC ANALYSES 
Efficacy analyses will be performed for the study eye and will be based on the randomised treatment 
group or treatment group for the study eye. 
 
The primary efficacy analysis will be performed for the FAS with the change from baseline 
in BCVA at Week 8 using an analysis of covariance (ANCOVA) model with the baseline  
BCVA as a covariate and country, specified in section 4.1) and treatment group as factors after the 
multiple imputation (MI) under the missing at random (MAR) assumption. 
7.1.Primary Efficacy Analysis 
 Analysis of Primary Efficacy Endpoint 
The primary efficacy analysis will be performed for the FAS with the change from baseline in 
BCVA at Week 8 using ANCOVA model with the baseline BCVA as a covariate and country and 
treatment group as factors. The equivalence between the main treatment groups will be declared if 


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the two-sided 90% CI of the difference of LSMean of change from baseline in BCVA at Week 8 is 
entirely contained within the pre-defined equivalence margin of [−3 letters, 3 letters].  
 
For the EMA submission, the primary efficacy analysis will be performed for the FAS with the 
change from baseline in BCVA at Week 8 using ANCOVA model with the baseline BCVA as a 
covariate and country and treatment group as factors. The equivalence between the main treatment 
groups will be declared if the two-sided 95% CI of the difference of LSMean of change from 
baseline in BCVA at Week 8 is entirely contained within the pre-defined equivalence margin of [−3 
letters, 3 letters].  
• Methodology for the total BCVA letter score: 
There are two test procedures specified for the BCVA scoring. 4-meter test with 14 parameters 
and 1-meter test with 6 parameters. In both the test procedures, if 3 letters or less are read 
correctly on any row, testing procedure will be stopped.  
4-meter test parameters: 20/200, 20/160, 20/125, 20/100, 20/80, 20/63, 20/50, 20/40, 20/32, 
20/25, 20/20, 20/16, 20/12.5 and 20/10. 
1-meter test parameters: 20/800, 20/640, 20/500, 20/400, 20/320, and 20/250. 
1) From 4-meter test, Total Number Correct at 4 meters will be obtained by adding ‘Number 
Correct at 4 meters’ for all the 14 parameters. 
2) If the Total Number Correct at 4 meters is greater than 19 then 1-meter test will not be 
performed. If the Total Number Correct at 4 meters is less than or equal to 19 then 1-meter 
test will be performed and obtain the ‘Total Number Correct at 1 meter’ by adding 
‘Number Correct at 1 meter ‘for all the 6 parameters.  
3) Total BCVA Letter Score will be computed as below,  
If Total Number Correct at 4 meters > 19 then Total Number Correct at 4 meters + 30 
Otherwise, Total Number Correct at 4 meters + Total Number Correct at 1 meter. 
 Missing Data Methods of Primary Efficacy Endpoint 
For the primary analysis with the FAS for BCVA, missing data will be imputed for subjects who have 
a missing value prior to or on the primary analysis time-point. A MAR approach will assume that 
subjects who had missing values are similar to similar subjects who completed the study in that main 
treatment group. 
For the components of BCVA, the missing letter will be imputed by MI method with Markov-Chain 
Monte Carlo (MCMC)/Monotone Regression procedures.  
The MI method will be applied as follows based on components of BCVA: 
− 
For the intermittent missing values, the missing value will be filled in using the MCMC 
method with multiple chains, monotone missing data imputing pattern. A total of 100 sets of 


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imputations will be performed. The seed used for these imputations will be 4238 and all other 
multiple imputation procedures described in this SAP will use this same seed as well.   
The resulting 100 imputed data sets will have a monotone missing pattern and will be imputed using 
a method for monotone missingness: 
− 
For monotone missing data, monotone regression will be used to impute missing data. The 
procedure will be based on the 100 imputed datasets generated from the MCMC procedure 
and will be performed by Imputation. This will be based on 100 sets of imputations.  
The SAS® PROC MI procedure will be used for the imputation. The sample SAS code for the multiple 
imputation can be found in APPENDIX 5 specifically.  
 Sensitive Analysis of Primary Efficacy Endpoint 
For the BCVA, available case analysis will be performed for PPS and FAS.  
An additional sensitivity analysis using the tipping-point approach which assume Missing-not-at-
Random (MNAR) will be conducted to assess the robustness of the primary analysis result. 
Assumptions (tipping point) under which the 90% CI or 95% CI no longer rules out unacceptable 
differences in efficacy as determined by BCVA change from baseline at Week 8 between SB15 and 
Eylea® will be identified. 
The analysis will be performed based on components of BCVA using a general three-step approach: 
(1) Achieve monotone missing data pattern by MCMC procedure, a total of 100 sets of imputations 
will be performed. Impute the missing data by monotone regression, and apply delta adjustments for 
Week 8 total BCVA letter score, subjects with missing data have, on average, worse or better 
efficacy compared to those who have values. The mean difference between the (unobserved) missing 
values and observed values can vary independently for the different treatment groups. 
(2) Each of these imputed datasets (which contains identical values of non-missing data but different 
values imputed for missing data) will be analysed using standard SAS procedure, e.g., PROC 
MIXED etc. 
(3) Results from all imputed datasets are then combined together for overall inference using PROC 
MIANALYZE. 
For BCVA change from baseline at Week 8, seven equally spaced shifts (-6 to 6 by 2) for the BCVA 
change from baseline for subjects with missing data will be explored. 
 Supportive Analysis of Primary Efficacy Endpoint 
Not applicable. 


