Clinical trial NCT03211234
Conditions: Age-Related Macular Degeneration
Sponsor: Santen Inc.
Start date: 2017-07-05; Completion date: 2020-01-31
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess the safety and efficacy of repeated intravitreal injections of DE-122 (low dose and high dose) given in combination with Lucentis® in subjects with wet age-related macular degeneration (AMD) compared with Lucentis® alone.

Detailed description:

Arms: arm 1: 2.0 mg DE-122 and Lucentis ® 0.5 mg arm 2: 4.0 mg DE-122 and Lucentis ® 0.5 mg arm 3: Sham and Lucentis ® 0.5 mg
Interventions: intervention 1: 2.0 mg DE-122 Injectable Solution + Lucentis intervention 2: 4.0 mg DE-122 Injectable Solution + Lucentis intervention 3: Lucentis
Intervention descriptions: intervention 1: Subjects will receive 6 monthly intravitreal injections of low dose DE-122 in the study eye, in combination with Lucentis. intervention 2: Subjects will receive 6 monthly intravitreal injections of high dose DE-122 in the study eye, in combination with Lucentis. intervention 3: Subjects will receive 6 monthly intravitreal injections of Sham in the study eye, in combination with Lucentis.

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
A Multi-Center, Randomized, Double Masked and Active 
Controlled Phase II Study Assessing the Efficacy and Safety of 
Intravitreal Injections of DE-122 in combination with Lucentis® 
Compared to Lucentis® Monotherapy in Subjects with Wet Age-
related Macular Degeneration - AVANTE study 
 
NCT Number:  
 NCT03211234 
 
Date of the document: 
08 Jan 2019 
 
 
 


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DE-122 
Protocol 36-002 
Amendment 07 
 
TITLE:  A Multi-Center, Randomized, Double Masked and Active Controlled Phase II Study 
Assessing the Efficacy and Safety of Intravitreal Injections of DE-122 in combination with 
Lucentis® Compared to Lucentis® Monotherapy in Subjects with Wet Age-related Macular 
Degeneration - AVANTE study 
SPONSOR: 
SANTEN PHILIPPINES INCORPORATED 
Units 2801 to 2802, 28th Floor SM Aura Tower 
26th Street corner McKinley Parkway, The Fort, 
Taguig City, 1630 Philippines 
STUDY DRUG: 
 
2.0 mg (20µL of 100 mg/mL) 
DE-122 injectable solution  
 
4.0 mg (40µL of 100 mg/mL)  
DE-122 injectable solution 
I have read the 36-002 protocol and agree to conduct the study as outlined and in accordance 
with the ethical principles in the Declaration of Helsinki, ICH GCPs, and applicable local 
regulations.  I will not initiate the study until I have obtained written approval by the 
appropriate Institutional Review Board (IRB) or Ethics Committee (EC) and have complied 
with all financial and administrative requirements of the governing body of the clinical 
institution and Santen as the Sponsor.  I will obtain written informed consent from each study 
subject prior to performing any study-specific procedures. 
I understand that my electronic signature on an electronic case report form indicates that the 
data therein has been reviewed and accepted by me as the Investigator.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
INVESTIGATOR: 
Signature/Date: 
_________________________________ / ______ 
 
Name:                   _________________________________ 
 
 
(Typed or Printed) 
 
Address:               _________________________________ 
 
 
_________________________________ 
 
Phone: 
_________________________________ 


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1.
PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company:  
Santen Philippines Incorporated 
Units 2801 to 2802, 28th Floor SM Aura Tower, 26th Street corner 
McKinley Parkway, The Fort, Taguig City 1630 Philippines  
Name of Investigational Product:  DE-122 injectable solution 
Name of Active Ingredient:  DE-122, a chimeric anti-CD105 (Endoglin) IgG1 antibody consisting of 
human Cκ and Cγ1 constant regions with murine Vκ and VH regions 
Title of Study:  A Multi-Center, Randomized, Double Masked and Active Controlled Phase II Study 
Assessing the Efficacy, Safety of Intravitreal Injections of DE-122 in combination with Lucentis® 
Compared to Lucentis® Monotherapy in Subjects with Wet Age-related Macular Degeneration 
- AVANTE study 
Study Period:  Approximately 31 months 
Estimated date first subject enrolled: July 2017 
Estimated date last subject completed: January 2020 
Phase of Development:  
Phase II 
Primary Objective:  
 
To assess the safety and efficacy of repeated intravitreal injections of DE-122 (2.0 mg/eye and  
4.0 mg/eye) given in combination with Lucentis® in subjects with wet age-related macular 
degeneration (AMD) compared with Lucentis® alone. 
Secondary Objective:  
 
To evaluate the pharmacokinetics and immunogenicity of DE-122 following repeated IVT 
injections of DE-122 in subjects with wet AMD in serum samples.  
 
To evaluate biomarker candidates of DE-122 following repeated IVT injections of DE-122 in 
subjects with wet AMD in both serum and aqueous humor samples. 
Methodology: 
This is a randomized, double masked and active controlled study assessing the safety and efficacy of 
repeated intravitreal injections of DE-122 (2.0 mg or 4.0 mg) in combination with Lucentis® compared 
to Lucentis® monotherapy in subjects with wet AMD.  Approximately seventy six (76) subjects with 
wet AMD will be randomly assigned to one of three treatment arms:  
Arm 1: Sham + Lucentis® 0.5 mg (N=17) 
Arm 2: DE-122, 2.0 mg + Lucentis® 0.5 mg (N=31) 
Arm 3: DE-122, 4.0 mg + Lucentis® 0.5 mg (N=28) 
Subjects will receive 6 monthly intravitreal injections of DE-122 (2.0 mg or 4.0 mg) or Sham, in 
combination with Lucentis®.  The primary analysis will be performed when all subjects complete the 
Week 24 visit.  
The first 6 subjects will be randomized to Arm 1 or Arm 2 in a 1:1 ratio in Stage 1.  The Safety Review 
Team will review the safety parameters of the 6 subjects in Stage 1 and determine if the safety and 
tolerability at Week 4 are acceptable.  If so, enrollment will be continued in a 1:2:2 ratio in the three 
arms for the remaining approximately 70 subjects in Stage 2.  
To be eligible, subjects must have a diagnosis of active CNV secondary to AMD, with some subfoveal 
component (CNV, fluid, or hemorrhage under the fovea) with lesions ≤ 12 disc areas and ≤ 50% 
hemorrhage in the study eye. Subjects must be previously treated (i.e., At least 3 IVT injections of  
Anti-VEGF for treatment naïve eyes or eyes adequately maintained on continuous intravitreal anti-


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VEGF therapy).  Subjects with Polypoidal Choroidal Vasculopathy (PCV) lesions will be allowed, but 
Retinal Angiomatous Proliferation (RAP) lesions will be excluded from this study.  Screening Visit 
SD-OCT images and Fluorescein Angiography from Investigator-identified eligible subjects will be 
sent to the central reading center to confirm eligibility based on AMD lesion attributes specified in the 
protocol.  To balance the randomization, subjects will be stratified by subgroups on the reading center’s 
assessment of lesion type, up to approximately one third (1/3) of the subjects in each arm should have 
PCV in Stage 2.  Subjects must satisfy all other inclusion and exclusion criteria. 
Subjects must have best corrected visual acuity (BCVA) of 65 to 25 ETDRS letters (equivalent to 20/50 
to 20/320 Snellen) in the study eye. 
Eligible subjects who are enrolled in the study will be seen for up to 14 visits.  
Subjects are eligible for rescue with any anti-VEGF IVT during the Week 24 and Week 28 if one of the 
following rescue criteria is met:  
Rescue Criteria: 
 BCVA decrease of ≥ 5 letters from the last visit  
 Central subfield thickness (CST) increase of ≥ 50 µm from the last visit  
 The discretion of investigator 
Number of Subjects (planned): 
Approximately 76 subjects with wet AMD will be enrolled at approximately 14 sites. 
Duration of the Study: 
The total study period for each subject will include a screening period (up to 14-days), then a treatment 
and follow up period (up to 32 weeks). 
Masking: 
This is a double-masked study, with subjects and examiners including the Principal Investigator (PI) 
masked to the treatment regimen.  However, the designated injecting physician (not the PI) will not be 
masked to the treatment regimen. 
The Sponsor will have masked and unmasked data review teams. The designated Safety Review Team 
will review the safety data of the 6 subjects in Stage 1 to determine if the safety and tolerability of the 
doses at Week 4 are acceptable. 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria: 
At Screening (Day -14 to Day -1) and Visit 1 (Day 1), subjects must meet all of the following inclusion 
criteria: 
1. Provide signed written informed consent on the Institutional Review Board (IRB)/Ethics 
Committee (EC) approved Informed Consent Form (ICF) and provide authorization as 
appropriate for local privacy regulations. 
2. Male or female 50 years of age or older on the date of signing the ICF and able and willing to 
comply with all treatment and follow-up study procedures. 
3. Diagnosis of active choroidal neovascularization (presence of subretinal or intraretinal fluid) 
secondary to wet AMD as assessed by SD-OCT in the study eye. 
4. Diagnosis of active leakage secondary to wet AMD as assessed by FA in the study eye.  
5. Diagnosis of wet AMD in the study eye prior to Screening visit (Visit 0) treated with repeated 


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intravitreal anti-VEGF medication (i.e., At least 3 IVT injections of Anti-VEGF for treatment 
naïve eyes or eyes adequately maintained on continuous intravitreal anti-VEGF therapy). 
6. Last treatment with intravitreal injection of anti-VEGF in the study eye > 20 days and < 80 
days prior to Screening visit (Visit 0). 
7. All lesion types except for Retinal Angiomatous Proliferation (RAP), total lesion size of  
≤ 12 disc areas, contain ≤ 50% hemorrhage and no fibrosis or atrophy involving the foveal 
center in the study eye 
8. BCVA of 65 to 25 ETDRS letters (equivalent to 20/50 to 20/320) in the study eye. 
9. BCVA of 25 ETDRS letters (equivalent to 20/320) or better in the fellow eye 
10. Reasonably clear media and some fixation in the study eye to allow for good quality SD-OCT 
and fundus photography. 
Exclusion Criteria: 
A subject with any of the following conditions is not eligible to participate in the study: 
Ocular: 
1. Use of any of the following treatments or anticipated use of any of the following treatments to 
the study eye: 
 
Intravitreal or periocular corticosteroid, within 90 days prior to Visit 1 (Day 1) and 
throughout the study; 
 
Fluocinolone acetonide intravitreal implant, within 12 months prior to Visit 1 (Day 1) and 
throughout the study;   
 
Visudyne photodynamic therapy, within 90 days prior to Visit 1 (Day 1) and throughout 
the study; 
2. Uncontrolled or advanced glaucoma, evidenced by an intraocular pressure (IOP) of >  
21 mmHg or cup/disc ratio > 0.8 while on medical therapy, or chronic hypotony (< 6 mmHg) 
in the study eye. 
3. Evidence of any other ocular disease other than wet AMD in the study eye that may confound 
the outcome of the study (e.g., active diabetic retinopathy, posterior uveitis, pseudovitelliform 
macular degeneration, moderate/severe myopia). 
4. History of vitrectomy in the study eye. 
5. Need for ocular surgery in the study eye during the course of the study. 
6. YAG laser capsulotomy within 30 days prior to Visit 1 (Day 1) in the study eye. 
7. Intraocular surgery, including lens removal or laser, within 90 days prior to Visit 1 (Day 1) in 
the study eye. 
8. Ocular or periocular infection in either eye. 
9. Pupillary dilation inadequate for quality stereoscopic fundus photography in the study eye. 
10. Media opacity that would limit clinical visualization, intravenous fluorescein angiography, or 
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11. History of herpetic infection in the study eye or adnexa. 
12. Presence of known active toxoplasmosis, inactive toxoplasmosis or toxoplasmosis scar in 
either eye. 
13. Presence of any form of ocular malignancy including choroidal melanoma in either eye. 
Non-Ocular: 
14. Prior treatment with DE-122 injectable solution. 
15. Use of any of the following treatments or anticipated use of any of the following treatments 
during the study: 
 
Systemic treatment with anti-VEGF agents (e.g., bevacizumab)  
 
Agents targeting the endoglin pathway 
16. Allergy or hypersensitivity to study drug product, fluorescein dye, or other study related 
procedures/medications.   
17. Inadequate renal function: e.g., serum creatinine > 1.3 mg/dL and BUN > 2 x the upper limit of 
normal (ULN). 
18. Inadequate hematologic function: e.g., hemoglobin < 10 g/dL; platelet count < 130 x 109 /L; 
WBC < 3.8 X 109 /L or > 10.9 X 109 /L. 
19. Inadequate liver function: e.g., serum bilirubin > 1.5 mg/dL, GGT, SGOT/ALT, SGPT/AST, 
and alkaline phosphatase outside 2 x ULN.  
20. History of bone marrow suppression. 
21. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g., hereditary 
hemorrhagic telangiectasia). 
22. History of hemorrhage, epistaxis, hemoptysis (> ½ teaspoon bright red blood), or treatment 
with anticoagulants within 90 days prior to Visit 1 (Day 1). 
23. Myocardial infarction, stroke or history of transient ischemic attacks within 180 days prior to 
Visit 1 (Day 1). 
24. Major surgery within 90 days prior to Visit 1 (Day 1).  Major surgery is defined as any surgery 
involving a risk to the life of the subject, including any operation upon an organ within the 
cranium, chest, abdomen, or pelvic cavity. 
25. Therapeutic radiation to the head or neck within 90 days prior to Visit 1 (Day 1). 
26. Participation in other investigational drug or device clinical trials within 30 days prior to  
Visit 1 (Day 1) or planning to participate in other investigational drug or device clinical trials 
for the duration of the study.  This includes both ocular and non-ocular clinical trials. 
27. Uncontrolled blood pressure (defined as systolic > 180 mmHg and/or diastolic > 110 while 
subject is sitting).  If a subject’s initial reading exceeds these values, a second reading may be 
taken 30 or more minutes later.  If a subject’s blood pressure needs to be controlled by 
antihypertensive medication, the subject can be eligible if medication is taken continuously for 
at least 30 days prior to Visit 1 (Day 1). 


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28. Atrial fibrillation not controlled by the subject’s primary care physician or cardiologist within 
30 days prior to Visit 1 (Day 1). 
29. Clinically significant concurrent illness, laboratory or EKG abnormality. 
30. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease condition that contraindicates the 
use of an investigational drug, might affect the interpretation of the results of the study, or 
renders the subject at high risk for treatment complications. 
31. Any systemic infection within 30 days prior to Visit 1 (Day 1). 
32. Females who are pregnant or lactating and females of child-bearing potential who are not using 
adequate contraceptive precautions (i.e., IUD, oral contraceptives, barrier method, or other 
contraception deemed adequate by the Clinical Investigator).  Men who do not agree to 
practice an acceptable method of contraception throughout the course of the study. 
33. Use of marijuana or illegal medication within 30 days prior to Visit 1 (Day 1) and throughout 
the study. 
34. Unable to comply with study procedures or follow-up visits. 
In addition, the Clinical Investigator or Santen Medical Monitor may declare a subject ineligible for 
any sound reason. 
Study Eye 
The study eye must meet all inclusion and exclusion criteria, including confirmation by the central 
reading center.  If both eyes are eligible based on inclusion and exclusion criteria, the study eye of an 
eligible subject is defined as the eye with the worse vision.  If both eyes have the same vision, the right 
eye (OD) should be determined as the study eye. 
Investigational product, dosage and mode of administration:  
Subjects will receive 6 monthly intravitreal injections of DE-122 (2.0 mg or 4.0 mg) or Sham in 
combination with Lucentis®.  Subjects will be randomly assigned to one of three treatment arms as 
follows: 
Stage 1: 
 
Arm 1: Sham + Lucentis® 0.5 mg (50 µL) 
 
Arm 2: DE-122, 2.0 mg (20 µL of 100 mg/mL) + Lucentis® 0.5 mg (50 µL) 
Stage 2: 
 
Arm 1: Sham + Lucentis® 0.5 mg (50 µL) 
 
Arm 2: DE-122, 2.0 mg (20 µL of 100 mg/mL) + Lucentis® 0.5 mg (50 µL) 
 
Arm 3: DE-122, 4.0 mg (40 µL of 100 mg/mL) + Lucentis® 0.5 mg (50 µL) 
Lucentis® will be administered first.  DE-122 2.0 or 4.0 mg, or Sham injection will be administered 
after Lucentis® administration.   
Route of Administration of Investigational product:  
Intravitreal injection in the study eye. 
 
 


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Criteria for Evaluation: 
Efficacy: 
The primary efficacy variable assessed at Week 24: 
 
Mean change from baseline in BCVA  
The secondary efficacy variables assessed at Week 24: 
 
Change from baseline in CST, macular volume and central retinal lesion thickness by SD-OCT, 
as determined by a reading center  
 
Proportion of subjects with BCVA: 1) gain of ≥ 15 ETDRS letters (3-line gainers); 2) < 15 
letters change (stable); and 3) ≥ 15 letter loss  
 
Change from baseline in total lesion area and total area of CNV by fluorescein angiogram (FA), 
as determined by a central reading center 
 
Change from baseline in greatest linear dimension of the total lesion area by FA, as determined 
by a central reading center 
A Follow-up Analysis is planned when all subjects complete the Week 32 visit.  The Analysis will 
include the number of anti-VEGF injections used for Rescue in addition to efficacy and safety data. 
Safety:  
The safety assessments will include adverse events (AEs), slit lamp biomicroscopy, indirect 
ophthalmoscopy, BCVA, IOP, fundus photography, fluorescein angiography, serum chemistry, 
hematology, urinalysis, vital signs, physical examination, EKG, and pregnancy. 
Immunogenicity:  
ADA titer will be measured in all subjects at prior to the Lucentis® injection of Day 1, and at Week 24. 
Pharmacokinetics (PK): 
Levels of DE-122 in serum will be determined and pharmacokinetic assessments will be performed on 
a subset of subjects.  
Pharmacogenomics/genomics: 
Subjects who have consented will provide a blood sample for a future Pharmacogenomics/genomics 
laboratory research.  The purpose of this Pharmacogenomics/genomics analysis is future exploratory 
research to identify possible genetic markers, associated with the study drug(s) and/or ophthalmologic 
disease conditions.  Blood sample will be collected once at Day 1 or any visit after Day 1 during the 
study. 
Biomarker Candidates: 
The exploratory investigation of biomarker candidates will be examined in serum and aqueous humor 
in subjects who give their consent. The samples will also be stored for future exploratory research to 
identify possible biomarkers associated with the study drug(s) and/or ophthalmologic disease 
conditions.  Serum samples and aqueous humor samples (optional) will be collected on certain 
scheduled visits.  SS-OCT angiography images will be taken at selected sites and stored. 
Statistical Methods: 
The primary analysis will be performed at Week 24. All safety and efficacy data will be summarized by 
treatment arms with descriptive statistics. BCVA and CST data will also be presented graphically. 
Due to the exploratory nature of this study, the sample size was not calculated for a statistical power. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
PROCEDURES IN CASE OF EMERGENCY ............................................................3 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............10 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16 
5. 
INTRODUCTION ......................................................................................................18 
6. 
OBJECTIVES .............................................................................................................20 
7. 
INVESTIGATIONAL PLAN .....................................................................................21 
7.1. 
Overall Study Design and Plan ...................................................................................21 
7.1.1. 
Selection of Concentrations in the Study ....................................................................22 
7.2. 
Number of Subjects ....................................................................................................23 
7.3. 
Treatment Assignment ................................................................................................23 
7.4. 
Dose Adjustment Criteria ...........................................................................................23 
7.4.1. 
Safety Criteria for 6 Subjects in Stage 1 .....................................................................23 
7.5. 
Study Procedures ........................................................................................................24 
7.5.1. 
Screening Phase ..........................................................................................................27 
7.5.1.1. 
Visit 0/Screening (Day -14 to Day -1) ........................................................................27 
7.5.2. 
Treatment/follow-up phase .........................................................................................28 
7.5.2.1. 
Visit 1 (Day 1) ............................................................................................................28 
7.5.2.2. 
Visit 2 (Day 3) ............................................................................................................32 
7.5.2.3. 
Visit 3 (Week 1 (D8±1)) .............................................................................................32 
7.5.2.4. 
Visit 4 (Week 4 (D29±3)) ...........................................................................................33 
7.5.2.5. 
Visit 5 (Week 8 (D57±3)) ...........................................................................................37 
7.5.2.6. 
Visit 6 (Week 12 (D85±4)) .........................................................................................38 
7.5.2.7. 
Visit 7 (Week 16 (D113±4)) .......................................................................................40 
7.5.2.8. 
Visit 8 (Week 20 (D141±4)) .......................................................................................42 
7.5.2.9. 
Visit 9 (Week 20 + 2 days) .........................................................................................44 
7.5.2.10. 
Visit 10 (Week 20 + 7 (±1) days) ...............................................................................44 
7.5.2.11. 
Visit 11 (Week 24 (D169±5)) .....................................................................................45 


