Clinical trial NCT04480463
Conditions: Wet Age-related Macular Degeneration Neovascular Age-related Macular Degeneration
Keywords: Age-related macular degeneration AMD Neovascular Exudative
Sponsor: Sam Chun Dang Pharm. Co. Ltd.
Start date: 2020-08-13; Completion date: 2022-09-08
Enrollment: 576 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Age-related macular degeneration (AMD) is a leading cause of vision loss in adults. Abnormal blood vessels grow under the macula at the back of the eye, and also leak blood and fluid, which damages and scars the macula, affecting vision. The current standard of care for patients with neovascular (exudative / wet) AMD is anti-vascular endothelial growth factor (anti-VEGF) therapy, which prevents or slows down the growth of the abnormal blood vessels. SCD411 is being developed as a biosimilar to the reference product Eylea® (aflibercept), an anti-VEGF drug. The study aims to prove equivalence of SCD411 to Eylea in adults with wet AMD, and will look at safety, tolerance, effectiveness, immune response and the movement of the drug through the body.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: SCD411 intervention 2: Aflibercept
Intervention descriptions: intervention 1: IVT (intravitreal) injection intervention 2: IVT injection

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
EUDRACT NUMBER: 2019-004132-37 
IND NUMBER: 144376 
 
A Phase III Randomized, Double-Masked, Parallel-Group, Multicenter 
Study to Compare the Efficacy, Safety, Tolerability, Pharmacokinetics, and 
Immunogenicity between SCD411 and Eylea® in Subjects with Neovascular 
Age-related Macular Degeneration 
 
SCD411-CP101 
Sponsor: 
SamChunDang Pharm. Co. Ltd. 
351, Hyoryeong-ro, Seocho-gu, Seoul 06643, 
Republic of Korea 
Sponsor Contact: 
Byung Jhip Ha 
Director of Bio Research Center 
Telephone: +82-31-888-6362 
Version of Protocol:  
Version 3.0, Final 
Date of Protocol:  
24 January 2022 
Previous Dates and Versions: 
Version 2.0, dated 24 November 2020 
Version 1.2 (Country-Specific [Slovakia]), dated 
22 July 2020 
Version 1.1 (Country-Specific [Republic of Korea]), dated 
03 August 2020 
Original (Version 1.0), dated 27 March 2020 
 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by SamChunDang 
Pharm. Co. Ltd. The concepts and information contained in this document or generated 
during the study are considered proprietary and may not be disclosed in whole or in part 
without the expressed, written consent of SamChunDang Pharm. Co. Ltd. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R2): Good Clinical Practice. 
 




SamChunDang Pharm. Co. Ltd. 
SCD411 
Protocol: SCD411-CP101, Version 3.0 
24 Jan 2022 
 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase III Randomized, 
Double-Masked, Parallel-Group, Multicenter Study to Compare the Efficacy, Safety, 
Tolerability, Pharmacokinetics, and Immunogenicity between SCD411 and Eylea® in 
Subjects with Neovascular Age-related Macular Degeneration” and the accompanying 
investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 3.0, dated 24 Jan 2022, the International Council 
for Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice and all 
applicable government regulations. I will not make changes to the protocol before consulting 
with SamChunDang Pharm. Co. Ltd. or implement protocol changes without independent 
ethics committee approval except to eliminate an immediate risk to subjects. I agree to 
administer study treatment only to subjects under my personal supervision or the supervision 
of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from SamChunDang Pharm. Co. Ltd. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 
Name of Institution/Organization of Principal 
Investigator 
 
 
 


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Table of Contents 
Table of Contents .......................................................................................................................4 
List of Tables ..............................................................................................................................8 
List of Figures ............................................................................................................................8 
Protocol Synopsis.......................................................................................................................9 
List of Abbreviations................................................................................................................22 
1 
Introduction ......................................................................................................................25 
1.1 
Background .............................................................................................................25 
1.2 
Nonclinical Studies .................................................................................................26 
1.3 
Study Rationale .......................................................................................................26 
1.4 
Benefit-risk Assessment ..........................................................................................27 
2 
Study Objectives, Estimands, and Endpoints ...................................................................28 
2.1 
Primary Objective ...................................................................................................28 
2.2 
Secondary Objectives..............................................................................................28 
2.3 
Exploratory Objectives ...........................................................................................28 
2.4 
Endpoints ................................................................................................................28 
2.4.1 
Primary Endpoint .....................................................................................28 
2.4.2 
Secondary Endpoints ...............................................................................28 
2.4.3 
Exploratory Endpoints .............................................................................29 
2.5 
Estimands ................................................................................................................29 
3 
Investigational Plan ..........................................................................................................31 
3.1 
Study Design ...........................................................................................................31 
3.1.1 
Rationale of Study Design .......................................................................34 
4 
Subject Selection and Withdrawal Criteria ......................................................................35 
4.1 
Selection of Study Population .................................................................................35 
4.1.1 
Inclusion Criteria .....................................................................................35 
4.1.2 
Exclusion Criteria ....................................................................................36 
4.1.3 
Women of Child-bearing Potential ..........................................................39 
4.1.4 
Approved Methods of Contraception ......................................................39 
4.2 
Selection of Study Eye ............................................................................................40 


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4.3 
Withdrawal of Subjects From Study Treatment and/or the Study ..........................40 
4.3.1 
Discontinuation From Study Treatment ...................................................40 
4.3.2 
Withdrawal From the Study .....................................................................41 
4.3.3 
Handling of Withdrawals .........................................................................42 
4.3.4 
Screen Failures .........................................................................................42 
4.3.5 
Lost to Follow-up ....................................................................................43 
4.3.6 
Study Termination ....................................................................................43 
4.3.7 
Replacements ...........................................................................................44 
5 
Study Treatments ..............................................................................................................45 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................45 
5.2 
Treatments Administered ........................................................................................45 
5.2.1 
Treatment of Fellow Eye .........................................................................46 
5.2.2 
Dose Modification ...................................................................................47 
5.3 
Identity of Investigational Product..........................................................................47 
5.4 
Management of Clinical Supplies ...........................................................................48 
5.4.1 
Study Drug Packaging and Storage .........................................................48 
5.4.2 
Test Article Accountability ......................................................................48 
5.5 
Overdose Management ...........................................................................................48 
5.5.1 
Medication Errors ....................................................................................49 
5.6 
Masking ..................................................................................................................49 
5.6.1 
Unmasking ...............................................................................................49 
5.7 
Treatment Compliance ............................................................................................50 
5.8 
Prior and Concomitant Therapy ..............................................................................50 
5.8.1 
Rescue Treatment .....................................................................................50 
5.8.2 
Prohibited Medications ............................................................................51 
6 
Study Assessments and Procedures ..................................................................................54 
6.1 
Study Visits .............................................................................................................58 
6.1.1 
Screening Phase .......................................................................................58 
6.1.2 
Treatment Phase .......................................................................................59 
6.1.2.1 
Baseline (Day 1) ......................................................................................59 
6.1.2.2 
Subsequent Treatment Period (Week 4, Week 8, Week 12, Week 16, 
Week 24, Week 28, Week 32, Week 40, Week 44, and Week 48) ............60 
6.1.3 
Early Termination/End-of-Study .............................................................67 


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6.2 
Efficacy Assessments ..............................................................................................68 
6.2.1 
Best Corrected Visual Acuity ...................................................................68 
6.2.2 
Ocular Imaging ........................................................................................69 
6.2.2.1 
Optical Coherence Tomography ..............................................................69 
6.2.2.2 
Fluorescein Angiography and Fundus Photography ................................70 
6.3 
Safety Assessments .................................................................................................70 
6.3.1 
Medical History and Concomitant Medications ......................................70 
6.3.2 
Ophthalmic Examinations .......................................................................71 
6.3.3 
Adverse Events ........................................................................................72 
6.3.3.1 
Definitions of Adverse Events .................................................................72 
6.3.3.2 
Serious Adverse Events ...........................................................................72 
6.3.3.3 
Eliciting and Documenting Adverse Events ............................................73 
6.3.3.4 
Reporting Adverse Events .......................................................................73 
6.3.3.5 
Reporting Serious Adverse Events ..........................................................74 
6.3.3.6 
Suspected Unexpected Serious Adverse Reactions .................................75 
6.3.3.7 
Assessment of Severity ............................................................................75 
6.3.3.8 
Assessment of Causality ..........................................................................76 
6.3.3.9 
Follow-Up of Subjects Reporting Adverse Events ..................................76 
6.3.4 
Clinical Laboratory Evaluations ..............................................................76 
6.3.5 
Vital Signs ................................................................................................77 
6.3.6 
Electrocardiograms ..................................................................................77 
6.4 
Pharmacokinetic Assessments ................................................................................78 
6.5 
Immunogenicity Assessments .................................................................................79 
6.6 
Independent Data Monitoring Committee ..............................................................79 
6.7 
Pregnancy ................................................................................................................80 
6.8 
Sample Collections .................................................................................................80 
7 
Statistical and Analytical Plan ..........................................................................................81 
7.1 
Estimands and Intercurrent Events .........................................................................81 
7.2 
Sample Size Determination.....................................................................................84 
7.3 
Analysis Sets ...........................................................................................................85 
7.4 
Description of Subgroups to be Analyzed ..............................................................86 
7.5 
Statistical Analysis Methodology ...........................................................................86 


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7.5.1 
Efficacy Analyses ....................................................................................86 
7.5.1.1 
Primary Efficacy Outcome Measures ......................................................87 
7.5.1.2 
Secondary Efficacy Outcome Measures ..................................................89 
7.5.2 
Pharmacokinetic Analyses .......................................................................90 
7.5.3 
Immunogenicity Analyses .......................................................................90 
7.5.4 
Safety Analyses ........................................................................................90 
7.5.5 
Other Analyses .........................................................................................92 
7.5.5.1 
Background Characteristics .....................................................................92 
7.5.5.1.1 
Subject Disposition ......................................................................92 
7.5.5.1.2 
Demographics and Baseline Characteristics ................................92 
7.5.5.1.3 
Prior and Concomitant Medications ............................................92 
7.5.5.1.4 
Medical History ...........................................................................92 
7.5.5.1.5 
Study Drug Exposure and Compliance ........................................93 
7.5.6 
Interim Analyses ......................................................................................93 
8 
Data Quality Assurance ....................................................................................................94 
8.1 
Data Management ...................................................................................................94 
9 
Ethics ................................................................................................................................95 
9.1 
Independent Ethics Committee or Institutional Review Board ..............................95 
9.2 
Ethical Conduct of the Study ..................................................................................95 
9.3 
Subject Information and Consent ...........................................................................95 
10 Investigator’s Obligations ................................................................................................97 
10.1 Confidentiality ........................................................................................................97 
10.2 Financial Disclosure and Obligations .....................................................................97 
10.3 Investigator Documentation ....................................................................................98 
10.4 Study Conduct .........................................................................................................98 
10.5 Adverse Events and Study Report Requirements ...................................................98 
10.6 Records Retention ...................................................................................................98 
10.7 Publications .............................................................................................................98 
11 Study Management ...........................................................................................................99 
11.1 Monitoring ..............................................................................................................99 
11.1.1 
External Data Monitoring Committee .....................................................99 
11.1.2 
Monitoring of the Study ...........................................................................99 


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11.1.3 
Inspection of Records ..............................................................................99 
11.2 Management of Protocol Amendments and Deviations........................................100 
11.2.1 
Protocol Amendments ............................................................................100 
11.2.2 
Protocol Deviations ...............................................................................100 
11.3 Study Termination .................................................................................................101 
11.4 Final Report ..........................................................................................................101 
12 Reference List.................................................................................................................102 
13 Appendices .....................................................................................................................104 
13.1 Appendix 1: Slit Lamp Examination - Grading Scale ..........................................104 
13.2 Appendix 2: Assessment of Vitreous Cells - Grading Scale .................................105 
14 Protocol Amendment ......................................................................................................106 
14.1 Protocol Amendment, Version 3.0, 24 January 2022 ............................................106 
14.2 Protocol Amendment, Version 2.0, 24 November 2020 ....................................... 118 
 
List of Tables 
Table 5-1: 
Prohibited Medications ................................................................................... 52 
Table 6-1: 
Schedule of Events .......................................................................................... 55 
Table 6-2: 
Clinical Laboratory Evaluations ..................................................................... 77 
Table 6-3: 
Sampling Window ........................................................................................... 78 
 
List of Figures 
Figure 3-1: 
Study Schema.................................................................................................. 33 
 


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Protocol Synopsis 
Protocol Number: 
SCD411-CP101 
Title: 
A Phase III Randomized, Double-Masked, Parallel-Group, 
Multicenter Study to Compare the Efficacy, Safety, Tolerability, 
Pharmacokinetics, and Immunogenicity between SCD411 and 
Eylea® in Subjects with Neovascular Age-related Macular 
Degeneration 
Sponsor: 
SamChunDang Pharm. Co. Ltd. 
351, Hyoryeong-ro, Seocho-gu, Seoul 06643, Republic of Korea 
Study Phase: 
Phase III 
Study Sites: 
Approximately 155 study sites and 14 countries 
Indication: 
Neovascular Age-related Macular Degeneration 
Rationale: 
SCD411 is being developed as a biosimilar to the reference product 
Eylea® (aflibercept). Based on the proposed extensive analytical 
comparability testing, comparative nonclinical testing, and 
comparative clinical studies using the same licensed reference 
product, the current study is designed to evaluate comparability 
between SCD411 and aflibercept. Based on the data from 
aflibercept clinical studies VIEW 1, VIEW 2, COPERNICUS, 
GALILEO, VIBRANT, VIVID, VISTA, and MYRROR, wet age-
related macular degeneration (AMD) is considered as the most 
suitable condition to prove similarity between SCD411 and 
aflibercept as the reference product. 
The available data regarding the pharmacokinetics (PK) of the 
reference product suggests that a proper PK characterization will not 
be possible after single intravitreal (IVT) administration. In a PK 
substudy of Eylea in 6 neovascular wet AMD patients with frequent 
sampling, maximum plasma concentrations (Cmax) of free 
aflibercept (systemic) 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 IVT 
injection and were undetectable 2 weeks following dosage in almost 
all patients. It is evident that in some cases no measurable systemic 
levels of free aflibercept were registered after IVT administration. 
Hence, a comparative PK evaluation in patients with AMD will 
likely not provide any information of relevance to support 
biosimilarity. Although the systemic exposure of SCD411 is 
expected to also be very low at steady state, there is no previous 
human data on SCD411, and thus this assumption requires 
experimental support. Hence, PK assessment will be performed in 
the current study following the first and the third doses of SCD411. 


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As aflibercept is a therapeutic protein, there is a potential for 
immunogenicity. No cases of active neutralizing antibodies (NAb) 
were observed after administration of Eylea. It is evident that 
immunogenicity is not presenting a substantial safety concern in 
patients treated with aflibercept injections. There was no substantial 
difference in the proportion of patients testing positive for anti-drug 
antibodies (ADA) in different indications, including wet AMD. 
Based on this observation, the indication chosen for this study is 
expected to provide sound data for comparing the immunogenicity 
of the test product (SCD411) with that of Eylea. 
The clinical part of the comparison will be based on clinical efficacy 
and safety data obtained after IVT administration to subjects with 
wet AMD in the current pivotal study. 
Objectives: 
The primary objective of this study is: 
• To prove the equivalence of SCD411 as compared to Eylea 
(aflibercept) in best corrected visual acuity (BCVA) after 
8 weeks of treatment among subjects with wet AMD. 
The secondary objectives of this study are: 
• To compare the safety and tolerability of SCD411 and 
aflibercept 
• To compare the efficacy of SCD411 and aflibercept after 
8 weeks and 52 weeks of treatment demonstrated by BCVA, 
central retinal thickness (CRT), and choroidal 
neovascularization (CNV) 
• To compare the immunogenicity of SCD411 and aflibercept 
by presenting information of the development of anti-
SCD411 antibodies. 
The exploratory objectives of this study are: 
• To compare PK parameters of SCD411 and aflibercept 
• To quantify free and bound aflibercept and SCD411. 
Estimands: 
The primary estimand for the primary objective is the mean 
treatment difference in BCVA change from baseline at Week 8. At 
Week 52, the primary estimand of interest is the mean treatment 
difference in BCVA change from baseline at Week 52. For the 
primary estimand, any observations post receipt of rescue therapy in 
the study eye will be set to missing, thereby estimating the treatment 
effect as though subjects do not receive rescue therapy. For each of 
the Week 8 and Week 52 analyses, the secondary estimand will be 
presented where post rescue will not be set to missing but will be 
included in the mixed-effects model for repeated measures 


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(MMRM) analysis. The secondary estimands are constructed to 
estimate the treatment effect while including the impact of rescue 
therapy, which may better reflect actual real-world outcomes, where 
rescue therapy would likely be given when lack of efficacy is seen. 
Study Population: 
Each subject must meet all of the following inclusion criteria to be 
enrolled in this study: 
1. Capable of understanding the written informed consent, provides 
signed and witnessed written informed consent, and agrees to 
comply with protocol requirements 
2. Age ≥50 years 
3. Active choroidal subfoveal, juxtafoveal, or extrafoveal 
neovascularization lesions secondary to AMD evidenced by 
fluorescein angiography (FA) in the study eye at screening and 
confirmed by the central reading center 
4. The BCVA letter score of 73 to 35 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 randomization. In addition, fellow eye should not 
be less than 35 letter score using the ETDRS chart or 2702 series 
number chart 
5. Women of child-bearing potential with a negative serum 
pregnancy test at screening must agree to use protocol-defined 
methods of contraception throughout the study until 3 months after 
the last injection of aflibercept/SCD411 
6. Males with female partners of child-bearing potential must agree 
to use protocol-defined methods of contraception and agree to 
refrain from donating sperm throughout the study until 3 months 
after the last injection of aflibercept/SCD411. 
7. The area of CNV making up either 50% or more of the total 
lesion area and confirmed by the central reading center 
 
Subjects meeting any of the following criteria at the Screening Visit 
will be excluded from the study: 
1. Any prior ocular (in the study eye and fellow eye) or systemic 
treatment or surgery for neovascular AMD except dietary 
supplements or vitamins 
2. Any prior or concomitant therapy with another investigational 
agent to treat neovascular AMD in the study eye, except dietary 
supplements or vitamins 


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3. Fellow eye shows signs of AMD that, in investigator’s medical 
opinion, may need any treatment during study period 
4. Any prior treatment with anti-vascular endothelial growth factor 
(VEGF) agents in the both eyes (ie, completely treatment naïve 
subjects only to be included) 
5. Total lesion size >30.5 mm2, including blood, scars, atrophy, 
fibrosis, and neovascularization as assessed by FA in the study eye 
and confirmed by the central reading center 
6. Central retina thickness of <300 µm in the study eye and 
confirmed by the central reading center 
7. Subretinal hemorrhage that is either 50% or more of the total 
lesion area, or if the blood is under the fovea and is 1 or more disc 
areas in size in the study eye and confirmed by the central reading 
center. (If the blood is under the fovea, then the fovea must be 
surrounded 270 degrees by visible CNV.) 
8. Scar or fibrosis, making up >50% of the total lesion in the study 
eye and confirmed by the central reading center 
9. Scar, fibrosis, or atrophy involving the center of the fovea in the 
study eye and confirmed by the central reading center 
10. Presence of retinal pigment epithelial tears or rips involving the 
macula in the study eye and confirmed by the central reading center 
11. Lens Opacity Classification System II (LOCS II) grade IV 
cataract in the study eye, or other significant cataract in the study 
eye that in the Investigator’s opinion interferes with visualization of 
retina or interferes with retinal imaging 
12. Active intraocular/periocular infection and inflammation in 
either eye 
13. History of any vitreous hemorrhage in the study eye within 
4 weeks prior to the Screening Visit 
14. Presence of other causes of CNV in the study eye as confirmed 
by central reading center 
15. History or clinical evidence of diabetic retinopathy, diabetic 
macular edema, or any other vascular disease affecting the retina, 
other than AMD, in either eye 
16. Prior vitrectomy in the study eye 
17. History of retinal detachment, treatment, or surgery for retinal 
detachment in the study eye 
18. History of macular hole of Stage 2 and above in the study eye as 
confirmed by central reading center 


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19. History of uncomplicated intraocular or periocular surgery 
within 3 months of Day 1 on the study eye, except lid surgery, 
which may not have taken place within 1 month of Day 1 
Note: A subject with uncomplicated neodymium yttrium aluminum 
garnet (Nd:YAG) laser capsulotomy performed for secondary 
opacification of the posterior capsule in intraocular lens implanted 
eye within 3 months prior to Day 1 in the study eye will be 
considered as eligible. 
20. Presence of aphakia in the study eye. 
21. History of glaucoma-filtering surgery within 3 months of Day 1 
in the study eye. Anti-glaucoma laser surgeries will not be 
considered exclusionary. 
22. History of corneal transplant in the study eye. 
23. History or evidence of any other clinically significant disorder, 
condition or disease (eg, co-existence of retinal vein occlusion, 
radiation retinopathy, diabetic retinopathy, glaucoma under 
treatment) in the study eye that, in the opinion of the investigator, 
would pose a risk to subject safety or interfere with the study 
evaluation, procedure or complication 
24. Uncontrolled hypertension defined as systolic blood pressure 
(BP) >160 mmHg or diastolic BP >100 mmHg under appropriate 
antihypertensive treatment 
25. Hypersensitivity to aflibercept or medications used in this study 
(fluorescein, mydriatic eye drops, etc.) 
26. Pregnancy or lactation at the Screening Visit and/or at baseline 
for women of child-bearing potential 
27. Any contraindication to IVT injection according to the 
investigator’s clinical judgment 
28. History of thrombotic events (eg, stroke, transient ischemic 
attacks, pulmonary embolism, deep vein thrombosis, or myocardial 
infarction) 
29. History or evidence of cardiac conditions with congestive 
cardiac failure resulting in marked limitation on physical activity or 
inability to perform any physical activity without discomfort; 
subjects with ventricular arrhythmia requiring ongoing treatment; or 
subjects with atrial fibrillation 
30. History of laser therapy in the macular region in the study eye 
31. Any prior or concomitant treatment with IVT corticosteroids 
injection, IVT corticosteroid implant, subtenon corticosteroids, or 


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peribulbar corticosteroids in the study eye 6 months before the 
Screening Visit 
Note: For IVT corticosteroid implant, the exclusion period would be 
36 months from the date of the procedure to the date of screening 
32. Any prior or concomitant treatment involving the macula with 
photodynamic therapy with verteporfin, transpupillary 
thermotherapy, radiation therapy, or retinal laser treatment (eg, focal 
laser photocoagulation) in the study eye 
33. Any prior or concomitant treatment with pan-retinal 
photocoagulation 90 days in the study eye before the Screening Visit 
34. Any concomitant or prior treatment with ethambutol (2 weeks 
prior to randomization); deferoxamine and topiramate (4 weeks 
prior to randomization); tamoxifen, hydroxychloroquine, 
chloroquine, or vigabatrin (8 weeks prior to randomization), and 
amiodarone (12 weeks prior to randomization) 
35. Any investigational product for the treatment of ocular 
conditions (in either eye) and systemic conditions 30 days or 5 half-
lives (whichever is longer), prior to randomization, and throughout 
the study, except dietary supplements or vitamins 
36. Intraocular pressure ≥25 mmHg in spite of anti-glaucoma 
treatment 
37. Any prior or ongoing systemic medical condition (including but 
not limited to infectious, inflammatory, psychiatric, neurological, 
renal, hepatic, respiratory conditions or malignancies) or clinically 
significant screening laboratory value that in the opinion of the 
investigator may present a safety risk, interfere with study 
compliance and follow-up, or confound data interpretation 
throughout the study period. 
Study Design: 
This is a Phase III, randomized, double-masked, parallel-group, 
multicenter study to demonstrate biosimilarity of SCD411 compared 
to Eylea (aflibercept) among adult subjects with neovascular (wet) 
AMD. Subjects will be randomly assigned in 1:1 ratio using 
Interactive Response Technology to receive either SCD411 or 
aflibercept injections. Subjects will receive their randomized first 
IVT injection on Day 1 and subsequent IVT injection on Weeks 4, 8, 
16, 24, 32, 40, and 48. The End-of-Treatment (EOT) Visit will be 
scheduled for Week 48. Subjects who discontinue the study 
treatment early should have the reasons for treatment 
discontinuation documented on the Treatment Discontinuation page 
of the electronic case report form (eCRF). Treatment 
discontinuation in the study is defined as subjects discontinuing the 


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study treatment due to adverse event/lack of efficacy/rescue 
treatment but not limited to these conditions. Every effort should be 
made to have such subjects remain in the study and continue with 
their regularly scheduled visits and assessments until Week 52 
except for study treatment administration. If a subject chooses to 
withdraw from the study or if, in the opinion of the investigator, the 
subject should be prematurely withdrawn from the study, then the 
Early Termination (ET) Visit should be completed as soon as 
possible after discontinuing the study treatment but no later than 28 
days after discontinuation. The End-of-Study (EOS) Visit will occur 
28 days after the EOT at Week 52. Subjects and study site staff 
involved in subject management and study assessments will be 
masked to study treatment assignment. The investigator involved in 
performing the IVT injections will be unmasked to study treatment. 
Estimated Study 
Duration: 
The total study duration is approximately 55 weeks, including a 
screening duration up to 3 weeks, treatment duration up to 
48 weeks, and a follow-up duration up to 4 weeks. 
Efficacy 
Assessments: 
Efficacy will be summarized for the study eye only. 
Primary endpoint: 
• Change from baseline in BCVA as measured by ETDRS 
letters score or 2702 charts at Week 8. 
Secondary endpoints: 
• Change from baseline in BCVA as measured by ETDRS 
letter score or 2702 charts at Week 52 
• Change from baseline in CRT at Week 8 as assessed by 
optical coherence tomography (OCT) 
• Change from baseline in CRT at Week 52 as assessed by 
OCT 
• Change from baseline in CNV area at Week 8 
• Change from baseline in CNV area at Week 52 
• Percentage of subjects who gain at least 15 letters in BCVA 
as measured by ETDRS letter score or 2702 charts compared 
with baseline at Week 8 
• Percentage of subjects who gain at least 15 letters in BCVA 
as measured by ETDRS letter score or 2702 charts compared 
with baseline at Week 52. 
Pharmacokinetic 
Assessments: 
Pharmacokinetic parameters include area under the concentration-
time curve from time zero to the last quantifiable time point (AUC0-
t), AUC from zero to the end of the dosing period (AUC0-tau), AUC 
from zero to infinite time (AUC0-inf), Cmax, time to reach maximum 


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plasma concentration (tmax), and elimination half-life (t1/2), of 
SCD411 and aflibercept. Quantification of free and bound 
aflibercept and SCD411 in plasma will be performed using blood 
samples at predose and at +1 day, +3 days, +7 days, +14 days, and 
+28 days after the first (Day 1) and third (Week 8) doses. 
Immunogenicity 
Assessments: 
Immunogenicity assessments and endpoints include the evaluation 
of development of anti-SCD411 or anti-aflibercept antibodies using 
blood samples taken at Baseline, at Weeks 4, 8, 20, 36, and 52. The 
samples will be evaluated for titer of anti-SCD411 or 
anti-aflibercept antibodies. 
Neutralizing antibodies will be tested when ADA results are 
confirmed to be positive. 
Safety 
Assessments: 
Safety endpoints include adverse events (AEs), vital signs, and 
laboratory assessments up to Week 52. Safety is also evaluated 
during follow-up (4 weeks after EOT). If a subject is discontinued 
from the study, all the ET Visit procedures should be performed 
even if they are outside the allowed study window. 
Study Drug, 
Dosage, and Route 
of Administration: 
One IVT injection containing 2 mg dose of either SCD411 or 
aflibercept (as per randomization) every 4 weeks for 3 consecutive 
doses, followed by 1 injection every 8 weeks. 
Rescue Treatment 
In the study eye, rescue treatment for neovascular AMD is not 
permitted at any point in time. If it is observed that efficacy is not 
achieved by the study treatment, as determined by the investigator, 
subjects can be considered for rescue treatment after Week 4 if any 
1 of the following conditions are met as assessed by the masked 
investigators: 
• Decrease of visual acuity letter score of 15 letters or more 
from the last assessment and/or 
• An increase in intraretinal fluid, subretinal fluid, or 
subretinal hyper-reflective material, that in the investigator’s 
opinion is related to progression of the subject’s neovascular 
AMD. 
Subjects who will receive rescue treatment need to discontinue the 
study treatment and should have the reason for treatment 
discontinuation documented on the Treatment Discontinuation page 
of the eCRF and continue with their regularly scheduled visits and 
assessments until Week 52 except for study treatment 
administration. If a subject chooses to withdraw from the study or if, 
in the opinion of the investigator, the subject should be prematurely 
withdrawn from the study, then the ET Visit should be completed as 


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soon as possible after discontinuing the study treatment but no later 
than 28 days after discontinuation. 
Sample Size: 
The equivalence margin agreed upon with European Medicines 
Agency (EMA) and Pharmaceuticals and Medical Devices Agency 
(PMDA) was determined using the data presented from MARINA 
(and ANCHOR) and VIEW studies. The data were used to estimate 
the efficacy of aflibercept compared to the placebo treatment in 
subjects with wet AMD. It was shown that in MARINA, subjects on 
average lost 2.5 BCVA letters over 2 months in the sham-treated 
control arm and gained 5 letters in the treatment arm of 2 mg dose, 
and that in the VIEW studies 6.8 to 7.5 letters were gained among 
subjects with wet AMD at Week 8 into treatment on a 2 mg dose. 
Combining both study data, the treatment effect compared to the 
placebo would be estimated as approximately 9.3 to 10 letters. A 
margin of 3.8 letters would be translated to a preservation of 59% to 
62% of the difference between Eylea and sham and is less than a 
1 line change in visual acuity. Equivalence discussions for EMA and 
PMDA were based upon a 95% confidence interval (CI) approach or 
2 one-sided tests (TOST) at the α=0.025 level. 
The US Food and Drug Administration (FDA) requested a tighter 
equivalence margin of 3 letters but agreed equivalence can be 
determined from a 90% CI approach (equivalent to TOST at the 
α=0.05 level). 
Standard deviation (SD) for the mean change from baseline at early 
visits (Weeks 4 to 12) based on observed data for the full analysis 
set (FAS) ranged from and 8.73 to 11.99 considering all treatment 
groups from VIEW1 and from 7.4 to 11.0 letters for the VIEW2 
study. For power calculations, a range of SD between 10.4 and 11.8 
was assumed to be conservative and cover the majority of larger SD 
values seen in the observed data. 
A sample size of 266 subjects per treatment arm was selected as it 
provides at least 80% power for the FDA, EMA, and PMDA 
analyses for the range of SD considered when using TOST on data 
from a parallel-group design. For the FDA analysis based on 
equivalence limits of -3.0 and 3.0 letters, α=0.05 significance level 
(90% CI), assuming the true difference between the means is 0.0, 
power of 91% is achieved for SD of 10.4 letters and power of 80% 
is achieved for SD of 11.8 letters. For the EMA and PMDA analyses 
based on equivalence limits of -3.8 and 3.8 letters, α=0.025 
significance level (95% CI), assuming the true difference between 
the means is 0.0, power of 98% is achieved for SD of 10.4 letters 
and power of 92% is achieved for SD of 11.8 letters when sample 


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size is 266 per treatment arm. Considering approximately 5% loss 
from randomization through Week 8, the total sample size required 
is 560. 
A subset of 40 subjects (20 per group) will be selected for collection 
of PK samples. The sample size is not test-driven since no 
equivalence test will be performed for PK parameters. 
Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
Full Analysis Set (FAS): All randomized subjects who received at 
least 1 injection of the study drug. 
Modified FAS (mFAS): All randomized subjects who received at 
least 1 injection of the study drug and had at least 1 postbaseline 
BCVA assessment in the study eye.  
Per-protocol Set (PPS): All subjects in the FAS, excluding those 
with significant protocol violations. 
Safety Set (SAF): All subjects receiving at least 1 injection of the 
study drug. 
Pharmacokinetic Analysis Set (PK Set): The subset of subjects in 
FAS who have sufficient evaluable blood samples to be included in 
the PK Set. 
The primary set for efficacy analysis will be the FAS; however, for 
the EMA submission, the primary efficacy endpoint must meet 
equivalence for both the FAS and PPS. PMDA also requires an 
efficacy analysis to be conducted based on the mFAS without 
multiple imputation (MI) as a supportive analysis. The SAF will be 
the primary analysis set for safety, tolerability, and immunogenicity 
analyses. 
Efficacy will be assessed for the study eye only. 
Statistical 
Methods: 
Primary Analysis: 
The primary analysis of the change from baseline in BCVA as 
measured by ETDRS letter score or 2702 charts through 8 weeks of 
treatment will be performed via MMRM including data for the 
Week 4 and Week 8 visits. The model will include the change from 
baseline as the dependent variable; treatment, visit, and visit-by-
treatment as fixed effects, and baseline BCVA as a covariate. 
Equivalence will be determined if the upper and lower CI limits for 
the difference between treatments are within the equivalence 
margins. 
The primary null hypothesis (H0) and alternative hypothesis (H1) 
are: 
H0: ∆ ≥M or ∆ ≤-M 


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H1: -M< ∆ <M 
where ∆ indicates the mean difference between the 2 treatment 
groups in the change from baseline in ETDRS letter score or 2702 
charts at Week 8 and M represents the equivalence margin. 
Based on discussions with regulatory agencies, separate equivalence 
CIs and equivalence margins will be used for FDA submissions and 
other regulatory agencies versus submissions to EMA and PMDA. 
For the FDA submission and other regulatory agencies, a 90% CI 
(equivalent to TOST evaluated at an α of 0.05) will be assessed 
using an equivalence margin of 3 letters. For the EMA and PMDA, 
a 95% CI (equivalent to TOST evaluated at an α of 0.025) will be 
assessed using an equivalence margin of 3.8 letters. Other regulatory 
submissions are assumed to follow the FDA guidance. 
Estimates of the treatment difference and corresponding 90% (FDA 
and other countries) and 95% (EMA/PMDA) CIs will be provided. 
The primary analysis set for the FDA, PMDA, and any other 
submissions will be the FAS. For the EMA submission, both the 
FAS and PPS are considered primary analysis and equivalence will 
need to be shown for both analysis sets. The analysis will be 
performed using multiple imputed data under the missing at random 
(MAR) assumption. The primary analysis will set post rescue 
assessments to missing prior to the MI procedure.  
 
Secondary Analyses: 
The estimated mean treatment difference in the change from 
baseline in BCVA as measured by ETDRS letter score or 2702 
charts through 52 weeks along with the corresponding 90% and 
95% CIs from the same MMRM model as used in the primary 
analysis but including data from all weeks through Week 52 will 
also be presented for the FAS and PPS. As done for Week 8, 
analysis will be performed using multiple imputed data, where post 
rescue assessments have been set to missing while including the 
post rescue assessments in the imputation model. Raw values and 
changes from baseline will be summarized by treatment group using 
descriptive statistics for each visit. 
The analysis of change from baseline in CRT as assessed by OCT or 
change from baseline in CNV will be based on the MMRM model 
similar to the one used for the analysis of change from baseline in 
BCVA, with the corresponding 95% CI for the estimates of 
treatment differences at Week 8 and Week 52 presented. Raw values 
and changes from baseline will be summarized by treatment group 


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using descriptive statistics. Data after the receipt of rescue therapy 
will be set to missing prior to the MMRM analysis. Multiple 
imputation will not be performed, and no sensitivity analyses will be 
performed. 
The percentage of subjects who gain ≥15 letters in BCVA as 
measured by ETDRS letter score or 2702 charts at postbaseline 
visits (Week 8 and Week 52) compared with baseline will be 
summarized and 95% CI for the proportions in each treatment arm 
and difference in proportions between treatment arms will be 
presented. For subjects who have missing assessments at 
corresponding postbaseline visits or who received rescue therapy 
prior to a visit will be assumed to have a gain of <15 letters in 
BCVA (eg, nonresponder imputation). No sensitivity analyses will 
be performed. 
 
Safety Analyses 
An overall summary of AEs will be presented, and treatment-
emergent AEs will be summarized by system organ class and 
preferred term. Results of the following safety evaluations will be 
summarized with observed values and change from baseline: vital 
signs, ECGs, laboratory examinations including chemistry, 
hematology, and urinalysis. The results of slit lamp examination, 
dilated fundoscopy, intraocular pressure, and vision check will be 
summarized using descriptive statistics at each visit and applicable 
time point, as applicable. 
 
Pharmacokinetic Analysis 
The PK parameters (AUC0-t, AUC0-tau, AUC0-inf, Cmax, tmax, t1/2) from 
the 2 treatment groups will be summarized using n, arithmetic mean, 
percent coefficient of variation (% CV), geometric mean, geometric 
%CV, SD, median, minimum and maximum values in the PK 
analysis set. 
 
Immunogenicity Analysis 
The analysis on immunogenicity will be descriptive. Results will be 
summarized with observed values and change from baseline for 
ADA titers (in log scale) by treatment group in the SAF. The 
number and proportion of ADA-positive subjects and ADA-negative 
subjects will be summarized by treatment group for each assessment 
time point. NAb will be tested when ADA results are confirmed to 


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be positive. The number and proportion of NAb subjects will be 
summarized by treatment group for each assessment time point. 
 
Interim Analyses 
An interim analysis of safety, secondary efficacy endpoints, and PK 
parameters will be performed once approximately 200 subjects 
complete the Week 52 Visit and all subjects complete the Week 24 
Visit or discontinue early from the study.  
The Week 8 analysis and interim analysis will be performed by an 
independent biostatistics group and results will be distributed to a 
limited group of recipients, including unmasked medical writing 
staff and limited sponsor representatives. The timing of the Week 8 
database lock and the interim analysis database lock may coincide 
depending on subject enrollment and data cleaning/programming 
activities. 
Version and Date 
of Protocol: 
Version 3.0 
24 January 2022 


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List of Abbreviations 
Abbreviation 
Definition 
ADA 
anti-drug antibodies 
AE 
adverse event 
AMD 
age-related macular degeneration 
ANCOVA 
analysis of covariance 
AUC0-inf 
area under the concentration-time curve from zero to an infinite time 
AUC0-t 
area under the concentration-time curve from zero to last quantifiable 
time point 
AUC0-tau 
area under the concentration-time curve from zero to the end of the 
dosing period 
BCVA 
best corrected visual acuity 
BOCF 
baseline observation carried forward 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CNV 
choroidal neovascularization 
CRO 
contract research organization 
CRT 
central retinal thickness 
CV 
coefficient of variation 
DME 
diabetic macular edema 
ECG 
electrocardiogram 
EDC 
Electronic Data Capture 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOS 
end-of-study 
EOT 
end-of-treatment 
ET 
early termination 
EU 
European Union 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
fluorescein angiography 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 


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Abbreviation 
Definition 
FP 
fundus photography 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
independent ethics committee 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
IVT 
intravitreal 
LH 
luteinizing hormone 
LOCF 
last observation carried forward 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed-effects model for repeated measures 
NAb 
neutralizing antibodies 
OCT 
optical coherence tomography 
OTC 
over-the-counter 
PDT 
photodynamic therapy 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PlGF 
placental growth factor 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
per-protocol set 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SAF 
safety set 
SAP 
statistical analysis plan 


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Abbreviation 
Definition 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
elimination half-life 
tmax 
time to reach the maximum plasma concentration 
TEAE 
treatment-emergent adverse event 
TOST 
2 one-sided tests 
VA 
visual acuity 
VEGF 
vascular endothelial growth factor 
WHODRUG 
World Health Organization Drug Dictionary 
 


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1 
Introduction 
1.1 Background 
SCD411 is a proposed biosimilar of Eylea® having aflibercept as the active substance that 
binds to vascular endothelial growth factor A (VEGF-A) and produced in Chinese hamster 
ovary cells by recombinant DNA technology. Aflibercept, the drug substance of Eylea, is a 
recombinant fusion protein consisting of 2 identical polypeptide chains, each comprising the 
second Ig domain of the human vascular endothelial growth factor (VEGF) receptor 1 and 
the third Ig domain of the human VEGF receptor 2, with both polypeptide chains fused to the 
Fc domain of human IgG1 (Avery et al 2017). 
Aflibercept acts as a soluble decoy receptor that binds VEGF-A and Placental Growth Factor 
(PlGF) with higher affinity than their natural receptors, and thereby can inhibit the binding 
and activation of these cognate VEGF receptors (Papadopoulos et al 2012). SCD411 is under 
development for the same indications approved for Eylea in United States of America (USA), 
European Union (EU), and Japan which are neovascular (wet) age-related macular 
degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, macular edema 
following retinal vein occlusion (RVO), and AMD with subfoveal choroidal 
neovascularization (CNV) (Eylea® 2019; European Medicines Agency 2018; Santen 2012). 
Neovascular (wet) AMD is characterized by pathological CNV. Leakage of blood and fluid 
from CNV may cause retinal thickening or edema and/or sub-/intra-retinal hemorrhage, 
resulting in loss of visual acuity (VA) (Schneider et al 2005). 
Other drugs of this class include ranibizumab (Lucentis®) and pegaptanib sodium 
(Macugen®). However, aflibercept shows some differences over other VEGF blockers, 
enabling prolongation of the interval between 2 intravitreal (IVT) injections and a decrease 
of the number of injections needed by year compared to the other drugs due to the following 
reasons: 
• A higher affinity (~0.5 pM dissociation constant for VEGF165 and ~0.36 pM for 
VEGF121) than a humanized monoclonal antibody (Papadopoulos et al 2012; García-
Quintanilla et al 2019) 
• A longer circulating half-life compared to soluble receptor constructs which have 
been studied in animals (García-Quintanilla et al 2019) 


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• A binding to the related angiogenic factors such as PlGF1 and PlGF2 (Dixon et al 
2009) and Galectin-1 (Kanda et al 2015), thought to be advantageous in certain 
disease situations, including retinal neovascularizations. 
The development of SCD411 involves stepwise similarity exercises starting with comparison 
of the structural characteristics, physicochemical properties, and biological activities, 
followed by a series of in vitro and in vivo nonclinical studies, followed by a Phase III 
equivalence study to demonstrate biosimilarity between SCD411 and Eylea. 
1.2 Nonclinical Studies 
A series of in vivo nonclinical studies were performed using the test articles of 500 L and 
2000 L batches to demonstrate similarity between SCD411 and Eylea, as follows: 
• In vivo repeated-dose toxicity study in cynomolgus monkeys of 13 weeks with a 
4-week recovery period was conducted. No SCD411-related mortality occurred. No 
SCD411- or Eylea-related macroscopic or microscopic observations or effects on 
organ weight parameters were noted. 
• A single-dose pharmacokinetic (PK) study in pigmented rabbits using the formulated 
500 L batch drug product. After the first rabbit study wherein, the investigational 
product (IP) was injected at the first stage followed by method development in that 
study, a single-dose PK study was repeated in pigmented rabbits using the formulated 
2000 L batch drug product. Eylea and SCD411 (free) exposure is relatively similar in 
serum and vitreous humor. There were no measurable concentrations of Eylea-VEGF 
complex in vitreous humor (right eye). Furthermore, there were no measurable 
concentrations of Eylea-VEGF complex or SCD411-VEGF complex in serum and no 
analytes measurable in vitreous humor left (eye not dosed). In order to secure safety 
in clinical studies, animal tests were conducted using 2000 L, a scale used for clinical 
studies. 
1.3 Study Rationale 
SCD411 is being developed as a biosimilar to the reference product Eylea® (aflibercept). 
Based on the proposed extensive analytical comparability testing, comparative nonclinical 
testing, and comparative clinical studies using the same licensed reference product, the 
current study is designed to evaluate comparability between SCD411 and aflibercept. Based 


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on the data from aflibercept clinical studies VIEW 1, VIEW 2, COPERNICUS, GALILEO, 
VIBRANT, VIVID, VISTA, and MYRROR, wet AMD is considered as the most suitable 
condition to prove similarity between SCD411 and aflibercept as the reference product. 
The available data regarding the PK of the reference product suggests that a proper PK 
characterization will not be possible after single IVT administration. In a PK substudy of 
Eylea in 6 neovascular wet AMD patients with frequent sampling, maximum plasma 
concentrations (Cmax) of free aflibercept (systemic) 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 IVT injection and were 
undetectable 2 weeks following dosage in almost all patients (Eylea® 2019). It is evident that 
in some cases no measurable systemic levels of free aflibercept were registered after IVT 
administration. Hence, a comparative PK evaluation in patients with AMD will likely not 
provide any information of relevance to support biosimilarity. Although the systemic 
exposure of SCD411 is expected to also be very low at steady state, there is no previous 
human data on SCD411, and thus this assumption requires experimental support. Hence, PK 
assessment will be performed in the current study following the first and the third doses of 
SCD411. 
As aflibercept is a therapeutic protein, there is a potential for immunogenicity. No cases of 
active neutralizing antibodies (NAb) were observed after administration of Eylea. It is 
evident that immunogenicity is not presenting a substantial safety concern in patients treated 
with aflibercept injections. There was no substantial difference in the proportion of patients 
testing positive for anti-drug antibodies (ADA) in different indications, including wet AMD 
(Eylea® 2019). Based on this observation, the indication chosen for this study is expected to 
provide sound data for comparing the immunogenicity of the test product (SCD411) with that 
of Eylea. 
The clinical part of the comparison will be based on clinical efficacy and safety data obtained 
after IVT administration to subjects with wet AMD in the current pivotal study. 
1.4 Benefit-risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of SCD411 may be found in the investigator’s brochure. 