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7.2. Secondary Efficacy Analysis 
 Secondary Efficacy Variables and Derivations 
The secondary efficacy endpoints are: 
Change from baseline in BCVA over time up to Week 32 and up to Week 56 
BCVA will be derived as described in section 7.1.1 of this analysis plan. 
Proportion of subjects who lost fewer than 15 letters in BCVA compared to baseline at 
Week 32 and Week 56 (proportion of subjects who maintained BCVA) 
BCVA will be derived as described in section 7.1.1 of this analysis plan. If change from 
baseline in BCVA is less than 15 letters loss then ‘Yes’, otherwise ‘No’. 
Proportion of subjects who gained 15 letters or more in BCVA compared to baseline at 
Week 32 and Week 56 
BCVA will be derived as described in section 7.1.1 of this analysis plan. If change from 
baseline in BCVA is equal to or greater than 15 letters gain then ‘Yes’, otherwise ‘No’. 
Change from baseline in CST and TRT at Week 4, and over time up to Week 32 and 
up to Week 56 (based on assessment by the central reading centre) 
CST measured from internal limiting membrane (ILM) to RPE in 1-mm central subfield 
TRT measured from ILM to Bruch’s membrane (BM) in 1-mm central subfield 
Proportion of subjects with intra- or sub-retinal fluid on OCT at Week 32 and Week 
56 (based on assessment by the central reading centre) 
If the presence of Intra- or sub-retinal fluid then ‘Yes’, otherwise ‘No’ 


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Change from baseline in CNV area at Week 32 and Week 56 (based on assessment by 
the central reading centre) 
Proportion of subjects with active CNV leakage at Week 32 and Week 56 (based on 
assessment by the central reading centre) 
 Analysis of Secondary Efficacy Endpoints 
In general, treatment comparison of interest for time points prior to re-randomisation (week 32 
included) include the comparison between main treatment SB15 and Eylea®; treatment comparison 
of interest for time points after re-randomisation include the comparison between treatment group 
SB15 and Eylea®, Eylea®+SB15 and Eylea®+Eylea®, SB15 and Eylea® overall. 
 
The following analyses will be performed for the secondary efficacy endpoints: 
Analysis of change from baseline in BCVA over time up to Week 32 and up to Week 56 
Change from baseline in BCVA at Week 32 and Week 56 will be analysed using the same model 
for primary analysis as described in section 7.1.1 for the FAS, based on available case, and multiple 
imputation assuming MAR. BCVA will be summarised descriptively by treatment group and visit 
based on available case. The BCVA change from baseline will be plotted by treatment group and 
visit up to Week 32 and Week 56 for the FAS with mean and standard error based on available case. 
Analysis of proportion of subjects who lost fewer than 15 letters in BCVA compared to 
baseline at Week 32 and Week 56 (proportion of subjects who maintained BCVA) 
The adjusted risk difference between the two treatment groups at Week 32 will be calculated using a 
stratified Cochran-Mantel-Haenszel (CMH) test and 95% Mantel-Haenszel CIs will be presented for 
FAS. The stratification factor for CMH test is Country. The adjusted risk difference between treatment 
group at Week 56 will also be calculated respectively using same method. 
The sample SAS codes for implementing the analyses can be found in APPENDIX 6. 
Analysis of proportion of subjects who gained 15 letters or more in BCVA compared to 
baseline at Week 32 and Week 56 
This secondary efficacy variable will be analysed similarly to the proportion of subjects who lost fewer 
than 15 letters in BCVA compared to baseline at Week 32/56 using FAS. 


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Analysis of change from baseline in CST and TRT at Week 4, and over time up to 
Week 32 and up to Week 56 (based on assessment by the central reading centre) 
Change from baseline in CST and TRT at Week 4 will be analysed similarly to primary analysis using 
FAS. 
Change from baseline in CST and TRT over time up to Week 32 and up to Week 56 will be analysed 
similarly to analysis of change from baseline in BCVA over time up to Week 32 and up to Week 56 
using FAS. 
Analysis of proportion of subjects with intra- or sub-retinal fluid on OCT at Week 32 
and Week 56 (based on assessment by the central reading centre) 
This secondary efficacy variable will be analysed similarly to the proportion of subjects who lost fewer 
than 15 letters in BCVA compared to baseline at Week 32/56 using FAS. 
Analysis of change from baseline in CNV area at Week 32 and Week 56 (based on 
assessment by the central reading centre) 
Change from baseline in CNV area at Week 32 and Week 56 will be analysed similarly to primary 
analysis using FAS. 
Analysis of proportion of subjects with active CNV leakage at Week 32 and Week 56 
(based on assessment by the central reading centre) 
This secondary efficacy variable will be analysed similarly to the proportion of subjects who lost fewer 
than 15 letters in BCVA compared to baseline at Week 32/56 using FAS. 
 Missing Data Methods for Secondary Efficacy Variables 
Unless otherwise specified, all analyses of secondary efficacy variables will be based on available data.  
For change from baseline in BCVA at Week 32 and Week 56, missing values will be imputed by 
multiple imputation assuming MAR as specified at Section 7.1.2.  
A MAR approach will assume that subjects who had missing values are similar to similar subjects who 
completed the study in the treatment group.  
− 
Week 32: Main treatment group (SB15, Eylea®) 
− 
Week 56: SB15 (SB15* / SB15+SB15), Eylea® (Eylea®* / Eylea®+Eylea®) and Eylea®+SB15. 


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7.3. Exploratory Efficacy Analysis  
 Proportion of subjects with sub-RPE fluid on OCT at Week 32 and Week 
56 (based on assessment by the central reading centre) 
Summary of proportion of subjects with sub-RPE fluid on OCT at Week 32 and Week 56 by overall 
treatment group will be performed for FAS. 
 Change from baseline in subscale scores and composite scores of NEI VFQ-
25 at Week 32 and Week 56 
The Quality of Life (QOL) is assessed using NEI VFQ-25.  
 
NEI VFQ-25 analyses on FAS: Subscale scores (general health, general vision, ocular pain, near 
activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-
specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision) and 
the composite score, which represent overall visual function, will be calculated, and the change from 
baseline will be summarised by treatment group and visit for FAS. 
 
Subscale scores and Composite score will be calculated according to the Scoring Methodology for 
VFQ-25 in APPENDIX 8. 
 
In addition, the subscale scores and composite score of NEI VFQ-25 will be summarised without 
subjects who received Eylea® in the fellow eye due to AMD during the study period after 
randomisation. 
 
