A Randomized, Active-Controlled, Double-Masked, Parallel-Group, Phase 3 Study to Compare Efficacy and Safety of CT-P42 in Comparison With Eylea in Patients With Diabetic Macular Edema
Phase: PHASE3
Conditions: Diabetic Macular Edema (DME)
Sponsor: Celltrion

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CLINICAL STUDY PROTOCOL 
A Randomized, Active-Controlled, Double-Masked, Parallel-Group, Phase 
3 Study to Compare Efficacy and Safety of CT-P42 in Comparison with 
Eylea in Patients with Diabetic Macular Edema 
PROTOCOL NUMBER CT-P42 3.1 
EudraCT Number: 
2020-004278-23 
Investigational Product: 
CT-P42 (proposed Eylea biosimilar) 
Sponsor: 
 
 
 
 
 
  
Sponsor Contact : 
 
 
 
 
  
SAE Reporting : 
 
,  
 
 
 
 
Version and Date of Protocol: Protocol Version 4.0, including country specific A.0, 15 
April 2022 
 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by CELLTRION, Inc. 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 CELTLRION, Inc. The study will 
be conducted according to the protocol and in compliance with the International Council for Harmonisation 
harmonized tripartite guideline E6(R2): Good Clinical Practice. With declaration of Helsinki (WMA 2013). 
Throughout this document, symbols indicating proprietary names (®, ™) are not displayed. The appearance 
of product names without these symbols does not imply that these names are not protected 

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Declaration of Investigator 
I have read and understood all sections of the protocol entitled ‘A Randomized, 
Active-Controlled, Double-Masked, Parallel-Group, Phase 3 Study to Compare Efficacy and 
Safety of CT-P42 in comparison with Eylea in Patients with Diabetic Macular Edema’ 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 Protocol Version 4.0, including country specific A.0, dated 15 April 2022, 
the International Council for Harmonisation harmonized tripartite guideline E6(R2): Good 
Clinical Practice and all applicable government regulations. I will not make changes to the 
protocol before consulting with CELLTRION, Inc. or implement protocol changes without 
independent ethics committee approval except to eliminate an immediate risk to patients. I 
agree to administer the study drug (mentioned as CT-P42 or Eylea) only to patients under my 
personal supervision or the supervision of a sub-investigator. 
I will not supply the study drug to any person not authorized to receive it. Confidentiality will 
be protected. Patient 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 CELLTRION, Inc. 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed name of Principal Investigator 
 
 
 

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Table of Contents 
CLINICAL STUDY PROTOCOL ............................................................................................ 1 
Protocol Approval ..................................................................................................................... 2 
Declaration of Investigator ....................................................................................................... 3 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 9 
List of Figure ............................................................................................................................. 9 
Protocol Synopsis .................................................................................................................... 10 
List of Abbreviations ............................................................................................................... 17 
1 
Introduction ...................................................................................................................... 19 
1.1 
Background .............................................................................................................. 19 
1.1.1 
Diabetic Macular Edema ................................................................................... 19 
1.2 
CT-P42 ..................................................................................................................... 20 
1.2.1 
Nonclinical Studies ........................................................................................... 20 
1.2.2 
Clinical Studies ................................................................................................. 20 
1.3 
Study Rationale ........................................................................................................ 21 
1.3.1 
Rationale for Study Population ......................................................................... 22 
1.4 
Benefit and Risk Assessment ................................................................................... 22 
2 
Study Objectives and Endpoints ...................................................................................... 24 
2.1 
Study Objectives ...................................................................................................... 24 
2.1.1 
Primary Objective ............................................................................................. 24 
2.1.2 
Secondary Objectives ........................................................................................ 24 
2.2 
Study Endpoints ....................................................................................................... 24 
2.2.1 
Primary Endpoint .............................................................................................. 24 
2.2.2 
Secondary Endpoints ......................................................................................... 24 
3 
Investigational Plan .......................................................................................................... 26 
3.1 
Study Design ............................................................................................................ 26 
3.2 
Study Overview ....................................................................................................... 26 
4 
Patient Selection and Withdrawal Criteria ....................................................................... 30 
4.1 
Selection of Study Population .................................................................................. 30 
4.1.1 
Inclusion Criteria ............................................................................................... 30 

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4.1.2 
Exclusion Criteria .............................................................................................. 31 
4.2 
Withdrawal of Patients from the Study .................................................................... 34 
4.2.1 
Replacement of Patients .................................................................................... 35 
4.3 
Premature Termination of the Study ........................................................................ 35 
5 
Study Treatment ............................................................................................................... 36 
5.1 
Method of Assigning Patients to Treatment Groups ................................................ 36 
5.2 
Identity of Investigational Product ........................................................................... 36 
5.3 
Study Drug Administration ...................................................................................... 37 
5.3.1 
CT-P42 and Eylea .............................................................................................. 37 
5.3.2 
Temporary Interruptions of Study Drug ............................................................ 39 
5.4 
Management of Clinical Supplies ............................................................................ 40 
5.4.1 
Study Drug Package, Labeling, and Storage ..................................................... 40 
5.4.2 
Study Drug Accountability ................................................................................ 40 
5.5 
Masking .................................................................................................................... 41 
5.5.1 
Breaking the Masking ....................................................................................... 41 
5.6 
Treatment Compliance ............................................................................................. 42 
5.7 
Prior and Concomitant Therapy ............................................................................... 42 
5.7.1 
Prior and Concomitant Treatment ..................................................................... 42 
5.8 
Prohibited Therapy ................................................................................................... 43 
6 
Study Assessments and Procedures .................................................................................. 45 
6.1 
Efficacy Assessments ............................................................................................... 45 
6.1.1 
Best Corrected Visual Acuity ............................................................................ 45 
6.1.2 
Optical Coherence Tomography ........................................................................ 45 
6.1.3 
Fundus Photography and Fluorescein Angiography ......................................... 45 
6.2 
Pharmacokinetic Assessments ................................................................................. 46 
6.3 
Usability Assessments ............................................................................................. 46 
6.4 
Safety Assessments .................................................................................................. 47 
6.4.1 
Medical/Ophthalmic History and Demographic Information ........................... 47 
6.4.2 
Adverse Events .................................................................................................. 47 
6.4.3 
Immunogenicity Assessments ........................................................................... 54 
6.4.4 
Hypersensitivity Monitoring ............................................................................. 54 
6.4.5 
Finger Count, Hand Motion, and Light Perception ........................................... 55 

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6.4.6 
Intraocular Pressure Test ................................................................................... 55 
6.4.7 
Slit Lamp Examination ...................................................................................... 56 
6.4.8 
Indirect Ophthalmoscopy .................................................................................. 56 
6.4.9 
Vital Signs and Weight ...................................................................................... 56 
6.4.10 Electrocardiogram ............................................................................................. 57 
6.4.11 New York Heart Association Functional Classification .................................... 57 
6.4.12 Physical Examination ........................................................................................ 57 
6.4.13 Pregnancy .......................................................................................................... 58 
6.4.14 Clinical Laboratory Analyses ............................................................................ 58 
6.5 
Sample Collections .................................................................................................. 59 
6.5.1 
Pharmacokinetic Blood Sampling ..................................................................... 59 
6.5.2 
Immunogenicity Blood Sampling ..................................................................... 59 
6.5.3 
Safety Blood Sampling ...................................................................................... 59 
6.5.4 
Urine Sampling ................................................................................................. 59 
6.6 
Labeling, Storage, and Transportation of Samples .................................................. 60 
6.6.1 
Sample Labeling ................................................................................................ 60 
6.6.2 
Sample Storage and Shipment ........................................................................... 60 
6.7 
Overdose Management ............................................................................................ 60 
7 
Statistical Analysis Plan ................................................................................................... 61 
7.1 
Sample Size Calculation .......................................................................................... 61 
7.2 
Analysis Sets ............................................................................................................ 61 
7.3 
Description of Subgroups to be Analyzed ............................................................... 62 
7.4 
Efficacy Analysis ..................................................................................................... 62 
7.4.1 
Primary Efficacy Analyses ................................................................................ 62 
7.4.2 
Secondary Efficacy Analyses ............................................................................ 63 
7.5 
Pharmacokinetic Analyses ....................................................................................... 63 
7.6 
Usability Analyses ................................................................................................... 64 
7.7 
Safety Analyses ........................................................................................................ 64 
7.7.1 
Demographics, Baseline, and Background Characteristics ............................... 64 
7.7.2 
Adverse Events .................................................................................................. 65 
7.7.3 
Immunogenicity ................................................................................................ 65 
7.7.4 
Clinical Laboratory Analyses ............................................................................ 65 

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7.7.5 
Electrocardiograms, Physical Examination, Vital Signs, and Weight ............... 65 
7.7.6 
Prior and Concomitant Treatment ..................................................................... 66 
7.7.7 
Other Safety Analyses ....................................................................................... 66 
7.8 
Interim Analysis ....................................................................................................... 66 
7.9 
Data Quality Assurance ........................................................................................... 66 
8 
Investigator’s Obligations ................................................................................................ 68 
8.1 
Confidentiality and Data Protection ......................................................................... 68 
8.2 
Independent Ethics Committee or Institutional Review Board ............................... 68 
8.3 
Patient Information and Consent ............................................................................. 69 
8.4 
Study Reporting Requirements ................................................................................ 70 
8.5 
Financial Disclosure and Obligations ...................................................................... 70 
8.6 
Investigator Documentation ..................................................................................... 70 
8.7 
Study Conduct .......................................................................................................... 71 
8.8 
Data Collection ........................................................................................................ 71 
8.8.1 
Electronic Case Report Forms and Source Documents .................................... 71 
8.9 
Adherence to Protocol .............................................................................................. 72 
8.10 Investigator’s Final Report ...................................................................................... 72 
8.11 Record Retention ..................................................................................................... 72 
8.12 Patient Identification Register .................................................................................. 73 
8.13 Publications .............................................................................................................. 73 
9 
Study Management ........................................................................................................... 74 
9.1 
Sponsor .................................................................................................................... 74 
9.2 
Vendor Contact ........................................................................................................ 74 
9.3 
Central Analytical Facilities .................................................................................... 74 
9.4 
Monitoring ............................................................................................................... 74 
9.4.1 
Data Safety Monitoring Board .......................................................................... 74 
9.4.2 
Monitoring of the Study .................................................................................... 75 
9.4.3 
Inspection of Records ........................................................................................ 76 
9.5 
Management of Protocol Amendments and Deviations .......................................... 76 
9.5.1 
Modification of the Protocol ............................................................................. 76 
9.5.2 
Protocol Deviations ........................................................................................... 76 
9.6 
Study Termination ................................................................................................... 77 

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9.7 
Final Report ............................................................................................................. 77 
10 References ........................................................................................................................ 78 
11 Appendices ....................................................................................................................... 81 
Appendix 1. Schedule of Assessments ................................................................................ 81 
Appendix 2. New York Heart Association Functional Classification ................................ 84 
Appendix 3. Usability Assessment Checklist ..................................................................... 85 
Appendix 4. Benefit and Risk Assessment and Risk Mitigation Plan for COVID-19 ........ 87 
 

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List of Tables 
Table 5-1 
Identity of investigational Products ............................................................ 37 
Table 9-1 
Meeting milestones of DSMB .................................................................... 75 
Table 11-1 
Summary of measures to prevent COVID-19 transmission while 
maintaining adequate care of IVT injections .............................................. 87 
 
List of Figure 
Figure 3-1 
Study Design Overview .............................................................................. 28 

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Protocol Synopsis 
Protocol Number: CT-P42 3.1 
Title: A Randomized, Active-Controlled, Double-Masked, Parallel-Group, Phase 3 Study to Compare Efficacy 
and Safety of CT-P42 in comparison with Eylea in Patients with Diabetic Macular Edema 
Study Phase: Phase 3 
Study Centers: 
 
Test Drug Formulation, Dose and Regimen: 
Main Study Period 
CT-P42, 2 mg/0.05 mL by intravitreal (IVT) injection via a single-dose vial every 4 weeks for 5 doses, then 
every 8 weeks for 4 doses 
Extension Study Period 
CT-P42, 2 mg/0.05 mL by IVT injection via a single-dose pre-filled syringe (PFS) at Extension Week 0 (1 
dose) 
Reference Drug, Dose and Regimen: 
Main Study Period 
European Union (EU)-approved Eylea, 2 mg/0.05 mL by IVT injection via a single-dose vial every 4 weeks 
for 5 doses, then every 8 weeks for 4 doses 
Objectives: 
Primary Objective 
 
To demonstrate that CT-P42 is similar to Eylea in terms of efficacy as determined by clinical response 
according to the mean change from baseline at Week 8 in Best Corrected Visual Acuity (BCVA) using 
Early Treatment of Diabetic Retinopathy Study (ETDRS) chart 
Secondary Objectives 
 
To evaluate additional efficacy, pharmacokinetics (PK), usability, and overall safety including 
immunogenicity 
Main Selection Criteria: 
Male or female patients aged ≥18 years with diabetic macular edema (DME), secondary to type 1 or type 2 
diabetes mellitus (DM) will be considered for enrollment in the study if they meet all of the inclusion criteria 
and none of the exclusion criteria. 
Inclusion Criteria: 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Male or female patient aged ≥18 years. 
2. Patient who has type 1 or 2 DM. 
3. Patient with DME secondary to DM involving the center of the macula (defined as the Optical Coherence 
Tomography [OCT] central subfield) in the study eye. 
4. Patient whose central subfield retinal thickness is ≥350 µm as assessed by OCT based on central results 
in the study eye at Screening. 
5. Patient who has BCVA score of 73 to 34 (approximate Snellen equivalent of 20/40 to 20/200) using 
ETDRS charts in the study eye at Screening and Day 1 (for more detailed BCVA procedures, see the study 
procedure manual). 
6. Decrease in vision determined to be primarily the result of DME in the study eye. 
7. Patient and/or their legally authorized representative are informed and will be given ample time and 
opportunity to read and/or understand the nature and purpose of this study including possible risks and 
side effects and must sign the informed consent form (ICF) before any specific procedures. 
8. Female patient must agree to use highly effective methods of contraception consistent with local 
regulations during the course of the study and for at least 3 months following discontinuation of study 
drug (excluding women who are not of childbearing potential). Examples include the following: 

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a) Combined (estrogen and progestogen containing) or progestogen-only hormonal contraceptives 
associated with inhibition of ovulation 
b) Intrauterine device or intrauterine hormone-releasing system 
c) True abstinence, when this is in line with the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of exposure to investigational drug, and withdrawal are not acceptable 
methods of contraception. 
A woman is considered of childbearing potential, following menarche and until becoming post-menopausal 
unless surgically sterile. Menopausal female patients must have experienced their last period more than 1 
year prior to the date of informed consent to be classified as not of childbearing potential. Male patient 
who is sexually active with a woman of childbearing potential must agree to use highly effective method 
described as above or 2 acceptable methods of contraception (e.g., Male or female condom AND additional 
hormonal or barrier contraceptive method other than condom by female partner) consistent with local 
regulations during the course of the study and for at least 3 months following discontinuation of study drug. 
Contraception is not required if either patient or his/her partner who has been surgically sterilized more 
than 24 weeks prior to the date of informed consent. 
Exclusion Criteria: 
A patient meeting any of the following criteria are not eligible for inclusion in this study: 
1. Patient who has only one functional eye, even if the eye met all other study requirements, or has and/or is 
likely to have amblyopia, amaurosis or ocular disorder with BCVA < 34 ETDRS letter score (approximate 
Snellen equivalent of < 20/200) in the fellow eye 
2. Patient who currently has, or has a history (where indicated) of ocular condition including one or more of 
the following in the study eye: 
a) Active proliferative diabetic retinopathy, or pre-retinal fibrosis involving the macula 
b) Aphakia 
c) Vitreomacular traction or epiretinal membrane that is expected to affect central vision 
d) Iris neovascularization, vitreous hemorrhage, or tractional retinal detachment 
e) Ocular inflammation (including trace or above) 
f) 
Uncontrolled glaucoma or filtration surgery for glaucoma in the past or likely to be needed in the 
future 
g) Intraocular pressure (IOP) ≥25 mmHg 
h) Spherical equivalent of the refractive error of worse than -6 diopters myopia 
i) 
Structural damage to the center of the macula that is likely to preclude improvement in BCVA 
following the resolution of macular edema including atrophy of the retinal pigment epithelium, 
subretinal fibrosis or scar, significant macular ischemia or organized hard exudates 
j) 
Concurrent and/or history of disease, other than DME, that could compromise visual acuity, require 
medical or surgical intervention during the study period, or could confound interpretation of the results 
(including retinal vascular occlusion, retinal detachment, macular hole, or choroidal 
neovascularization of any cause) as assessed by the investigator 
k) Inability to obtain fundus and OCT images due to, but not limited to, insufficient media clarity or 
inadequate pupil dilation 
3. Patient who currently has, or has a history (where indicated) of ocular condition including one or more of 
the following in either eye: 
a) Concurrent and/or history of idiopathic or autoimmune uveitis 
b) Evidence or suspicion of infection including blepharitis, keratitis, scleritis, or conjunctivitis 
However, a patient who has completely recovered from the infection at Day 1 is allowed to be enrolled 
at the investigator’s discretion. 
4. Patient who currently has, or has a history of (where indicated) systemic condition including one or more 
of the following: 
a) Uncontrolled DM as defined by hemoglobin A1c >10% 
b) Uncontrolled blood pressure defined as systolic ≥160 mmHg or diastolic ≥100 mmHg measured after 
5 minutes of rest while sitting 
c) History of vascular disease such as cerebrovascular accident, myocardial infarction, transient ischemic 