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2 
Study Objectives, Estimands, and Endpoints 
2.1 Primary Objective 
The primary objective of this study is: 
• To prove the equivalence of SCD411 as compared to Eylea (aflibercept) in best 
corrected visual acuity (BCVA) after 8 weeks of treatment among subjects with wet 
AMD 
2.2 Secondary Objectives 
The secondary objectives of this study are: 
• To compare the safety and tolerability of SCD411 and aflibercept 
• To compare the efficacy of SCD411 and aflibercept after 8 weeks and 52 weeks of 
treatment demonstrated by BCVA, central retinal thickness (CRT), and CNV 
• To compare the immunogenicity of SCD411 and aflibercept by presenting 
information of the development of anti-SCD411 antibodies 
2.3 Exploratory Objectives 
The exploratory objectives of this study are: 
• To compare PK parameters of SCD411 and aflibercept 
• To quantify free and bound aflibercept and SCD411. 
2.4 Endpoints 
Efficacy will be summarized for the study eye only. 
2.4.1 Primary Endpoint 
• Change from baseline in BCVA as measured by Early Treatment Diabetic 
Retinopathy Study (ETDRS) letters score or 2702 charts at Week 8 
2.4.2 Secondary Endpoints 
• Safety endpoints include AEs, vital signs, and laboratory assessments up to Week 52. 


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• Efficacy endpoints are: 
o Change from baseline in BCVA as measured by ETDRS letter score or 
2702 charts at Week 52. 
o Change from baseline in CRT at Week 8 as assessed by optical coherence 
tomography (OCT). 
o Change from baseline in CRT at Week 52 as assessed by OCT. 
o Change from baseline in CNV area at Week 8. 
o Change from baseline in CNV area at Week 52. 
o Percentage of subjects who gain at least 15 letters in BCVA as measured 
by ETDRS letter score or 2702 charts compared with baseline at Week 8. 
o Percentage of subjects who gain at least 15 letters in BCVA as measured 
by ETDRS letter score or 2702 charts compared with baseline at Week 52. 
• Immunogenicity endpoints include the evaluation of development of anti-SCD411 or 
anti-aflibercept antibodies using blood samples taken at Baseline, at Weeks 4, 8, 20, 
36, and 52. Neutralizing antibodies will be tested when ADA results are confirmed to 
be positive. 
2.4.3 Exploratory Endpoints 
PK parameters include area under the concentration-time curve from time zero to the last 
quantifiable time point (AUC0-t), AUC from zero to the end of the dosing period (AUC0-tau), 
AUC from zero to infinite time (AUC0-inf), Cmax, time to reach maximum plasma 
concentration (tmax), and elimination half-life (t1/2), of SCD411 and aflibercept. 
Quantification of free and bound aflibercept and SCD411 in plasma will be performed using 
blood samples at predose, and at +1 day, +3 days, +7 days, +14 days, and +28 days following 
the first dose. At Week 8, PK samples will be taken predose, and at +1 day, +3 days, +7 days, 
+14 days, and +28 days following the third (Week 8) dose (Table 6-3). 
2.5 
Estimands 
The primary estimand for the primary objective is the mean treatment difference in BCVA 
change from baseline at Week 8. At Week 52, the primary estimand of interest is the mean 
treatment difference in BCVA change from baseline at Week 52. For the primary estimand, 


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any observations post receipt of rescue therapy in the study eye will be set to missing, 
thereby estimating the treatment effect as though subjects do not receive rescue therapy. For 
each of the Week 8 and Week 52 analyses, the secondary estimand will be presented where 
post rescue will not be set to missing but will be included in the mixed-effects model for 
repeated measures (MMRM) analysis. The secondary estimands are constructed to estimate 
the treatment effect while including the impact of rescue therapy, which may better reflect 
actual real-world outcomes, where rescue therapy would likely be given when lack of 
efficacy is seen. 


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3 
Investigational Plan 
3.1 Study Design 
This is a Phase III, randomized, double-masked, parallel-group, multicenter study to 
demonstrate biosimilarity of SCD411 compared to Eylea (aflibercept) among adult subjects 
with neovascular (wet) AMD. 
Approximately 560 subjects with wet AMD will be enrolled in this study across 
approximately 155 sites in 14 countries. Upon entry into the study, subjects will be assigned 
a screening number. Subjects who meet all inclusion and none of the exclusion criteria will 
return to the clinic on Day 1 for further evaluation. Subjects who continue to meet all 
inclusion and none of the exclusion criteria will be randomly assigned and treated on Day 1. 
At this visit, the subjects will be randomly assigned in 1:1 ratio to receive IVT SCD411 or 
aflibercept injections. Randomization will be stratified by subject participation in the PK 
substudy. Subjects in Israel will not participate in the PK substudy. Randomization will also 
be stratified by subjects enrolled in Japan. Subjects will be treated with study treatment every 
4 weeks for the first 3 injections and every 8 weeks thereafter until Week 48 as detailed in the 
Schedule of Events (Table 6-1). A schematic of the study design is presented in Figure 3-1. 
The details of the implementation in Interactive Response Technology (IRT) will be provided 
in the IRT manual and the randomization specification form. 
This study includes a screening duration up to 3 weeks, treatment duration up to 48 weeks, 
and follow-up duration up to 4 weeks; thus, the total duration of study participation is 
approximately up to 55 weeks. 
All subjects will be assessed once every 4 weeks as detailed in the Schedule of Events 
(Table 6-1). The End-of-Treatment (EOT) Visit will be scheduled for Week 48. Subjects who 
discontinue the study treatment early should have the reasons for treatment discontinuation 
documented on the Treatment Discontinuation page of the electronic case report form 
(eCRF). Treatment discontinuation in the study is defined as subjects discontinuing the study 
treatment due to AE/lack of efficacy/rescue treatment but not limited to these conditions. 
Every effort should be made to have such subjects remain in the study and continue with 
their regularly scheduled visits and assessments until Week 52 except for study treatment 
administration. If a subject chooses to withdraw from the study or if, in the opinion of the 
investigator, the subject should be prematurely withdrawn from the study, then the Early 


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Termination (ET) Visit should be completed as soon as possible after discontinuing the 
treatment but no later than 28 days after discontinuation. The End-of-Study (EOS) Visit will 
occur 28 days after the EOT at Week 52. The end of the study is defined as the date of the 
last visit of the last subject in the study. 
The study design incorporates an Independent Data Monitoring Committee (IDMC) that will 
review ongoing safety and will also make recommendations to the sponsor as described in 
the IDMC Charter. Details of the IDMC are given in Section 6.6. 
An interim analysis will be performed once approximately 200 subjects complete the 
Week 52 Visit and all subjects complete the Week 24 Visit or discontinue early from the 
study. Details of the interim analysis are given in Section 7.5.6. 


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Figure 3-1: 
Study Schema 
 
Abbreviations: EOS, end-of-study; EOT, end-of-treatment; ET, early termination; IVT, intravitreal. 
 


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3.1.1 Rationale of Study Design 
The current study design and choice of endpoints are mainly based on the data from 
aflibercept clinical studies VIEW 1, VIEW 2, COPERNICUS, GALILEO, VIBRANT, 
VIVID, VISTA, and MYRROR, which indicates that the model of wet AMD can be regarded 
as representative of approved therapeutic indications of the reference product and sensitive 
for detecting potential differences between the biosimilar, SCD411 and the reference product, 
aflibercept. 
Selection of Doses in the Study 
Eylea has been approved for the treatment of wet AMD when administered as IVT injection 
of 2 mg (0.05 mL) every 4 weeks (approximately every 28 days, monthly) for the first 
3 months, followed by 2 mg (0.05 mL) injection once every 8 weeks (2 months). This dosage 
has been found to be efficacious in subjects with wet AMD and has an acceptable safety 
profile. 


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4 
Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 560 subjects will be enrolled at 155 sites in 14 countries. Subjects will be 
assigned to study treatment only if they meet all of the inclusion criteria and none of the 
exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed as they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1 Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Capable of understanding the written informed consent, provides signed and witnessed 
written informed consent, and agrees to comply with protocol requirements. 
2. Age ≥50 years. 
3. Active choroidal subfoveal, juxtafoveal, or extrafoveal neovascularization lesions 
secondary to AMD evidenced by fluorescein angiography (FA) in the study eye at 
screening and confirmed by the central reading center. 
4. The BCVA letter score of 73 to 35 using original series ETDRS charts or 2702 series 
number charts in the study eye at screening and at Week 0 (Day 1) prior to 
randomization. In addition, fellow eye should not be less than 35 letter score using the 
ETDRS chart or 2702 series number chart 
5. Women of child-bearing potential with a negative serum pregnancy test at screening 
must agree to use protocol-defined methods of contraception throughout the study 
until 3 months after the last injection of aflibercept/SCD411 (Section 4.1.3 and 
Section 4.1.4). 
6. Males with female partners of child-bearing potential must agree to use 
protocol-defined methods of contraception and agree to refrain from donating sperm 
throughout the study until 3 months after the last injection of aflibercept/SCD411. 


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7. The area of CNV making up either 50% or more of the total lesion area and confirmed 
by the central reading center. 
4.1.2 Exclusion Criteria 
Subjects meeting any of the following criteria at the Screening Visit will be excluded from 
the study: 
1. Any prior ocular (in the study eye and fellow eye) or systemic treatment or surgery for 
neovascular AMD except dietary supplements or vitamins 
2. Any prior or concomitant therapy with another investigational agent to treat 
neovascular AMD in the study eye, except dietary supplements or vitamins 
3. Fellow eye shows signs of AMD that, in investigator’s medical opinion, may need any 
treatment during study period 
4. Any prior treatment with anti-VEGF agents in the both eyes (ie, completely treatment 
naïve subjects only to be included) 
5. Total lesion size >30.5 mm2, including blood, scars, atrophy, fibrosis, and 
neovascularization as assessed by FA in the study eye and confirmed by the central 
reading center 
6. Central retina thickness of <300 µm in the study eye and confirmed by the central 
reading center 
7. Subretinal hemorrhage that is either 50% or more of the total lesion area, or if the 
blood is under the fovea and is 1 or more disc areas in size in the study eye and 
confirmed by the central reading center. (If the blood is under the fovea, then the fovea 
must be surrounded 270 degrees by visible CNV.) 
8. Scar or fibrosis, making up >50% of the total lesion in the study eye and confirmed by 
the central reading center 
9. Scar, fibrosis, or atrophy involving the center of the fovea in the study eye and 
confirmed by the central reading center 
10. Presence of retinal pigment epithelial tears or rips involving the macula in the study 
eye and confirmed by the central reading center 


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11. Lens Opacity Classification System II (LOCS II) grade IV cataract in the study eye, or 
other significant cataract in the study eye that in the Investigator’s opinion interferes 
with visualization of retina or interferes with retinal imaging 
12. Active intraocular/periocular infection and inflammation in either eye 
13. History of any vitreous hemorrhage in the study eye within 4 weeks prior to the 
Screening Visit 
14. Presence of other causes of CNV in the study eye as confirmed by central reading 
center 
15. History or clinical evidence of diabetic retinopathy, DME, or any other vascular 
disease affecting the retina, other than AMD, in either eye 
16. Prior vitrectomy in the study eye 
17. History of retinal detachment, treatment, or surgery for retinal detachment in the study 
eye 
18. History of macular hole of Stage 2 and above in the study eye as confirmed by central 
reading center 
19. History of uncomplicated intraocular or periocular surgery within 3 months of Day 1 
on the study eye, except lid surgery, which may not have taken place within 1 month 
of Day 1 
Note: A subject with uncomplicated neodymium yttrium aluminum garnet (Nd:YAG) 
laser capsulotomy performed for secondary opacification of the posterior capsule in 
intraocular lens implanted eye within 3 months prior to Day 1 in the study eye will be 
considered as eligible. 
20. Presence of aphakia in the study eye 
21. History of glaucoma-filtering surgery within 3 months of Day 1 in the study eye. Anti-
glaucoma laser surgeries will not be considered exclusionary. 
22. History of corneal transplant in the study eye 
23. History or evidence of any other clinically significant disorder, condition or disease 
(eg, co-existence of RVO, radiation retinopathy, diabetic retinopathy, glaucoma under 
treatment) in the study eye that, in the opinion of the investigator, would pose a risk to 
subject safety or interfere with the study evaluation, procedure or complication 


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24. Uncontrolled hypertension defined as systolic blood pressure (BP) >160 mmHg or 
diastolic BP >100 mmHg under appropriate antihypertensive treatment 
25. Hypersensitivity to aflibercept or medications used in this study (fluorescein, 
mydriatic eye drops, etc.) 
26. Pregnancy or lactation at the Screening Visit and/or at baseline for women of 
child-bearing potential 
27. Any contraindication to IVT injection according to the investigator’s clinical judgment 
28. History of thrombotic events (eg, stroke, transient ischemic attacks, pulmonary 
embolism, deep vein thrombosis, or myocardial infarction) 
29. History or evidence of cardiac conditions with congestive cardiac failure resulting in 
marked limitation on physical activity or inability to perform any physical activity 
without discomfort; subjects with ventricular arrhythmia requiring ongoing treatment; 
or subjects with atrial fibrillation 
30. History of laser therapy in the macular region in the study eye 
31. Any prior or concomitant treatment with IVT corticosteroids injection, IVT 
corticosteroid implant, subtenon corticosteroids, or peribulbar corticosteroids in the 
study eye 6 months before the Screening Visit 
Note: For IVT corticosteroid implant, the exclusion period would be 36 months from 
the date of the procedure to the date of screening. 
32. Any prior or concomitant treatment involving the macula with photodynamic therapy 
(PDT) with verteporfin, transpupillary thermotherapy, radiation therapy, or retinal 
laser treatment (eg, focal laser photocoagulation) in the study eye 
33. Any prior or concomitant treatment with pan-retinal photocoagulation 90 days in the 
study eye before the Screening Visit 
34. Any concomitant or prior treatment with ethambutol (2 weeks prior to randomization); 
deferoxamine and topiramate (4 weeks prior to randomization); tamoxifen, 
hydroxychloroquine, chloroquine, or vigabatrin (8 weeks prior to randomization), and 
amiodarone (12 weeks prior to randomization) 


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35. Any IP for the treatment of ocular conditions (in either eye) and systemic conditions 
30 days or 5 half-lives (whichever is longer), prior to randomization, and throughout 
the study, except dietary supplements or vitamins 
36. Intraocular pressure ≥25 mmHg in spite of anti-glaucoma treatment  
37. Any prior or ongoing systemic medical condition (including but not limited to 
infectious, inflammatory, psychiatric, neurological, renal, hepatic, respiratory 
conditions or malignancies) or clinically significant screening laboratory value that in 
the opinion of the investigator may present a safety risk, interfere with study 
compliance and follow-up, or confound data interpretation throughout the study 
period. 
4.1.3 Women of Child-bearing Potential 
Women of child-bearing potential are defined as premenopausal women physiologically 
capable of becoming pregnant. 
Women of non-child-bearing potential are defined as women meeting any of the following 
criteria: 
• Older than 50 years with amenorrhea for >2 years or older than 60 years with 
amenorrhea for >1 year. In both cases, follicle-stimulating hormone (FSH) and 
luteinizing hormone (LH) levels are performed at screening to ensure these subjects 
are not pregnant. 
• Has undergone hysterectomy. 
• Has undergone bilateral oophorectomy. 
• Has undergone bilateral salpingectomy. 
4.1.4 Approved Methods of Contraception 
Approved methods of contraception include oral contraceptives, intrauterine device, 
medically acceptable barrier methods (diaphragm or condom), implantable or injectable 
contraceptives or removable birth control device, and/or sterilization. Subjects practicing 
abstinence and coitus interruptus (pull out method) must agree to use an approved method of 
contraception during the study and until 3 months after their last injection. 


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4.2 Selection of Study Eye 
Only one eye (study eye) must meet all the inclusion criteria and none of the exclusion 
criteria. 
Fellow eye should not show any signs of AMD that, in the investigator’s medical opinion, 
may need any treatment during study period. 
4.3 Withdrawal of Subjects From Study Treatment and/or the Study 
The duration of the study for each subject is defined as the date the subject signs the written 
informed consent form (ICF) up to the last EOS Visit, which is 28 days after the 
End-of-Treatment (EOT) Visit. 
Subjects may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator and/or sponsor for safety, 
behavioral, or administrative reasons. If the subject withdraws consent for disclosure of 
future information, the sponsor may retain and continue to use any data collected before such 
a withdrawal of consent.  
4.3.1 Discontinuation From Study Treatment 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) the study treatment. If the IP is definitively discontinued, the Treatment 
Discontinuation page of the eCRF should be completed. Every effort should be made to have 
such subjects remain in the study and continue with their regularly scheduled visits and 
assessments until Week 52 except for study treatment administration. If a subject chooses to 
withdraw from the study or if, in the opinion of the investigator, the subject should be 
prematurely withdrawn from the study, then the subject should undergo ET Visit assessments 
as soon as possible after discontinuing the study treatment but no later than 28 days after 
discontinuation, as described in the Schedule of Events (Table 6-1).  
A subject may discontinue from the study treatment for any of the following reasons: 
• Subject has a serious or intolerable AE that, in the investigator’s opinion, requires 
discontinuation from the study treatment. 


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• Decision by the investigator that the subject requires alternate treatment for 
neovascular AMD in the study eye. 
• Pregnancy. 
• A subject misses either of the first 2 doses (IVT injection of IP at Week 0 [Day 1] or 
Week 4) after randomization. 
• Decision by the Sponsor or administrative decision for a reason (eg, a suspicion of 
fraud, the subject enrolling in multiple clinical studies, lack of compliance) other than 
that of an AE. 
• Certain specific criteria for treatment discontinuation include: 
• Development of rhegmatogenous retinal detachment or stage 3 or 4 macular holes. 
• A decrease in BCVA of ≥30 letters compared with the last assessment of VA. 
• A subretinal hemorrhage involving the center of the fovea or if the size of the 
hemorrhage is ≥50% of the total lesion area. 
• Clinical signs of irreversible ischemic visual function loss. 
4.3.2 Withdrawal From the Study 
A subject may withdraw from the study for any of the following reasons: 
• Death. 
• Lost to follow-up. 
• Protocol deviation 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. 
• The subject has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal. 
• The subject withdraws consent. 
• If a subject withdraws his/her consent, the investigator must inquire the reasons for 
consent withdrawal as to whether it is related to the study (eg, documented lack of 
efficacy, AE or pregnancy); however, the subject may refuse to provide such reason. 


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4.3.3 Handling of Withdrawals 
Subjects are free to withdraw from the study or study treatment at any time upon request. 
Subject participation in the study may be stopped at any time at the discretion of the 
investigator or at the request of the sponsor. 
Subjects who discontinue study treatment or active participation in the study will no longer 
receive study drug. When a subject withdraws from the study treatment or active 
participation in the study, the reason(s) for withdrawal shall be recorded by the investigator 
on the relevant page of the eCRF.  
Every effort should be made to have such subjects remain in the study and continue with 
their regularly scheduled visits and assessments until Week 52 except for study treatment 
administration after discontinuation of the study treatment unless the subjects withdraw 
consent. All subjects who withdraw from the study prematurely will be asked to complete the 
ET Visit procedures as soon as possible after discontinuing the study treatment but no later 
than 28 days after discontinuation. If a subject discontinues the study treatment due to an 
AE/serious AE (SAE) or if AEs/SAEs were ongoing at the time of discontinuation, the 
subject will be followed-up until resolution or stabilization.  
4.3.4 Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized to the study treatments. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAEs. 
Subjects who do not meet the criteria for participation in this study may not be rescreened. 
Image retransmission requested from the central image center due to any possible technical 
issues is not considered to be rescreening. 


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4.3.5 Lost to Follow-up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. The following actions must 
be taken if a subject fails to return to the clinic for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study 
• In cases in which the subject is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
subject’s medical record 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4.3.6 Study Termination 
The sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. 
A study site is considered closed when all required documents, study supplies have been 
collected (if required), and a study site closure visit has been performed. Reasons for study 
termination may include, but are not limited to: 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of subjects 
• Cancellation of drug development. 
The investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. Reasons for the 
early closure of a study site by the sponsor or investigator may include, but are not limited to: 


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• Failure of the investigator to comply with the protocol, the requirements of the 
institutional review board (IRB)/ independent ethics committee (IEC) or local health 
authorities, the sponsor's procedures, or Good Clinical Practice (GCP) guidelines 
• Inadequate recruitment of participants by the investigator. 
4.3.7 Replacements 
Dropout subjects will not be replaced in the study. 


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5 
Study Treatments 
5.1 Method of Assigning Subjects to Treatment Groups 
All subjects will be centrally randomized in a 1:1 ratio to receive SCD411 or aflibercept IVT 
injections at the baseline/randomization visit (Day 1) using IRT. Randomization will be 
stratified by participation in the PK substudy (yes/no). Before the study is initiated, the log in 
information and directions for the IRT will be provided to each site. Only qualified study 
staff and those delegated the responsibility of study drug administration should administer 
the study drug injections. 
If a subject visits the site outside of the visit window for a dosing visit until Week 8:  
• During the 4-week intervals dosing: assessment and dosing can be done within a 
window of ±2 days. In this case, the interval between the 2 doses should not be less 
than 24 days and more than 32 days. If the subject IP dosing window is out of the 
allowed window interval, dosing should be skipped.  
• During the 8-week intervals dosing: assessment and dosing should be done within the 
window of ±7 days. In this case, the interval between the 2 doses should not be less 
than 49 days and not more than 63 days. 
Study treatment will be dispensed at the study visits summarized in the Schedule of Events 
(Table 6-1). 
5.2 Treatments Administered 
Subjects who complete the study screening and baseline assessments and meet all the 
eligibility criteria will enter the study and will be randomly assigned in a 1:1 ratio on Day 1 
to receive SCD411 or aflibercept. Details of study treatments that will be administered during 
the study are provided below in Section 5.3. 
Subjects will receive their randomized study treatment injections as per the Schedule of 
Events (Table 6-1) and according to the procedure manual. Clinic staff involved in the 
injection tray assembly, anesthetic preparation, and study drug preparation and administration 
will follow appropriate aseptic techniques to minimize the risk of potential AEs associated 
with IVT injections. If the pre-procedure IOP is equal to or greater than 30 mmHg, the IVT 


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injection will not be administered (either withheld or delayed) until the IOP is decreased to 
acceptable safety levels as per the investigator’s medical judgment. 
The IVT injection procedure should be carried out under controlled aseptic conditions. 
Adequate anesthesia and a topical broad-spectrum microbicide and antibiotics can be given 
as per the system organ class in World Health Organization Drug Dictionary (WHODRUG) 
and this information should be recorded in the eCRF. 
Immediately following the IVT injection, subjects should be checked by the unmasked staff 
for hand movement/finger counting vision for subject safety. The information will not be 
captured in the eCRF. If subjects can recognize hand movement/finger counting vision 
immediately following the IVT injection, then the subjects should be transferred from the 
unmasked staff to the masked staff. If subjects cannot recognize hand movement/finger 
counting vision immediately following the IVT injection, then the unmasked staff should 
further investigate the reason. If required, a sterile paracentesis needle should be available for 
the injecting physician to ensure control of excessive IOP elevation. 
The safety data for IOP and dilated fundoscopy after administration of the study treatment 
will be collected by the masked staff. The information will be captured in the eCRF. 
Following the injection, the masked team will measure IOP and evaluate subjects for any 
injection-related ophthalmic changes and AEs. 
Subjects should be instructed to report any symptoms suggestive of endophthalmitis or 
retinal detachment (eg, eye pain, redness of the eye, photophobia, blurring of vision) without 
delay. 
Dosing visits will be allowed within ±2 days for the second and third injections and within 
±7 days for the fourth injection onwards of the scheduled dosing visit date (except Week 0 
[Day 1], visit window not allowed). All applications outside of the specified windows will be 
captured a protocol deviation. 
5.2.1 Treatment of Fellow Eye 
Treatment of fellow eye will be allowed at any time during the study if a subject is newly 
diagnosed with neovascular AMD or has worsening neovascular AMD in the fellow eye. The 
fellow eye should be treated only with Eylea as per investigator’s discretion. In this case, 


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fellow eye data of dilated fundoscopy, IOP, fellow eye treatment date and medication 
name will be collected via eCRF. Also, the fellow eye treatment injection is not permitted on 
the same day as the study eye treatment.  
The cost of the fellow eye treatment will be covered by the sponsor in terms of either 
providing open-label Eylea or reimbursement after the site stock of Eylea is used up. 
5.2.2 Dose Modification 
Dose reductions will not be allowed. 
5.3 Identity of Investigational Product 
The study treatment solution is colorless to pale yellow. If particulates, cloudiness, or 
discoloration are visible, the vial must not be used. The glass vial is for a single-use only. The 
study injections should be inspected visually prior to administration. 
The active substances are aflibercept and SCD411. One vial contains 100 µL, equivalent to 
4 mg aflibercept. One vial delivers a dose of 2 mg aflibercept in 50 µL.
 
Each vial should only be used for the treatment of a single eye. After injection, the used vial 
should be placed back within the box and resealed at the site to prevent unintentional 
unmasking. 
Manufacturer details of the study treatment and Eylea will be provided in the pharmacy 
manual. 
The following drug supplies will be used in the study: 


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Study Treatment Name: 
SCD411 
Eylea (Aflibercept) 
Dosage Formulation: 
Solution for intravitreal injection 
Solution for intravitreal injection 
Unit Dose Strength(s)/ 
Dosage Level(s): 
Single-use vial containing 0.1 mL 
(40 mg/mL) aflibercept biosimilar 
solution 
Single-use vial containing 0.1 mL 
(40 mg/mL) aflibercept solution 
Route of 
Administration:  
Intravitreal injection 
Intravitreal injection 
Dosing Instructions: 
0.05 mL 
of solution containing 2 mg 
0.05 mL 
of solution containing 2 mg 
Packaging and 
Labeling: 
Study injection formulations will be 
provided in vials in cartons. Each 
carton and vial will have the multi-
country booklet label along with them 
which follows regulatory 
requirements.  
The current study will use EU-licensed 
Eylea as comparator drug. Study 
injection formulations will be provided 
in vials in cartons. Each carton and 
vial will have the multi-country 
booklet label along with them which 
follows regulatory requirements. 
5.4 Management of Clinical Supplies 
5.4.1 Study Drug Packaging and Storage 
Study treatment products should be stored in a refrigerator (2ºC to 8ºC) and should not be 
frozen. The vial should be kept in its outer carton in order to protect from light. 
5.4.2 Test Article Accountability 
The investigator will maintain accurate records of receipt of all test articles, including dates 
of receipt. In addition, accurate records will be kept regarding when and how much test 
article is dispensed and used by each subject in the study. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drugs will be reconciled and 
retained or destroyed according to applicable regulations. 
5.5 Overdose Management 
An overdose is any dose of study treatment given to a subject or taken by a subject that 
exceeds the dose described in the protocol. Any overdose, with or without associated AEs, 
must be promptly reported to the PPD Drug Safety Center. Overdoses without signs or 
symptoms do not need to be recorded as AEs; in case of any AEs associated with the 
overdose, these should be reported on relevant AE/SAE sections in the eCRF. 


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Currently there is no information available on the overdose effects of the study drug in 
humans. 
5.5.1 Medication Errors 
Medication errors include overdose, incorrect dose, incorrect drug, incorrect administration 
or incorrect kit used in the study. Usually, an overdose or incorrect administration of study 
treatments is not itself an AE, but it may result in an AE. Medication errors will be reported 
by the unmasked investigator in a masked manner to the masked investigator. 
5.6 Masking 
This is a double-masked study. To prevent bias in treatment assignment, eligible subjects will 
be randomly assigned using the IRT. 
Subjects and study site staff involved in subject management and study assessments will be 
masked to study treatment assignment. The sponsor, the delegated contract research 
organization (CRO), and imaging teams will also be masked to the study treatment. Only the 
unmasked investigator involved in performing the IVT injections will be unmasked to study 
treatment. These individuals are not allowed to discuss treatment and/or subject outcome 
with masked study staff, including the evaluating investigator. 
5.6.1 Unmasking 
A subject’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the subject depends on knowing the study treatment the subject received. In the 
event that the treatment assignment needs to be unmasked because of a medical emergency, 
the PI may unmask an individual subject’s treatment allocation. 
The PI is encouraged to first contact the sponsor representatives to discuss the medical 
emergency and the reason for revealing the actual treatment received by that subject as soon 
as possible. The investigator should not share any unmasked information with the sponsor 
and monitoring team. The treatment assignment will be unmasked through IRT. Reasons for 
treatment unmasking must be clearly explained and justified in the eCRF. The date on which 
the code was broken along with the identity of the person responsible for breaking the code, 
must also be documented in the eCRF. 


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5.7 Treatment Compliance 
Study procedures at the study center are to be performed under the direct supervision of the 
investigator and qualified study center personnel. All injections must be taken in accordance 
with the original schedule outlined at subject’s Day 1 Visit with the first dose. 
The study drug is administered as an IVT injection at the study site, so it is not necessary to 
monitor subject compliance with the study drug regimen. 
5.8 Prior and Concomitant Therapy 
Use of all concomitant medications will be recorded in the subject’s eCRF. The minimum 
requirement is that drug name and the dates of administration are to be recorded. This will 
include all prescription drugs, herbal products, vitamins, minerals, and over-the-counter 
(OTC) medications. Any changes in concomitant medications also will be recorded in the 
subject’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
eCRF. Information on prior and concomitant medications is collected within 30 days prior to 
signing the ICF or longer if the investigator considers relevant. Prohibited medications are 
collected from prior to duration of prohibition of use for this study (Table 5-1). 
5.8.1 Rescue Treatment 
In the study eye, rescue treatment for neovascular AMD is not permitted at any point in time. 
If it is observed that efficacy is not achieved by the study treatment, as determined by the 
investigator, subjects can be considered for rescue treatment after Week 4 if any 1 of the 
following conditions are met as assessed by the masked investigators: 
• Decrease of VA letter score of 15 letters or more from the last assessment and/or 
• An increase in intraretinal fluid, subretinal fluid, or subretinal hyper-reflective 
material that, in the investigator’s opinion, is related to progression of the subject’s 
neovascular AMD 


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Subjects who will receive rescue treatment need to discontinue the study treatment and 
should have the reason for treatment discontinuation documented on the Treatment 
Discontinuation page of the eCRF and continue with their regularly scheduled visits and 
assessments until Week 52 except for study treatment administration. If a subject chooses to 
withdraw from the study or if, in the opinion of the investigator, the subject should be 
prematurely withdrawn from the study, then the ET Visit should be completed as soon as 
possible after discontinuing the study treatment but no later than 28 days after 
discontinuation. 
5.8.2 Prohibited Medications 
The details of the prohibited medications during the study are presented in Table 5-1. 
Concurrent use of systemic or IVT anti-VEGF agents; IVT, subtenon, or peribulbar 
corticosteroids in study eye are not permitted, except as required to treat AEs. 
In addition, the use of photocoagulation or PDT with verteporfin are prohibited during the 
study. Antimicrobial drops can be used at the discretion of the investigator.


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Table 5-1: 
Prohibited Medications 
Medication/Therapy 
Eye (Study Eye or Study Eye and Fellow Eye or Either) 
Duration of Prohibition 
Ocular therapy/treatment list 
IVT anti-VEGF treatment to treat 
neovascular AMD 
Study eye 
Note: Treatment of fellow eye will be allowed at any time during the 
study if a subject has newly diagnosed neovascular AMD or 
worsening neovascular AMD in fellow eye. The fellow eye should be 
treated only with Eylea as per investigator’s discretion. 
Ever before and to EOS/ET Visit 
IVT injection of corticosteroids (eg, 
triamcinolone acetonide) or intravitreal  
- Corticosteroid implant 
-Subtenon corticosteroids 
-Peribulbar corticosteroids 
Study eye 
6 months before screening and 
throughout the study period 
 
For IVT corticosteroid implant, the 
exclusion period would be 36 months 
from the date of the procedure to the 
date of screening 
Treatment involving macula with PDT with 
verteporfin, transpupillary thermotherapy, 
radiation therapy, or retinal laser treatment 
(eg, focal laser photocoagulation) 
Study eye 
Prior to screening and throughout the 
study period 
Treatment with pan-retinal photocoagulation 
Study eye 
90 days prior to screening and 
throughout the study period 
Systemic medications 
Systemic anti-VEGF agents 
NA 
Within 90 days prior to randomization 
and throughout the study 
Deferoxamine 
NA 
4 weeks prior to randomization and 
throughout the study period 
Tamoxifen 
NA 
8 weeks before randomization and 
throughout the study period 
Hydroxychloroquine, 
Chloroquine 
NA 
8 weeks before randomization and 
throughout the study period 


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Medication/Therapy 
Eye (Study Eye or Study Eye and Fellow Eye or Either) 
Duration of Prohibition 
Vigabatrin 
NA 
8 weeks before randomization and 
throughout the study period 
Ethambutol 
NA 
2 weeks before randomization and 
throughout the study period 
Topiramate 
NA 
4 weeks prior to randomization and 
throughout the study period 
Amiodarone 
NA 
12 weeks prior to randomization and 
throughout the study period 
Other investigational products 
Systemic IP to treat neovascular AMD 
NA 
Prior to screening and throughout the 
study period 
Ocular IP to treat neovascular AMD 
Study eye and fellow eye 
Prior to screening and throughout the 
study period 
Ocular IP to treat any ocular disease 
Study eye and fellow eye 
30 days or 5 half-lives prior to 
randomization (whichever is longer), 
and throughout the study period 
Systemic IP (excluding dietary supplements, 
vitamins and minerals) to treat systemic 
diseases  
NA 
30 days or 5 half-lives prior to 
randomization (whichever is longer), 
and throughout the study period 
Abbreviations: AE, adverse event; AMD, age-related macular degeneration; EOS, end-of-study; ET, early termination; IP, investigational product; IVT, 
intravitreal; NA, not applicable; PDT, photodynamic therapy; VEGF, vascular endothelial growth factor. 


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6 
Study Assessments and Procedures 
Before performing any study procedures, all potential subjects will sign an ICF. Subjects will 
have the opportunity to have any questions answered before signing the ICF. The investigator 
must address all questions raised by the subject. The investigator or designee will also sign 
the ICF. 
The Schedule of Events is presented in Table 6-1. 


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Table 6-1: 
Schedule of Events 
Assessment 
Screening 
Treatment 
ETa/EOSb 
Study Day 
–21 to 0 
Baseline/1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
EOT/337 
365 
Study Week 
-3 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Visit Time Window (days) 
 
 
±2 
±2 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information (incl. 
height and weight) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ocular and systemic medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Slit lamp examinationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dilated fundoscopyd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Prior and concomitant ocular and 
systemic medicationsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCD411 or aflibercept injection h 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pre-injection IOPi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-injection IOP and vision 
checki 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
BCVAj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCTk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FA and FPl 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory assessmentsm 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Vital signsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 


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Assessment 
Screening 
Treatment 
ETa/EOSb 
Study Day 
–21 to 0 
Baseline/1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
EOT/337 
365 
Study Week 
-3 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Visit Time Window (days) 
 
 
±2 
±2 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity sampleso 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
PK samplesp 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AEs, adverse events; BCVA, best corrected visual acuity; ECG, electrocardiogram; EOS, end-of-study; EOT, end-of-treatment; ET, early termination; FA, 
fluorescein angiography; FP, fundus photography; FSH, follicle-stimulating hormone; IOP, intraocular pressure; IVT, intravitreal; LH, luteinizing hormone; OCT, optical 
coherence tomography; PDT, photodynamic therapy; PK, pharmacokinetics; SAE, serious adverse event; VA, visual acuity; VEGF, vascular endothelial growth factor. 
a 
For subjects who discontinue study treatment and choose to withdraw from the study or if, in the opinion of the investigator, the subject should be prematurely withdrawn 
from the study, ET Visit assessments are to be performed as soon as possible after discontinuing the study treatment but no later than 28 days after discontinuation. 
b 
End-of-study assessments are to be performed 28 days after the EOT. 
c 
Slit lamp examination will be performed on both eyes at all the planned scheduled visits during the study. 
d 
Dilated fundoscopy will be performed on the study eye at all the planned scheduled visits during the study, including the time prior to IVT injection of the study drug, and 
within 60±30 minutes after IVT injection of the study drug, and at any time during the visit at ET/EOS Visit. 
e 
Serum pregnancy test will be done at screening, and urine pregnancy test at baseline, ET, and EOS Visits for female subjects of child-bearing potential. If urine pregnancy test 
is positive, serum pregnancy test should be performed; if found positive, study treatment will be discontinued, and the subject should continue with their regularly scheduled 
visits and assessments until Week 52 except for study treatment administration. Pregnancy cases should be followed until resolution of the pregnancy. 
f 
Concurrent use of systemic or intravitreal anti-VEGF agents, IVT, subtenon, or peribulbar corticosteroids in study eye, except as required to treat AEs, and use of 
photocoagulation or PDT with verteporfin are prohibited during the study. Antimicrobial drops can be used at the discretion of the investigator. For IVT corticosteroid 
implant, the exclusion period would be 36 months from the date of the procedure to the date of screening. 
g 
The investigator must confirm that the subject meets all inclusion and none of the exclusion criteria at both screening and Day 1. This is inclusive of BCVA scoring. 
h 
Rescue treatment for the study eye is not permitted at any point in time. Subjects can be considered for rescue treatment after Week 4 if the following conditions are met as 
assessed by the masked investigator: VA letter score decrease of 15 letters or more from the last assessment, an increase in intraretinal fluid, subretinal fluid, or subretinal 
hyper-reflective material, that in the investigator’s opinion is related to progression of the subject’s neovascular AMD. Subjects who will receive rescue treatment need to 
discontinue the study treatment and should have the reason for treatment discontinuation documented on the Treatment Discontinuation page of the eCRF and continue with 
all their regularly scheduled visits and assessments until Week 52 except for study treatment administration. If a subject chooses to withdraw from the study or if, in the 
opinion of the investigator, the subject should be prematurely withdrawn from the study, then the ET Visit should be completed as soon as possible after discontinuing the 
study treatment but no later than 28 days after discontinuation. 