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7.5.2.12. 
Visit 12 (Week 28 (D197±5)) .....................................................................................46 
7.5.3. 
Study Exit ...................................................................................................................47 
7.5.3.1. 
Visit 13/Exit (Week 32 (D225±5)) .............................................................................47 
7.5.4. 
Unscheduled Visits .....................................................................................................48 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................49 
8.1. 
Subject Inclusion Criteria ...........................................................................................49 
8.2. 
Subject Exclusion Criteria ..........................................................................................49 
8.3. 
Subject Withdrawal Criteria .......................................................................................52 
9. 
TREATMENT OF SUBJECTS ..................................................................................53 
9.1. 
Description of Study Drug ..........................................................................................53 
9.2. 
Concomitant Medications ...........................................................................................53 
9.2.1. 
Prohibited Medications or Treatments ........................................................................53 
9.2.2. 
Rescue Therapy ..........................................................................................................53 
9.3. 
Treatment Compliance ................................................................................................53 
9.4. 
Randomization and Masking ......................................................................................53 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................55 
10.1. 
Study Drug ..................................................................................................................55 
10.1.1. 
Investigational Drug ...................................................................................................55 
10.1.2. 
Concomitant drug .......................................................................................................55 
10.1.3. 
Study Drug Complaint Reporting ...............................................................................55 
10.1.4. 
Other Study Supplies ..................................................................................................55 
10.2. 
Study Drug Packaging and Labeling ..........................................................................55 
10.3. 
Study Drug Storage .....................................................................................................55 
10.4. 
Study Drug Preparation ..............................................................................................56 
10.5. 
Loading the Syringe ....................................................................................................56 
10.6. 
Eye Preparation ...........................................................................................................57 
10.7. 
Study Drug Administration.........................................................................................58 
10.8. 
Study Drug Accountability .........................................................................................59 
10.9. 
Study Drug Handling and Return ...............................................................................59 
11. 
ASSESSMENT OF EFFICACY ................................................................................60 
11.1. 
Best Corrected Visual Acuity (BCVA) ......................................................................60 
11.2. 
Central Subfield Thickness (CST), Macular Volume (MV), Central Retinal 
Lesion Thickness (CRLT) ..........................................................................................60 


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11.3. 
Lesion area ..................................................................................................................60 
12. 
ASSESSMENT OF SAFETY .....................................................................................61 
12.1. 
Adverse Events ...........................................................................................................61 
12.1.1. 
Definition of Adverse Events .....................................................................................61 
12.1.1.1. 
Assessment of Adverse Events ...................................................................................61 
12.1.1.2. 
Reporting Adverse Events ..........................................................................................62 
12.1.2. 
Serious Adverse Events ..............................................................................................63 
12.1.2.1. 
Reporting Serious Adverse Events .............................................................................64 
12.1.2.2. 
Expedited Reporting of Serious Adverse Events ........................................................64 
12.1.3. 
Events of Special Interest ...........................................................................................65 
12.1.4. 
Follow-up of Adverse Events .....................................................................................65 
12.1.5. 
Manual Back-Up Reporting Procedures .....................................................................66 
12.2. 
Safety Parameters .......................................................................................................66 
12.2.1. 
Physical Examination .................................................................................................66 
12.2.2. 
Electrocardiogram (EKG) ...........................................................................................66 
12.2.3. 
Vital Signs ..................................................................................................................66 
12.2.4. 
Best Corrected Visual Acuity .....................................................................................66 
12.2.5. 
Slit-lamp Biomicroscopy ............................................................................................67 
12.2.6. 
Intraocular Pressure ....................................................................................................67 
12.2.7. 
Indirect Ophthalmoscopy ............................................................................................67 
12.2.8. 
Urine Pregnancy Test .................................................................................................67 
12.2.9. 
Serum Pregnancy Test ................................................................................................67 
12.2.10. 
Serum Chemistry, Hematology and Urinalysis ..........................................................67 
12.2.11. 
Fundus Photography ...................................................................................................67 
12.2.12. 
Fluorescein Angiography ............................................................................................67 
12.2.13. 
Adverse Events ...........................................................................................................68 
13. 
PHARMACOKINETIC ASSESSMENTS .................................................................69 
13.1. 
Serum Sample Collection ...........................................................................................69 
13.2. 
Sample Analysis .........................................................................................................69 
14. 
OTHER ASSESSMENTS ..........................................................................................70 
14.1. 
Demographics and Baseline Characteristics ...............................................................70 
14.2. 
Immunogenicity ..........................................................................................................70 
15. 
OTHERS .....................................................................................................................71 


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15.1. 
Biomarker ...................................................................................................................71 
15.1.1. 
Serum Sample Collection ...........................................................................................71 
15.1.2. 
Aqueous Humor Sample Collection ...........................................................................71 
15.2. 
SS-OCT Angiography ................................................................................................71 
15.3. 
M-CHARTS™ .............................................................................................................71 
16. 
STATISTICAL METHODS .......................................................................................72 
16.1. 
Analysis Time Points ..................................................................................................72 
16.1.1. 
Primary Analysis ........................................................................................................72 
16.2. 
General Considerations ...............................................................................................72 
16.2.1. 
Sample Size ................................................................................................................72 
16.2.2. 
Statistical Hypotheses and Level of Significance .......................................................72 
16.2.3. 
Randomization ............................................................................................................73 
16.2.4. 
Study Eye ....................................................................................................................73 
16.3. 
Study Populations .......................................................................................................73 
16.4. 
Handling of Missing Values .......................................................................................73 
16.5. 
Demographics and Baseline Characteristics ...............................................................73 
16.6. 
Efficacy Analyses .......................................................................................................74 
16.6.1. 
Analysis of Primary Efficacy Endpoints ....................................................................74 
16.6.2. 
Analysis of Secondary Efficacy Endpoints ................................................................74 
16.7. 
Safety Analysis ...........................................................................................................74 
16.8. 
Pharmacokinetics Analysis .........................................................................................74 
16.9. 
Immunogenicity Analysis ...........................................................................................74 
16.10. 
Other Analysis ............................................................................................................75 
16.10.1. 
Biomarker Analysis ....................................................................................................75 
16.10.2. 
M-CHARTS™ .............................................................................................................75 
17. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................76 
17.1. 
Study Monitoring ........................................................................................................76 
17.2. 
Audits and Inspections ................................................................................................76 
17.3. 
Institutional Review Board .........................................................................................77 
18. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
18.1. 
Quality Control ...........................................................................................................78 
18.2. 
Quality Assurance .......................................................................................................78 
19. 
ETHICS ......................................................................................................................79 


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19.1. 
Ethics Review .............................................................................................................79 
19.2. 
Ethical Conduct of the Study ......................................................................................79 
19.3. 
Written Informed Consent ..........................................................................................79 
20. 
DATA HANDLING AND RECORDKEEPING .......................................................80 
20.1. 
Inspection of Records .................................................................................................80 
20.2. 
Retention of Records ..................................................................................................80 
20.2.1. 
Source Documents ......................................................................................................80 
20.2.2. 
Data Collection ...........................................................................................................81 
21. 
PUBLICATION POLICY ..........................................................................................82 
22. 
REFERENCES ...........................................................................................................83 
23. 
APPENDICES ............................................................................................................85 
23.1. 
Appendix A - Obligations of Investigators .................................................................85 
23.2. 
Appendix B - Elements of Informed Consent ............................................................87 
23.3. 
Appendix C - Declaration of Helsinki ........................................................................89 
23.4. 
Appendix D - Procedures for Examinations ...............................................................95 
23.4.1. 
Demographics/Eligibility, Medical/Surgical History and Concomitant 
Medication ..................................................................................................................95 
23.4.2. 
Physical Examination .................................................................................................95 
23.4.3. 
Vital Signs ..................................................................................................................95 
23.4.4. 
EKG ............................................................................................................................96 
23.4.5. 
Best Corrected Visual Acuity .....................................................................................96 
23.4.6. 
M-CHARTS™ ............................................................................................................96 
23.4.7. 
Slit-Lamp Biomicroscopy ...........................................................................................96 
23.4.8. 
Intraocular Pressure ....................................................................................................98 
23.4.9. 
Indirect Ophthalmoscopy ............................................................................................99 
23.4.10. 
Spectral Domain Optical Coherence Tomography ...................................................100 
23.4.11. 
Swept Source Optical Coherence Tomography Angiography..................................100 
23.4.12. 
Fundus Photography .................................................................................................100 
23.4.13. 
Fluorescein Angiography ..........................................................................................100 
23.4.14. 
Urine Pregnancy Test ...............................................................................................100 
23.4.15. 
Serum Pregnancy Test ..............................................................................................101 
23.4.16. 
Hematology, Chemistry and Urinalysis ....................................................................101 


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23.4.17. 
Procedures for Pharmacokinetic Serum Sample Collection, Storage and 
Shipment ...................................................................................................................102 
23.4.18. 
Procedure for Immunogenicity Serum Sample .........................................................102 
23.4.19. 
Procedures for Pharmacogenomics/genomics Blood Sample Collection, 
Storage and Shipment ...............................................................................................103 
23.4.20. 
Procedure for Biomarker Serum Sample ..................................................................103 
23.4.21. 
Procedure for Biomarker Aqueous Humor Sample ..................................................103 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................16 
Table 3:  
Schedule of Events .....................................................................................................25 
Table 4: 
DE-122 Dosing ...........................................................................................................55 
Table 5: 
Protocol Amendment 07 Summary of Changes .......................................................104 
 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................22 
Figure 2: 
0.3 mL fill in a 2 mL vial ............................................................................................57 
Figure 3: 
Alignment of the syringe (20 µL example) ................................................................57 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation/Term 
Definition 
ADA 
anti-drug antibody 
AE(s) 
adverse event(s) 
ALKs 
activin receptor-like kinases 
ALT 
alanine amino transferase 
AMD 
age-related macular degeneration 
AST 
aspartate amino transferase 
BCVA 
best corrected visual acuity 
BMP 
bone morphogenic protein 
BUN 
blood urea nitrogen 
CD105 
endoglin 
CNV 
choroidal neovascularization 
CST 
central subfield thickness 
CRLT 
central retinal lesion thickness 
DE-122 
a chimeric anti-CD105 (endoglin) IgG1 antibody consisting of human Cκ and 
Cγ1 constant regions with murine Vκ and VH regions for ophthalmology studies 
dL 
deciliter 
eCRF(s) 
electronic case report form(s) 
EDC  
electronic data capture 
EKG 
Electrocardiogram (= ECG) 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
ESI(s) 
event(s) of special interest 
FA 
Fluorescein Angiography 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
HIF-1-α 
hypoxia-inducible factor-1-α 
ICF 
informed consent form 


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Table 2: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation/Term 
Definition 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IOP 
intraocular pressure 
IRB 
institutional review board 
ITT 
intention-to-treat 
IUD 
intrauterine device 
IVT 
intravitreal 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
µL 
microliter 
mL 
milliliter 
mmHg 
millimeter of mercury 
MV 
macular volume 
SS-OCT 
Angiography 
swept source optical coherence tomography angiography 
PCV 
Polypoidal Choroidal Vasculopathy 
RAP 
Retinal Angiomatous Proliferation 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD-OCT 
spectral domain optical coherence tomography 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
TGF-β 
transforming growth factor-β 
TRC105 
a chimeric anti-CD105 (endoglin) IgG1 antibody consisting of human Cκ and 
Cγ1 constant regions with murine Vκ and VH regions for oncology studies 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 


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5. 
INTRODUCTION 
AMD is the leading cause of irreversible vision loss in developed countries.  AMD is 
characterized by extracellular matrix deposits, known as drusen, accumulating between the 
retinal pigment epithelium and Bruch’s membrane.  In exudative or wet AMD unwanted blood 
vessels grow into the macula which leads to hemorrhage and subretinal fluid.  In addition, retinal 
pigment epithelial detachment, retinal tears, fibrovascular scarring and vitreous hemorrhage may 
occur.  The aberrant growth of leaky vessels is the result of local inflammatory responses leading 
to disruption of the balance of cytokines that control angiogenesis (Lim et al., 2008). 
Angiogenesis is a complex and coordinated process of the growth and sprouting of new blood 
vessels from pre-existing vasculature.  Although several angiogenic factors have been identified, 
VEGF family proteins, their receptors and intracellular signaling molecules appear to be the key 
mediators of angiogenesis (Kane et al., 2008).  
Exciting advances have been made in understanding the pathogenesis of AMD in recent years.  
Since 2004, several anti-VEGF medications, such as ranibizumab (Lucentis®), pegaptanib 
(Macugen®) and aflibercept (Eylea®) have been approved by the FDA for patients with wet 
AMD.  Although Eylea®, which is the most recently approved anti-VEGF medication for wet 
AMD, showed more than 95% of the subjects maintained vision defined as losing < 15 ETDRS 
letters for 12 months, only 30% of subjects gained > 15 ETDRS letters.  Moreover, 
approximately 30% of subjects still showed cystic intraretinal edema and subretinal fluid after 
12 months of treatment (Heier et al., 2012).  Therefore, anti-VEGF treatment may not represent 
the only pathway towards anti-angiogenesis.  New or novel approaches to inhibit angiogenesis 
are needed to elicit further improvements in visual acuity, macular edema, and quality of life in 
wet AMD patients. 
Endoglin (also known as CD105) is a member of the TGF-β receptor family that is expressed by 
proliferating endothelial cells and is considered as one of the essential factors for angiogenesis.  
Normal levels of endoglin are needed for endothelial cell proliferation (Guo et al., 2004; 
Warrington et al., 2005).  Endoglin expression is increased by cellular hypoxia through the 
production of hypoxia-inducible factor-1-α (HIF-1-α), and endoglin protects hypoxic cells from 
apoptosis (Li et al., 2003). 
Endoglin acts to modulate signaling of multiple kinase receptor complexes of the TGF-β 
superfamily, including TGF-β receptors, bone morphogenic protein (BMP) receptors, activin 
receptor-like kinases (ALKs) and activin receptors (Barbara et al., 1999).  In the absence of 
endoglin, activation of TGF-β receptors results in phosphorylation of SMAD 2/3 proteins that 
inhibit endothelial cell growth.  However, activation of endoglin by BMP modulates SMAD 
protein phosphorylation, through phosphorylation of SMAD 1/5/8 (Nolan-Stevaux et al., 2012).  
The end result is release of the growth inhibitory effects of TGF-β receptor activation on 
endothelial cells (Lebrin et al., 2004).  Similarly, endoglin is required for proliferation of 
endothelium in response to BMP.  BMP-9 and BMP-10 bind to endoglin and phosphorylate 
SMAD 1/5/8 to signal endothelial cell proliferation (Park et al., 2008).  


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A recent study has demonstrated that endoglin is highly expressed in choroidal 
neovascularization (CNV) membranes surgically excised from wet AMD patients (Yasukawa et 
al., 2000). 
TRC105 is an anti-angiogenic mouse/human chimeric antibody against human endoglin 
developed by TRACON Pharmaceuticals, Inc.  TRC105 binds endoglin on proliferating 
endothelial cells to inhibit ligand binding by BMP, interrupting signal transduction, resulting in 
growth inhibition and apoptosis.  TRC105 also mediates antibody-dependent cell-mediated 
cytotoxicity (ADCC).  
A series of pharmacology studies in the TRACON oncology program have characterized 
TRC105 as a potent anti-angiogenic agent.  TRC105 alone inhibits VEGF- and bFGF-induced 
endothelial cell proliferation, suggesting that TRC105 can achieve similar therapeutic effects as 
anti-VEGF agents but through a different mechanism and specific or shared signaling pathway. 
It may be that TRC105 and anti-VEGF agents work synergistically to inhibit neovascularization 
and that TRC105 suppresses the escape mechanism underlying resistance to the long-term anti-
VEGF treatment, both of which are mediated by overexpression of endoglin.  
Several clinical trials for various cancer patients have been conducted by TRACON 
Pharmaceuticals, Inc.  As of December 06, 2015, over 438 patients had been treated with 
TRC105.  The majority of the patients have been Caucasian with ages ranging from 18 to 
87 years.  TRC105 has been well tolerated and exhibited a remarkably consistent adverse event 
profile, whether dosed as a single agent or dosed in combination with VEGF inhibitors or 
chemotherapy.  Activity of TRC105 in combination has been particularly noteworthy and 
represents the current development strategy. 
Santen is developing an ophthalmic formulation of TRC105, DE-122 injectable solution, suitable 
for intravitreal injection for the treatment of wet AMD. 
Santen has conducted a Phase I/II, open-label, dose-escalating, sequential cohort study assessing 
the safety, tolerability, immunogenicity, and bioactivity of a single IVT injection of DE-122 
injectable solution in the study eye of approximately twelve subjects with refractory wet AMD 
(Protocol 36-001).  Four dose levels of DE-122 were assessed in this Phase I/II study,  
0.5 mg/eye, 1.0 mg/eye, 2.0 mg/eye and 4.0 mg/eye.  The doses selected for use in this study 
were based on the results from non-clinical studies.  Additional information regarding the non-
clinical studies is provided in the Investigator’s Brochure. 
As of July 2017, all 12 subjects completed the study.  There were no reported SAEs.  No dose-
dependent events were reported and no new safety concerns were identified at all investigated 
doses. Ocular AEs were reported in 5 subjects (41.7%).  Most common AE was Subconjunctival 
haemorrhage (3 subjects, 25%) and all were considered to be due to the injection procedure.  
Santen believes that the Phase I/II study results mentioned above, in addition to the results of the 
non-clinical studies, supports the use of repeated IVT injections of the 2.0 mg and 4.0 mg 
concentrations of DE-122 in humans in the Phase II clinical trial (Protocol 36-002).  