Listing on Composite and Subscale Score (NEI VFQ-25) will be generated for FAS. 
7.4. Pharmacokinetic Analysis 
The PK analysis will be performed for the PK population. 
 
 
Individual PK blood sampling time and serum concentrations (pre-dose, Ctrough and post-dose, Cmax) 
will be listed for the PK population. All raw PK data will be reported and analysed with the same 
precision as the source regardless of how many significant figures or decimals the data carry.   
 
If the fellow eye received Eylea® due to AMD during the study period after randomisation, all 
concentrations measured after treatment for the fellow eye will be listed but excluded from the 
summary statistics.  
 
Serum concentrations will be summarised descriptively at each scheduled sampling time for main 
treatment group (number of subjects (n), arithmetic mean, SD, median, minimum, maximum, 
coefficient variation (CV%), geometric mean, geometric SD, and geometric CV%). Below the limit of 
quantitation (BLQ) concentrations will be set to zero for the computation of descriptive statistics, 
except for geometric mean, geometric SD, and geometric CV%, for which they will be excluded. If 


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serum concentration is not collected within sampling window, it will be excluded from summary 
statistics. But it will be listed. 
 
The following figures of the serum concentration will be provided:  
• 
The arithmetic mean (±SD) serum concentration-versus time of SB15 and Eylea® will be 
presented by main treatment group on a linear scale for Week 0 and Week 24. The 
treatments will be overlaid on the same plot. 
• 
Individual serum concentration versus time of SB15 and Eylea® will be presented by 
subject on a linear scale for Week 0 and Week 24.  
8. SAFETY ANALYSES  
Safety analyses will be performed for main period (or screening + main period to include assessments 
and events occurred at screening period), transition period, and overall study period unless specified 
otherwise. Analyses for screening and main period will be performed in the SAF1 by actual treatment 
group received at main period, and analyses for transition period will be performed in the SAF2 by 
actual treatment group (SB15+SB15, Eylea®+SB15, Eylea®+Eylea®, and Eylea® overall 
(Eylea®+SB15 and Eylea®+Eylea®)), and analyses for the overall study period will be performed in 
the SAF1 by actual treatment group (SB15, Eylea®+SB15, Eylea®+Eylea®, and Eylea® overall 
(subjects received Eylea® treatment at initial randomisation)). 
There will be no statistical comparisons for safety data, unless otherwise specified with the relevant 
section. 
8.1. Study Medication Exposure 
The duration of exposure to intravitreal (IVT) injection of IP will be calculated as follows for each 
study period. 
Exposure duration (days) up to Week 32/Week 56: 
• 
If IP is completed or discontinued after week 8, and prior to cut-off date,  
Exposure duration up to Week 32 = Minimum (Last IVT injection date before Week 32 + 56 
days, cut-off date + 1 day) - first IVT injection date; 
Exposure duration up to Week 56 = Minimum (Last IVT injection date + 56 days, cut-off 
date + 1 day) - first IVT injection date. 
• 
If IP is discontinued prior to cut-off date and before week 8,  
Exposure duration up to Week 32/Week 56 = Minimum (Last IVT injection date + 28 days, 
cut-off date + 1 day) - first IVT injection date. 
• 
If ongoing at cut-off date and before Week 32,  


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Exposure duration up to Week 32/Week 56 = Cut-off date - first IVT injection date + 1 day. 
• 
If ongoing at cut-off date and on or after Week 32,  
Exposure duration up to Week 32 = Minimum (Last IVT injection date before Week 32 + 56 
days, cut-off date + 1 day) - first IVT injection date;  
Exposure duration up to Week 56 = Cut-off date - first IVT injection date + 1 day. 
 
Transition Period: 
• 
If IP is completed or discontinued at transition period prior to cut-off date,  
Exposure duration = Minimum (Last IVT injection date + 56 days, cut-off date + 1 day) - 
first IVT injection date at transition period. 
• 
If ongoing at cut-off date and on or after Week 32, 
Exposure duration = Cut-off date - first IVT injection date at transition period + 1 day. 
There are no ongoing subjects for final CSR, the pre-defined cut-off date and rule for ongoing subjects 
will not be considered for final CSR. 
The analyses of exposure to study drug will be performed for different study period specified in Section 
8. 
Interruptions, compliance, and dose changes are not considered for duration of exposure.  
The duration of exposure to IVT injection of IP (days) will be summarised descriptively including n, 
mean, median, SD, minimum, and maximum by treatment group. 
The exposure duration on IVT injection of IP will be categorized in different time period:   
Main period: >=1 day, >=29 days, >=57 days, >=113 days, >=169 days. 
Transition period: >=1 day, >=57 days, >=113 days. 
Overall study period: >=1 day, >=29 days, >=57 days, >=113 days, >=169 days, >=225 days, >=281 
days, >=337 days.  
Extent of exposure will be summarised according to the number and percentage of subjects in each 
category for treatment group. 
In addition, the number of IVT injections of IP will be summarised descriptively including n, mean, 
median, SD, minimum, and maximum by treatment group.  
A by-subject listing of IP administration will be provided. And listing of Non-IP administration 
(Eylea® for fellow eye treatment) will include injection start date/time and injected eye and whether 
it is injected to the fellow eye. 