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attack, or thromboembolic reaction including pulmonary embolism within 180 days prior to the first 
study drug administration 
d) New York Heart Association Functional Classification Class III or IV heart failure, or severe 
uncontrolled cardiac disease (i.e., unstable angina) 
e) Current treatment for serious systemic infection 
f) 
History of recurrent significant infections in the opinion of the investigator 
g) Renal failure requiring dialysis or renal transplant 
h) History of malignancies within 5 years prior to the first study drug administration, except adequately 
treated squamous or basal cell carcinoma of the skin or cervical carcinoma in situ 
i) 
History of other disease, metabolic dysfunction, physical examination finding, electrocardiogram 
(ECG) finding or clinical laboratory finding giving reasonable suspicion of a disease or condition that, 
in the opinion of the investigator, contraindicates the use of the study drug or that might affect 
interpretation of the results of the study or render the patient at high risk for treatment complications 
j) 
Evidence of significant uncontrolled concomitant diseases including cardiovascular system, nervous 
system, pulmonary, renal, hepatic, endocrine, gastrointestinal disorders, or psychiatric condition as 
assessed by the investigator. 
5. Patient who has one or more previous/concomitant treatments of the following: 
a) Previous systemic or ocular treatment with aflibercept including potential biosimilars 
b) Previous treatment with ocular anti-angiogenic agents (pegaptanib sodium, bevacizumab, 
ranibizumab etc.) in the study eye 
c) Administration of systemic anti-angiogenic agents and/or ocular anti-angiogenic agents in fellow 
(non-study) eye within 180 days prior to the first study drug administration 
d) Previous use of intraocular or periocular corticosteroids including dexamethasone implant (e.g., 
Ozurdex) within 180 days, or fluocinolone acetonide implant (e.g., Iluvien) within 36 months prior to 
the first study drug administration in the study eye 
e) Laser photocoagulation (panretinal or macular) in the study eye within 90 days prior to the first study 
drug administration 
f) 
More than two previous macular laser treatments, and/or focal laser scars in the fovea that could limit 
BCVA improvement in the study eye 
g) History of vitreoretinal surgery including scleral buckling in the study eye 
h) Any intraocular surgery including cataract surgery in the study eye within 90 days prior to the first 
study drug administration or planned or expected during the study 
i) 
Yttrium-aluminum-garnet capsulotomy in the study eye within 30 days prior to the first study drug 
administration 
j) 
Treatment with any investigational medicinal product and/or device within 30 days or 5 half-lives, 
whichever is longer, prior to the first study drug administration. 
6. Patient with a hypersensitivity to immunoglobulin products, or patient who has allergies to any of the 
excipients or components of study drug, any other human proteins, or diagnostic process (e.g., anesthetics, 
topical broad–spectrum microbicides, fluorescein). 
7. Female patient who is currently pregnant or breastfeeding. 
8. Patient who, in the opinion of the investigator, should not participate in the study. 
Study Design: 
This study is a randomized, active-controlled, double-masked, parallel-group, multicenter, Phase 3 study 
designed to evaluate the efficacy, PK, usability, and overall safety including immunogenicity of CT-P42 and 
Eylea via IVT injection using a single-dose vial kit in the Main Study Period. An open-label, single-arm, single 
dose extension study can be followed to evaluate usability, efficacy, and safety of CT-P42 via IVT injection 
using a single-dose PFS. 
During the Main Study Period, approximately 360 patients will be administered CT-P42 or Eylea via IVT 
injection (in 1:1 ratio) using a single-dose vial every 4 weeks for 5 doses, then every 8 weeks for 4 doses. After 
the completion of the Main Study Period, approximately 30 patients can enter Extension Study Period to 
receive one additional dose of CT-P42 via IVT injection using a single-dose PFS at Extension Week 0 
regardless of the treatment group in the Main Study Period. The study design and patient assessment overview 
are presented in the figure below. 

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Study Design Overview 
 
Abbreviations: BCVA=Best Corrected Visual Acuity; EOS=End-of-Study; Ext 0=Extension Week 0; Ext 4=Extension Week 4; PFS=Pre-filled syringe; 
PK=Pharmacokinetics; EU=European Union 
* The first EOS (EOS1) assessments will be performed at Week 52 for all patients who complete the Main Study Period. Patients who 
discontinue early from the study will visit the study center for the EOS1 evaluations at least 4 weeks after the last dose of study drug 
administration. For the patients who discontinued the study drug prior to the completion of Week 8 visit, the patients will be asked to 
return to the site at Week 8 to complete all planned assessments for the EOS1 visit. 
* Blood samples for PK assessment will be collected for approximately 40 patients (20 patients per treatment group). 
* Usability assessments of CT-P42 and Eylea vial kit will be performed at Week 0 for approximately 60 patients (30 patients per treatment 
group).  
* Approximately 30 patients who complete the Main Study Period up to Week 52 can receive a single dose of CT-P42 PFS at Extension 
Week 0 to evaluate usability in the Extension Study Period. 
Screening Period (Day -28 to Day -1): 
Screening will take place between Day –28 and Day –1 (4 weeks), prior to the first study drug administration. 
Main Study Period (Week 0 to Week 52): 
On Day 1 (Week 0), patients who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled in the study. Only 1 eye per patient will be considered in this study and called as the ‘study eye’. For 
patients who met criteria in both eyes, the eye with the worst BCVA will be selected as the study eye. If a 
patient has DME with similar BCVA in both eyes, the eye with the clearest media will be selected as the study 
eye. If the ocular media of both eyes are similar in clarity, the patient’s non-dominant eye (if identifiable) will 
be selected as the study eye. If neither eye is dominant, the right eye will be designated as the study eye. 
Eligible patients will be randomly assigned to either the CT-P42 or Eylea treatment group in a 1:1 ratio. The 
randomization to treatment assignment will be stratified as follows: 
 
BCVA score (<55 letters versus ≥55 letters) using the ETDRS chart on Day 1 
 
Country 
 
PK subgroup (Yes versus No) 
The First End-of-Study (EOS1) Visit (Week 52): 

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The first EOS visit will occur at Week 52, 4 weeks after the last dose at Week 48. Patients who discontinue 
early from the study will visit the study center at least 4 weeks after the last dose of study drug administration 
for EOS1 evaluations. For the patients who discontinued the study drug prior to the completion of Week 8 visit, 
the patients will be asked to return to the site at Week 8 to complete all planned assessments for the EOS1 visit. 
Extension Study Period (Extension Week 0 to Extension Week 4): 
Approximately 30 patients who complete the Main Study Period up to Week 52, regardless of the treatment 
groups that they were randomized to, can participate in the open-label Extension Study Period. The patients 
must sign the ICF before participation in Extension Study Period. At Extension Week 0, patients will receive 
a single dose of CT-P42 PFS. CT-P42 PFS on Extension Week 0 is recommended 8 weeks after the last study 
drug administration in Main Study Period (Week 48). However, the actual dosing interval from the last 
administration of study drug in Main Study Period (Week 48) can be determined based on investigator’s 
discretion considering the approved regimen of Eylea where treatment interval after first 12 months of 
treatment with Eylea may be extended based on investigator’s judgement of visual and/or anatomic outcomes, 
and there are limited data for treatment interval longer than 4 months.  
The Second End-of-Study (EOS2) Visit (Extension Week 4): 
The second EOS visit will occur at Extension Week 4, 4 weeks after the dose of Extension Study Period. 
During the whole study, patients will be asked to comply with all appropriate visits and assessments. All 
patients will return to the study center at specified visits in schedule of assessments for study drug 
administration, clinical assessments, and blood samplings. To minimize the risk of potential adverse events 
(AEs) associated with serial IVT injections, aseptic techniques will be performed. At each visit, the patients 
will be monitored for AEs and questioned about concomitant treatments until the last EOS visit. 
Efficacy Assessments: 
Primary Endpoint: 
 
Mean change from baseline in BCVA using the ETDRS chart at Week 8 
Secondary Endpoints: 
The following secondary efficacy endpoints will be assessed at each applicable visit up to Week 52, Extension 
Week 0 and 4: 
 
Mean change in BCVA using the ETDRS chart from baseline 
 
Proportion of patients who gained ≥5, ≥10, and ≥15 ETDRS letters from baseline in BCVA using the 
ETDRS chart 
 
Proportion of patients who lost ≥5, ≥10, and ≥15 ETDRS letters from baseline in BCVA using the 
ETDRS chart 
 
Mean change in central subfield thickness from baseline as determined by spectral-domain OCT 
 
Percentage of patients with a ≥2-step improvement from baseline in the ETDRS Diabetic Retinopathy 
Severity Scale (DRSS) score as assessed by fundus photography  
Pharmacokinetic Assessment: Blood samples for assessment of Cmax and Tmax of free (VEGF-unbound) study 
drug concentrations in plasma will be collected at pre-dose within 60 minutes, 24 ± 2 hours, 48 ± 2 hours, and 
72 ± 6 hours after the first and the fifth study drug administration, respectively. 
Secondary Endpoints: 
 
Cmax1: Maximum plasma concentration after the first study drug administration 
 
Cmax2: Maximum plasma concentration after the fifth study drug administration 
 
Tmax1: Time of observed maximum plasma concentration after the first study drug administration 
 
Tmax2: Time of observed maximum plasma concentration after the fifth study drug administration 
Usability Assessment: 
Secondary Endpoints: 
The following usability endpoint will be assessed: 
 
Number of injections with vial kit successfully administered by healthcare professionals at Week 0 
 
Number of injections with PFS successfully administered by healthcare professionals at Extension 
Week 0 
Safety Assessments: 

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Secondary Endpoints: 
Safety assessments will be performed in both groups on AEs (ocular and non-ocular) including serious adverse 
events (SAEs), AEs of special interest (AESIs; arterial thromboembolic events and AEs related to IVT injection 
procedure), IOP test, slit lamp examination, indirect ophthalmoscopy, finger count/hand motion/light 
perception, immunogenicity assessments including anti-drug antibody and neutralizing antibody, 
hypersensitivity monitoring, vital signs and weight measurements, ECGs, New York Heart Association 
Functional Classification assessment, physical examination findings, pregnancy testing, clinical laboratory 
analyses including hemoglobin A1c, and prior and concomitant treatments monitored throughout the study. 
Adverse events will be recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) 
v5.0. 
Sample Size: 
Assuming an equivalence margin of ±3 letters with two one-sided significance level of 0.05, a sample size of 
316 patients (158 patients in each treatment group) provides an 89% statistical power to demonstrate 
therapeutic equivalence of CT-P42 to Eylea based on the mean change from baseline in BCVA at Week 8. In 
the sample size calculation, the common standard deviation (SD) of the mean change from baseline in BCVA 
was assumed as 8.2 and expected mean difference was assumed to be 0. The dropout rate has been hypothesized 
at 12%; therefore, approximately 360 patients (180 patients in each treatment group of CT-P42 and Eylea) will 
be required to be enrolled in this study. 
 
 
Statistical Methods: 
Data analysis: 
This study will be unmasked for the reporting purposes. The first code break will occur after database lock for 
data up to Week 24 for all patients and the study results up to Week 24 will be reported in a first Clinical Study 
Report. The unmasked personnel will be predefined and documented before performing the analyses. The 
randomization codes for the Main Study Period will not be revealed to patients, investigators, and predefined 
masked study center personnel until the final Clinical Study Report has been generated except for predefined 
unmasked personnel from Sponsor and Contract Research Organization.  
Statistical Analysis: 
 
 The statistical methods for this study will be described in a detailed Statistical 
Analysis Plan (SAP), which will be finalized prior to database lock. Changes from analyses planned in this 
protocol will be documented in the SAP. Continuous variables will be summarized by reporting descriptive 
statistics: the number of observations (n), mean, SD, median, minimum, and maximum. Categorical variables 
will be summarized using frequency tables showing the number and percentage of patients within a particular 
category. 
Definition of Analysis Set: 
All data collected during the Main Study Period will be analyzed in the following analysis sets. 
 
Intent-to-Treat (ITT) set is defined as all patients who are randomly assigned to receive either of the 
study drugs, regardless of whether or not any study drug was administered 
 
Full analysis set (FAS) is defined as all randomly assigned patients who receive at least one full dose 
of study drug 
 
Per-Protocol (PP) set is defined as all randomly assigned patients who receive all full doses of study 
drug up to Week 4 (total 2 injections) and have a BCVA assessment at Week 8. A major protocol 
deviation that may affect the interpretation of study results of primary efficacy endpoint will lead to 
the exclusion from PP set. Final determinations of the PP set will be made at the masked data review 
meeting before unmasking 
 
Safety set for Main Study Period is defined as all randomized patients who receive at least one full or 
partial dose of study drug 
 
Pharmacokinetic set is defined as patients who receive at least one full dose of study drug and have 
at least one post-treatment PK concentration data. A major protocol deviation that may affect the 
interpretation of study results of PK endpoints will lead to exclusion from PK set. Final determinations 
of the PK set will be made at the masked data review meeting for the PK endpoints before unmasking. 
 
Usability set for vial kit is defined as all patients in the Safety set for Main Study Period who have 

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evaluable usability measurements. 
All data collected from the Extension Study Period will be analyzed in the following analysis sets.  
 
Safety set for Extension Study Period is defined as all patients who receive full or partial dose of study 
drug via PFS in the Extension Study Period. 
 
Usability set for PFS is defined as all patients in the Safety set for Extension Study Period who have 
evaluable usability measurements.   
Efficacy Analysis: 
The primary efficacy analysis (mean change from baseline in BCVA at Week 8) will be performed for the FAS 
using an analysis of covariance (ANCOVA) model with the baseline BCVA and country as covariates and 
treatment group as a factor. Therapeutic equivalence of CT-P42 with respect to Eylea will be concluded if 
two-sided 90% confidence interval of difference falls entirely within an equivalence margin (±3 letters). The 
primary endpoint will also be analyzed using the PP set. The sensitivity analysis will be performed in the FAS 
to evaluate the impact of missing data on the primary efficacy results. Missing data will be imputed using 
multiple imputation with the missing at random assumption. Also, in case the missing rate is higher than 
expected, the trimmed means approach will be considered to address the possible bias from the potentially high 
and/or imbalanced missing rates in the treatment groups. The details will be described in the SAP.  
Other secondary efficacy endpoints will be analyzed using the FAS and PP Set for Main Study Period and 
Safety set for Extension Study Period. These will be summarized using descriptive statistics (n, mean, median, 
SD, minimum, and maximum) for quantitative variables and frequency counts and percentages for categorical 
variables. 
Safety Analysis: 
Severity grading of AEs will be recorded based on the CTCAE v5.0. All reported terms for AE and medical 
history will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Prior and 
concomitant medication will be coded using the World Health Organization drug dictionary, non-drug therapies 
will be coded according to the MedDRA. All safety data, including immunogenicity, will be listed and 
summarized by treatment group as appropriate in the Safety set for Main Study Period and Safety set for 
Extension Study Period. 
Pharmacokinetic Analysis: 
The PK set will be the primary analysis set for the summary of PK data. Plasma concentrations and PK 
parameters will be summarized using descriptive statistics (including geometric mean and coefficient of 
variation, as appropriate). 
Usability Analysis: 
The secondary usability endpoint will be summarized using the Usability set for vial kit and PFS, respectively. 
The number of injections successfully administered will be summarized using frequency tables. 
 