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6. 
OBJECTIVES 
Primary Objective:  
 To assess the safety and efficacy of repeated IVT injections of DE-122 (2.0 mg/eye 
and 4.0 mg/eye) given in combination with Lucentis® in subjects with wet AMD 
compared with Lucentis® alone. 
Secondary Objective:  
 To evaluate the pharmacokinetics and immunogenicity of DE-122 following repeated 
IVT injections of DE-122 in subjects with wet AMD in serum samples.  
 To evaluate biomarker candidates of DE-122 following repeated IVT injections of 
DE-122 in subjects with wet AMD in both serum and aqueous humor samples.  
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a randomized, double masked and active controlled study assessing the safety and 
efficacy of repeated intravitreal injections of DE-122 (2.0 mg or 4.0 mg) in combination with 
Lucentis® compared to Lucentis® monotherapy in subjects with wet AMD.  Approximately 
seventy six (76) subjects with wet AMD will be randomly assigned to one of three treatment 
arms:  
Arm 1: Sham + Lucentis® 0.5 mg (N=17) 
Arm 2: DE-122, 2.0 mg + Lucentis® 0.5 mg (N=31) 
Arm 3: DE-122, 4.0 mg + Lucentis® 0.5 mg (N=28) 
Subjects will receive 6 monthly intravitreal injections of DE-122 (2.0 mg or 4.0 mg) or Sham in 
the study eye, in combination with Lucentis®.  
The first 6 subjects will be randomized to Arm 1 or Arm 2 in a 1:1 ratio in Stage 1.  The Safety 
Review Team will review the safety parameters of the 6 subjects in Stage 1 and determine if the 
safety and tolerability at Week 4 are acceptable.  If so, enrollment will be continued in a 
1:2:2 ratio in the three arms for the remaining approximately 70 subjects in Stage 2.   
To be eligible, subjects must have a diagnosis of active CNV secondary to AMD, with some 
subfoveal component (CNV, fluid, or hemorrhage under the fovea) with lesions ≤ 12 disc areas 
and ≤ 50% hemorrhage in the study eye. Subjects must be previously treated (i.e., At least 3 IVT 
injections of Anti-VEGF for treatment naïve eyes or eyes adequately maintained on continuous 
intravitreal anti-VEGF therapy).  Subjects with Polypoidal Choroidal Vasculopathy (PCV) 
lesions will be allowed, but Retinal Angiomatous Proliferation (RAP) lesions will be excluded 
from this study. 
Screening Visit SD-OCT images and Fluorescein Angiography from Investigator-identified 
eligible subjects will be sent to the central reading center to confirm eligibility based on AMD 
lesion attributes specified in the protocol.  To balance the randomization, subjects will be 
stratified by subgroups on the reading center’s assessment of lesion type, up to approximately 
one third (1/3) of the subjects in each arm should have PCV in Stage 2.  Subjects must satisfy all 
other inclusion and exclusion criteria. 
Subjects must have best corrected visual acuity (BCVA) of 65 to 25 ETDRS letters (equivalent 
to 20/50 to 20/320 Snellen) in the study eye. 
Eligible subjects who are enrolled in the study will be seen for up to 14 visits. 
The Primary Analysis is planned when all subjects complete the Week 24 visit.  The Follow-up 
Analysis is planned at Week 32 to assess the number of anti-VEGF injections used for Rescue in 
addition to efficacy and safety data. 
Subjects are eligible for rescue with any anti-VEGF IVT injection during the Week 24 and Week 
28 if one of the following rescue criteria is met:  
 


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Rescue Criteria: 
 BCVA decrease of ≥ 5 letters from the last visit score 
 CST increase from the last visit of ≥ 50µm 
 The discretion of investigator 
 
Figure 1: 
Study Schematic 
 
 
7.1.1. 
Selection of Concentrations in the Study 
In this clinical study, two dose levels of DE-122 (2.0 mg and 4.0 mg) are being tested in subjects 
with wet AMD.  The maximum amount of DE-122 that a subject can possibly receive is 24 mg 
over a 20 week period. Systemic exposure of DE-122 in this study given 6 times by IVT 
injection is anticipated to be significantly lower than the systemic exposure in over 500 cancer 


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subjects (most of whom received 10 mg/kg of TRC105 by weekly intravenous infusion).  
Therefore, no concerns regarding systemic toxicity are anticipated in this study. 
In pre-clinical studies, the highest tested DE-122 IVT dose of 5 mg/injection in the monkey eye 
would correlate to 10 mg/eye in human eyes due to the difference in volume, hence the 
difference in vitreous volume between human and monkey (2:1 ratio) conveys a margin of safety. 
In the mouse model of laser-induced CNV efficacy study, animals were given an IVT injection 
of DE-122 at 0.5, 1.5 and 5.0 μg/eye.  DE-122 inhibited CNV in a dose-dependent manner.  The 
highest effective dose was 5 μg/eye.  Considering the vitreous volume difference between human 
and mouse (~1000:1 ratio), a range of 0.5 to 5 mg/eye is considered a logical effective dose level 
for humans.   
In Phase I/II clinical study (Protocol 36-001), four dose levels of DE-122 (0.5 mg, 1.0 mg, 
2.0 mg and 4.0 mg) were tested in subjects with refractory wet AMD.  No dose-dependent events 
were reported and no new safety concerns were identified at all investigated doses. Most 
common AE was Subconjunctival haemorrhage (3 subjects, 25%) and all were considered to be 
due to the injection procedure.  
7.2. 
Number of Subjects 
Approximately 76 subjects (Arm 1: 17 subjects, Arm 2: 31 subjects, Arm 3: 28 subjects) with 
wet AMD will be enrolled at approximately 14 sites in the Philippines and the US.  The final 
number of subjects enrolled may be adjusted up to 80 based on drop-out rate. 
7.3. 
Treatment Assignment 
Two dose levels of DE-122 and Lucentis® will be administered by IVT injection in the study eye. 
 DE-122 injectable solution 2.0 mg (20 µL of 100 mg/mL)  
 DE-122 injectable solution 4.0 mg (40 µL of 100 mg/mL)  
 Ranibizumab (Lucentis®) 0.5 mg (50 µL of 10 mg/mL)  
7.4. 
Dose Adjustment Criteria 
The Safety Review Team will review safety parameters after the 6 subjects in Stage 1 have 
completed Week 4.  If the safety criteria for adjusting or stopping doses and the criteria for study 
termination are not met, the remaining subjects in three Arms will be enrolled in the study. 
7.4.1. 
Safety Criteria for 6 Subjects in Stage 1 
If more than one of the following events is observed by Week 4 visit in Stage 1, planned doses 
may be adjusted or stopped by the Safety Review Team. 
 Visual acuity loss from baseline defined as: 
 Loss of best corrected visual acuity (BCVA) of 30 or more letters not due to 
vitreous hemorrhage or injection procedure OR  
 Transition to no light perception (NLP) not due to injection procedure 
 Clinically significant inflammation defined as:  


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 > 3+ vitreous haze as measured by the National Eye Institute Grading Scheme 
(Nussenblatt et al., 1985) OR 
 Sterile endophthalmitis (including the presence of hypopyon) 
 Severe IOP elevation as measured by tonometry, on two separate exams, at least one 
day apart, excluding day of injection (despite pharmaceutical intervention): 
 > 35 mmHg OR 
 Increase of > 15 mmHg from baseline 
 Retinal non-perfusion of the study eye/vascular occlusion 
 Vasculitis  
 Retinitis  
 > 2+ disc edema 
 > 2 quadrants of retinal hemorrhage 
If there is insufficient safety information in either in the 6 subjects in Stage 1, the Safety Review 
Team may decide to treat additional subjects before continuing enrollment in the study. 
Criteria for Study Termination 
Unacceptable safety signals that prevent continuing to other subjects in all arms or result in 
stopping the study may include any of the following, if deemed to be related to DE-122 study 
drug (not DE-122 administration procedures): 
 Pattern of systemic AEs 
 Any of the following AEs in any 2 subjects in any cohort: 
 Retinal non-perfusion of the study eye/vascular occlusion 
 Vasculitis  
 Retinitis  
 > 2+ disc edema 
 > 2 quadrants of retinal hemorrhage 
7.5. 
Study Procedures 
All subjects must sign a written ICF before participating in any study-related activity, and the 
subject will be assigned a unique screening number.  Central randomization will occur at Visit 1 
(Day 1) after a subject meets all eligibility requirements at Screening.  Each randomized subject 
will be assigned a unique subject number.  If a subject is discontinued from the study for any 
reason, the subject number will remain in effect and will not be reused. 
A Schedule of Events can be found below and detailed procedures for examinations can be found 
in Section 23.4, Appendix D – Procedures for Examinations. 
 


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Table 3:  
Schedule of Events  
*Only the subjects who have consented under the protocol prior to Version 4.0 (Amendment 07) require the grayed-out 
examinations in the table.  
Visit Number 
Visit 0 
(SCRN) 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 Visit 12 Visit 13 
/Exit 
Visit Schedule 
(Time window; days) 
D-14 
to -1 
D1 
D3 
W1 
W4 
W8 
W12 
W16 
W20 
W20 
+ 2 days 
W20 
+ 7 days 
W24 
W28 
W32 
D3 
D8 
(±1) 
D29 
(±3) 
D57 
(±3) 
D85 
(±4) 
D113 
(±4) 
D141 
(±4) 
W20 
 + 2 days 
W20 
+ 7(±1) 
days 
D169 
(±5) 
D197 
(±5) 
D225 
(±5) 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history, 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EKG 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
BCVA (ETDRS) 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
M-CHARTS™ 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Slit-lamp biomicroscopyb 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Intraocular pressure (IOP)c 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Indirect ophthalmoscopyb 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SD-OCT 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SS-OCT angiographyd 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Fundus photography 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
Fluorescein angiography 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
Urine pregnancy teste 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisf 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
Serum pregnancy teste 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hematology, chemistry 
serum samplef 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
PK serum sampleg 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 


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Table 3:  
Schedule of Events (Continued) 
Visit Number 
Visit 0 
(SCRN) 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 Visit 12 Visit 13 
/Exit 
Visit Schedule 
(Time window; days) 
D-14 
to -1 
D1 
D3 
W1 
W4 
W8 
W12 
W16 
W20 
W20 
+ 2 days 
W20 
+ 7 days 
W24 
W28 
W32 
D3 
D8 
(±1) 
D29 
(±3) 
D57 
(±3) 
D85 
(±4) 
D113 
(±4) 
D141 
(±4) 
W20 
 + 2 days 
W20 
+ 7(±1) 
days 
D169 
(±5) 
D197 
(±5) 
D225 
(±5) 
Biomarker serum sampleg 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
Immunogenicity serum 
sample 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacogenomics/genomics 
blood samplea, h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker aqueous humor 
samplea 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
Lucentis® IVT injectioni 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
DE-122 or Sham IVT 
Injectioni 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse event 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SCRN= Screening; D=Day; W=Week; PK=Pharmacokinetic 
a. Informed Consent - obtain prior to conducting any study-related activities. Separate informed consent is required to participate in the ancillary Biomarker aqueous humor sample 
collection and Pharmacogenomics/genomics blood sample collection. 
b. On days when either Lucentis®/DE-122 or Lucentis®/Sham IVT injections are administered, slit lamp biomicroscopy and indirect ophthalmoscopy will be performed prior to 
injection and within 30 minutes after DE-122 or Sham injection. This will be also applied for the post IVT injection of Rescue treatment. 
c. On days when either Lucentis®/DE-122or Lucentis® /Sham IVT injections are administered, IOP will be performed before and after Lucentis® IVT injection. In addition, after 
DE-122 or Sham injection, IOP will be performed again. This will be also applied for the post injection of Rescue treatment. 
d. Selected sites will conduct. 
e. Serum and urine pregnancy tests are to be performed on all females of child-bearing potential. 
f. Subjects should fast for a minimum of 8 hours prior to urine specimen and blood draw for serum chemistry tests. 
g. At baseline (Day 1, Visit 1), serum sample for DE-122 concentration (if applicable) and biomarker will be collected  
1) 
prior to the Lucentis® injection;  
2) 
post DE-122 or Sham injection: 3 hours, 48 hours, 1 week and 4 weeks (prior to the Lucentis® injection).  
At Week 20, serum sample for DE-122 concentration (if applicable) and biomarker will also be collected  
1) 
prior to the Lucentis® injection;  
2) 
post DE-122 or Sham injection: 3 hours, 48 hours, 1 week and 4 weeks. 
h. Pharmacogenomics/genomics blood sample can be drawn once at Day 1 or any visit after Visit 1(Day 1) during the study.  
i. Lucentis® will be administered first, and then DE-122 or Sham will be injected. Rescue treatment with any anti-VEGF IVT injection can be performed during the Week 24 and 
Week 28 visits. 


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7.5.1. 
Screening Phase 
7.5.1.1. 
Visit 0/Screening (Day -14 to Day -1) 
 Explain the purpose and details of the study to the subject and obtain written 
informed consent prior to the subject’s participation in any study related activity. 
 Obtain separate informed consent for participant in the ancillary Biomarker aqueous 
humor sample collection and Pharmacogenomics/genomics blood sample collection.  
Ensure that the subject understands that if they do not wish to provide aqueous humor 
sample and blood sample for the Biomarker research study and the 
Pharmacogenomics/genomics study that it will not affect the subject’s enrollment in 
the trial. 
 Obtain subject’s demographic information, medical, surgical and medication history. 
 Perform the following assessments: (all ophthalmic procedures to be performed OU).  
The procedures of each assessment are described in Section 23.4, Appendix D. 
 Physical examination (if not performed by external internist) 
 Vital signs 
 EKG 
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 
 IOP  
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Fundus photography 
 Fluorescein angiography 
 Review the inclusion and exclusion criteria.  Do not continue screening any subject 
who does not meet the screening eligibility requirements. 
 If the subject continues to be eligible for the study, collect more than 8 hours fasting 
urine and blood specimen for the following examinations:  
 Urinalysis 
 Serum pregnancy test (for females of child-bearing potential) 
 Hematology, chemistry serum sample 
 If subject has not been fasting, schedule the subject as soon as possible for fasting 
blood draw and urine specimen. 


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 Upload collected images (Fluorescein angiography, Fundus photography and  
SD-OCT) of both eyes to the central reading center for confirmation of subject 
eligibility. 
 Schedule the subject to return for Visit 1 (Day 1). 
7.5.2. 
Treatment/follow-up phase 
7.5.2.1. 
Visit 1 (Day 1) 
 Review results of the following procedures performed at Screening (Day -14 to  
Day -1) to determine continuation in the study: 
 Physical examination 
 EKG 
 Urinalysis 
 Blood chemistry and hematology tests 
 Serum pregnancy test (for females of child-bearing potential) 
 Eligibility determination by the central reading center 
 If the subject continues to be eligible for the study, the following assessments must be 
performed prior to administration of study drugs to confirm eligibility and obtain 
baseline characteristics: (all ophthalmic procedures to be performed OU) 
 Query for AEs 
 Update medical history and medications 
 Vital signs  
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 
 IOP 
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 If the subject continues to be eligible for the study, collect urine and blood specimen 
for the following examinations:  
 Urine pregnancy test (for females of child-bearing potential) 
 PK serum sample (for only the subjects who have consented under the 
protocol prior to Version 4.0) 
 Immunogenicity serum sample 


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 Biomarker serum sample 
 If the subject has consented to the Pharmacogenomics/genomics study, collect blood 
sample for the Pharmacogenomics/genomics study.  Blood collection for the 
Pharmacogenomics/genomics study can be alternatively collected once at any visit 
during the study after Visit 1(Day 1). 
 Perform final review of inclusion/exclusion criteria.  If the subject has met all 
eligibility criteria, including confirmation of the lesion eligibility by the central 
reading center (which will also confirm lesion type), determine the study eye.  The 
subject is then randomized, via IWRS. 
 After the subject has been randomized to a treatment Arm, Lucentis® will be 
administered as per drug labeling.  
 If the subject has consented to the Biomarker aqueous humor sample collection, 
collect the aqueous humor sample before Lucentis® administration.  
 Perform Lucentis® administration as per drug labeling, and then perform the 
following procedures after Lucentis® administration. 
 IOP will be measured at 40 (±10) minutes post-injection. 
 
If post-injection IOP is ≤ 21 mmHg AND increased < 10 mmHg from  
pre-injection IOP and there is no concern regarding retinal artery perfusion, 
DE-122 or Sham IVT will be administered.  
 
If post-injection IOP is > 21 mmHg OR increased ≥ 10 mmHg from  
pre-injection IOP, IOP measurement will be repeated at 60 (±10) minutes 
post-injection. 
 IOP will be measured at 60 (±10) minutes post-injection, if applicable.  
 
If post-injection IOP at 60 (±10) minutes is ≤ 21 mmHg AND increased < 
10 mmHg from pre-injection IOP and there is no concern regarding retinal 
artery perfusion, DE-122 or Sham IVT will be administered.  
 
If post-injection IOP at 60 (±10) minutes is > 21 mmHg, however the IOP is 
< 30 mmHg AND increased < 10 mmHg from pre-injection IOP and there is 
no concern regarding retinal artery perfusion, DE-122 or Sham IVT will be 
administered per the Clinical Investigator’s discretion. 
If the Clinical Investigator determine that DE-122 or Sham IVT will Not be 
administered, the subject will be treated according to the Clinical 
Investigator’s discretion. In addition, the Clinical Investigator has the 
discretion on whether to have the subject continue or exit the study. 
 
If post-injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR increased  
≥ 10 mmHg from pre-injection IOP, DE-122 or Sham IVT will not be 
administered.  The subject should be prescribed a topical IOP-lowering 
medication until he or she returns for follow-up per the Clinical Investigator’s 
discretion (an unscheduled visit may apply), and the event will be reported as 


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an AE.  In addition, the Clinical Investigator has the discretion on whether to 
have the subject continue or exit the study. 
 Perform DE-122 or Sham administration, and then perform the following 
procedures after DE-122 or Sham administration. 
 After DE-122 or Sham administration, the following will be performed: (all 
ophthalmic procedures to be performed OU) 
 Within 30 minutes following DE-122 or Sham IVT  
 
Slit-lamp biomicroscopy 
 
Indirect ophthalmoscopy 
 IOP measurement 40 (±10) minutes following DE-122 or Sham IVT injection 
 
If post-DE-122 or Sham injection IOP is > 21 mmHg OR increased ≥ 
10 mmHg from pre-Lucentis® injection, IOP measurement will be repeated at 
60 (±10) minutes post-injection.   
 IOP will be measured at 60 (±10) minutes following DE-122 or Sham IVT 
injection, if applicable.  
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR 
increased ≥ 10 mmHg from pre-Lucentis® injection IOP, the subject should be 
prescribed a topical IOP-lowering medication, and the IOP elevation will be 
reported as an AE.  Per the Clinical Investigator’s discretion, the subject can 
return for follow-up (an unscheduled visit may apply). 
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is > 21 mmHg 
AND < 30 mmHg, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 AE assessments must be performed after each IVT injection. 
 Collect blood specimen for the following examinations at 3 hrs (±10 mins) post  
DE-122 or Sham injection.  If DE-122 or Sham IVT injection is skipped, the blood 
sampling will be done at 3 hrs (±10 mins) post Lucentis® administration. 
 PK serum sample (for only the subjects who have consented under the 
protocol prior to Version 4.0)  
 Biomarker serum sample  
 Upload collected images (SD-OCT) of the study eye to the central reading center. 
 Schedule the subject to return for Visit 2 (Day 3) or Visit 3 (Week 1 (D8±1)). 
 
 


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7.5.2.2. 
Visit 2 (Day 3) 
For only the subjects who have consented under the protocol prior to Version 4.0 
 Perform the following assessments: 
 Query for AEs 
 Update medical history and medications 
 Collect blood specimen for the following examinations at 48 (±2) hrs post DE-122 or 
Sham injection. If DE-122 or Sham IVT injection was skipped at Visit 1, blood 
specimen will be collected at 48 (±2) hrs post Lucentis® IVT injection. 
 PK serum sample 
 Biomarker serum sample 
 Schedule the subject to return for Visit 3 (Week 1 (D8±1)).  
7.5.2.3. 
Visit 3 (Week 1 (D8±1))  
 Perform the following assessments: (all ophthalmic procedures to be performed OU) 
 Query for AEs 
 Update medical history and medications 
 Vital signs 
 EKG 
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 
 IOP  
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Collect blood specimen for the following examinations:  
 PK serum sample (for only the subjects who have consented under the 
protocol prior to Version 4.0) 
 Biomarker serum sample 
 Upload collected images (SD-OCT) of the study eye to the central reading center. 
 Schedule the subject to return for Visit 4 (Week 4 (D29±3)).  Remind subjects to fast 
8 hours prior to next visit. 
 


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7.5.2.4. 
Visit 4 (Week 4 (D29±3))  
 Perform the following assessments: (all ophthalmic procedures to be performed OU) 
 Query for AEs 
 Update medical history and medications 
 Vital signs  
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 
 IOP 
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Fundus photography  
 Fluorescein angiography 
 Collect urine and blood specimen for the following examinations:  
 Urinalysis  
 Hematology, chemistry serum sample  
 PK serum sample (for only the subjects who have consented under the 
protocol prior to Version 4.0)  
 Biomarker serum sample 
 Perform Lucentis® administration as per drug labeling, and then perform the 
following procedures after Lucentis® administration. 
 IOP will be measured at 40 (±10) minutes post-injection. 
 
If post-injection IOP is ≤ 21 mmHg AND increased < 10 mmHg from  
pre-injection IOP and there is no concern regarding retinal artery perfusion, 
DE-122 or Sham IVT will be administered.  
 