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i 
Intraocular pressure will be measured on both eyes at screening, and on the study eye prior to IVT injection of the study drug, and 60±30 mins after IVT injection of the study 
drug at each visit from baseline/Day 1 to EOT (48 weeks). If the pre-procedure IOP is equal to or greater than 30 mmHg, IVT injection will not be administered (either 
withheld or delayed) until IOP is decreased to acceptable safety levels as per investigator’s medical judgment. IOP should be measured after OCT and FA are completed to 
avoid corneal erosion. Finger counting test to be performed immediately after the IVT injection of the study drug. IOP will also be performed at any time during the ET/EOS 
Visit. 
j 
Best corrected VA testing will be done for both eyes and should be performed prior to the dilation of pupils, FA, and OCT assessments, and prior to the IVT injection of the 
study drug. BCVA will also be performed at any time during the visit at ET/EOS Visit. A decrease in VA of ≥15 letters from the last assessment of VA should be reported as 
AEs/SAEs as appropriate. If there is a decrease in VA of ≥30 letters from the last assessment of VA or if there is a decrease in VA to the level of Light Perception or worse, it 
should be reported as SAE. 
k 
OCT imaging should be performed on the study eye prior to the IVT injection of the study drug. Those images will be sent to the central reading center. Site staff who will 
perform OCT scans in this study must be certified by the central reading center before study starts. OCT devices registered in an investigational site should be all from the 
same manufacturer and meet the minimum software requirement. The subject should use the OCT device registered by the central reading center from Screening to Week 52 
(EOS visit) or ET Visit. 
l 
At screening, FA and FP will be performed on both eyes and those images will be sent to the central reading center. At Week 8 and ET/EOS, FA and FP will be performed on 
the study eye (prior to IVT injection of the study drug at Week 8). Those images will be sent to the central reading center. Site staff who will perform FA and FP in this study 
must be certified by the central reading center before study starts. Only FP/FA devices certified by central reading center are allowed to be used in this study. If 1 or more 
FP/FA devices are certified at an investigational site, a subject must use the same FP/FA device consistently from Screening to Week 52 (EOS Visit) or ET Visit. 
m 
Hematology, chemistry, and urinalysis samples will be collected prior to IVT injection of the study drug. Urine samples will be collected prior to performing FA to avoid false 
elevations in urine protein values. No pregnancy test is required for women of non-child-bearing potential. For women of child-bearing potential, serum pregnancy test will be 
performed at screening and in case of a positive urine test during the study; urine pregnancy test will be performed at the Baseline, ET and EOS Visits; the FSH and LH levels 
to be measured at screening for women of child-bearing potential. Hematology, chemistry, and urinalysis samples will also be performed at any time during the visit at 
ET/EOS Visit. 
n 
Includes blood pressure, respiratory rate, heart rate, and temperature. On days when study injections will be administered, vital signs should be measured prior to IVT 
injection of the study drug. Vital signs will also be performed at any time during the ET/EOS Visit. 
o 
Immunogenicity samples should be collected prior to IVT injection of the study drug and prior to FA assessment when performed on the same day. Immunogenicity will also 
be performed at any time during the visit at ET/EOS Visit. Neutralizing antibodies will be tested when anti-drug antibodies results are confirmed to be positive. 
p 
Quantification of free and bound SCD411 and aflibercept will be performed for subjects who agree to participate in the PK substudy using blood samples at predose, and at 
+1 day, +3 days, +7 days, +14 days, and +28 days following the first and the third injection (Week 8). 
 


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6.1 Study Visits 
6.1.1 Screening Phase 
Subjects will sign the ICF prior to any screening procedures. Screening will take place within 
21 days before the baseline/study treatment. The following information will be recorded and 
procedures will be performed at the Screening Visit: 
• Eligibility (inclusion/exclusion) criteria 
• Demographic information including height and weight 
• Ocular and systemic medical history 
• Prior and concomitant ocular and systemic medications  
• Vital signs 
• ECG 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP of both eyes 
• Dilated fundoscopy 
• OCT 
• FA 
• Fundus photography (FP) 
• Laboratory assessments including hematology, chemistry, and urinalysis 
• Serum pregnancy test, FSH, and LH levels will be measured for women of 
child-bearing potential 
• AEs 


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6.1.2 Treatment Phase 
6.1.2.1 
Baseline (Day 1) 
During the Day 1 Visit at baseline, all inclusion/exclusion criteria should be reviewed prior to 
randomization and study treatment injection. Subjects will be randomly assigned to 1 of the 
study treatments, SCD411 or aflibercept. Randomized subjects will receive their first 
treatment injection on Day 1. 
Assessments on Day 1 include the following: 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
• Post-injection IOP and vision check 
The IOP is measured on both eyes at screening, and on the study eye prior to IVT injection of 
the study drug, and 60±30 mins after IVT injection of the study drug at each visit from 
baseline/Day 1 to EOT (48 weeks). The IOP is to be measured after OCT and FA are 
completed to avoid corneal erosion. 
Dilated fundoscopy is measured on the study eye prior to IVT injection of the study drug and 
within 60±30 minutes after IVT injection of the study drug. 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• Urine pregnancy test for female subjects of child-bearing potential 
• Laboratory assessments including hematology, chemistry, and urinalysis 


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• AEs 
• Immunogenicity sample collection 
• PK sample collection. 
Other baseline assessments will be same as that for other visits as detailed in Section 6.1.2.2. 
6.1.2.2 
Subsequent Treatment Period (Week 4, Week 8, Week 12, 
Week 16, Week 24, Week 28, Week 32, Week 40, Week 44, and 
Week 48) 
All study procedures should be performed on the same day. Following completion of the 
evaluations, the IVT injection will be administered on the same day of every visit. Only in 
rare circumstances with reason well documented on the eCRF, the IVT injection may be 
administered the next day. 
Study treatment will be injected on Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, 
and Week 48. 
Week 8 is the most critical visit for assessment of the primary endpoint assessment for US 
Food and Drug Administration (FDA), Japan Pharmaceuticals and Medical Devices Agency 
(PMDA), and European Medicines Agency (EMA) Committee on Human Medicinal 
Products submissions. Thus, every effort should be made to adhere to the visit schedule for 
the subjects. 
The following procedures/assessments will be performed and information will be recorded 
during the treatment period: 
Week 4 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 


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• OCT 
• Post-injection IOP and vision check 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• Laboratory assessments including hematology, chemistry, and urinalysis 
• AEs 
• Immunogenicity sample collection 
Week 8 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
• FA 
• FP 
• Post-injection IOP and vision check 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• Laboratory assessments including hematology, chemistry, and urinalysis 
• ECG 
• AEs 


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• Immunogenicity sample collection 
• PK sample collection 
Week 12 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• AEs 
Week 16 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
• Post-injection IOP and vision check 
Nonocular: 
• Concomitant ocular and systemic medications 


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• Vital signs 
• AEs 
Week 20: 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• Laboratory assessments including hematology, chemistry, and urinalysis 
• AEs 
• Immunogenicity sample collection 
Week 24 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
• Post-injection IOP and vision check 


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Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• AEs 
Week 28 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• AEs 
Week 32 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
• Post-injection IOP and vision check 


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Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• AEs 
Week 36 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• AEs 
• Immunogenicity sample collection 
Week 40 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 


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• Post-injection IOP and vision check 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• AEs 
Week 44 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• AEs 
Week 48 
Ocular: 
• BCVA measured by ETDRS letter score or 2702 charts 
• Slit lamp examination 
• Pre-injection IOP 
• Dilated fundoscopy 
• OCT 


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• Post-injection IOP and vision check 
Nonocular: 
• Concomitant ocular and systemic medications 
• Vital signs 
• AEs 
Note: PK samples will be collected on the first and the third injection on Day 1 and Week 8 
at the following time points: predose, +1 day, +3 days, +7 days, +14 days, and +28 days after 
the study treatment injections. 
6.1.3 Early Termination/End-of-Study 
The end of the study is defined as the date of the last visit of the last subject in the study. 
For subjects who discontinue study treatment, the Treatment Discontinuation page of the 
eCRF should be completed. Every effort should be made to have such subjects remain in the 
study and continue with their regularly scheduled visits and assessments until Week 52 
except for study treatment administration. If a subject chooses to withdraw from the study or 
if, in the opinion of the investigator, the subject should be prematurely withdrawn from the 
study, then the subject should return for the ET Visit as soon as possible after the 
discontinuation but no later than 28 days after discontinuation. End-of-Study Visit 
assessments will be conducted 28 days after the EOT at Week 52. 
The following procedures/assessments will be performed at the ET/EOS Visit: 
Ocular: 
• Slit lamp examination 
• Dilated fundoscopy 
• IOP 
• BCVA measured by ETDRS letter score or 2702 charts 
• OCT 
• FA (at ET/EOS) 


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• FP (at ET/EOS) 
Nonocular: 
• Urine pregnancy test for female subjects of child-bearing potential (at ET/EOS) 
• Concomitant ocular and systemic medications 
• Laboratory assessments (at ET/EOS) 
• Vital signs 
• ECG (at ET and EOS Visits) 
• AEs 
• Immunogenicity samples (at ET and EOS Visits) 
If a subject is discontinued from the study, all the ET Visit procedures should be performed 
even if they are outside the allowed study window. 
6.2 Efficacy Assessments 
In this study, efficacy is assessed using BCVA by ETDRS letter score or 2702 charts, OCT 
measures CRT, and CNV area is assessed using FA and FP. 
6.2.1 Best Corrected Visual Acuity 
Best corrected visual acuity will be measured at the scheduled visits as indicated in the 
Schedule of Events (Table 6-1) by certified study staff. BCVA will also be performed at any 
time during the visit at ET/EOS Visit. If the light bulbs are not changed yearly or burned in 
properly, it will be considered a deviation. The VA examiners are masked to study arm 
assignments. Visual acuity testing will be done for both eyes and should be performed prior 
to the dilation of pupils, FA, and OCT assessments and prior to the IVT injection of the study 
drug. Visual acuity testing will be consistently assessed from Screening to Week 52 (EOS 
visit) or ET Visit using either original series ETDRS charts or 2702 charts at a starting 
distance of 4 meters, performed by a certified VA examiner. The same method of BCVA must 
be used in each subject from Screening to Week 52 (EOS Visit) or ET Visit. 


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A Visual Acuity Specifications Procedure Manual and training materials will be provided to 
all sites. All examiners will require certification prior to performing this assessment as part of 
the study.  
A decrease in VA of ≥15 letters from the last assessment of VA should be reported as 
AEs/SAE as appropriate. If there is a decrease in VA of ≥ 30 letters from the last assessment 
of VA or if there is a decrease in VA to the level of Light Perception or worse, it should be 
reported as an SAE. 
6.2.2 Ocular Imaging 
Central retinal thickness will be measured using OCT and FA/FP will be used to measure 
CNV. 
6.2.2.1 
Optical Coherence Tomography  
A reading center manual along with training materials will be provided to all sites which will 
provide information on standardized procedures for the collection, storage, and transmission 
of the images. Prior to any study images being taken at the sites, site personnel and 
equipment must be assessed and certified through test images using instruments and software 
approved by the central reading center. Only trained and certified site staff delegated with the 
responsibility of image collection should perform this test. The OCT imaging should be 
performed on the study eye prior to the IVT injection of the study drug. Those images will be 
sent to the central reading center. 
All OCT devices must be registered in an investigational site by the central reading center 
and meet the minimum software requirement. The subject should consistently use the same 
OCT device from Screening to Week 52 (EOS Visit) or ET Visit. The devices should be 
registered by the central reading center from Screening to Week 52 (EOS Visit) or ET Visit 
and OCT images will be sent to the central reading center. 
If a subject misses a visit during which ocular images should be taken, the images should be 
collected at the next scheduled visit. 


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6.2.2.2 
Fluorescein Angiography and Fundus Photography 
At screening, FA and FP will be performed on both eyes and those images will be sent to the 
central reading center. At Week 8 and ET/EOS Visit, FA and FP will be performed on the 
study eye (prior to IVT injection of the study drug at Week 8) and those images will be sent 
to the central reading center. Site staff who will perform FA and FP in this study must be 
certified by the central reading center before the start of the study. Only FA/FP devices 
certified by central reading center are allowed to be used in this study. If 1 or more FA/FP 
devices are certified at an investigational site, the same FA/FP device should be consistently 
used from Screening to Week 52 (EOS Visit) or ET Visit in each subject. 
In the event a subject is suspected to have a new active CNV in the study eye, an OCT should 
be performed to confirm the diagnosis. An optional FA will be performed. 
6.3 Safety Assessments 
Safety endpoints include AEs, vital signs, ECGs, ophthalmological examinations, and 
laboratory assessments up to Week 52. Safety is also evaluated during follow-up (4 weeks 
after EOT). 
6.3.1 Medical History and Concomitant Medications 
All significant ocular and systemic medical conditions and surgeries within the past 5 years 
should be captured for all subjects. Any significant previous ocular surgeries, procedures 
and/or medications or treatments used for these conditions should be recorded. History of 
thrombotic events, IVT anti-VEGF treatment, treatment involving macula with PDT with 
verteporfin, transpupillary thermotherapy, radiation therapy, or retinal laser treatment should 
be reviewed in detail. 


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6.3.2 Ophthalmic Examinations 
Routine ophthalmological examinations will be performed at indicated visits in the Schedule 
of Events (Table 6-1) and include the following: 
• Biomicroscopy slit lamp examination (anterior chamber flare, anterior chamber cells, 
vitreous cells opacities and haze) will be performed on both eyes at screening and 
prior to IVT injection of the study drug. Slit lamp will also be performed at any time 
during the visit at ET/EOS Visit. Please see Section 13.1 (Appendix 1) and 
Section 13.2 (Appendix 2) for grading scales. 
• Dilated fundoscopy includes evaluation of retina and vitreous (vitreal overall 
assessment; macular overall assessment; retina overall assessment; and optic nerve 
overall assessment). A standard method of indirect ophthalmoscopy (ie, using a 
head-mounted light source and a 20-30 lens) will be performed by the masked 
team/study staff on the study eye prior to IVT injection of the study drug and within 
60±30 minutes after IVT injection of the study drug. Dilated fundoscopy will also be 
performed at any time during the visit at ET/EOS Visit. Dilated fundoscopy 
assessments should be performed at all assessment visits as mentioned in Table 6-1. 
Intraocular pressure is a part of routine study assessment. A measurement of IOP will be 
conducted using either Goldmann applanation tonometer or Tono-pen.  
The same method of IOP measurement must be used in each subject from Screening to 
Week 52 (EOS Visit) or ET Visit. Intraocular pressure will be measured by the masked 
team/study staff on both eyes at screening, and on the study eye prior to IVT injection of the 
study drug, and 60±30 minutes after IVT injection of the study drug at each visit from 
baseline/Day 1 to EOT (48 weeks). When IOP is measured prior to IVT injection of the study 
drug, IOP should be measured after OCT and FA are completed to avoid corneal erosion. IOP 
will also be performed at any time during the visit at ET/EOS Visit. 
Finger counting test is a part of post-injection procedures and is to be performed by the 
unmasked investigator immediately after the IVT injection of the study drug. 


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6.3.3 Adverse Events 
6.3.3.1 
Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or to IVT injection procedure or their 
clinical significance. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study drug or to IVT injection procedure. Subjects will 
be instructed to contact the investigator at any time if any symptoms develop. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
study drug or any event already present that worsens in either intensity or frequency after 
exposure to study drug. 
6.3.3.2 
Serious Adverse Events 
An SAE is defined as any event that: 
• results in death 
• is immediately life threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. Simple emergency room visits (excluding hospital stay that 
crosses midnight) are not reported as an SAE. 


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In addition to the above criteria, the following criteria would be considered as SAEs and are 
to be reported as SAEs: 
• Development of rhegmatogenous retinal detachment or stage 3 or 4 macular holes. 
• A decrease in BCVA of ≥30 letters compared with the last assessment of VA. 
A decrease in VA of ≥15 letters from the last assessment of VA should be reported as 
AEs/SAE as appropriate. If there is a decrease in VA of ≥30 letters from the last assessment 
of VA or if there is a decrease in VA to the level of Light Perception or worse, it should be 
reported as an SAE. 
6.3.3.3 
Eliciting and Documenting Adverse Events 
Adverse events will be assessed beginning at enrollment (date of signed informed consent) 
and up to 28 days after the last dose of study drug. 
Serious AEs that occur more than 28 days after the last dose of study drug need not be 
reported unless the investigator considers them related to study drug. 
At every study visit, subjects will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and OTC medications). 
In addition to subject observations, AEs identified from any study data (eg, laboratory values, 
electrocardiogram [ECG] changes, etc.) or identified from review of other documents (eg, 
subject diaries) that are relevant to subject safety will be documented on the AE page in the 
eCRF. 
6.3.3.4 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes the following: 
• drug treatment 
• dose 
• event term 


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• time of onset 
• investigator-specified assessment of severity and relationship to study drug and to 
IVT injection procedure 
• time of resolution of the event 
• seriousness 
• any required treatment or evaluations 
• outcome 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed to adequate resolution. The Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
A decrease in VA of ≥15 letters from the last assessment of VA should be reported as an 
AE/SAE, as appropriate. If there is a decrease in VA of ≥30 letters from the last assessment 
of VA or if there is a decrease in VA to the level of Light Perception or worse, it should be 
reported as an SAE. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs or vital sign measurements), including those that worsen from 
baseline, felt to be clinically significant in the medical and scientific judgment of the 
investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be worse than the subject’s baseline condition, 
are not to be reported as AEs or SAEs. 
6.3.3.5 
Reporting Serious Adverse Events 
Any AE that meets SAE criteria (Section 6.3.3.2) must be reported by the investigator to 
PPD, Inc immediately (ie, within 24 hours) after the time site personnel first learn about the 


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event through the Electronic Data Capture (EDC) system, or if unable to do so due to 
technical issues, by 1 of the back-up mechanisms provided (eg, fax). The following contact 
information is to be used for SAE reporting: 
 
PPD, Inc, Pharmacovigilance 
 
 
SAE NA Safety Hotline - 
 
 
SAE NA Fax line- 
 
 
SAE EMEA/APAC Safety Hotline - 
 
 
SAE EMEA/APAC Fax line- 
 
6.3.3.6 
Suspected Unexpected Serious Adverse Reactions 
The sponsor will promptly evaluate all suspected unexpected serious adverse reactions 
(SUSARs) against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, IRBs/IECs, and applicable health authorities 
based on applicable legislation. 
To determine reporting requirements for single AE cases, the sponsor will assess the 
expectedness of these events using the investigator’s brochure. 
The sponsor will compare the severity of each SUSAR and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. 
6.3.3.7 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria: 


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Mild: 
These events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
Moderate: 
These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
normal functioning. 
Severe: 
These events interrupt a subject’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually 
incapacitating. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. 
6.3.3.8 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug and IVT injection 
procedure is part of the documentation process, but it is not a factor in determining what is or 
is not reported in the study. If there is any doubt as to whether a clinical observation is an AE, 
the event should be reported. 
The relationship or association of the test article in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Unrelated: 
This relationship suggests that there is no association between the study drug 
or the IVT injection procedure and the reported event. 
Related: 
This relationship suggests that there is an association between the study drug 
or the IVT injection procedure and the reported event. 
6.3.3.9 
Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable. 
6.3.4 Clinical Laboratory Evaluations 
Clinical laboratory assessments will be performed as indicated in Table 6-1. Collection of 
blood and urine will occur at the study site and the samples will be shipped to a central 
laboratory for analysis. All samples (including urine) should be collected prior to IVT 


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injection of the study drug; urine samples will be collected prior to FA assessment to avoid 
false elevations in urine protein values. Hematology, chemistry, and urinalysis samples will 
also be performed at any time during the visit at ET/EOS Visit. Procedures for collection and 
processing of blood and urine are provided in the laboratory manual. 
Table 6-2 presents the laboratory analyses that will be performed during the study. 
Table 6-2: 
Clinical Laboratory Evaluations 
Clinical Chemistry 
Hematology 
Urinalysis 
For Women 
Alanine 
aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate 
aminotransferase 
Blood urea nitrogen 
Creatinine 
Creatine kinase 
Total and direct 
bilirubin 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Lymphocytes 
MCV 
Monocytes 
Neutrophils 
Platelet count 
RBC count 
RBC morphology 
WBC count 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Serum pregnancy test: At 
Screening Visit for women of 
child-bearing potential (serum 
β-hCG, follicle-stimulating 
hormone, luteinizing 
hormone) 
Urine pregnancy test: At 
baseline, ET, and EOS visits 
for women of child-bearing 
potentiala 
Abbreviations: EOS, end-of-study; ET, early termination; hCG, human chorionic gonadotropin; MCV, mean 
corpuscular volume; RBC, red blood cell; WBC, white blood cell. 
a. 
If urine pregnancy test is positive, serum pregnancy test should be performed; if found positive, study 
treatment will be discontinued. 
6.3.5 Vital Signs 
Vital signs consist of body temperature, respiratory rate, blood pressure (systolic and 
diastolic), and heart rate measurement. 
On injection visits, vital signs will be measured prior to IVT injection of the study drug. Vital 
signs will also be performed at any time during the ET/EOS Visit. Vital signs should be taken 
with the subject in a seated position after resting for 5 minutes. Vital signs will be measured 
before venipuncture. 
6.3.6 Electrocardiograms 
An ECG could be done for safety and assessed by the investigator only at Screening, Week 8, 
and at the EOS/ET Visit. 


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6.4 Pharmacokinetic Assessments 
Blood samples, for determination of concentrations of SCD411 and aflibercept, will be 
collected at the time points specified in the Schedule of Events (Table 6-1) and detailed 
sampling window is provided in Table 6-3. As per the Schedule of Events, additional visits 
will be arranged for collecting the PK blood samples. Quantification of free and bound 
SCD411 and aflibercept will be performed for subjects who agree to participate in the PK 
substudy using blood samples drawn at predose, and at +1 day, +3 days, +7 days, +14 days, 
and +28 days following the first and the third injection (Week 8). Samples should be 
collected before performing FA, when performed on the same day. Plasma concentrations of 
SCD411 and aflibercept will be determined using validated analytical procedures. PK 
parameters assessed in the study include AUC0-t, AUC0-tau, AUC0-inf, Cmax, tmax, and t1/2. 
Additional details of PK analysis are available in the PK manual. 
Table 6-3: 
Sampling Window 
Study Day/Week 
Time 
(Relative to Dosing) 
Time in Hours  
(Visit Window) 
PK 
Immunogenicity  
Day 1 
 
0 (Predose) 
0 
X 
X 
+1 day  
24 (±1 hour) 
X 
 
+ 3 days  
72 (±2 hours) 
X 
 
+7 days  
168 (±6 hours) 
X 
 
+14 days  
336 (±1 day) 
X 
 
+28 days (Week 4)1 
672 (±2 days) 
X 
X 
Week 8 
0 (Predose) 
0 
X 
X 
+1 day  
24 (±1 hour) 
X 
 
+ 3 days  
72 (±2 hours) 
X 
 
+7 days  
168 (±6 hours) 
X 
 
+14 days  
336 (±1 day) 
X 
 
+28 days 
672 (±2 days) 
X 
 
Week 20 
 
 
 
X 
Week 36 
 
 
 
X 
Week 52/End-of-Study  
 
 
X 
1 This blood sample should be collected before Week 4 injection. 
 


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6.5 Immunogenicity Assessments 
Blood samples for immunogenicity analysis will be collected at Baseline (predose), at 
Weeks 4, 8, 20, 36, and 52 as indicated in the Schedule of Events (Table 6-1). Detailed 
sampling window is provided in Table 6-3. Samples should be collected before the IVT 
injection of the study drug and prior to FA assessment when performed on the same day. The 
samples will be evaluated for anti-SCD411 or anti-aflibercept antibodies. 
Neutralizing antibodies (NAb) will also be evaluated only if ADA test positive. 
6.6 Independent Data Monitoring Committee 
An IDMC will be established for the study. The IDMC and associated parties (CRO 
Pharmacovigilance, Data management, sponsor as well as the CRO for IDMC management) 
will function under the terms of an IDMC Charter. The IDMC will comprise 3 voting 
members (including 1 independent [unmasked] biostatistician) and 2 clinicians with 
significant experience in wet AMD and who are not involved in the study. The duty of this 
IDMC is to protect the safety interests of subjects and all others who may possibly be 
exposed to the study drug and to make recommendations to the sponsor. The IDMC (without 
the sponsor or CRO personnel involved in the conduct of the study) will review efficacy and 
safety data in an unmasked manner. 
The voting members of the IDMC will participate in a closed, unmasked session, following 
the blinded presentation of data to discuss recommendations. During these sessions, the 
IDMC members will be able to review unmasked safety data and efficacy data. Only the 
voting members, unblinded independent biostatistician, and the PPD Data Monitoring 
Coordinators will be present in the closed meetings. 
Two IDMC meetings will be held: one safety meeting will be held approximately 6 months 
after the IDMC organizational meeting and the second safety meeting will be held after all 
subjects have completed the Week 8 Visit. After each meeting, the IDMC members will make 
a decision to continue the study without change, modify the study or enrollment to be placed 
on hold, or study termination. Any decision to terminate the study will be based on clinical 
judgment only and no formal stopping rules are defined. The sponsor is obligated to inform 
the study sites, IRB/IEC and Competent Authorities of the IDMC recommendations 
according to country-specific requirements. 


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6.7 Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an IP may have interfered 
with the effectiveness of a contraceptive medication. Any pregnancy that occurs during study 
participation must be reported using the same procedures as an SAE (Section 6.3.3.5) eg, a 
clinical study pregnancy form. To ensure subject safety, each pregnancy must be reported to 
the sponsor within 24 hours of learning of its occurrence. The pregnancy must be 
followed-up to determine outcome (including spontaneous miscarriage, elective termination, 
normal birth, or congenital abnormality) and status of mother and child, even if the subject 
was discontinued from the study. Pregnancy complications and elective terminations for 
medical reasons must be reported as an AE or SAE. Spontaneous miscarriages must be 
reported as an SAE. Pregnancy outcomes can be collected for the female partners of any 
male subjects who participated in this study, provided their verbal consent is obtained prior to 
collecting this information. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention 
after the subject has completed the study, and considered by the investigator as possibly 
related to the study treatment, must be promptly reported to the sponsor. 
No pregnancy test is required for women of non-child-bearing potential. Serum pregnancy 
test will be performed for women of child-bearing potential at the Screening Visit. At 
Baseline, ET, and EOS Visits, a urine pregnancy test will be performed and if found positive, 
then the serum pregnancy test should be performed. If serum pregnancy test results are 
positive, the study treatment should be discontinued, and the subjects should continue with 
regularly scheduled visits and assessments until Week 52 after discontinuation, unless the 
subjects withdraw consent, in which circumstance ET Visit procedures should be conducted; 
the subject or the female partner of any male subject should be followed for safety until the 
outcome of the pregnancy is known. 
6.8 Sample Collections 
Sample collection, processing, and shipping should be performed according to the local 
laboratory requirements. The amount of blood to be collected per subject during the study for 
PK, immunogenicity, and safety evaluations will be provided in the laboratory manual. 


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7 
Statistical and Analytical Plan 
The objectives and endpoints for this study are described in Section 2. This section focuses 
on key aspects for the analysis and reporting of efficacy and safety endpoints. Details for all 
endpoint analyses will be provided in the final statistical analysis plan (SAP), which will be 
finalized prior to the Week 8 and interim database lock.  
Based on discussions with regulatory agencies which resulted in acceptance of different 
equivalence margins, different efficacy analyses will be performed for FDA submissions and 
other regulatory agencies versus submissions to EMA and PMDA. As the agencies will 
independently assesses efficacy based on their specific criteria, no adjustment for multiple 
comparisons will be required. 
7.1 Estimands and Intercurrent Events 
Week 8 
Primary Estimand: The primary estimand is the mean treatment difference in BCVA change 
from baseline at Week 8. For the EMA, the primary analysis will be assessed for both the full 
analysis set (FAS) and per-protocol set (PPS). For the FDA, PMDA, and any other 
submissions, the primary analysis will be performed for the FAS. The primary estimand 
treats subjects in the analysis as if subjects do not receive rescue therapy.  
Target Population: Subjects with wet AMD as defined in the enrollment criteria. 
Endpoint: Change from baseline in BCVA at Week 8. 
Treatment Condition(s): Dosing at Day 1, Week 4, and Week 8 with one of the following: 
SCD411 or aflibercept, both without rescue therapy. 
Population-level Summary: The difference in mean change from baseline in BCVA at 
Week 8 between SCD411 and aflibercept and the corresponding confidence interval (CI) for 
the mean difference. 
Intercurrent Events and Strategies to Address Intercurrent Events 
• Discontinuation of study eye study treatment with continued participation in study 
without receipt of rescue therapy 


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o Treatment Policy – no imputation; use observed data 
• Receipt of rescue therapy in the study eye 
o Hypothetical approach – data after receipt of rescue will be set to missing and 
post rescue data will be imputed employing multiple imputation (MI) assuming 
missing at random (MAR) using randomized treatment-based Markov Chain 
Monte Carlo (MCMC) methodology. 
• Discontinuation from study, regardless of reason 
o Hypothetical approach – missing data after discontinuation will be imputed via 
MI assuming MAR using randomized treatment-based MCMC methodology. 
Rationale for Strategy: As the primary objective of this study is to show biosimilar 
equivalence between SCD411 and aflibercept, the primary estimand is constructed to 
estimate the treatment effect under the assumption that all subjects take study treatments 
without the use of rescue therapy while allowing for subjects to discontinue study treatment. 
Multiple imputation under MAR assumptions results in treatment estimates as if subjects 
continued as on their original treatment. Treating discontinuation as MAR and setting the 
post rescue assessment to missing prior to performing MI was chosen to avoid inflation of 
the SCD411 treatment effect. Subjects who receive rescue therapy or discontinue will have 
shown lack of efficacy in assessments, so the MAR approach should be conservative if the 
test treatment is not equivalent to or less efficacious than the reference product. 
Secondary Estimand: A secondary estimand for the primary efficacy endpoint is the mean 
treatment difference in BCVA change from baseline at Week 8 while allowing for receipt of 
rescue therapy. The estimand will be constructed as above, but the intercurrent event of 
rescue therapy use will be handled using the treatment policy approach. Data post rescue will 
not be set to missing. This estimand is constructed to estimate the treatment effect including 
the impact of rescue therapy, which may better reflect actual real-world outcomes, where 
rescue would likely be given when lack of efficacy is seen. 
Week 52 
Primary Estimand: The primary estimand is the mean treatment difference in BCVA change 
from baseline at Week 52. For the EMA, the primary analysis will be assessed for both the 
FAS and PPS. For the FDA, PMDA, and any other submissions, the primary analysis will be 


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performed for the FAS. The primary estimand treats subjects in the analysis as if subjects do 
not receive rescue therapy. 
Target Population: Subjects with wet AMD as defined in the enrollment criteria. 
Endpoint: Change from baseline in BCVA at Week 52 
Treatment Condition(s): Dosing at Day 1, Week 4, Week 8, Week 16, Week 24, Week 32, 
Week 40, and Week 48 with one of the following: SCD411 or aflibercept, both without 
rescue therapy. 
Population-level Summary: The difference in mean change from baseline in BCVA at Week 
52 between SCD411 and aflibercept and the corresponding CI for the mean difference. 
Intercurrent Events and Strategies to Address Intercurrent Events 
• Discontinuation of study eye study treatment with continued participation in study 
without receipt of rescue therapy 
o Treatment Policy – no imputation; use observed data 
• Receipt of rescue therapy in the study eye 
o Hypothetical approach – Data after receipt of rescue will be set to missing and 
post rescue data will be imputed employing MI assuming MAR using randomized 
treatment-based MCMC methodology. 
• Discontinuation from study, regardless of reason  
o Hypothetical approach – Missing data after discontinuation will be imputed via 
MI assuming MAR using randomized treatment-based MCMC methodology. 
Rationale for Strategy: As the primary objective of this study is to show biosimilar 
equivalence between SCD411 and aflibercept, the primary estimand is constructed to 
estimate the treatment effect under assumption that all subjects take study treatments without 
the use of rescue therapy while allowing for subjects to discontinue study treatment. Multiple 
imputation under MAR assumptions results in treatment estimates as if subjects continued on 
their original treatment. Treating discontinuation as MAR and setting the post rescue 
assessment to missing prior to performing MI was chosen to avoid inflation of the SCD411 
treatment effect. Subjects who receive rescue therapy or discontinue will have shown lack of 


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efficacy in assessments, so the MAR approach should be conservative if the test treatment is 
not equivalent to or less efficacious than the reference product. 
Secondary Estimand: A secondary estimand for the secondary efficacy endpoint is the mean 
treatment difference in BCVA change from baseline at Week 52 while allowing for receipt of 
rescue therapy. The estimand will be constructed as above, but the intercurrent event of 
rescue therapy use will be handled using the treatment policy approach. Data post rescue will 
not be set to missing. This estimand is constructed to estimate the treatment effect including 
the impact of rescue therapy, which may better reflect actual real-world outcomes, where 
rescue would likely be given when lack of efficacy is seen. 
7.2 Sample Size Determination 
The equivalence margin agreed upon with EMA and PMDA was determined using the data 
presented from MARINA (and ANCHOR) and VIEW studies. These data were used to 
estimate the efficacy of aflibercept compared to the placebo treatment in subjects with wet 
AMD. It was shown that in MARINA, subjects on average lost 2.5 letters of BCVA over 
2 months in the sham-treated control arm and gained 5 letters in the treatment arm of 2 mg 
dose, and that in the VIEW studies 6.8 to 7.5 letters were gained among subjects with wet 
AMD at Week 8 into treatment on a 2 mg dose. Combining both study data, the treatment 
effect compared to the placebo would be estimated as approximately 9.3 to 10 letters. A 
margin of 3.8 letters would be translated to a preservation of 59% to 62% of the difference 
between Eylea and sham and is less than a 1 line change in VA. Equivalence discussions for 
EMA and PMDA were based upon a 95% CI approach or 2 one-sided tests (TOST) at the 
α=0.025 level.  
Given that the statistical justification of the 3.8 letter equivalence margin is not included in 
the current version of the protocol, this will be added in the SAP and provided to the 
regulatory agencies upon request. 
The FDA requested a tighter equivalence margin of 3 letters but agreed equivalence can be 
determined from a 90% CI approach (equivalent to TOST at the α=0.05 level). 
Standard deviation (SD) for the mean change from baseline at early visits (Weeks 4 to 12) 
based on observed data for the FAS ranged from and 8.73 to 11.99 considering all treatment 
groups from VIEW1 and from 7.4 to 11.0 letters for the VIEW2 study (DHHS 2011 [Eylea 


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Statistical Review, Appendix Tables A.1 and A.2]). For power calculations, a range of SD 
between 10.4 and 11.8 was assumed to be conservative and cover the majority of larger SD 
values seen in the observed data. 
A sample size of 266 subjects per treatment arm was selected as it provides at least 80% 
power for the FDA, EMA, and PMDA analyses for the range of SD considered when using 
TOST on data from a parallel-group design. For the FDA analysis based on equivalence 
limits of -3.0 and 3.0 letters, α=0.05 significance level (90% CI), assuming the true 
difference between the means is 0.0, power of 91% is achieved for SD of 10.4 letters and 
power of 80% is achieved for SD of 11.8 letters. For the EMA and PMDA analyses based on 
equivalence limits of -3.8 and 3.8 letters, α=0.025 significance level (95% CI), assuming the 
true difference between the means is 0.0, power of 98% is achieved for SD of 10.4 letters and 
power of 92% is achieved for SD of 11.8 letters when sample size is 266 per treatment arm. 
Considering approximately 5% loss from randomization through Week 8, the total sample 
size required is 560. 
A subset of 40 subjects (20 per group) will be selected for collection of PK samples. The 
sample size is not test-driven since no equivalence test will be performed for PK parameters. 
7.3 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Full Analysis Set (FAS): All randomized subjects who received at least 1 injection of the 
study drug. 
Modified FAS (mFAS): All randomized subjects who received at least 1 injection of the 
study drug and had at least 1 postbaseline BCVA assessment in the study eye.  
Per-protocol Set (PPS): All subjects in the FAS, excluding those with significant protocol 
violations. 
Safety Set (SAF): All subjects receiving at least 1 injection of the study drug. 
Pharmacokinetic Analysis Set (PK Set): The subset of subjects in FAS who have sufficient 
evaluable blood samples to be included in the PK Set. 


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The primary set for efficacy analysis will be the FAS; however, for the EMA submission, the 
primary efficacy endpoint must meet equivalence for both the FAS and PPS. PMDA also 
requires an efficacy analysis to be conducted based on the mFAS without MI as a supportive 
analysis. The SAF will be the primary analysis set for safety, tolerability, and 
immunogenicity analyses. 
7.4 Description of Subgroups to be Analyzed 
Subgroup analyses will be performed by region/country and important demographic/baseline 
characteristics; however, the study is not powered for treatment comparisons within 
subgroups. Details of subgroups analyses will be provided in the SAP. 
7.5 Statistical Analysis Methodology 
The data will be analyzed by the sponsor and/or designated CRO. Any data analysis carried 
out independently by the investigator should be submitted to the sponsor before publication 
or presentation. 
Tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed with SAS® software, version 9.4 or higher. 
Descriptive statistics for continuous variables in summary tables will include the number of 
subjects in the analysis (n), mean, SD, median, and range (minimum, maximum). Descriptive 
statistics for categorical variables in summary tables will include counts and percentages. 
Graphical summaries of the data may be presented. 
The most recent nonmissing measurement collected prior to the first administration of study 
drug will be used as the baseline value. 
All data obtained on the eCRF will be provided in separate data listings showing individual 
subject values by treatment group and visit, if applicable. 
Unless otherwise specified, the missing data will not be imputed. 
7.5.1 Efficacy Analyses 
Efficacy analyses will be based on the study eye only. 


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7.5.1.1 
Primary Efficacy Outcome Measures 
The pre-postchange in BCVA as measured by ETDRS letter score or 2702 charts provides 
direct information regarding the primary clinical effect of a product intended to preserve or 
improve VA. This endpoint was used as a primary endpoint in most of the clinical studies 
performed for Eylea: GALILEO, COPERNICUS, VISTA, VIVID, and MYRROR and was 
also assessed as a secondary endpoint in the clinical studies VIEW 1 and VIEW 2. The 
increase in BCVA under treatment with aflibercept generally reaches a plateau within the first 
24 weeks of treatment in all therapeutic indications studied. Evaluating the effect after 
8 weeks of treatment allows a comparison at a time when a substantial proportion of the 
maximum effect is achieved but before the plateau of the effect is reached. This makes a 
comparison between 2 similar products after 8 weeks of treatment more sensitive as 
compared to an endpoint after 52 weeks of treatment. 
The primary analysis of the change from baseline in BCVA as measured by ETDRS letter 
score or 2702 charts through 8 weeks of treatment will be performed via MMRM including 
data for the Week 4 and Week 8 visits. The model will include the change from baseline as 
the dependent variable; treatment, visit, and visit-by-treatment as fixed effects, and baseline 
BCVA as a covariate. An unstructured covariance matrix will be used. In the event of 
convergence issues, compound-symmetry will be used instead. Rubin’s rules will be used to 
combine the estimates from the MMRM analyses and the estimated mean treatment 
difference at Week 8 along with the corresponding 90% and 95% CIs will be presented. 
Equivalence will be determined if the upper and lower CI limits for the difference between 
treatments are within the equivalence margins. Raw values and changes from baseline at 
Week 4 and Week 8 will be summarized by treatment group using descriptive statistics based 
on observed data. 
The primary null hypothesis (H0) and alternative hypothesis (H1) are: 
H0: ∆ ≥M or ∆ ≤-M 
H1: -M< ∆ <M 
where ∆ indicates the mean difference between the 2 treatment groups in the change from 
baseline in ETDRS letter score or 2702 charts at Week 8 and M represents the equivalence 
margin. 


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Based on discussions with regulatory agencies, separate equivalence CIs and equivalence 
margins will be used for FDA submissions and other regulatory agencies versus submissions 
to EMA and PMDA. Submissions to other regulatory agencies will be assumed to follow 
FDA guidance. 
For the FDA submission and other countries submission, a 90% CI (equivalent to TOST 
evaluated at an α of 0.05) will be assessed using an equivalence margin of 3 letters. If the 
upper bound of the 90% CI is less than 3 and the lower bound is greater than -3, then study 
success will be claimed. For the EMA and PMDA, a 95% CI (equivalent to TOST evaluated 
at an α of 0.025) will be assessed using an equivalence margin of 3.8 letters. If the upper 
bound of the 95% CI is less than 3.8 and the lower bound is greater than -3.8, then study 
success will be claimed. 
The least squares mean estimate of treatment difference and corresponding 90% (FDA and 
other countries) and 95% (EMA/PMDA) CIs will be provided. The primary analysis set for 
the FDA, PMDA, and any other submissions will be the FAS. For the EMA submission, both 
the FAS and PPS are considered primary analysis and equivalence will need to be shown for 
both analysis sets. 
As a sensitivity analysis, an analysis of covariance (ANCOVA) model comparing the change 
from baseline in BCVA at Week 8 and including the baseline BCVA value as a covariate will 
be performed using multiple imputed data. 
Additional sensitivity analyses to the primary analysis will be performed using single 
imputation approaches for post study discontinuation/rescue therapy BCVA scores using the 
LOCF and BOCF prior to MMRM analysis (intermittent missing data will be considered 
MAR and not imputed) for both the FAS and PPS. In addition, an ANCOVA model 
comparing the change from baseline in BCVA at Week 8 and including the baseline BCVA 
value as a covariate will be performed by imputing the post study discontinuation/rescue 
therapy BCVA values using LOCF and BOCF approaches for the FAS and PPS. 
Additionally, the MMRM analysis will be performed using data from MI including a tipping 
point approach. Observations after receipt of rescue therapy will be set to missing prior to the 
MI. Multiple imputation assuming MAR will be applied to all missing data. After conclusion 
of MI, post study discontinuation/rescue therapy observations for the SCD411 arm will have 
fixed value C added to the imputed values. The imputed data, including the fixed penalty, 


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will be analyzed by the same MMRM model as for the primary analysis. A range of values 
for C will be considered to identify the point at which equivalence can no longer be claimed. 
Details will be provided in SAP. 
Supportive analysis for the primary endpoint will be performed based on the mFAS per the 
PMDA’s request. Data after receipt of rescue therapy will be set to missing without 
employing MI. Both the MMRM and ANCOVA analyses will be performed using the non-
imputed data. 
7.5.1.2 
Secondary Efficacy Outcome Measures 
The estimated mean treatment difference in the change from baseline in BCVA as measured 
by ETDRS letter score or 2702 charts through 52 weeks along with the corresponding 90% 
and 95% CIs from the same MMRM model as used in the primary analysis but including data 
from all weeks through Week 52 will also be presented for the FAS and PPS. 
The estimated mean treatment difference at Week 52 along with the corresponding 90% and 
95% CIs will also be presented using the same MMRM and ANCOVA models as used in the 
Week 8 analysis. As done for Week 8, analysis will be performed using MI data, where post 
rescue assessments have been set to missing while including the post rescue assessments in 
the imputation model. Raw values and changes from baseline will be summarized by 
treatment group using descriptive statistics for each visit.  
Sensitivity analyses will be performed using LOCF and BOCF for post study discontinuation 
assessments or after receipt of rescue therapy prior to performing the MMRM and ANCOVA 
analysis (intermittent missing data will be considered MAR and not imputed). Additionally, 
the MMRM analysis will be performed using data from MI including a tipping point 
approach. 
The analysis of change from baseline in CRT as assessed by OCT or change from baseline in 
CNV are will be based on the MMRM model similar to the one used for the analysis of 
change from baseline in BCVA, with the corresponding 95% CI for the estimates of treatment 
differences at Week 8 and Week 52 presented. Raw values and changes from baseline will be 
summarized by treatment group using descriptive statistics. Data after receipt of rescue 
therapy will be set to missing prior to the MMRM analysis. Multiple imputation will not be 
performed, and no sensitivity analyses will be performed. 