 

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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
AMD 
age-related macular degeneration 
ATE 
arterial thromboembolic event 
BCVA 
Best Corrected Visual Acuity 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
COVID-19 
Disease caused by SARS-CoV-2 
CRO 
contract research organization 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for AEs 
DM 
diabetes mellitus 
DME 
diabetic macular edema 
DR 
diabetic retinopathy 
DRSS 
Diabetic Retinopathy Severity Scale  
DSMB 
Data Safety Monitoring Board  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOS 
end-of-study 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EU 
European Union 
FA 
fluorescein angiography 
FDA 
Food and Drug Administration 
FP 
fundus photography 
GCP 
Good Clinical Practice 
HbA1c 
hemoglobin A1c 
IAI 
intravitreal aflibercept injection 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG1 
immunoglobulin gamma 1 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IVT 
intravitreal 
 
  
MedDRA 
Medical Dictionary for Regulatory Activities 
n 
number of observations 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography 
PFS 
Pre-filled syringe 

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PK 
pharmacokinetics  
PT 
preferred term 
PVG 
RVO 
pharmacovigilance 
retinal vein occlusion 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
SD-OCT 
spectral-domain optical coherence tomography 
SmPC 
Summary of Product Characteristics 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event  
US 
United States 
USPI 
United States Prescribing information 
VA 
visual acuity 
VEGF 
vascular endothelial growth factor 
 
 

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1 Introduction 
1.1 Background 
1.1.1 Diabetic Macular Edema 
Diabetic macular edema (DME) is a leading cause of vision impairment related to diabetes 
mellitus (DM) among people within the working-age population (Wenick and Bressler, 2012). 
It is a common microvascular complication in patients with DM along with diabetic 
retinopathy (DR). Diabetic macular edema may have a sudden and debilitating impact on visual 
acuity (VA), eventually leading to blindness (Ciulla et al. 2003). 
Diabetic macular edema is a consequence of DR in the macular area and is secondary to 
blood-retinal barrier rupture resulting in leakage of dilated hyperpermeable capillaries and 
microaneurysms, which is in turn secondary to a range of metabolic changes brought about by 
hyperglycemia (Romero-Aroca et al. 2016). Chronic hyperglycemia leads to the upregulation 
of vascular endothelial growth factor (VEGF), resulting in angiogenesis, increased vascular 
permeability, and the production of proinflammatory cytokines (Boyer et al. 2013). The most 
important molecule in retinal barrier rupture is the VEGF. The VEGF is a molecule present in 
the vitreous of patients with DR and DME, with its levels being proportional to the severity of 
the diseases (Romero-Aroca et al. 2016). Over time, ongoing microvascular damage triggers a 
well-defined succession of pathogenic events in the retina, including capillary nonperfusion 
and inner retinal ischemia, upregulation of VEGF-A, macular edema, and retinal 
neovascularization. Thickening of the basement membrane and pericyte loss, both key 
hallmarks of DR, as well as sheer stress on endothelial cells, may further stimulate VEGF 
production (Boyer et al. 2013). 
The intravitreal (IVT) anti-VEGF agents are now widely used for DME in countries with 
high-resource settings. However, in low- or intermediate-resource settings, issues with access, 
availability, and administration of anti-VEGF agents may not allow the intensive treatment 
schedule and regimen needed to provide the outcomes seen in clinical trials (Wong et al. 2018; 
Schmidt-Erfurth et al. 2017). In countries with low or intermediate resources, where possible, 
physicians can consider off-label alternatives such as bevacizumab (Avastin), or focal or grid 
laser treatment might be considered as a primary method of treatment for DME (Wong et al. 
2018). Thus, availability of more cost-effective biosimilars to the anti-VEGF therapy can 
broaden patient access to the standard treatment. 
Aflibercept is a recombinant protein composed of the extracellular domains of two human 
VEGF receptors (VEGFR-1 and VEGFR-2) fused with the Fc portion of human 

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immunoglobulin gamma 1 (IgG1). It is a soluble decoy receptor that binds to VEGF-A and 
placental growth factor with a greater affinity than the body’s native receptors. This way, 
VEGF more favorably binds with aflibercept instead of its native receptors, reducing VEGF's 
activity. VEGF-A is a biochemical signal protein that promotes angiogenesis throughout the 
body and in the eye. By decreasing VEGF-A’s activation of its native receptors, aflibercept 
reduces subsequent growth of new blood vessels and vascular permeability (Eylea Summary 
of product characteristics[SmPC] 2022; Eylea United States Prescribing information [USPI] 
2021). 
1.2 CT-P42 
CT-P42, containing the active ingredient aflibercept, is a recombinant fusion protein consisting 
of portions of human VEGFR-1 and VEGFR-2 extracellular domains fused to the Fc portion 
of human IgG1 and is developed as a proposed biosimilar to reference product Eylea 
(aflibercept) by CELLTRION, Inc. 
The reference product, Eylea (aflibercept ophthalmic solution) was originally approved for 
treatment of wet age-related macular degeneration (AMD) in European Union (EU) in 
November 2012 and United States (US) in November 2011. In the EU, Eylea is indicated for 
the following conditions: wet AMD, macular edema following retinal vein occlusion (RVO), 
DME, and myopic choroidal neovascularization; in the US, Eylea is indicated for wet AMD, 
macular edema following RVO, DME, and DR. 
CT-P42 will be formulated as a solution for injection at the same strength as Eylea (40 mg/mL) 
containing qualitatively and quantitatively the same or similar excipients. The CT-P42 and 
Eylea vial will be used for Main Study Period and the CT-P42 pre-filled syringe (PFS) will be 
used for Extension Study Period. CT-P42 or Eylea is referred as “study drug” further in this 
protocol. 
1.2.1 Nonclinical Studies 
Detailed information regarding the nonclinical pharmacology and toxicology of CT-P42 can 
be found in the Investigator’s Brochure (IB). 
1.2.2 Clinical Studies 
No clinical studies have yet been conducted with CT-P42. However, clinical data on Eylea has 
been published in the scientific literature, regulatory submissions, and approved product 
information (Eylea SmPC 2022; Eylea USPI 2021). As CT-P42 is being developed as a 

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proposed biosimilar to reference product Eylea, the clinical findings for CT-P42 are expected 
to be similar with the reference product in terms of safety, pharmacokinetics (PK), and efficacy. 
The efficacy and safety of aflibercept in DME was established based on two randomized, 
double-masked, active-controlled pivotal Phase 3 studies (Korobelnik et al. 2014). 
VISTA and VIVID studies were conducted in 872 patients with DME, who were randomized 
in a 1:1:1 ratio to receive either 2 mg intravitreal aflibercept injection (IAI) every 4 weeks 
(2q4), 2 mg IAI every 8 weeks (2q8) after 5 initial doses every 4 weeks (from baseline to 
Week 16) with sham injections on non-treatment visits (2q8), or macular laser 
photocoagulation at baseline and sham injections at every visit (laser control group). The 
1-year results of the VISTA and VIVID studies demonstrate that IAI 2q4 and IAI 2q8 
significantly improved visual outcomes and significantly decreased severe vision loss, while 
simultaneously improving the Diabetic Retinopathy Severity Scale (DRSS) score, compared 
with focal laser photocoagulation. In safety aspects, the overall incidences of adverse events 
(AEs) were similar across treatment groups. There were no clinically relevant differences 
between the treatment groups in terms of frequency or pattern of ocular serious adverse events 
(SAEs). The incidence of intraocular inflammation based on the total number of IVT injections 
in the IAI 2q4, IAI 2q8, and laser groups was 0.2% (4/1832 injections), 0.1% (1/1284 
injections), and 0.5% (1/212 injections) in VISTA, and 0.2% (4/1656 injections), 0.4% (5/1168 
injections), and 0.7% (1/135 injections) in VIVID, respectively. The incidence of non-ocular 
SAEs was slightly higher for some events in the combined IAI group (e.g., congestive cardiac 
failure and anemia), and for others in the laser group (e.g., acute myocardial infarction and 
osteoarthritis), with no apparent general trend. The incidences and patterns of deaths were not 
clinically different among treatment groups (Korobelnik et al. 2014). 
1.3 Study Rationale 
CT-P42 is currently being developed as a proposed biosimilar to reference product Eylea. For 
a proposed biosimilar to be approved, it must show no clinically meaningful differences in 
comparison with its reference product. The stepwise ‘totality of evidence’ approach adopted 
by regulatory authorities for biosimilars means that the type of clinical studies needed varies 
on a case-by-case basis. 
Generally, statistically-proven equivalence between the proposed biosimilar and reference 
product regarding PK and efficacy is required, as is a demonstration of acceptable safety and 
immunogenicity. However, in view of the limited detectability of aflibercept in patient’s blood 
and high interpatient variability during historical Eylea trials, a PK equivalence study is neither 

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meaningful nor ethical in healthy volunteers considering IVT injection. Hence, no PK 
equivalence study is proposed for the development of CT-P42. 
Therefore, assessment of the efficacy, PK, safety, and immunogenicity will be carried out in 
this proposed comparative clinical study in patients with DME. Sponsor considers that the 
proposed clinical development program will be sufficient to demonstrate therapeutic 
equivalence and safety of CT-P42 to the reference product (Study CT-P42 3.1 comparative 
clinical similarity). 
The design of this study takes into account the EU Guideline on Similar Biological Medicinal 
Products Containing Monoclonal Antibodies: Nonclinical and Clinical Issues (European 
Medicines Agency [EMA] 2012) and the Food and Drug Administration (FDA) Guideline on 
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (FDA 2015). 
1.3.1 Rationale for Study Population 
International regulations (World Health Organization 2013; EMA 2012; FDA 2015; FDA 2019) 
suggest that proposed biosimilars should be tested in a population representative of the 
approved therapeutic indications of the reference product and sufficiently sensitive for 
detecting potential differences between the proposed biosimilar and the reference product. 
In patients with DME, the results from two pivotal studies showed robust, large, and clinically 
relevant improvement in Best Corrected Visual Acuity (BCVA) and morphological ocular 
visual outcomes in patients receiving aflibercept in comparison with macular laser 
photocoagulation (Korobelnik et al. 2014). In addition, the variability of mean changes from 
baseline BCVA in patients with DME was relatively low, and hemoglobin A1c (HbA1c) did 
not have significant impact on anti-VEGF treatment effect based on subgroup analysis (Singh 
et al. 2017). Furthermore, the mechanism of action of aflibercept in DME is representative for 
the other indications and the incidence of AEs with aflibercept was similar across indications 
(Fogli et al. 2018; Pham et al. 2019). 
Consequently, the study population, DME, in this study was selected in order to align with the 
indications approved for the reference product and to be representative of the original 
placebo-controlled studies supporting the development of the reference product, facilitating 
the detection of potential differences between CT-P42 and the reference product Eylea. 
1.4 Benefit and Risk Assessment 
The CT-P42 drug product will have the same pharmaceutical form and strength as the reference 
product Eylea (40 mg/mL). The proposed dosing regimen is with the same as the approved 
labeling for Eylea (Eylea SmPC 2022; Eylea USPI 2021). 

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The proposed safety monitoring is deemed sufficient to monitor potential risks of CT-P42 
administration. In view of the structural, biological, and toxicological similarity to Eylea, 
CT-P42 is expected to display a similar safety profile. Eylea has been studied extensively and 
has been shown to be effective at improving VA in patients with AMD, DME, and RVO (Eylea 
SmPC 2022; Eylea USPI 2021). 
Based on the current clinical evidence, as well as the safety profile of Eylea, the benefits of the 
conduct of the proposed clinical study outweigh the associated risks. 
The benefit and risk assessments and the risk mitigation plans for coronavirus disease 2019 
(COVID-19) are specified in the Appendix 4. Risk assessments will be conducted during the 
study by the sponsor through a sufficient discussion with the investigators and data safety 
monitoring board (DSMB).

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2 Study Objectives and Endpoints 
2.1 Study Objectives 
2.1.1 Primary Objective 
 
To demonstrate that CT-P42 is similar to Eylea in terms of efficacy as determined by 
clinical response according to the mean change from baseline at Week 8 in BCVA using 
the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart 
2.1.2 Secondary Objectives 
 
To evaluate additional efficacy, PK, usability, and overall safety including immunogenicity 
2.2  Study Endpoints 
2.2.1 Primary Endpoint 
The primary efficacy endpoint is the mean change from baseline in BCVA using the ETDRS 
chart at Week 8. 
2.2.2 Secondary Endpoints 
2.2.2.1 Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed at each applicable visit up to 
Week 52, Extension Week 0 and 4: 
 
Mean change in BCVA using the ETDRS chart from baseline 
 
Proportion of patients who gained ≥ 5, ≥ 10, and ≥ 15 ETDRS letters from baseline in 
BCVA using the ETDRS chart 
 
Proportion of patients who lost ≥ 5, ≥ 10, and ≥ 15 ETDRS letters from baseline in BCVA 
using the ETDRS chart 
 
Mean change in central subfield thickness from baseline as determined by spectral-domain 
optical coherence tomography (SD-OCT) 
 
Percentage of patients with a ≥ 2-step improvement from baseline in the ETDRS DRSS 
score as assessed by fundus photography (FP) 
2.2.2.2 Pharmacokinetic Endpoints 
The following secondary PK endpoints will be assessed: 

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 
Maximum plasma concentration after the first study drug administration (Cmax1) 
 
Maximum plasma concentration after the fifth study drug administration (Cmax2) 
 
Time of observed maximum plasma concentration after the first study drug administration 
(Tmax1) 
 
Time of observed maximum plasma concentration after the fifth study drug administration 
(Tmax2) 
2.2.2.3 Usability Endpoint 
The following secondary usability endpoint will be assessed: 
 
Number of injections with vial kit successfully administered by healthcare professionals 
at Week 0 
 
Number of injections with PFS successfully administered by healthcare professionals at 
Extension Week 0 
2.2.2.4 Safety Endpoints 
The following secondary safety endpoints will be assessed: 
 
Incidence and severity of AEs (ocular and non-ocular) including SAEs 
 
Incidence and severity of adverse event of special interest (AESI) 
a) Arterial thromboembolic events (ATEs) 
b) All AEs related to IVT injection procedure including but not limited to the following: 
endophthalmitis, increases in intraocular pressure (IOP), intraocular inflammation, 
rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. 
 
Intraocular pressure test, slit lamp examination, indirect ophthalmoscopy, finger 
count/hand motion/light perception, hypersensitivity monitoring, vital signs and weight 
measurement, electrocardiogram (ECG), New York Heart Association (NYHA) Functional 
Classification assessment, physical examination findings, pregnancy testing, clinical 
laboratory analyses including hemoglobin A1c (HbA1c) 
 
Immunogenicity, as assessed by incidence of anti-drug antibody and neutralizing antibody 
 
Prior and concomitant treatments 

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3 Investigational Plan 
3.1 Study Design 
This is a randomized, active-controlled, double-masked, parallel-group, multicenter, Phase 3 
study designed to evaluate the efficacy, PK, usability, and overall safety including 
immunogenicity of CT-P42 and Eylea via IVT injection using a single-dose vial kit followed 
by a 4-week open-label, single-arm extension study to evaluate the usability, efficacy, and 
safety of CT-P42 via IVT injection using a single-dose PFS. 
There will be 3 study periods: a Screening Period of 4 weeks, Main Study Period of 52 weeks 
and Extension Study Period of 4 weeks. 
During the Screening Period, the eligibility of the patients for study enrollment will be checked. 
During the Main Study Period, approximately 360 patients will be administered CT-P42 or 
Eylea in 1:1 ratio via IVT injection using a single-dose vial every 4 weeks for 5 doses, then 
every 8 weeks for 4 doses. 
After the completion of the Main Study Period, approximately 30 patients can enter the 
Extension Study Period to receive one additional dose of CT-P42 via IVT injection using a 
single-dose PFS at Extension Week 0 regardless of the treatment group in the Main Study 
Period. 
A database lock is planned once data up to Week 24 for all patients are collected and the study 
results up to Week 24 will be reported in the first Clinical Study Report (CSR). The results will 
be generated by the predefined unmasked personnel from Sponsor and contract research 
organization (CRO). The randomization codes for the Main Study Period will not be revealed 
to patients, investigators, and predefined masked study center personnel until the final CSR 
has been generated except for predefined unmasked personnel from Sponsor and CRO. 
3.2 Study Overview 
The study design and patient assessment overview are presented in Figure 3-1. The schedule 
of assessments is presented in the schedule of assessment (Appendix 1). 
Screening Period (Day –28 to Day –1) 
Screening will take place between Day –28 and Day –1 (4 weeks), prior to the first study drug 
administration. 

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Main Study Period (Week 0 to Week 52) 
On Day 1 (Week 0), patients who meet all of the inclusion criteria and none of the exclusion 
criteria will be enrolled in the study. Only one eye per patient will be considered in this study 
and called as the ‘study eye’. Detailed criteria for selection of the study eye are described in 
Section 4.1.  
Eligible patients will be randomly assigned to either the CT-P42 or Eylea treatment group in a 
1:1 ratio. The randomization to treatment assignment will be stratified as follows: 
 BCVA score (< 55 letters versus ≥ 55 letters) using the ETDRS chart on Day 1 
 Country 
 PK subgroup (Yes versus No) 
During the Main Study Period, all randomized patients will receive the study drug every 
4 weeks for 5 doses, then every 8 weeks for 4 doses. Among them, approximately 40 patients 
(20 patients per treatment group) will make additional visits for PK evaluation. 
Usability assessments of vial kit will be performed at Week 0 for approximately 60 patients 
(30 patients per treatment group). 
First End-of-Study (EOS1) Visit (Week 52): 
The first EOS visit (referred as EOS1) will occur at Week 52, 4 weeks after the last dose at 
Week 48. Patients who discontinue early from the study will visit the study center at least 
4 weeks after the last dose of study drug, or at Week 8 in case of patients who discontinue study 
drug prior to the completion of Week 8 for EOS1 evaluations. 
Extension Study Period (Extension Week 0 to Extension Week 4) 
Approximately 30 patients who completed the Main Study Period up to Week 52, regardless 
of the treatment groups that they were randomized to, can participate in the open-label 
Extension Study Period. The patients must sign the ICF before participation in Extension Study 
Period. At Extension Week 0, patients will receive a single dose of CT-P42 PFS.  
CT-P42 PFS on Extension Week 0 is recommended to be administered 8 weeks after last study 
drug administration in Main Study Period (Week 48). However, the actual dosing interval from 
the last administration of study drug in Main Study Period (Week 48) can be determined based 
on investigator’s discretion considering the approved regimen of Eylea where treatment 

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interval after first 12 months of treatment with Eylea may be extended based on investigator’s 
judgement of visual and/or anatomic outcomes, and there are limited data for treatment interval 
longer than 4 months (Eylea SmPC 2022).   
The Second End-of-Study (EOS2) Visit (Extension Week 4): 
The second EOS visit (referred as EOS2) will occur at Extension Week 4, 4 weeks after the 
dose of Extension Study Period. 
General considerations for study visits 
Patients will be asked to comply with all appropriate visits and assessments. All patients will 
return to the study center at scheduled visits for study drug administration, clinical assessments, 
and blood samplings. To minimize the risk of potential AEs associated with serial IVT 
injections, aseptic techniques will be performed (Section 5.3.1). At each visit, the patients will 
be monitored for AEs and questioned about concomitant treatments until the last EOS visit 
(Section 6.4). 
If any abnormal signs and symptoms are reported (e.g., any decreases in vision, eye pain, 
unusual redness, or any other new ocular symptoms in the study eye), patients will be instructed 
to visit the study center. 
Figure 3-1 
Study Design Overview 

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Abbreviations: BCVA = Best Corrected Visual Acuity; EOS = End-of-Study; Ext 0 = Extension Week 0; Ext 4 = Extension 
Week 4; PFS = Pre-filled syringe; PK = Pharmacokinetics; EU = European Union. 