If post-injection IOP is > 21 mmHg OR increased ≥ 10 mmHg from  
pre-injection IOP, IOP measurement will be repeated at 60 (±10) minutes 
post-injection. 
 IOP will be measured at 60 (±10) minutes post-injection, if applicable.  
 
If post-injection IOP at 60 (±10) minutes is ≤ 21 mmHg AND increased < 
10 mmHg from pre-injection IOP and there is no concern regarding retinal 
artery perfusion, DE-122 or Sham IVT will be administered.  


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 
If post-injection IOP at 60 (±10) minutes is > 21 mmHg, however the IOP is 
< 30 mmHg AND increased < 10 mmHg from pre-injection IOP and there is 
no concern regarding retinal artery perfusion, DE-122 or Sham IVT will be 
administered per the Clinical Investigator’s discretion. 
If the Clinical Investigator determine that DE-122 or Sham IVT will Not be 
administered, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 
If post-injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR increased ≥ 
10 mmHg from pre-injection IOP, DE-122 or Sham IVT should not be 
administered.  The subject should be prescribed a topical IOP-lowering 
medication until he or she returns for follow-up per the Clinical Investigator’s 
discretion (an unscheduled visit may apply), and the event will be reported as 
an AE.  
 Perform DE-122 or Sham administration, and then perform the following 
procedures after DE-122 or Sham administration. 
 After DE-122 or Sham administration, the following will be performed: (all 
ophthalmic procedures to be performed OU). 
 Within 30 minutes following DE-122 or Sham IVT  
 
Slit-lamp biomicroscopy 
 
Indirect ophthalmoscopy 
 IOP measurement 40 (±10) minutes following DE-122 or Sham IVT injection 
 
If post-DE-122 or Sham injection IOP is > 21 mmHg OR increased ≥ 
10 mmHg from pre-Lucentis® injection, IOP measurement will be repeated at 
60 (±10) minutes post-injection. 
 IOP will be measured at 60 (±10) minutes following DE-122 or Sham IVT 
injection, if applicable.  
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR 
increased ≥ 10 mmHg from pre-Lucentis® injection IOP, the subject should be 
prescribed a topical IOP-lowering medication, and the IOP elevation will be 
reported as an AE.  Per the Clinical Investigator’s discretion, the subject can 
return for follow-up (an unscheduled visit may apply). 
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is > 21 mmHg 
AND < 30 mmHg, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 AE assessments must be performed after each IVT injection. 
 If the subject has consented to Biomarker aqueous humor sample collection, collect 
the aqueous humor sample after DE-122 or Sham IVT.  If DE-122 or Sham IVT is 
not administered, the aqueous humor sample should be collected with no time 
restriction. 


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 If subject has not been fasting, schedule the subject as soon as possible for fasting 
blood draw and urine specimen. 
 Upload collected images (Fluorescein angiography, Fundus photography and  
SD-OCT) of the study eye to the central reading center. 
 Schedule the subject to return for Visit 5 (Week 8 (D57±3)). 
 


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7.5.2.5. 
Visit 5 (Week 8 (D57±3)) 
 Perform the following assessments: (all ophthalmic procedures to be performed OU) 
 Query for AEs 
 Update medical history and medications 
 Vital signs  
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 
 IOP 
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Perform Lucentis® administration as per drug labeling, and then perform the 
following procedures after Lucentis® administration. 
 IOP will be measured at 40 (±10) minutes post-injection. 
 
If post-injection IOP is ≤ 21 mmHg AND increased < 10 mmHg from  
pre-injection IOP and there is no concern regarding retinal artery perfusion, 
DE-122 or Sham IVT will be administered.  
 
If post-injection IOP is > 21 mmHg OR increased ≥ 10 mmHg from  
pre-injection IOP, IOP measurement will be repeated at 60 (±10) minutes 
post-injection. 
 IOP will be measured at 60 (±10) minutes post-injection, if applicable.  
 
If post-injection IOP at 60 (±10) minutes is ≤ 21 mmHg AND increased < 
10 mmHg from pre-injection IOP and there is no concern regarding retinal 
artery perfusion, DE-122 or Sham IVT will be administered.  
 
If post-injection IOP at 60 (±10) minutes is > 21 mmHg, however the IOP is 
< 30 mmHg AND increased < 10 mmHg from pre-injection IOP and there is 
no concern regarding retinal artery perfusion, DE-122 or Sham IVT will be 
administered per the Clinical Investigator’s discretion. 
If the Clinical Investigator determine that DE-122 or Sham IVT will Not be 
administered, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 
If post-injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR increased ≥ 
10 mmHg from pre-injection IOP, DE-122 or Sham IVT should not be 
administered.  The subject should be prescribed a topical IOP-lowering 
medication until he or she returns for follow-up per the Clinical Investigator’s 


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discretion (an unscheduled visit may apply), and the event will be reported as 
an AE.  
 Perform DE-122 or Sham administration, and then perform the following 
procedures after DE-122 or Sham administration. 
 After DE-122 or Sham administration, the following will be performed: (all 
ophthalmic procedures to be performed OU) 
 Within 30 minutes following DE-122 or Sham IVT  
 
Slit-lamp biomicroscopy 
 
Indirect ophthalmoscopy 
 IOP measurement 40 (±10) minutes following DE-122 or Sham IVT injection 
 
If post-DE-122 or Sham injection IOP is > 21 mmHg OR increased ≥ 
10 mmHg from pre-Lucentis® injection, IOP measurement will be repeated at 
60 (±10) minutes post-injection. 
 IOP will be measured at 60 (±10) minutes following DE-122 or Sham IVT 
injection, if applicable.  
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR 
increased ≥ 10 mmHg from pre-Lucentis® injection IOP, the subject should be 
prescribed a topical IOP-lowering medication, and the IOP elevation will be 
reported as an AE. Per the Clinical Investigator’s discretion, the subject can 
return for follow-up (an unscheduled visit may apply). 
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is > 21 mmHg 
AND < 30 mmHg, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 AE assessments must be performed after each IVT injection. 
 Upload collected images (SD-OCT) of the study eye to the central reading center. 
 Schedule the subject to return for Visit 6 (Week 12 (D85±4)).  Remind subjects to 
fast 8 hours prior to next visit. 
7.5.2.6. 
Visit 6 (Week 12 (D85±4))  
 Perform the following assessments: (all ophthalmic procedures to be performed OU) 
 Query for AEs 
 Update medical history and medications 
 Vital signs  
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 


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 IOP 
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Fundus photography  
 Fluorescein angiography 
 Collect urine and blood specimen for the following examinations:  
 Urinalysis 
 Hematology, chemistry serum sample 
 Perform Lucentis® administration as per drug labeling, and then perform the 
following procedures after Lucentis® administration. 
 IOP will be measured at 40 (±10) minutes post-injection. 
 
If post-injection IOP is ≤ 21 mmHg AND increased < 10 mmHg from  
pre-injection IOP and there is no concern regarding retinal artery perfusion, 
DE-122 or Sham IVT will be administered.  
 
If post-injection IOP is > 21 mmHg OR increased ≥ 10 mmHg from  
pre-injection IOP, IOP measurement will be repeated at 60 (±10) minutes 
post-injection. 
 IOP will be measured at 60 (±10) minutes post-injection, if applicable.  
 
If post-injection IOP at 60 (±10) minutes is ≤ 21 mmHg AND increased < 
10 mmHg from pre-injection IOP and there is no concern regarding retinal 
artery perfusion, DE-122 or Sham IVT will be administered.  
 
If post-injection IOP at 60 (±10) minutes is > 21 mmHg, however the IOP is 
< 30 mmHg AND increased < 10 mmHg from pre-injection IOP and there is 
no concern regarding retinal artery perfusion, DE-122 or Sham IVT will be 
administered per the Clinical Investigator’s discretion. 
If the Clinical Investigator determine that DE-122 or Sham IVT will Not be 
administered, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 
If post-injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR increased ≥ 
10 mmHg from pre-injection IOP, DE-122 or Sham IVT should not be 
administered.  The subject should be prescribed a topical IOP-lowering 
medication until he or she returns for follow-up per the Clinical Investigator’s 
discretion (an unscheduled visit may apply), and the event will be reported as 
an AE.  
 Perform DE-122 or Sham administration, and then perform the following 
procedures after DE-122 or Sham administration. 


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 After DE-122 or Sham administration, the following will be performed: (all 
ophthalmic procedures to be performed OU). 
 Within 30 minutes following DE-122 or Sham IVT  
 
Slit-lamp biomicroscopy 
 
Indirect ophthalmoscopy 
 IOP measurement 40 (±10) minutes following DE-122 or Sham IVT injection 
 
If post-DE-122 or Sham injection IOP is > 21 mmHg OR increased ≥ 
10 mmHg from pre-Lucentis® injection, IOP measurement will be repeated at 
60 (±10) minutes post-injection. 
 IOP will be measured at 60 (±10) minutes following DE-122 or Sham IVT 
injection, if applicable.  
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR 
increased ≥ 10 mmHg from pre-Lucentis® injection IOP, the subject should be 
prescribed a topical IOP-lowering medication, and the IOP elevation will be 
reported as an AE. Per the Clinical Investigator’s discretion, the subject can 
return for follow-up (an unscheduled visit may apply). 
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is > 21 mmHg 
AND < 30 mmHg, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 AE assessments must be performed after each IVT injection. 
 If subject has not been fasting, schedule the subject as soon as possible for fasting 
blood draw and urine specimen. 
 Upload collected images (Fluorescein angiography, Fundus photography and  
SD-OCT) of the study eye to the central reading center. 
 Schedule the subject to return for Visit 7 (Week 16 (D113±4)).  
7.5.2.7. 
Visit 7 (Week 16 (D113±4)) 
 Perform the following assessments: (all ophthalmic procedures to be performed OU) 
 Query for AEs 
 Update medical history and medications 
 Vital signs  
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 
 IOP 
 Indirect ophthalmoscopy 


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 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Perform Lucentis® administration as per drug labeling, and then perform the 
following procedures after Lucentis® administration. 
 IOP will be measured at 40 (±10) minutes post-injection. 
 
If post-injection IOP is ≤ 21 mmHg AND increased < 10 mmHg from  
pre-injection IOP and there is no concern regarding retinal artery perfusion, 
DE-122 or Sham IVT will be administered. 
 
If post-injection IOP is > 21 mmHg OR increased ≥ 10 mmHg from  
pre-injection IOP, IOP measurement will be repeated at 60 (±10) minutes 
post-injection. 
 IOP will be measured at 60 (±10) minutes post-injection, if applicable.  
 
If post-injection IOP at 60 (±10) minutes is ≤ 21 mmHg AND increased < 
10 mmHg from pre-injection IOP and there is no concern regarding retinal 
artery perfusion, DE-122 or Sham IVT will be administered.  
 
If post-injection IOP at 60 (±10) minutes is > 21 mmHg, however the IOP is 
< 30 mmHg AND increased < 10 mmHg from pre-injection IOP and there is 
no concern regarding retinal artery perfusion, DE-122 or Sham IVT will be 
administered per the Clinical Investigator’s discretion. 
If the Clinical Investigator determine that DE-122 or Sham IVT will Not be 
administered, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 
If post-injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR increased ≥ 
10 mmHg from pre-injection IOP, DE-122 or Sham IVT should not be 
administered.  The subject should be prescribed a topical IOP-lowering 
medication until he or she returns for follow-up per the Clinical Investigator’s 
discretion (an unscheduled visit may apply), and the event will be reported as 
an AE.  
 Perform DE-122 or Sham administration, and then perform the following 
procedures after DE-122 or Sham administration. 
 After DE-122 or Sham administration, the following will be performed: (all 
ophthalmic procedures to be performed OU). 
 Within 30 minutes following DE-122 or Sham IVT  
 
Slit-lamp biomicroscopy 
 
Indirect ophthalmoscopy 
 IOP measurement 40 (±10) minutes following DE-122 or Sham IVT injection 
 
If post-DE-122 or Sham injection IOP is > 21 mmHg OR increased ≥ 
10 mmHg from pre-Lucentis® injection, IOP measurement will be repeated at 
60 (±10) minutes post-injection. 


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 IOP will be measured at 60 (±10) minutes following DE-122 or Sham IVT 
injection, if applicable.  
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR 
increased ≥ 10 mmHg from pre-Lucentis® injection IOP, the subject should be 
prescribed a topical IOP-lowering medication, and the IOP elevation will be 
reported as an AE.  Per the Clinical Investigator’s discretion, the subject can 
return for follow-up (an unscheduled visit may apply). 
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is > 21 mmHg 
AND < 30 mmHg, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 AE assessments must be performed after each IVT injection. 
 Upload collected images (SD-OCT) of the study eye to the central reading center. 
 Schedule the subject to return for Visit 8 (Week 20 (D141±4)). 
7.5.2.8. 
Visit 8 (Week 20 (D141±4)) 
 Perform the following assessments: (all ophthalmic procedures to be performed OU) 
 Query for AEs 
 Update medical history and medications 
 Vital signs  
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 
 IOP 
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Collect blood specimen for the following examinations:  
 PK serum sample (for only the subjects who have consented under the 
protocol prior to Version 4.0)  
 Biomarker serum sample 
 Perform Lucentis® administration as per drug labeling, and then perform the 
following procedures after Lucentis® administration. 
 IOP will be measured at 40 (±10) minutes post-injection. 
 
If post-injection IOP is ≤ 21 mmHg AND increased < 10 mmHg from  
pre-injection IOP and there is no concern regarding retinal artery perfusion, 
DE-122 or Sham IVT will be administered.  


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 
If post-injection IOP is > 21 mmHg OR increased ≥ 10 mmHg from  
pre-injection IOP, IOP measurement will be repeated at 60 (±10) minutes 
post-injection. 
 IOP will be measured at 60 (±10) minutes post-injection, if applicable.  
 
If post-injection IOP at 60 (±10) minutes is ≤ 21 mmHg AND increased < 
10 mmHg from pre-injection IOP and there is no concern regarding retinal 
artery perfusion, DE-122 or Sham IVT will be administered.  
 
If post-injection IOP at 60 (±10) minutes is > 21 mmHg, however the IOP is 
< 30 mmHg AND increased < 10 mmHg from pre-injection IOP and there is 
no concern regarding retinal artery perfusion, DE-122 or Sham IVT will be 
administered per the Clinical Investigator’s discretion. 
If the Clinical Investigator determine that DE-122 or Sham IVT will Not be 
administered, the subject will be treated according to the Clinical 
Investigator’s discretion. The DE-122 or Sham IVT injection can be 
performed at the follow up visit (within the time window of Visit 8) per the 
Clinical Investigator’s discretion.  
 
If post-injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR increased ≥ 
10 mmHg from pre-injection IOP, DE-122 or Sham IVT should not be 
administered at the day of the visit. Per the Clinical Investigator and 
Medical Monitor, the DE-122 or Sham IVT injection can be performed if IOP 
at the follow up visit (within the time window of Visit 8) is < 30 mmHg AND 
increased < 10 mmHg from pre-injection IOP and there is no concern 
regarding retinal artery perfusion. 
If DE-122 or Sham IVT injection will not be performed, the subject should be 
prescribed a topical IOP-lowering medication until he or she returns for 
follow-up per the Clinical Investigator’s discretion (an unscheduled visit may 
apply), and the event will be reported as an AE.  
 Perform DE-122 or Sham administration, and then perform the following 
procedures after DE-122 or Sham administration. 
 After DE-122 or Sham administration, the following will be performed: (all 
ophthalmic procedures to be performed OU) 
 Within 30 minutes following DE-122 or Sham IVT  
 
Slit-lamp biomicroscopy 
 
Indirect ophthalmoscopy 
 IOP measurement 40 (±10) minutes following DE-122 or Sham IVT injection 
 
If post-DE-122 or Sham injection IOP is > 21 mmHg OR increased ≥ 
10 mmHg from pre-Lucentis® injection, IOP measurement will be repeated at 
60 (±10) minutes post-injection. 
 IOP will be measured at 60 (±10) minutes following DE-122 or Sham IVT 
injection, if applicable. 


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 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR 
increased ≥ 10 mmHg from pre-Lucentis® injection IOP, the subject should be 
prescribed a topical IOP-lowering medication, and the IOP elevation will be 
reported as an AE.  Per the Clinical Investigator’s discretion, the subject can 
return for follow-up (an unscheduled visit may apply). 
 
If post-DE-122 or Sham injection IOP at 60 (±10) minutes is > 21 mmHg 
AND < 30 mmHg, the subject will be treated according to the Clinical 
Investigator’s discretion. 
 AE assessments must be performed after each IVT injection. 
 If the subject has consented to Biomarker aqueous humor sample collection, collect 
the aqueous humor sample after DE-122 or Sham IVT. 
 Collect blood specimen for the following examinations at 3 hrs (±10 mins) post 
DE-122 or Sham injection.  If DE-122 or Sham IVT injection is skipped, the blood 
sampling will be done at 3 hrs (±10 mins) post Lucentis® administration: 
 PK serum sample (for only the subjects who have consented under the 
protocol prior to Version 4.0)  
 Biomarker serum sample 
 Upload collected images (SD-OCT) of the study eye to the central reading center. 
 Schedule the subject to return for Visit 9 (Week 20 + 2 days) or Visit 10 (Week 20  
+ 7 (±1) days).  
7.5.2.9. 
Visit 9 (Week 20 + 2 days) 
For only the subjects who have consented under the protocol prior to Version 4.0 
 Perform the following assessments: 
 Query for AEs 
 Update medical history and medications 
 Collect blood specimen for the following examinations at 48 (±2) hrs post DE-122 or 
Sham injection.  If DE-122 or Sham IVT injection was skipped at Visit 8, blood 
specimen will be collected at 48 (±2) hrs post Lucentis® IVT injection.  
 PK serum sample 
 Biomarker serum sample 
 Schedule the subject to return for Visit 10 (Week 20 + 7 (±1) days). 
7.5.2.10. Visit 10 (Week 20 + 7 (±1) days) 
 Perform the following assessments: 
 Query for AEs 
 EKG 


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 Update medical history and medications 
 Collect blood specimen for the following examinations: 
 PK serum sample (for only the subjects who have consented under the 
protocol prior to Version 4.0)  
 Biomarker serum sample 
 Schedule the subject to return for Visit 11 (Week 24 (D169±5)).  Remind subjects to 
fast 8 hours prior to next visit. 
7.5.2.11. Visit 11 (Week 24 (D169±5)) 
 Perform the following assessments: (all ophthalmic procedures to be performed OU) 
 Query for AEs 
 Update medical history and medications 
 Physical examination (if not performed by external internist) 
 Vital signs  
 EKG 
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 
 IOP 
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Fundus photography  
 Fluorescein angiography 
 Collect urine and blood specimen for the following examinations:  
 Urinalysis 
 Serum pregnancy test (for females of child-bearing potential)  
 Hematology, chemistry serum sample 
 PK serum sample (for only the subjects who have consented under the 
protocol prior to Version 4.0)  
 Immunogenicity serum sample 
 Biomarker serum sample 


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 Rescue therapy with any anti-VEGF medication may be allowed if the following 
rescue criteria are met:  
 BCVA decrease of ≥ 5 letters from the last visit score OR 
 CST increase from the last visit of ≥ 50µm OR 
 The discretion of investigator 
 If rescue is performed, the following assessments must be performed after the 
administration of Rescue treatment: (all ophthalmic procedures to be performed OU) 
 Within 30 minutes following Rescue treatment 
 
Slit-lamp biomicroscopy 
 
Indirect ophthalmoscopy 
 IOP:  40 (±10) minutes following injection 
 
If post-injection IOP is > 21 mmHg OR increased ≥ 10 mmHg from  
pre-injection IOP, IOP measurement will be repeated at 60 (±10) minutes 
post-injection. 
 IOP will be measured at 60 (±10) minutes post-injection, if applicable.   
 
If post-injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR increased ≥ 
10 mmHg from pre-injection IOP, the subject should be prescribed a topical 
IOP-lowering medication, and the IOP elevation will be reported as an AE.  
Per the Clinical Investigator’s discretion, the subject can return for follow-up 
(an unscheduled visit may apply). 
 