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The percentage of subjects who gain ≥15 letters in BCVA as measured by ETDRS letter score 
or 2702 charts at postbaseline visits (Week 8 and Week 52) compared with baseline will be 
summarized and 95% CI for the proportions in each treatment arm and difference in 
proportions between treatment arms will be presented. For subjects who have missing 
assessments at corresponding postbaseline visits or who received rescue therapy prior to a 
visit will be assumed to have a gain of <15 letters in BCVA (eg, nonresponder imputation). 
No sensitivity analyses will be performed. 
7.5.2 Pharmacokinetic Analyses 
The PK parameters (AUC0-t, AUC0-tau, AUC0-inf, Cmax, tmax, t1/2,) from the 2 treatment groups 
will be summarized using n, arithmetic mean, percent coefficient of variation (% CV), 
geometric mean, geometric %CV, SD, median, minimum and maximum values in the PK 
analysis set. 
7.5.3 Immunogenicity Analyses 
The analysis on immunogenicity will be descriptive. Results will be summarized with 
observed values and change from baseline for ADA titers (in log scale) by treatment group in 
the SAF. The number and proportion of ADA-positive subjects and ADA-negative subjects 
will be summarized by treatment group for each assessment time point. NAb will be tested 
when ADA results are confirmed to be positive. The number and proportion of NAb subjects 
will be summarized by treatment group for each assessment time point. 
7.5.4 Safety Analyses 
Safety variables include incidence of AEs (or TEAEs), laboratory test results, ECG results, 
and vital signs. All safety analyses will be based on the SAF. No formal statistical analysis of 
the safety data will be performed.  
Adverse events will be coded according to the MedDRA in the study. The number and 
percentage of subjects experiencing an AE will be summarized by the MedDRA system 
organ class and preferred term. AEs will be classified as pretreatment or treatment-emergent. 
Pretreatment AEs are defined as AEs that are reported or worsened after signing the ICF up 
to the first dose date of study drug. 


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Treatment-emergent AEs are defined as AEs that are reported or worsened on or after the 
first dose date of study drug through 28 days after the last dose date of study drug. 
Only TEAEs will be summarized in tables. The AE summary tables will include counts of 
subjects. Therefore, if a subject experiences more than 1 episode of a particular AE, the 
subject will be counted only once for that event. If a subject has more than 1 AE that is coded 
to the same preferred term, the subject will be counted only once for that preferred term. 
Only the maximum severity level will be presented in the severity summary, and only the 
worst relationship level will be presented in the relationship summary. Adverse events 
leading to death, SAEs, dose interruption, and permanent discontinuation will be listed 
separately. All AEs through the EOS, including pretreatment AEs, will be listed in a data 
listing. Ocular AEs will be summarized separately for the study and fellow eyes. 
Laboratory test variables will be summarized by treatment group and visit using descriptive 
statistics (number of subjects, mean, SD, minimum, maximum, and mean change from 
baseline). Shift tables (low, normal, high) between baseline and postbaseline time points will 
be presented by laboratory test and treatment group. Laboratory tests with categorical results 
that cannot be analyzed by change from baseline or shift table analysis will not be included in 
these summaries but will be listed. Data obtained from laboratory tests not required by the 
protocol will not be summarized but will be listed. 
The results of slit lamp examination, dilated fundoscopy, IOP, and vision check will be 
summarized using descriptive statistics at each visit and applicable time point, as applicable. 
Separate summaries will be presented. 
Descriptive statistics of vital signs and change from baseline at each visit will be presented 
by treatment group. 
Descriptive statistics of ECG parameters and change from baseline at each visit will be 
presented by treatment group. 


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7.5.5 Other Analyses 
7.5.5.1 
Background Characteristics 
7.5.5.1.1 
Subject Disposition 
The number and percentage of subjects who are included in each analysis set and who 
complete and discontinue the study will be summarized by treatment group and overall. 
7.5.5.1.2 
Demographics and Baseline Characteristics 
Demographic information: age, sex, ethnicity, height, weight, body mass index, and other 
baseline measures such as ETDRS letter score or 2702 chart, CRT and CNV, will be 
summarized by treatment group and overall, using descriptive statistics. Ocular measures will 
be summarized for the study eye only. 
7.5.5.1.3 
Prior and Concomitant Medications 
Medications taken from the informed consent date up to 28 days after the EOT will be coded 
using the latest version of WHODRUG Enhanced during the study, and tabulated by 
treatment group and overall in the SAF, using counts and percentages, separately for: 
• Prior medication: medication that starts before the first dose of study drug, regardless 
of when the medication stops. 
• Concomitant medication: medication first received at or after the first dose of study 
drug, medication received before first dose of study drug and continued after first 
dose, or medication with missing stop date. 
Medication that starts before the first dose of study drug and continued after the first dose 
will be classified as both prior and concomitant medication. Medications with a missing start 
date will be considered to have a start date before the first dose of study drug. Ocular 
medications will be summarized separately for the study eye and fellow eye. 
7.5.5.1.4 
Medical History 
Systemic and ocular medical history data will be listed by subject. 


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7.5.5.1.5 
Study Drug Exposure and Compliance 
Exposure to study drug and dosing compliance will be summarized for the SAF using 
summary statistics. 
The compliance will be summarized by treatment group for the SAF and is calculated as the 
actual number of dosing occasions at which study drug was administered, as a percentage of 
the planned number of dosing occasions. 
7.5.6 Interim Analyses 
The primary analysis of efficacy and all other efficacy and safety analyses will be conducted 
at the Week 8 database lock; ie, after all subjects have completed the Week 8 Visit or have 
been discontinued from the study prior to this visit. Distribution of the Week 8 analysis will 
be restricted only to the IDMC members in order to minimize bias through the end of the 
study. 
An interim analysis of safety, secondary efficacy endpoints, and PK parameters will be 
performed once approximately 200 subjects complete the Week 52 Visit and all subjects 
complete the Week 24 Visit or discontinue early from the study.  
The Week 8 analysis and interim analysis will be performed by an independent biostatistics 
group and results will be distributed to a limited group of recipients, including unmasked 
medical writing staff and limited sponsor representatives. The timing of the Week 8 database 
lock and the interim analysis database lock may coincide depending on subject enrollment 
and data cleaning/programming activities.  
As the primary study endpoint is the bioequivalence comparison at Week 8, no type I error 
adjustments are required as the analysis performed after the Week 8 database lock are 
considered final for the primary efficacy endpoint. No type I error adjustments are planned 
for the secondary efficacy endpoints; therefore, no error adjustments will be performed due 
to the interim analysis as all analyses after the primary analysis at the Week 8 database lock 
are considered secondary analyses. 


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8 
Data Quality Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) 
E6(R2) risk and quality processes described in the applicable procedural documents. The 
quality management approach to be implemented in this study will be documented and will 
comply with the current ICH guidance on quality and risk management. 
8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain accurate eCRFs and source documentation as adequate case histories for the 
subjects treated as part of the research under this protocol. These source documents may 
include laboratory reports, ECG strips, etc. 
Investigative site personnel will enter subject data into an EDC system. The analysis data sets 
will be a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable PPD standards 
and data cleaning procedures to ensure the integrity of the data, eg, removing errors and 
inconsistencies in the data. Adverse event terms will be coded using the MedDRA, an 
internal validated medical dictionary, and concomitant medications will be coded using 
WHODRUG. 
After database lock, each study site will receive a CDROM containing all of their site 
specific eCRF data. 


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9 
Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an 
IRB/IEC before participation of human subjects in research studies. Before study onset, the 
protocol, ICF, advertisements to be used for the recruitment of study subjects, and any other 
written information regarding this study to be provided to the subject must be approved by 
the IRB/IEC. Documentation of all IRB/IEC approvals and of the IRB/IEC compliance with 
ICH harmonised tripartite guideline E6(R2): GCP will be maintained by the site and will be 
available for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
9.3 Subject Information and Consent 
A written informed consent in compliance with regulatory authority regulations (eg, US Title 
21 Code of Federal Regulations [CFR] Part 50) shall be obtained from each subject before 
entering the study or performing any unusual or nonroutine procedure that involves risk to 
the subject. An informed consent template may be provided by the sponsor to investigative 
sites. If any institution-specific modifications to study-related procedures are proposed or 
made by the site, the consent should be reviewed by the sponsor or its designee or both 
before the investigator submits it to the IRB/IEC for review and approval prior to the start of 


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the study. If the ICF is revised during the course of the study, all active participating subjects 
must sign the revised form. 
Before recruitment and enrollment, each prospective subject will be given a full explanation 
of the study and be allowed to read the approved ICF. Once the investigator is assured that 
the subject understands the implications of participating in the study, the subject will be 
asked to give consent to participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the subject. 


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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject, except as necessary for monitoring, inspection by regulatory 
agencies, and auditing by the sponsor, its designee, the FDA, other countries regulatory 
agencies, or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor PPD is financially responsible for 
further treatment of the subject’s disease. 


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10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 8.2 
and Title 21 of the CFR by providing all essential documents. 
10.4 Study Conduct 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
the principles of ICH E6(R2) and all applicable national, state, and local laws, guidelines, or 
regulations. Study information from this protocol will be posted on publicly available clinical 
trial registers before enrollment of subjects begins. 
10.5 Adverse Events and Study Report Requirements 
By participating in this study the investigator agrees to submit reports of SAEs to the sponsor 
and/or IRB/IEC according to the timeline and method outlined in the protocol. In addition, 
the investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 
10.6 Records Retention 
Essential documents should be retained until at least 3 years after the last approval of a 
marketing application in an ICH region or after the completion or formal discontinuation of 
clinical development of the IP, whichever is the longer period. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements 
or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
10.7 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 


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11 Study Management 
11.1 Monitoring 
11.1.1 External Data Monitoring Committee 
An IDMC will be established for the study. Two IDMC meetings will be held: one safety 
meeting will be held approximately 6 months after the IDMC organizational meeting and the 
second safety meeting will be held after all subjects have completed the Week 8 Visit. After 
each meeting, the IDMC will make a recommendation to the sponsor regarding the study to 
continue without change, modify the study or enrollment to be placed on hold, or study 
termination. The sponsor is obligated to inform the study sites, IRB/IEC, and regulatory 
agency of the IDMC recommendations according to country-specific requirements 
(Section 6.6).  
11.1.2 Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals, 
in addition to maintaining necessary telephone and letter contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit or inspection, the investigator agrees to allow the sponsor, 
representatives of the sponsor, or a regulatory agency (eg, FDA) access to all study records. 
The investigator should promptly notify the sponsor and PPD of any audits or inspections 
scheduled by any regulatory authorities and promptly forward copies of any audit or 
inspection reports received to the sponsor. 


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11.2 Management of Protocol Amendments and Deviations 
11.2.1 Protocol Amendments 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC for approval before subjects can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the sponsor for agreement, 
and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant, additional risk to the subject. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, or nonadherence to 
FDA regulations or ICH GCP guidelines, and will lead to the subject being withdrawn from 
the study (Section 4.3). Significant protocol deviations may include below but not limited to 
the following deviations: 
• ICH/GCP deviation 
• Deviation from inclusion/exclusion criteria 
• Deviation on study treatment randomization 
The IRB/IEC should be notified of all protocol deviations in a timely manner. 


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11.3 Study Termination 
Although the sponsor has every intention of completing the study, the sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes the last visit. 
11.4 Final Report 
Upon completion of the interim and final analyses of the study, the investigator, where 
applicable, should inform the institution; the investigator/institution should provide the 
IRB/IEC with a summary report of the study’s outcome and the sponsor and regulatory 
authorities with any reports required. 
The sponsor will ensure that the clinical study reports are prepared and provided to the 
regulatory agencies as required by the applicable regulatory requirements. The sponsor will 
also ensure that the clinical study reports in marketing applications meet the standards of the 
ICH harmonised tripartite guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study reports. 
Upon completion of the clinical study reports, the sponsor will provide the investigator with 
the full summary of the study results. The investigator is encouraged to share the summary 
results with the study subjects, as appropriate. The study results will be posted on publicly 
available clinical trial registers. 


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12 Reference List 
Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al. Systemic 
pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and 
ranibizumab. Retina (Philadelphia, Pa). 2017;37(10):1847-58. 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research, Office of Translational Sciences, Office of Biostatistics 
(US). Statistical Review and Evaluation. Aflibercept ophthalmic solution (VEGF Trap-Eye). 
2011 [cited 2022 Jan 24] [application number 125387Orig1s000]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125387Orig1s000StatR.pdf 
Dixon JA, Oliver SC, Olson JL, Mandava N. VEGF Trap-Eye for the treatment of 
neovascular age-related macular degeneration. Expert Opin Investig Drugs. 
2009;18(10):1573-80. 
European Medicines Agency (EMA). Eylea (aflibercept). An overview of Eylea and why it is 
authorised in the EU. EMA/481361/2018. [cited 2020 Jul 23] Available from: 
https://www.ema.europa.eu/en/documents/overview/eylea-epar-medicine-overview_en.pdf 
Eylea® (aflibercept) Injection, for Intravitreal Use. Full Prescribing Information. Regeneron 
Pharmaceuticals, Inc. August 2019. Available from: 
https://www.regeneron.com/sites/default/files/EYLEA_FPI.pdf 
García-Quintanilla L, Luaces-Rodriguez A, Gil-Martinez M, Mondelo-Garcia C, Maronas O, 
Mangas-Sanjuan V, et al. Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related 
Macular Degeneration. Pharmaceutics. 2019;11(8). 
Kanda A, Noda K, Saito W, Ishida S. Aflibercept Traps Galectin-1, an Angiogenic Factor 
Associated with Diabetic Retinopathy. Sci Rep. 2015;5:17946. 
Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, et al. Binding and 
neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF 
Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171-85. 
Santen Pharmaceutical Co., Ltd. Intravitreal VEGF Inhibitor “EYLEA® (aflibercept) 
Solution for Intravitreal Injection” Released on the Market for the Treatment of Wet Age-


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Related Macular Degeneration. 2012 News release (Japan). Available from: 
https://www.santen.com/en/news/20121127_2.pdf  
Schneider U, Gelisken F, Inhoffen W. Natural course of occult choroidal neovascularization 
in age-related macular degeneration: development of classic lesions in fluorescein 
angiography. Acta Ophthalmol Scand. 2005;83(2):141-7. 


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13 Appendices 
13.1 Appendix 1: Slit Lamp Examination - Grading Scale 
Grading Scheme 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) 
Source: Jabs DA, Nussenblatt RB, Rosenbaum JT, et al., Standardization of uveitis nomenclature for 
reporting clinical data. Results of the First International Workshop, Am J Ophthalmol, 2005;140:509–16. 
 
Grading Scheme for Anterior Chamber Cells 
Grade 
Number of Cells 
0 
<1 
0.5+ 
1-5 
1+ 
6–15 
2+ 
16–25 
3+ 
26–50 
4+ 
>50 
Source: Jabs DA, Nussenblatt RB, Rosenbaum JT, et al., Standardization of uveitis nomenclature for 
reporting clinical data. Results of the First International Workshop, Am J Ophthalmol, 2005;140:509–16. 
 


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13.2 Appendix 2: Assessment of Vitreous Cells - Grading Scale 
Grade 
Description 
0 
Clear 
Trace 
Few opacities 
1 
Scattered opacities 
2 
Moderate opacities 
3 
Many opacities 
4 
Dense opacities 
Source: Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: fundamentals and clinical practice. 2nd rev. ed. 
New York:Mosby, 1996, p. 64. 
 
Grading Scheme for Vitreous Haze 
Grade 
Description 
Cells in Retro-Illuminated Field 
0 
Nil 
None 
1 
Minimal 
Posterior pole clearly visible 
2 
Mild 
Posterior pole details slightly hazy 
3 
Moderate 
Posterior pole details very hazy 
4 
Marked 
Posterior pole details barely visible 
5 
Severe 
Fundal details not visible 
Source: Nussenblatt RB, Palestine AG, Chan CC, et al., Standardization of vitreal inflammatory activity in 
intermediate and posterior uveitis, Ophthalmology, 1985;92:467–71. 


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14 Protocol Amendment 
14.1 Protocol Amendment, Version 3.0, 24 January 2022 
This global protocol amendment is considered substantial for the following reasons because 
they represent significant changes to the study conduct: 
1. An interim analysis is planned to be performed once approximately 200 subjects 
complete the Week 52 Visit and once all planned (approximately 560) treated subjects 
complete Week 24 Visit or discontinue early from the study. The purpose of the 
interim analysis is to support regulatory filing to the PMDA.  
2. Text regarding the IDMC analyses has been updated to reflect that the IDMC will 
meet throughout the study and not only when all subjects complete the Week 8 Visit.  
The amendment also incorporates the changes that were explained in protocol clarification 
letters dated 18 December 2020 and 29 April 2021, and the details to include the causality 
assessment of AEs for an IVT injection procedure. 
Additions to the protocol text are shown in bold and deletions are shown in strikethrough 
text. Minor editorial and administrative changes and grammatical corrections are not 
specified.  
Chapter/Section  
Initial Wording 
Amended or New Wording 
Reason/Justification 
for Change 
Synopsis 
(Exclusion 
Criteria); 4.1.2 
Exclusion Criteria 
29. History or evidence of 
cardiac conditions including 
congestive cardiac failure 
leading to marked limitation 
on physical activity, or 
inability to perform any 
physical activity without 
discomfort, ventricular 
arrhythmia requiring ongoing 
treatment, and atrial 
fibrillation 
29. History or evidence of 
cardiac conditions including 
with congestive cardiac failure 
leading to resulting in marked 
limitation on physical activity, 
or inability to perform any 
physical activity without 
discomfort,; subjects with 
ventricular arrhythmia requiring 
ongoing treatment, and; or 
subjects with atrial fibrillation 
To clarify the 
exclusion criterion 
for subjects with a 
history or evidence of 
cardiac conditions.  
Synopsis (Study 
Design) 
This is a Phase III, 
randomized, parallel-group, 
double-masked, multicenter 
This is a Phase III, randomized, 
double-masked, parallel-group, 
double-masked, multicenter 
study in to demonstrate 
biosimilarity of SCD411 
To be consistent with 
Section 3.1. 


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Reason/Justification 
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study in adult subjects with 
neovascular (wet) AMD 
compared to Eylea 
(aflibercept) among adult 
subjects with neovascular (wet) 
AMD 
Synopsis 
(Immunogenicity 
Assessments); 
2.4.2 Secondary 
Endpoints 
Immunogenicity assessments 
and endpoints include the 
evaluation of development of 
anti-SCD411 antibodies 
using blood samples taken at 
Baseline, at Weeks 4, 8, 20, 
36, and 52. 
Immunogenicity assessments 
and endpoints include the 
evaluation of development of 
anti-SCD411 or 
anti-aflibercept antibodies 
using blood samples taken at 
Baseline, at Weeks 4, 8, 20, 36, 
and 52. 
To be consistent with 
Section 6.5. 
Synopsis (Rescue 
Treatment) 
Subjects who will receive 
rescue treatment need to 
discontinue the study 
treatment and should have 
the reason for treatment 
discontinuation documented 
on the Treatment 
Discontinuation page of the 
eCRF and continue with their 
regularly scheduled visits. 
Subjects who will receive rescue 
treatment need to discontinue 
the study treatment and should 
have the reason for treatment 
discontinuation documented on 
the Treatment Discontinuation 
page of the eCRF and continue 
with their regularly scheduled 
visits and assessments until 
Week 52 except for study 
treatment administration. 
To be consistent with 
other protocol 
sections. 
Synopsis (Sample 
Size) 
Considering approximately 
5% loss from Day 1 through 
Week 8, the total sample size 
required is 560. 
Considering approximately 5% 
loss from Day 1randomization 
through Week 8, the total 
sample size required is 560. 
To be consistent with 
Section 7.2. 
Synopsis 
(Analysis Sets); 
7.3 Analysis Sets 
- 
Modified FAS (mFAS): all 
randomized subjects who 
received at least 1 injection of 
the study drug and had at least 
1 postbaseline BCVA 
assessment in the study eye. 
To be in line with the 
SAP.  
The primary set for efficacy 
analysis will be the FAS; 
however, for the EMA 
submission, the primary 
efficacy endpoint must meet 
equivalence for both the FAS 
and PPS sets. 
The primary set for efficacy 
analysis will be the FAS; 
however, for the EMA 
submission, the primary efficacy 
endpoint must meet equivalence 
for both the FAS and PPS sets. 
PMDA also requires an 
efficacy analysis to be 
conducted based on the mFAS 
without multiple imputation 
(MI) as a supportive analysis. 


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Chapter/Section  
Initial Wording 
Amended or New Wording 
Reason/Justification 
for Change 
Synopsis 
(Statistical 
Methods); 7.5.1.1 
Primary Efficacy 
Outcome 
Measures 
The model will include the 
change from baseline as the 
dependent variable; treatment 
and visit as fixed effects, and 
baseline BCVA as a 
covariate. 
The model will include the 
change from baseline as the 
dependent variable; treatment, 
visit, and visit-by-treatment as 
fixed effects, and baseline 
BCVA as a covariate. 
To be in line with the 
SAP. 
Synopsis 
(Statistical 
Methods) 
Secondary Analyses: 
The estimated mean 
treatment difference in the 
change from baseline in 
BCVA as measured by 
ETDRS letter score or 2702 
charts through 52 weeks 
along with the corresponding 
90% and 95% CIs from the 
same MMRM model as used 
in the primary analysis will 
be presented for the FAS and 
PPS. As per the Week 8 
analyses, the primary 
analysis will be performed 
using multiple imputed data 
under the MAR assumptions 
with post rescue assessments 
set to missing prior to 
imputation. The estimated 
mean treatment difference at 
each visit along with the 
corresponding 90% and 95% 
CIs will also be presented. 
Raw values and changes 
from baseline will be 
summarized by treatment 
group using descriptive 
statistics. 
The analysis of change from 
baseline in CRT as assessed 
by OCT or change from 
baseline in CNV will be 
based on a MMRM model 
similar to the one used for 
the analysis of change from 
baseline in BCVA, with the 
corresponding 95% CI for 
the estimates of treatment 
Secondary Analyses: 
The estimated mean treatment 
difference in the change from 
baseline in BCVA as measured 
by ETDRS letter score or 2702 
charts through 52 weeks along 
with the corresponding 90% and 
95% CIs from the same MMRM 
model as used in the primary 
analysis but including data 
from all weeks through Week 
52 will also be presented for the 
FAS and PPS. As per the done 
for Week 8 analyses, the 
primary, analysis will be 
performed using multiple 
imputed data under the MAR 
assumptions with, where post 
rescue assessments have been 
set to missing prior to while 
including the post rescue 
assessments in the imputation. 
The estimated mean treatment 
difference at each visit along 
with the corresponding 90% and 
95% CIs will also be presented 
model. Raw values and changes 
from baseline will be 
summarized by treatment group 
using descriptive statistics for 
each visit. 
The analysis of change from 
baseline in CRT as assessed by 
OCT or change from baseline in 
CNV will be based on a the 
MMRM model similar to the 
one used for the analysis of 
change from baseline in BCVA, 
with the corresponding 95% CI 
To be consistent with 
Section 7.5.1.2. 


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Chapter/Section  
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Reason/Justification 
for Change 
differences at Week 8 and 
Week 52 will be presented. 
Raw values and changes 
from baseline will be 
summarized by treatment 
group using descriptive 
statistics. Multiple 
imputation will not be 
performed. Data after the 
receipt of rescue therapy will 
be set to missing prior to 
analysis. 
The percentage of subjects 
who gain ≥15 letters in 
BCVA as measured by 
ETDRS letter score or 2702 
charts at postbaseline visits 
(Week 8 and Week 52) 
compared with baseline will 
be summarized and 95% CI 
for the proportions in each 
treatment arm and difference 
in proportions between 
treatment arms will be 
presented. For subjects who 
have missing assessments at 
corresponding postbaseline 
visits or received rescue 
therapy prior to visit, will be 
assumed to have a gain 
<15 letters in BCVA (eg, 
nonresponder imputation). 
for the estimates of treatment 
differences at Week 8 and Week 
52 will be presented. Raw values 
and changes from baseline will 
be summarized by treatment 
group using descriptive 
statistics. Multiple imputation 
will not be performed. Data after 
the receipt of rescue therapy will 
be set to missing prior to the 
MMRM analysis. Multiple 
imputation will not be 
performed and no sensitivity 
analyses will be performed. 
The percentage of subjects who 
gain ≥15 letters in BCVA as 
measured by ETDRS letter score 
or 2702 charts at postbaseline 
visits (Week 8 and Week 52) 
compared with baseline will be 
summarized and 95% CI for the 
proportions in each treatment 
arm and difference in 
proportions between treatment 
arms will be presented. For 
subjects who have missing 
assessments at corresponding 
postbaseline visits or who 
received rescue therapy prior to 
a visit, will be assumed to have 
a gain of <15 letters in BCVA 
(eg, nonresponder imputation). 
No sensitivity analyses will be 
performed. 
Synopsis 
(Statistical 
Methods) 
Immunogenicity Analysis 
The analysis on 
immunogenicity will be 
descriptive. Results will be 
summarized with observed 
values and change from 
baseline for titers (in log 
scale) ADA for the SAF. The 
number and proportion of 
ADA-positive subjects and 
ADA-negative subjects will 
be summarized for each 
assessment time point. NAb 
will be tested when ADA 
Immunogenicity Analysis 
The analysis on immunogenicity 
will be descriptive. Results will 
be summarized with observed 
values and change from baseline 
for ADA titers (in log scale) 
ADA for by treatment group 
in the SAF. The number and 
proportion of ADA-positive 
subjects and ADA-negative 
subjects will be summarized by 
treatment group for each 
assessment time point. NAb will 
be tested when ADA results are 
To be consistent with 
text elsewhere in the 
protocol. 


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Amended or New Wording 
Reason/Justification 
for Change 
results are confirmed to be 
positive. The number and 
proportion of NAb subjects 
will be summarized by 
treatment group for each 
assessment time point. 
confirmed to be positive. The 
number and proportion of NAb 
subjects will be summarized by 
treatment group for each 
assessment time point. 
Synopsis 
(Statistical 
Methods) 
- 
Interim Analyses  
An interim analysis of safety, 
secondary efficacy endpoints, 
and PK parameters will be 
performed once approximately 
200 subjects complete the 
Week 52 Visit and all subjects 
complete the Week 24 Visit or 
discontinue early from the 
study.  
The Week 8 analysis and 
interim analysis will be 
performed by an independent 
biostatistics group and results 
will be distributed to a limited 
group of recipients, including 
unmasked medical writing 
staff and limited sponsor 
representatives. The timing of 
the Week 8 database lock and 
the interim analysis database 
lock may coincide depending 
on subject enrollment and 
data cleaning/programming 
activities. 
To add an interim 
analysis to support 
regulatory filing to 
the PMDA. 
1.1 Background 
• 
A higher affinity (~ 0.5 
pM dissociation constant 
for VEGF165 and 
VEGF121) than a 
humanized monoclonal 
antibody (Papadopoulos 
et al 2012; García-
Quintanilla et al 2019) 
• 
A higher affinity (~0.5 pM 
dissociation constant for 
VEGF165 and ~0.36 pM 
for VEGF121) than a 
humanized monoclonal 
antibody (Papadopoulos et 
al 2012; García-Quintanilla 
et al 2019) 
To be consistent with 
the investigator 
brochure, version 3.0. 
3.1 Study Design 
This is a Phase III, 
randomized, double-masked, 
parallel-group, multicenter 
study to demonstrate 
biosimilarity of SCD411 
This is a Phase III, randomized, 
double-masked, parallel-group, 
multicenter study to demonstrate 
biosimilarity of SCD411 
compared to Eylea (aflibercept) 
To be consistent with 
synopsis. 


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for Change 
compared to Eylea 
(aflibercept) among adult 
subjects with wet AMD. 
among adult subjects with 
neovascular (wet) AMD. 
The study design 
incorporates an Independent 
Data Monitoring Committee 
(IDMC) that will review 
ongoing safety and will also 
make recommendations to 
the sponsor as described in 
the IDMC Charter. Details of 
the IDMC are given in 
Section 6.6. 
The study design incorporates an 
Independent Data Monitoring 
Committee (IDMC) that will 
review ongoing safety and will 
also make recommendations to 
the sponsor as described in the 
IDMC Charter. Details of the 
IDMC are given in Section 6.6.  
An interim analysis will be 
performed once approximately 
200 subjects complete the 
Week 52 Visit and all subjects 
complete the Week 24 Visit or 
discontinue early from the 
study. Details of the interim 
analysis are given in 
Section 7.5.6. 
To add an interim 
analysis to support 
regulatory filing to 
the PMDA. 
5.1 Method of 
Assigning 
Subjects to 
Treatment Groups 
• 
During the 4-week 
intervals dosing: 
assessment and dosing 
can be done within a 
window of ±2 days. In 
this case, the interval 
between the 2 doses 
should not be less than 
24 days and more than 
32 days. If the subject 
visit window is out of 
the allowed window 
interval, dosing should 
be skipped. 
• 
During the 4-week intervals 
dosing: assessment and 
dosing can be done within a 
window of ±2 days. In this 
case, the interval between 
the 2 doses should not be 
less than 24 days and more 
than 32 days. If the subject 
IP dosing visit window is 
out of the allowed window 
interval, dosing should be 
skipped.  
To clarify the text in 
alignment with the 
specification of IP 
dosing. 
5.8.1 Rescue 
Treatment 
If a subject chooses to 
withdraw from the study or 
if, in the opinion of the 
investigator, the subject 
should be prematurely 
withdrawn, then the ET Visit 
should be completed as soon 
as possible after 
discontinuing the study 
treatment but no later than 28 
days after discontinuation. 
If a subject chooses to withdraw 
from the study or if, in the 
opinion of the investigator, the 
subject should be prematurely 
withdrawn from the study, then 
the ET Visit should be 
completed as soon as possible 
after discontinuing the study 
treatment but no later than 28 
days after discontinuation. 
To clarify the text 
throughout.  


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5.8.2 Prohibited 
Medications 
Concurrent use of systemic 
or IVT anti-VEGF agents; 
IVT, subtenon, or peribulbar 
corticosteroids in study eye, 
except as required to treat 
AEs. 
Concurrent use of systemic or 
IVT anti-VEGF agents; IVT, 
subtenon, or peribulbar 
corticosteroids in study eye are 
not permitted, except as 
required to treat AEs. 
To clarify the text. 
Table 5-1: 
Prohibited 
Medications 
Topiramate (duration of 
prohibition): 4 weeks prior to 
screening and throughout the 
study period 
Amiodarone (duration of 
prohibition): 12 weeks prior 
to screening and throughout 
the study period 
Topiramate (duration of 
prohibition): 4 weeks prior to 
screening randomization and 
throughout the study period 
Amiodarone (duration of 
prohibition): 12 weeks prior to 
screening randomization and 
throughout the study period 
To be consistent with 
exclusion criterion 
34. 
Table 6-1: 
Schedule of 
Events 
Study Day: 199 
Study Day: 199197 
Per calculation, a 
correction was made 
for the study day of 
the Week 28 Visit. 
l 
At screening, FA 
and FP will be performed on 
both eyes and those images 
will be sent to the central 
reading center. At Week 8 
and ET/EOS, FA and FP will 
be performed on the study 
eye prior to IVT injection of 
the study drug. 
l 
At screening, FA and 
FP will be performed on both 
eyes and those images will be 
sent to the central reading 
center. At Week 8 and ET/EOS, 
FA and FP will be performed on 
the study eye (prior to IVT 
injection of the study drug at 
Week 8). 
To clarify the time 
point. 
6.1.3 Early 
Termination/End-
of-Study 
End-of-Study Visit 
assessments will be 
conducted 28 days after the 
end of treatment for Week 
52. 
End of Study Visit assessments 
will be conducted 28 days after 
the EOT at end of treatment for 
Week 52. 
To clarify the text 
throughout. 
6.2.2.2 
Fluorescein 
Angiography and 
Fundus 
Photography 
At screening, FA and FP will 
be performed on both eyes 
and those images will be sent 
to the central reading center. 
At Week 8 and ET/EOS 
Visit, FA and FP will be 
performed on the study eye 
prior to IVT injection of the 
study drug and those images 
will be sent to the central 
reading center. 
At screening, FA and FP will be 
performed on both eyes and 
those images will be sent to the 
central reading center. At 
Week 8 and ET/EOS Visit, FA 
and FP will be performed on the 
study eye (prior to IVT injection 
of the study drug at Week 8) 
and those images will be sent to 
the central reading center. 
To clarify the time 
point. 


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6.3.3.1 Definitions 
of Adverse Events 
The investigator is 
responsible for reporting all 
AEs that are observed or 
reported during the study, 
regardless of their 
relationship to study drug or 
their clinical significance. 
The investigator is responsible 
for reporting all AEs that are 
observed or reported during the 
study, regardless of their 
relationship to study drug or to 
IVT injection procedure or 
their clinical significance. 
To include an 
assessment of AEs 
for IVT injection 
procedure. 
An AE is defined as any 
untoward medical occurrence 
in a subject enrolled into this 
study regardless of its causal 
relationship to study drug. 
An AE is defined as any 
untoward medical occurrence in 
a subject enrolled into this study 
regardless of its causal 
relationship to study drug or to 
IVT injection procedure. 
6.3.3.4 Reporting 
Adverse Events 
• 
investigator-specified 
assessment of severity 
and relationship to study 
drug 
• 
investigator-specified 
assessment of severity and 
relationship to study drug 
and to IVT injection 
procedure 
To include an 
assessment of AEs 
for IVT injection 
procedure. 
6.3.3.8 
Assessment of 
Causality 
The investigator’s 
assessment of an AE’s 
relationship to study drug is 
part of the documentation 
process, but it is not a factor 
in determining what is or is 
not reported in the study. 
The investigator’s assessment of 
an AE’s relationship to study 
drug and IVT injection 
procedure is part of the 
documentation process, but it is 
not a factor in determining what 
is or is not reported in the study. 
To include an 
assessment of AEs 
for IVT injection 
procedure. 
Unrelated: This relationship 
suggests that there is no 
association between the study 
drug and the reported event. 
Related: This relationship 
suggests that there is an 
association between the study 
drug and the reported event. 
Unrelated: This relationship 
suggests that there is no 
association between the study 
drug or the IVT injection 
procedure and the reported 
event. 
Related: This relationship 
suggests that there is an 
association between the study 
drug or the IVT injection 
procedure and the reported 
event. 
6.3.5 Vital Signs 
On injection visits, vital signs 
will be measured prior to 
IVT injection of the study 
drug.  
On injection visits, vital signs 
will be measured prior to IVT 
injection of the study drug. Vital 
signs will also be performed at 
any time during the ET/EOS 
Visit.  
To be consistent with 
footnote n of the 
Table 6-1. 


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6.4 
Pharmacokinetic 
Assessments 
Quantification of free and 
bound SCD411 and 
aflibercept will be performed 
for subjects who agree to 
participate in the PK 
substudy using blood 
samples drawn at predose, 
and at +1 day, +3 days, 
+7 days, +14 days, and 
+28 days following the first 
and the third injection.  
Quantification of free and bound 
SCD411 and aflibercept will be 
performed for subjects who 
agree to participate in the PK 
substudy using blood samples 
drawn at predose, and at +1 day, 
+3 days, +7 days, +14 days, and 
+28 days following the first and 
the third injection (Week 8).  
To be consistent with 
footnote p of the 
Table 6-1. 
6.6 Independent 
Data Monitoring 
Committee 
An IDMC meeting will be 
held after all subjects have 
completed Week 8 Visit. 
From this meeting, the IDMC 
members will make a 
decision to continue the 
study without change, 
modify study, or study 
termination. Any decision to 
terminate the study will be 
based on clinical judgment 
only and no formal stopping 
rules are defined. The 
sponsor is obligated to 
inform the study sites, 
IRB/IEC and Competent 
Authorities of the IDMC 
recommendations according 
to country specific 
requirements. 
An Two IDMC meeting 
meetings will be held: one 
safety meeting will be held 
approximately 6 months after 
the IDMC organizational 
meeting and the second safety 
meeting will be held after all 
subjects have completed the 
Week 8 Visit. From this meeting 
After each meeting, the IDMC 
members will make a decision to 
continue the study without 
change, modify the study or 
enrollment to be placed on 
hold, or study termination. Any 
decision to terminate the study 
will be based on clinical 
judgment only and no formal 
stopping rules are defined. The 
sponsor is obligated to inform 
the study sites, IRB/IEC and 
Competent Authorities of the 
IDMC recommendations 
according to country-specific 
requirements. 
To reflect the 
addition of an interim 
analysis. 
7 Statistical and 
Analytical Plan 
Details for all endpoint 
analyses will be provided in 
the final statistical analysis 
plan (SAP), which will be 
finalized prior to the database 
lock. 
Details for all endpoint analyses 
will be provided in the final 
statistical analysis plan (SAP), 
which will be finalized prior to 
the Week 8 and interim 
database lock. 
To add an interim 
analysis to support 
regulatory filing to 
the PMDA. 
7.2 Sample Size 
Determination 
Standard deviation (SD) for 
the mean change from 
baseline at early visits 
(Weeks 4 to 12) based on 
observed data for the FAS 
Standard deviation (SD) for the 
mean change from baseline at 
early visits (Weeks 4 to 12) 
based on observed data for the 
FAS ranged from and 8.73 to 
To insert the correct 
reference. 


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Chapter/Section  
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Amended or New Wording 
Reason/Justification 
for Change 
ranged from and 8.73 to 
11.99 considering all 
treatment groups from 
VIEW1 and from 7.4 to 11.0 
letters for the VIEW2 study 
(Eylea Statistical Review, 
Appendix Tables A.1 and 
A.2). 
11.99 considering all treatment 
groups from VIEW1 and from 
7.4 to 11.0 letters for the VIEW2 
study (DHHS 2011 [Eylea 
Statistical Review, Appendix 
Tables A.1 and A.2]). 
7.5.1.1 Primary 
Efficacy Outcome 
Measures 
- 
Supportive analysis for the 
primary endpoint will be 
performed based on the mFAS 
per the PMDA’s request. Data 
after receipt of rescue therapy 
will be set to missing without 
employing MI. Both the 
MMRM and ANCOVA 
analyses will be performed 
using the non-imputed data. 
To be in line with the 
SAP. 
7.5.1.2 Secondary 
Efficacy Outcome 
Measures 
The estimated mean 
treatment difference in the 
change from baseline in 
BCVA as measured by 
ETDRS letter score through 
52 weeks along with the 
corresponding 90% and 95% 
CIs from the same MMRM 
model as used in the primary 
analysis but including data 
from all weeks through Week 
52 will also be presented. 
The estimated mean treatment 
difference in the change from 
baseline in BCVA as measured 
by ETDRS letter score or 2702 
charts through 52 weeks along 
with the corresponding 90% and 
95% CIs from the same MMRM 
model as used in the primary 
analysis but including data from 
all weeks through Week 52 will 
also be presented for the FAS 
and PPS. 
To be consistent with 
the text in the 
synopsis.  
The percentage of subjects 
who gain ≥15 letters in 
BCVA as measured by 
ETDRS letter score at 
postbaseline visits (Week 8 
and Week 52) compared with 
baseline will be summarized 
and 95% CI for the 
proportions in each treatment 
arm and difference in 
proportions between 
treatment arms will be 
presented. 
The percentage of subjects who 
gain ≥15 letters in BCVA as 
measured by ETDRS letter score 
or 2702 charts at postbaseline 
visits (Week 8 and Week 52) 
compared with baseline will be 
summarized and 95% CI for the 
proportions in each treatment 
arm and difference in 
proportions between treatment 
arms will be presented. 
7.5.6 Interim 
Analyses 
No interim analyses are 
planned for this study. The 
primary analysis of efficacy 
and all other efficacy and 
No interim analyses are planned 
for this study. The primary 
analysis of efficacy and all other 
efficacy and safety analyses will 
To add an interim 
analysis to support 
regulatory filing to 
the PMDA. 