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4 Patient Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
It is expected that approximately 360 patients will be enrolled at approximately 104 study 
centers in 13 countries. Patients with DME secondary to type 1 or type 2 DM will be 
considered for enrollment in the study if they meet all the inclusion criteria and none of the 
exclusion criteria. 
For patients who met criteria in both eyes, the eye with the worst BCVA will be selected as the 
study eye. If a patient has DME with similar BCVA in both eyes, the eye with the clearest 
media will be selected as the study eye. If the ocular media of both eyes are similar in clarity, 
the patient’s non-dominant eye (if identifiable) will be selected as the study eye. If neither eye 
is dominant, the right eye will be designated as the study eye. Eligible patients will be randomly 
assigned to either the CT-P42 or Eylea treatment group in a 1:1 ratio.  
4.1.1 Inclusion Criteria 
Each patient must meet all the following criteria to be enrolled in this study: 
1. Male or female patient aged ≥ 18 years. 
2. Patient who has type 1 or 2 DM. 
3. Patient with DME secondary to DM involving the center of the macula (defined as the OCT 
central subfield) in the study eye. 
4. Patient whose central subfield retinal thickness is ≥ 350 μm as assessed by OCT based on 
central results in the study eye at Screening. 
5. Patient who has BCVA score of 73 to 34 (approximate Snellen equivalent of 20/40 to 
20/200) using ETDRS charts in the study eye at Screening and Day 1 (for more detailed 
BCVA procedures, see the study procedure manual). 
6. Decrease in vision determined to be primarily the result of DME in the study eye. 
7. Patient and/or their legally authorized representative are informed and will be given ample 
time and opportunity to read and/or understand the nature and purpose of this study 
including possible risks and side effects and must sign the informed consent form (ICF) 
before any specific procedures. 
8. Female patient must agree to use highly effective methods of contraception consistent with 
local regulations during the course of the study and for at least 3 months following 
discontinuation of study drug (excluding women who are not of childbearing potential). 
Examples include the following: 

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a) Combined (estrogen and progestogen containing) or progestogen-only hormonal 
contraceptives associated with inhibition of ovulation 
b) Intrauterine device or intrauterine hormone-releasing system 
c) True abstinence, when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to investigational drug, and 
withdrawal are not acceptable methods of contraception. 
A woman is considered of childbearing potential, following menarche and until becoming 
post-menopausal unless surgically sterile. Menopausal female patients must have 
experienced their last period more than 1 year prior to the date of informed consent to be 
classified as not of childbearing potential. Male patient who is sexually active with a 
woman of childbearing potential must agree to use highly effective method described as 
above or 2 acceptable methods of contraception (e.g., male or female condom AND 
additional hormonal or barrier contraceptive method other than condom by female partner) 
consistent with local regulations during the course of the study and for at least 3 months 
following discontinuation of study drug. Contraception is not required if either patient or 
his/her partner who has been surgically sterilized more than 24 weeks prior to the date of 
informed consent. 
4.1.2 Exclusion Criteria 
A patient meeting any of the following criteria are not eligible for inclusion in this study: 
1. Patient who has only one functional eye, even if the eye met all other study requirements, 
or has and/or is likely to have amblyopia, amaurosis or ocular disorder with BCVA < 34 
ETDRS letter score (approximate Snellen equivalent of < 20/200) in the fellow eye. 
2. Patient who currently has, or has a history (where indicated) of ocular condition including 
one or more of the following in the study eye: 
a) Active proliferative DR, or pre-retinal fibrosis involving the macula 
b) Aphakia 
c) Vitreomacular traction or epiretinal membrane that is expected to affect central vision 
d) Iris neovascularization, vitreous hemorrhage, or tractional retinal detachment 
e) Ocular inflammation (including trace or above) 
f) Uncontrolled glaucoma or filtration surgery for glaucoma in the past or likely to be 
needed in the future 

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g) Intraocular pressure ≥ 25 mmHg 
h) Spherical equivalent of the refractive error of worse than -6 diopters myopia 
i) Structural damage to the center of the macula that is likely to preclude improvement in 
BCVA following the resolution of macular edema including atrophy of the retinal 
pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or 
organized hard exudates 
j) Concurrent and/or history of disease, other than DME, that could compromise VA, 
require medical or surgical intervention during the study period, or could confound 
interpretation of the results (including retinal vascular occlusion, retinal detachment, 
macular hole, or choroidal neovascularization of any cause) as assessed by the 
investigator 
k) Inability to obtain fundus and OCT images due to, but not limited to, insufficient media 
clarity or inadequate pupil dilation 
3. Patient who currently has, or has a history (where indicated) of ocular condition including 
one or more of the following in either eye: 
a) Concurrent and/or history of idiopathic or autoimmune uveitis 
b) Evidence or suspicion of infection including blepharitis, keratitis, scleritis, or 
conjunctivitis. However, a patient who has completely recovered from the infection at 
Day 1 is allowed to be enrolled at the investigator’s discretion. 
4. Patient who currently has, or has a history of (where indicated) systemic condition 
including one or more of the following: 
a) Uncontrolled DM as defined by HbA1c > 10% 
b) Uncontrolled blood pressure (BP) defined as systolic ≥ 160 mmHg or diastolic 
≥ 100 mmHg measured after 5 minutes of rest while sitting 
c) History of vascular disease such as cerebrovascular accident, myocardial infarction, 
transient ischemic attack, or thromboembolic reaction including pulmonary embolism 
within 180 days prior to the first study drug administration 
d) New York Heart Association Functional Classification Class III or IV heart failure, or 
severe uncontrolled cardiac disease (i.e., unstable angina) 
e) Current treatment for serious systemic infection 
f) History of recurrent significant infections in the opinion of the investigator 
g) Renal failure requiring dialysis or renal transplant 

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h) History of malignancies within 5 years prior to the first study drug administration, 
except adequately treated squamous or basal cell carcinoma of the skin or cervical 
carcinoma in situ 
i) History of other disease, metabolic dysfunction, physical examination finding, ECG 
finding or clinical laboratory finding giving reasonable suspicion of a disease or 
condition that, in the opinion of the investigator, contraindicates the use of the study 
drug or that might affect interpretation of the study results or render the patient at high 
risk for treatment complications 
j) Evidence of significant uncontrolled concomitant diseases including cardiovascular 
system, nervous system, pulmonary, renal, hepatic, endocrine, gastrointestinal 
disorders, or psychiatric condition as assessed by the investigator 
5. Patient who has one or more previous/concomitant treatments of the following: 
a) Previous systemic or ocular treatment with aflibercept including potential biosimilars 
b) Previous treatment with ocular anti-angiogenic agents (e.g., pegaptanib sodium, 
bevacizumab, ranibizumab) in the study eye 
c) Administration of systemic anti-angiogenic agents and/or ocular anti-angiogenic agents 
in fellow (non-study) eye within 180 days prior to the first study drug administration 
d) Previous use of intraocular or periocular corticosteroids including dexamethasone 
implant (e.g., Ozurdex) within 180 days, or fluocinolone acetonide implant (e.g., 
Iluvien) within 36 months prior to the first study drug administration in the study eye 
e) Laser photocoagulation (panretinal or macular) in the study eye within 90 days prior to 
the first study drug administration  
f) More than two previous macular laser treatments, and/or focal laser scars in the fovea 
that could limit BCVA improvement in the study eye 
g) History of vitreoretinal surgery including scleral bucking in the study eye 
h) Any intraocular surgery including cataract surgery in the study eye within 90 days prior 
to the first study drug administration or planned or expected during the study 
i) Yttrium-aluminum-garnet capsulotomy in the study eye within 30 days prior to the first 
study drug administration 
j) Treatment with any investigational medicinal product and/or device within 30 days or 
5 half-lives, whichever is longer, prior to the first study drug administration 
6. Patient with a hypersensitivity to immunoglobulin products, or patient who has allergies to 

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any of the excipients or components of study drug, any other human proteins, or diagnostic 
process (e.g., anesthetics, topical broad-spectrum microbicides, fluorescein). 
7. Female patient who is currently pregnant or breastfeeding. 
8. Patient who, in the opinion of the investigator, should not participate in the study. 
4.2 Withdrawal of Patients from the Study 
Patients are free to withdraw from the study at any time for any reason. If the therapeutic effect 
is considered insufficient by either the patient or the investigator, the patient may discontinue 
the study drug and is able to receive whatever treatment is considered necessary. The 
investigator may also discontinue the study drug at any time in the interest of patient’s safety. 
The primary reason for the discontinuation of the study drug must be recorded in the patient’s 
medical record and in the electronic case report form (eCRF), with any comments (spontaneous 
or elicited) or complaints made by the patient. 
For patients who discontinue the study drug during the Main Study Period, all attempts should 
be made to undertake protocol-specified safety procedures including assessments for the EOS1 
visit. The EOS1 visit will be performed at least 4 weeks after the last dose of study drug 
administration.  
If the patients discontinue the study drug prior to the completion of Week 8 visit, they will be 
asked to return to the site at Week 8 to complete all planned assessments for the EOS1 visit. 
Additional visits for the safety monitoring can be made at the investigator’s discretion. 
Whenever the EOS1 visit is made at Week 8, the BCVA data of the EOS1 visit needs to be 
recorded in the relevant page of Week 8 in the eCRF.  
Reasons for withdrawal include the following: 
 
Patient withdraws consent or refuses to continue procedures/observations or study drug 
 
Patient develops signs of disease progression in the judgment of the investigator 
 
Patient has any ocular AE in the study eye or non-ocular AE that would compromise his 
or her safety if he or she continues to participate in the study. The AEs are including but 
not limited to: 
a) Rhegmatogenous retinal detachment or stage 3 or 4 macular holes 
b) Transient ischemic attack or a stroke 
c) Decrease in BCVA of ≥ 30 letters compared with the last study visit assessment 

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d) Subretinal hemorrhage involving the center of the fovea, or if the size of the 
hemorrhage is ≥ 50% of the total lesion area 
e) Any AEs requiring intraocular surgery 
f) Any AEs for which he or she cannot continue to participate in this study 
 
Patient has a significant protocol deviation(s) 
 
Patient is pregnant 
 
Investigator’s decision 
 
Study termination by the Sponsor 
 
Patient is lost to follow-up 
When possible, the Sponsor should be notified of the withdrawal of a patient from the study. 
If necessary, the investigator may discuss with Sponsor or its designee any patient’s reason for 
withdrawal. The Sponsor may be contacted if clarification is required on a case-by-case basis. 
All patients who terminate from the study will retain their patient number. Patient numbers will 
not be reused. 
4.2.1 Replacement of Patients 
Patients who receive the study drug and discontinue prior to study completion will not be 
replaced. Patients, who failed screening for any reason, can be rescreened only once. If there 
is an unusual situation that justifies consideration for additional rescreening, the investigator 
is recommended to discuss with the Sponsor. Rescreened patient will be assigned with new 
patient identification number. 
4.3 Premature Termination of the Study 
The Sponsor reserves the right to terminate the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. 
If the study is terminated prematurely by the Sponsor, all patients will be kept fully informed 
and an appropriate follow-up examination of the patients will be arranged. The investigator 
will inform the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) of 
any premature termination or suspension of the study, where applicable. 

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5 Study Treatment 
5.1 Method of Assigning Patients to Treatment Groups 
 
 
 
Patients who qualify for randomization will be randomly assigned at Day 1 (Week 0) in a 
1:1 ratio to the CT-P42 or Eylea treatment group. The randomization will be stratified by BCVA 
score (< 55 letters versus ≥ 55 letters) using the ETDRS chart on Day 1, country, and PK 
subgroup (Yes versus No). 
Baseline BCVA is considered as a stratification factor since it is considered one of important 
prognostic factors (Nguyen et al. 2012; Brown et al. 2015). Country will be also used as one 
of stratification factors because it is expected to be confounded with other known or unknown 
prognostic factors. Following that PK evaluation will be conducted in a subgroup of patients, 
it is considered as a stratification factor to resolve imbalance between subgroups. 
Stratification details will be described in the randomization specification document, which will 
be provided separately. 
For the open-label, single arm Extension Study Period, randomization is not applicable.  
5.2 Identity of Investigational Product 
The company code of the investigational product is CT-P42. It is a recombinant fusion protein 
consisting of portions of human VEGFR-1 and VEGFR-2 extracellular domains fused to the 
Fc portion of human IgG1, which is being developed by Sponsor as a proposed biosimilar to 
Eylea. 
The International Non-proprietary name of the commercially available reference material 
(Eylea) is aflibercept and the Anatomical Therapeutic Chemical Classification System code is 
L01XX44. CT-P42 and Eylea are dimeric IgG1 fusion glycoprotein with a protein 
 
 
. In this study, EU-approved Eylea will be used as a reference drug in Main 
Study Period. Further details can be found in the IB. 
The CT-P42 and Eylea solution for injection will be provided in a single-dose vial kit for the 
Main Study Period and CT-P42 in a single-dose PFS for the Extension Study Period.  

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2 mg/0.05 mL CT-P42 IVT injection via a single-dose PFS at Extension Week 0 during the 
open-label Extension Study Period. 
During the Main Study Period, study drug will be administered at the fixed visit schedule with 
an allowed visit window of ± 7 days, based on the first study drug administration (Appendix 
1). Except for Week 4, study drug should be administered preferably within 2 weeks from the 
planned dosing date with a minimum of 21 days between doses considering dose delay 
including temporary interruption. At Week 4, study drug should be administered within visit 
window of ± 7 days unless temporary interruption of the study drug is required. If study drug 
administration cannot be done within an allowed visit window or missed dose is expected, it 
should be discussed with Sponsor or its designee regarding the patient’s eligibility to continue 
study treatment. 
Injecting the entire volume of the vial or PFS could result in overdose and thus, excess volume 
should be expelled before injection to deliver intended amount (2 mg/0.05 mL) to the patients. 
To eliminate all of the bubbles and to expel excess study drug, slowly depress the plunger to 
align the plunger tip with the line that marks 0.05 mL on the syringe (preparation for 
administration of vial) or align the plunger dome edge with the 0.05 mL dosing marker on the 
syringe (preparation for administration of PFS). Each sterile vial or PFS should only be used 
for the treatment of a single eye. After injection, any unused product must be discarded. 
The study drug in vials will be supplied in kits. When CT-P42 and Eylea vial kit or CT-P42 
PFS are removed from the refrigerator, the solution should be visually inspected, and should 
have no evidence of turbidity. If any particulates, cloudiness, or discoloration is visible in the 
vials or PFS, they must not be used. Prior to usage, the unopened vial or blister of study drug 
may be stored at room temperature (below 25°C) for up to 24 hours. Details of the study drug 
accountability and destruction will be specified in the pharmacy manual. 
Intravitreal injections must be carried out according to medical standards and applicable 
guidelines by a qualified physician experienced in administering IVT injections. In general, 
adequate anesthesia and asepsis, including topical broad–spectrum microbicide (e.g., povidone 
iodine applied to the periocular skin, eyelid and ocular surface), will be given prior to the 
injection. Surgical hand disinfection and use of sterile gloves, a sterile drape, and a sterile 
eyelid speculum (or equivalent) are recommended. 
The injection needle should be inserted 3.5 to 4.0 mm posterior to the limbus into the vitreous 
cavity, avoiding the horizontal meridian and aiming toward the center of the globe. The 
injection volume of 0.05 mL is then delivered; a different scleral site should be used for 
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Following the IVT injection, patients should be instructed to report any symptoms suggestive 
of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, 
blurring of vision) immediately. Patients will be monitored for elevation in IOP. Appropriate 
monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If 
required, a sterile paracentesis needle should be available. 
Other ancillary components, including injection needle for PFS, required for the administration 
of CT-P42 or Eylea will be supplied by the study center. All preparation steps have to take 
place under aseptic conditions after opening the vial or blister. The study drug in vials will be 
withdrawn using aseptic technique through the filter needle attached to the syringe. The filter 
needle will be discarded after withdrawal of the vial contents and should not be used for IVT 
injection. The sterile 30-gauge needle should be attached for the IVT injection for both 
presentations. 
5.3.2 Temporary Interruptions of Study Drug 
Temporary interruptions of study drug should be considered for the following cases as per 
Eylea SmPC 2022 and Eylea USPI 2021. Study drug will be resumed at investigator’s 
discretion and dosing schedule will be adjusted as described in Section 5.3.1 considering 
patient’s safety. 
 