If post-injection IOP at 60 (±10) minutes is > 21 mmHg AND < 30 mmHg, 
the subject will be treated according to the Clinical Investigator’s discretion. 
 AE assessments must be performed after Rescue treatment, if applicable. 
 If subject has not been fasting, schedule the subject as soon as possible for fasting 
blood draw and urine specimen. 
 Upload collected images (Fluorescein angiography, Fundus photography and  
SD-OCT) of the study eye to the central reading center. 
 Schedule the subject to return for Visit 12 (Week 28 (D197±5)).  
7.5.2.12. Visit 12 (Week 28 (D197±5)) 
 Perform the following assessments: 
 Query for AEs 
 Update medical history and medications 
 Vital signs  
 BCVA (ETDRS) 
 M-CHARTS™ 


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 Slit-lamp biomicroscopy 
 IOP 
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Rescue therapy with any anti-VEGF medication may be allowed if the following 
rescue criteria are met:  
 BCVA decrease of ≥ 5 letters from the last visit score OR 
 CST increase from the last visit of ≥ 50µm OR 
 The discretion of investigator 
 If rescue is performed, the following assessments must be performed after the 
administration of Rescue treatment: (all ophthalmic procedures to be performed OU) 
 Within 30 minutes following Rescue treatment 
 
Slit-lamp biomicroscopy 
 
Indirect ophthalmoscopy 
 IOP:  40 (±10) minutes following injection 
 
If post-injection IOP is > 21 mmHg OR increased ≥ 10 mmHg from  
pre-injection IOP, IOP measurement will be repeated at 60 (±10) minutes 
post-injection. 
 IOP will be measured at 60 (±10) minutes post-injection, if applicable.   
 
If post-injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR increased ≥ 
10 mmHg from pre-injection IOP, the subject should be prescribed a topical 
IOP-lowering medication, and the IOP elevation will be reported as an AE. 
Per the Clinical Investigator’s discretion, the subject can return for follow-up 
(an unscheduled visit may apply). 
 
If post-injection IOP at 60 (±10) minutes is > 21 mmHg AND < 30 mmHg, 
the subject will be treated according to the Clinical Investigator’s discretion. 
 AE assessments must be performed after Rescue treatment, if applicable. 
 Upload collected images (SD-OCT) of the study eye to Reading center. 
 Schedule the subject to return for Visit 13/Exit (Week 32 (D225±5)).  Remind 
subjects to fast 8 hours prior to next visit. 
7.5.3. 
Study Exit 
7.5.3.1. 
Visit 13/Exit (Week 32 (D225±5)) 
 Perform the following assessments: (all ophthalmic procedures to be performed OU) 


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 Query for AEs 
 Update medical history and medications 
 Physical examination (if not performed by external internist) 
 Vital signs  
 EKG 
 BCVA (ETDRS) 
 M-CHARTS™ 
 Slit-lamp biomicroscopy 
 IOP 
 Indirect ophthalmoscopy 
 SD-OCT 
 SS-OCT angiography (for selected sites) 
 Fundus photography  
 Fluorescein angiography 
 Collect urine and blood specimen for the following examinations:  
 Urinalysis 
 Serum pregnancy test (for females of child-bearing potential)  
 Hematology, chemistry serum sample 
 If subject has not been fasting, schedule the subject as soon as possible for fasting 
blood draw and urine specimen. 
 Upload collected images (Fluorescein angiography, Fundus photography and  
SD-OCT) of the study eye to the central reading center. 
 Exit subject from study. 
7.5.4. 
Unscheduled Visits 
If a subject requires evaluation between scheduled visits, complete all applicable study specified 
procedures as necessary and record the information on the Unscheduled Visit form(s). 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Eligible subjects must meet all eligibility criteria described in Section 8.1 and Section 8.2. 
8.1. 
Subject Inclusion Criteria 
At Screening (Day -14 to Day -1) and Visit 1 (Day 1), subjects must meet all of the following 
inclusion criteria: 
1. Provide signed written informed consent on the IRB/EC approved ICF and provide 
authorization as appropriate for local privacy regulations. 
2. Male or female 50 years of age or older on the date of signing the ICF and able and 
willing to comply with all treatment and follow-up study procedures. 
3. Diagnosis of active choroidal neovascularization (presence of subretinal or intraretinal 
fluid) secondary to wet AMD as assessed by SD-OCT in the study eye. 
4. Diagnosis of active leakage secondary to wet AMD as assessed by FA in the study eye.  
5. Diagnosis of wet AMD in the study eye prior to Screening visit (Visit 0) treated with 
repeated intravitreal anti-VEGF medication (i.e., At least 3 IVT injections of Anti-VEGF 
for treatment naïve eyes or eyes adequately maintained on continuous intravitreal anti-
VEGF therapy). 
6. Last treatment with intravitreal injection of anti-VEGF in the study eye > 20 days and  
< 80 days prior to Screening visit (Visit 0). 
7. All lesion types except for RAP, total lesion size of ≤ 12 disc areas, contain ≤ 50% 
hemorrhage and no fibrosis or atrophy involving the foveal center in the study eye. 
8. BCVA of 65 to 25 ETDRS letters (equivalent to 20/50 to 20/320) in the study eye. 
9. BCVA of 25 ETDRS letters (equivalent to 20/320) or better in the fellow eye. 
10. Reasonably clear media and some fixation in the study eye to allow for good quality  
SD-OCT and fundus photography. 
8.2. 
Subject Exclusion Criteria  
A subject with any of the following conditions is not eligible to participate in the study: 
Ocular: 
1. Use of any of the following treatments or anticipated use of any of the following 
treatments to the study eye: 
 Intravitreal or periocular corticosteroid, within 90 days prior to Visit 1 (Day 1) and 
throughout the study; 
 Fluocinolone acetonide intravitreal implant, within 12 months prior to Visit 1 (Day 1) 
and throughout the study; 


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 Visudyne photodynamic therapy, within 90 days prior to Visit 1 (Day 1) and 
throughout the study; 
2. Uncontrolled or advanced glaucoma, evidenced by an IOP of > 21 mmHg or cup/disc 
ratio > 0.8 while on medical therapy, or chronic hypotony (< 6 mmHg) in the study eye. 
3. Evidence of any other ocular disease other than wet AMD in the study eye that may 
confound the outcome of the study (e.g., active diabetic retinopathy, posterior uveitis, 
pseudovitelliform macular degeneration, moderate/severe myopia). 
4. History of vitrectomy in the study eye. 
5. Need for ocular surgery in the study eye during the course of the study. 
6. YAG laser capsulotomy within 30 days prior to Visit 1 (Day 1) in the study eye. 
7. Intraocular surgery, including lens removal or laser, within 90 days prior to Visit 1  
(Day 1) in the study eye. 
8. Ocular or periocular infection in either eye. 
9. Pupillary dilation inadequate for quality stereoscopic fundus photography in the study 
eye. 
10. Media opacity that would limit clinical visualization, intravenous fluorescein 
angiography, or SD-OCT evaluation in the study eye. 
11. History of herpetic infection in the study eye or adnexa. 
12. Presence of known active toxoplasmosis, inactive toxoplasmosis or toxoplasmosis scar in 
either eye. 
13. Presence of any form of ocular malignancy including choroidal melanoma in either eye. 
Non-Ocular: 
14. Prior treatment with DE-122 injectable solution. 
15. Use of any of the following treatments or anticipated use of any of the following 
treatments during the study: 
 Systemic treatment with anti-VEGF agents (e.g., bevacizumab) 
 Agents targeting the endoglin pathway 
16. Allergy or hypersensitivity to study drug product, fluorescein dye, or other study related 
procedures/medications. 
17. Inadequate renal function: e.g., serum creatinine > 1.3 mg/dL and BUN > 2 x the ULN. 
18. Inadequate hematologic function: e.g., hemoglobin < 10 g/dL; platelet count < 130 x 109 
/L; WBC < 3.8 X 109 /L or > 10.9 X 109 /L.  
19. Inadequate liver function: e.g., serum bilirubin > 1.5 mg/dL, GGT, SGOT/ALT, 
SGPT/AST, and alkaline phosphatase outside 2 x ULN. 
20. History of bone marrow suppression. 


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21. Active bleeding or pathologic condition that carries a high risk of bleeding  
(e.g., hereditary hemorrhagic telangiectasia). 
22. History of hemorrhage, epistaxis, hemoptysis (> ½ teaspoon bright red blood), or 
treatment with anticoagulants within 90 days prior to Visit 1 (Day 1). 
23. Myocardial infarction, stroke or history of transient ischemic attacks within 180 days 
prior to Visit 1 (Day 1). 
24. Major surgery within 90 days prior to Visit 1 (Day 1).  Major surgery is defined as any 
surgery involving a risk to the life of the subject, including any operation upon an organ 
within the cranium, chest, abdomen, or pelvic cavity.  
25. Therapeutic radiation to the head or neck within 90 days prior to Visit 1 (Day 1). 
26. Participation in other investigational drug or device clinical trials within 30 days prior to 
Visit 1 (Day 1) or planning to participate in other investigational drug or device clinical 
trials for the duration of the study.  This includes both ocular and non-ocular clinical 
trials. 
27. Uncontrolled blood pressure (defined as systolic > 180 mmHg and/or diastolic > 110 
while subject is sitting).  If a subject’s initial reading exceeds these values, a second 
reading may be taken 30 or more minutes later.  If a subject’s blood pressure needs to be 
controlled by antihypertensive medication, the subject can be eligible if medication is 
taken continuously for at least 30 days prior to Visit 1 (Day 1). 
28. Atrial fibrillation not controlled by the subject’s primary care physician or cardiologist 
within 30 days prior to Visit 1 (Day 1). 
29. Clinically significant concurrent illness, laboratory or EKG abnormality. 
30. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease condition that contraindicates 
the use of an investigational drug, might affect the interpretation of the results of the 
study, or renders the subject at high risk for treatment complications. 
31. Any systemic infection within 30 days prior to Visit 1 (Day 1). 
32. Females who are pregnant or lactating and females of child-bearing potential who are not 
using adequate contraceptive precautions (i.e., IUD, oral contraceptives, barrier method, 
or other contraception deemed adequate by the Clinical Investigator).  Men who do not 
agree to practice an acceptable method of contraception throughout the course of the 
study. 
33. Use of marijuana or illegal medication within 30 days prior to Visit 1 (Day 1) and 
throughout the study. 
34. Unable to comply with study procedures or follow-up visits. 
In addition, the Clinical Investigator or Santen Medical Monitor may declare a subject 
ineligible for any sound reason. 


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8.3. 
Subject Withdrawal Criteria  
An early termination occurs when a subject who provides written informed consent ceases 
participation in the study, regardless of circumstances, before the completion of the study.  
Subjects may voluntarily withdraw from the study at any time for any reason.  In addition, the 
Clinical Investigator or the Medical Monitor may terminate a subject’s study participation for 
reasons related to the best interest of the subject.  Subjects who terminate from the study may be 
replaced.  Subjects may be terminated from the study due to any of the following reasons: 
 Non-compliance 
 Lost to follow-up 
 Protocol violation 
 Withdrawal by subject 
 AEs 
 Death 
 Other 
If a subject is discontinued from the study before completing Visit 13/Exit (Week 32  
(Day 225±5)), then to the extent possible, all assessments, including safety, that are scheduled to 
be performed at Visit 13/Exit should be performed on the day of discontinuation. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
DE-122 is a chimeric anti-CD105 IgG1 antibody consisting of human Cκ and Cγ1 constant 
regions with murine Vκ and VH regions.  DE-122 is composed of two light chains of 213 amino 
acids and two heavy chains of 448 amino acids and has an approximate molecular weight of  
148 kDa.  DE-122 is utilized in this clinical study in a formulation designed for IVT injection. 
9.2. 
Concomitant Medications 
The use of any concomitant prescription or over-the-counter medication will be recorded during 
the study.  Therapy considered necessary for the subject’s welfare may be given at the discretion 
of the Clinical Investigator during the study.  Whenever possible, concomitant medications 
should be administered in dosages that remain constant throughout the study.  The generic name, 
indication, route of administration, frequency, dose, start date and stop date (if applicable) will 
be recorded for each medication. 
9.2.1. 
Prohibited Medications or Treatments 
Any treatments for wet AMD in the study eye other than DE-122 and Lucentis® are prohibited 
during the study. 
Any systemic treatments with anti-VEGF agents (e.g., bevacizumab) are prohibited during the 
study. 
The decision to administer a prohibited concomitant medication or treatment during the study 
should be made with the safety of the subject as the primary consideration.  Whenever possible, 
Santen should be notified before any prohibited medication or treatment is administered or if the 
permissibility of a specific medication or treatment is in question. 
9.2.2. 
Rescue Therapy 
Rescue therapy is defined as IVT injection of Anti-VEGF medication in the study eye.  
Eligibility for Rescue therapy to be determined as per rescue criteria in Section 7.1. 
9.3. 
Treatment Compliance 
In order to obtain efficacy and safety data, it is critical that the treatment regimen and visit 
schedule specified in this protocol are followed.  The Clinical Investigator is required to 
administer the DE-122 injection and Lucentis®, and is responsible for scheduling the subject for 
follow-up visits as specified in the protocol.  Study monitors will verify pertinent data to confirm 
the study is conducted according to the protocol. 
9.4. 
Randomization and Masking 
The first 6 subjects will be randomized in a 1:1 ratio to Arm 1 or Arm 2 at Visit 1 in Stage 1.  If 
the safety and tolerability at Week 4 for the 6 subjects are acceptable, randomization will be 


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continued in a 1:2:2 ratio in the three arms for the remaining approximately 70 subjects in  
Stage 2.  
To balance the randomization, subjects will be stratified by subgroups on the reading center’s 
assessment of lesion type, up to approximately one third (1/3) of the subjects in each arm should 
have PCV in Stage 2. 
One of arms will have sham injection which is a mimic procedure of a real intravitreal injection 
but does not penetrate the eye.  To keep masking of the clinical trial, investigator and authorized 
study staffs must follow the points below.   
 The designated unmasked injecting physician and the designated unmasked injection 
staff must ensure any information regarding clinical study drugs injection during the 
study is inaccessible to other study staff. 
 The designated unmasked injecting physician and the designated unmasked injection 
staff cannot perform any assessments or examinations for the study other than clinical 
study drug injection procedures and examinations post drug injections. 
 Masked study staff not designated to study drug injections, including investigators, 
examiner and other clinical site staff, cannot participate in any procedures for clinical 
study drug injections and examinations post drug injections. 
In case of a medical emergency, the Principal Investigator or site staff may reveal the treatment 
information by unmasking in IWRS to know which treatment the subject has received.  The 
Principal Investigator should contact Santen, or Santen’s designee, before taking this measure, if 
there is sufficient time. Santen, or Santen’s designee, must be informed of all instances where the 
code is broken and of the reasons for such instances. 
Additionally, the adverse event or serious adverse event for which study treatment was 
unmasked should be reported to Santen Drug Safety (see Section 12.1). 
 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
10.1.1. 
Investigational Drug  
DE-122 for IVT injection is formulated in a proprietary, clear, aqueous solution.  The 2 dose 
levels of DE-122 to be administered in the study eye are shown in Table 4. 
Table 4: 
DE-122 Dosing 
Injection Volume of: 
Will deliver approximately: 
20 microliters of 100 mg/mL DE-122 
2.0 mg DE-122 
40 microliters of 100 mg/mL DE-122 
4.0 mg DE-122 
The Clinical Investigator will use syringes and needles supplied by Santen/Representative.  
10.1.2. 
Concomitant drug 
Lucentis® 0.5 mg (50 µL) is administered in all groups. 
10.1.3. 
Study Drug Complaint Reporting 
Complaints regarding the DE-122 for IVT injection should be reported to Santen/Representative 
Product Complaint at clinicalsupplies@santen.com or +1-415-268-9100. 
10.1.4. 
Other Study Supplies 
Santen/Representative will supply a fluoroquinolone equivalent antibiotic eye drop, needles and 
syringes, and would supply 10 % povidone iodine and sharps container. 
10.2. 
Study Drug Packaging and Labeling 
DE-122 injectable solutions are filled (0.3 mL fill) in 2-mL Type 1 Glass (borosilicate) clear 
vials, capped with 13 mm Gray Butyl stoppers with B2-40 coating, and sealed with a 13 mm 
colored Flip-Off Truedge.  Each single use vial will be placed in a unit carton, and the labeling 
will include protocol number, kit number, and storage conditions. 
The vial packaging and carton labeling for Sham is the same as DE-122 injectable solutions, but 
no DE-122 is filled in the Sham vial.  
Commercially available Lucentis® will be provided by Santen/Representative for use as 
concomitant therapy in all groups and will be labeled for the study. 
10.3. 
Study Drug Storage 
Investigational drug (DE-122 injectable solutions and Sham) will be provided by 
Santen/Representative and will be stored in an appropriate secure area at the investigational site.  
DE-122 and Sham vials should be protected from light, stored upright, and kept refrigerated at  
2° to 8°C (36° to 46°F). 


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Lucentis® storage will be as per Lucentis® drug labeling. 
10.4. 
Study Drug Preparation 
<Concomitant drug: Lucentis® > 
Lucentis® preparation to be done as per Lucentis® drug labeling. 
<Investigational drug:  DE-122> 
Once an investigational drug vial number has been assigned to the subject, the vial of 
investigational drug with the assigned vial number will be removed from the refrigerator.  Care 
should be taken to protect the product from light.  Investigational drug should be drawn into the 
provided sterile single-use custom marked syringe (see Section 10.5) within 30 minutes after 
removing the vial from the refrigerator.  Investigational drug should be injected within 1 hour of 
being drawn up into the single-use syringe.  Study drug preparation should be performed by the 
designated injecting physician.  
Each vial contains enough DE-122 to inject one subject.  Each vial will be used one time only.  
Write the subject number on the carton label.  After use, return the vial in the unit carton, seal 
and initial the carton. 
<Investigational drug: Sham> 
The study drug preparation for Sham injection is same as DE-122. 
10.5. 
Loading the Syringe  
<Concomitant drug: Lucentis®> 
Lucentis® administration to be done as per Lucentis® drug labeling. 
<Investigational drug:  DE-122> 
A sterile, single-use 250 μL syringe custom marked at 20 µL or 40 µL will be provided 
separately for IVT injection of DE-122.  Instructions for filling the syringe are as follows: 
1. Remove the sterile, single-use 250 μL syringe, custom marked at 20 µL or 40 µL, from 
the packaging. 
2. Attach a 19-gauge x 1 ½ inch filter needle to the syringe.  DE-122 is dispensed in a  
0.3 ml fill in a 2 mL vial.  See Figure 2. 
3. Using sterile technique, carefully draw up approximately 200 μL of DE-122 into the 
syringe.  (Sufficiently larger volume than 20 or 40 µL is needed to allow for dead space 
in syringe and needles prior to IVT injection). 
4. Remove the 19-gauge x 1½ inch filter needle from the syringe and replace with a  
30-gauge x 0.5-inch needle for the IVT injection.   
a. Ensure that the 30-gauge x 0.5-inch needle is affixed tightly to the syringe. 
b. Align the top edge of the red O-ring of the plunger with the 20 µL or 40 µL black 
mark on the syringe, expelling the excess fluid drawn up.  See Figure 3. 


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c. Ensure there are no air bubbles within the syringe or the needle hub prior to injection, 
and prior to expelling the excess fluid drawn up. 
 
Figure 2: 
0.3 mL fill in a 2 mL vial 
 
 
 
 
Figure 3: 
Alignment of the syringe (20 µL example) 
 
<Investigational drug:  Sham> 
Loading syringe procedure for Sham injection is similar to DE-122; no drug product will be 
drawn up into the syringe. 
10.6. 
Eye Preparation  
<Concomitant drug: Lucentis®> 
Eye preparation for Lucentis® administration to be done as per Lucentis® drug labeling. 
<Investigational drug:  DE-122> 
Prior to DE-122 administration, the study eye should be prepared as follows: 
1. Dilate pupil (1 % mydriacyl and 2.5 % phenylephrine or equivalent applied topically) 
approximately 10 minutes prior to injection. 
2. Administer 1 eye drop of topical anesthetic (0.5 % proparacaine hydrochloride 
ophthalmic solution or an equivalent topical ophthalmic anesthetic). 
3. Administer 10 % povidone iodine. 