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Chapter/Section  
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Reason/Justification 
for Change 
safety analyses will be 
conducted at the Week 8 
database lock; ie, after all 
subjects have completed the 
Week 8 Visit or have been 
discontinued from the study 
prior to this visit. 
Distribution of the Week 8 
analysis will be restricted 
only to the IDMC members 
in order to minimize bias 
through the end of the study. 
be conducted at the Week 8 
database lock; ie, after all 
subjects have completed the 
Week 8 Visit or have been 
discontinued from the study 
prior to this visit. Distribution of 
the Week 8 analysis will be 
restricted only to the IDMC 
members in order to minimize 
bias through the end of the 
study. 
An interim analysis of safety, 
secondary efficacy endpoints, 
and PK parameters will be 
performed once approximately 
200 subjects complete the 
Week 52 Visit and all subjects 
complete the Week 24 Visit or 
discontinue early from the 
study.  
The Week 8 analysis and 
interim analysis will be 
performed by an independent 
biostatistics group and results 
will be distributed to a limited 
group of recipients, including 
unmasked medical writing 
staff and limited sponsor 
representatives. The timing of 
the Week 8 database lock and 
the interim analysis database 
lock may coincide depending 
on subject enrollment and 
data cleaning/programming 
activities.  
As the primary study endpoint 
is the bioequivalence 
comparison at Week 8, no type 
I error adjustments are 
required as the analysis 
performed after the Week 8 
database lock are considered 
final for the primary efficacy 
endpoint. No type I error 
adjustments are planned for 
the secondary efficacy 
endpoints; therefore, no error 
adjustments will be performed 


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Chapter/Section  
Initial Wording 
Amended or New Wording 
Reason/Justification 
for Change 
due to the interim analysis as 
all analyses after the primary 
analysis at the Week 8 
database lock are considered 
secondary analyses. 
11.1.1 External 
Data Monitoring 
Committee 
An IDMC will be established 
for the study. An IDMC 
meeting will be held after all 
subjects have completed 
Week 8 Visit. From this 
meeting, the IDMC will 
make a recommendation to 
the sponsor regarding the 
study to continue without 
change, modify study or 
enrollment to be placed on 
hold, or study termination. 
An IDMC will be established for 
the study. An Two IDMC 
meeting meetings will be held: 
one safety meeting will be held 
approximately 6 months after 
the IDMC organizational 
meeting and the second safety 
meeting will be held after all 
subjects have completed the 
Week 8 Visit. From this meeting 
After each meeting, the IDMC 
will make a recommendation to 
the sponsor regarding the study 
to continue without change, 
modify the study or enrollment 
to be placed on hold, or study 
termination. 
To reflect the 
addition of an interim 
analysis. 
11.4 Final Report 
Upon completion of the 
study, the investigator, where 
applicable, should inform the 
institution; the 
investigator/institution 
should provide the IRB/IEC 
with a summary report of the 
study’s outcome and the 
sponsor and regulatory 
authorities with any reports 
required. 
Upon completion of the interim 
and final analyses of the study, 
the investigator, where 
applicable, should inform the 
institution; the 
investigator/institution should 
provide the IRB/IEC with a 
summary report of the study’s 
outcome and the sponsor and 
regulatory authorities with any 
reports required. 
To reflect the 
addition of an interim 
analysis.  
12 Reference List 
- 
Department of Health and 
Human Services (DHHS), 
Food and Drug 
Administration, Center for 
Drug Evaluation and 
Research, Office of 
Translational Sciences, Office 
of Biostatistics (US). Statistical 
Review and Evaluation. 
Aflibercept ophthalmic 
solution (VEGF Trap-Eye). 
2011 [cited 2022 Jan 24] 
[application number 
125387Orig1s000]. Available 
To insert the correct 
reference. 


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Chapter/Section  
Initial Wording 
Amended or New Wording 
Reason/Justification 
for Change 
from: 
https://www.accessdata.fda.go
v/drugsatfda_docs/nda/2011/1
25387Orig1s000StatR.pdf 
Throughout 
- 
Editorial and administrative 
changes, typographical error 
corrections, and document 
formatting revisions. 
To improve the 
readability and 
overall quality of the 
document. 
14.2 Protocol Amendment, Version 2.0, 24 November 2020 
This global protocol amendment is considered substantial mainly for the following reasons. 
The amendment incorporated the changes that had been updated in the country-specific 
protocol amendments, including the Slovakia- and Korea-specific protocol amendments, as 
per the requests from the regulatory agencies in both countries. Additionally, the amendment 
incorporated the recommendations from the US FDA to 1) change the FAS population and 2) 
keep subjects in the study to continue with their regularly scheduled visits and assessments 
until Week 52 after study treatment discontinuation. To meet these recommendations, the 
analysis sets and statistical methods were changed. In addition, treatment of fellow eye was 
allowed during the whole duration of the study. These revisions are considered substantial 
because they represent significant changes to the study conduct. Additional non-substantial 
changes were made for clarity. 
Additions to the protocol text are shown in bold, and deletions are shown in strikethrough 
text. Minor editorial and grammatical corrections are not specified. Any notes for the section 
are included in brackets. 
Initial Wording 
Amended or New Wording 
Reason/Justification for Change 
Chapter/section concerned 
Section 2.5 Estimands 
 
The estimand for the primary 
objective is the mean treatment 
difference for BCVA change from 
baseline at Week 8. At Week 52, 
the estimand of interest is the 
mean treatment difference for 
BCVA change from baseline at 
Week 52. 
The primary estimand for the 
primary objective is the mean 
treatment difference for in BCVA 
change from baseline at Week 8. 
At Week 52, the primary 
estimand of interest is the mean 
treatment difference for BCVA 
change from baseline at Week 52. 
For the primary estimands, any 
observations post receipt of 
rescue therapy in the study eye 
will be set to missing, thereby 
The section of estimands has been 
revised as per the US FDA 
requirement of changing the FAS 
population and the 
recommendation to not 
discontinue subjects from the 
study when they discontinue study 
treatment. 


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estimating treatment effect as 
though subjects do not receive 
rescue therapy. For each of the 
Week 8 and Week 52 analyses, 
the secondary estimand will be 
presented where post rescue will 
not be set to missing but will be 
included in the mixed-effects 
model for repeated measures 
(MMRM) analysis. The 
secondary estimands are 
constructed to estimate the 
treatment effect while including 
the impact of rescue therapy, 
which may better reflect actual 
real-world outcomes where 
rescue would likely be given 
when lack of efficacy is seen. 
Chapter/section concerned 
Section 3.1 Study Design 
... 
Approximately 560 subjects with 
wet AMD will be enrolled in this 
study across approximately 155 
sites in 14 countries. Upon entry 
into the study, subjects will be 
assigned a screening number. 
Subjects who meet all inclusion 
and none of the exclusion criteria 
will return to the clinic on Day 1 
for further evaluation. Subjects 
who continue to meet all inclusion 
and none of the exclusion criteria 
will be randomly assigned and 
treated on Day 1. At this visit, the 
subjects will be randomly 
assigned in 1:1 ratio to receive 
IVT SCD411 or aflibercept 
injections. Randomization will be 
stratified by subject participation 
in the PK substudy. Subjects will 
be treated with study treatment 
every 4 weeks for the first 3 
injections and every 8 weeks 
thereafter until Week 48 as 
detailed in the Schedule of Events 
(Table 6-1). A schematic of the 
study design is presented in 
Figure 3-1. The details of the 
implementation in Interactive 
... 
Approximately 560 subjects with 
wet AMD will be enrolled in this 
study across approximately 155 
sites in 14 countries. Upon entry 
into the study, subjects will be 
assigned a screening number. 
Subjects who meet all inclusion 
and none of the exclusion criteria 
will return to the clinic on Day 1 
for further evaluation. Subjects 
who continue to meet all inclusion 
and none of the exclusion criteria 
will be randomly assigned and 
treated on Day 1. At this visit, the 
subjects will be randomly 
assigned in 1:1 ratio to receive 
IVT SCD411 or aflibercept 
injections. Randomization will be 
stratified by subject participation 
in the PK substudy. Subjects in 
Israel will not participate in the 
PK substudy. Randomization 
will also be stratified by 
subjects enrolled in Japan. ... 
... 
All subjects will be assessed once 
every 4 weeks as detailed in the 
Schedule of Events (Table 6-1). 
The End-of-Treatment (EOT) 
Visit will be scheduled for 
Week 48. Subjects who 
The PK substudy in Israel was 
clarified as per the request from 
the Israel regulatory agency. 
 
Stratification by subjects in Japan 
has been added to the protocol as 
per sponsor’s decision. 
 
The paragraph on study treatment 
discontinuation has been updated 
as per the US FDA 
recommendation to minimize 
missing data by keeping subjects 
who discontinue study treatment 
in the study to continue with 
regularly scheduled visits, so that 
their efficacy and safety data after 
treatment discontinuation can be 
collected to support sensitivity 
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Response Technology (IRT) will 
be provided in the IRT manual and 
the randomization specification 
form. 
... 
All subjects will be assessed once 
every 4 weeks as detailed in the 
Schedule of Events (Table 6 1). 
Subjects who discontinue the 
study treatment should be 
encouraged to return for the Early 
Termination (ET) Visit as soon as 
possible after discontinuing the 
treatment but no later than 28 days 
after discontinuation. The End-of-
Study (EOS) Visit will occur 28 
days after the end of treatment. 
The end of the study is defined as 
the date of the last visit of the last 
subject in the study. 
discontinue the study treatment 
early should have the reasons 
for treatment discontinuation 
documented on the Treatment 
Discontinuation page of the 
electronic case report form 
(eCRF). Treatment 
discontinuation in the study was 
defined as subjects 
discontinuing the study 
treatment due to adverse 
event/lack of efficacy/rescue 
treatment but not limited to 
these conditions. Every effort 
should be made to have such 
subjects remain in the study and 
continue with their regularly 
scheduled visits and assessments 
until Week 52 except for study 
treatment administration. If a 
subject chooses to withdraw 
from the study or if, in the 
opinion of the investigator the 
subject should be prematurely 
withdrawn, then should be 
encouraged to return for the Early 
Termination (ET) Visit should be 
completed as soon as possible 
after discontinuing the treatment 
but no later than 28 days after 
discontinuation. The End-of-
Study (EOS) Visit will occur 28 
days after the end of treatment for 
Week 52. The end of the study is 
defined as the date of the last visit 
of the last subject in the study. 
Chapter/section concerned 
Section 4.1.1 Inclusion Criteria 
 
3. Active choroidal 
neovascularization lesions 
secondary to AMD evidenced by 
fluorescein angiography (FA) in 
the study eye at screening and 
confirmed by the central reading 
center. 
... 
... 
3. Active choroidal subfoveal, 
juxtafoveal, or extrafoveal 
neovascularization lesions 
secondary to AMD evidenced by 
fluorescein angiography (FA) in 
the study eye at screening and 
confirmed by the central reading 
center 
... 
7. The area of CNV making up 
either 50% or more of the total 
lesion area and confirmed by 
the central reading center. 
Inclusion criterion (IC) #3 has 
been updated by adding the range 
of choroidal neovascular lesions 
as per the request from the Korean 
Ministry of Food and Drug Safety 
(MFDS), which has been 
incorporated into the 
Korea-specific protocol 
amendment. 
 
IC#7 was added as per the request 
from the Korean MFDS to clarify 
that CNV should be either 50% or 
more of the total lesion area in the 


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inclusion criteria. This change has 
been applied to the Korea-specific 
protocol amendment. 
Chapter/section concerned 
Section 4.1.2 Exclusion Criteria 
 
12. Active extraocular 
inflammation in either eye or 
intraocular inflammation in study 
eye 
... 
24. Uncontrolled hypertension 
defined as systolic blood pressure 
(BP) >180 mmHg or diastolic 
BP >100 mmHg under appropriate 
antihypertensive treatment 
... 
12. Active extraocular 
inflammation in either eye or 
intraocular 
intraocular/periocular infection 
and inflammation in either eye 
... 
24. Uncontrolled hypertension 
defined as systolic blood pressure 
(BP) >180 160 mmHg or diastolic 
BP >100 mmHg under 
appropriate antihypertensive 
treatment 
... 
36. Intraocular pressure 
≥25 mmHg in spite of 
anti-glaucoma treatment 
 
37. Any prior or ongoing 
systemic medical condition 
(including but not limited to 
infectious, inflammatory, 
psychiatric, neurological, renal, 
hepatic, respiratory conditions 
or malignancies) or clinically 
significant screening laboratory 
value that in the opinion of the 
investigator may present a 
safety risk, interfere with study 
compliance and follow-up, or 
confound data interpretation 
throughout the study period. 
Exclusion criterion (EC) #12 was 
updated to clarify that subjects 
with the conditions of 
intraocular/periocular infection 
and inflammation in either eye 
should be excluded at screening. 
This change has been applied to 
the Korea-specific protocol 
amendment. 
 
The limit of systolic blood 
pressure was decreased from 180 
to 160 mmHg in EC#24, as per 
the request from the Slovakia 
regulatory agency. The change has 
been applied to the 
Slovakia-specific protocol 
amendment. 
 
As per the requests from the 
Slovakia regulatory agency and 
the Korean MFDS, EC#36 
regarding the IOP condition in 
spite of anti-glaucoma treatment 
was added according to the SmPC 
with the IOP. The change has been 
applied to both Slovakia- and 
Korea-specific protocol 
amendments. 
 
As per the request from the 
Slovakia regulatory agency, 
subjects with a systemic medical 
condition should be excluded 
from the study; therefore, EC#37 
was added. 
Chapter/section concerned 
Section 4.2 Selection of Study Eye 
 
The section does not exist in the 
original protocol (version 1.0). 
Only one eye (study eye) must 
meet all the inclusion criteria 
and none of the exclusion 
criteria. 
 
Fellow eye should not show any 
signs of AMD that, in the 
investigator’s medical opinion, 
may need any treatment during 
study period. 
The section of selection of study 
eye was added as per the US FDA 
requirement to clearly define 
study eye in the protocol. 


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Chapter/section concerned 
Section 4.3.1 Discontinuation 
From Study Treatment 
Section 4.3.2 Withdrawal From 
the Study 
 
Subjects may withdraw from the 
study at any time at his/her own 
request or may be withdrawn at 
any time at the discretion of the 
investigator and/or sponsor for 
safety, behavioral, or 
administrative reasons. If the 
subject withdraws consent for 
disclosure of future information, 
the sponsor may retain and 
continue to use any data collected 
before such a withdrawal of 
consent. Subjects should undergo 
ET Visit assessments as soon as 
possible after discontinuing the 
study treatment, but no later than 
28 days after discontinuation, as 
described in the Schedule of 
Events (Table 6-1). 
 
General reasons for 
discontinuation can include, but 
are not limited to: 
• 
Death. 
• 
Subject has a serious or 
intolerable AEs that in the 
Investigator’s opinion 
requires withdrawal from the 
study. 
• 
Lost to follow-up. 
• 
Decision by the investigator 
that the subject requires 
alternate treatment for 
neovascular AMD in the 
study eye. 
• 
Decision by the Sponsor or 
administrative decision for a 
reason (eg, a suspicion of 
fraud, the subject enrolling in 
multiple clinical studies, lack 
of compliance, etc.) other 
than that of an AE. 
Section 4.3.1 Discontinuation 
From Study Treatment 
 
Subjects may withdraw from the 
study at any time at his/her own 
request or may be withdrawn at 
any time at the discretion of the 
investigator and/or sponsor for 
safety, behavioral, or 
administrative reasons. If the 
subject withdraws consent for 
disclosure of future information, 
the sponsor may retain and 
continue to use any data collected 
before such a withdrawal of 
consent. In rare instances, it 
may be necessary for a 
participant to permanently 
discontinue (definitive 
discontinuation) the study 
treatment. If the investigational 
product is definitively 
discontinued, the Treatment 
Discontinuation page of the 
eCRF should be completed. 
Every effort should be made to 
have such subjects remain in the 
study and continue with their 
regularly scheduled visits and 
assessments until Week 52 
except for study treatment 
administration. If a subject 
chooses to withdraw from the 
study or if, in the opinion of the 
investigator, the subject should 
be prematurely withdrawn, 
then the Ssubjects should 
undergo ET Visit assessments as 
soon as possible after 
discontinuing the study treatment, 
but no later than 28 days after 
discontinuation, as described in 
the Schedule of Events 
(Table 6-1). 
 
A subject may discontinue from 
the study treatment for any of 
the following reasons: 
• 
Subject has a serious or 
intolerable AEs that in the 
As per the US FDA 
recommendation to keep subjects 
who discontinue study treatment 
in the study to continue with their 
regularly scheduled visits, the 
reasons for 
withdrawal/discontinuation need 
to be introduced separately. As per 
the latest PPD protocol template, 
the above reasons were placed in 
the corresponding sections (The 
Section 4.2.1 Reason for 
Withdrawal/Discontinuation in the 
original protocol was divided into 
two sections: Discontinuation 
From Study Treatment, and 
Withdrawal From the Study). 
 
For clarity, certain specific criteria 
for treatment discontinuation were 
moved to the section of 
discontinuation of study 
treatment. 


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• 
Pregnancy. 
• 
Protocol deviation 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. 
• 
New diagnosis or worsening 
neovascular AMD in the 
fellow eye at any point 
during the study. 
o Before 8 weeks of the 
study: Study treatment is 
continued till 8 weeks 
and then discontinued. 
o After 8 weeks of the 
study: Study treatment is 
immediately 
discontinued. 
• 
The subject has symptoms or 
an intercurrent illness not 
consistent with the protocol 
requirements or that justify 
withdrawal. 
• 
The subject withdraws 
consent. 
• 
If a subject withdraws his/her 
consent, the Investigator 
must inquire the reasons for 
consent withdrawal as to 
whether it is related to the 
study (eg, documented lack 
of efficacy, AE or 
pregnancy); however, the 
subject may refuse to provide 
such reason. 
• 
A subject misses any of first 
2 doses (IVT injection of IP 
at Week 0 [Day 1] or Week 
4) after randomization. 
 
Certain specific criteria for 
treatment discontinuation include: 
• 
Development of 
rhegmatogenous retinal 
detachment or stage 3 or 4 
macular holes 
• 
A decrease in BCVA of ≥30 
letters compared with the last 
Investigator’s opinion 
requires withdrawal from the 
study. 
• 
Decision by the investigator 
that the subject requires 
alternate treatment for 
neovascular AMD in the 
study eye. 
• 
Pregnancy. 
• 
New diagnosis or worsening 
neovascular AMD in the 
fellow eye at any point 
during the study. 
o 
Before 8 weeks of the 
study: Study treatment 
is continued till 8 
weeks and then 
discontinued. 
o 
After 8 weeks of the 
study: Study treatment 
is immediately 
discontinued. 
• 
A subject misses either any 
of the first 2 doses (IVT 
injection of IP at Week 0 
[Day 1] or Week 4) after 
randomization. 
• 
Decision by the Sponsor or 
administrative decision for a 
reason (eg, a suspicion of 
fraud, the subject enrolling 
in multiple clinical studies, 
lack of compliance, etc.) 
other than that of an AE. 
 
Certain specific criteria for 
treatment discontinuation include: 
• 
Development of 
rhegmatogenous retinal 
detachment or stage 3 or 4 
macular holes 
• 
A decrease in BCVA of ≥30 
letters compared with the 
last assessment of VA 
• 
A subretinal hemorrhage 
involving the center of the 
fovea or, if the size of the 
hemorrhage is ≥50% of the 


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assessment of VA 
• 
A subretinal hemorrhage 
involving the center of the 
fovea or, if the size of the 
hemorrhage is ≥50% of the 
total lesion area 
• 
Clinical signs of irreversible 
ischemic visual function loss. 
total lesion area 
• 
Clinical signs of irreversible 
ischemic visual function 
loss. 
 
 
Section 4.3.2 Withdrawal From 
the Study 
A subject may withdraw from 
the study for any of the 
following reasons: 
• 
Death. 
• 
Lost to follow-up. 
• 
Protocol deviation which 
may adversely affect the 
subject’s safety and/or 
integrity of data as agreed by 
the Iinvestigator and/or upon 
request from the Sponsor. 
• 
The subject has symptoms or 
an intercurrent illness not 
consistent with the protocol 
requirements or that justify 
withdrawal. 
• 
The subject withdraws 
consent. 
• 
If a subject withdraws 
his/her consent, the 
Iinvestigator must inquire 
the reasons for consent 
withdrawal as to whether it 
is related to the study (eg, 
documented lack of efficacy, 
AE or pregnancy); however, 
the subject may refuse to 
provide such reason. 
Chapter/section concerned 
Section 4.3.3 Handling of 
Withdrawals 
 
Subjects who discontinue study 
treatment or active participation in 
the study will no longer receive 
study drug. When a subject 
withdraws from the study 
treatment or active participation in 
the study, the reason(s) for 
withdrawal shall be recorded by 
... 
Subjects who discontinue study 
treatment or active participation in 
the study will no longer receive 
study drug. When a subject 
withdraws from the study 
treatment or active participation in 
the study, the reason(s) for 
withdrawal shall be recorded by 
the investigator on the relevant 
page of the electronic case report 
form (eCRF). Every effort 
The section was updated as per 
the US FDA recommendation to 
keep subjects who discontinue 
study treatment in the study and 
continue with their regularly 
scheduled visits. 


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the investigator on the relevant 
page of the electronic case report 
form (eCRF). All subjects who 
discontinue study treatment or 
withdraw from the study 
prematurely will be asked to 
complete the ET Visit procedures 
as soon as possible after 
discontinuing the study treatment, 
but no later than 28 days after 
discontinuation. If a subject 
discontinues the study treatment 
due to an AE/serious adverse 
event (SAE) or if AEs/SAEs were 
ongoing at the time of 
discontinuation, the subject will 
be followed-up until resolution or 
stabilization. 
should be made to have such 
subjects continue with their 
regularly scheduled visits and 
assessments until Week 52 
except for study treatment 
administration after 
discontinuation of the study 
treatment, unless the subjects 
withdraw consent. All subjects 
who discontinue study treatment 
or withdraw from the study 
prematurely will be asked to 
complete the ET Visit procedures 
as soon as possible after 
discontinuing the study treatment, 
but no later than 28 days after 
discontinuation. If a subject 
discontinues the study treatment 
due to an AE/serious adverse 
event (SAE) or if AEs/SAEs were 
ongoing at the time of 
discontinuation, the subject will 
be followed-up until resolution or 
stabilization. 
Chapter/section concerned 
Section 4.3.4 Screen Failures 
... 
Subjects who do not meet the 
criteria for participation in this 
study may not be rescreened 
unless an image retransmission is 
requested from the central image 
vendor due to any possible 
technical issues. However, this is 
not considered to be rescreening. 
... 
Subjects who do not meet the 
criteria for participation in this 
study may not be rescreened. 
unless an image Image 
retransmission is requested from 
the central image center vendor 
due to any possible technical 
issues. However, this is not 
considered to be rescreening. 
The text was revised for clarity. 
Chapter/section concerned 
Section 5.2 Treatments 
Administered 
... 
Subjects will receive their 
randomized study treatment 
injections as per the Schedule of 
Events (Table 6 1) and according 
to the procedure manual. Clinic 
staff involved in the injection tray 
assembly, anesthetic preparation, 
and study drug preparation and 
administration will follow 
appropriate aseptic techniques to 
... 
Subjects will receive their 
randomized study treatment 
injections as per the Schedule of 
Events (Table 6-1) and according 
to the procedure manual. Clinic 
staff involved in the injection tray 
assembly, anesthetic preparation, 
and study drug preparation and 
administration will follow 
appropriate aseptic techniques to 
minimize the risk of potential AEs 
associated with IVT injections. If 
the pre-procedure IOP is equal 
to or greater than 30 mmHg, the 
To further ensure safety of 
subjects, the condition of 
pre-injection IOP was added and 
clarified in the protocol as per the 
request from the Russian 
regulatory agency.  
 
To avoid duplicated post-injection 
assessments of IOP and dilated 
fundoscopy by the masked and 
unmasked staff, both assessments 
were removed for the unmasked 
staff and will only be conducted 
by the masked staff. The sponsor 


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minimize the risk of potential AEs 
associated with IVT injections. 
... 
Immediately following the IVT 
injection, subjects should be 
checked for presence of optic 
nerve perfusion, formed vision, 
and excessive level of intraocular 
pressure (IOP) elevation or 
decrease. Appropriate monitoring 
consists of a fundoscopy check for 
perfusion of the optic nerve head, 
hand movement/finger counting 
vision and tonometry. If required, 
a sterile paracentesis needle 
should be available for the 
injecting physician to ensure 
control of excessive IOP 
elevation. 
 
Assessment of perfusion and 
presence of formed vision and 
hard globe due to excessive 
pressure is done immediately 
following the injection by the 
physician who injects the subject. 
There is technological time 
between the subject leaving the 
injecting room and going to the 
room where the IOP will be 
followed until safe to let the 
subject go home. 
IVT injection will not be 
administered (either withheld or 
delayed) until the IOP is 
decreased to acceptable safety 
levels as per the investigator’s 
medical judgement. 
... 
Immediately following the IVT 
injection, subjects should be 
checked by the unmasked staff 
for presence of optic nerve 
perfusion, formed vision, and 
excessive level of intraocular 
pressure (IOP) elevation or 
decrease. Appropriate monitoring 
consists of a fundoscopy check 
for perfusion of the optic nerve 
head, hand movement/finger 
counting vision and tonometry for 
subject safety. The information 
will not be captured in the 
eCRF. If subjects can recognize 
hand movement/finger counting 
vision immediately following the 
IVT injection, then the subjects 
should be transferred from the 
unmasked staff to the masked 
staff. If subjects cannot 
recognize hand 
movement/finger counting 
vision immediately following the 
IVT injection, then the 
unmasked staff should further 
investigate the reason. If 
required, a sterile paracentesis 
needle should be available for the 
injecting physician to ensure 
control of excessive IOP 
elevation. 
Assessment of perfusion and 
presence of formed vision and 
hard globe due to excessive 
pressure is done immediately 
following the injection by the 
physician who injects the subject. 
There is technological time 
between the subject leaving the 
injecting room and going to the 
room where the IOP will be 
followed until safe to let the 
confirmed that the hand 
movement/finger counting checks 
by the unmasked team are 
sufficient for safety assessment.  


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subject go home. 
The safety data after 
administration of the study 
treatment is collected by the 
masked staff for IOP and 
dilated fundoscopy. The 
information will be captured in 
the eCRF. 
Chapter/section concerned 
Section 5.2.1 Treatment of Fellow 
Eye 
 
If a subject is newly diagnosed 
with neovascular AMD or has 
worsening neovascular AMD in 
the fellow eye before completion 
of 8 weeks of treatment, the same 
schedule is followed until Week 8. 
Fellow eye treatment with Eylea is 
allowed and the cost of this 
treatment will be covered by the 
sponsor until Week 8. The subject 
should perform ET Visit 
assessments after Week 8. In this 
case, fellow eye data of dilated 
fundoscopy, IOP, fellow eye 
treatment date and medication 
name will be collected via eCRF. 
Also, the fellow eye treatment 
injection is not permitted on the 
same day as the study eye 
treatment. 
 
If the subject is newly diagnosed 
with neovascular AMD or has 
worsening neovascular AMD in 
fellow eye after Week 8, the 
principal investigator (PI) will 
perform ET/EOS Visits, 
discontinue the subject from the 
study, and will continue treatment 
of neovascular AMD in both eyes 
as per PI’s standard of care (SOC) 
and his/her discretion. 
Treatment of fellow eye will be 
allowed at any time during the 
study if If a subject is newly 
diagnosed with neovascular AMD 
or has worsening neovascular 
AMD in the fellow eye. The 
fellow eye should be treated 
only with Eylea as per 
investigator’s discretion. before 
completion of 8 weeks of 
treatment, the same schedule is 
followed until Week 8. Fellow eye 
treatment with Eylea is allowed 
and the cost of this treatment will 
be covered by the sponsor until 
Week 8. The subject should 
perform ET Visit assessments 
after Week 8. In this case, fellow 
eye data of dilated fundoscopy, 
IOP, fellow eye treatment date and 
medication name will be collected 
via eCRF. Also, the fellow eye 
treatment injection is not 
permitted on the same day as the 
study eye treatment.  
 
The cost of the fellow eye 
treatment will be covered by the 
sponsor in terms of either 
providing open-label Eylea or 
reimbursement after the site 
stock of Eylea is used up. 
 
If the subject is newly diagnosed 
with neovascular AMD or has 
worsening neovascular AMD in 
fellow eye after Week 8, the 
principal investigator (PI) will 
perform ET/EOS Visits, 
discontinue the subject from the 
study, and will continue treatment 
of neovascular AMD in both eyes 
The section was revised as per the 
sponsor’s decision to allow 
treatment of fellow eye only with 
Eylea for the whole duration of 
the study. 


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as per PI’s standard of care (SOC) 
and his/her discretion. 
Section 5.8.1 Rescue Treatment 
... 
Subjects who will receive rescue 
treatment will need to perform 
ET/EOS Visits and discontinue 
from the study. 
... 
In the study eye, rescue treatment 
for neovascular AMD is not 
permitted at any point in time. If it 
is observed that efficacy is not 
achieved by the study treatment, 
as determined by the investigator, 
subjects can be considered for 
rescue treatment after Week 4 if 
any 1 of the following conditions 
are met as assessed by the masked 
investigators: 
• 
Decrease of VA letter score 
of 15 letters or more from 
the last assessment and/or 
• 
Increase in the central 
subfield thickness of 100 µm 
compared to the latest 
assessment (OCT) by the 
investigator, an An increase 
in intraretinal fluid, 
subretinal fluid, or subretinal 
hyper-reflective material, 
that in the investigator’s 
opinion is related to 
progression of the subject’s 
neovascular AMD 
 
Subjects who will receive rescue 
treatment need to discontinue the 
study treatment and should 
have the reason for treatment 
discontinuation documented on 
the Treatment Discontinuation 
page of the eCRF and continue 
with their regularly scheduled 
visits and assessments until 
Week 52 except for study 
treatment administration. If a 
subject chooses to withdraw 
from the study or if, in the 
opinion of the investigator, the 
subject should be prematurely 
withdrawn, then the ET Visit 
should be completed as soon as 
possible after discontinuing the 
study treatment but no later 
than 28 days after 
The section was updated as per 
the US FDA recommendation to 
remain subjects who discontinue 
study treatment due to receipt of 
rescue treatment in the study 
continuing with their regularly 
scheduled visits.  
 
Due to SCD’s concern on the 
potential error caused by the IOP 
device, the condition for rescue 
treatment of an increase in the 
central subfield thickness of 
100 µm compared to the latest 
assessment (OCT) by the 
investigator was removed. 


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discontinuation will need to 
perform ET/EOS Visits and 
discontinue from the study. 
Chapter/section concerned 
Section 5.8.2 Prohibited 
Medications 
 
The details of the prohibited 
medications during the study are 
presented in Table 5-1. Concurrent 
use of systemic or IVT anti-VEGF 
agents; IVT, subtenon, or 
peribulbar corticosteroids in either 
eye, except as required to treat 
AEs. 
... 
The details of the prohibited 
medications during the study are 
presented in Table 5-1. 
Concurrent use of systemic or 
IVT anti-VEGF agents; IVT, 
subtenon, or peribulbar 
corticosteroids in either study 
eye, except as required to treat 
AEs. 
... 
Prohibited medications applied to 
the fellow eye have been 
removed, as per sponsor’s 
decision to allow fellow eye 
treatment only with Eylea for the 
whole duration of the study.  
Chapter/section concerned 
Section 6.1.3 Early 
Termination/End-of-Study 
 
All subjects who discontinue 
study treatment should return for 
the ET Visit as soon as possible 
after the discontinuation but no 
later than 28 days after 
discontinuation. End-of-study 
Visit assessments will be 
conducted 28 days after the end of 
treatment. 
... 
The end of the study is defined 
as the date of the last visit of the 
last subject in the study. 
 
All For subjects who discontinue 
study treatment, the Treatment 
Discontinuation page of the 
eCRF should be completed. 
Every effort should be made to 
have such subjects remain in 
the study and continue with 
their regularly scheduled visits 
and assessments until Week 52 
except for study treatment 
administration. If a subject 
chooses to withdraw from the 
study or if, in the opinion of the 
investigator, the subject should 
be prematurely withdrawn, 
then the subject should return for 
the ET Visit as soon as possible 
after the discontinuation but no 
later than 28 days after 
discontinuation. End of Sstudy 
Visit assessments will be 
conducted 28 days after the end of 
treatment for Week 52. 
... 
The section was updated as per 
the US FDA request to keep 
subjects who discontinue study 
treatment in the study to continue 
with their regularly scheduled 
visits. 
Chapter/section concerned 
Section 6.3.3.6 Suspected 
Unexpected Serious Adverse 
Reactions and Nonserious 
Section 6.3.3.6 Suspected 
Unexpected Serious Adverse 
Reactions and Nonserious 
Adverse Events of Special Interest 
The title of the section and the 
body text on nonserious adverse 
events of special interest (AESIs) 
were removed because there is no 


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Adverse Events of Special Interest 
 
The sponsor will promptly 
evaluate all suspected unexpected 
serious adverse reactions 
(SUSARs) and nonserious AEs of 
special interest against cumulative 
product experience to identify and 
expeditiously communicate 
possible new safety findings to 
investigators, IRBs/IECs, and 
applicable health authorities based 
on applicable legislation. 
... 
 
The sponsor will promptly 
evaluate all suspected unexpected 
serious adverse reactions 
(SUSARs) and nonserious AEs of 
special interest against cumulative 
product experience to identify and 
expeditiously communicate 
possible new safety findings to 
investigators, IRBs/IECs, and 
applicable health authorities based 
on applicable legislation. 
,,, 
definition of AESI in the protocol. 
Chapter/section concerned 
Section 6.4 Pharmacokinetic 
Assessments 
 
Blood samples, for determination 
of concentrations of SCD411 and 
aflibercept, will be collected at the 
timepoints specified in the 
Schedule of Events (Table 6 1) 
and detailed sampling window is 
provided in Table 6 3. 
Quantification of free and bound 
SCD411 and aflibercept will be 
performed for subjects who agree 
to participate in the PK substudy 
using blood samples drawn at 
predose, and at +1 day, +3 days, 
+7 days, +14 days, and +28 days 
following the first and the third 
injection. Samples should be 
collected before performing FA, 
when performed on the same day. 
Plasma concentrations of SCD411 
and aflibercept will be determined 
using validated analytical 
procedures. PK parameters 
assessed in the study include 
AUC0-t, AUC0-tau, AUC0-inf, 
Cmax, tmax, and t1/2. 
… 
Blood samples, for determination 
of concentrations of SCD411 and 
aflibercept, will be collected at the 
timepoints specified in the 
Schedule of Events (Table 6 1) 
and detailed sampling window is 
provided in Table 6 3. As per the 
Schedule of Events, additional 
visits will be arranged for 
collecting the PK blood samples. 
Quantification of free and bound 
SCD411 and aflibercept will be 
performed for subjects who agree 
to participate in the PK substudy 
using blood samples drawn at 
predose, and at +1 day, +3 days, 
+7 days, +14 days, and +28 days 
following the first and the third 
injection. Samples should be 
collected before performing FA, 
when performed on the same day. 
Plasma concentrations of SCD411 
and aflibercept will be determined 
using validated analytical 
procedures. PK parameters 
assessed in the study include 
AUC0-t, AUC0-tau, AUC0-inf, 
Cmax, tmax, and t1/2. 
… 
For clarity, the sentence on the 
additional visits to be arranged for 
collecting the PK blood samples 
was added. 
Chapter/section concerned 
Section 6.7 Pregnancy 
 
… 
No pregnancy test is required 
for women of non-child-bearing 
potential. Serum pregnancy test 
will be performed for women of 
child-bearing potential at the 
The section was updated to clarify 
that the serum pregnancy test will 
be only administered to women of 
child-bearing potential and to 
implement the change to keep 


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Serum pregnancy test will be 
performed at the Screening Visit. 
At Baseline, ET, and EOS Visits, a 
urine pregnancy test will be 
performed and if found positive, 
then the serum pregnancy test 
should be performed. If serum 
pregnancy test results are positive, 
the study treatment should be 
discontinued and ET Visit 
procedures should be conducted. 
Screening Visit. At Baseline, ET, 
and EOS Visits, a urine pregnancy 
test will be performed and if 
found positive, then the serum 
pregnancy test should be 
performed. If serum pregnancy 
test results are positive, the study 
treatment should be discontinued, 
and the subjects should 
continue with regularly 
scheduled visits and assessments 
until Week 52 after 
discontinuation, unless the 
subjects withdraw consent, in 
which circumstance ET Visit 
procedures should be conducted, 
the subject or the female 
partner of any male subject 
should be followed for safety 
until the outcome of the 
pregnancy is known. 
 
 
subjects in the study to continue 
regularly scheduled visits and 
assessments after study treatment 
discontinuation. Additionally, 
follow-up for safety until the 
outcome of the pregnancy is 
known was emphasized.  
Chapter/section concerned 
Section 7.1 Estimands and 
Intercurrent Events 
 
Intercurrent events of interest are 
receipt of rescue therapy and 
treatment/study discontinuation. 
Subjects who discontinue 
treatment are to discontinue the 
study. 
 
Week 8 
 
The estimand is the mean 
treatment difference for BCVA 
change from baseline at Week 8. 
For the EMA, the primary analysis 
will be assessed for both the full 
analysis set (FAS) and per-
protocol set (PPS). For the FDA, 
PMDA, and any other 
submissions, the primary analysis 
will be performed for the FAS. 
The primary analysis will be 
based on a mixed model for 
repeated measures (MMRM) 
Intercurrent events of interest are 
receipt of rescue therapy and 
treatment/study discontinuation. 
Subjects who discontinue 
treatment are to discontinue the 
study. 
 
Week 8 
The estimand is the mean 
treatment difference for BCVA 
change from baseline at Week 8. 
For the EMA, the primary 
analysis will be assessed for both 
the full analysis set (FAS) and 
per-protocol set (PPS). For the 
FDA, PMDA, and any other 
submissions, the primary analysis 
will be performed for the FAS. 
The primary analysis will be 
based on a mixed model for 
repeated measures (MMRM) 
including data for Week 4 and 
Week 8 based on observed data 
and baseline BCVA value as a 
covariate. Subjects who 
discontinue treatment are to 
discontinue the study and 
The section on estimands and 
intercurrent events have been 
updated as per the US FDA 
request to change the FAS 
population and to not discontinue 
subjects from the study when they 
discontinue study treatment due to 
AE/lack of efficacy/rescue 
treatment. 


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including data for Week 4 and 
Week 8 based on observed data 
and baseline BCVA value as a 
covariate. Subjects who 
discontinue treatment are to 
discontinue the study and 
observations after receipt of 
rescue therapy should be missing; 
however, in the event the subject 
continues follow-up, BCVA values 
after treatment discontinuation or 
receipt of rescue therapy will be 
set to missing prior to performing 
the MMRM. The MMRM 
approach assumes data is missing 
at random (MAR) and treatment 
estimates are as if subjects 
continued as on their original 
treatment. Sensitivity analyses 
will be performed using single 
imputation approaches of last 
observation carried forward 
(LOCF) and baseline observation 
carried forward (BOCF) 
approaches for observations after 
treatment discontinuation/receipt 
of rescue therapy prior to 
performing the MMRM analysis 
(intermittent missing data will be 
considered MAR and not 
imputed). An ANCOVA model 
comparing the Week 8 BCVA 
change from baseline and 
including baseline BCVA value as 
covariate will be performed based 
on observed data, using LOCF, 
and BOCF approaches. As with 
the MMRM analysis, for the 
ANCOVA, intermittent missing 
data at Week 8 will be considered 
MAR and observations after 
treatment discontinuation/receipt 
of rescue therapy will be set to 
missing. LOCF also approaches 
treatment estimates as if subjects 
who discontinue had continued on 
their original treatments and 
BOCF approaches treatment 
estimates as if subjects who 
discontinue received no treatment 
or returned to their original 
observations after receipt of 
rescue therapy should be missing; 
however, in the event the subject 
continues follow-up, BCVA 
values after treatment 
discontinuation or receipt of 
rescue therapy will be set to 
missing prior to performing the 
MMRM. The MMRM approach 
assumes data is missing at random 
(MAR) and treatment estimates 
are as if subjects continued as on 
their original treatment. 
Sensitivity analyses will be 
performed using single imputation 
approaches of last observation 
carried forward (LOCF) and 
baseline observation carried 
forward (BOCF) approaches for 
observations after treatment 
discontinuation/receipt of rescue 
therapy prior to performing the 
MMRM analysis (intermittent 
missing data will be considered 
MAR and not imputed). An 
ANCOVA model comparing the 
Week 8 BCVA change from 
baseline and including baseline 
BCVA value as covariate will be 
performed based on observed 
data, using LOCF, and BOCF 
approaches. As with the MMRM 
analysis, for the ANCOVA, 
intermittent missing data at Week 
8 will be considered MAR and 
observations after treatment 
discontinuation/receipt of rescue 
therapy will be set to missing. 
LOCF also approaches treatment 
estimates as if subjects who 
discontinue had continued on their 
original treatments and BOCF 
approaches treatment estimates as 
if subjects who discontinue 
received no treatment or returned 
to their original condition. 
Multiple imputation approached 
including tipping point analyses 
will also be performed for 
sensitivity. 
Primary Estimand: The 


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condition. Multiple imputation 
approached including tipping 
point analyses will also be 
performed for sensitivity. 
 
Week 52 
The estimand is the mean 
treatment difference for BCVA 
change from baseline at Week 52. 
For the FDA, PMDA and any 
other submissions, the primary 
analysis will be performed for 
FAS. For the EMA, the primary 
analysis will be assessed for both 
the FAS and PPS. The primary 
analysis will be based on an 
MMRM including data from all 
study visits through Week 52 and 
baseline BCVA value as a 
covariate. As in the Week 8 
analysis, observations after 
treatment discontinuation or 
receipt of rescue therapy will be 
set to missing prior to analysis. 
Sensitivity analyses will be 
performed using single imputation 
LOCF and BOCF approaches for 
post-treatment 
discontinuation/rescue therapy 
assessments prior to performing 
the MMRM analysis (intermittent 
missing data will be considered 
MAR and not imputed). An 
ANCOVA model comparison the 
Week 52 BCVA change from 
baseline and including baseline 
BCVA value as covariate will be 
performed using observed data 
with LOCF, and BOCF 
approaches for post-treatment 
discontinuation/rescue therapy 
observations. Multiple imputation 
approached including tipping 
point analyses will also be 
performed for sensitivity. 
 
Data imputation/analysis methods 
which generate treatment 
estimates as if subjects continued 
original treatment are considered 
primary estimand is the mean 
treatment difference in BCVA 
change from baseline at Week 8. 
For the EMA, the primary 
analysis will be assessed for 
both the full analysis set (FAS) 
and per-protocol set (PPS). For 
the FDA, PMDA, and any other 
submissions, the primary 
analysis will be performed for 
the FAS. The primary estimand 
treats subjects in the analysis as 
if subjects do not receive rescue 
therapy.  
 
Target Population: Subjects 
with wet AMD as defined in the 
enrollment criteria. 
 
Endpoint: Change from 
baseline in BCVA at Week 8. 
 