In the event of a retinal break in the study eye, the dose should be withheld and should not 
be resumed until the break is adequately repaired. 
 
In the event of IOP ≥ 30 mmHg in the study eye, study drug may be resumed when the 
IOP is normalized to a safe range as determined by the investigator, either spontaneously 
or with treatment. 
 
The dose should be withheld within the previous or next 28 days in the event of a 
performed or planned intraocular surgery in the study eye. 
 
In the event of any active intraocular inflammation in the study eye, study drug should be 
withheld and should not be resumed until the active intraocular inflammation is repaired 
adequately.  
 
Administration of study drug can be interrupted temporarily when the patient has ocular 
and/or periocular infection(s) in either eye as determined by the investigator, and should 
not be resumed until the condition is repaired adequately. 

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5.4 Management of Clinical Supplies 
5.4.1 Study Drug Package, Labeling, and Storage 
The appropriate number of study drug (kit with vial) will be allocated to each patient 
 
at each visit in Main Study Period. In Extension Study Period, study drug (PFS) will be 
allocated manually. 
A label will be attached to the outer carton of each study drug, as well as to the vial and PFS 
blister.  
All study drug supplies must be stored in a secured area with limited access, in a refrigerator 
between 2°C and 8°C and must not be frozen. The immediate containers, as well as sterile PFS 
blister, must be kept in the outer carton until use to protect the study drug from light. The 
recommended storage conditions and expiry date, where required, will be stated in the product 
label approved by each regulatory authority. 
5.4.2 Study Drug Accountability 
It is the responsibility of the investigator to ensure that all study drug received at the study 
center will be inventoried and accounted for throughout the study and the result recorded in 
the drug accountability form will be maintained at the study center. The study drug 
accountability will be verified by the monitor during on-center monitoring visits. The study 
drug will be stored in a limited access area under appropriate environmental conditions. 
The investigator will not supply the study drug to any person other than sub-investigators, 
designated staff, and the patients participating in the study. The study drug may not be relabeled 
or reassigned for use by other patients, unless approved by the Sponsor. 
Unused study drugs (vial and PFS) should be returned to sponsor. Study drug accountability 
must be completed at the study center level and discrepancies, if any, need to be resolved prior 
to return. The used vials and syringes can only be destroyed if it is written in local Standard 
Operating Procedures (SOP) and a specific authorization is given by the Sponsor, which is 
required prior to patient randomization. Permission will be granted by the Sponsor on a study 
center-by-study-center basis after reviewing the study center destruction policy. This 
authorization may also be granted to destroy used vials and syringes immediately after 
administering to patients. Authorization from the Sponsor is required before a patient is 
enrolled. The list of destroyed vials and syringes must be recorded. The investigator will 
neither dispense nor store the study drug from any study center other than the study centers 
agreed with the Sponsor. 

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5.5 Masking 
The study will be conducted in a double-masked manner during the Main Study Period and in 
an open-label manner during the Extension Study Period. The randomization codes for the 
Main Study Period will not be revealed to study patients, investigators, and study center 
personnel until the final CSR has been generated except for predefined unmasked personnel 
from Sponsor and CRO.  
5.5.1 Breaking the Masking 
Under normal circumstances, the masking should not be broken. The masking should be 
broken only if specific emergency treatment and medical management requires the study drug 
to be known. In such emergencies, the investigator may determine the identity of the study 
drug by using the applicable procedure 
 (instructions in the study manual, which 
is provided as a separate document). 
The date, time, and reason for the unmasking must be documented in source document and the 
appropriate field of the eCRF and the medical monitor will be informed as soon as possible. 
All calls resulting in an unmasking event will be recorded and reported 
 to the 
medical monitor and the Sponsor. In cases where there are ethical reasons for the patient to 
remain in the study, the investigator will consult with the Sponsor or its designee for the patient 
to continue in the study. 
The Sponsor and/or delegate responsible for pharmacovigilance (PVG) will have access to the 
randomization code, if suspected unexpected serious adverse reactions (SUSARs), which are 
patient to expedited reporting, should be unmasked before submission to the regulatory 
authorities. 
The Data Safety Monitoring Board (DSMB) and the assigned staff who provide the safety 
analyses for the DSMB can also be unmasked on a case-by-case basis upon the request from 
DSMB members during closed session. 
The overall randomization code will be broken only for reporting purposes. This will occur 
after database lock for data up to Week 24 for each patient. Efficacy, PK, usability, and safety 
endpoints including immunogenicity will be evaluated by the predefined unmasked personnel 
from Sponsor and CRO. The unmasked personnel will be predefined and documented before 
performing the analyses. The randomization codes for the Main Study Period will not be 
revealed to study patients, investigators, and study center personnel until the final CSR has 
been generated except for predefined unmasked personnel from Sponsor and CRO.  

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5.6 Treatment Compliance 
Treatment compliance with the dosing protocol will be monitored by reviewing clinical records 
as all study drugs will be administered in a medical facility by authorized center personnel. 
Every effort will be made to encourage patients’ compliance with the study day visits. When a 
patient does not show up at planned visit, the study center must make every effort to regain 
contact with the patient (when possible, at least 3 contact attempts before the patient is deemed 
lost to follow-up). The date and time of the study drug administration will be documented in 
both the source documents and eCRF. 
5.7 Prior and Concomitant Therapy 
All prior and concomitant therapies will be recorded in both the source documents and eCRF. 
5.7.1 Prior and Concomitant Treatment 
Information (e.g., drug name, date[s] of administration, etc.) about prior medications taken by 
the patients within 30 days prior to the first study drug administration will be recorded in both 
the source documents and eCRF. This will include all prescription drugs, vitamins, minerals, 
and over-the-counter medications. In addition, in order to check eligibility, prior medications 
will be reviewed from the date specified in the exclusion criterion #5 (Section 4.1.2). In 
particular, use of any potential previous treatments for DME including anti-VEGF medication, 
steroids, or lasers will be recorded in the eCRF from the diagnosis of disease. 
Any concomitant medication deemed necessary for the welfare of the patient 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 source 
documents and eCRF. Any changes in concomitant medications also will be recorded in the 
patient’s eCRF and source documents. All concomitant medications used during the study will 
be recorded until the last EOS visit. The non-drug therapies (e.g., laser, surgery) will be also 
collected in both the source documents and eCRF. 
Treatments that are related to the IVT injection procedure or planned assessments will be used 
in accordance to local health authorities’ guidelines for each site and be recorded in both the 
source documents and eCRF (e.g., drugs or agents for anesthesia, asepsis, mydriatics, 
fluorescein or topical broad-spectrum microbicide). 
The participant in this study will not replace the standard of care treatment of the underlying 
DM. The treatment of DM itself has to be continued over the duration of the trial as 
recommended by the responsible physician. 

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5.7.1.1 Fellow Eye Treatment 
If the fellow (non-study) eye requires any treatment, the most applicable treatment option that 
is approved by the governing health authorities may be selected at the investigator’s discretion 
and in the patient’s best interest. 
Only intravitreal aflibercept will be permitted when anti-VEGF agents are considered for the 
fellow eye treatment during the whole study period. For the first 18 weeks of the Main Study 
Period, the IVT injection of aflibercept in the fellow eye should be administered at least 2 
weeks after and prior to the scheduled study drug administration. Afterwards, the IVT 
injections of aflibercept in the fellow eye can be administered anytime including the same day 
as the study eye. The fellow eye will not be considered an additional study eye even though 
treated with aflibercept. 
If bilateral treatment of aflibercept is performed on the same day, this could lead to increased 
risk of systemic AEs theoretically. Therefore, the fellow eye treatment should be performed 
with caution. 
5.8 Prohibited Therapy 
The following medications, treatments, or procedures during the whole study period are 
prohibited: 
Study eye 
Patients will not receive any standard or investigational agents for DME treatment in the study 
eye other than their assigned study drug as specified in this protocol. This includes medications 
administered locally (e.g., IVT, by juxtascleral or periorbital routes), laser photocoagulation 
(panretinal or macular), and any intraocular surgeries. 
Fellow eye 
Anti-VEGF agents except aflibercept is not allowed. 
Systemic 
Systemic therapies including anti-angiogenic agents and anti-angiopoietin-2 agents for DME 
treatment of either eye are not permitted. Any medications that may be associated with macular 
edema in the opinion of the investigator are prohibited. Also, systemic medications which 
include any medications that can cause vision loss or known to be toxic to the lens, retina, or 
optic nerve, including (but not limited to) deferoxamine, chloroquine/hydroxychloroquine 
(Plaquenil), tamoxifen, phenothiazine, and ethambutol are prohibited. Any other 
investigational device, medical product, or interventions of any type suspected to influence 
outcome (i.e., which might influence the course of the underlying ocular disease or the study 

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drug results, respectively) are not allowed. 

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6 Study Assessments and Procedures 
6.1 Efficacy Assessments 
6.1.1 Best Corrected Visual Acuity 
Visual function of the study eye and the fellow eye will be assessed using ETDRS (1985) 
protocol at an initial distance of 4 meters at each study visit as scheduled in the schedule of 
assessment (Appendix 1). 
The person performing the assessments of refraction and BCVA will be qualified to ensure 
consistent measurement of BCVA. Refraction is to be done at each visit before BCVA 
assessment. The overall BCVA score will be calculated and be kept in the source data and 
recorded in the eCRF. Best Corrected Visual Acuity will be the first assessment made at every 
visit, before any other ocular procedures are performed, and prior to dilating the pupils. 
A detailed method for conducting refraction and BCVA assessments can be found in the study 
procedure manual. 
6.1.2 Optical Coherence Tomography 
Retinal characteristics will be evaluated at each study visit using the SD-OCT after pupil 
dilation as scheduled in the schedule of assessment (Appendix 1).  
Spectral-domain optical coherent tomography images will be captured for both eyes at 
Screening and only the study eye at other scheduled visits. Assessments will be performed 
prior to study drug administration. Images will be sent to an independent reading center and 
read by masked readers. All OCT images will be electronically archived at the study centers as 
a part of the source documentation. Optical coherence tomography is to be performed by a 
qualified technician on an acceptable device. The same device will be used at all time points 
at a patient level to avoid variability in the patient’s measurements. Image acquisition with 
another OCT device should be discussed and approved by the central image center prior to 
being used. If a switch is inevitable, the switched machine type should be used for the 
remainder of the study. All details for acceptable OCT machines and OCT image 
acquisition/transmission will be provided in the study procedure manual. 
6.1.3 Fundus Photography and Fluorescein Angiography 
The anatomical state of the retinal vasculature of the study eye will be evaluated by FP and 
fluorescein angiography (FA) after pupil dilation as scheduled in the schedule of assessment 
(Appendix 1). Fundus photography and FA images for both eyes at Screening and only the 

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study eye at other scheduled visits will be captured and transmitted to an independent reading 
center to ensure a standardized evaluation by masked readers.  
The 7-field or 4 wide-field FP images will be sent to an independent reading center for ETDRS 
DRSS grading. The same field image, 7-field or 4 wide-field, will be used for each individual 
patient throughout the whole study period.  
All FA and FP images will be performed by qualified photographers and archived electronically 
at the center as part of the source documentation. Further details will be provided in the study 
procedure manual. For screening, FA images which are obtained within 4 weeks prior to first 
study drug administration can be used as screening data if the FA images were acquired by 
qualified photographers according to the procedures described in the study procedure manual. 
6.2 Pharmacokinetic Assessments 
Pharmacokinetic blood samples for the determination of plasma concentration of study drug 
will be collected in approximately 40 patients (20 patients per treatment group) at the time 
points specified in the schedule of assessments (Appendix 1). Blood samples for assessment 
of Cmax and Tmax of free (VEGF-unbound) study drug concentrations in plasma will be collected 
at pre-dose within 60 minutes, 24 ± 2 hours, 48 ± 2 hours, and 72 ± 6 hours after the first and 
the fifth study drug administration, respectively. 
Analysis will be performed at the central laboratory. 
Actual sampling times for each patient will be recorded in both the source documents and eCRF. 
Instructions for the blood collection, storage, and shipment to the central laboratory are 
described in Section 6.6. 
6.3 Usability Assessments 
In Main Study Period, usability assessments for vial kit of CT-P42 or Eylea will be performed 
at Week 0 in approximately 60 patients (30 patients per treatment group) who are administered 
the study drug (CT-P42 or Eylea vial) at Week 0. In Extension Study Period, usability 
assessments for CT-P42 PFS will be performed at Extension Week 0 in approximately 30 
patients who are administered with the study drug (CT-P42 PFS) at Extension Week 0. 
Usability will be assessed to evaluate the ability of healthcare professionals to follow the 
instructions for use to prepare and administer the IVT injection to patients while maintaining 
aseptic conditions in the intended use environment, and to document any use errors on all tasks. 

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Tasks specific to the unpacking, preparing, properly administering, and disposing the study 
drug will be assessed by the study center personnel. At the time of usability assessment, 
injections will be administered by investigators assisted with the study drug preparation by 
assistants. The study center personnel will observe and evaluate the procedures for use errors 
and close calls on all tasks, and will complete the injection assessment checklist (Appendix 3. 
Usability Assessment Checklist) during the injection. 
6.4 Safety Assessments 
Safety assessments will include the evaluation of AEs (ocular and non-ocular) including SAEs, 
AESIs, IOP test, slit lamp examination, indirect ophthalmoscopy, finger count/hand 
motion/light perception, immunogenicity assessments including anti-drug antibody and 
neutralizing antibody, hypersensitivity monitoring, vital signs and weight measurements, 
ECGs, NYHA Functional Classification assessment, physical examination findings, pregnancy 
testing, clinical laboratory analyses including HbA1c, and prior and concomitant treatments 
monitored throughout the study. Retest of any assessments during the Screening Period in 
terms of safety may be done only once at the investigator’s discretion if medically justifiable. 
6.4.1 Medical/Ophthalmic History and Demographic Information 
Medical/ophthalmic history (general medical history including DM and DME) and 
demographic information (age, sex, ethnicity, race, body weight and height, smoking history) 
will be recorded on the source documents and eCRF. 
6.4.2 Adverse Events 
6.4.2.1 Definitions of Adverse Events 
The investigator is responsible for reporting all AEs observed or reported by the patient during 
the study, regardless of their relationship to study drug or their clinical significance. 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study drug. Patients will be instructed to contact the 
investigator at any time after the ICF was signed if any symptoms develop. Any new condition 
noted at Screening will be regarded as an AE, but not a treatment-emergent adverse event 
(TEAE). 
A TEAE is defined as any event not present before exposure to study drug or any event already 
present that worsens in severity after exposure to study drug. This includes any occurrence that 
is new in onset or aggravated in severity from the baseline condition. 

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Abnormal results of diagnostic procedures, including laboratory test abnormalities, are 
considered AEs if they fulfill the following: 
 
Result in discontinuation from the study 
 
Require treatment or any other therapeutic intervention 
 
Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality) 
 
Are associated with clinical signs or symptoms judged by the investigator to have a 
significant clinical impact 
Disease progression of DME in the study eye will not be recorded as an AE or SAE. 
Medical interventions such as surgery, diagnostic procedures, and therapeutic procedures are 
not AEs, but are actions taken to treat medical conditions. They should be recorded as 
treatment(s) of the AEs, if medical condition for which the procedure was performed meets the 
definition of an AE. The AE term of primary cause should be recorded and reported instead of 
the term of surgery, diagnostic procedure, or therapeutic procedure. 
6.4.2.1.1 
Adverse Events of Special Interest 
Adverse events of special interest should be closely monitored. 
The following AEs are considered as AESIs and will be reported using the same process as for 
AEs: 
 
Arterial thromboembolic events: Arterial thromboembolic events are defined as nonfatal 
stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown 
cause) according to the Antiplatelet Trialists' Collaboration. The Preferred Terms (PTs) for 
ATE analysis will be reviewed and determined in a masked manner prior to database lock 
and final determination for the PTs will be specified in the statistical analysis plan (SAP). 
 