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A by-subject listing of randomised allocation to IP treatment consisting of randomisation number, 
treatment allocation and randomised date will be provided for the RAN.  
A by-subject listing of randomised allocation to IP treatment by centre consisting of randomisation 
number, treatment allocation and randomised date will be provided for the RAN.  
A by-subject listing of allocated Investigational Products Information consisting IWRS dispensed 
Med ID, treatment and lot no., actual Med ID, treatment and lot no. will be provided for the RAN. 
8.2. Prior/Concomitant Medications 
Prior and concomitant medications will be coded using the WHO Drug dictionary Global Mar 2020 
B3. Any medications, including prescription drugs, non-prescription drugs, or any therapy received 
locally (in the study eye and/or fellow eye) or systemically reported until Week 56 (EOS visit) or ET 
visit (including a safety follow-up visit or telephone interview) will be included for the analyses. 
A summary of prior and concomitant medication giving the number and percentage of subjects and 
the number of events will be provided by Anatomical Therapeutic Chemistry (ATC) Drug Class 
and/or preferred term for each treatment group.  
• 
Concomitant medications will contain medications ended on or after the first dose of IVT 
injection of IP or medications started prior to the first dose of IVT injection of IP and continue 
(missing end date) on therapy. Summary of concomitant medications will be performed for 
different study period specified in Section 8. Concomitant medications started at main period 
and ended after main period will only be included for main period analysis and not included 
for transition period analysis. 
• 
Prior medications will contain medications ended prior to the first dose of IVT injection of IP. 
Summary of Prior medications will be analysed in SAF1 and provided for main treatment 
group and all subjects. 
Handling method of partial or missing dates is described in APPENDIX 1. For the medication, 
which is impossible to define as prior or concomitant, the medication will be considered as 
concomitant medication (i.e., worst case). 
By-subject listings of prior and concomitant medications will be provided. 
8.3. Prohibited Medications 
Prohibited medications with ATC code/Preferred term will be defined in APPENDIX 2.  
Summary of prohibited medication giving the number and percentage of subjects and the number of 
events will be provided by ATC drug class and/or preferred term for different study period (screening 
and main period, transition period, and overall study period) specified in Section 8, in the similar 
manner as concomitant medications analysis. 
By-subject listing of prohibited medications will be provided. 


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8.4. Laboratory Evaluations 
The following laboratory test results from the central laboratory will be reported in International 
System of Units (SI) unit and analyse in SAF1: 
 
• 
Haematology: Haemoglobin (HGB), Haematocrit (HCT), Platelet count (PLT), White Blood Cell 
(WBC), Neutrophils (NEU), Lymphocytes (LYM), Monocytes (MON), Basophils (BAS), 
Eosinophils (EOS) 
In case only percent (%) of NEU, LYM, MON, BAS, and EOS are collected from a subject, the 
following formula will be used to derive absolute count (10^9/L) and vice versa.  
Absolute count (10^9/L) = Percent (%) ⅹ 0.01 ⅹ White Blood Cells (10^9/L) 
Derived percent (%) and absolute count (10^9/L) will be used for summary of Haematology 
parameters and included in the listing.  
• 
Chemistry: Sodium (SOD), Potassium (POT), Creatinine (CREA), Glucose (GLUC), Calcium 
(CALC), 
Phosphorus 
(PHOS), 
Total 
Bilirubin 
(TBIL), 
Albumin 
(ALB), 
Alanine 
Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALK PHS), 
Lactate dehydrogenase (LDH) 
• 
Urinalysis: Protein, Blood, Leucocytes, Nitrite, Glucose, Ketone, pH, Specific Gravity, Bilirubin, 
Urobilinogen. 
The quantitative lab values with <x will be replaced by x and >y will be replaced by y where x and y 
are lower limit of quantification and upper limit of quantification respectively. The following 
summaries will be provided for laboratory tests: 
• 
Summary of actual value and change from baseline for Haematology and Chemistry by visit and 
overall treatment group in SAF1. 
• 
Summary of the overall assessment (Normal, Abnormal NCS, and Abnormal CS) results for 
Urinalysis by visit and overall treatment group in SAF1. 
• 
Shift from baseline to timepoint Week 8, Week 32, Week 40 and Week 56 (worst case change 
from baseline) by overall treatment group in SAF1 for haematology and chemistry parameters 
with respect to normal range where low, normal and high was defined in relation with the normal 
range. Unscheduled/repeated measurements (except for the baseline value) will contribute to the 
worst-case value for shift tables. The denominator of percentages at each visit will be based the 
number of subjects with available assessment results at each visit. 
By-subject listings of haematology, chemistry, urinalysis parameters and pregnancy test results will 
be provided respectively. Significant abnormalities for haematology and chemistry will be listed 
separately. Laboratory normal range of haematology and chemistry parameters will be listed with 
corresponding low and high range in SI unit.  


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8.5. Vital Signs  
Vital signs (blood pressure, pulse rate and body temperature) will be reported for this study using 
SAF1. 
 
• 
A summary of actual value, and change from baseline by visit and overall treatment group. 
• 
Incidence of clinically significant abnormalities for vital sign parameters. Unscheduled/repeated 
measurements (except for the baseline value) will contribute to the worst-case value for incidence 
of significant abnormalities. In addition, subjects with at least one significant abnormal value until 
Week 32 and Week 56 will be summarised as overall incidence. The denominator of percentages 
at each visit will be based the number of subjects with available assessment results at each visit.  
By-subject listings of vital sign parameters will be provided. 
Clinically Significant Abnormal Criteria 
Clinically significant abnormal quantitative vital signs measurements will be identified in accordance 
with the following predefined clinically significant abnormal criteria: 
Table 2. Clinically Significant Abnormal Criteria of Vital Signs 
Variable 
Unit 
Low 
High 
Systolic Blood 
Pressure 
(SBP) 
mmHg 
≤ 90 mmHg AND  
change from baseline ≤ -20 mmHg 
≥ 180 mmHg AND 
change from baseline ≥ 20 mmHg 
Diastolic 
Blood 
Pressure  
(DBP) 
mmHg 
≤ 50 mmHg AND 
change from baseline ≤ -15 mmHg 
≥ 100 mmHg AND 
change from baseline ≥ 15 mmHg 
Pulse rate 
bpm 
≤ 50 bpm AND 
change from baseline ≤ -15 bpm 
≥ 110 bpm AND 
change from baseline ≥ 15 bpm 
Body  
temperature 
˚C 
≤ 35˚C AND 
change from baseline ≤ - 1.1˚C 
≥ 38.3˚C AND 
change from baseline ≥ 1.1˚C 
 
8.6. Immunogenicity Analysis 
The number and percentage of subjects with ADA results (i.e., Positive, Negative) and neutralizing 
antibodies (NAbs) results (i.e., Positive, Negative) will be presented by overall treatment group and 
visit using SAF1.  