Treatment Condition(s): Dosing 
at Day 1, Week 4 and Week 8 
with one of the following: 
SCD411 or aflibercept, both 
without rescue therapy. 
 
Population-level Summary: The 
difference in mean change from 
baseline in BCVA at Week 8 
between SCD411 and 
aflibercept and the 
corresponding confidence 
interval for the mean difference. 
 
Intercurrent Events and 
Strategies to Address 
Intercurrent Events 
• 
Discontinuation of study 
eye study treatment with 
continued participation in 
study without receipt of 
rescue therapy 
o Treatment Policy – no 
imputation; use 
observed data 
• 
Receipt of rescue therapy 


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appropriate for the primary 
estimand methodology as the goal 
of the study is to show treatment 
equivalence. Subjects which 
receive rescue therapy will have 
shown lack of efficacy in 
assessments prior to rescue, so 
carrying forward their data should 
be conservative if the test 
treatment is not equivalent/less 
efficacious to the reference 
product. Sample Size 
Determination 
 
The equivalence margin agreed 
upon with EMA and PMDA was 
determined using the data 
presented from MARINA (and 
ANCHOR) and VIEW studies. 
These data were used to estimate 
the efficacy of aflibercept 
compared to the placebo treatment 
in subjects with wet AMD. It was 
shown that in MARINA, subjects 
on average lost 2.5 letters of 
BCVA over 2 months in the sham-
treated control arm and gained 5 
letters in the treatment arm of 2 
mg, and that in the VIEW studies 
6.8 to 7.5 letters were gained 
among subjects with wet AMD at 
Week 8 into treatment on a 2 mg 
dose. Combining both study data, 
the treatment effect compared to 
the placebo would be estimated as 
approximately 9.3 to 10 letters. A 
margin of 3.8 letters would be 
translated to a preservation of 
59% to 62% of the difference 
between Eylea and sham and is 
less than a 1 line change in VA. 
Equivalence discussions for EMA 
and PMDA were based upon a 
95% CI approach or 2 one-sided 
tests (TOST) at the α=0.025 level. 
The FDA requested a tighter 
equivalence margin of 3 letters but 
agreed equivalence can be 
determined from a 90% CI 
approach (equivalent to TOST at 
in the study eye 
o Hypothetical approach 
– data after receipt of 
rescue will be set to 
missing and post rescue 
data will be imputed 
employing multiple 
imputation (MI) 
assuming missing at 
random (MAR) using 
randomized treatment-
based Markov Chain 
Monte Carlo (MCMC) 
methodology. 
• 
Discontinuation from 
study, regardless of reason 
o Hypothetical approach 
- missing data after 
discontinuation will be 
imputed via MI 
assuming MAR using 
randomized treatment 
based MCMC 
methodology. 
 
Rationale for Strategy: As the 
primary objective of this study 
is to show biosimilar 
equivalence between SCD411 
and aflibercept, the primary 
estimand is constructed to 
estimate the treatment effect 
under the assumption that all 
subjects take study treatments 
without the use of rescue 
therapy while allowing for 
subjects to discontinue study 
treatment. Multiple imputation 
under MAR assumptions results 
in treatment estimates as if 
subjects continued as on their 
original treatment. Treating 
discontinuation as MAR and 
setting the post rescue 
assessment to missing prior to 
performing MI was chosen to 
avoid inflation of the SCD411 
treatment effect. Subjects who 
receive rescue therapy or 
discontinue will have shown 


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the α=0.05 level). 
 
Standard deviation (SD) for the 
mean change from baseline at 
early visits (Weeks 4 to 12) based 
on observed data for the FAS 
ranged from and 8.73 to 11.99 
considering all treatment groups 
from VIEW1 and from 7.4 to 11.0 
letters for the VIEW2 study (Eylea 
Statistical Review, Appendix 
Tables A.1 and A.2). For power 
calculations, a range of SD of 
between 10.4 and 11.8 was 
assumed to be conservative and 
cover the majority of larger SD 
values seen in the observed data. 
 
A sample size of 266 subjects per 
treatment arm was selected as it 
provides at least 80% power for 
the FDA, EMA, and PMDA 
analyses for the range of SD 
considered when using 2 one-
sided t-tests on data from a 
parallel-group design. For the 
FDA analysis based on 
equivalence limits of -3.0 and 3.0 
letters, α=0.05 significance level 
(90% CI), assuming the true 
difference between the means is 
0.0, power of 91% is achieved for 
SD is 10.4 letters and power of 
80% is achieved for SD of 11.8 
letters. For the EMA and PMDA 
analyses based on equivalence 
limits of -3.8 and 3.8 letters, 
α=0.025 significance level (95% 
CI), assuming the true difference 
between the means is 0.0, power 
of 98% is achieved for SD is 10.4 
letters and power of 92% is 
achieved for SD of 11.8 letters 
when sample size is 266 per 
treatment arm. Considering 
approximately 5% loss from 
randomization through Week 8, 
the total sample size required is 
560. 
A subset of 40 subjects (20 per 
lack of efficacy in assessments, 
so the MAR approach should be 
conservative if the test 
treatment is not equivalent to or 
less efficacious than the 
reference product. 
  
Secondary Estimand: A 
secondary estimand for the 
primary efficacy endpoint is the 
mean treatment difference in 
BCVA change from baseline at 
Week 8 while allowing for 
receipt of rescue therapy. The 
estimand will be constructed as 
above, but the intercurrent 
event of rescue therapy use will 
be handled using the treatment 
policy approach. Data post 
rescue will not be set to missing. 
This estimand is constructed to 
estimate the treatment effect 
including the impact of rescue 
therapy, which may better 
reflect actual real-world 
outcomes, where rescue would 
likely be given when lack of 
efficacy is seen. 
 
Week 52 
Primary Estimand: The 
primary estimand is the mean 
treatment difference in BCVA 
change from baseline at Week 
52. For the EMA, the primary 
analysis will be assessed for 
both the FAS and PPS. For the 
FDA, PMDA, and any other 
submissions, the primary 
analysis will be performed for 
the FAS. The primary estimand 
treats subjects in the analysis as 
if subjects do not receive rescue 
therapy. 
 
Target Population: Subjects 
with wet AMD as defined in the 
enrollment criteria. 
 


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group) will be selected for 
collection of PK samples. The 
sample size is not test-driven since 
no equivalence test will be 
performed for PK parameters. 
Endpoint: Change from 
baseline in BCVA at Week 52 
 
Treatment Condition(s): Dosing 
at Day 1, Week 4 and Week 8, 
Week 16, Week 24, Week 32, 
Week 40, and Week 48 with one 
of the following: SCD411 or 
aflibercept, both without rescue 
therapy. 
 
Population-level Summary: The 
difference in mean change from 
baseline in BCVA at Week 52 
between SCD411 and 
aflibercept and the 
corresponding confidence 
interval for the mean difference. 
 
Intercurrent Events and 
Strategies to Address 
Intercurrent Events 
• 
Discontinuation of study 
eye study treatment with 
continued participation in 
study without receipt of 
rescue therapy 
o Treatment Policy – no 
imputation; use 
observed data 
• 
Receipt of rescue therapy 
in the study eye 
o Hypothetical approach 
– Data after receipt of 
rescue will be set to 
missing and post rescue 
data will be imputed 
employing MI assuming 
MAR using randomized 
treatment-based 
MCMC methodology. 
• 
Discontinuation from 
study, regardless of reason  
o  Hypothetical approach 
- Missing data after 
discontinuation will be 
imputed via MI 
assuming MAR using 
randomized treatment-


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based MCMC 
methodology. 
 
Rationale for Strategy: As the 
primary objective of this study 
is to show biosimilar 
equivalence between SCD411 
and aflibercept, the primary 
estimand is constructed to 
estimate the treatment effect 
under assumption that all 
subjects take study treatments 
without the use of rescue 
therapy while allowing for 
subjects to discontinue study 
treatment. Multiple imputation 
under MAR assumptions results 
in treatment estimates as if 
subjects continued as on their 
original treatment. Treating 
discontinuation as MAR and 
setting the post rescue 
assessment to missing prior to 
performing MI was chosen to 
avoid inflation of the SCD411 
treatment effect. Subjects who 
receive rescue therapy or 
discontinue will have shown 
lack of efficacy in assessments, 
so the MAR approach should be 
conservative if the test 
treatment is not equivalent to or 
less efficacious than the 
reference product. 
 
Secondary Estimand: A 
secondary estimand for the 
secondary efficacy endpoint is 
the mean treatment difference 
for BCVA change from baseline 
at Week 52 while allowing for 
receipt of rescue therapy. The 
estimand will be constructed as 
above, but the intercurrent 
event of rescue therapy use will 
be handled using the treatment 
policy approach. Data post 
rescue will not be set to missing. 
This estimand is constructed to 
estimate the treatment effect 


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including the impact of rescue 
therapy, which may better 
reflect actual real-world 
outcomes where rescue would 
likely be given when lack of 
efficacy is seen. 
Chapter/section concerned 
Section 7.2 Sample Size 
Determination 
 
The equivalence margin agreed 
upon with EMA and PMDA was 
determined using the data 
presented from MARINA (and 
ANCHOR) and VIEW studies. 
These data were used to estimate 
the efficacy of aflibercept 
compared to the placebo treatment 
in subjects with wet AMD. It was 
shown that in MARINA, subjects 
on average lost 2.5 letters of 
BCVA over 2 months in the sham-
treated control arm and gained 5 
letters in the treatment arm of 2 
mg, and that in the VIEW studies 
6.8 to 7.5 letters were gained 
among subjects with wet AMD at 
Week 8 into treatment on a 2 mg 
dose. Combining both study data, 
the treatment effect compared to 
the placebo would be estimated as 
approximately 9.3 to 10 letters. A 
margin of 3.8 letters would be 
translated to a preservation of 
59% to 62% of the difference 
between Eylea and sham and is 
less than a 1 line change in VA. 
Equivalence discussions for EMA 
and PMDA were based upon a 
95% CI approach or 2 one-sided 
tests (TOST) at the α=0.025 level.  
The equivalence margin agreed 
upon with EMA and PMDA was 
determined using the data 
presented from MARINA (and 
ANCHOR) and VIEW studies. 
These data were used to estimate 
the efficacy of aflibercept 
compared to the placebo treatment 
in subjects with wet AMD. It was 
shown that in MARINA, subjects 
on average lost 2.5 letters of 
BCVA over 2 months in the 
sham-treated control arm and 
gained 5 letters in the treatment 
arm of 2 mg, and that in the 
VIEW studies 6.8 to 7.5 letters 
were gained among subjects with 
wet AMD at Week 8 into 
treatment on a 2 mg dose. 
Combining both study data, the 
treatment effect compared to the 
placebo would be estimated as 
approximately 9.3 to 10 letters. A 
margin of 3.8 letters would be 
translated to a preservation of 
59% to 62% of the difference 
between Eylea and sham and is 
less than a 1 line change in VA. 
Equivalence discussions for EMA 
and PMDA were based upon a 
95% CI approach or 2 one-sided 
tests (TOST) at the α=0.025 level.  
 
Given that the statistical 
justification of the 3.8 letter 
equivalence margin is not 
included in the current version 
of the protocol, this will be 
added in the SAP and provided 
to the regulatory agencies upon 
request. 
Upon agreement within the 
internal PPD team, justification 
for the 3.8 letter margin was 
briefly mentioned in the protocol 
amendment. 
Chapter/section concerned 
Section 7.3 Analysis Sets 
... 
Full Analysis Set (FAS): aAll 
randomized subjects who received 
The definition of FAS has been 
updated as per the request from 
US FDA.  


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Full Analysis Set (FAS): all 
randomized subjects who received 
at least 1 injection of the study 
drug and had at least 1 
postbaseline BCVA assessment in 
the study eye. 
... 
Safety Set (SAF): all randomized 
subjects receiving at least 1 
injection of the study drug. 
 
Pharmacokinetic Analysis Set 
(PK Set): the subset of subjects in 
SAF who have sufficient 
evaluable blood samples to be 
included in the PK Set. 
at least 1 injection of the study 
drug and had at least 1 
postbaseline BCVA assessment in 
the study eye. 
 
Per-protocol Set (PPS): aAll 
subjects in the FAS, excluding 
those with significant protocol 
violations. 
 
Safety Set (SAF): aAll 
randomized subjects receiving at 
least 1 injection of the study drug. 
 
Pharmacokinetic Analysis Set 
(PK Set): tThe subset of subjects 
in SAF FAS who have sufficient 
evaluable blood samples to be 
included in the PK Set. 
 
The definitions of SAF and PK set 
were updated for clarity. 
Chapter/section concerned 
Section 7.5.1.1 Primary Efficacy 
Outcome Measures 
... 
The primary analysis of the 
change from baseline in BCVA as 
measured by ETDRS letter score 
or 2702 charts through 8 weeks of 
treatment will be performed via 
MMRM including data for the 
Week 4 and Week 8 visits. The 
model will include the change 
from baseline as the dependent 
variable; treatment and visit as 
fixed effects, and baseline BCVA 
as a covariate. An appropriate 
covariance matrix will be selected, 
and details will be provided in the 
SAP. The estimated mean 
treatment difference at Week 8 
along with the corresponding 90% 
and 95% CIs will also be 
presented. Equivalence will be 
determined if the upper and lower 
CI limits for the difference 
between treatments are within the 
equivalence margins. Raw values 
and changes from baseline at 
Week 4 and Week 8 will be 
summarized by treatment group 
... 
The primary analysis of the 
change from baseline in BCVA as 
measured by ETDRS letter score 
or 2702 charts through 8 weeks of 
treatment will be performed via 
MMRM including data for the 
Week 4 and Week 8 visits. The 
model will include the change 
from baseline as the dependent 
variable; treatment and visit as 
fixed effects, and baseline BCVA 
as a covariate. An appropriate 
unstructrued covariance matrix 
will be selected used. In the 
event of convergence issues, 
compound-symmetry will be 
used instead. Rubin’s rules will 
be used to combine the 
estimates from the MMRM 
analyses and the and details will 
be provided in the SAP. The 
estimated mean treatment 
difference at Week 8 along with 
the corresponding 90% and 95% 
CIs will also be presented. 
Equivalence will be determined if 
the upper and lower CI limits for 
the difference between treatments 
are within the equivalence 
The section of primary efficacy 
outcome measures was updated as 
per the US FDA request to change 
the FAS population and to not 
discontinue subjects from the 
study when they discontinue study 
treatment due to AE/lack of 
efficacy/rescue treatment. 
 
The covariance structure was 
specified as per the request from 
US FDA. 


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using descriptive statistics. 
... 
For the FDA submission and other 
countries submission, a 90% CI 
(equivalent to 2 one-sided tests 
evaluated at an α of 0.05) will be 
assessed using an equivalence 
margin of 3 letters. If the upper 
bound of the 90% CI from the 
MMRM model is less than 3 and 
the lower bound is greater than -3, 
then study success will be 
claimed. For the EMA and 
PMDA, a 95% CI (equivalent to 2 
one-sided tests evaluated at an α 
of 0.025) will be assessed using an 
equivalence margin of 3.8 letters. 
If the upper bound of the 95% CI 
from the MMRM model is less 
than 3.8 and the lower bound is 
greater than -3.8, then study 
success will be claimed. 
 
The least squares mean estimate 
of treatment difference and 
corresponding 90% (FDA and 
other countries) and 95% 
(EMA/PMDA) CIs will be 
provided. The primary analysis set 
for the FDA, PMDA, and any 
other submissions will be the FAS. 
For the EMA submission, both the 
FAS and PPS are considered 
primary analysis and equivalence 
will need to be shown for both 
analysis sets. As the extent of 
missing data and/or treatment 
discontinuation/rescue therapy is 
expected to be less than 5%, the 
primary analysis will be based on 
observed data assuming data is 
missing at random. Non-missing 
observations after treatment 
discontinuation/receipt of rescue 
therapy will be set to missing prior 
to analysis. Sensitivity analyses to 
the primary analysis will be 
performed by imputing the post 
treatment discontinuation/rescue 
therapy BCVA scores using the 
margins. Raw values and changes 
from baseline at Week 4 and 
Week 8 will be summarized by 
treatment group using descriptive 
statistics based on observed 
data. 
... 
For the FDA submission and 
other countries submission, a 90% 
CI (equivalent to 2 one-sided tests 
evaluated at an α of 0.05) will be 
assessed using an equivalence 
margin of 3 letters. If the upper 
bound of the 90% CI from the 
MMRM model is less than 3 and 
the lower bound is greater than -3, 
then study success will be 
claimed. For the EMA and 
PMDA, a 95% CI (equivalent to 2 
one-sided tests evaluated at an α 
of 0.025) will be assessed using 
an equivalence margin of 3.8 
letters. If the upper bound of the 
95% CI from the MMRM model 
is less than 3.8 and the lower 
bound is greater than -3.8, then 
study success will be claimed. 
 
The least squares mean estimate 
of treatment difference and 
corresponding 90% (FDA and 
other countries) and 95% 
(EMA/PMDA) CIs will be 
provided. The primary analysis 
set for the FDA, PMDA, and any 
other submissions will be the 
FAS. For the EMA submission, 
both the FAS and PPS are 
considered primary analysis and 
equivalence will need to be shown 
for both analysis sets. As the 
extent of missing data and/or 
treatment discontinuation/rescue 
therapy is expected to be less than 
5%, the primary analysis will be 
based on observed data assuming 
data is missing at random. 
Nonmissing observations after 
treatment discontinuation/receipt 
of rescue therapy will be set to 


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LOCF and BOCF prior to the 
MMRM analysis (intermittent 
missing data will be considered 
MAR and not imputed). In 
addition, analyses will also be 
repeated for the PPS using 
observed data as well as imputing 
missing data using the LOCF and 
BOCF approaches. 
 
An ANCOVA model comparing 
the change from baseline in BCVA 
at Week 8 and including baseline 
BCVA value as covariate will be 
performed based on observed data 
with nonmissing observations 
after treatment 
discontinuation/receipt of rescue 
therapy being set to missing prior 
to analysis. The ANCOVA model 
will also be performed by 
imputing the post-treatment 
discontinuation/rescue therapy 
BCVA values using LOCF and 
BOCF approaches. 
 
Additionally, the MMRM analysis 
will be performed using data from 
multiple imputation (MI) 
including a tipping point 
approach. Observations after 
treatment discontinuation/receipt 
of rescue therapy will be set to 
missing prior to the MI. Multiple 
imputation assuming MAR will be 
applied to all missing data. After 
conclusion of MI, post treatment 
discontinuation/rescue therapy 
observations for the SCD411 arm 
will have fixed value C added to 
the imputed values. The imputed 
data included the fixed penalty 
will be analyzed by the same 
MMRM model as for the primary 
analysis. A range of values for C 
will be considered to identify the 
point at which equivalence can no 
longer be claimed. Details will be 
provided in SAP. 
missing prior to analysis.  
 
As a senstitivity analysis an 
ANCOVA model comparing the 
change from the baseline in 
BCVA at Week 8 and including 
baseline BCVA value as a 
covariate will be performed 
using the multiple imputed 
data. 
 
Additional Sensitivity sensitivity 
analyses to the primary analysis 
will be performed by imputing the 
using single imputation 
approaches for post study 
treatment discontinuation/rescue 
therapy BCVA scores using the 
LOCF and BOCF prior to the 
MMRM analysis (intermittent 
missing data will be considered 
MAR and not imputed) for both 
the FAS and PPS. In addition, 
analyses will also be repeated for 
the PPS using observed data as 
well as imputing missing data 
using the LOCF and BOCF 
approaches. An an ANCOVA 
model comparing the change from 
baseline in BCVA at Week 8 and 
including the baseline BCVA 
value as a covariate will be 
performed based on observed data 
with nonmissing observations 
after treatment 
discontinuation/receipt of rescue 
therapy being set to missing prior 
to analysis. The ANCOVA model 
will also be performed by 
imputing the post study treatment 
discontinuation/rescue therapy 
BCVA values using LOCF and 
BOCF approaches for the FAS 
and PPS. 
 
Additionally, the MMRM analysis 
will be performed using data from 
multiple imputation (MI) 
including a tipping point 
approach. Observations after 


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treatment discontinuation/receipt 
of rescue therapy will be set to 
missing prior to the MI. Multiple 
imputation assuming MAR will 
be applied to all missing data. 
After conclusion of MI, post 
study treatment 
discontinuation/rescue therapy 
observations for the SCD411 arm 
will have fixed value C added to 
the imputed values. The imputed 
data included the fixed penalty 
will be analyzed by the same 
MMRM model as for the primary 
analysis. A range of values for C 
will be considered to identify the 
point at which equivalence can no 
longer be claimed. Details will be 
provided in SAP. 
Chapter/section concerned  
Section 7.5.1.2 Secondary 
Efficacy Outcome Measures 
 
The estimated mean treatment 
difference in the change from 
baseline in BCVA as measured by 
ETDRS letter score through 52 
weeks along with the 
corresponding 90% and 95% CIs 
from the same MMRM model as 
used in the primary analysis but 
including data from all weeks 
through Week 52 will also be 
presented. Data after the treatment 
discontinuation or receipt of 
rescue therapy will be set to 
missing prior to analysis. 
 
The estimated mean treatment 
difference at Week 52 along with 
the corresponding 90% and 95% 
CIs will also be presented using 
the same MMRM and ANCOVA 
models as used in the Week 8 
analysis. Raw values and changes 
from baseline will be summarized 
by treatment group using 
descriptive statistics for each visit. 
Sensitivity analyses will be 
performed using LOCF and BOCF 
The estimated mean treatment 
difference in the change from 
baseline in BCVA as measured by 
ETDRS letter score through 52 
weeks along with the 
corresponding 90% and 95% CIs 
from the same MMRM model as 
used in the primary analysis but 
including data from all weeks 
through Week 52 will also be 
presented. Data after the treatment 
discontinuation or receipt of 
rescue therapy will be set to 
missing prior to analysis. 
 
The estimated mean treatment 
difference at Week 52 along with 
the corresponding 90% and 95% 
CIs will also be presented using 
the same MMRM and ANCOVA 
models as used in the Week 8 
analysis. As done for the Week 
8, analysis will be performed 
using MI data, where post 
rescue assessments have been 
set to missing while including 
the post rescue assessments in 
the imputation model. Raw 
values and changes from baseline 
will be summarized by treatment 
group using descriptive statistics 
The section on secondary efficacy 
outcome measures was updated as 
per the US FDA request to change 
the FAS population and to not 
discontinue subjects from the 
study when they discontinue study 
treatment due to AE/lack of 
efficacy/rescue treatment. 


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for post-treatment discontinuation 
assessments or after receipt of 
rescue therapy prior to performing 
the MMRM and ANCOVA 
analysis (intermittent missing data 
will be considered MAR and not 
imputed). Additionally, the 
MMRM analysis will be 
performed using data from 
multiple imputation (MI) 
including a tipping point 
approach. 
 
The analysis of change from 
baseline in CRT as assessed by 
OCT or change from baseline in 
CNV are will be based on a 
MMRM model similar to the one 
used for the analysis of change 
from baseline in BCVA, with the 
corresponding 95% CI for the 
estimates of treatment differences 
at Week 8 and Week 52 will be 
presented. Raw values and 
changes from baseline will be 
summarized by treatment group 
using descriptive statistics. Data 
post treatment discontinuation or 
after receipt of rescue therapy will 
be set to missing prior to the 
MMRM analysis. No sensitivity 
analyses will be performed. 
for each visit.  
 
Sensitivity analyses will be 
performed using LOCF and 
BOCF for post-treatment study 
discontinuation assessments or 
after receipt of rescue therapy 
prior to performing the MMRM 
and ANCOVA analysis 
(intermittent missing data will be 
considered MAR and not 
imputed). Additionally, the 
MMRM analysis will be 
performed using data from 
multiple imputation (MI) 
including a tipping point 
approach. 
 
The analysis of change from 
baseline in CRT as assessed by 
OCT or change from baseline in 
CNV are will be based on a 
MMRM model similar to the one 
used for the analysis of change 
from baseline in BCVA, with the 
corresponding 95% CI for the 
estimates of treatment differences 
at Week 8 and Week 52 will be 
presented. Raw values and 
changes from baseline will be 
summarized by treatment group 
using descriptive statistics. Data 
post treatment discontinuation or 
after receipt of rescue therapy will 
be set to missing prior to the 
MMRM analysis. Multiple 
imputation will not be 
performed and no No sensitivity 
analyses will be performed. 
Chapter/section concerned 
Section 11.2.2 Protocol Deviations 
... 
A deviation from the protocol is 
an unintended or unanticipated 
departure from the procedures or 
processes approved by the sponsor 
and the IRB/IEC and agreed to by 
the investigator. A significant 
deviation occurs when there is 
... 
A deviation from the protocol is 
an unintended or unanticipated 
departure from the procedures or 
processes approved by the 
sponsor and the IRB/IEC and 
agreed to by the investigator. A 
significant deviation occurs when 
there is nonadherence to the 
protocol by the subject or 
investigator that results in a 
Section 11.2.2 was updated as per 
the request from the Korean 
MFDS to list serious protocol 
violations in the protocol. The 
update has been applied to the 
Korea-specific protocol 
amendments. 


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nonadherence to the protocol by 
the subject or investigator that 
results in a significant, additional 
risk to the subject. Significant 
deviations can include 
nonadherence to inclusion or 
exclusion criteria, or 
nonadherence to FDA regulations 
or ICH GCP guidelines, and will 
lead to the subject being 
withdrawn from the study (Section 
4.2). 
significant, additional risk to the 
subject. Significant deviations can 
include nonadherence to inclusion 
or exclusion criteria, or 
nonadherence to FDA regulations 
or ICH GCP guidelines, and will 
lead to the subject being 
withdrawn from the study 
(Section 4.2). Significant 
protocol deviations may include 
below but not limited to the 
following deviations: 
 
• 
ICH/GCP deviation 
• 
Deviation from 
inclusion/exclusion criteria 
• 
Deviation on study 
treatment randomization 
... 
Chapter/section concerned 
Section 12 Reference List 
The reference does not exist in 
version 1.0. 
... 
European Medicines Agency 
(EMA). Eylea (aflibercept). An 
overview of Eylea and why it is 
authorised in the EU. 
EMA/481361/2018. [cited 2020 
Jul 23] Available from: 
https://www.ema.europa.eu/en/
documents/overview/eylea-epar-
medicine-overview_en.pdf 
The reference was added as it was 
missing in the original protocol. 


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Chapter/section concerned 
Section 5.3  
Identity of Investigational Product 
Initial wording 
 
 
Amended or new wording 
 
 


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Reason/Justification for Change 
As per the US FDA request, the column regarding the treatment of Eylea (aflibercept) was updated to clarify the source of Eylea. 
 
Table concerned 
Table 5-1 
 Prohibited Medications 
Initial wording 
 
… 
Abbreviations: AE, adverse event; AMD, age-related macular degeneration; EOS, end-of-study; ET, early termination; IP, investigational product; IVT, intravitreal; NA, not applicable; PDT, 
photodynamic therapy; SOC, standard of care; VEGF, vascular endothelial growth factor. 
 


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Amended or new wording 
 
… 
Abbreviations: AE, adverse event; AMD, age-related macular degeneration; EOS, end-of-study; ET, early termination; IP, investigational product; IVT, intravitreal; NA, not applicable; PDT, 
photodynamic therapy; SOC, standard of care; VEGF, vascular endothelial growth factor. 
 
Reason/Justification for Change 
Due to the sponsor’s decision to allow treatment of fellow eye only with Eylea for the whole duration of the study, the VEGF treatment was updated as a 
prohibited medication only applicable to the study eye. Additionally, the note on treatment of fellow eye was updated. 
 
Table concerned 
Table 6-1 
 Schedule of Events 
Amended or new wording 
Footnote: 
a. 
For subjects who discontinue study treatment and choose to withdraw from the study or if, in the opinion of the investigator, the subject should be 
prematurely withdrawn, ET Visit assessments are to be performed as soon as possible after discontinuing the study treatment but no later than 28 days 
after discontinuation 
c. 
Slit lamp examination will be performed on both eyes at screening and prior to IVT injection of the study drug. Slit lamp will also be performed at any time 
during the visit at ET/EOS Visit all the planned scheduled visits during the study. 


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d. Dilated fundoscopy will be performed on the study eye at all the planned scheduled visits during the study, including the time prior to IVT injection of 
the study drug, and within 60±30 minutes after IVT injection of the study drug,. Dilated fundoscopy will also be performed and at any time during the visit 
at ET/EOS Visit. 
e. 
Serum pregnancy test will be done at screening, and urine pregnancy test at baseline, ET, and EOS Visits for female subjects of child-bearing potential. If 
urine pregnancy test is positive, serum pregnancy test should be performed; and if found positive, study treatment will be discontinued and the subject should 
complete ET Visit procedures continue with their regularly scheduled visits and assessments until Week 52 except for study treatment 
administration. Pregnancy cases should be followed until resolution of the pregnancy. 
f. 
Concurrent use of systemic or intravitreal anti-VEGF agents, IVT, subtenon, or peribulbar corticosteroids in either study eye, except as required to treat 
AEs, and use of photocoagulation or PDT with verteporfin are prohibited during the study. Antimicrobial drops can be used at the discretion of the 
investigator. For IVT corticosteroid implant, the exclusion period would be 36 months from the date of the procedure to the date of screening. 
h. Rescue treatment for the study eye is not permitted at any point in time if it observed that efficacy is not achieved by the study treatment, as determined by 
the investigator. Subjects can be considered for rescue treatment after Week 4 if the following conditions are met as assessed by the masked investigator: 
visual acuity letter score decrease of 15 letters or more from the last assessment and/or increase in the central subfield thickness of 100 µm compared to the 
latest assessment (OCT) by the investigator, an increase in intraretinal fluid, subretinal fluid, or subretinal hyper-reflective material, that in the investigator’s 
opinion is related to progression of the subject’s neovascular AMD. Subjects who will receive rescue treatment need to perform ET/EOS Visits and 
discontinue from the study discontinue the study treatment and should have the reason for treatment discontinuation documented on the Treatment 
Discontinuation page of the eCRF and continue with all their regularly scheduled visits and assessments until Week 52 except for study treatment 
administration. If a subject chooses to withdraw from the study or if, in the opinion of the investigator, the subject should be prematurely 
withdrawn, then the ET Visit should be completed as soon as possible after discontinuing the study treatment but no later than 28 days after 
discontinuation. 
i. 
Intraocular pressure will be measured on both eyes at screening, and on the study eye prior to IVT injection of the study drug, and 60±30 mins after IVT 
injection of the study drug at each visit from baseline/Day 1 to EOT (48 weeks). If the pre-procedure IOP is equal to or greater than 30 mmHg, IVT 
injection will not be administered (either withheld or delayed) until IOP is decreased to acceptable safety levels as per investigator’s medical 
judgement. IOP should be measured after OCT and FA are completed to avoid corneal erosion. Finger counting test to be performed immediately after the 
IVT injection of the study drug. IOP will also be performed at any time during the ET/EOS Visit. 
… 
m. Hematology, chemistry, and urinalysis samples will be collected prior to IVT injection of the study drug. Urine samples will be collected prior to performing 
FA to avoid false elevations in urine protein values. No pregnancy test is required for women of non-child-bearing potential. For women of child-


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bearing potential, serum pregnancy test will be performed at screening and in case of a positive urine test during the study; urine pregnancy test 
will be performed at the Baseline, ET and EOS Visits; Tthe FSH and LH levels to be measured at screening for women of child-bearing potential. 
Hematology, chemistry, and urinalysis samples will also be performed at any time during the visit at ET/EOS Visit. 
 
Reason/Justification for Change 
The following changes were made to the footnotes of Table 6-1. 
• 
Footnote a: As per the US FDA request to keep subjects in the study to continue with their regularly scheduled visits after study treatment discontinuation, 
the relevant text has been updated. 
• 
Footnote c: For clarity, the timing of slit lamp examination has been updated to all planned scheduled visits during the study. 
• 
Footnote d: For clarity, the timing of dilated fundoscopy has been updated to all planned scheduled visits during the study. 
• 
Footnote e: As per the US FDA recommendation on collecting data after study treatment discontinuation, women who have a positive serum pregnancy test 
will continue with their regularly scheduled visits after study treatment discontinuation and should be followed-up until the resolution of pregnancy. 
• 
Footnote f: As per the sponsor’s decision to allow treatment of fellow eye for the whole duration of the study, prohibited medications that were initially 
applied to both eyes have been changed to only study eye. 
• 
Footnote h: Part of the text on rescue treatment was updated due to the US FDA recommendation of collecting data after study treatment discontinuation 
due to receiving rescue treatment. Additionally, the condition for rescue treatment of an increase in the central subfield thickness of 100 µm compared to 
the latest assessment (OCT) by the investigator was removed. 
• 
Footnote i: The pre-injection IOP pressure was added as per the request from the Russian regulatory agency to add this condition to ensure participant 
safety. 
• 
Footnote m: The pregnancy tests were specified for women of non-child-bearing potential and women of child-bearing potential. 


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Table concerned 
Table 6-2 
Clinical Laboratory Evaluations 
Initial wording 
 
 
 
 
 
 
 
 
 
 
 


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Amended or new wording 
 
Reason/Justification for Change 
The table of clinical laboratory evaluations was updated to include all the laboratory tests provided by Covance. 


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Figure concerned 
Figure 3-1 
 Study Schema 
Initial wording 
 
 
 
 
 
 


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Amended or new wording 
 
Reason/Justification for Change 
In Figure 3-1 Study Schema, the laboratory assessments at the Week 48 EOT Visit have been removed. 
 

SAP_001.pdf: 


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SAP Version History 
Version no. 
Approved date Changed part and short reason 
For which event 
Version 1.0 
14DEC2021 
   
IDMC 
2nd meeting 
Version 2.0 
25MAY2022 
Changed per protocol version 3.0: 
1. Updated reference to ‘DHHS 2011 
[Eylea Statistical Review, Appendix 
Tables A.1 and A.2]’ in section 4.1. 
2. Updated missing data assumption of 
tipping point approach in section 4.5.1.  
3. Added analysis of ‘Relationship to 
IVT injection procedure’ in section 
4.5.2 and section 9.1. 
4. Added treatment compliance 
category of ‘>100’ to satisfy the 
analysis in section 7.2.1. 
5. Deleted standard deviation from the 
description of BCVA and OCT figure 
in section 8.4.1 and 8.4.2 by referring 
to Eylea® study. 
6. Changed all ‘patients’ to ‘subjects’ 
through whole SAP in order to keep the 
text uniform. 
7. For PK analysis and PK sampling 
time out of window, changed ‘excluded 
from the calculation’ to ‘included in the 
calculation’ in section 10.2. 
8. In section 10.3: WinNonlin version 
updated from 8.0 to 8.3;  Renamed PK 
Parameters to be consistent with 
protocol (Tmax to tmax, AUCtau to AUC0-
tau, AUCinf to AUC0-inf); AUClast 
parameter replaced with AUC0-t to be 
consistent with protocol;  
Interim Analysis 
and Final Analysis  


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Additional text added to explain the 
reason for missing parameters “If the 
number of data points used to calculate 
λz is less than 3 (not including Cmax), or 
the calculated coefficient of 
determination (R2) value for λz is < 
0.800, λz and the parameters that 
utilize λz for determination AUC0-inf, 
t1/2 will not be reported”. 
9. Updated wording for interim 
analysis per protocol version 3.0 in 
section 12. 
10. Updated wording for Independent 
Data Monitoring Committee per 
protocol version 3.0 in section 13. 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... VI 
1. 
INTRODUCTION .............................................................................................................. 1 
2. 
OBJECTIVES ..................................................................................................................... 2 
2.1. 
Primary Objective ............................................................................................................... 2 
2.2. 
Secondary Objectives .......................................................................................................... 2 
2.3. 
Exploratory Objectives ....................................................................................................... 2 
3. 
INVESTIGATIONAL PLAN ............................................................................................. 2 
3.1. 
Overall Study Design and Plan ........................................................................................... 2 
3.2. 
Study Endpoints .................................................................................................................. 4 
3.2.1. 
Primary Endpoint ............................................................................................................... 4 
3.2.2. 
Secondary Endpoints ......................................................................................................... 4 
3.2.3. 
Exploratory Endpoints ....................................................................................................... 5 
3.3. 
Estimands ............................................................................................................................ 5 
3.4. 
Treatments........................................................................................................................... 7 
3.4.1. 
Treatment of Fellow Eye ................................................................................................... 7 
3.4.2. 
Rescue Treatment .............................................................................................................. 7 
3.5. 
Dose Adjustment/Modifications ......................................................................................... 8 
4. 
GENERAL STATISTICAL CONSIDERATIONS ............................................................ 8 
4.1. 
Sample Size ......................................................................................................................... 9 
4.1.1. 
Statistical Justification of the 3.8 Letter Equivalence Margin ......................................... 10 
4.2. 
Randomization, Stratification, and Blinding .................................................................... 11 
4.3. 
Analysis Set ...................................................................................................................... 12 
4.3.1. 
Full Analysis Set (FAS) ................................................................................................... 12 
4.3.2. 
Modified Full Analysis Set (mFAS) ................................................................................ 12 
4.3.3. 
Per-Protocol Set (PPS)..................................................................................................... 12 
4.3.4. 
Safety Set (SAF) .............................................................................................................. 12 
4.3.5. 
Pharmacokinetic Analysis Set (PK Set) .......................................................................... 13 
4.4. 
Analysis Window/Visit ..................................................................................................... 13 
4.5. 
Handling of Missing Data ................................................................................................. 13 
4.5.1. 
BCVA Data...................................................................................................................... 13 
4.5.2. 
Adverse Event Data ......................................................................................................... 14 
4.5.3. 
Prior/Concomitant Medication Data ................................................................................ 14 
5. 
SUBJECT DISPOSITION ................................................................................................ 14 
5.1. 
Disposition ........................................................................................................................ 14 
5.2. 
Protocol Deviations ........................................................................................................... 16 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................... 16 
6.1. 
Demographics and Baseline Characteristics ..................................................................... 16 
6.2. 
Baseline Ocular Characteristics ........................................................................................ 17 
6.3. 
Medical History ................................................................................................................ 17 
6.4. 
Inclusion and Exclusion Criteria ....................................................................................... 18 
7. 
TREATMENTS AND MEDICATIONS .......................................................................... 18 
7.1. 
Prior and Concomitant Medications ................................................................................. 18 
7.1.1. 
Prior Medications ............................................................................................................ 18 
7.1.2. 
Concomitant Medications ................................................................................................ 18 
7.2. 
Study Treatments .............................................................................................................. 19 


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7.2.1. 
Extent of Exposure and Compliance ............................................................................... 19 
8. 
EFFICACY ANALYSIS .................................................................................................. 19 
8.1. 
Estimands and Strategies for Managing Intercurrent Events ............................................ 20 
8.2. 
Primary Efficacy Endpoint ............................................................................................... 22 
8.2.1. 
Primary Analysis ............................................................................................................. 22 
8.2.2. 
Assumption Testing ......................................................................................................... 23 
8.2.3. 
Sensitivity Analysis ......................................................................................................... 24 
8.2.4. 
Supportive Analysis ......................................................................................................... 24 
8.3. 
Secondary Efficacy Endpoint ........................................................................................... 24 
8.3.1. 
Secondary Analysis ......................................................................................................... 25 
8.3.2. 
Sensitivity Analysis ......................................................................................................... 25 
8.4. 
Efficacy Assessments ........................................................................................................ 26 
8.4.1. 
Best Corrected Visual Acuity (BCVA) ........................................................................... 26 
8.4.2. 
Optical Coherence Tomography (OCT) .......................................................................... 26 
8.4.3. 
Fluorescein Angiography (FA) and Fundus Photography (FP)....................................... 27 
9. 
SAFETY ANALYSIS ....................................................................................................... 27 
9.1. 
Adverse Events ................................................................................................................. 27 
9.1.1. 
Incidence of Adverse Events ........................................................................................... 28 
9.1.2. 
Relationship of Adverse Events to Study Drug or IVT Injection Procedure .................. 29 
9.1.3. 
Severity of Adverse Event ............................................................................................... 29 
9.1.4. 
Serious Adverse Events ................................................................................................... 29 
9.1.5. 
Adverse Events Leading to Treatment Discontinuation .................................................. 29 
9.1.6. 
Adverse Events Leading to Study Discontinuation ......................................................... 30 
9.1.7. 
Death ................................................................................................................................ 30 
9.2. 
Clinical Laboratory Evaluations ....................................................................................... 30 
9.3. 
Vital Sign Measurements .................................................................................................. 31 
9.4. 
Electrocardiogram ............................................................................................................. 32 
9.5. 
Ophthalmological assessments ......................................................................................... 32 
9.5.1. 
Slit Lamp Biomicroscopy ................................................................................................ 32 
9.5.2. 
Dilated Fundoscopy ......................................................................................................... 32 
9.5.3. 
Intraocular Pressure (IOP) and Vision Check ................................................................. 32 
10. 
PHARMACOKINETICS .................................................................................................. 33 
10.1. Data Handling ................................................................................................................... 33 
10.2. Plasma Concentrations ...................................................................................................... 33 
10.3. Plasma Pharmacokinetic Parameters ................................................................................ 34 
11. 
IMMUNOGENICITY ANALYSIS .................................................................................. 35 
12. 
INTERIM ANALYSIS ..................................................................................................... 36 
13. 
INDEPENDENT DATA MONITORING COMMITTEE ............................................... 36 
14. 
REFERENCES ................................................................................................................. 37 
15. 
APPENDICES .................................................................................................................. 38 
15.1. Schedule of Events ............................................................................................................ 38 
15.2. Guideline of Missing Date Imputation for Safety Analysis .............................................. 41 
 
 
 
 
 


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List of Abbreviations 
 
Abbreviation 
Definition 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
AMD 
age-related macular degeneration 
ANCOVA 
analysis of covariance  
ATC 
Anatomical Therapeutic Chemical  
AUC0-inf 
area under the concentration-time curve from zero to an infinite time 
AUC0-t 
area under the concentration-time curve from zero to last quantifiable 
time point 
AUC0-tau 
area under the concentration-time curve from zero to the end of the 
dosing period 
BCVA 
best corrected visual acuity 
BOCF 
baseline observation carried forward 
BLQ 
limit of quantification 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CM 
concomitant medication  
CNV 
choroidal neovascularization 
CRO 
contract research organization 
CRT 
central retinal thickness 
CS 
clinically significant. 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOS 
end-of-study 
EOT 
end-of-treatment 
ET 
early termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
fluorescein angiography 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
FP 
fundus photography 


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FSH 
follicle-stimulating hormone 
GMT 
geometric mean titer 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
independent ethics committee 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
IVT 
intravitreal 
LH 
luteinizing hormone 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo  
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
modified full analysis set 
MI 
multiple imputation 
MMRM 
mixed-effects model for repeated measures 
NCS 
not clinically significant 
NAb 
neutralizing antibodies 
OCT 
optical coherence tomography 
PDT 
photodynamic therapy 
PI 
principal investigator 
PK 
Pharmacokinetic 
PlGF 
placental growth factor 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
per-protocol set 
PT 
preferred term  
SAE 
serious adverse event 
SAF 
safety set 
SD 
standard deviation 
SOC 
standard of care 
t1/2 
elimination half-life 
tmax 
time to reach the maximum plasma concentration 


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TEAE 
treatment-emergent adverse event 
TOST 
2 one-sided tests 
ULOQ 
upper limit of quantification  
VA 
visual acuity 
VEGF 
vascular endothelial growth factor 
WHODD 
World Health Organization Drug Dictionary 


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1. Introduction 
SCD411 is a proposed biosimilar of Eylea® having aflibercept as the active substance that binds 
to vascular endothelial growth factor A (VEGF-A) and produced in Chinese hamster ovary cells 
by recombinant DNA technology. Aflibercept, the drug substance of Eylea, is a recombinant 
fusion protein consisting of 2 identical polypeptide chains, each comprising the second Ig domain 
of the human vascular endothelial growth factor (VEGF) receptor 1 and the third Ig domain of the 
human VEGF receptor 2, with both polypeptide chains fused to the Fc domain of human IgG1 
(Avery et al 2017). 
Aflibercept acts as a soluble decoy receptor that binds VEGF-A and Placental Growth Factor 
(PlGF) with higher affinity than their natural receptors, and thereby can inhibit the binding and 
activation of these cognate VEGF receptors (Papadopoulos et al 2012). 
Neovascular (wet) age-related macular degeneration (AMD) is characterized by pathological 
choroidal neovascularization (CNV). Leakage of blood and fluid from CNV may cause retinal 
thickening or edema and/or sub-/intra-retinal hemorrhage, resulting in loss of visual acuity (VA) 
(Schneider et al 2005). 
SCD411 is being developed as a biosimilar to the reference product Eylea® (aflibercept). Based 
on the proposed extensive analytical comparability testing, comparative nonclinical testing, and 
comparative clinical studies using the same licensed reference product, the current study is 
designed to evaluate comparability between SCD411 and aflibercept. Based on the data from 
aflibercept clinical studies VIEW 1, VIEW 2, COPERNICUS, GALILEO, VIBRANT, VIVID, 
VISTA, and MYRROR, wet AMD is considered as the most suitable condition to prove similarity 
between SCD411 and aflibercept as the reference product. 
The available data regarding the PK of the reference product suggests that a proper PK 
characterization will not be possible after single IVT administration. In a PK substudy of Eylea in 
6 neovascular wet AMD patients with frequent sampling, maximum plasma concentrations (Cmax) 
of free aflibercept (systemic) 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 IVT injection and were undetectable 2 weeks following 
dosage in almost all patients (Eylea® 2019). It is evident that in some cases no measurable systemic 
levels of free aflibercept were registered after IVT administration. Hence, a comparative PK 
evaluation in patients with AMD will likely not provide any information of relevance to support 
biosimilarity. Although the systemic exposure of SCD411 is expected to also be very low at steady 
state, there is no previous human data on SCD411, and thus this assumption requires experimental 
support. Hence, PK assessment will be performed in the current study following the first and the 
third doses of SCD411. 