All AEs related to IVT injection procedure including but not limited to the following: 
endophthalmitis, increases in IOP, intraocular inflammation, rhegmatogenous retinal 
detachment, retinal tear, and iatrogenic traumatic cataract. Adverse events considered by 
the investigator to be related to the IVT injection procedure will be included in safety 
analysis. 
6.4.2.1.2 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that: 

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 
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, are life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the patient or may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples or 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. 
Adverse events associated with hospitalization or prolongations of hospitalization are 
considered SAEs. Any admission (even if less than 24 hours) to a healthcare facility meets 
these criteria. Admission also includes transfer within the hospital to an acute/intensive care 
unit (e.g., from the psychiatric wing to a medical floor, from medical floor to a coronary care 
unit, from neurological floor to a tuberculosis unit). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical AE 
is not in itself an SAE. Examples include the following: 
 
Admission for treatment of a preexisting condition not associated with the development of 
a new AE or worsening of the preexisting condition (for workup of persistent pretreatment 
laboratory abnormality) 
 
Social admission (e.g., patient has no place to sleep) 
 
Purely for convenience (e.g., for easier performance of study assessments) 
 
Administrative admission (e.g., for yearly physical examination) 
 
Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol) 
 
Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery) 
 
Hospitalization for observation without a medical AE 

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 
Pre-planned treatments or surgical procedures; these should be noted in the baseline 
documentation for the whole study period and/or for the individual patient 
 
Hospitalization solely due to disease progression without any other AEs as decided by the 
investigator 
6.4.2.1.3 
Unlisted (Unexpected) Serious Adverse Events 
An unlisted or unexpected SAE is defined as an event of which the nature or severity is not 
consistent with the applicable reference documents (e.g., study drug IB). 
6.4.2.2 Eliciting and Documenting Adverse Events 
Adverse events will be assessed from the date the patient signs the ICF until the last EOS visit, 
regardless of the relationship to the study drug. The condition of the patient will be monitored 
throughout the study for any signs or symptoms. After the last EOS visit, serious adverse drug 
reactions will be reported to the Sponsor or its designee. 
At every study visit, patients will be asked a standard non-leading 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 treatments 
regimens (both prescription and over-the-counter medications). 
In addition to patient observations, AEs identified from any study data (e.g., ophthalmologic 
assessments findings, laboratory values, physical examination findings, ECG changes) or 
identified from review of other documents that are relevant to patient safety will be 
documented on the AE page in the eCRF and the source documents. 
6.4.2.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded in both the source documents 
and AE page in the eCRF. Information to be collected includes drug treatment, dose, event 
term, date and/or time of onset, investigator-specified assessment of severity and relationship 
to study drug or injection procedure, assessment category (non-ocular, ocular in study eye, 
ocular in fellow eye), date and/or time of resolution of the event, seriousness, action taken with 
study drug, any required treatment or evaluations, and outcome. 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, or 
concurrent medications, or worsening of preexisting conditions must also be reported. 

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Adverse events will be graded for severity according to the Common Terminology Criteria for 
AEs (CTCAE) v5.0. 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 patient 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. 
The investigator’s assessment of an AE’s relationship to study drug or 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 will 
be reported. 
The severity and the relationship or association of the study drug or injection procedure in 
causing or contributing to the AE will be characterized as defined in Section 6.4.2.6 and Section 
6.4.2.7, respectively. 
6.4.2.4 Reporting Serious Adverse Events 
Any AE considered serious by the investigator or which meets SAE criteria (Section 6.4.2.1.2) 
must be reported to CRO PVG within 24 hours from the time study center staff first learns 
about the event. The following contact information is to be used for SAE reporting: 
 
 
Data entry should be completed in the remote data capture system by the investigator within 
24 hours of awareness of an SAE. In the event that this is not possible (e.g., system failure or 
access problems), the study center should complete an SAE report form and e-mail or FAX it 
to CRO PVG within 24 hours of awareness of the event per the contact information specified 
above. The remote data capture system should be updated as soon as it is available. Withdrawal 
from the study and all therapeutic measures will be at the discretion of the principal investigator 
or sub-investigator. All SAEs will be followed up as specified in this protocol (Section 6.4.2.8). 
The Sponsor or its designee is responsible for reporting relevant SAEs to the competent 
authority, other applicable regulatory authorities, and participating investigators, in accordance 
with European Clinical Trials Directive (Directive 2001/20/EC), International Council for 
Harmonisation (ICH) guidelines, and/or local regulatory requirements. 
The Sponsor or its designee is responsible for reporting fatal or life-threatening SUSARs 

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(expedited reports) to the regulatory agencies and competent authorities within 7 calendar days 
after being notified of the event. Sponsor or its designee should report other relevant SAEs 
associated with the use of the study drug to the appropriate competent authorities (according 
to local guidelines), investigators, and IECs by a written safety report within 15 calendar days 
of notification. 
6.4.2.5 Suspected Unexpected Serious Adverse Reactions 
The Sponsor will promptly evaluate all 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 SAE cases, the Sponsor will assess the 
expectedness of these events using the applicable reference documents (e.g., study drug IB). 
Reporting requirements will also be based on the investigator’s assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
6.4.2.6 Assessment of Severity 
The severity of an AE refers to the extent to which an AE affects the patient’s daily activities. 
The severity of the AE will be graded based on the CTCAE v5.0, based on the following 
general guidelines (a semicolon indicates “or” within each description): 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of daily living (ADL)* 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL** 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 

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The investigator will assess of the maximum severity that occurred over the duration of the 
event. However, if an AE changes from a non-serious to a serious event, a new SAE needs to 
be reported separately. 
6.4.2.7 Assessment of Causality 
6.4.2.7.1 
Relationship of Adverse Events to Study Drug 
As discussed in Section 6.4.2.3, 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. If there is any doubt as to whether a clinical observation is an AE, the 
event will be reported. 
The relationship or association of CT-P42 or Eylea 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 
and the reported event 
Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed to the AE, e.g., the event follows a reasonable temporal sequence 
from the time of study drug administration or follows a known response 
pattern to the study drug but could also have been produced by other factors 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known 
pharmacological action of the study drug, known or previously reported 
adverse reactions to the study drug or class of drugs, or judgment based on 
the investigator’s clinical experience, the association of the event with the 
study drug seems likely. The event disappears or decreases on cessation or 
reduction of the dose of study drug 
Definite: 
This relationship suggests that a definite causal relationship exists between 
study drug administration and the AE, and other conditions (concurrent 
illness, progression/expression of disease state, or concurrent medication 
reaction) do not appear to explain the event. The event reappears or worsens 
if the study drug is re-administered 
6.4.2.7.2 
Relationship of Adverse Events to Injection Procedure 
The relationship of AEs to IVT injection procedure will be assessed using the following 
classification and criteria and will be a clinical decision based on all available information. 

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Unrelated: 
There is no reasonable possibility that the AE may have been caused by the 
injection procedure. Adverse events that were clearly and incontrovertibly 
due to causes other than the IVT injection procedure (e.g., disease, 
environment), or were felt with a reasonable degree of certainty to be 
unrelated to the IVT injection procedure 
Related: 
There is a reasonable possibility that the event may have been caused by the 
injection procedure. Adverse events for which a connection with the IVT 
injection procedure could not be ruled out with certainty, or which were felt 
with a reasonable degree of certainty to be related to the IVT injection 
procedure, or which were incontrovertibly related to the IVT injection 
procedure 
6.4.2.8 Follow-up of Adverse Events 
All reported AEs will be followed up until one of the following: resolution or improvement 
from baseline, confirmed by the investigator that no further improvement could be expected, 
no more collection of clinical or safety data, or final database closure. 
6.4.3 Immunogenicity Assessments 
The immunogenicity of CT-P42 and Eylea will be assessed by anti-drug antibody and 
neutralizing antibody test in validated immunoassay. Neutralizing antibody test will be 
performed only on samples that are confirmed to have drug-specific anti-drug antibody. Serum 
samples for immunogenicity testing will be collected prior to dosing of study drug at the time 
points specified in the schedule of assessments (Appendix 1). Additional immunogenicity will 
be assessed when immune-related AEs occur. Immune-related AEs are defined as 
hypersensitivity events including intraocular inflammation with no clear underlying cause. 
Blood samples for immunogenicity for patients with immune-related AEs will be obtained on 
the onset date of immune-related AEs, if possible. Blood samples obtained at the same date of 
study drug administration can also be used. 
Sample analysis will be performed at the central laboratory. 
6.4.4 Hypersensitivity Monitoring 
Hypersensitivity monitoring will be assessed by vital signs (including BP, heart and respiratory 
rates, and body temperature) at the following time points at each visit specified in the schedule 
of assessments (Appendix 1): 
 
Within 1 hour after study drug administration 

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If patients have signs and symptoms of hypersensitivity at home (such as but not limited to 
rash, pruritus, urticaria, anaphylactic/anaphylactoid reactions, or intraocular inflammation), 
patients or caregivers should be advised to call the study center or get immediate help. Patients 
should be instructed to report any signs or symptoms of intraocular inflammation, e.g., pain, 
photophobia, or redness, which may be a clinical sign attributable to hypersensitivity. 
In addition, hypersensitivity will also be monitored by patient-reported signs and symptoms. 
In case of hypersensitivity, emergency equipment, such as adrenaline, antihistamines, 
corticosteroids, and respiratory support including inhalational therapy, oxygen, and artificial 
ventilation, must be available; in addition, any type of ECG can be performed, if deemed 
necessary. For patients who experience or develop life-threatening treatment-related 
anaphylactic reactions, study drug must be stopped immediately, and the patient must be 
withdrawn from the study if necessary. 
6.4.5 Finger Count, Hand Motion, and Light Perception 
Finger count, hand motion, and light perception will be done within 15 minutes after the IVT 
injection for study eye at the time points specified in the schedule of assessments (Appendix 
1). It is to detect severe loss of vision following the IVT injection (from vitreous hemorrhage, 
central retinal artery occlusion, etc.). This starts with counting fingers. If the patient is unable 
to count fingers, hand motions will be shown. Finally, if patient cannot catch hand motion, 
light perception will be checked. When the patient fails in any of these steps, it will be recorded 
as AE at investigator’s discretion. Details will be recorded in both the source documents and 
the eCRF.  
6.4.6 Intraocular Pressure Test 
Intraocular pressure will be measured pre-dose prior to pupil dilation for both eyes and within 
60 minutes after the study drug administration for study eye, using Goldmann applanation 
tonometry or Tono-pen at time points specified in the schedule of assessment (Appendix 1). 
For the post-dose assessment, the last measured IOP within 60 minutes will be recorded as 
post-dose value. The same method of IOP measurement will be used throughout the study for 
each individual patient. If using same method is not available, the center should discuss with 
Sponsor in advance. The measurement of IOP will be performed by the investigator or trained 
staff and the values will be recorded in mmHg and will be entered into the eCRF and source 
documents. The results will be categorized using normal; abnormal, not clinically significant; 
abnormal, clinically significant and recorded in both the source documents and the eCRF. Any 
clinically significant abnormality will be recorded as an AE at investigator’s discretion. 
If the IOP in the study eye is ≥ 30 mmHg at any time during the study for any reason, it will 
be considered as clinically significant abnormality and the study treatment will be temporarily 

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withheld. It is recommended to resume the study drug administration after the IOP has been 
normalized to a safe range as determined by the investigator. 
6.4.7 Slit Lamp Examination 
The anterior segments structures and ocular adnexa of both eyes will be carefully examined 
before IVT injection at every scheduled visit as per the schedule of assessment (Appendix 1). 
Additional examination may also be performed at any time during the study at the 
investigator’s discretion, if required. During the examination, the investigator will examine the 
eyelids, conjunctiva, sclera, cornea, anterior chamber, iris, pupil, and lens according to local 
medical practice and medical standards at the site. The results will be categorized using normal; 
abnormal, not clinically significant; abnormal, clinically significant and recorded in both the 
source documents and the eCRF. Any clinically significant abnormality will be recorded as an 
AE at investigator’s discretion. 
6.4.8 Indirect Ophthalmoscopy 
Indirect ophthalmoscopy will be performed pre-dose after pupil dilation for both eyes and 
within 60 minutes for the study eye after the study drug administration at time point specified 
in the schedule of assessment (Appendix 1). The investigator will examine the posterior 
segment on dilated pupil and also the peripheral retina to ensure if the IVT injection can be 
safely performed (i.e., iatrogenic retinal detachment, should not receive IVT injections). After 
IVT injection, the investigator will examine the study eye as part of the safety check up to be 
able to detect procedure related complications. The results will be categorized using normal; 
abnormal, not clinically significant; abnormal, clinically significant and recorded in both the 
source documents and the eCRF. Any clinically significant abnormality will be recorded as an 
AE at investigator’s discretion. 
6.4.9 Vital Signs and Weight 
Vital signs and weight measurements will be performed at the time points specified in the 
Schedule of Assessments (Appendix 1). Vital signs (including systolic and diastolic BP, heart 
rate, respiratory rate, and body temperature) while sitting will be measured after 5 minutes of 
rest. All measurements will be documented at each study visit. Details will be recorded in both 
the source documents and the eCRF. 
Vital sign measurements will also be monitored after study drug injection as part of the 
hypersensitivity monitoring (Section 6.4.4). 

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6.4.10 Electrocardiogram 
All scheduled 12-lead ECGs will be performed locally after the patient has rested quietly for 
at least 5 minutes in a supine position. A 12-lead ECG will be performed at the time points 
specified in the schedule of assessments (Appendix 1), and at any time when a patient 
experiences any cardiac symptoms during the study. If following the ECG review by the 
investigator there are any ECG findings that would indicate clinically significant abnormalities, 
the patient will be referred to a cardiologist to confirm the abnormality. For some sites requiring 
support in ECG reading, any abnormal ECG strips will be sent to independent reading center, 
and read by masked reader to confirm abnormality in further details. The investigator will then 
assess the clinical significance, and report the event in the source documents and the eCRF.  
All ECG results will be archived as a part of the source documentation and will be recorded in 
the eCRF by the investigator.  
Regardless of the 12-lead ECG result, further evaluation with a cardiologist can be done 
depending on the investigator’s discretion. In case of hypersensitivity, any type of ECG can be 
performed if necessary. 
6.4.11 New York Heart Association Functional Classification 
The NYHA functional classification (Appendix 2) assessment will be performed at the time 
points specified in the Schedule of Assessments (Appendix 1). Results will be recorded in both 
the source documents and the eCRF. 
6.4.12 Physical Examination 
A detailed physical examination will be performed at the time points specified in the schedule 
of assessments (Appendix 1). Physical examinations will be performed as verbal assessment 
of the health status. Additionally, other physical assessments may be performed at the 
investigators’ discretion. In case of any complaints, the patient will be referred to an 
appropriate specialist by the investigator. Investigators should carefully evaluate patients for 
any indication of ATEs and AEs related to IVT injection procedure and pursue further 
investigation and treatment indicated in accordance with the investigator’s medical judgment. 
Information about the physical examinations will be recorded by the investigator or designee 
in both the source documents and the eCRF. Any abnormalities will be recorded in the source 
documents. Clinically significant findings and illnesses reported after the start of the study that 
meet the definition of an AE will be recorded in both the source documents and eCRF. 

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6.4.13 Pregnancy 
A woman is considered of childbearing potential, following menarche and until becoming post-
menopausal unless surgically sterile. For women of childbearing potential, serum pregnancy 
test will be conducted at Screening and analyzed at the central laboratory. Only patients with a 
negative serum pregnancy test result can be enrolled in the study. For women of childbearing 
potential, a urine pregnancy test will be used to confirm patients are not pregnant prior to 
dosing on each scheduled visit specified in the Schedule of Assessments (Appendix 1) or more 
frequently if required by country-specific legislation. Urine pregnancy test will be performed 
locally. If a urine pregnancy test result is positive or equivocal, a confirmatory serum 
pregnancy test will be performed at the local laboratory. 
In the event of an unexpected pregnancy during study participation and within 3 months after 
the last dose of study drug, patients should inform the investigator. If a patient becomes 
pregnant, the study drug must be discontinued immediately. If a female patient or the partner 
of a male patient becomes pregnant, the pregnancy must be reported to the Sponsor or designee 
Safety Department within 24 hours of the study center’s knowledge of the pregnancy while 
confirmation is pending. Once the pregnancy is confirmed with a serum pregnancy test, female 
patients must permanently discontinue the study drug and be withdrawn from the study. The 
study center must complete the supplied pregnancy form (female patient or partner of a male 
patient) and return it to the Sponsor or designee Safety Department within 24 hours after 
acquisition of the consent for the pregnancy form. 
Pregnant patients or the pregnant partners of male patients will be followed up until the end of 
the pregnancy (e.g., delivery, stillbirth, miscarriage) and the mother and the baby will be 
followed up for 1 year after the birth, provided consent is obtained. Any SAE that occurs during 
pregnancy (e.g., maternal serious complications, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, birth defect) must be reported within 24 hours in accordance with the 
procedure for reporting SAEs (Section 6.4.2.1.2). 
6.4.14 Clinical Laboratory Analyses 
Blood and urine samples for clinical laboratory assessments will be collected prior to study 
drug administration at the time points specified in the Schedule of Assessments (Appendix 1). 
Blood samples do not need to be collected in a fasting state unless required in the opinion of 
the investigator. At Week 40, only HbA1c will be assessed.  
The following clinical laboratory analyses will be performed: 
 
Clinical chemistry: total protein, total serum bilirubin, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, blood urea nitrogen, uric acid, creatinine, creatine 
kinase, albumin, sodium, potassium, calcium, chloride, inorganic phosphorus, glucose, 

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lactate dehydrogenase, total cholesterol, triglyceride, high-density lipoprotein cholesterol, 
and C-reactive protein 
 
Hematology: red blood cells, total and differential white blood cell count, absolute 
lymphocytes count, absolute neutrophils count, platelet count, hemoglobin, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, hematocrit, and HbA1c 
 
Urinalysis: color, bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, protein, 
specific gravity, urobilinogen, and microscopic examination 
Clinical laboratory (clinical chemistry, hematology, and urinalysis including microscopy) test 
samples will be analyzed at the central laboratory. 
6.5 Sample Collections 
The total volume of blood collected for each assessment is discussed in each specific laboratory 
manual. The sample collection tube may be changed during the study and details will be 
provided in the laboratory manual. 
All samples should be collected as close as possible to the scheduled time point, and the actual 
sampling date must be recorded in both the source documents and the eCRF. 
Samples should be stored and shipped as detailed in Section 6.6.2. 
6.5.1 Pharmacokinetic Blood Sampling 
Blood samples for PK assessments will be obtained in accordance with the laboratory manual 
from each patient at the time points specified in the schedule of assessments (Appendix 1). 
6.5.2 Immunogenicity Blood Sampling 
Blood samples for immunogenicity assessments will be obtained prior to study drug 
administration at the time points specified in the Schedule of Assessments (Appendix 1), or 
when immune-related AEs occur. 
6.5.3 Safety Blood Sampling 
Blood samples for routine safety (clinical laboratory testing) will be collected for analysis 
throughout the study at the time points specified in the schedule of assessments (Appendix 1). 
6.5.4 Urine Sampling 
Urine samples for routine safety (clinical laboratory testing) will be collected for analysis 
throughout the study at the time points specified in the Schedule of Assessments (Appendix 1). 