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In addition, the number and percentages of subject with ADA positive will be summarised by titre and 
overall treatment group in each visit using SAF1.   
The incidence of overall ADA results (i.e., Positive, Negative, Inconclusive) up to Week 8, Week 32, 
and Week 56 will be presented by overall treatment group using SAF1. Unscheduled measurements 
will contribute to the incidence of overall assessment results. Overall ADA result is defined as below:  
 
“Positive” for a subject with treatment-induced or treatment-boosted ADA, where treatment-
induced ADA indicates at least one positive result after pre-dose of Week 0 for subjects with 
negative ADA at pre-dose of Week 0, and treatment-boosted ADA indicates at least one positive 
result with higher titre level compared to pre-dose of Week 0 after pre-dose of Week 0 for subjects 
with positive ADA at pre-dose of Week 0.  
 
“Negative” for a subject with negative ADA at Week 0 and without positive ADA until Week 8, 
Week 32, and Week 56. 
 
“Inconclusive” for a subject with positive ADA at Week 0 and without positive result with higher 
titre level observed after pre-dose of Week 0 up to Week 8, Week 32, and Week 56. 
In addition, the incidence of overall ADA results (i.e., Positive, Negative, Inconclusive) for transition 
period from Baseline (up to Week 32) to Week 56 will be presented by transition treatment group 
using SAF2. Overall ADA results for transition period at Week 56 will be summarised for subjects 
with at least one ADA result after transition up to Week 56 respectively. Overall ADA result for 
transition period is defined as below:  
 
“Positive” for a subject with transition treatment-induced or transition treatment-boosted ADA, 
where transition treatment-induced ADA indicates at least one positive result after Week 32 for 
subjects with overall negative ADA up to Week 32, and transition treatment-boosted ADA 
indicates at least one positive result with higher titre level after Week 32 compared to maximum 
positive ADA up to Week 32, for subjects with at least one positive ADA result up to Week 32.  
 
“Negative” for a subject with overall negative ADA at Baseline (up to Week 32), and without 
positive ADA after Week 32 until Week 56. 
 
“Inconclusive” for a subject with at least one positive ADA result up to Week 32 and without 
positive result with higher titre level observed after Week 32 up to Week 56, compared to the 
maximum positive ADA up to Week 32. 
For exploratory purposes, the summary for immunogenicity results will be provided by visit with the 
following statistics:  
 
The association between ADA result and main treatment group will be assessed using Chi-
square test or Fisher’s exact test for SAF1 in overall period. 


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 
The association between ADA result and transition treatment group (just Eylea®+Eylea® vs. 
Eylea®+SB15) will be assessed using Chi-square test or Fisher’s exact test for SAF2 in 
transition period. 
A by-subject listing of immunogenicity assessment will be provided. 
If the fellow eye received Eylea® due to AMD during the study period after randomisation, the ADA 
and NAb results obtained after treatment for the fellow eye will be listed but excluded from the 
summary statistics. 
8.7. Other observations related to Safety Analyses 
Slit Lamp Examination 
Incidence of Slit Lamp Examination for study eye by Visit and overall treatment group for each of the 
parameters (Anterior chamber flare, Anterior chamber cells, Lens status) will be summarised in SAF1.  
In addition, the incidence of overall assessment results up to Week 32 and Week 56 by overall 
treatment group for each of the parameters (Anterior chamber flare, Anterior chamber cells) will be 
summarised. Unscheduled/repeated measurements (except for the baseline value) will contribute to 
the severe result for incidence of overall assessment results. Overall assessment result is counted only 
once for the highest result up to the timepoint except for the baseline value. 
By-subject listing for slit Lamp Examination will be provided. 
Intraocular pressure (IOP) measurement 
Summary Statistics of Intraocular Pressure (Pre-Injection) actual value and change from baseline will 
be generated by visit and overall treatment group in SAF1. 
Summary Statistics of Change in Intraocular Pressure (change will be calculated using subjects with 
both Pre-Injection and Post-injection at each visit) will be generated by visit and overall treatment 
group in SAF1. 
By-subject listing for Intraocular Pressure will be provided. 
Indirect ophthalmoscopy 
Incidence of the vitreous inflammation for study eye by Visit (including overall assessment until Week 
32 and Week 56) and overall treatment group in SAF1. 
By-subject listing for indirect ophthalmoscopy will be provided. 


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Ocular Surgery and Intervention 
Incidence of Ocular Surgery and Intervention in the study eye will be performed for different study 
period specified in Section 8.  
By-subject listing for Ocular Surgery and Intervention will be provided. 
9.  ADVERSE EVENTS 
All reported terms for Adverse Events (AEs) will be coded using MedDRA version 23.0 and the AEs 
reported until Week 56 (EOS visit) or ET visit (including a safety follow-up visit or telephone 
interview) will be reported for the study. 
• 
Pre-treatment AE will be defined as any AE with an onset date before the date of first 
administration of IVT of IP.  
• 
Treatment-emergent AE (TEAE) will be defined as any AE with an onset date on or after the 
date of first dose of IP. If pre-treatment AEs increase in severity during the treatment period, 
they will be considered as TEAEs. Pre- treatment AEs with no increase in severity during the 
treatment period will not be considered as TEAEs. 
• 
AE of Special Interest (AESI) is defined as the following AEs in the study eye: 
a) Intraocular pressure increase 
- 
New onset pre-injection IOP of ≥ 25 mmHg 
- 
Post-injection IOP ≥ 35 mmHg 
b) Any case of intraocular infection (suspected infection) such as endophthalmitis 
c) Any case of non-infectious intraocular inflammation such as iritis, vitritis, and 
iridocyclitis. 
d) Iatrogenic traumatic cataract 
e) Retinal pigment epithelial tear 
f) Subretinal haemorrhage with the size of 1 DA or more involving the centre of the fovea, 
or if the size of the haemorrhage is ≥ 50% of the total lesion area 
• 
Other, non-ocular, AESIs include the following: 


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g) Arterial thromboembolic events including non-myocardial infarction ATEs and 
cardiovascular ischaemic events 
h) Non-ocular haemorrhage 
In general, AEs will be summarised using the number of subjects reporting at least one AE and the 
total number of events reported by SOC, PT for different study period and treatment group as 
specified at Section 8. AE started at main period and ended after main period will only be included 
for main period analysis, and will not be included for transition period analysis. AE started in 
transition period will be summarised in transition period analysis.  
 