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4. Use a sterile cotton-tipped applicator to remove excess fluid from the lower conjunctival 
sac. 
5. Take 2 sterile cotton tipped applicators and thoroughly soak with 0.5 % proparacaine 
topical anesthetic eye drops or an equivalent topical ophthalmic anesthetic.  Place the 
soaked applicators, side by side, gently but firmly on the conjunctival surface at the area 
of the entry site described below in Step 2 (Section 10.7) and hold in place for 
approximately 1 minute. 
6. Insert sterile eyelid speculum. 
7. Place sterile eye drape over study eye. 
<Investigational drug:  Sham> 
Eye preparation for Sham injection is the same as DE-122. 
10.7. 
Study Drug Administration  
<Concomitant drug: Lucentis®> 
Lucentis® administration to be done as per Lucentis® drug labeling. 
<Investigational drug: DE-122> 
1. Prior to starting the injection procedure, DE-122 should have been prepared as described 
in Section 10.4 and Section 10.5, and the study eye should have been prepared as 
described in Section 10.6.  
2. If the subject is phakic, the entry site is 4.0 mm from the limbus.  If the subject is 
pseudophakic or aphakic, the entry site is 3.5 mm from the limbus.  A caliper may be 
used to identify the needle entry site.  The entry site location for the investigational drug 
should be the same quadrant as the concomitant drug, but not at the same entry point.  
3. Insert the needle perpendicular to the eye wall at the location specified in Step 2  
(Section 10.7).  The needle should be inserted until the tip is just visible through the 
dilated pupil.  Note:  If paracentesis is considered necessary, it should be performed after 
injection of the DE-122 and noted in the source documents. 
4. Very slowly, inject the entire DE-122 dose volume (20 µL or 40 µL) and slowly 
withdraw the needle.  Do not pull back on the plunger at any time prior to withdrawing 
the needle. 
5. Briefly apply pressure for approximately 1 minute to the needle entry site with sterile 
cotton tipped applicator (may be skipped per Clinical Investigator’s discretion). 
6. Remove the eyelid speculum. 
7. Patch the study eye at the Clinical Investigator’s discretion. 
8. Prescribe fluoroquinolone equivalent antibiotic eye drops three times/day for two days 
following injection, to be initiated as soon as possible. 
 
 


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<Investigational drug:  Sham> 
Sham is injection that simulates DE-122 drug administration.  Sham intravitreal injections will 
be administered to subjects according to the same dosing schedule and procedure as DE-122 
injections.  However, the Sham intravitreal injection procedure will only mimic DE-122 
intravitreal injection in that the blunt end of an empty syringe is pressed against an anesthetized 
eye, instead of a needle attached to DE-122 syringe injected into the anesthetized eye.  Therefore, 
Step #3 and #4 of above DE-122 administration procedure will be skipped for the Sham injection. 
To keep masking of the study, investigator and authorized staff must follow the points described 
in Section 9.4.  
10.8. 
Study Drug Accountability 
The Principal Investigator is responsible for ensuring that an inventory is conducted upon receipt 
of the clinical supplies.  The temperature recorder from the shipment will be deactivated and 
authorized study staff will verify that the temperature was maintained at 2° to 8°C (36° to 46°F) 
during transit.   
The Principal Investigator will keep a current record of the inventory, storage conditions and 
dispensing of all study drugs.  This record will be made available to Santen (or designee) for the 
purpose of accounting for all clinical supplies.  Any significant discrepancy and/or deficiency 
must be recorded with an explanation.  
All supplies sent to the Principal Investigator must be accounted for and in no case will study 
drugs be used in any unauthorized situation.  It is the responsibility of the Principal Investigator 
to ensure that any used and unused supplies are available to Santen (or designee) throughout the 
study. 
10.9. 
Study Drug Handling and Return 
All investigational products including used/unused vials of DE-122/Lucentis® and syringes 
supplied by Santen/Representative will be fully accounted for by the monitor with the help of the 
unmasked person responsible for dispensing the DE-122 and will be returned to 
Santen/Representative or designee.  Accountability will be documented by use of drug 
accountability forms. 
Refer to Study Drug Manual for study drug handling. 
 


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Best Corrected Visual Acuity (BCVA) 
BCVA is the primary efficacy variable for this study, and mean change from baseline in BCVA 
at Week 24 is the primary efficacy endpoint.  Proportion of subjects with BCVA Improvement of 
≥ 15 letters, <15 letters change (stable) and loss of ≥ 15 letters from baseline at Week 24 are 
secondary endpoints. 
The visual acuity will be recorded using the ETDRS chart and total number of letters at 4 meter 
and 1 meter will be recorded.  If a subject could not read ETDRS chart, Finger Counts, Hand 
Motion, Light Perception, or No Light Perception will be recorded. 
11.2. 
Central Subfield Thickness (CST), Macular Volume (MV), Central 
Retinal Lesion Thickness (CRLT) 
CST, MV, and CRLT measured by SD-OCT are secondary efficacy variables, and change in 
CST, MV, and CRLT from baseline at Week 24 are secondary endpoints.  All 3 parameters will 
be measured by the central reading center.  
11.3. 
Lesion area 
Change in total lesion area, total area of CNV, greatest linear dimension of the total lesion area 
by FA from baseline at Week 24 are secondary efficacy endpoints.  Lesion areas will be 
measured by the central reading center. 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events 
12.1.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with the study drug(s).  An AE, 
therefore, can be an unintended sign (including an abnormal laboratory finding), symptom, or 
disease that has clinical significance and is temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
In clinical studies, an undesirable medical condition occurring at any time, including baseline or 
pre-treatment period, may be recorded as an AE even if no study drug has been administered. 
Any significant adverse change in a subject’s condition from baseline, regardless of causality, is 
to be considered an AE, unless the change is determined to be a continuation of a pre-existing 
condition that is documented in the subject’s medical history.  However, a clinically significant 
worsening in severity, intensity, or frequency of a pre-existing condition may indicate an AE.  In 
addition, all conditions that lead to hospitalizations, defined as an overnight hospital stay, are 
considered as AEs.  This includes planned elective surgeries.  
Lack of efficacy of the study drug(s) for the condition being investigated is not considered an AE 
unless a clinically significant change is assessed by the Clinical Investigator.  An elective 
surgical procedure scheduled or planned prior to study entry is not considered an AE if an 
overnight hospital stay is not required, and the underlying diagnosis for which surgery is to be 
performed should be captured in the medical history as a pre-existing condition.  The surgical 
procedure should also include the term “elective” in all reports.  
12.1.1.1. Assessment of Adverse Events 
Clinical Investigators will seek information on AEs at each subject contact.  Subjects should be 
asked, using a general, non-direct question, if there has been any change in their general health.  
Direct questioning and examination should then be performed as appropriate. 
Severity of the AE should be assessed according to the following criteria: 
Mild:  No interference with the subject’s daily activities; no medical intervention/therapy 
required 
Moderate:  Possible interference with the subject’s daily activities; no or minimal 
medical intervention/therapy required 
Severe:  Considerable interference with the subject’s daily activities; medical 
intervention/therapy required 
Regardless of severity, some AEs may also meet regulatory serious criteria.  Refer to definitions 
and reporting of serious adverse events (SAEs) in Section 12.1.2. 
A Clinical Investigator who is qualified in medicine must make the determination of the 
relationship of the study drug(s) to each AE (related or not related).  The Clinical Investigator 


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should decide whether, in his or her medical judgment, there is a reasonable possibility that the 
DE-122, Lucentis® or the Sham injection could have caused the AE/SAE based on facts, 
evidence, scientific rationales, and clinical judgment.  When assessing causality, the Clinical 
Investigator may consider the following information when determining the relationship to the 
study drug(s) for each AE: mechanism of action, biologic plausibility, confounding risk factors 
(i.e., medical history, concomitant medications), temporal relationship, dechallenge/rechallenge, 
and lack of alternative explanation.  It should be specified if the AE is related to the injection 
procedure and not the study drug.  
 The AE may be recorded as Related to the study drug(s) if there is a plausible 
temporal relationship between the onset of the AE and administration of the study 
drug(s), and the AE cannot be readily explained by the subject’s clinical state, 
concurrent illness, or concomitant therapies; and/or the AE follows a known pattern 
of response to the study drug(s),; and/or the AE abates or resolves upon 
discontinuation of the study drug(s).  
 Reporting the AE as Not Related to study drug(s), may be considered if, for example, 
there is good evidence that the AE has an etiology other than the study drug(s)  
(e.g., pre-existing medical condition, underlying disease, concurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
administration of the study drug(s) (e.g., cancer diagnosed 2 days after dose of study 
drug(s)). 
12.1.1.2. Reporting Adverse Events  
AEs, whether spontaneously reported by the subject or noted by authorized study personnel, will 
be recorded in the subject’s medical record and on the appropriate AE eCRF.  Each recorded AE 
will be described by its duration (i.e., start and end dates), frequency, severity, regulatory 
seriousness criteria if applicable, suspected relationship to the study drug(s), relation to injection 
procedure, location, actions taken and outcome. 
AEs that occur after any subject has provided written informed consent, before treatment, during 
treatment, or until study exit visit, whether or not they are related to the study, must be recorded.  
To improve the quality and precision of acquired AE data, Clinical Investigators should observe 
the following guidelines: 
 Whenever possible, use recognized medical terms when recording.  Do not use 
colloquialisms and/or abbreviations. 
 If known, record the diagnosis (i.e., disease or syndrome) rather than component 
signs and symptoms and /or laboratory or test findings (e.g., record congestive heart 
failure rather than dyspnea, rales, and cyanosis, and enlarged heart on chest x-ray).  
However, other events that are considered unrelated to an encountered syndrome or 
disease should be recorded as individual AEs (e.g., if congestive heart failure and 
severe headache are observed at the same time and are clinically unrelated, each event 
should be recorded as an individual AE). 
If the diagnosis is not known, then record the leading component sign, symptom or 
test finding and describe the other clinically related findings in the narrative 
description of the case.  A suspected diagnosis can be used and described as such 


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(e.g., record suspected or probable myocardial infarction); this has to be updated in 
the clinical database once the diagnosis is confirmed.  
AEs occurring secondary to other events (e.g., sequelae) should be identified by the 
primary cause.  A primary AE, if clearly identifiable, generally represents the most 
accurate clinical term.  If a primary AE is recorded, events occurring secondary to the 
primary event should be described in the narrative description of the case.  For 
example: 
The subject developed orthostatic hypotension and subsequently fainted and fell to 
the floor wherein she experienced a head trauma and neck pain. 
The primary AE in this example is orthostatic hypotension.  The fall, head trauma and 
neck pain should be described in the narrative description of the case.  
 For intermittent events (e.g., intermittent headache), the event onset date should be 
recorded as the date the subject first started to experience the event and resolution 
date should reflect when the last occurrence resolved or stopped.  Separate AEs for 
each event should not be recorded.  For example, if a subject experienced headache 
on 14SEP2015 lasting for three hours, then subsequently experienced intermittent 
episodes of headache every day for approximately 3 hours until 21SEP2015, then the 
AE date of onset is 14SEP2015 and the resolution date is 21SEP2015. 
 For intermittent events, record the maximum severity of the individual events.  For 
example, if a subject complains of intermittent headaches for one week and the 
severity of each headache ranges from mild to moderate, then the severity would be 
moderate. 
 For intermittent hospitalizations occurring for a primary AE (e.g., in a subject with 
multiple sclerosis, commonly known for its relapsing and remitting course, in some 
cases leading to multiple hospital confinements), the subsequent hospitalizations 
should be described in the narrative description of the case.  
 If treatment was initiated, include the treatment and duration of the medication(s) in 
the eCRF. 
12.1.2. 
Serious Adverse Events 
SAEs are defined as any findings that suggest a significant hazard, contraindication, side effect, 
or precaution.  Any adverse event is considered a serious adverse event if it results in any of the 
following outcomes: 
 Death 
 Life threatening: 
A life-threatening event is any event that places the subject at immediate risk of death 
from the event as it occurred; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 
 Hospitalization, at the minimum an overnight stay  
 A persistent or significant disability/incapacity  


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 A congenital anomaly/birth defect 
 Other medically significant events:  
Other medically significant events are events that may not result in death, be life-
threatening, or require hospitalization but may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above.  
 Sight threatening event:  
A sight-threatening event is any event that places the subject at immediate risk of 
permanently losing vision in either eye as a direct result of the event.  It is defined as 
a loss of ≥ 30 letters or 6 lines of vision from Baseline.  
12.1.2.1. Reporting Serious Adverse Events 
A SAE eCRF must be completed with as much information available within 24 hours of 
knowledge of the event. 
To improve the quality and precision of acquired SAE data, Clinical Investigators should observe 
the following guidelines: 
 Death - Death is an outcome of an event.  The event that resulted in the death should 
be recorded and reported as a SAE. 
 Hospitalizations for Surgical or Diagnostic Procedures - The illness 
leading to the surgical or diagnostic procedure should be recorded as the 
SAE, not the procedure itself.  The procedure should be captured in the case 
narrative as part of the action taken in response to the illness. 
When new significant information (including the outcome of the event) is obtained, the Clinical 
Investigator should enter the information directly into the eCRF within 24 hours or as soon as 
possible after knowledge of the information. 
Depending on the nature and seriousness of the AE, Santen may request additional 
documentation, for example, copies of the ophthalmic and medical record of the subject as well 
as results of laboratory tests.  If the subject was hospitalized, the site should summarize the 
hospital discharge summary and provide to Santen upon request. 
12.1.2.2. Expedited Reporting of Serious Adverse Events 
Santen (or designee) will provide the Principal Investigator with a reporting cover letter and an 
anonymized MedWatch 3500A or CIOMs form as appropriate for expedited reporting of SAEs 
to the IRB or IEC and the Philippines or the US regulatory agency.  The Principal Investigator is 
responsible for receiving and reviewing expedited safety reports, submitting expedited safety 
reports to the IRB or IEC, and maintaining copies of expedited safety reports in the study 
records. 


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12.1.3. 
Events of Special Interest 
Events of Special Interest (ESIs) are events that may require special attention for the purposes of 
on-going patient safety review during this study.  The following are considered ESIs and should 
be reported on the appropriate eCRF with as much information as available within 24 hours of 
knowledge of the event: 
 Study medication administration error – Study medication administration errors 
determined to be significant by the Clinical Investigator will be reported and 
evaluated as ESIs.  Examples of study medication administration errors may include, 
but are not limited to:  overdose of study medication and administration of study 
medication from an incorrect kit. 
 Pregnancy - There are no controlled data with the investigational product in human 
pregnancy.  It is required that females of childbearing potential use effective 
contraception during the study and recommended for 12 weeks after the completion 
of the study.  Any pregnancy occurring during study treatment should be reported and 
the subject removed from the study.  The subject should be followed until the end of 
pregnancy or until the end of the study, whichever is longer. 
 Ocular telangiectasia and bleeding events – There is no data showing that the 
investigational product is related to these events.  However, these are seen in the 
Osler-Weber-Rendu (OWR) syndrome, a genetic condition that causes endoglin 
dysfunction.  DE-122 binds to and suppresses human endoglin, thus information 
about the ocular manifestations of OWR are of value in predicting possible ocular 
adverse events following IVT injection of DE-122.  The following events will be 
considered ESIs and the subject followed until the end of the study or resolution of 
the event.  
 Ocular telangiectasia (Conjunctival and intraocular) 
 Intra- and extra-ocular bleeding (hemorrhage) not attributed to the injection 
procedure and/or AMD 
 Common systemic OWR signs: Epistaxis, gingival bleeding and mucocutaneous 
telangiectasia 
12.1.4. 
Follow-up of Adverse Events 
All reported AEs should be followed until resolution or until the subject’s participation in the 
study ends.  Subjects with the following types of events should be followed by the Investigator 
until the event is determined to be resolved, irreversible, chronic, stable, the subject withdraws 
consent, or no further information can be reasonably obtained.  
 On-going SAEs 
 On-going ESIs (excluding medication errors not resulting in AEs) 
 Early termination and withdrawal from the study due to study drug related AEs 
In addition, on a case by case basis, Santen (or designee) may request follow up beyond the 
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The follow-up information on an individual SAE, AE, or ESI will be entered into the eCRF prior 
to database lock.  If the information requested by Santen is not part of the eCRF, or when 
database lock has already been completed, the site’s response to follow-up requests should be 
emailed, faxed or reported to Santen Pharmacovigilance: globalPVAmericas@santen.com or 
+63-2-857-2111 (fax for the Philippines sites) or +1-415-276-5882 (fax for the US sites). 
12.1.5. 
Manual Back-Up Reporting Procedures 
This study is utilizing an electronic data capture (EDC) system for data collection.  In the event 
that the EDC system is unavailable for electronic reporting, the manual back-up reporting 
procedures below should be followed. 
 Complete an AE and SAE form manually 
 Attach a cover sheet with your contact information, including site number. 
 Email (preferred) or Fax the cover sheet and the AE and SAE form to Santen 
Pharmacovigilance at globalPVAmericas@santen.com or +63-2-857-2111 (for the 
Philippines sites) or +1-415-276-5882 (for the US sites). 
When the EDC system becomes available, update the EDC system with all previously reported 
information. 
12.2. 
Safety Parameters 
The safety assessments will include AEs, slit lamp biomicroscopy, indirect ophthalmoscopy, 
BCVA, IOP, fundus photography, fluorescein angiography, serum chemistry, hematology, 
urinalysis, vital signs, physical examination, EKG, and pregnancy. 
12.2.1. 
Physical Examination 
A full body systematic physical examination will be conducted by the Clinical Investigator or an 
external internist. 
12.2.2. 
Electrocardiogram (EKG) 
The Clinical Investigator will review the EKG report for abnormalities. 
12.2.3. 
Vital Signs 
Blood pressure and heart rate will be measured using an automated or manual blood pressure 
monitor.  Systolic and diastolic blood pressures will be recorded in millimeters of mercury 
(mmHg), and heart rate will be recorded in beats per minute (bpm). 
12.2.4. 
Best Corrected Visual Acuity 
The BCVA will be recorded using the ETDRS chart and total number of letters at 4 meters and  
1 meter will be recorded.  If a subject could not read ETDRS chart, Finger Counts, Hand Motion, 
Light Perception, or No Light Perception will be recorded. 


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12.2.5. 
Slit-lamp Biomicroscopy 
The Clinical Investigator will assess Slit-lamp biomicroscopy examination using Slit-lamp 
microscope.  On the visit of any IVT treatment, a biomicroscopy examination will be performed 
prior to Lucentis® injection and a second one within 30 minutes after DE-122 or Sham injection.  
This will be also applied for the post IVT injection of Rescue treatment. 
12.2.6. 
Intraocular Pressure 
IOP will be measured by applanation tonometry and reported in millimeters of mercury (mmHg).  
On the visit of any IVT injection, IOP will be measured before Lucentis® and 40 (±10) minutes 
after Lucentis® injection.  If post-injection IOP is > 21 mmHg or increased ≥ 10 mmHg from  
pre-injection IOP, the IOP will be measured again 60 (±10) minutes following Lucentis® 
injection.  If there is an increase of ≥ 10 mmHg at 60 (±10) minutes post-injection, the IOP 
increase of ≥ 10 mmHg will be reported as an AE.  
Moreover, IOP will be measured after DE-122 or Sham injection.  If post-DE-122 or Sham 
injection IOP is > 21 mmHg or increased ≥ 10 mmHg from pre-injection IOP, the IOP will be 
measured again 60 (±10) minutes following injection.  If there is an increase of ≥ 10 mmHg at 60 
(±10) minutes post-injection compared to pre-injection IOP, the IOP increase of ≥ 10 mmHg will 
be reported as an AE.  This will be also applied for the post IVT injection of Rescue treatment.  
12.2.7. 
Indirect Ophthalmoscopy 
The Clinical Investigator will assess Indirect ophthalmoscopy using indirect ophthalmoscope.  
On the visit of any IVT treatment, an ophthalmoscopy examination will be performed prior to 
Lucentis® injection and a second one within 30 minutes after DE-122 or Sham injection.  This 
will be also applied for the post IVT injection of Rescue treatment. 
12.2.8. 
Urine Pregnancy Test  
A urine pregnancy test will be conducted for all females of childbearing potential.   
12.2.9. 
Serum Pregnancy Test  
A serum pregnancy test will be conducted for all females of childbearing potential. 
12.2.10. 
Serum Chemistry, Hematology and Urinalysis 
Serum Chemistry, Hematology and Urinalysis will be measured by laboratory test company.  
The blood sample should be fasted for a minimum of 8 hours prior to blood draw for serum 
chemistry tests. 
12.2.11. 
Fundus Photography 
Digital color fundus photography will be taken following the procedure provided by the central 
reading center. 
12.2.12. 
Fluorescein Angiography  
Fundus fluorescein angiography will be taken following the procedure provided by the central 
reading center. 