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6.6 Labeling, Storage, and Transportation of Samples 
6.6.1 Sample Labeling 
Each sample tube will be clearly labeled with the following information: study number, patient 
number, tube identification, and scheduled sampling time point. 
6.6.2 Sample Storage and Shipment 
During the study, blood samples will be collected for PK, immunogenicity, and safety analyses. 
Where appropriate, blood samples should be transferred into a sufficient number of transfer 
tubes for transportation to the assigned testing facilities. Primary and back-up samples will be 
shipped to the central laboratory according to the laboratory manual, and primary samples 
should be shipped separately from the back-up samples. 
Additionally, back-up samples for PK and immunogenicity should be retained at the central 
laboratory as a back-up for up to 5 years after the end of the study in case additional analysis 
is required. Regardless of additional analysis for PK and immunogenicity, the sample will be 
stored at the Sponsor or a designated biobank for a further 5 years (after the end of the study) 
unless a specific authorization is given by the Sponsor to destroy the sample. Additional tests 
can be conducted at the Sponsor or the biobank if it is required from a regulatory or medical 
perspective. Details in storage and shipment will be followed according to the laboratory 
manual. 
6.7 Overdose Management 
The CT-P42 and Eylea vials and CT-P42 PFS will contain more than the recommended dose 
of 2 mg/0.05 mL. The excess volume needs to be expelled before injection to avoid overdose 
due to injecting the entire volume.  
The excess study drug and the air bubbles should be expelled by slowly depressing the plunger 
to align the plunger tip with the line that marks 0.05 mL on the syringe (preparation for 
administration of vial) or align the plunger dome edge with the 0.05 mL dosing marker (shown 
on the inside barrel) on the syringe (preparation for administration of PFS). The details will be 
provided in the pharmacy manual. 
Overdosing with increased injection volume may increase IOP. Therefore, in case of overdose, 
IOP should be monitored and if deemed necessary by the treating physician, adequate treatment 
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7 Statistical Analysis Plan 
 
 Continuous variables will be summarized by 
reporting descriptive statistics: number of observations (n), mean, standard deviation (SD), 
median, minimum, and maximum. Categorical variables will be summarized using frequency 
tables showing the number and percentage of patients within a particular category. 
Changes from analyses planned in this protocol will be documented in the SAP. Any deviations 
from the planned analysis as described in the SAP will be justified and recorded in the CSR. 
Full details of the statistical methods will be described in the SAP, which will be finalized 
before database lock. 
7.1 Sample Size Calculation 
Assuming an equivalence margin of ±3 letters with two one-sided significance levels of 0.05, 
a sample size of 316 patients (158 patients in each treatment group) provides an 89% statistical 
power to demonstrate the therapeutic equivalence of CT-P42 to Eylea based on the mean 
change from baseline in BCVA at Week 8. In the sample size calculation, the common SD of 
the mean change from baseline in BCVA was assumed as 8.2 and the expected mean difference 
was assumed to be 0. The dropout rate has been hypothesized at 12%; therefore, approximately 
360 patients (180 patients in each treatment group of CT-P42 and Eylea) will be required to be 
enrolled in this study. 
 
 
7.2 Analysis Sets 
All data collected during the Main Study Period will be analyzed in the following analysis sets. 
Intent-to-Treat (ITT) set is defined as all patients who are randomly assigned to receive either 
of the study drugs, regardless of whether or not any study drug was administered. 
Full analysis set (FAS) is defined as all randomly assigned patients who receive at least one 
full dose of study drug. 
Per-Protocol (PP) set is defined as all randomly assigned patients who receive all full doses 
of study drug up to Week 4 (total 2 injections) and have a BCVA assessment at Week 8. A major 
protocol deviation that may affect the interpretation of study results of primary efficacy 
endpoint will lead to exclusion from PP set. Final determinations of the PP set will be made at 
the masked data review meeting before unmasking. 

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Safety set for Main Study Period is defined as all randomized patients who receive at least 
one full or partial dose of study drug. 
The PK set is defined as patients who receive at least one full dose of study drug and have at 
least one post-treatment PK concentration data. A major protocol deviation that may affect the 
interpretation of study results of PK endpoints will lead to exclusion from PK set. Final 
determinations of the PK set will be made at the masked data review meeting for the PK 
endpoints before unmasking. 
The Usability set for vial kit is defined as all patients in the Safety set for Main Study Period 
who have evaluable usability measurements. 
All data collected from the Extension Study Period will be analyzed in the following analysis 
sets.  
Safety set for Extension Study Period is defined as all patients who receive full or partial 
dose of study drug via PFS in the Extension Study Period. 
Usability set for PFS is defined as all patients in the Safety set for Extension Study Period 
who have evaluable usability measurements.  
7.3 Description of Subgroups to be Analyzed 
Subgroup analysis will be detailed out in the SAP. 
7.4 Efficacy Analysis 
All efficacy data collected during the Main Study Period will be analyzed in the FAS and/or 
PP set unless otherwise specified. All efficacy data collected during Extension Study Period 
will be analyzed in the Safety set for Extension Study Period. 
7.4.1 Primary Efficacy Analyses 
7.4.1.1 Best Corrected Visual Acuity at Week 8 
The primary efficacy analysis will be performed for the FAS with the mean change from 
baseline in BCVA at Week 8 using an analysis of covariance model with the baseline BCVA 
and country as covariates and treatment group as a factor. Therapeutic equivalence of CT-P42 
with respect to Eylea will be concluded if the two-sided 90% confidence interval of difference 
falls entirely within an equivalence margin [± 3 letters]. Primary endpoint will also be analyzed 
using the PP set.  

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The sensitivity analysis will be performed in the FAS to evaluate the impact of missing data 
on the primary efficacy results. Missing data will be imputed using multiple imputation with 
the missing at random assumption. Also, in case the missing rate is higher than expected, the 
trimmed means approach will be considered to address the possible bias from the potentially 
high and/or imbalanced missing rates in the treatment groups (Permutt and Li. 2016). The 
details will be described in the SAP. 
7.4.2 Secondary Efficacy Analyses 
All secondary efficacy endpoints will be analyzed using the FAS and PP set for Main Study 
Period and Safety set for Extension Study Period. These will be summarized using descriptive 
statistics (n, mean, median, SD, minimum, and maximum) for quantitative variables and 
frequency counts and percentages for categorical variables and listed by treatment arm as 
appropriate. 
7.4.2.1 Best Corrected Visual Acuity 
The actual value and mean change from baseline in BCVA at each time point will be 
summarized descriptively by treatment group. The mean (± SD) BCVA score versus scheduled 
visit profiles will be presented graphically. The proportion of patients who gained/lost ≥ 5, ≥ 10, 
and ≥ 15 ETDRS letters from baseline in BCVA will be summarized using frequency tables 
and will also be presented using bar plot by treatment group and each scheduled visit. 
7.4.2.2 Central Subfield Thickness by Optical Coherence Tomography 
The actual value and mean change from baseline in central subfield thickness by OCT will be 
summarized descriptively by each treatment group. 
7.4.2.3 Diabetic Retinopathy Severity Scale Score 
The percentage of patients with a ≥ 2-step improvement from baseline in the ETDRS DRSS 
score as assessed by FP will be summarized using frequency tables. 
7.5 Pharmacokinetic Analyses 
Plasma concentration and PK parameters will be summarized using quantitative descriptive 
statistics (including geometric mean and coefficient of variation, as appropriate) by treatment 
group, study visit, and time point. All analyses will be performed based on the PK set. 

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7.6 Usability Analyses 
The secondary usability endpoint will be summarized using the Usability set for vial kit and 
PFS, respectively. The number of injections successfully administered will be summarized 
using frequency tables. 
7.7 Safety Analyses 
For following assessments, all safety data collected will be analyzed in the Safety set for the 
Main Study Period and Extension Study Period, respectively. 
 
Adverse events (ocular and non-ocular) including SAEs 
 
Adverse events of special interest 
 
Immunogenicity assessments including anti-drug antibody and neutralizing antibody 
 
Hypersensitivity monitoring 
 
Finger count, hand motion, light perception 
 
Intraocular pressure test 
 
Slit lamp examination 
 
Indirect ophthalmoscopy 
 
Vital signs and weight 
 
Electrocardiogram 
 
New York Health Association functional classification 
 
Physical examination 
 
Pregnancy 
 
Clinical laboratory analyses including HbA1c 
 
Prior and concomitant treatments 
7.7.1 Demographics, Baseline, and Background Characteristics 
Baseline demographics (age, sex, ethnicity, and race) and background characteristics will be 

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summarized on ITT set by presenting data in summary tables. Qualitative data (e.g., 
medical/ophthalmic history) will be summarized in contingency tables, and quantitative data 
(e.g., age and height) will be summarized using quantitative descriptive statistics. 
7.7.2 Adverse Events 
AEs will be recorded according to the CTCAE v5.0 and will be coded to system organ class 
and PT according to MedDRA. A TEAE is defined as described in Section 6.4.2.1. Non-ocular, 
ocular AEs in the study eye, and ocular AEs in the fellow eye will be displayed separately. The 
following TEAE summaries will be reported by system organ class, PT, severity, relationship, 
and treatment group: 
 
Number and percentage of patients reporting at least 1 TEAE 
 
Number and percentage of patients reporting at least 1 treatment-emergent SAE 
 
Number and percentage of patients discontinuing the study drug due to a TEAE 
 
Number and percentage of patients with TEAE of special interest 
7.7.3 Immunogenicity 
All data will be listed and summarized by treatment group, where appropriate. 
7.7.4 Clinical Laboratory Analyses 
Clinical laboratory tests (clinical chemistry, hematology, urinalysis) including HbA1c, and 
pregnancy testing will be summarized by treatment at each scheduled collection time of Main 
Study Period. For continuous parameters, change from baseline will also be summarized for 
all scheduled collection times of Main Study Period after the first administration of study drug, 
if applicable. 
7.7.5 Electrocardiograms, Physical Examination, Vital Signs, and Weight 
Electrocardiograms, vital signs (systolic and diastolic BP, heart rate, respiratory rate, and body 
temperature) including hypersensitivity monitoring, and weight will be summarized by 
treatment for each scheduled collection time of Main Study Period. Physical examination will 
be listed by treatment group, where appropriate. Changes from baseline will also be 
summarized for all scheduled collection times of Main Study Period after the first 
administration of study drug, if applicable. 

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7.7.6 Prior and Concomitant Treatment 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. All prior and concomitant medications data will be listed and summarized by 
treatment group as appropriate. The non-drug therapies will be coded according to the 
MedDRA. 
7.7.7 Other Safety Analyses 
All other safety data will be listed and summarized by treatment group as appropriate. 
7.8 Interim Analysis 
Although no formal interim analysis is planned, the Sponsor plans to prepare 2 CSRs 
(Section 9.7). 
7.9 Data Quality Assurance 
This study will be conducted according to the ICH Good Clinical Practice (GCP) 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 GCP guidelines on quality and risk management. 
Steps will be taken to ensure the accuracy and reliability of data include the selection of 
qualified investigators and appropriate study centers, review of protocol procedures with the 
investigator and associated staff prior to the study, periodic monitoring visits by the Sponsor 
or designee, and direct transmission of clinical laboratory data from a central laboratory into 
the clinical database. The eCRF will be reviewed for accuracy and completeness by the monitor 
during on-center monitoring visits and after their return to the Sponsor or designee; any 
discrepancies will be resolved with the investigator or designees, as appropriate. The data will 
be entered into the clinical study database and verified for accuracy. 
Quality assurance staff from the Sponsor or designee may visit the study center to carry out an 
audit of the study in compliance with regulatory guidelines and company policy. Such audits 
will require access to all study records, including source documents, for inspection and 
comparison with the eCRF. Patient privacy must, however, be respected. Enough prior notice 
will be provided to allow the investigator to prepare properly for the audit. 
Similar auditing procedures may also be conducted by agents of any regulatory body reviewing 
the results of this study in support of a licensing application. The investigator should 

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immediately notify the Sponsor or designee if contacted by a regulatory agency concerning an 
upcoming inspection. 

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8 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to changes based on industry and government SOP, working practice 
documents, or guidelines. Changes will be reported to the IRB/IEC but will not result in 
protocol amendment. 
8.1 Confidentiality and Data Protection 
All laboratory samples, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient 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 patient (or the patient’s legally authorized representative), except as 
necessary for monitoring and auditing by the Sponsor, designee, the regulatory authorities, or 
the IRB/IEC. 
The investigator, 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. 
8.2 Independent Ethics Committee or Institutional Review Board 
Regulations and the ICH guidelines require an approval to be obtained from an IRB/IEC before 
participation of human patients in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for the recruitment of study patients, and any other written 
information regarding this study to be provided to the patient or the patient’s legally authorized 
representative must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals 
and of the IRB/IEC compliance with ICH harmonized tripartite guideline E6(R2): GCP will be 
maintained by the study center and will be available for review by the Sponsor or 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 data 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 risk to patients. 

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8.3 Patient Information and Consent 
A written ICF in compliance with the ICH E6(R2) guidelines shall be obtained from each 
patient before entering the study or performing any unusual or non-routine procedure that 
involves risk to the patient. An informed consent template may be provided by the Sponsor to 
the study centers. If any institution-specific modifications to study-related procedures are 
proposed or made by the study center, the ICF should be reviewed by the Sponsor, designee, 
or both before IRB/IEC submission. Once reviewed, the consent will be submitted by the 
investigator to his or her IRB/IEC for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participating patients must sign the 
revised form. 
Before recruitment and enrollment, each prospective patient or his or her legally authorized 
representative will be given a full explanation of the study and be allowed to read the approved 
ICF. Once the investigator is assured that the patient/legally authorized representative 
understands the implications of participating in the study, the patient/legally authorized 
representative will be asked to give consent to participate in the study by signing the ICF. 
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 
A description of the objectives of the study and how it will be organized 
 
The type of treatment 
 
Any potential negative effects attributable to the study drug 
 
The freedom to ask for further information at any time 
 
The patient’s right to withdraw from the clinical study at any time without giving reason 
and without jeopardizing the patient’s further course of medical treatment 
 
The existence of patient insurance coverage and a summary of what is included in this 
coverage 
 
Adequate time and opportunity to satisfy questions 
The investigator will be supplied with an adequate number of ICFs to be used. The forms will 
be signed and dated by both the principal investigator (or sub-investigator) and the patient or 
patient’s legal representatives (according to the local regulations) before the beginning of the 
study. The investigator shall retain the signed original ICF(s) and give a copy of the signed 
original form to the patient or legally authorized representative. 