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As aflibercept is a therapeutic protein, there is a potential for immunogenicity. No cases of active 
neutralizing antibodies (NAb) were observed after administration of Eylea. It is evident that 
immunogenicity is not presenting a substantial safety concern in patients treated with aflibercept 
injections. There was no substantial difference in the proportion of patients testing positive for 
anti-drug antibodies (ADA) in different indications, including wet AMD (Eylea® 2019). Based on 
this observation, the indication chosen for this study is expected to provide sound data for 
comparing the immunogenicity of the test product (SCD411) with that of Eylea. 
The clinical part of the comparison will be based on clinical efficacy and safety data obtained after 
IVT administration to subjects with wet AMD in the current pivotal study. 
2. Objectives 
2.1. Primary Objective 
• 
To prove the equivalence of SCD411 as compared to Eylea (aflibercept) in best corrected 
visual acuity (BCVA) after 8 weeks of treatment among subjects with wet AMD. 
2.2. Secondary Objectives 
• 
To compare the safety and tolerability of SCD411 and aflibercept. 
• 
To compare the efficacy of SCD411 and aflibercept after 8 weeks and 52 weeks of 
treatment demonstrated by BCVA, central retinal thickness (CRT), and CNV. 
• 
To compare the immunogenicity of SCD411 and aflibercept by presenting information of 
the development of anti-SCD411 antibodies. 
2.3. Exploratory Objectives 
• 
To compare PK parameters of SCD411 and aflibercept. 
• 
To quantify free and bound aflibercept and SCD411. 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a Phase III, randomized, double-masked, parallel-group, multicenter study to demonstrate 
biosimilarity of SCD411 compared to Eylea (aflibercept) among adult subjects with neovascular 
(wet) AMD. 
Approximately 560 subjects with wet AMD will be enrolled in this study across approximately 
155 sites in 14 countries. Upon entry into the study, subjects will be assigned a screening number. 
Subjects who meet all inclusion and none of the exclusion criteria will return to the clinic on Day 
1 for further evaluation. Subjects who continue to meet all inclusion and none of the exclusion 


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criteria will be randomly assigned and treated on Day 1. At this visit, the subjects will be randomly 
assigned in 1:1 ratio to receive IVT SCD411 or aflibercept injections. Randomization will be 
stratified by subject participation in the PK substudy. Subjects in Israel will not participate in the 
PK substudy. Randomization will also be stratified by subjects enrolled in Japan. Subjects will be 
treated with study treatment every 4 weeks for the first 3 injections and every 8 weeks thereafter 
until Week 48 as detailed in the Schedule of Events (Appendix 15.1). A schematic of the study 
design is presented in Figure 1.  
This study includes a screening duration up to 3 weeks, treatment duration up to 48 weeks, and 
follow-up duration up to 4 weeks; thus, the total duration of study participation is approximately 
up to 55 weeks. 
All subjects will be assessed once every 4 weeks as detailed in the Schedule of Events (Appendix 
15.1). The End-of-Treatment (EOT) Visit will be scheduled for Week 48. Subjects who 
discontinue the study treatment early should have the reasons for treatment discontinuation 
documented on the Treatment Discontinuation page of the electronic case report form (eCRF). 
Treatment discontinuation in the study is defined as subjects discontinuing the study treatment due 
to adverse event (AE)/lack of efficacy/rescue treatment but not limited to these conditions. Every 
effort should be made to have such subjects remain in the study and continue with their regularly 
scheduled visits and assessments until Week 52 except for study treatment administration. If a 
subject chooses to withdraw from the study or if, in the opinion of the investigator, the subject 
should be prematurely withdrawn from the study, then the Early Termination (ET) Visit should be 
completed as soon as possible after discontinuing the treatment but no later than 28 days after 
discontinuation. The End-of-Study (EOS) Visit will occur 28 days after the EOT at Week 52. The 
end of the study is defined as the date of the last visit of the last subject in the study. 
The study design incorporates an Independent Data Monitoring Committee (IDMC) that will 
review ongoing safety and will also make recommendations to the sponsor as described in the 
IDMC Charter. Details of the IDMC are given in Section 13.  
An interim analysis will be performed once approximately 200 subjects complete Week 52 and all 
subjects complete Week 24 or have discontinued early from the study with details given in Section 
12. 


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Figure 1:  Study Schema 
 
Abbreviations: EOS, end-of-study; EOT, end-of-treatment; ET, early termination; IVT, intravitreal 
3.2. Study Endpoints 
3.2.1. Primary Endpoint 
• 
Change from baseline in BCVA as measured by Early Treatment Diabetic Retinopathy 
Study (ETDRS) letters score or 2702 charts at Week 8. 
3.2.2. Secondary Endpoints 
• 
Safety endpoints include AEs, vital signs, and laboratory assessments up to Week 52. 
• 
Efficacy endpoints are: 
o 
Change from baseline in BCVA as measured by ETDRS letter score or 2702 charts at 
Week 52. 
o 
Change from baseline in CRT at Week 8 as assessed by optical coherence tomography 
(OCT). 
o 
Change from baseline in CRT at Week 52 as assessed by OCT. 
o 
Change from baseline in CNV area at Week 8. 
o 
Change from baseline in CNV area at Week 52. 
o 
Percentage of subjects who gain at least 15 letters in BCVA as measured by ETDRS 
letter score or 2702 charts compared with baseline at Week 8. 
o 
Percentage of subjects who gain at least 15 letters in BCVA as measured by ETDRS 
letter score or 2702 charts compared with baseline at Week 52. 


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• 
Immunogenicity endpoints include the evaluation of development of anti-SCD411 or anti-
aflibercept antibodies using blood samples taken at Baseline, at Weeks 4, 8, 20, 36, and 
52. Neutralizing antibodies will be tested when ADA results are confirmed to be positive. 
3.2.3. Exploratory Endpoints 
PK parameters include area under the concentration-time curve from time zero to the last 
quantifiable time point (AUC0-t), AUC from zero to the end of the dosing period (AUC0-tau), AUC 
from zero to infinite time (AUC0-inf), Cmax, time to reach maximum plasma concentration (tmax), 
and elimination half-life (t1/2), of SCD411 and aflibercept. Blood samples, for determination of 
concentrations of SCD411 and aflibercept, will be collected at the timepoints specified in the 
Schedule of Events (Appendix 15.1). As per the Schedule of Events, additional visits will be 
arranged for collecting the PK blood samples. Quantification of free and bound aflibercept and 
SCD411 in plasma will be performed using blood samples at predose, and at +1 day, +3 days, 
+7 days, +14 days, and +28 days following the first dose. At Week 8, PK samples will be taken 
predose, and at +1 day, +3 days, +7 days, +14 days, and +28 days following the third (Week 8) 
dose. 
3.3. Estimands 
The primary estimand for the primary objective is the mean treatment difference in BCVA change 
from baseline at Week 8. At Week 52, the primary estimand of interest is the mean treatment 
difference in BCVA change from baseline at Week 52. For the primary estimand, any observations 
post receipt of rescue therapy in the study eye will be set to missing, thereby estimating the 
treatment effect as though subjects do not receive rescue therapy. For each of the Week 8 and 
Week 52 analyses, the secondary estimand will be presented where post rescue will not be set to 
missing but will be included in the mixed-effects model for repeated measures (MMRM) analysis. 
The secondary estimands are constructed to estimate the treatment effect while including the 
impact of rescue therapy, which may better reflect actual real-world outcomes, where rescue 
therapy would likely be given when lack of efficacy is seen. 
Potential intercurrent events to the estimands are listed in Table 1. The relationship between 
objectives, endpoints and estimands are listed in Table 2-1 and Table 2-2 separately. 


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Table 1: Intercurrent Event Types 
Label 
Intercurrent Event Type 
IcEv1 
(Treatment discontinuation 
without receipt of rescue therapy) 
Discontinuation of study eye treatment with continued 
participation in study without receipt of rescue therapy 
IcEv2 
(Rescue therapy) 
Receipt of rescue therapy in the study eye 
IcEv3 
(Study discontinuation) 
Discontinuation from study, regardless of reason 
Abbreviation: IcEv, intercurrent event. 
 
Table 2-1 Objectives, Endpoints, and Estimands (at Week 8) 
Objective 
Estimand 
Label 
Endpoint 
Estimand Description 
To prove the equivalence of 
SCD411 as compared to Eylea 
(aflibercept) in best corrected 
visual acuity (BCVA) after 8 
weeks of treatment among 
subjects with wet AMD 
Primary 
Estimand 
Change from baseline 
in BCVA as measured 
by ETDRS letters 
score or 2702 charts at 
Week 8 
Mean treatment difference 
in BCVA change from 
baseline at Week 8 as if 
subjects do not receive 
rescue therapy 
As above 
Secondary 
Estimand 
As above 
Mean treatment difference 
in BCVA change from 
baseline at Week 8 while 
allowing for receipt of 
rescue therapy 
 
Table 2-2: Objectives, Endpoints, and Estimands (at Week 52) 
Objective 
Estimand 
Label 
Endpoint 
Estimand Description 
To prove the equivalence of 
SCD411 as compared to Eylea 
(aflibercept) in BCVA after 52 
weeks of treatment among 
subjects with wet AMD 
Primary 
Estimand 
Change from baseline 
in BCVA as measured 
by ETDRS letters 
score or 2702 charts at 
Week 52 
Mean treatment difference 
in BCVA change from 
baseline at Week 52 as if 
subjects do not receive 
rescue therapy 
As above 
Secondary 
Estimand 
As above 
Mean treatment difference 
in BCVA change from 
baseline at Week 52 while 
allowing for receipt of 
rescue therapy 
 


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3.4. Treatments   
Subjects who complete the study screening and baseline assessments and meet all the eligibility 
criteria will enter the study and will be randomly assigned in a 1:1 ratio on Day 1 to receive 
SCD411 or aflibercept. The study treatment solution is stored in glass vial. One vial delivers a 
dose of 2 mg aflibercept or SCD411 in 50 µL. Each vial should only be used for the treatment of 
a single eye. 
The IVT injection procedure should be carried out under controlled aseptic conditions. Adequate 
anesthesia and a topical broad-spectrum microbicide and antibiotics can be given as per the system 
organ class in World Health Organization Drug Dictionary (WHODD) and this information should 
be recorded in the eCRF. 
Study treatment will be dispensed every 4 weeks for the first 3 injections and every 8 weeks 
thereafter until Week 48 as detailed in the Schedule of Events (Appendix 15.1). Dosing visits will 
be allowed within ±2 days for the second and third injections and within ±7 days for the fourth 
injection onwards of the scheduled dosing visit date (except Week 0 [Day 1], visit window not 
allowed). All applications outside of the specified windows will be captured a protocol deviation. 
3.4.1. Treatment of Fellow Eye 
Treatment of fellow eye will be allowed at any time during the study if a subject is newly diagnosed 
with neovascular AMD or has worsening neovascular AMD in the fellow eye. The fellow eye 
should be treated only with Eylea as per investigator’s discretion. In this case, fellow eye data of 
dilated fundoscopy, intraocular pressure (IOP), fellow eye treatment date and medication name 
will be collected via eCRF. Also, the fellow eye treatment injection is not permitted on the same 
day as the study eye treatment.  
3.4.2. Rescue Treatment 
In the study eye, rescue treatment for neovascular AMD is not permitted at any point in time. If it 
is observed that efficacy is not achieved by the study treatment, as determined by the investigator, 
subjects can be considered for rescue treatment after Week 4 if any 1 of the following conditions 
are met as assessed by the masked investigators: 
• 
Decrease of VA letter score of 15 letters or more from the last assessment and/or 
• 
An increase in intraretinal fluid, subretinal fluid, or subretinal hyper-reflective material 
that, in the investigator’s opinion, is related to progression of the subject’s neovascular 
AMD 


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Subjects who will receive rescue treatment need to discontinue the study treatment and should 
have the reason for treatment discontinuation documented on the Treatment Discontinuation page 
of the eCRF and continue with their regularly scheduled visits and assessments until Week 52 
except for study treatment administration. If a subject chooses to withdraw from the study or if, in 
the opinion of the investigator, the subject should be prematurely withdrawn from the study, then 
the ET Visit should be completed as soon as possible after discontinuing the study treatment but 
no later than 28 days after discontinuation. 
3.5. Dose Adjustment/Modifications 
Dose reductions will not be allowed. 
4. General Statistical Considerations 
Tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed with SAS® software, version 9.4 or higher. 
In general, continuous variables will be summarized descriptively using the number of 
observations (n), mean, standard deviation (SD), median, first quartile (Q1), third quartile (Q3), 
minimum (Min), and maximum (Max). Categorical variables will be summarized using frequency 
counts and percentages. 
Descriptive statistics for continuous variables in summary tables will include the number of 
subjects in the analysis (n), mean, SD, median, first quartile (Q1), third quartile (Q3) and range 
(minimum, maximum). Descriptive statistics for categorical variables in summary tables will 
include counts and percentages. Graphical summaries of the data may be presented. 
For summary precision, mean, median, Q1 and Q3 will have one more decimal place than the 
reported value, SD will have two more decimal places than the reported value, minimum and 
maximum will have the same decimal place as the reported value. Percentages and 95% CI will 
have one decimal place. When count data are presented, the percentage will be suppressed when 
the count is zero in order to draw attention to the non-zero counts. A row denoted “Missing” will 
be included in count tabulations where specified on the shells to account for dropouts and missing 
values. 
The most recent non-missing measurement collected prior to the first administration of study drug 
will be used as the baseline value. 
Subgroup analyses will be performed by region/country (Japan, non-Japan). Demographics and 
baseline characteristics, safety, efficacy and immunogenicity endpoints may be analyzed in 


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subgroups. Subgroup summaries will be descriptive only with no statistical hypothesis testing 
performed.  
All data obtained on the eCRF will be provided in separate data listings showing individual subject 
values by treatment group and visit, if applicable. 
4.1. Sample Size 
The equivalence margin agreed upon with EMA and PMDA was determined using the data 
presented from MARINA (and ANCHOR) and VIEW studies. These data were used to estimate 
the efficacy of aflibercept compared to the placebo treatment in subjects with wet AMD. It was 
shown that in MARINA, subjects on average lost 2.5 letters of BCVA over 2 months in the sham-
treated control arm and gained 5 letters in the treatment arm of 2 mg, and that in the VIEW studies 
6.8 to 7.5 letters were gained among subjects with wet AMD at Week 8 into treatment on a 2 mg 
dose. Combining both study data, the treatment effect compared to the placebo would be estimated 
as approximately 9.3 to 10 letters. A margin of 3.8 letters would be translated to a preservation of 
59% to 62% of the difference between Eylea and sham and is less than a 1 line change in VA. 
Equivalence discussions for EMA and PMDA were based upon a 95% CI approach or 2 one-sided 
tests (TOST) at the α=0.025 level. The statistical justification of the 3.8 letter equivalence margin 
is described in Section 4.1.1. 
The FDA requested a tighter equivalence margin of 3 letters but agreed equivalence can be 
determined from a 90% CI approach (equivalent to TOST at the α=0.05 level). 
Standard deviation (SD) for the mean change from baseline at early visits (Weeks 4 to 12) based 
on observed data for the FAS ranged from 8.73 to 11.99 considering all treatment groups from 
VIEW1 and from 7.4 to 11.0 letters for the VIEW2 study (DHHS 2011 [Eylea Statistical Review, 
Appendix Tables A.1 and A.2]). For power calculations, a range of SD between 10.4 and 11.8 was 
assumed to be conservative and cover the majority of larger SD values seen in the observed data. 
A sample size of 266 subjects per treatment arm was selected as it provides at least 80% power for 
the FDA, EMA, and PMDA analyses for the range of SD considered when using  TOST on data 
from a parallel-group design. For the FDA analysis based on equivalence limits of -3.0 and 3.0 
letters, α=0.05 significance level (90% CI), assuming the true difference between the means is 0.0, 
power of 91% is achieved for SD of 10.4 letters and power of 80% is achieved for SD of 11.8 
letters. For the EMA and PMDA analyses based on equivalence limits of -3.8 and 3.8 letters, 
α=0.025 significance level (95% CI), assuming the true difference between the means is 0.0, power 
of 98% is achieved for SD of 10.4 letters and power of 92% is achieved for SD of 11.8 letters when 
sample size is 266 per treatment arm. Considering approximately 5% loss from randomization 
through Week 8, the total sample size required is 560. 


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A subset of 40 subjects (20 per group) will be selected for collection of PK samples. The sample 
size is not test-driven since no equivalence test will be performed for PK parameters. 
4.1.1. Statistical Justification of the 3.8 Letter Equivalence Margin 
For all purposes, the clinical equivalence question of 3.8 letters is to demonstrate that 3.8 letters 
of difference between treatments is immaterial to a clinician in determining the choice of treatment 
for their patients.   
As there is no direct comparison in the literature of Eylea to placebo/sham an indirect comparison 
is made by first comparing Eylea to Lucentis and then Lucentis to Placebo. The primary efficacy 
endpoint for the biosimilar comparison will be made at 8 weeks. As the primary efficacy endpoints 
for the phase III studies for Lucentis (Marina, Anchor) and Eylea (VIEW 1, VIEW 2) were at 52 
weeks, there is limited published data for the BCVA mean change from baseline at Week 8.   
The Statistical Review from the FDA Summary Basis of Approval for the original Eylea AMD 
submission contains appendices which provide summary statistics on the ITT observed data for 
the BCVA mean and BCVA mean change from baseline by study visit, including week 8.  This 
data, along with data from the Lucentis label will be used to estimate a difference between Eylea 
and Sham at Week 8 from the estimated 95% CI lower limit for the difference between (Lucentis 
– Sham). 
Study 
Eylea 
Lucentis 
Difference 
(Eylea – Lucentis) 
n 
Mean 
SD 
n 
Mean 
SD 
VIEW 1 
298 
7.5 
10 
293 
7.1 
9.95 
0.4 
VIEW 2 
305 
5.3 
9.2 
287 
6.5 
8.6 
-1.2 
Average 
9.6 
9.275 
-0.4 
 
From VIEW 1 and VIEW 2, the average SD for BCVA change from baseline at 8 weeks for 
Lucentis is 9.3 letters.  From the Lucentis label, at Week 52, the SD for BCVA change from 
baseline is 17.9 letters for sham and 14.1 for Lucentis, a Sham/Lucentis ratio of ~1.3. The Lucentis 
average SD for BCVA change from baseline at week 8 of 9.3 letters from VIEW 1 and VIEW 2 
studies is inflated by 1.3 to estimate the SD for Sham arm at Week 8 of 12.1 letters. 
From the Lucentis label, for AMD-1 study (Marina), the BCVA mean change from baseline at 
Week 8 shows an approximate 2.5 letters decrease for sham and an approximate 5 letters increase 
for Lucentis. The Marina study enrolled 229 sham subjects and 230 Lucentis subjects.  These 
numbers with the estimated SD values will be used to estimate the 95% CI lower limit for the 
difference (Lucentis – Sham) at Week 8. 


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Study 
Lucentis 
Sham 
Difference 
(Lucentis – Sham) 
Lower 
95% CI 
(z=1.96) 
n 
Mean 
SD 
n 
Mean 
SD 
Estimate 
Pooled SE 
Estimate 
for Marina 
230 
5.0 
9.3 
229 
-2.5 
12.1 
7.5 
1.0076 
5.5249 
 
Adjusting the estimated 95% CI lower limit for (Lucentis – Sham) with the average difference 
(Eylea – Lucentis) from the View 1 and View 2 studies, the estimate of minimal effect size for 
Eylea to sham is (5.5 – 0.4) = 5.1 letters for Week 8 which is larger than the proposed margin of 
3.8 letters. Based upon the NEI CATT study which compared efficacy across anti-VEGF products, 
an acceptable non inferiority margin was defined as that which is smaller than the believed smallest 
effect size for the reference treatment. This further corroborates the case as 3.8 is less than 5.1. 
4.2. Randomization, Stratification, and Blinding 
All subjects will be centrally randomized in a 1:1 ratio to receive SCD411 or aflibercept IVT 
injections at the baseline/randomization visit (Day 1) using Interactive Response Technology 
(IRT). Randomization will be stratified by participation in the PK substudy (yes/no). Subjects in 
Israel will not participate in the PK substudy. Randomization will also be stratified by subjects 
enrolled in Japan. Before the study is initiated, the log in information and directions for the IRT 
will be provided to each site. Only qualified study staff and those delegated the responsibility of 
study drug administration should administer the study drug injections. Biostatistics will generate 
the randomization schedule using SAS® software Version 9.4 for the IRT, which will link 
sequential subject randomization numbers to treatment codes. The randomization schedule will be 
created by the dedicated randomization team, stored in a separate project area, and will be blinded 
to the project team with the exception for the unblinded investigator involved in performing the 
IVT injections. 
This is a double-blinded study. Subjects and study site staff involved in subject management and 
study assessments will be blinded to study treatment assignment. The sponsor, the delegated 
contract research organization (CRO), and imaging teams will also be blinded to the study 
treatment. Only the unblinded investigator involved in performing the IVT injections will be 
unblinded to study treatment. These individuals are not allowed to discuss treatment and/or subject 
outcome with masked study staff, including the evaluating investigator. 
A subject’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the subject depends on knowing the study treatment the subject received. In the event 


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that the treatment assignment needs to be unblinded because of a medical emergency, the principal 
investigator (PI) may unblind an individual subject’s treatment allocation. 
The PI is encouraged to first contact the sponsor representatives to discuss the medical emergency 
and the reason for revealing the actual treatment received by that subject as soon as possible. The 
investigator should not share any unblinded information with the sponsor and monitoring team. 
The treatment assignment will be unblinded through IRT. Reasons for treatment unblinding must 
be clearly explained and justified in the eCRF. The date on which the code was broken along with 
the identity of the person responsible for breaking the code, must also be documented in the eCRF. 
4.3. Analysis Set 
The following analysis sets will be used in the statistical analyses. 
4.3.1. Full Analysis Set (FAS) 
The Full Analysis Set includes all randomized subjects who received at least 1 injection of the 
study drug. Subjects will be analyzed according to the treatment group to which they were 
randomized. The primary set for efficacy analysis will be the FAS. 
4.3.2. Modified Full Analysis Set (mFAS) 
The Modified Full Analysis Set includes all randomized subjects who received at least 1 injection 
of the study drug and had at least 1 postbaseline BCVA assessment in the study eye. Subjects will 
be analyzed according to the treatment group to which they were randomized. PMDA requires the 
efficacy analysis also need to be conducted based on mFAS without multiple imputation as 
supportive analysis.  
4.3.3. Per-Protocol Set (PPS) 
The Per-Protocol Set includes all subjects in the FAS, excluding those with significant protocol 
deviations. Subjects will be analyzed according to the treatment group to which they were 
randomized. For the EMA submission, the primary efficacy endpoint must also meet equivalence 
for PPS. 
4.3.4. Safety Set (SAF) 
The Safety Analysis Set includes all subjects receiving at least 1 injection of the study drug. 
Subjects will be analyzed according to the treatment group they actually received. The SAF will 
be the primary analysis set for safety, tolerability, and immunogenicity analyses. 


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4.3.5. Pharmacokinetic Analysis Set (PK Set) 
The Pharmacokinetic Analysis Set is the subset of subjects in FAS who have sufficient evaluable 
blood samples. A subset of 40 subjects (20 per group) will be selected for collection of PK samples. 
Subjects will be analyzed according to the treatment group they actually received. The PK set will 
be used for estimation of PK endpoints. 
4.4. Analysis Window/Visit 
For non-efficacy analysis, no analysis window mapping will be applied. Any scheduled and 
unscheduled visits will be reported by the nominal visits reported on the eCRF. As Early 
Termination (ET) and Week 52 are recorded together as ‘Week 52 ET’ on the eCRF, they will be 
separated as ‘Week 52’ and ‘Early Termination’ during the analysis. 
For efficacy analysis, the analysis visits will be handled in the same way as non-efficacy analysis 
except for the ET visit. The ET assessments will be summarized based on visit window of when 
the visit occurred (e.g., if the subject discontinued study at Week 12, the ET assessment will be 
included in the Week 12 by-visit summaries). Below is the derivation rule: 
a. If visit date of ET – visit date of the previous scheduled visit <=14, then the analysis visit 
window for ET will be the same as the previous scheduled visit. If there are two valid records 
in a scheduled visit, only the record closer to the target study day will be used for summary 
statistics and analyses. 
b. If visit date of ET – visit date of the previous scheduled visit >14, then the analysis visit 
window for ET will be the previous scheduled visit + 4 weeks (e.g., the analysis visit for ET 
will be Week 12 if the previous scheduled visit is Week 8). 
4.5. Handling of Missing Data 
Data will be presented in the listings as reported. For summaries and analysis, the following 
conventions apply. 
4.5.1. BCVA Data 
For the efficacy analysis, missing BCVA data will be imputed using several imputation methods. 
• 
Multiple Imputation (MI) is a statistical technique that replaces each missing value with 
a set of plausible values that represent the uncertainty about the right value. MI has the 
advantages such as providing results in unbiased estimates, more validity than ad hoc 
approaches to missing data; using all available data, preserving sample size and statistical 
power; providing readily interpreted results. The details are described in Section 8.2.1. 


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• 
Tipping point approach is an alternative strategy for handling missing data. This analysis 
is under the missing not at random assumption and doesn’t involve model uncertainty and 
assumptions. It can be used to evaluate the robustness of statistical significance when the 
extent of missing data is reasonable. The details are described in Section 8.2.3. 
• 
Single imputation methods (BOCF, LOCF) will be used for the sensitivity analysis.  
o 
LOCF: Last Observation Carried Forward, this analysis type imputes missing data 
by using a subject's data from their most recent visit.  
o 
BOCF: Baseline Observation Carried Forward, this analysis type imputes missing 
data by using a subject’s baseline result. 
4.5.2. Adverse Event Data 
Missing information regarding ‘Relationship to Study Treatment’ or ‘Relationship to IVT injection 
procedure’ or ‘Severity’ will be imputed as related to study treatment and severe, as the worst-case 
scenario. 
Partially missing AE start dates will be imputed as described in Appendix 15.2, but partially 
missing AE end dates will not be imputed. Completely missing start date will remain missing, with 
no imputation applied.   
In listings of AE data, the partial dates as entered will be displayed. 
4.5.3. Prior/Concomitant Medication Data 
Partially missing concomitant medication (CM) start or end dates will be imputed as described in 
Appendix 15.2. Completely missing start or end dates will remain missing, with no imputation 
applied.  
In listings of CM data, the partial dates as entered will be displayed. 
5. Subject Disposition 
5.1. Disposition 
The number of subjects who were randomized and not randomized, the eligibility criteria 
met/failed will be summarized based on all screened subjects. The number and percentage of 
screen failure subjects will be summarized for each exclusion criteria met and/or inclusion criteria 
failed. A listing will be provided for subjects who were randomized.  
Disposition of all randomized subjects will be summarized by treatment group including: 
• 
Full Analysis Set 


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• 
Modified Full Analysis Set 
• 
Safety Set 
• 
Per-Protocol Set 
• 
Pharmacokinetic Analysis Set 
• 
Number of subjects who completed study treatment 
• 
Number of subjects who prematurely discontinued the study treatment 
• 
Primary reason for treatment discontinuation 
• 
Number of subjects who completed week 8 
• 
Number of subjects who completed study 
• 
Number of subjects who prematurely discontinued the study (early termination) 
• 
Primary reason for study discontinuation 
Primary reasons for treatment/study discontinuation collected on the eCRF will be summarized 
with the following categories separately: 
• 
Death 
• 
Adverse Event 
• 
Lost to Follow-up 
• 
Decision by the investigator that the subject requires alternate treatment for neovascular 
AMD in the study eye 
• 
Decision by the Sponsor or administrative decision 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 
• 
Pregnancy 
• 
Protocol deviation 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 
• 
 New diagnosis or worsening neovascular AMD in the fellow eye at any point during the 
study 
• 
The subject has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal 
• 
The subject withdraws consent 


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• 
A subject misses any of first 2 doses (IVT injection of IP at Week 0 [Day 1] or Week 4) 
after randomization 
• 
Development of rhegmatogenous retinal detachment or stage 3 or 4 macular holes 
• 
A decrease in BCVA of ≥30 letters compared with the last assessment of VA 
• 
A subretinal hemorrhage involving the center of the fovea or, if the size of the hemorrhage 
is ≥50% of the total lesion area 
• 
Clinical signs of irreversible ischemic visual function loss 
• 
Other 
Disposition data will be listed by subjects as collected based on the all randomized subjects. 
5.2. Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the sponsor and the IRB/IEC and agreed to by the investigator. A significant 
deviation occurs when there is nonadherence to the protocol by the subject or investigator that 
results in a significant, additional risk to the subject. Significant deviations can include 
nonadherence to inclusion or exclusion criteria, or nonadherence to FDA regulations or ICH GCP 
guidelines, and will lead to the subject being withdrawn from the study.  
Protocol deviations will be summarized in a table and displayed in a listing based on the all 
randomized subjects. 
6. Demographics and Baseline Characteristics 
6.1. Demographics and Baseline Characteristics 
Demographic and baseline characteristics data to be analyzed will include age, sex, race, ethnicity, 
country, weight, height, and body mass index based on the FAS.  
Descriptive statistics will be calculated for the following continuous characteristics: 
• 
Age (years) 
• 
Weight (kg) 
• 
Height (cm) 
• 
Body Mass Index (BMI) (kg/m2), derived by Weight in kilograms / (Height in meters)2 
Number and percentage of subjects will be provided for the following categorical variables: 
• 
Sex (Male, Female) 


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• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multiple, Other) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• 
Country 
6.2. Baseline Ocular Characteristics 
Following baseline ocular characteristics will be summarized for study eye only based on the FAS.  
Descriptive statistics will be calculated for the following continuous characteristics: 
• 
BCVA Score (Letters) 
• 
CRT (um) 
• 
Total Lesion Area (mm2) 
• 
CNV Area (mm2) 
• 
Leakage Area (mm2) 
• 
IOP (mmHg) 
Number and percentage of subjects will be provided for the following categorical variables: 
• 
Anterior Chamber Flare Grade (0, 1+, 2+, 3+, 4+) 
• 
Anterior Chamber Cells Grade (0, 0.5+, 1+, 2+, 3+, 4+) 
• 
Vitreous Cells Grade (0, Trace, 1, 2, 3, 4) 
• 
Vitreous Haze Grade (0, 1, 2, 3, 4, 5) 
• 
Slit Lamp Examination Overall Assessment (‘Normal’, ‘Abnormal, NCS’, ‘Abnormal, 
CS’) 
• 
Vitreous Overall Assessment (‘Normal’, ‘Abnormal, NCS’, ‘Abnormal, CS’) 
• 
Macula Overall Assessment (‘Normal’, ‘Abnormal, NCS’, ‘Abnormal, CS’) 
• 
Retina Overall Assessment (‘Normal’, ‘Abnormal, NCS’, ‘Abnormal, CS’) 
• 
Optic Nerve Overall Assessment (‘Normal’, ‘Abnormal, NCS’, ‘Abnormal, CS’) 
6.3. Medical History 
Medical history will be summarized based on the SAF. Medical history will be coded according 
to Medical Drug Regulatory Activities (MedDRA) version 23.0 or above and will be summarized 


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by system organ class (SOC) and preferred term (PT), with SOCs sorted alphabetically and PTs 
within each SOC in descending order of frequency.  
Ocular and non-ocular medical histories are captured separately on the eCRF. Ocular medical 
history will be summarized separately from non-ocular medical history. Ocular medical history 
will be summarized for the study eye and fellow eye. Also, a by-subject listing of ocular and non-
ocular medical histories will be presented. 
6.4. Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria deviations noted in the eCRF will be presented for all informed 
consent subjects in a data listing. 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
Medications taken from the informed consent date up to 28 days after the EOT will be coded using 
the latest version of World Health Organization Drug Dictionary (WHODD) during the study. 
Medications will be summarized based on the SAF, sorted by alphabetical order of Anatomical 
Therapeutic Chemical (ATC) level, and then descending frequencies of preferred name. Also, a 
by-subject listing of prior and concomitant medications will be presented. 
Partial missing start or end dates will be imputed as described in Appendix 15.2 for medications 
analysis.  
7.1.1. Prior Medications 
Prior medications are defined as medications that start before the first dose of study drug, 
regardless of when the medications stop. Medication with a missing start date will be considered 
to have a start date before the first dose of study drug.  
Ocular prior medications will be summarized separately from non-ocular prior medications. 
Ocular prior medications will be summarized for the study eye and fellow eye.  
7.1.2. Concomitant Medications 
Concomitant medications are defined as medications first received at or after the first dose of study 
drug, medications received before first dose of study drug and continued after first dose, or 
medications with missing stop date. Medication with a missing stop date will be treated as a 
continuing medication. Medication that starts before the first dose of study drug and continued 
after the first dose will be classified as both prior and concomitant medication.  


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Ocular concomitant medications will be summarized separately from non-ocular concomitant 
medications. Ocular concomitant medications will be summarized for the study eye and fellow 
eye.  
7.2. Study Treatments 
Study treatment will be dispensed every 4 weeks for the first 3 injections and every 8 weeks 
thereafter until Week 48 as detailed in the Schedule of Events (Appendix 15.1). Dosing visits will 
be allowed within ±2 days for the second and third injections and within ±7 days for the fourth 
injection onwards of the scheduled dosing visit date (except Week 0 [Day 1], visit window not 
allowed). 
7.2.1. Extent of Exposure and Compliance 
Extent of exposure will be summarized on study eye only for duration of exposure, planned number 
of injections, actual number of injections, compliance by treatment group. The number (%) of 
subjects who have injection interruptions, and the reasons will be summarized. The number (%) 
of subjects in each compliance category (>100, >= 75 to <=100, >=50 to <75, >=25 to <50, <25, 
Not Calculable) will also be summarized. 
Duration of exposure (days) = end date of study treatment – start date of study treatment + 1. 
Treatment Compliance： 
Planned number of injections refers to the total planned injections as per the protocol up to the 
last date of study drug administration.  
Actual number of injections refers to the total actual injections administered, over the duration 
for which the subject is on the study treatment as documented in the Study Drug Injection page of 
(e)CRF. 
Treatment Compliance (%) = actual number of injections / planned number of injections *100. 
Subject level listings of all injections administered (including fellow eye treatment) along with 
injection interruption reasons will be provided.  
The SAF will be used for all summaries and listings of study treatment. 
8. Efficacy Analysis 
In this study, efficacy is assessed using BCVA by ETDRS letter score or 2702 charts, OCT 
measures CRT, and CNV area is assessed using FA and FP. 


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Unless otherwise specified, all primary and secondary efficacy analyses with statistical hypothesis 
testing performed will be analyzed for the study eye only. Assessments collected for the fellow 
eye will be summarized using descriptive statistics and presented in listings. 
8.1. Estimands and Strategies for Managing Intercurrent Events 
Week 8 
Primary Estimand: The primary estimand is the mean treatment difference in BCVA change 
from baseline at Week 8. For the EMA, the primary analysis will be assessed for both the FAS and 
PPS. For the FDA, PMDA, and any other submissions, the primary analysis will be performed for 
the FAS. The primary estimand treats subjects in the analysis as if subjects do not receive rescue 
therapy. 
Target Population: Subjects with wet AMD as defined in the enrollment criteria. 
Endpoint: Change from baseline in BCVA at Week 8. 
Treatment Condition(s): Dosing at Day 1, Week 4 and Week 8 with one of the following: 
SCD411 or aflibercept, both without rescue therapy. 
Population-level Summary: The difference in mean change from baseline in BCVA at Week 8 
between SCD411 and aflibercept and the corresponding confidence interval (CI) for the mean 
difference. 
Intercurrent Events and Strategies to Address Intercurrent Events: 
• 
Discontinuation of study eye study treatment with continued participation in study without 
receipt of rescue therapy 
o 
Treatment Policy – no imputation; use observed data 
• 
Receipt of rescue therapy in the study eye 
o 
Hypothetical approach – data after receipt of rescue therapy will be set to missing 
and post rescue data will be imputed employing multiple imputation (MI) 
assuming missing at random (MAR) using randomized treatment-based Markov 
Chain Monte Carlo (MCMC) methodology. 
• 
Discontinuation from study, regardless of reason 
o 
Hypothetical approach – missing data after discontinuation will be imputed via MI 
assuming MAR using randomized treatment-based MCMC methodology. 