See APPENDIX 1 for handling of partial dates for AEs. In the case where it is not possible to define 
as AE as treatment-emergent or not, the AE will be classified by the worst case: i.e., treatment-
emergent. 
Summary of all adverse events 
All AEs will be summarised by number, percentage of subjects and number of events. The following 
categories will be presented in the summary of adverse events for different study periods as specified 
at Section 8. 
• 
AEs 
• 
TEAEs by severity and causality 
• 
Ocular TEAEs in the study eye by severity and causality 
• 
Ocular TEAEs in the fellow eye by severity and causality 
• 
Non-ocular TEAEs by severity and causality 
• 
AESIs by category  
• 
Intraocular Inflammation TEAEs 
• 
Intraocular Inflammation TEAEs in the study eye 
• 
Intraocular Inflammation TEAEs in the fellow eye 
• 
Treatment Emergent Adverse Events leading to IP discontinuation 
• 
Ocular TEAEs leading to IP discontinuation in the study eye 
• 
Ocular TEAEs leading to IP discontinuation in the fellow eye 
• 
Non-ocular TEAEs leading to IP discontinuation  
• 
Serious Adverse Events (SAEs) by causality 


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• 
Serious TEAEs by causality 
• 
Ocular Serious TEAEs in the study eye 
• 
Ocular Serious TEAEs in the fellow eye 
• 
Non-Ocular Serious TEAEs  
• 
TEAEs leading to death 
In addition, the following category will be presented in the summary of adverse events for main 
period (including screening period) : 
• 
Pre-treatment Adverse Events (Pre-AEs)  
Summary of TEAEs for COVID-19 
The following categories will be presented in the summary of adverse events for overall study period. 
• 
TEAEs of COVID-19: COVID-19 were defined using specific PTs which are ‘v23.0’ in 
‘Version added’ of the MedDRA version 23.0 for COVID-19, which include ‘Suspected 
COVID-19’ (Defined in APPENDIX 7) 
• 
TEAEs related to COVID-19 (TEAE other than COVID-19): TEAEs other than COVID-19 
which have a relationship with COVID-19 infection/disease (excluding COVID-19 
vaccination itself) 
• 
TEAEs among COVID-19 positive subjects (TEAE other than COVID-19) 
Summary of SAEs for COVID-19 
The following categories will be presented in the summary of adverse events for overall study period. 
• 
Serious adverse events of COVID-19: COVID-19 were defined using specific PTs which 
are ‘v23.0’ in ‘Version added’ of the MedDRA version 23.0 for COVID-19, which include 
‘Suspected COVID-19’ (Defined in APPENDIX 7) 
• 
Serious adverse events related to COVID-19 (SAE other than COVID-19): SAEs other than 
COVID-19 which have a relationship with COVID-19 infection/disease (excluding 
COVID-19 vaccination itself) 
• 
Serious adverse events among COVID-19 positive subjects (SAE other than COVID-19) 
TEAEs 
The following TEAEs will be summarised by treatment group for different study periods as specified 
at Section 8 (TEAEs for fellow eye will only be summarised for overall study period). 


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Incidence of all TEAEs by treatment group will be presented by SOC and PT using number and 
percentage of subjects and number of events.  
Incidence of ocular TEAEs in the study eye and fellow eye, and non-ocular TEAEs by treatment 
group will be presented by SOC and PT using number and percentage of subjects and number of 
events.  
Incidence of TEAEs with incidence > 5% of Patients in either treatment group by System Organ 
Class and Preferred Term will be presented. 
Incidence of other Adverse Events (TEAE excluding serious adverse events) with incidence > 5% of 
Patients in either treatment group by System Organ Class and Preferred Term will be presented for 
overall study period. 
By-subject listing for TEAEs will be provided. 
TEAEs by Severity 
The following TEAEs by severity will be summarised by treatment group for different study periods 
as specified at Section 8 (TEAEs for fellow eye will only be summarised for overall study period). 
Incidence of ocular TEAEs in study eye and fellow eye, and non-ocular TEAEs by treatment group 
will be presented by SOC, PT, and severity using number and percentage of subjects and number of 
events.  
Severity will be reported as mild, moderate, or severe. TEAEs with a missing severity will be 
considered as severe TEAE (i.e., worst case). If a subject reported TEAEs in the same SOC (or PT) 
more than once with different severity, the subject will be counted once in the worst-case severity.  
TEAEs by Causality (Relationship to drug or IVT injection) 
The following TEAEs by causality will be summarised by treatment group for different study periods 
as specified at Section 8 (TEAEs for fellow eye will only be summarised for overall study period). 
Incidence of ocular TEAEs in study eye and fellow eye, and non-ocular TEAEs by treatment group 
will be presented by SOC, PT, and causality (Drug) using number and percentage of subjects and 
number of events. 
Incidence of ocular TEAEs in study eye by treatment group will be presented by SOC, PT, and 
causality (IVT injection) using number and percentage of subjects and number of events. 
Causality will be reported as Related (Drug) or not related (Drug), Related (IVT injection) or not 
related (IVT injection), causality with both Drug & IVT injection will be reported as Related (Drug) 
and Related (IVT injection) respectively. If a subject report the same AE more than once within that 
SOC/PT, the AE with the worst-case relationship to IP will be used in the corresponding relationship 
summaries. 