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To ensure medical confidentiality and data protection, the signed ICFs will be stored in the 
investigator’s study file. The investigator will allow inspection of the forms by authorized 
representatives of the Sponsor, IRB/IEC members, and regulatory authorities. The investigator 
will confirm, by signing and dating the eCRFs, that ICF has been obtained. 
8.4 Study Reporting Requirements 
By participating in this study, the principal investigators or sub-investigator agrees to submit 
reports of SAEs according to the timeline and method outlined in Section 6.4.2.1.2. In addition, 
the principal investigator or sub-investigator agrees to submit annual report to his or her 
IRB/IEC as appropriate. 
8.5 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 per regional 
requirements. 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 study 
and for 1 year following the completion of the study. 
Neither the Sponsor nor its designee is financially responsible for further testing or treatment 
or any medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the Sponsor nor its designee is financially 
responsible for further treatment of the patient’s disease. 
8.6 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 Code of Federal Regulations (CFR) by providing the following essential 
documents, including but not limited to: 
 
Institutional Review Board/ Independent Ethics Committee approval 
 
Original investigator-signed investigator agreement page of the protocol 
 
Curriculum vitae of the principal investigator and each sub-investigator. Current licensure 
must be noted in the curriculum vitae. The curriculum vitae will be signed and dated by 
the principal investigators and sub-investigators at the study start-up, indicating that they 
are accurate and current 
 
Financial disclosure information to allow the Sponsor to submit complete and accurate 
certification or disclosure statements in accordance with local regulations. In addition, the 

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investigators 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 after the completion of the study 
 
Institutional Review Board/ Independent Ethics Committee-approved ICF, samples of 
study center advertisements for recruitment for this study, and any other written 
information regarding this study that is to be provided to the patient or legally authorized 
representative, and 
 
Laboratory certifications and normal ranges for any local laboratories used by the study 
center, in accordance with local regulations 
8.7 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The investigator will conduct all aspects of this study in accordance with all national, 
state, and local laws or regulations.  
Prior to the study onset, the protocol, ICF, advertisements to be used for patient recruitment, 
and any other written information regarding this study to be provided to the patient or the 
patient’s legally authorized representative must be approved by the IRB/IEC. Documentation 
of all IRB/IEC approvals and of the IRB/IEC compliance with the ICH E6(R2) guidelines will 
be maintained by the study center and will be available for review by the Sponsor or designee. 
All IRB/IEC approvals will be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title and/or protocol number and the 
date approval and/or favorable opinion was granted. 
The principal investigator or designated sub-investigator is responsible for obtaining continued 
review of the clinical research at intervals not exceeding 1 year or otherwise specified by the 
IRB/IEC. The principal investigator or designated sub-investigator must supply the Sponsor or 
its designee with written documentation of continued review of the clinical research. 
8.8 Data Collection 
8.8.1 Electronic Case Report Forms and Source Documents 
It is the intent of this study to acquire study data via electronic format. As part of the 
responsibilities assumed by participating in the study, the principal investigator or 
sub-investigator agrees to maintain adequate case histories for the patients treated as part of 
the research under this protocol. The principal investigator or sub-investigator agrees to 

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maintain source documentation (e.g., laboratory reports), enter patient data into the eCRF as 
accurately as possible, and respond to any reported discrepancies rapidly. These source 
documents may include diaries, laboratory reports, ECG strips, etc. 
The analysis data sets will be combination of these data and data from other sources (e.g., 
laboratory data). 
An eCRF is accessed through the appropriate system, which allows for on-center data entry 
and data management. Study center users can read from and write to the Sponsor’s database 
where the clinical data are collected. This provides immediate, direct data transfer to the 
database, as well as immediate detection of discrepancies, enabling study center coordinators 
to resolve and manage discrepancies in a timely manner. 
Each study center staff involved with the study at each study center will have an individual 
logon account and password that allows for record traceability. Thus, the system, and 
subsequently any investigative reviews, can identify coordinators, investigators and 
individuals who have entered or modified records. 
8.9 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
8.10 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the institution; 
the investigator/institution should provide IRB/IEC with a summary of the study’s outcome 
and the Sponsor and regulatory authorities with any reports required. 
8.11 Record Retention 
All correspondence (e.g., with Sponsor, IRB/IEC, or center monitors) relating to this clinical 
study will be kept in appropriate file folders. Records of patients, source documents, eCRFs, 
and drug inventory sheets pertaining to the study must kept on file. 
Essential documents should be retained until at least 15 years after the date on which the results 
of the study are submitted to the regulatory authorities in support of an allocation for a research 
or marketing permit, or completion date for study by approval or disapproval of any application, 
whichever is later. 
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 

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Sponsor to inform the investigator/institution as to when these documents no longer need to be 
retained. 
If an investigator moves, withdraws from an investigation, or retires, the responsibility for 
maintaining the records may be transferred to another person, who will accept the responsibility. 
Notice of transfer must be made to and agreed upon by the Sponsor. 
8.12 Patient Identification Register 
The investigator agrees to complete a patient identification register. This form will be treated 
as confidential and will be filed in the investigator site file. Otherwise, all reports and 
communications relating to the study will identify patients by assigned number only. 
8.13 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 publication thereof will not be unduly withheld. 

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9 Study Management 
9.1 Sponsor 
 
 
 
 
 
 
 
 
 
 
 
 
9.2 Vendor Contact 
 
 
  
 
 
 
 
  
 
 
 
9.3 Central Analytical Facilities 
Any analytical facilities and procedures utilized for this study must be Good Laboratory 
Practice compliant. Details of analytical facilities are presented in the ICF. 
9.4 Monitoring 
9.4.1 Data Safety Monitoring Board 
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SOPs. 
9.4.3 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, the investigator agrees to allow the Sponsor, representatives of the 
Sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the Sponsor and CRO of any audits scheduled by any 
regulatory authorities. 
9.5 Management of Protocol Amendments and Deviations 
9.5.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the patient, 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 patients are enrolled under an amended protocol. This will be fully 
documented. 
The investigator must not implement any deviation from or change to the protocol without 
discussion and agreement from the Sponsor or its designee, and prior review, documented 
approval, and favorable opinion of the amendment from the relevant IRB/IEC and/or 
regulatory authorities, except where it is necessary to eliminate an immediate hazard to patients 
or where the changes involve only logistical or administrative aspects of the clinical study. The 
eCRF and source documents will describe any departure from the protocol and the 
circumstances requiring it. 
Protocol amendments will be submitted to the appropriate authorities as required by the 
applicable regulatory requirements. 
9.5.2 Protocol Deviations 
The investigator or designee must document and explain in the patient’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 patients 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. 

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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 
major deviation occurs when there is non-adherence to the protocol by the patient or 
investigator that results in a major and additional risk to the patient’s right, safety and 
well-being. Major deviations can include non-adherence to inclusion or exclusion criteria, or 
non-adherence to regulations or ICH GCP guidelines, and will lead to the patient being 
withdrawn from the study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Deviations will be defined before unmasking. Principal investigators will be 
notified in writing by the monitor of deviations. The IRB/IEC should be notified of all protocol 
deviations in a timely manner. 
9.6 Study Termination 
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 of the final CSR generated. 
9.7 Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
CSRs are prepared and provided to the regulatory authorities as required by the applicable 
regulatory requirement(s). The Sponsor will also ensure that the CSRs in marketing 
applications meet the standards of the ICH harmonized tripartite guideline E3: Structure and 
content of CSRs. 
The Sponsor plans to prepare 2 CSRs to report the following: 
 
Data for each patient up to Week 24 
 
All data after completion of the whole study period 
If additional CSRs are required for regulatory or academic purposes, CSRs will be generated 
after the first database lock and unmasking process. 

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10 References 
Brown DM, Schmidt-Erfurth U, Do DV, Holz FG, Boyer DS, Midena E, et al. Intravitreal 
Aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. 
Ophthalmol. 2015;122(10):2044-52. 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic 
macular edema. Arch Ophthalmol 1985; 103: 1796-1806. 
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Available 
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Guidelines 
on 
evaluation 
of 
similar 
biotherapeutic 
products. 
Available 
at: 
http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_
WEB_22APRIL2010.pdf 
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Q&A 
On 
Coronaviruses 
(COVID-19). 
[online] 
Available 
at: 
<https://www.who.int/emergencies/diseases/novel-coronavirus-2019/question-and-answers-
hub/q-a-detail/q-a-coronaviruses#:~:text=symptoms> [Accessed 13 October 2020]. 
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Appendix 2. New York Heart Association Functional Classification 
As defined in Zhang et al. 2018, the NYHA classification is used in patients with heart failure. 
Class 
Symptoms 
I (Mild) 
No limitation of physical activity. Ordinary physical activity does not cause under fatigue, 
palpitation, dyspnea (shortness of breath) 
II (Mild) 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea (shortness of breath) 
III (Moderate) 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, dyspnea 
IV (Severe) 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases 
 
 

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Appendix 3. Usability Assessment Checklist 
1. Usability Assessment Checklist for Vial Kit 
No. 
Product Use Tasks 
1 
Using aseptic technique, place the vial kit on a clean, flat surface. 
2 
Look at the vial and make sure you have the correct medicine and dosage. 
3 
Check the expiration date on the label to make sure it has not passed. 
4 
Remove the protective plastic cap from the vial. 
5 
Clean the top of the vial with an alcohol wipe. 
6 
Remove the filter needle and the 1-mL syringe from their packaging. 
7 
Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip. 
8 
Push the filter needle into the center of the vial stopper until the needle is completely inserted 
into the vial and the tip touches the bottom or bottom edge of the vial.  
9 
Using aseptic technique withdraw all of the vial contents into the syringe, keeping the vial in an 
upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, 
ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during 
withdrawal keeping the bevel of the filter needle submerged in the liquid. 
10 
Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to 
completely empty the filter needle.  
11 
Remove the filter needle from the syringe and properly dispose of the filter needle.  
12 
Remove the injection needle from its packaging and attach the injection needle to the syringe by 
firmly twisting the injection needle onto the Luer lock syringe tip. 
13 
When ready to administer the study drug, remove the plastic needle shield from the needle. 
14 
Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, 
gently tap the syringe with your finger until the bubbles rise to the top. 
15 
To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so that the 
plunger tip aligns with the line that marks 0.05 mL on the syringe. 
16 
Insert syringe at injection site. 
17 
Slowly inject full dose. 
18 
Remove syringe from injection site. 
19 
Dispose of used syringe and needle. 
 

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2. Usability Assessment Checklist for PFS 
No. 
Product Use Tasks 
1 
Open the carton  
2 
Remove contents from carton 
3 
Carefully peel open the blister pack ensuring the sterility of its contents  
4 
Remove the syringe from the sterilized blister using aseptic technique 
5 
Twist off the syringe cap to remove the syringe cap 
6 
Using aseptic technique, firmly twist the injection needle onto the Luer lock syringe tip 
7 
Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are 
bubbles, gently tap the syringe with your finger until the bubbles rise to the top 
8 
Remove the needle cap 
9 
Slowly depress the plunger rod to align the plunger dome edge to eliminate all bubbles 
10 
To expel excess drug and prepare the dose by aligning the plunger dome edge with the 0.05 mL 
dosing marker on the syringe 
11 
Insert syringe at injection site 
12 
Slowly inject full dose 
13 
Remove syringe from injection site 
14 
Dispose of used syringe and needle 
 

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Appendix 4. Benefit and Risk Assessment and Risk Mitigation Plan for 
COVID-19 
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially 
identified during an outbreak of atypical viral pneumonia cases of unknown cause in the 
People’s Republic of China in December 2019 and the disease caused by SARS-CoV-2 has 
been designated as coronavirus disease 2019, known as COVID-19. On 11 March 2020, WHO 
declared the SARS-CoV-2 infection outbreak a global pandemic as there were over 1 million 
deaths have been reported globally (WHO disease outbreak new, 2020).  
Due to the global impact of the COVID-19 pandemic, the Sponsor is taking proactive measures 
to guarantee that all site staff and patients involved in trial are secure and the patients remain 
in the study until their last visit, with continuation of treatment during study period. 
1. Benefit and Risk Assessment on Study Population 
Diabetic macular edema has low chance to be deteriorated due to concurrent COVID-19 itself, 
considering the most common symptoms of COVID-19 are fever, dry cough, and tiredness 
(Q&A On Coronaviruses [COVID-19], 2020) and the irrelevance between cause of COVID-
19 and DME disease. But diabetic and elderly patients are at a high risk for COVID-19 
complications and should not be exposed to avoidable risk; however, continuation of care 
where possible is important to avoid irreversible vision loss (Korobelnik et al. 2020). Without 
appropriate treatment in short time periods, the visual loss could be definitive by fibrosis of 
edematous macular and photoreceptors death. Therefore, the SARS-CoV-2 pandemic might 
have poor consequences for visual acuity of patients. Because of this, finding a positive benefit-
risk balance is very difficult, between evidence for a functional emergency (vision loss) and a 
high risk of life-and death emergency in vulnerable elderly patients (Navel et al. 2020).  
Basically, the quarantine of COVID-19 should be carried out based on the SOP of each site 
and local regulatory guidelines. Sponsor plans to further implement and recommend the 
following procedures to minimize the risk of COVID-19 infection for the patients with DME 
and healthcare professionals during the IVT injection of study drug (Shmueli et al. 2020, Table 
11-1). Taking this into account, the risk of COVID-19 infection for each patients is not expected 
to increase by participating in this study. Yet there is a possibility of increasing safety risk as 
being involved in this study, risk assessment will be conducted during the study by the sponsor 
through a sufficient discussion with the investigators and data safety monitoring board 
(DSMB). 
Table 11-1 
Summary of measures to prevent COVID-19 transmission while 

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maintaining adequate care of IVT injections 
Reschedule  
 
Confirmed COVID-19 patients. 
 
In isolation. 
 
Travelled or exposed to somebody who travelled to high-risk 
areas. 
 
Suspected COVID-19 (fever or flu-like symptoms) 
Clinic 
injection 
control 
 
Wear surgical masks at all times. 
 
Frequent hand sanitation by all personnel and patients. 
 
Sanitation of equipment between patients. 1~2 meter(s) distance 
between personnel and patients, except when required for 
examination and treatment. 
 
Only one visitor, unless an aide or assistant is required. 
 
Alertness to patients who present with conjunctivitis or with flu-
like symptoms. 
Injection procedure Routine measures to prevent post injection endophthalmitis: 
 
Topical povidone-iodine. 
 
Retraction of eyelids to avoid eyelashes. 
 
Postpone injection in active blepharitis. 
 
Avoid extensive eyelid manipulation. 
 
Hand hygiene and gloves. 
 
Surgical mask and refrainment from speaking. 
 
Measures to prevent COVID-19 transmission during the injection 
procedure: 
 
Not suspected as COVID-19 case: 
- 
Prefer same-day bilateral injections where applicable. 
- 
Face mask and non-talking policy. 
- 
Cover the patient’s nose and mouth with a drape. 
 
Suspected/confirmed COVID-19 case: 
- 
Injection rescheduled, unless permanent vision loss is 
anticipated. 
- 
If injecting: use full personal protective equipment including 
gloves, N-95 respirator facemask, gown and eye-
shield/goggles. 
 
2. Mitigation Plans 
Investigational Medical Product Management 
To better cope with the sudden imposition of movement restriction and/or increase shipment 
lead time due to frequent flight cancellation and limited staff at customs, sufficient IMP will 
be supplied to cover patient visit for longer period. Inter-country study drug transfer using 
regional airways will be considered in case intercontinental flights are repeatedly cancelled. In 
addition, Sponsor will prepare site-to-site transfer of study drug from nearby clinical sites in 

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case agile resupply is required (e.g., patients are enrolled in a site more than anticipated but 
additional supplied IMP could not be sufficient).  
Rescheduling of Visit and Study Drug Administration Schedule of Patients 
The COVID-19 screening tests will be performed locally based on each site and/or local 
regulatory guidelines upon the investigator’s discretion throughout the study period. If 
COVID-19 is confirmed positive during the Screening period, the patient should not be 
enrolled in this study until confirmation of complete recover from COVID-19 as per site and/or 
local regulatory guidelines. Although patients can be screened only once in normal 
circumstance as specified in Section 4.2.1, additional rescreening can be performed only in 
limited cases considering COVID-19. If COVID-19 is confirmed after randomization, the 
investigators will discuss a case-by-case about the position of patient with the Sponsor. In case 
of patient who has contact with COVID-19 patients within 14 days from any site visit, 
investigator will reconsider the enrollment or visit schedule following the site and/local 
regulatory guidelines 
Investigators will promptly notify to the Sponsor if any unfavorable situation is occurred in 
relation to local COVID-19 status (e.g., site shut down, lock down of city, cohort isolation, 
etc.). For sites where the patients are unable to travel or use public transportation, the Sponsor 
will support the patients with alternative transportation or reimbursement for travel to ensure 
the visits can be made within the window or the visit can be proceeded at the earliest. 
In case patients cannot visit the study center on scheduled day, the treatment schedule will be 
adjusted following Section 5.3.1. However, if study drug administration cannot be done within 
an allowed visit window or missed dose is expected, whether to continue with the subsequent 
study treatment will be discussed with the Sponsor, ensuring the compliance with the trial 
protocol to such an extent that an ongoing benefit-risk assessment for the clinical trial and 
patients is still possible. Even if study visit cannot be made, possible data will be collected via 
phone call and during the next visit, if applicable. Investigator will keep following up with 
patients regarding any safety issues by phone call before the patients visit the site. 
Although the COVID-19 pandemic situation is likely to introduce more protocol deviations 
than normal circumstance, protocol deviations will be managed in accordance with the 
standard procedures. The number and type of deviations will be monitored periodically to 
assess whether a protocol amendment or other modifications are needed. 
Site Monitoring and Audit 
In case where a monitoring visit cannot be made because of the situation of COVID-19, 
centralized monitoring will be performed by the Sponsor and/or CRO as alternatives 
particularly considering the situation of the site, for the sites where the first patient is 
randomized but the first monitoring visit is not performed. Manual data review on eCRF will 
be performed and if any mistakes or deviations are observed, proper guidance will be provided 
to avoid them in the future on the site. Sponsor and/or CRO will review the data entered in 

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CRF continuously and ensure raising queries and support the sites as necessary. If necessary, 
Sponsor will create and review a report based on the eCRF data to check whether visits, 
assessments and administrations of study treatment are in progress according to protocol and 
the same will be shared with CRO for site management. 
Audits are needed as part of implementing quality assurance throughout the study period in 
order to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the 
applicable regulatory requirements. In case where an audit cannot be made due to COVID-19 
pandemic situation, Sponsor will postpone audits or consider the remote audits after careful 
consideration of COVID-19 pandemic situation according to Guidance on the management of 
clinical trials during the COVID-19 (coronavirus) Pandemic (EMA 2020). Audits will be 
conducted only when permitted under national, local and/or organizational social distancing 
restrictions. 
Handling of Missing Data 
To assess any possible risks on data collection, data will be routinely reviewed according to 
Centralized monitoring plan and Risk based monitoring plan. After data collection, missing 
data on the primary analysis due to COVID-19 will be handled equally as specified in Section 
7.4.1 as other missing cases. However, if a different approach is required for missing data due 
to COVID-19, it will be discussed at the masked data review meeting in a case-by-case manner 
and method of handling missing data will be specified in the SAP.