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12.2.13. 
Adverse Events 
AEs will be elicited from the subjects starting at the Screening through study exit.  The 
information will include at least a description of the event, whether or not it is serious, onset and 
duration, frequency, severity, relation to masked study therapy, relation to injection procedure, 
location (OD, OS, OU or NA), action taken and outcome.  Prior to evaluating the incidences, all 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDra, 2013). 
Ocular and non-ocular AEs will be summarized separately.  See Section 12.1 for complete 
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13. 
PHARMACOKINETIC ASSESSMENTS 
The DE-122 concentration in serum will be measured before and after Visit 1 (Day 1) and Visit 8 
(Week 20) IVT administrations of DE-122 (2.0 mg and 4.0 mg) or Sham. 
13.1. 
Serum Sample Collection 
Serum samples will be collected according to the examination schedule.  On days when Visit 1 
(Day 1) and Visit 8 (Week 20) DE-122 IVT or Sham injections are administered, serum samples 
will be collected pre-Lucentis® injection and 3 hours (±10 min) post DE-122 IVT or Sham 
injections.  On day of the Visit 4 (Week 4) DE-122 IVT or Sham injection, serum samples will be 
collected prior to Lucentis® injection.  See Section 23.4.16 and/or separate procedure manual for 
the pharmacokinetic serum sample collection, storage and shipment. 
13.2. 
Sample Analysis 
Serum concentrations of DE-122 will be determined by ELISA (enzyme-linked immunosorbent 
assay) method at inVentiv Health Clinical, Inc. 


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14. 
OTHER ASSESSMENTS 
14.1. 
Demographics and Baseline Characteristics 
Subject demographics include age, race, sex, and ethnicity.  Baseline characteristics include 
medical history, prior medications, and baseline results of physical examination, EKG, vital 
signs, BCVA, slit-lamp biomicroscopy, IOP, indirect ophthalmoscopy, SD-OCT, pregnancy test, 
laboratory tests (hematology, chemistry, and urinalysis), fundus photography, and fluorescein 
angiography.  For assessments performed multiple times before the IVT injection of DE-122, the 
last pre-injection value will be used as the baseline value. 
14.2. 
Immunogenicity 
ADA titers will be measured in serum samples collected according to the examination schedule. 


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15. 
OTHERS 
15.1. 
Biomarker 
15.1.1. 
Serum Sample Collection 
For the biomarker finding, serum samples will be collected according to the examination 
schedule and measured for levels of angiogenesis-related proteins.  The serum samples will be 
also stored for future exploratory research to identify possible biomarkers associated with the 
study drug(s) and/or ophthalmologic disease conditions.  See Section 23.4.19, Appendix D for 
procedures for the serum sample collection, storage and shipment. 
15.1.2. 
Aqueous Humor Sample Collection 
For the biomarker finding, aqueous humor samples from the study eye will be collected 
according examination schedule only from subjects who has consented and measured for levels 
of angiogenesis-related proteins.  Aqueous humor samples will be also stored for future 
exploratory research to identify possible biomarkers associated with the study drug(s) and/or 
ophthalmologic disease conditions.  See Section 23.4.20, Appendix D for procedures for the 
aqueous humor sample collection, storage and shipment. 
15.2. 
SS-OCT Angiography 
SS-OCT angiography will be taken following examination schedule at selected sites. 
15.3. 
M-CHARTS™ 
The degree of metamorphopsia will be recorded using the M-CHARTS™, and vertical 
metamorphopsia score (MV) and horizontal metamorphopsia score (MH) will be recorded.  
 
 


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16. 
STATISTICAL METHODS 
16.1. 
Analysis Time Points 
One primary analysis (Week 24) and follow-up analysis (Week 32) will be performed. 
16.1.1. 
Primary Analysis  
Descriptive summaries of the following efficacy and safety measures will be provided by 
treatment arms at the Week 24: 
 Mean change in BCVA from baseline 
 Change in CST and macular volume from baseline 
 Change in central retinal lesion thickness from baseline 
 Proportion of subjects with BCVA Improvement of ≥ 15 letters, < 15 letters change 
(stable) and loss of ≥ 15 letters from baseline 
 Change in total lesion area and total area of CNV from baseline 
 Change in greatest linear dimension of the total lesion area from baseline 
 Safety assessment include AEs, BCVA, slit lamp biomicroscopy, IOP, indirect 
ophthalmoscopy, serum chemistry, hematology, urinalysis, vital signs, physical 
examination, fundus photography, fluorescein angiography, EKG, and pregnancy 
Additional variables of interest will also be provided. 
16.2. 
General Considerations 
All study parameters will be listed and a selected list of parameters will be summarized 
descriptively by treatment arm.  The descriptive statistics will include number of observations 
(n), mean, standard deviation, minimum, and maximum for continuous parameter and frequency 
(n) and percent (%) for categorical parameters. 
Details about the statistical analyses for this study will be provided in the statistical analysis plan 
(SAP). 
All data manipulations and descriptive summaries will be implemented using SAS®, Version 
9.1.3 or later. 
16.2.1. 
Sample Size 
Approximately 76 subjects (Arm 1: 17, Arm 2: 31, Arm 3: 28) with wet AMD will be enrolled at 
approximately 14 sites.  The final number of subjects enrolled may be adjusted based on the 
judgments from Safety Review Team.  This sample size is not planned based on statistical 
considerations.  
16.2.2. 
Statistical Hypotheses and Level of Significance 
No statistical hypothesis is defined for this study. 


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16.2.3. 
Randomization  
The first 6 subjects will be randomized to Arm 1 and Arm 2 in a 1:1 ratio in Stage 1.  If the 
safety and tolerability at Week 4 are acceptable, remaining approximately 70 subjects will be 
randomized to all Arms in a 1:2:2 ratio in Stage 2.  To balance the randomization, subjects will 
be stratified by subgroups on the central reading center’s assessment of lesion type, up to 
approximately one third (1/3) of the subjects in each arm should have PCV in Stage 2. 
16.2.4. 
Study Eye 
The study eye must meet all inclusion and exclusion criteria, including confirmation by the 
central reading center.  If both eyes are eligible based on inclusion and exclusion criteria, the 
study eye is defined as the eye with worse vision.  If both eyes have the same vision, the right 
eye (OD) should be determined as the study eye. 
16.3. 
Study Populations 
The following study populations are defined for analysis:  Intention-to-treat (ITT) and Safety. 
ITT Population: The ITT population will include all randomized subjects in the study.   
Safety Population: The Safety population will include all randomized subjects who 
received at least one study medication.  It will be the study population for safety analyses.   
PK Population: The PK population will include all subjects who received at least one 
DE-122 and have at least one post-injection PK assessment.  It will be the study 
population for PK analyses performed with subjects as treated.  
Full Analysis Set: The Full Analysis Set (FAS) will include all randomized subjects who 
received at least one study medication and provided at least one post-baseline BCVA 
measurement. The efficacy analysis will be performed on the FAS or a subset of the FAS. 
Per-Protocol Set: The Per-Protocol Set (PPS) Population is a subset of the FAS.  It 
includes all FAS subjects without major protocol violations that could affect the primary 
efficacy endpoint.  
16.4. 
Handling of Missing Values 
Primary analysis of the primary efficacy endpoint will be based on the observed cases.  Missing 
BCVA measurements will be imputed using the Last-Observation-Carried-Forward (LOCF) 
approach as a sensitivity analysis.  For safety measures, missing scores will not be imputed for 
data summaries.  
Completely or partially missing onset and resolution dates for AEs and completely or partially 
missing start and end dates of concomitant medications will be imputed in a conservative fashion 
that will be detailed in the SAP. 
16.5. 
Demographics and Baseline Characteristics 
Age, sex, race, ethnicity, and baseline assessments will be summarized descriptively by 
treatment arms. 
Subjects with abnormal medical history will be tabulated by treatment arm and body system. 


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Subjects using any prior medications will be tabulated by treatment arms, Anatomical 
Therapeutic Chemical levelbyrs, and preferred term specified in the World Health Organization 
Drug Dictionary Enhanced (World Health Organization Drug Dictionary, 2011).  
16.6. 
Efficacy Analyses 
16.6.1. 
Analysis of Primary Efficacy Endpoints 
The primary efficacy endpoint, BCVA mean change from baseline at Week 24 will be analyzed 
based on observed cases using descriptive statistics.  Observed BCVA in the study eye as well as 
imputed data using LOCF approach will be presented descriptively and graphically by study 
visit. 
The primary analysis will be based on the FAS and repeated analysis will be performed on the 
PP Population. 
16.6.2. 
Analysis of Secondary Efficacy Endpoints 
Change from baseline in CST, MV, CRLT, total lesion area and total CNV by SD-OCT, greatest 
linear dimension of the total lesion area by FA at Week 24 will be calculated and analyzed.  
Percentage/Proportion of subjects with BCVA :1) gain of ≥ 15 ETDRS letters (3-line gainers);  
2) < 15 letters change (stable); and 3) ≥ 15 letter loss will be summarized and tabulated. 
16.7. 
Safety Analysis 
All safety outcome measures will be summarized descriptively for the Safety Population.  The 
safety outcome measures include adverse events (AEs), BCVA, slit-lamp biomicroscopy, 
indirect ophthalmoscopy, intraocular pressure (IOP), serum chemistry, hematology, urinalysis, 
vital signs, physical examination, fundus photography, fluorescein angiography, EKG and 
pregnancy.  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Subjects with any AEs will be tabulated by system organ classification and preferred term 
specified in the MedDRA.  Similarly, subjects with any ocular and non-ocular AEs and ESIs will 
be tabulated separately.  AEs, ocular and non-ocular, as well as ESIs will also be summarized by 
relationship to treatment and maximum severity.  In addition, SAEs and discontinuations due to 
AEs will be summarized. 
Ocular safety outcome measures will be summarized using descriptive statistics. 
16.8. 
Pharmacokinetics Analysis 
To assess pharmacokinetic profile, pharmacokinetic parameters (Cmax, AUC, Tmax, t1/2) will be 
summarized for after the Visit 1 (Day 1) and Visit 8 (Week 20) DE-122 IVT injections. 
16.9. 
Immunogenicity Analysis 
To assess immunogenicity, the incidence of DE-122 antibody development in each Arm will be 
summarized by frequency counts and percentages. 


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16.10. 
Other Analysis 
16.10.1. 
Biomarker Analysis 
To explore the biomarkers, serum and aqueous humor samples will be collected at specified time 
points and measured for levels of angiogenesis-related proteins.  Changes from baseline in levels 
of biomarkers will be summarized descriptively by treatment arms. 
16.10.2. 
M-CHARTS™ 
To explore the degree of metamorphopsia change in vertical metamorphopsia score (MV) and 
horizontal metamorphopsia score (MH) from baseline will be analyzed.  


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17. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Principal Investigator will allow representatives of Santen’s monitoring team (or designee), 
the governing institutional review board (IRB), the Philippines FDA, the FDA in the US and 
other applicable regulatory agencies to inspect all study records, eCRFs, recruitment materials 
and corresponding portions of the subject’s medical records at regular intervals throughout the 
study.  These inspections are for the purpose of verifying adherence to the protocol, 
completeness, and exactness of the data being entered onto the eCRF, and compliance with the 
Philippines FDA, the FDA in the US or other regulatory agency regulations. 
17.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Santen (or 
designee) will evaluate the investigational study site to: 
 Determine the adequacy of the study facilities. 
 Review with the Principal Investigator(s) and authorized study staff their 
responsibilities with regard to protocol procedures adherence, and the responsibilities 
of Santen (or designee). 
During the study, Santen (or designee) will have regular contact with the investigational site, for 
the following: 
 Provide information and support to the Principal Investigator(s). 
 Confirm that facilities remain acceptable. 
 Assess adherence to the protocol and GCP.  
 Perform investigational product accountability checks and quality control procedures. 
 Ensure the on-going implementation of accurate data entry in the eCRF. 
 Perform source data verification, including a comparison of the data in the eCRFs 
with the subject’s medical records and other records relevant to the study.  This will 
require direct access to all original records for each subject (e.g., clinic charts). 
 Record and report any protocol deviations not previously sent to Santen. 
 Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Santen and those SAEs that met criteria for reporting 
have been forwarded to the IRB or Independent Ethics Committee (IEC). 
Santen (or designee) may remotely access the eCRFs at any time during the study for centralized 
monitoring.  Santen (or designee) will be available between visits if authorized study staff needs 
study related information or support. 
17.2. 
Audits and Inspections 
The Principal Investigator will allow Santen (or designee), the governing IRB or IEC, and 
applicable regulatory agencies to audit and inspect any aspect of the study, including all study 


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records, eCRFs, recruitment materials, and corresponding portions of the subject’s charts and 
medical records at any time during the study.  These study records must be retained at the study 
site and made available for audits and inspections.  The purpose of these audits and inspections is 
to verify adherence to the protocol, completeness and accuracy of the eCRF data, and 
compliance with Good Clinical Practice (GCP) guidelines and applicable regulatory 
requirements. 
The Principal Investigator or authorized study staff will notify Santen (or designee) should the 
site be audited or inspected by the governing IRB or IEC, and applicable regulatory agencies.  
Santen (or designee) will also notify the investigational site of any known pending site audits or 
inspections planned by Santen (or designee), governing IRB or IEC and regulatory agencies. 
17.3. 
Institutional Review Board 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the subject consent form and 
recruitment materials must be maintained by the Principal Investigator and made available for 
inspection. 


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18. 
QUALITY CONTROL AND QUALITY ASSURANCE 
18.1. 
Quality Control 
Santen (or designee) will provide instructional material to the study sites, as appropriate; 
including but not limited to instruction on the protocol, the completion of eCRFs, and study 
procedures.  Santen (or designee) will communicate regularly with site personnel via mail, email, 
telephone, and/or fax; and make periodic visits to the study site.  During those visits, Santen (or 
designee) will perform source data verification with the subject’s medical records and other 
records relevant to the study.  Upon receiving the eCRFs, Santen (or designee) will review and 
evaluate eCRF data and use standard system edits and may use centralized monitoring to detect 
errors in data collection. 
18.2. 
Quality Assurance 
Santen (or designee) may conduct a quality assurance audit at any time. 


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19. 
ETHICS 
19.1. 
Ethics Review 
The final study protocol and the final version of the ICF, and other study related material, as 
appropriate, must be approved or given a favorable opinion in writing by an IRB or IEC as 
appropriate.  The Principal Investigator must submit written approval to Santen (or designee) 
before study initiation.  See Section 23.1 Appendix A for a list of obligations of Investigators. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local regulations and guidelines.  In addition, the IRB or IEC must 
approve all advertising used to recruit subjects for the study.  The protocol must be re-approved 
by the IRB or IEC upon receipt of amendments and at least annually. 
The Principal Investigator is also responsible for providing the IRB or IEC with progress reports 
and notifications of any reportable serious adverse drug reactions from the investigational 
product.  
19.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with IRB or IEC, and regulatory requirements.  This 
study will also be conducted in compliance with the protocol, GCP guidelines, International 
Conference on Harmonization (ICH) guidelines, the Declaration of Helsinki. 
19.3. 
Written Informed Consent 
The Principal Investigator at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and possible benefit of the 
study.  Subjects must also be notified that they are free to withdraw from the study at any time.  
Subjects should be given the opportunity to ask questions and allowed time to consider the 
information provided.  Before participating in any study-related activity, voluntary informed 
consent must be documented by the use of a written ICF approved by the IRB or IEC and signed 
and dated by the subject or the subject’s legally authorized representative at the time of consent.  
The original signed and dated ICF will be retained with the study records, and a copy of the 
signed ICF will be given to the subject or the subject’s legally authorized representative.  


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20. 
DATA HANDLING AND RECORDKEEPING 
20.1. 
Inspection of Records 
The Principal Investigator will allow Santen (or designee), the governing IRB or IEC and 
applicable regulatory agencies to inspect any aspect of the study, including all study records, 
eCRFs, recruitment materials and corresponding portions of the subject’s charts and medical 
records at any time during the study.  The purpose of these inspections is to verify adherence to 
the protocol, completeness and accuracy of the eCRF data, and compliance with GCP guidelines 
and applicable regulatory requirements. 
20.2. 
Retention of Records 
All records relating to the conduct of this study are to be retained by the Principal Investigator 
until notified by Santen (or designee) that the records may be destroyed. 
20.2.1. 
Source Documents 
The Principal Investigator must maintain detailed source documents on all study subjects who 
provide informed consent.  Source documents include subject medical records, hospital charts, 
study files, as well as the results of diagnostic tests (e.g., laboratory tests). 
The following minimum information should be entered into the subject’s medical record: 
 The date the subject was enrolled and the subject number 
 The study protocol number and the name of Santen Inc. 
 The date that informed consent was obtained 
 Evidence that the subject meets study eligibility requirements (e.g., medical history, 
study procedures and/or evaluations) 
 The dates of all study-related subject visits 
 Evidence that required procedures and/or evaluations were completed 
 Use of any concomitant medications 
 Documentation of study drug accountability 
 Occurrence and status of any AEs 
 The date the subject exited the study and a notation as to whether the subject 
completed or terminated early from the study, including the reason for early 
termination 
 
 


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20.2.2. 
Data Collection 
The Principal Investigator must maintain detailed records on all subjects who provide informed 
consent.  Data for screened and enrolled subjects will be entered into eCRFs.  Review of the 
eCRFs will be completed remotely by Santen (or designee).  At designated intervals, a study 
monitor will perform source data verification on site.  During those visits, Santen (or designee) 
will monitor the subject data recorded in the eCRF against source documents at the study site.  
Santen (or designee) will review and evaluate eCRF data and use standard system edits, and may 
use centralized monitoring evaluations, to detect errors in data collection.  At the end of the 
study, a copy of the completed eCRFs will be sent to the site to be maintained as study records. 


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21. 
PUBLICATION POLICY 
The existence of this clinical study is confidential, and it should not be discussed with persons 
outside of the study.  Additionally, the information in this document and regarding this study 
contains trade secrets and commercially sensitive information that is confidential and may not be 
disclosed unless such disclosure is required by federal or state law or regulations.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who 
have a need to know, but all such persons must be instructed not to further disseminate this 
information to others.  These restrictions of disclosure will apply equally to all future 
information supplied that is indicated as confidential.  Information pertaining to this study will 
be published on www.clinicaltrials.gov and http://registry.healthresearch.ph/. 
The data generated by this clinical study are the property of Santen and should not be disclosed 
without the prior written permission of Santen.  These data may be used by Santen now and in 
the future for presentation or publication at Santen’s discretion or for submission to 
governmental regulatory agencies.  Santen reserves the right of prior review of any publication 
or presentation of data from this study. 
In signing this protocol, the Principal Investigator agrees to the release of the data from this 
study and acknowledges the above publication policy. 