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TEAEs by overall ADA result  
As specified in Section 8.6, all TEAEs based on categories of overall ADA result (Positive, Negative, 
Inconclusive) will be summarised by treatment group, SOC and PT, including the number and 
percentage of subjects experiencing events. 
 
- 
Ocular TEAEs in the study eye, fellow eye, and non-ocular TEAEs by overall ADA result up to 
Week 56, overall treatment group, system organ class and preferred term for SAF1 and overall 
period 
- 
Ocular TEAEs in the study eye, fellow eye, and non-ocular TEAEs by overall ADA result up to 
Week 32, main treatment group, system organ class and preferred term for SAF1 and main 
period 
- 
Ocular TEAEs in the study eye, fellow eye, and non-ocular TEAEs by overall ADA result after 
transition up to Week 56, transition treatment group, system organ class and preferred term for 
SAF2 and transition period 
SAEs 
The following SAEs will be summarised by treatment group for different study periods as specified 
at Section 8. 
Incidence of all SAEs by treatment group will be presented by SOC and PT using number and 
percentage of subjects and number of events.  
By-subject listing for SAEs will be provided. 
Serious TEAEs 
The following serious TEAEs will be summarised by treatment group for different study periods as 
specified at Section 8. 
Incidence of serious TEAEs by treatment group will be presented by SOC and PT using number and 
percentage of subjects and number of events.  
Incidence of ocular serious TEAEs in the study eye and fellow eye, and non-ocular serious TEAEs 
by treatment group will be presented by SOC and PT using number and percentage of subjects and 
number of events.  
Incidence of ocular serious TEAEs in the study eye and fellow eye, and non-ocular serious TEAEs 
by treatment group will be presented by SOC, PT, and severity using number and percentage of 
subjects and number of events. 
Incidence of ocular serious TEAEs in the study eye and fellow eye, and non-ocular serious TEAEs 
by treatment group will be presented by SOC, PT, and causality (Drug) using number and percentage 
of subjects and number of events. 


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Incidence of ocular serious TEAEs in the study eye by treatment group will be presented by SOC, 
PT, and causality (IVT injection) using number and percentage of subjects and number of events. 
AESIs 
The following AESIs will be summarised by treatment group for different study periods as specified 
at Section 8. 
Incidence of ocular AESIs in the study eye, and non-ocular AESIs by treatment group will be 
presented by SOC and PT using number and percentage of subjects with number of events. 
By-subject listing for AESIs will be provided. 
Intraocular Inflammation 
The following TEAEs for intraocular inflammation will be summarised by treatment group for 
different study period as specified at Section 8 (TEAEs for intraocular inflammation for fellow eye 
will only be summarised for overall study period). 
Incidence of TEAEs for intraocular inflammation by treatment group in study eye and fellow eye 
will be presented by SOC and PT using number and percentage of subjects with number of events. 
TEAEs leading to discontinuation of study medication 
The following TEAEs leading to discontinuation of study medication will be summarised by 
treatment group for different study periods as specified at Section 8. 
Incidence of TEAEs leading to discontinuation of study medications by treatment group will be 
presented by SOC and PT using number and percentage of subjects and number of events.  
By-subject listing for TEAEs leading to discontinuation of study medication will be provided. 
TEAEs leading to death 
The following TEAEs leading to death will be summarised by treatment group for different study 
periods as specified at Section 8. 
Incidence of TEAEs leading to death by treatment group be presented by SOC and PT using number 
and percentage of subjects and number of events.  
By-subject listing for TEAEs leading to death will be provided. 


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10. REFERENCES  
Chakravarthy U, Wong T, Fletcher A, et al. Clinical risk factors for age-related macular 
degeneration: a systematic review and meta-analyses. BMC Ophthalmology. 2010,10(31) 
 
 


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APPENDIX 1. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. However, in general, when calculating relative 
days, partial dates with missing day only will be assumed to be 15th of the month, and partial dates 
with both missing day and month will be assumed to be June 30. Otherwise, the following rules in 
the given table will be applied for each case. 
Algorithm for Adverse Events and Medications 
When the start date is missing, 
 
Case 
Imputed Value 
Missing Day 
year and month  
= year and month of first IP taken date 
first IP taken date 
year and month  
<> year and month of first IP taken date 
the 1st of the month 
Missing Day and Month 
year = year of first IP taken date 
first IP taken date 
year <> year of first IP taken date 
1st of January 
Completely Missing 
N/A 
 
When the end date is missing, 
 
Case 
Imputed Value 
Missing Day 
year and month  
< year and month of last visit date 
last day of the month  
year and month  
= year and month of last visit date 
last visit date 
Missing Day and Month 
year < year of last visit date 
31st of December 
year = year of last visit date 
last visit date 
Completely Missing 
N/A 
 
Algorithm for Treatment-Emergent 
After imputation for partial dates is implemented, whether AE is TEAE will be decided. 
 
When start date is present, 
• 
If known/imputed start date ≥ the date of first dose of IP, then AE is considered as TEAE  
 
When start date is completely missing but end date is present 


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• 
If known/imputed end date ≥ the date of first dose of IP, then AE is considered as TEAE 
 
When both start date and end date are completely missing 
• 
AE is considered as TEAE  
Algorithm for Concomitant 
After imputation for partial dates is implemented, whether medication is concomitant will be 
decided. 
 