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Rationale for Strategy: As the primary objective of this study is to show biosimilar equivalence 
between SCD411 and aflibercept after 8 weeks of treatment, the primary estimand is constructed 
to estimate the treatment effect under the assumption that all subjects take study treatments without 
the use of rescue therapy while allowing for subjects to discontinue study treatment. Multiple 
imputation under MAR assumptions results in treatment estimates as if subjects continued as on 
their original treatment. Treating discontinuation as MAR and setting the post rescue assessment 
to missing prior to performing MI was chosen to avoid inflation of the SCD411 treatment effect. 
Subjects who receive rescue therapy or discontinue will have shown lack of efficacy in 
assessments, so the MAR approach should be conservative if the test treatment is not equivalent 
to or less efficacious than the reference product. 
Secondary Estimand: A secondary estimand for the primary efficacy endpoint is the mean 
treatment difference in BCVA change from baseline at Week 8 while allowing for receipt of rescue 
therapy. The estimand will be constructed as above, but the intercurrent event of rescue therapy 
use will be handled using the treatment policy approach. Data post rescue therapy will not be set 
to missing. This estimand is constructed to estimate the treatment effect including the impact of 
rescue therapy, which may better reflect actual real-world outcomes, where rescue would likely be 
given when lack of efficacy is seen. 
Week 52 
Primary Estimand: The primary estimand is the mean treatment difference in BCVA change 
from baseline at Week 52. The analysis will be assessed for both the FAS and PPS. The primary 
estimand treats subjects in the analysis as if subjects do not receive rescue therapy. 
Target Population: Subjects with wet AMD as defined in the enrollment criteria. 
Endpoint: Change from baseline in BCVA at Week 52. 
Treatment Condition(s): Dosing at Day 1, Week 4,Week 8, Week 16, Week 24, Week 32, Week 
40, and Week 48 with one of the following: SCD411 or aflibercept, both without rescue therapy. 
Population-level Summary: The difference in mean change from baseline in BCVA at Week 52 
between SCD411 and aflibercept and the corresponding CI for the mean difference. 
Intercurrent Events and Strategies to Address Intercurrent Events: 
• 
Discontinuation of study eye study treatment with continued participation in study without 
receipt of rescue therapy 
o 
Treatment Policy – no imputation; use observed data 


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• 
Receipt of rescue therapy in the study eye 
o 
Hypothetical approach – data after receipt of rescue therapy will be set to missing 
and post rescue data will be imputed employing MI assuming MAR using 
randomized treatment-based MCMC methodology. 
• 
Discontinuation from study, regardless of reason 
o 
Hypothetical approach – missing data after discontinuation will be imputed via MI 
assuming MAR using randomized treatment-based MCMC methodology. 
Rationale for Strategy: As the primary objective of this study is to show biosimilar equivalence 
between SCD411 and aflibercept after 8 weeks of treatment, the primary estimand is constructed 
to estimate the treatment effect under the assumption that all subjects take study treatments without 
the use of rescue therapy while allowing for subjects to discontinue study treatment. Multiple 
imputation under MAR assumptions results in treatment estimates as if subjects continued as on 
their original treatment. Treating discontinuation as MAR and setting the post rescue assessment 
to missing prior to performing MI was chosen to avoid inflation of the SCD411 treatment effect. 
Subjects who receive rescue therapy or discontinue will have shown lack of efficacy in 
assessments, so the MAR approach should be conservative if the test treatment is not equivalent 
to or less efficacious than the reference product. 
Secondary Estimand: A secondary estimand for the secondary efficacy endpoint is the mean 
treatment difference in BCVA change from baseline at Week 52 while allowing for receipt of 
rescue therapy. The estimand will be constructed as above, but the intercurrent event of rescue 
therapy use will be handled using the treatment policy approach. Data post rescue therapy will not 
be set to missing. This estimand is constructed to estimate the treatment effect including the impact 
of rescue therapy, which may better reflect actual real-world outcomes, where rescue would likely 
be given when lack of efficacy is seen. 
8.2. Primary Efficacy Endpoint 
The primary endpoint is the change from baseline in BCVA as measured by ETDRS letters score 
or 2702 charts at Week 8. 
8.2.1. Primary Analysis 
 
The primary analysis of the change from baseline in BCVA as measured by ETDRS letter score 
or 2702 charts through 8 weeks of treatment will be performed via Mixed-effects Model for 
Repeated Measures (MMRM) including data for the Week 4 and Week 8 visits. The model will 
include the change from baseline as the dependent variable; treatment, visit and visit-by-treatment 
as fixed effects, and baseline BCVA as a covariate. An unstructured covariance matrix will be 
used. In the event of convergence issues, compound-symmetry will be used instead. MMRM 


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analysis will be performed based on multiply imputed data sets. Rubin’s rules will be used to 
combine the estimates from the MMRM analyses and the estimated mean treatment difference at 
Week 8 along with the corresponding 90% and 95% CIs will be presented. Equivalence will be 
determined if the upper and lower CI limits for the difference between treatments are within the 
equivalence margins. The analysis will be based on both the FAS and PPS.  
Primary Estimand (Week 8):  
Data after receipt of rescue therapy will be set to missing. Post rescue therapy data or missing data 
after discontinuation from study will be imputed employing Multiple Imputation (MI) assuming 
missing at random (MAR) using randomized treatment-based Markov Chain Monte Carlo 
(MCMC) methodology. Multiple Imputation model impute 50 values for each missing value. The 
multiply imputed data sets are then analyzed by using MMRM analysis. Rubin’s method will be 
used to pool estimates and standard errors from MMRM across the 50 multiply imputed datasets.  
Secondary Estimand (Week 8):  
Data post rescue therapy will not be set to missing, others are the same as the analysis for primary 
estimand. 
8.2.2. Assumption Testing 
The primary null hypothesis (H0) and alternative hypothesis (H1) are: 
H0: ∆ ≥M or ∆ ≤-M 
H1: -M< ∆ <M 
where ∆ indicates the mean difference between the 2 treatment groups in the change from baseline 
in ETDRS letter score or 2702 charts at Week 8 and M represents the equivalence margin. 
Based on discussions with regulatory agencies, separate equivalence CIs and equivalence margins 
will be used for FDA submissions and other regulatory agencies versus submissions to EMA and 
PMDA. Submissions to other regulatory agencies will be assumed to follow FDA guidance. 
For the FDA submission and other countries submission, a 90% CI (equivalent to TOST evaluated 
at an α of 0.05) will be assessed using an equivalence margin of 3 letters. If the upper bound of the 
90% CI is less than 3 and the lower bound is greater than -3, then study success will be claimed. 
For the EMA and PMDA, a 95% CI (equivalent to TOST evaluated at an α of 0.025) will be 
assessed using an equivalence margin of 3.8 letters. If the upper bound of the 95% CI is less than 
3.8 and the lower bound is greater than -3.8, then study success will be claimed. 
The least squares mean estimate of treatment difference and corresponding 90% (FDA and other 
countries) and 95% (EMA/PMDA) CIs will be provided. The primary analysis set for the FDA, 


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PMDA, and any other submissions will be the FAS. For the EMA submission, both the FAS and 
PPS are considered primary analysis and equivalence will need to be shown for both analysis sets. 
8.2.3. Sensitivity Analysis 
The sensitivity analysis will be performed based on the FAS and PPS. Data after receipt of rescue 
therapy will be set to missing. 
An analysis of covariance (ANCOVA) model comparing the change from baseline in BCVA at 
Week 8 and including the change from baseline as dependent variable, treatment group as fixed 
effect and baseline BCVA score as a covariate will be performed using multiply imputed data sets. 
Additional sensitivity analyses to the primary analysis will be performed using single imputation 
approaches for post study discontinuation/rescue therapy BCVA scores using the LOCF and  
BOCF prior to MMRM analysis (intermittent missing data will be considered MAR and not 
imputed) for both the FAS and PPS. In addition, an ANCOVA model comparing the change from 
baseline in BCVA at Week 8 and including the change from baseline as dependent variable, 
treatment group as fixed effect and baseline BCVA score as a covariate will be performed by 
imputing the post study discontinuation/rescue therapy BCVA values using LOCF and BOCF 
approaches. 
Additionally, the MMRM analysis will be performed using data from MI including a tipping point 
approach. Multiple imputation assuming MAR will be applied to all missing data. After conclusion 
of MI, post study discontinuation/rescue therapy observations for the SCD411 arm will have fixed 
value C added to the imputed values. The imputed data including the fixed penalty will be analyzed 
by the same MMRM model as for the primary analysis. A range of values for C will be considered 
to identify the point at which equivalence can no longer be claimed. The tipping point analysis is 
used to investigate robustness of results.  
8.2.4. Supportive Analysis 
Supportive analysis for the primary endpoint will be performed based on mFAS per PMDA’s 
request. Data after receipt of rescue therapy will be set to missing without employing MI. Both 
MMRM and ANCOVA analyses will be performed using the non-imputed data. 
8.3. Secondary Efficacy Endpoint 
The secondary efficacy endpoints include: change from baseline in BCVA at Week 52, change 
from baseline in CRT at Week 8 and Week 52, change from baseline in CNV area at Week 8 and 
Week 52, percentage of subjects who gain at least 15 letters in BCVA at Week 8 and Week 52. 


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8.3.1. Secondary Analysis  
The estimated mean treatment difference in the change from baseline in BCVA through 52 weeks 
along with the corresponding 90% and 95% CIs from the same MMRM model as used in the Week 
8 analysis but including data from all weeks through Week 52 will also be presented based on the 
FAS and PPS.  
Primary Estimand (Week 52):  
Data after receipt of rescue therapy will be set to missing. Post rescue therapy data or missing data 
after discontinuation from study will be imputed employing MI. The analysis method will be the 
same as in primary estimand at Week 8. 
The estimated mean change from baseline of BCVA at week 8 and week 52 based on the FAS and 
PPS will be plotted, with corresponding 95% confidence intervals.  
Secondary Estimand (Week 52):  
Data post rescue therapy will not be set to missing, others are the same as the analysis for primary 
estimand. 
The analysis of change from baseline in CRT as assessed by OCT or change from baseline in CNV 
area will be based on the MMRM model similar to the one used for the analysis of change from 
baseline in BCVA, with the corresponding 95% CIs for the estimates of treatment differences at 
Week 8 and Week 52 presented. Data after receipt of rescue therapy will be set to missing prior to 
the MMRM analysis. Multiple imputation will not be performed. The FAS will be used for the 
analyses. 
The percentage of subjects who gain ≥15 letters in BCVA at postbaseline visits (Week 8 and Week 
52) compared with baseline will be summarized and 95% CI for the proportions in each treatment 
arm and difference in proportions between treatment arms will be presented. 95% CI for the 
proportions in each treatment arm will be calculated using Clopper-Pearson method. 95% CI for 
the difference in proportions between treatment arms is based on exact unconditional confidence 
interval. For subjects who have missing assessments at corresponding postbaseline visits or who 
received rescue therapy prior to a visit will be assumed to have a gain of <15 letters in BCVA (i.e., 
non-responder imputation). The FAS will be used for the analyses. 
The percentage of subjects who gain ≥15 letters in BCVA at week 8 and week 52 based on the 
FAS will be plotted, with corresponding 95% confidence intervals.  
8.3.2. Sensitivity Analysis 
The sensitivity analysis will be performed for the analysis of BCVA through Week 52 based on 
the FAS and PPS. Data after receipt of rescue therapy will be set to missing. 


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As done for Week 8, the same ANCOVA model comparing the change from baseline in BCVA at 
Week 52 and including the change from baseline as dependent variable, treatment group as fixed 
effect and baseline BCVA score as a covariate will be performed using multiply imputed data sets. 
Additional sensitivity analyses will be performed using LOCF and BOCF for post study 
discontinuation assessments or after receipt of rescue therapy prior to performing the MMRM and 
ANCOVA analysis (intermittent missing data will be considered MAR and not imputed). 
Additionally, the MMRM analysis will be performed using data from MI including a tipping point 
approach. 
8.4. Efficacy Assessments 
BCVA will be measured at sites by certified study staff. All imaging efficacy assessments (OCT, 
FA/FP) will be interpreted by a central reading center. Efficacy assessments will be performed at 
the indicated visits in the Schedule of Events (Appendix 15.1).   
All efficacy assessments will be summarized and listed with no statistical hypothesis testing 
performed based on the FAS. 
8.4.1. Best Corrected Visual Acuity (BCVA) 
BCVA is measured by ETDRS letter score or 2702 charts.  
BCVA testing will be done for both eyes and should be performed prior to the dilation of pupils, 
FA, and OCT assessments, and prior to the IVT injection of the study drug. BCVA will also be 
performed at any time during the visit at ET/EOS Visit. A decrease in visual acuity of ≥15 letters 
from the last assessment of VA should be reported as AEs/SAEs as appropriate. If there is a 
decrease in VA of ≥30 letters from the last assessment of VA or if there is a decrease in VA to 
the level of Light Perception or worse, it should be reported as SAE. 
Raw values of BCVA and change from baseline will be summarized by treatment group using 
descriptive statistics at each visit for study eye and fellow eye separately. Data after receipt of 
rescue therapy will be set to missing. A by-subject listing will also be provided for both eyes. The 
mean change from baseline of BCVA for study eye by visit based on FAS will be plotted. 
8.4.2. Optical Coherence Tomography (OCT) 
Central Retinal Thickness (CRT) is measured by OCT. 
OCT imaging should be performed on the study eye prior to the IVT injection of the study drug. 
Those images will be sent to the central reading center. Site staff who will perform OCT scans in 
this study must be certified by the central reading center before study starts. OCT devices 
registered in an Investigational site should be all from the same manufacturer and meet the 


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minimum software requirement. The subject should use the OCT device must be registered by the 
central reading center from Screening to Week 52 (EOS visit) or ET Visit 
Raw values of CRT and change from baseline will be summarized by treatment group using 
descriptive statistics at each visit for study eye. Data after receipt of rescue therapy will be set to 
missing. Other selected assessments performed by OCT may also be summarized using descriptive 
statistics at each visit for study eye. A by-subject listing will be provided for all the selected 
assessments performed by OCT. 
The mean change from baseline of CRT for study eye by visit based on FAS will be plotted. 
8.4.3. Fluorescein Angiography (FA) and Fundus Photography (FP) 
Choroidal neovascularization (CNV) area is assessed by FA and FP. 
At screening, FA and FP will be performed on both eyes and those images will be sent to the 
central reading center. At Week 8 and ET/EOS, FA and FP will be performed on the study eye 
(prior to IVT injection of the study drug at Week 8). Those images will be sent to the central 
reading center. Site staff who will perform FA and FP in this study must be certified by the central 
reading center before study starts. Only FA/FP devices certified by central reading center are 
allowed to be used in this study. If 1 or more FA/FP devices are certified at an investigational site, 
a subject must use the same FA/FP device consistently from Screening to Week 52 (EOS Visit) or 
ET Visit. 
Raw values of CNV area and change from baseline will be summarized by treatment group using 
descriptive statistics at each visit for study eye. Data after receipt of rescue therapy will be set to 
missing. Other selected assessments performed by FA/FP may also be summarized using 
descriptive statistics at each visit for study eye. A by-subject listing will be provided for study eyes 
for all the selected assessments performed by FA/FP. 
9. Safety Analysis 
The purpose of this section is to define the safety endpoints for the study, which consist of 
incidence of AEs (or Treatment-emergent AEs (TEAEs)), laboratory test results, and vital signs. 
Other safety parameters include ECG results, slit lamp examination, dilated fundoscopy, IOP and 
vision check. 
All safety analyses will be based on the SAF. No formal statistical analysis of the safety data will 
be performed. 
9.1. Adverse Events 
Adverse Events are one of the secondary safety endpoints. Summary of AEs will be based on the 
SAF. 


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An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study drug or to IVT injection procedure. 
Pretreatment AEs are defined as AEs that are reported or worsened after signing the ICF up to 
the first dose date of study drug. 
Treatment-emergent AEs are defined as AEs that are reported or worsened on or after the first 
dose date of study drug through 28 days after the last dose date of study drug. 
Adverse events will be coded according to Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.0 or above. Unless otherwise specified, AEs will be summarized by System 
Organ Class (SOC) and Preferred Term (PT), with SOCs sorted in the alphabetical order and PTs 
within each SOC in descending order of subject incidence. Partial missing AE start dates will be 
imputed based on Appendix 15.2. 
When summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once. Subjects will be presented 
according to the highest severity (the strongest relationship) in the summaries by severity (of 
related AEs), if subjects reported multiple events under the same SOC and/or PT.  
Ocular TEAEs will be summarized separately from non-ocular TEAEs. Ocular TEAEs will be 
summarized for the study eye and the fellow eye. Also, by-subject listings of ocular and non-ocular 
AEs will be presented. 
9.1.1. Incidence of Adverse Events 
An overall summary of TEAEs including the number and percentage of subjects who experience 
the following will be presented: 
• 
Any TEAE  
• 
Any TEAE Related to Study Drug 
• 
Any TEAE Related to Injection Procedure 
• 
Any Severe TEAE 
• 
Any Serious TEAE 
• 
Any Serious TEAE Related to Study Drug 
• 
Any Serious TEAE Related to Injection Procedure 
• 
Any TEAE Leading to Dose Interruption  
• 
Any TEAE Leading to Treatment Discontinuation  
• 
Any TEAE Leading to Study Discontinuation  


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• 
Any TEAE Leading to Death 
Also, separate listings containing individual subject adverse event data for all AEs, SAEs, AEs 
leading to dose interruption, AEs leading to treatment discontinuation, AEs leading to study 
discontinuation, and AEs leading to death will be provided separately. 
In addition, any treatment-emergent AE of Special Interest (AESI) may also be summarized. 
9.1.2. Relationship of Adverse Events to Study Drug or IVT Injection Procedure 
Study drug or injection procedure related TEAEs will be summarized by SOC and PT. Study drug 
or injection procedure related AEs are those with a relationship to study drug or injection procedure 
of ‘Related’ based on the eCRF page. AEs assessed as ‘Not Related’ will be considered unrelated 
for reporting purpose. Missing relationship will be counted as related to study drug or injection 
procedure. 
9.1.3. Severity of Adverse Event 
TEAEs will be rated as Mild, Moderate, or Severe based on the following criteria: 
• 
Mild: These events require minimal or no treatment and do not interfere with the subject’s 
daily activities.  
• 
Moderate: These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with normal 
functioning.  
• 
Severe: These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
The adverse events with missing severity grade will be imputed as ‘Severe’. In the TEAE severity 
table, if a subject reports multiple occurrences of the same TEAE, only the most severe (mild < 
moderate < severe) occurrence will be presented.  
9.1.4. Serious Adverse Events 
Serious AEs are those identified on the eCRF as meeting the protocol defined serious criteria. 
Serious TEAEs will be summarized by SOC and PT. A by-subject listing will also be provided for 
all SAEs. 
9.1.5. Adverse Events Leading to Treatment Discontinuation 
TEAEs with a study treatment action taken of ‘Drug Withdrawn’ will be summarized by SOC and 
PT. A by-subject listing will also be provided for all adverse events leading to treatment 
discontinuation. 


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9.1.6. Adverse Events Leading to Study Discontinuation 
TEAEs leading to study discontinuation (the primary reason for subject terminated study early 
recorded as ‘Adverse Event’ on the eCRF) will be summarized by SOC and PT. A by-subject 
listing will also be provided for all adverse events leading to study discontinuation. 
9.1.7. Death 
TEAEs with AE outcome as ‘Fatal’ (recorded as ‘Death Related to Adverse Event’ on the eCRF) 
will be summarized by SOC and PT. A by-subject listing will also be provided for all adverse 
events leading to death. 
9.2. Clinical Laboratory Evaluations 
Clinical laboratory evaluations are one of the secondary safety endpoints. Summary of laboratory 
results will be based on the SAF. 
Clinical laboratory assessments (chemistry, hematology, urinalysis, pregnancy tests) will be 
performed as indicated in the Schedule of Events (Appendix 15.1). Collection of blood and urine 
will occur at the study site and the samples will be shipped to a central laboratory for analysis. On 
injection visits, all samples (including urine) should be collected prior to IVT injection of the study 
drug; urine samples will be collected prior to FA assessment to avoid false elevations in urine 
protein values. Hematology, chemistry, and urinalysis samples will also be performed at any time 
during the visit at ET/EOS Visit. 
No pregnancy test is required for women of non-child-bearing potential. For women of child-
bearing potential, serum pregnancy test will be performed at screening and in case of a positive 
urine test during the study; urine pregnancy test will be performed at the Baseline, ET/EOS Visits; 
the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels to be measured at 
screening for women of child-bearing potential.  
Table 3 presents the laboratory analyses that will be performed during the study. 


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Table 3: Clinical Laboratory Evaluations 
Clinical Chemistry 
Hematology 
Urinalysis 
For Women 
Alanine 
aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate 
aminotransferase 
Blood urea nitrogen 
Creatinine 
Creatine kinase 
Total and direct 
bilirubin 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Lymphocytes 
MCV 
Monocytes 
Neutrophils 
Platelet count 
RBC count 
RBC morphology 
WBC count 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte Esterase 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Serum pregnancy test: At 
screening visit for women of 
child-bearing potential 
(serum β-HCG, follicle 
stimulating hormone, 
luteinizing hormone) 
Urine pregnancy test: At 
baseline, ET, and EOS visits 
for women of child-bearing 
potentiala 
Abbreviations: EOS, end of study; ET, early termination; HCG, human chorionic gonadotropin; MCV, mean 
corpuscular volume; RBC, red blood cell; WBC, white blood cell. 
a. 
If urine pregnancy test is positive, serum pregnancy test should be performed; if found positive, study treatment 
will be discontinued. 
If any laboratory value falls below the lower limit of quantification (LLOQ), the value of half of 
the LLOQ will be taken (e.g. <0.5 will become 0.25); if any laboratory value falls above the upper 
limit of quantification (ULOQ), the value of the ULOQ will be taken (e.g. >1000 will become 
1000). The imputed values will be used for summaries but left as recorded in the listing. 
Laboratory test variables will be summarized by treatment group and visits using descriptive 
statistics and change from baseline. Shift tables (low, normal, high) between baseline and 
postbaseline time points will be presented by laboratory test and treatment group. Laboratory tests 
with categorical results that cannot be analyzed by change from baseline or shift table analysis will 
not be included in these summaries but will be listed.  
9.3. Vital Sign Measurements 
Vital sign measurements are one of the secondary safety endpoints. Summary of vital signs will 
be based on the SAF. 
Vital signs consist of body temperature, respiratory rate, blood pressure (systolic and diastolic), 
and heart rate measurement. Vital sign measurements will be performed on all the scheduled visits. 
On injection visits, vital signs will be measured prior to IVT injection of the study drug. Vital 
signs will also be performed at any time during the ET/EOS Visit. 
Vital signs should be taken with the subject in a seated position after resting for 5 minutes. Vital 
signs will be measured before venipuncture. 


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Vital sign measurements will be summarized using descriptive statistics for reported values and 
change from baseline at each scheduled visit by treatment group. Vital signs data for all safety 
subjects will also be presented in a listing. 
9.4. Electrocardiogram 
An ECG could be assessed by the investigator only at Screening, Week 8, and at the EOS/ET Visit. 
Interpretation results include ‘Normal’, ‘Abnormal, Not Clinically Significant’ and ‘Abnormal, 
Clinically Significant’. 
The ECG interpretations will be summarized using descriptive statistics at each visit based on the 
SAF. Electrocardiogram data for all safety subjects will also be presented in a listing. 
9.5. Ophthalmological assessments 
Routine ophthalmological examinations will be performed at indicated visits in the Schedule of 
Events (Appendix 15.1). Summary of ophthalmological examinations will be based on the SAF. 
9.5.1. Slit Lamp Biomicroscopy 
Slit lamp examination (anterior chamber flare, anterior chamber cells, vitreous cells opacities and 
haze, overall assessment) will be performed on both eyes at all the planned scheduled visits during 
the study and prior to IVT injection of the study drug. Slit lamp will also be performed at any time 
during the visit at ET/EOS Visit. The grading scales can be found from protocol Section 13.1 
(Appendix 1) and Section 13.2 (Appendix 2). 
The results of slit lamp examination will be summarized using descriptive statistics at each visit 
for study eye and fellow eye separately. A by-subject listing will also be provided. 
9.5.2. Dilated Fundoscopy 
Dilated fundoscopy includes evaluation of retina and vitreous (vitreal overall assessment; macular 
overall assessment; retina overall assessment; and optic nerve overall assessment). Dilated 
fundoscopy will be performed on the study eye at all the planned scheduled visits during the study, 
including the time prior to IVT injection of the study drug, and within 60±30 minutes after IVT 
injection of the study drug, and at any time during the visit at ET/EOS Visit. 
The results of slit lamp examination will be summarized using descriptive statistics at each visit 
and applicable time point for study eye. A by-subject listing will also be provided. 
9.5.3. Intraocular Pressure (IOP) and Vision Check 
The same method of IOP measurement must be used in each subject from Screening to Week 52 
(EOS Visit) or ET Visit. Intraocular pressure will be measured on both eyes at screening, and on 
the study eye prior to IVT injection of the study drug, and 60±30 minutes after IVT injection of 


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the study drug at each visit from baseline/Day 1 to EOT (48 weeks). If the pre-procedure IOP is 
equal to or greater than 30 mmHg, IVT injection will not be administered (either withheld or 
delayed) until IOP is decreased to acceptable safety levels as per investigator’s medical judgement. 
IOP should be measured after OCT and FA are completed to avoid corneal erosion. IOP will also 
be performed at any time during the ET/EOS Visit. 
Finger counting test is a part of post-injection procedures and is to be performed immediately after 
the IVT injection of the study drug. 
The results of IOP will be summarized using descriptive statistics at each visit and applicable time 
point for study eye. A by-subject listing will be provided for study eyes including IOP and vision 
check results. 
10. Pharmacokinetics 
10.1. Data Handling 
Data rounding specifications for PK data are documented in the PK TLF shells.  
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero for 
calculation of concentration descriptive statistics. For PK analysis, all BLQ values will be treated 
as zero, with the exception of BLQ values observed between 2 quantifiable concentrations which 
will be set to missing. 
10.2. Plasma Concentrations 
Serial blood samples will be collected at the following time points for PK assessment:  
 
• Day 1 (week 1, First dose/injection): Pre-dose, Days 1, 3, 7, 14 and 28 post first dose 
• Day 57 (week 8, Third dose/injection): Pre-dose, Days 1, 3, 7, 14 and 28 post third dose 
 
The permitted windows for PK sample collection are as follows: 
Pharmacokinetic time points 
Window  
+1 day  
± 1 hour 
+ 3 days  
± 2 hours 
+ 7 days 
± 6 hours  
+ 14 days 
± 1 day 
+28 days 
± 2 days 
 
PK collections that have an actual sampling time that deviates from the predefined collection time 
windows will be flagged in the data listings and included in the calculation of concentration 
summary statistics. 


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Individual free and bound plasma concentrations will be presented in data listings and summarized 
separately using descriptive statistics (number of observations, arithmetic mean, SD, CV, median, 
minimum, and maximum) by treatment, injection and time point.  
Individual free and bound plasma concentrations will be plotted by actual time on both linear and 
semi-logarithmic scales. Mean free and bound plasma concentrations will be plotted by injection 
and nominal time on both linear and semi-logarithmic scales with both treatments overlaid on the 
same plots. All concentration listings and individual concentration-time profiles will be presented 
using the PK set.  
10.3. Plasma Pharmacokinetic Parameters 
Plasma concentration-time data will be analyzed by non-compartmental analysis using Phoenix® 
WinNonlin® Version 8.3 or higher (Certara USA, Inc., Princeton, NJ). The following PK 
parameters will be calculated for SCD411 and Aflibercept, where data permit: 
Cmax 
Maximum plasma concentration. 
tmax 
Time to reach the maximum plasma concentration. 
 
 
AUC0-t 
area under the concentration-time curve from time zero to last quantifiable 
time point, calculated using the linear up/log down trapezoidal rule. 
AUC0-tau 
area under the concentration-time curve within a dosing interval, 
calculated using the linear up/log down trapezoidal rule. 
AUC0-inf 
area under the concentration-time curve from zero to an infinite time, 
calculated as [AUC0-t + (Clast / λz)] where Clast is the last observed 
measurable concentration. 
t1/2 
elimination half-life, calculated as: ln (2) / λz. 
 
In addition to the above PK parameters, which will be listed and summarized, the following 
parameters will also be listed to document the selection of data points used to estimate t1/2 using 
non-compartmental procedures: 
λz 
Apparent terminal elimination rate constant, where λz is the magnitude of 
the slope of the linear regression of the log concentration versus time 
profile during the terminal phase. 
Number 
points 
Number of data points used to estimate λz; a minimum of 3 data points 
must be used, and Cmax must not be included. 
λz lower 
Lower bound used for the estimation of λz. 
λz upper 
Upper bound used for the estimation of λz. 
Rsq 
r2, the coefficient of determination (goodness of fit statistic); λz and all 
associated parameters will only be reported where r2 ≥ 0.80. 
%AUCext 
Percentage of AUC0-inf due to extrapolation; AUC0-inf values will be 
flagged and excluded from summary statistics where %AUCext > 20%. 
 


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Actual sampling times will be used for the estimation of all plasma PK parameters, and all 
concentrations will be included in the analysis (including concentrations collected outside 
predefined collection windows). All PK tables, mean figures and all statistical analyses will be 
presented using the PK set. 
Free and bound plasma PK parameters will be presented in data listings and summarized separately 
using descriptive statistics (number of observations, arithmetic mean, SD, CV, geometric mean, 
geometric CV, median, minimum, and maximum) by treatment, injection and study day. tmax will 
be summarized using number of observations, median, minimum, and maximum only.  
If the number of data points used to calculate λz is less than 3 (not including Cmax), or the calculated 
coefficient of determination (R2) value for λz is < 0.800, λz and the parameters that utilize λz for 
determination AUC0-inf, t1/2 will not be reported. In addition, free and bound plasma PK parameters 
will be presented in data listings and summarized by ADA status (positive/negative). 
A simple comparison of summary statistics of PK parameters (Cmax and AUC) will be performed 
between the treatments to understand PK similarity. 
11. Immunogenicity Analysis 
Immunogenicity analysis is one of the secondary safety endpoints. Summary of immunogenicity 
results will be based on the SAF.  
Immunogenicity endpoints include the evaluation of development of anti-SCD411 antibodies 
using blood samples taken at Baseline, at Weeks 4, 8, 20, 36, and 52. Immunogenicity samples 
should be collected prior to IVT injection of the study drug and prior to FA assessment when 
performed on the same day. Immunogenicity will also be performed at any time during the visit at 
ET/EOS Visit. Neutralizing antibodies (NAb) will be tested when Anti-drug antibodies (ADA) 
results are confirmed to be positive. ADA concentration with signal above cut point of 10.0 ng/mL 
is defined as ADA - positive.  
The analysis on immunogenicity will be descriptive. Geometric mean titer (GMT) and other 
descriptive statistics (number of subjects (n), median, minimum and maximum) will be provided 
at each time point by treatment group. The descriptive statistics will be calculated based on the t-
distribution of the log-transformed values then back transformed to the original scale for 
presentation. The number and proportion of ADA-positive subjects and ADA-negative subjects 
will be summarized by treatment group for each assessment time point. The number and proportion 
of NAb subjects will be summarized by treatment group for each assessment time point. Also, a 
by-subject listing will be provided. 
The GMT will be calculated using the following formula: 


SamChunDang Pharm. Co. Ltd. 
 
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  Page 36
 
where 
 are n observed immunogenicity titers or levels. 
12. Interim Analysis 
The primary analysis of efficacy and all other efficacy and safety analyses will be conducted at the 
Week 8 database lock; i.e., after all subjects have completed the Week 8 Visit or have been 
discontinued from the study prior to this visit. Distribution of the Week 8 analysis will be restricted 
only to the IDMC members in order to minimize bias through the end of the study.   
An interim analysis of safety , secondary efficacy endpoints, and PK parameters will be performed 
once approximately 200 subjects complete Week 52 and all subjects complete Week 24 or have 
early discontinued from the study. 
The Week 8 analysis and interim analysis will be performed by an independent biostatistics group 
and results will be distributed to a limited group of recipients included unmasked medical writing 
staff and limited sponsor representatives.  The timing of the Week 8 database lock and the interim 
analysis database lock may coincide depending on subject enrollment and data 
cleaning/programming activities.  
As the primary study endpoint is the bioequivalence comparison at Week 8, no type I error 
adjustments are required as the analysis performed at the Week 8 database lock are considered 
final for the primary efficacy endpoint. No type I error adjustments are planned for the secondary 
efficacy endpoints; therefore, no error adjustments will be performed due to the interim analysis 
as all analyses after the primary analysis at the Week 8 database lock are considered secondary 
analyses.   
13. Independent Data Monitoring Committee 
An IDMC will be established for the study. The IDMC and associated parties (CRO 
Pharmacovigilance, Data management, sponsor as well as the CRO for IDMC management) will 
function under the terms of an IDMC Charter. The duty of this IDMC is to protect the safety 
interests of subjects and all others who may possibly be exposed to the study drug and to make 
recommendations to the sponsor. The IDMC (without the sponsor or CRO personnel involved in 
the conduct of the study) will review efficacy and safety data in an unmasked manner. 
The voting members of the IDMC will participate in a closed, unmasked session, following the 
blinded presentation of data to discuss recommendations. During these sessions, the IDMC 
members will be able to review unmasked safety data and efficacy data. Only the voting members, 
( )













∑
=
n
t
n
i
i
1
10
log
10
nt
t
t
,
,
, 2
1



SamChunDang Pharm. Co. Ltd. 
 
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  Page 37
unblinded independent biostatistician, and the PPD Data Monitoring Coordinators will be present 
in the closed meetings. 
Two IDMC meetings will be held: one safety meeting held approximately 6 months after the 
IDMC organizational meeting and second safety meeting will be held after all subjects have 
completed the Week 8 Visit. After each of these meetings, the IDMC members will make a 
decision to continue the study without change, modify the study or enrollment to be placed on 
hold, or study termination. Any decision to terminate the study will be based on clinical judgment 
only and no formal stopping rules are defined. The sponsor is obligated to inform the study sites, 
IRB/IEC and Competent Authorities of the IDMC recommendations according to country specific 
requirements. 
14. References 
Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al. Systemic 
pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and 
ranibizumab. Retina (Philadelphia, Pa). 2017;37(10):1847-58. 
Eylea® (aflibercept) Injection, for Intravitreal Use. Full Prescribing Information. Regeneron 
Pharmaceuticals, 
Inc. 
August 
2019. 
Available 
from: 
https://www.regeneron.com/sites/default/files/EYLEA_FPI.pdf 
Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, et al. Binding and 
neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, 
ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171-85. 
Schneider U, Gelisken F, Inhoffen W. Natural course of occult choroidal neovascularization in 
age-related macular degeneration: development of classic lesions in fluorescein angiography. Acta 
Ophthalmol Scand. 2005;83(2):141-7. 
 


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Page 38 
15. Appendices 
15.1. Schedule of Events 
Assessment 
Screening 
Treatment 
ETa/EOSb 
Study Day 
–21 to 0 
Baseline/1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
EOT/337 
365 
Study Week 
-3 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Visit Time Window (days) 
 
 
±2 
±2 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information (incl. 
height and weight) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ocular and systemic medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Slit lamp examinationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dilated fundoscopyd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Prior and concomitant ocular and 
systemic medicationsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCD411 or aflibercept injection h 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pre-injection IOPi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-injection IOP and vision 
checki 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
BCVAj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCTk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FA and FP l 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory assessmentsm 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Vital signsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity sampleso 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 


SamChunDang Pharm. Co. Ltd.                                                                                                                                                                                                             Statistical Analysis Plan, Version 2.0 
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PK samplesp 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AEs, adverse events; ECG, electrocardiogram; EOS, end of study; EOT, end-of-treatment; ET, early termination; FA, fluorescein angiography; FP, fundus 
photography; FSH, follicle-stimulating hormone; IOP, intraocular pressure; IVT, intravitreal; LH, luteinizing hormone; NAb, neutralizing antibodies; OCT, optical 
coherence tomography; PDT, photodynamic therapy; PK, pharmacokinetics; VEGF, vascular endothelial growth factor. 
a 
For subjects who discontinue study treatment and choose to withdraw from the study or if, in the opinion of the investigator, the subject should be prematurely withdrawn, 
ET Visit assessments are to be performed as soon as possible after discontinuing the study treatment but no later than 28 days after discontinuation. 
b 
End-of-study assessments are to be performed 28 days after the EOT. 
c 
Slit lamp examination will be performed on both eyes at all the planned scheduled visits during the study. 
d 
Dilated fundoscopy will be performed on the study eye at all the planned scheduled visits during the study, including the time prior to IVT injection of the study drug, and 
within 60±30 minutes after IVT injection of the study drug, and at any time during the visit at ET/EOS Visit. 
e 
Serum pregnancy test will be done at screening, and urine pregnancy test at baseline, ET, and EOS Visits for female subjects of child-bearing potential. If urine pregnancy 
test is positive, serum pregnancy test should be performed; if found positive, study treatment will be discontinued, and the subject should continue with their regularly 
scheduled visits and assessments until Week 52 except for study treatment administration. Pregnancy cases should be followed until resolution of the pregnancy. 
f 
Concurrent use of systemic or intravitreal anti-VEGF agents, IVT, subtenon, or peribulbar corticosteroids in study eye, except as required to treat AEs, and use of 
photocoagulation or PDT with verteporfin are prohibited during the study. Antimicrobial drops can be used at the discretion of the investigator. For IVT corticosteroid 
implant, the exclusion period would be 36 months from the date of the procedure to the date of screening. 
g 
The investigator must confirm that the subject meets all inclusion and none of the exclusion criteria at both screening and Day 1. This is inclusive of BCVA scoring. 
h 
Rescue treatment for the study eye is not permitted at any point in time. Subjects can be considered for rescue treatment after Week 4 if the following conditions are met as 
assessed by the masked investigator: visual acuity letter score decrease of 15 letters or more from the last assessment, an increase in intraretinal fluid, subretinal fluid, or 
subretinal hyper-reflective material, that in the investigator’s opinion is related to progression of the subject’s neovascular AMD. Subjects who will receive rescue 
treatment need to discontinue the study treatment and should have the reason for treatment discontinuation documented on the Treatment Discontinuation page of the 
eCRF and continue with all their regularly scheduled visits and assessments until Week 52 except for study treatment administration. If a subject chooses to withdraw from 
the study or if, in the opinion of the investigator, the subject should be prematurely withdrawn, then the ET Visit should be completed as soon as possible after 
discontinuing the study treatment but no later than 28 days after discontinuation. 
i 
Intraocular pressure will be measured on both eyes at screening, and on the study eye prior to IVT injection of the study drug, and 60±30 mins after IVT injection of the 
study drug at each visit from baseline/Day 1 to EOT (48 weeks). If the pre-procedure IOP is equal to or greater than 30 mmHg, IVT injection will not be administered 
(either withheld or delayed) until IOP is decreased to acceptable safety levels as per investigator’s medical judgement. IOP should be measured after OCT and FA are 
completed to avoid corneal erosion. Finger counting test to be performed immediately after the IVT injection of the study drug. IOP will also be performed at any time 
during the ET/EOS Visit. 
j 
Best corrected visual acuity testing will be done for both eyes and should be performed prior to the dilation of pupils, FA, and OCT assessments, and prior to the IVT 
injection of the study drug. BCVA will also be performed at any time during the visit at ET/EOS Visit. A decrease in visual acuity of ≥15 letters from the last assessment 
of VA should be reported as AEs/SAEs as appropriate. If there is a decrease in VA of ≥30 letters from the last assessment of VA or if there is a decrease in VA to the level 
of Light Perception or worse, it should be reported as SAE. 
k 
OCT imaging should be performed on the study eye prior to the IVT injection of the study drug. Those images will be sent to the central reading center. Site staff 
who will perform OCT scans in this study must be certified by the central reading center before study starts. OCT devices registered in an Investigational site should be all 
from the same manufacturer and meet the minimum software requirement. The subject should use the OCT device registered by the central reading center from Screening 
to Week 52 (EOS visit) or ET Visit. 
l 
At screening, FA and FP will be performed on both eyes and those images will be sent to the central reading center. At Week 8 and ET/EOS, FA and FP will be performed 
on the study eye prior to IVT injection of the study drug at Week 8. Those images will be sent to the central reading center. Site staff who will perform FA and FP in this 
study must be certified by the central reading center before study starts. Only FP/FA devices certified by central reading center are allowed to be used in this study. If 1 or 
more FP/FA devices are certified at an investigational site, a subject must use the same FP/FA device consistently from Screening to Week 52 (EOS Visit) or ET Visit. 


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m 
Hematology, chemistry, and urinalysis samples will be collected prior to IVT injection of the study drug. Urine samples will be collected prior to performing FA to avoid 
false elevations in urine protein values. No pregnancy test is required for women of non-child-bearing potential. For women of child-bearing potential, serum pregnancy 
test will be performed at screening and in case of a positive urine test during the study; urine pregnancy test will be performed at the Baseline, ET and EOS Visits; the FSH 
and LH levels to be measured at screening for women of child-bearing potential. Hematology, chemistry, and urinalysis samples will also be performed at any time during 
the visit at ET/EOS Visit. 
n 
Includes blood pressure, respiratory rate, heart rate, and temperature. On days when study injections will be administered, vital signs should be measured prior to IVT 
injection of the study drug. V/S will also be performed at any time during the visit at ET/EOS Visit. 
o 
Immunogenicity samples should be collected prior to IVT injection of the study drug and prior to FA assessment when performed on the same day. Immunogenicity will 
also be performed at any time during the visit at ET/EOS Visit. NAb will be tested when ADA results are confirmed to be positive. 
p 
Quantification of free and bound SCD411 and aflibercept will be performed for subjects who agree to participate in the PK substudy using blood samples at predose, and at 
+1 day, +3 days, +7 days, +14 days, and +28 days following the first and the third injection (Week 8). 


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15.2. Guideline of Missing Date Imputation for Safety Analysis 
Impute Missing Date of Adverse Events/ Prior or Concomitant Medications  
Incomplete Start Date: If the stop date is non-missing and the imputed start date is after the stop date, the start date will be imputed by 
the stop date. 
Missing day and month 
• 
If the year is same as the year of the first dosing date, then the day and month of the first dosing date will be assigned to the 
missing fields 
• 
If the year is prior to the year of the first dosing date, then December 31 will be assigned to the missing fields. 
• 
If the year is after the year of the first dosing date, then January 1 will be assigned to the missing fields. 
Missing day only  
• 
If the month and year are same as the month and year of the first dosing date, then the first doing date will be assigned to the 
missing day. 
• 
If the month and year are before the month and year of the first dosing date, then the last day of the month will be assigned to 
the missing day. 
• 
If the month and year are after the month and year of the first dosing date, then the first day of the month will be assigned to 
the missing day. 
Missing day, month, and year 
• 
No imputation is needed. The corresponding AE will be included as TEAE if the AE end date is after the first dosing date or 
the end date is also missing. The corresponding medication will be considered to have a start date before the first dose of study 
drug. 
Incomplete Stop Date: If the imputed stop date is before the start date then the imputed stop date will be equal to the start date. 
Missing day and month 
• 
If the year of the incomplete stop date is the same as the year of the last dosing date, then the day and month of the last dosing 
date will be assigned to the missing fields.  


SamChunDang Pharm. Co. Ltd.                                                                                                                                                                                                             Statistical Analysis Plan, Version 2.0 
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• 
If the year of the incomplete stop date is prior to the year of the last dosing date, then December 31 will be assigned to the 
missing fields.  
• 
If the year of the incomplete stop date is after the year of the last dosing date, then January 1 will be assigned to the missing 
fields. 
Missing day only  
• 
If the month and year of the incomplete stop date are the same as the month and year of the last dosing date, then the last dosing 
date will be assigned to the missing day.  
• 
If the month and year of the incomplete stop date are before the month and year of the last dosing date, then the last day of the 
month will be assigned to the missing day.  
• 
If the month and year of the incomplete stop date are after the month and year of the last dosing date, then the first day of the 
month will be assigned to the missing day. 
Missing day, month, and year 
• 
No imputation is needed. The corresponding medication will be treated as a continuing medication.