When both start date and end date are present 
• 
If known/imputed end date ≥ the date of first dose of IP and known/imputed start date≤the date 
of last participation, then medication is considered as concomitant 
 
When start date is present and end date is completely missing 
• 
If known/imputed start date ≤ the date of last participation, then medication is considered as 
concomitant 
 
When start date is completely missing but end date is present 
• 
If known/imputed end date ≥ the date of first dose of IP, then medication is considered as 
concomitant 
 
When both start date and end date are completely missing 
• 
Medication is considered as concomitant 
 
 
 


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APPENDIX 2. CODE FOR PROHIBITIVE MEDICATION 
SB15 Prohibitive 
Medication List for  
APPENDIX 3. 
LABORATORY TEST PARAMETERS 
 
SB15 Lab Normal 
Range.xlsx
 
 


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APPENDIX 4. VISIT LABEL FOR STDUY PERIOD 
 
Time Point 
Visit Name 
Source Visit Name 
Screening Period 
VISIT 1 
VISIT 1 (Screening) 
Main Period 
VISIT 2 
VISIT 2 (W0) 
VISIT 3 
VISIT 3 (W4) 
VISIT 4 
VISIT 4 (W8) 
VISIT 5 
VISIT 5 (W16) 
VISIT 6 
VISIT 6 (W24) 
Transition Period 
VISIT 7 
VISIT 7 (W32) 
VISIT 8  
VISIT 8 (W40) 
VISIT 9  
VISIT 9 (W48, EOT) 
VISIT 10  
VISIT 10 (W56, EOS) or ET 
  
SAFETY FOLLOW-UP VISIT 
VISIT 10 (W56, EOS) or ET 
FOLLOW UP <X> 
FU 
<VISIT> UNSCHEDULED <Y>  
For example: VISIT 1 UNSCHEDULE
D 01 
UNS 
 
APPENDIX 5. SAMPLE CODES FOR PRIMARY ANALYSIS 
SB15 Missing 
Imputation.docx


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APPENDIX 6. SAS CODE OF ADJUSTED RISK DIFFERENCE 
PROC FREQ DATA = <input_dataset>; 
TABLES <strata_var>*<treat_var>*<response_var>/commonriskdiff 
(CL=MH) ALPHA=0.05; 
RUN; 
APPENDIX 7. CODE FOR COVID-19 RELATED TERMS 
 
SB15 COVID-19 
Related Terms in M 
APPENDIX 8. SCORING METHODOLOGY FOR VFQ-25: 
The VFQ- 25 generates the following vision-targeted subscales: 
global vision rating (1), difficulty with near vision activities (3), difficulty with distance vision 
activities (3), limitations in social functioning due to vision (2), role limitations due to vision (2), 
dependency on others due to vision (3), mental health symptoms due to vision (4),  
driving difficulties (3), limitations with peripheral (1) and color vision (1), and ocular pain (2). 
 
First, original numeric values are re-coded following the scoring rules. All items are scored so that a 
high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the 
lowest and highest possible scores are set at 0 and 100 points, respectively.  
Scoring Key: Recoding of Items 
 
Item Numbers 
Change 
original 
response 
category 
To recoded value of: 
1,3,4,15c@ 
1 
100 
 
2 
75 
 
3 
50 
 
4 
25 
 
5 
0 
2 
1 
100 
 
2 
80 
 
3 
60 
 
4 
40 
 
5 
20 
 
6 
0 
5,6,7,8,9,10,11,12,13,14,16,16a 
1 
100 


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2 
75 
 
3 
50 
 
4 
25 
 
5 
0 
 
6 
* 
17,18,19,20,21,22,23,24,25 
1 
0 
 
2 
25 
 
3 
50 
 
4 
75 
 
5 
100 
 
@Item 15c has four-response levels but is expanded to a five-levels using item 15b.  
Note: If 15b=1, then 15c should be recoded to “0”  
If 15b=2, then 15c should be recoded to missing.  
If 15b=3, then 15c should be recoded to missing. 
 
Next, items within each sub-scale are averaged together to create the 12 sub-scale scores. Below table 
indicates which items contribute to each specific sub-scale. Items that are left blank (missing data) are 
not taken into account when calculating the scale scores. Sub-scales with at least one item answered 
can be used to generate a sub-scale score. Hence, scores represent the average for all items in the 
subscale that the respondent answered. 
Averaging of Items to Generate VFQ-25 Sub-Scales 
 
Scale 
Number of items 
Items to be averaged 
 
 
 
General Health 
1 
1 
General Vision 
1 
2 
Ocular Pain 
2 
4, 19 
Near Activities 
3 
5, 6, 7 
Distance Activities 
3 
8, 9, 14 
Vision Specific: 
 
 
    Social Functioning 
2 
11, 13 
    Mental Health 
4 
3, 21, 22, 25 
    Role Difficulties 
2 
17, 18 
    Dependency 
3 
20, 23, 24 
Driving 
3 
15c, 16, 16a 
Color Vision 
1 
12 
Peripheral Vision 
1 
10 
 
Sub scale score calculation: 
Items within each sub-scale are averaged together to create the 12 sub-scale scores. Items that are left 
blank (missing data) are not taken into account when calculating the scale scores. Sub-scales with at 
least one item answered can be used to generate a sub-scale score. Hence, scores represent the average 
for all items in the subscale that the respondent answered. 
 


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Mean= (Score for each item with a non-missing answer) / Total number of items with non-missing 
answers 
Composite Score Calculation 
To calculate an overall composite score for the VFQ-25, simply average the vision-targeted subscale 
scores, excluding the general health rating question. By averaging the sub-scale scores rather than the 
individual items we have given equal weight to each sub-scale, whereas averaging the items would 
give more weight to scales with more items. 
 


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STATISTICAL ANALYSES PLAN SIGNATURE PAGES 
 
SIGNATURE PAGE 
Declaration of the authors 
Protocol Title Applicable to this Statistical Analyses Plan: A Phase III Randomised, Double-masked, 
Parallel Group, Multicentre Study to Compare the Efficacy, Safety, Pharmacokinetics, and 
Immunogenicity between SB15 (proposed aflibercept biosimilar) and Eylea® in Subjects with 
Neovascular Age-related Macular Degeneration 
Protocol Number: SB15-3001 
Protocol Version and Effective Date:  
Version 1.0     Oct 30, 2019 
 
 
 
 
 
 
Authors 
Name: 
 
Institution: 
 
Signature: 
 
Date: 
 
 
 
 
(Mmm dd, yyyy) 
Name: 
 
Institution: 
Samsung Bioepis Co., Ltd. 
Signature: 
 
Date: 
 
 
 
 
(Mmm dd, yyyy) 
 
PPD
PPD
PPD