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22. 
REFERENCES 
1. 
Barbara, N., Wrana, J., Letarte, M. (1999).  Endoglin Is an Accessory Protein That 
Interacts with the Signaling Receptor Complex of Multiple Members of the Transforming 
Growth Factor-ß Superfamily. The Journal of Biological Chemistry. 274(2):584-94. 
2. 
Gordon, M., Kass, M. (2001).  Ocular Hypertension Treatment Study (OHTS), Manual of 
Procedures, Version 3.0. National Technical Information Service. 
3. 
Guo, B., Slevin, M., Li, C., Parameshwar, S., Liu, D., Kumar, P., Bernabeu, C., Kumar, S. 
(2004).  CD105 Inhibits Transforming Growth Factor-ß-Smad3 Signalling. Anticancer 
Research. 24(3a):1337-45. 
4. 
Heier, J., Brown, D., Chong, V., Korobelnik, J., Kaiser, P., Nguyen, Q., Kirchhof, B., Ho, 
A., Ogura, Y., Yancopoulos, G., Stahl, N., Vitti, R., Berliner, A., Soo, Y., Anderesi, M., 
Groetzbach, G., Sommerauer, B., Sandbrink, R., Simader, C., Schmidt-Erfurth, U. (2012).  
Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-related Macular Degeneration. 
Ophthalmology. 119(12):2537-48. 
5. 
Kane, F., Campochiaro, P. Choroidal Neovascularization. In: Lim J, editor. Age-Related 
Macular Degeneration. 2nd2008. p. 87-95. 
6. 
Lebrin, F., Goumans, M., Jonker, L., Carvalho, R., Valdimarsdottir, G., Thorikay, M., 
Mummery, C., Arthur, H., ten Dijke, P. (2004).  Endoglin promotes endothelial cell 
proliferation and TGF-ß/ALK1 signal transduction. The EMBO Journal. 23(20):4018-28. 
7. 
Li, C., Issa, R., Kumar, P., Hampson, I., Lopez-Novoa, J., Bernabeu, C., Kumar, S. 
(2003).  CD105 prevents apoptosis in hypoxic endothelial cells. Journal of Cell Science. 
116(13):2677-85. 
8. 
Lim, J., Tsong, J. Exudative (Neovascular) Age-Related Macular Degeneration. In: Lim J, 
editor. Age-Related Macular Degeneration. 2nd2008. p. 125-57. 
9. 
MedDra. MedDRA MSSO, Medical Dictionary for Regulatory Activities, Version 16.1 
2013. 
10. 
Nolan-Stevaux, O., Zhong, W., Culp, S., Shaffer, K., Hoover, J., Wickramasinghe, D., 
Ruefli-Brasse, A. (2012).  Endoglin Requirement for BMP9 Signaling in Endothelial 
Cells Reveals New Mechanism of Action for Selective Anti-Endoglin Antibodies. PLoS 
ONE. 7(12):1-12. 
11. 
Nussenblatt, R., Palestine, A., Chan, C., Roberge, F. (1985).  Standardization of Vitreal 
Inflammatory Activity in Intermediate and Posterior Uveitis. Ophthalmology. 92(4):467-
71. 
12. 
Park, S., Lee, Y., Seki, T., Hong, K., Fliess, N., Jiang, Z., Park, A., Wu, X., Kaartinen, V., 
Roman, B., Oh, S. (2008).  ALK5- and TGFBR2-independent role of ALK1 in the 
pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood. 111(2):633-42. 


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13. 
Sun Working, G. (2005).  PERSPECTIVES Standardization of Uveitis Nomenclature or 
Reporting Clinical Data. Results of the First International Workshop. American Journal 
of Ophthalmology. 140(3):509-16. 
14. 
US_Dept_Health_And_Human_Services. The Seventh Report of the Joint National 
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.  
The Seventh Report of the Joint National Committee on Prevention, Detection, 
Evaluation, and Treatment of High Blood Pressure. Bethesda (MD)2004. 
15. 
Warrington, K., Hillarby, M., Li, C., Letarte, M., Kumar, S. (2005).  Functional Role of 
CD105 in TGF-ß1 Signalling in Murine and Human Endothelial Cells. Anticancer 
Research. 25(3B):1851-64. 
16. 
World Health Organization Drug Dictionary, E. World Health Organization Drug 
Dictionary Enhanced (WHO-DDE), September 2011 Version2011. 
17. 
Yasukawa, T., Kimura, H., Tabata, Y., Miyamoto, H., Honda, Y., Ikada, Y., Ogura, Y. 
(2000).  Active drug targeting with immunoconjugates to choroidal neovascularization. 
Current Eye Research. 21(6):952-61. 
 
 


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23. 
APPENDICES 
23.1. 
Appendix A - Obligations of Investigators 
In summary, the Clinical Investigator has agreed to the following obligations: 
 Obtaining informed consent from every subject prior to the subject’s participation in 
any study related activity and maintaining records of consent as part of the study 
records. 
 Obtaining approval from the IRB before involving any subject in any study related 
activity; submitting verification of the approval to the Sponsor; submitting periodic 
progress reports (at least annually) and final report to IRB and to the Sponsor. 
 Approving the protocol and conducting the study according to the protocol and 
applicable regulations; informing the Sponsor of all deviations from the protocol. 
 Informing the IRB of all protocol amendments/modifications; sending the Sponsor a 
copy of the letter from the IRB approving the amendment/modification. 
 Reporting to the Sponsor and the IRB any adverse experiences that occur in the 
course of the investigation, this includes Serious Adverse Events within 24 hours. 
 Keeping careful and accurate records of all clinical study data (study records must be 
considerably more exact and complete than those kept in ordinary medical practice); 
maintaining records of all materials submitted to the IRB and of all action by the IRB 
regarding the study. 
 Making study records available for inspection by the Sponsor and representatives of 
the Food and Drug Administration and other regulatory agencies; keeping records 
until notified by the Sponsor that they may be destroyed. 
 Maintaining proper control and documentation of all test and control articles. 
 Submitting the following records and reporting to the Sponsor (Section 23.1). 
I. 
Prior to the Beginning of the Study 
 A current curriculum vitae (CV) if not submitted to Santen previously or if updated. 
 CVs for all sub-Investigators. 
 A letter from the IRB indicating that the protocol was approved, including the name 
and address of the IRB.  
 A copy of the consent form approved by IRB.  
 A list of current members of the IRB. 
II. 
While the Study Is in Progress 
 Acknowledgment of receipt of the test and control articles; documentation of 
disposition of all test and control articles. 
 Original Case Report Forms for each subject enrolled in the study. 


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 Information regarding all deviations from the protocol. 
 Information regarding all adverse medical events occurring to a subject while 
enrolled in the study. 
 Annual progress report (if study is ongoing for more than one year).  Letter from the 
IRB indicating approval of the annual progress report. 
III. 
Once the Study Is Completed 
 Disposition of all used and/or unused test and control articles, as well as 
documentation of all drug accountability. 
 A final study report. 
 


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23.2. 
Appendix B - Elements of Informed Consent 
I. 
Elements of Informed Consent 
The following information must be provided to each subject in obtaining informed consent.  If 
written consent is being obtained, the subject (or subject’s legal representative) should be 
provided with a copy of the signed written ICF.  
1. State that the study involves RESEARCH. 
A. 
Explain the PURPOSE of the research. 
B. 
Trial treatments and the probability for random assignment to each treatment. 
C. 
State the expected DURATION of the subject’s participation. 
D. 
Describe the PROCEDURES to be followed. 
E. 
Identify any EXPERIMENTAL procedures. 
2. Describe any reasonably foreseeable RISKS OR DISCOMFORTS to the subject. 
3. Describe any BENEFITS to the subject and responsibility for the subject or to others that 
may reasonably be expected from the research.  
4. Note appropriate ALTERNATIVE procedures or courses of treatment, if any, that might 
be advantageous to the subject. 
5. A. 
Describe the extent, if any, to which CONFIDENTIALITY of records identifying 
the subject will be maintained. 
B. 
Note that the FDA MAY INSPECT the records. 
6. For research involving more than minimal risk, explain if any COMPENSATION or 
medical treatments are available should injury occur.  If so, explain (a) what they consist 
of, OR (b) where further information may be obtained. 
7. A. 
Tell whom to contact for ANSWERS to pertinent questions about (a) the research, 
and (b) research subjects’ rights. 
B. 
Tell whom to contact in the event of a research-related INJURY to the subject. 
8. State that: 
A. 
Participation is VOLUNTARY, 
B. 
Refusal to participate will involve NO PENALTY or loss of benefits to which the 
subject is otherwise entitled 
C. 
The subject MAY DISCONTINUE participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled. 
II. 
Additional Elements of Informed Consent 
When appropriate, one or more of the following elements of information shall also be provided 
to each subject:  


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1. A statement that particular treatment or procedure may involve risks to the subject (or to 
the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable. 
2. Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent. 
3. Any additional costs to the subject that may result from participation in the research. 
4. The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject. 
5. A statement that significant new findings developed during the course of the research, 
which may relate to the subject’s willingness to continue participation, will be provided 
to the subject. 
6. The approximate number of subjects involved in the study. 
The informed consent requirements in this protocol are not intended to preempt any applicable 
Federal, State, or local laws which require additional information to be disclosed for informed 
consent to be legally effective. 
Nothing in this protocol is intended to limit the authority of a physician to provide emergency 
medical care to the extent the physician is permitted to do so under applicable Federal, State, or 
local law. 
REFERENCE: 21 CFR Part 50.25 – PROTECTION OF HUMAN SUBJECTS, Elements of 
Informed Consent. 


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23.3. 
Appendix C - Declaration of Helsinki 
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians.  The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles.  
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the patient's best interest when providing 
medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research.  The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments).  Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 


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7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects.  The responsibility for the protection of 
research subjects must always rest with the physician or other health care professionals 
and never with the research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards.  No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications.  Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits  
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected 
by the condition under investigation. 
Measures to minimize the risks must be implemented.  The risks must be continuously 
monitored, assessed and documented by the researcher. 


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18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group.  In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation.  The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins.  This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified.  It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration.  
The committee must have the right to monitor ongoing studies.  The researcher must 
provide monitoring information to the committee, especially information about any 


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serious adverse events.  No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s findings 
and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary.  Although it may be appropriate to consult family members 
or community leaders, no individual capable of giving informed consent may be enrolled 
in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, post-
study provisions and any other relevant aspects of the study.  The potential subject must 
be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal.  Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to 
deliver the information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-
given informed consent, preferably in writing.  If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress.  In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorized representative.  These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorized representative.  The 
potential subject’s dissent should be respected. 


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30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research group.  
In such circumstances the physician must seek informed consent from the legally 
authorized representative.  If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 
research ethics committee.  Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorized representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research.  The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse.  There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research.  In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial.  This information must also be disclosed to 
participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 


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36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research.  Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports.  All parties should adhere 
to accepted guidelines for ethical reporting.  Negative and inconclusive as well as 
positive results must be published or otherwise made publicly available.  Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the 
publication.  Reports of research not in accordance with the principles of this Declaration 
should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, 
with informed consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgment it offers hope of saving life, re-
establishing health or alleviating suffering.  This intervention should subsequently be 
made the object of research, designed to evaluate its safety and efficacy.  In all cases, 
new information must be recorded and, where appropriate, made publicly available. 


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23.4. 
Appendix D - Procedures for Examinations 
23.4.1. 
Demographics/Eligibility, Medical/Surgical History and Concomitant 
Medication 
Demographics/Eligibility, medical/surgical history and concomitant medication will be obtained 
through subject interviews at Screening (Day -14 to Day -1).  Medical history and concomitant 
medications will be obtained through subject interviews at each visit.  
23.4.2. 
Physical Examination 
A full body systematic physical examination will be conducted during Visit 0/Screening  
(Day -14 to Day -1), Visit 11 (Week 24) and Visit 13 (Week 32).  Clinical Investigator or an 
external internist will confirm subject’s overall condition noting any abnormalities by a review 
of the following systems: e.g., head, eyes, ears, nose and throat (HEENT), cardiopulmonary, 
endocrine, gastrointestinal, musculoskeletal/rheumatic, neurologic/psychiatric, dermatologic, 
hepatic/renal systems, and other. 
The Clinical Investigator will assess subject’s overall condition to determine qualification for 
study entry considering possible class effects of DE-122.  Newly noted abnormalities or 
worsening of previously noted abnormalities found at Study Exit, or at any safety assessment 
visit, will be assessed as an AE.  The Clinical Investigator should use his or her clinical judgment 
for appropriate treatment and/or medical referral. 
23.4.3. 
Vital Signs 
Blood pressure and heart rate will be measured at each visit except Visit 2 (Day 3), Visit 9 
(Week 20 + 2 days) and Visit10 (Week 20 + 7 days) using an automated or manual blood 
pressure monitor.  Systolic and diastolic blood pressures will be recorded in millimeters of 
mercury (mmHg) and heart rate will be recorded in beats per minute (bpm).  
In accordance with the recommendations of the Joint National Committee on Prevention, 
Detection, Evaluation, and Treatment of High Blood Pressure  
(US_Dept_Health_And_Human_Services, 2004), the following measurement procedure will be 
used to measure vital signs: 
 Subject should not smoke or ingest caffeine within the 30-minute period immediately 
before the measurement. 
 Subject should be seated quietly in a chair with the back supported, feet on the floor, 
arm bared, and arm supported at heart level. 
 Begin the measurement after at least 5 minutes of rest. 
 To ensure an accurate measurement, use an appropriately sized cuff.  The cuff 
bladder should encircle at least 80 % of the arm.  Many adults need a large cuff. 
 Take two (2) systolic/diastolic pressure and heart rate measurements separated by at 
least 30 seconds.  Record each measurement in the subject’s source document. 


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 If the two pressure measurements differ by 5 mmHg or less, then the average of the 
two becomes the recorded pressure.  For example, if the two measurements are 
120/90 and 125/95, then 122.5/92.5 is the recorded systolic/diastolic pressure. 
 If the two pressure measurements differ by more than 5 mmHg, then a third reading 
measurement is made, and the average of the three becomes the recorded pressure.  
For example, if the three measurements are 115/90, 124/96, and 120/92, then 
119.7/92.7 is the recorded systolic/diastolic pressure.  The recorded blood pressure 
will be the average of the measurements. 
 Record the heart rate.  For heart rate, the average of the two (or three, if performed) 
measurements obtained becomes the recorded heart rate.  
23.4.4. 
EKG 
EKGs will be recorded at Visit 0/Screening (Day -14 to Day -1) and reviewed for abnormalities 
by the Clinical Investigator prior to enrollment. EKGs will also be performed at Visit 3 (Week 1), 
Visit 10 (Week 20 + 7 days), Visit 11 (Week 24) and Visit 13 (Week 32). 
23.4.5. 
Best Corrected Visual Acuity 
ETDRS chart will be used to examine BCVA at each study visit except Visit 2 (Day 3), Visit 9 
(Week 20 + 2 days) and Visit10 (Week 20 + 7 days).  See Study Procedures manual for the 
detailed procedure for measuring visual acuity. 
23.4.6. 
M-CHARTS™  
M-CHARTS™ will be used to examine metamorphopsia at each study visit except Visit 2  
(Day 3), Visit 9 (Week 20 + 2 days) and Visit10 (Week 20 + 7 days).  Two types of values which 
are vertical metamorphopsia score (MV) and horizontal metamorphopsia score (MH) will be 
assessed. See instruction for measuring metamorphopsia. 
23.4.7. 
Slit-Lamp Biomicroscopy 
Slit-lamp biomicroscopy will be used to examine eye structures at each study visit except Visit 2 
(Day 3), Visit 9 (Week 20 + 2 days) and Visit 10 (Week 20 + 7 days).  Slit-lamp biomicroscopy 
will be performed prior to injection and then again within 30 minutes after injection on the visit 
of DE-122.  This will be also applied for the post IVT injection of Rescue treatment.  
The lid, conjunctiva, cornea, and lens will be observed with the slit-lamp beam approximately 
0.3 mm in width and 1.0 mm in length and graded on a 4-point scale (0-3 scale) as described 
below: 
Lid Redness 
None 
(0) = Normal 
Mild 
(1) = Redness of most or all the lid(s) margin OR skin 
Moderate (2) = Redness of most or all the lid(s) margin AND skin 
Severe 
(3) =  Marked diffuse redness of both lid(s) margin AND skin  


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Lid Edema 
None 
(0) = Normal 
Mild 
(1) = Localized to a small region of the lid(s) 
Moderate (2) = Diffuse, most or all the lid(s) but not  prominent/protruding 
Severe 
(3) = Diffuse, most or all the lid(s) AND prominent/protruding 
Conjunctival (Palpebral and Bulbar) Hyperemia 
None 
(0) = Normal 
Mild 
(1) = Slight localized injection 
Moderate (2) = Pink color, confined to palpebral OR bulbar conjunctiva 
Severe 
(3) = Red color of the palpebral AND/OR bulbar conjunctiva 
Conjunctival Edema 
None 
(0) = Normal 
Mild 
(1) = Slight localized swelling 
Moderate (2) = Mild/medium localized swelling or mild diffuse swelling 
Severe 
(3) = Moderate diffuse swelling 
Corneal Edema 
None 
(0) = Normal 
Mild 
(1) = Mild, diffuse stromal haze 
Moderate (2) = Dense, diffuse stromal haze or bullae 
Severe 
(3) = Dense, diffuse bullae or stromal haze AND stromal edema 
Lens 
The lens will be noted as phakic, aphakic, or pseudophakic.  Phakic lens will be graded as 
described below: 
None 
(0) = No lens discoloration nor opacification 
Mil d 
(1) = Yellow lens discoloration or small lens opacity (axial or peripheral) 
Moderate (2) = Amber lens discoloration or medium lens opacity (axial or peripheral) 
Severe 
(3) = Brunescent lens discoloration or complete lens opacification (no red reflex) 
 
Anterior chamber cells and flare will be observed with a 1.0 mm in width and 1.0 mm in length 
slit beam and graded using the Standardization of Uveitis Nomenclature (SUN) scale (Sun 
Working, 2005).  The iris and the pupil will be evaluated for the presence of clinically significant 
abnormalities. 


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Anterior Chamber Cells  
(0) = No cells 
(0.5) = 1-5 cells 
(1) = 6-15 cells 
(2) = 16-25 cells 
(3) = 26-50 cells 
(4) = >50 cells 
Anterior Chamber Flare  
(0) = None 
(1) = Faint 
(2) = Moderate (iris/lens details clear) 
(3) = Marked (iris/lens details hazy) 
(4) = Intense (fibrin/plastic aqueous) 
Iris 
The iris will be evaluated for the presence of any clinically significant abnormalities, and 
graded as either normal (within normal limits) or abnormal (clinically significant abnormality 
present).  A description of any clinically significant abnormalities will be noted. 
Pupil 
The pupil will be evaluated for the presence of any clinically significant abnormalities, and 
graded as either normal (within normal limits) or abnormal (clinically significant abnormality 
present).  A description of any clinically significant abnormalities will be noted. 
23.4.8. 
Intraocular Pressure 
IOP will be measured by applanation tonometry at each study visit except Visit 2 (Day 3), Visit 9 
(Week 20 + 2 days) and Visit 10 (Week 20 + 7 days).   
At visits with IVT injection, IOP will be measured before Lucentis® injection and 40 (±10) 
minutes after injection.  If post-Lucentis® injection IOP is > 21 mmHg or increased ≥ 10 mmHg 
from pre-injection IOP, the IOP measurement will be repeated at 60 (±10) minutes following 
Lucentis® injection. 
If post-injection IOP at 60 (±10) minutes is ≥ 30 mmHg OR increased ≥ 10 mmHg from pre-
injection IOP, the subject should be prescribed a topical IOP-lowering medication until he or she 
returns for follow-up per the Clinical Investigator’s discretion, and the event will be reported as 
an AE. 
IOP will be also measured after DE-122 or Sham injection.  If post-DE-122 or Sham injection 
IOP is > 21 mmHg OR increased ≥ 10 mmHg from pre-Lucentis® injection at 40 (±10) minutes 
after injection, the IOP measurement will be repeated at 60 (±10) minutes after the injection.  If 
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≥ 10 mmHg from pre-Lucentis® injection IOP, the subject should be prescribed a topical IOP-
lowering medication, and the IOP elevation will be reported as an AE. If post-injection IOP at  
60 (±10) minutes is > 21 mmHg AND < 30 mmHg, the subject will be managed according to the 
Clinical Investigator’s discretion. 
If rescue IVT injection is performed, IOP will be measured 40 (±10) minutes after the injection.  
If post-injection IOP is > 21 mmHg OR increased ≥ 10 mmHg from pre-injection IOP, IOP 
measurement will be repeated at 60 (±10) minutes post-injection.  If post-injection IOP at 60 
(±10) minutes is ≥ 30 mmHg OR increased ≥ 10 mmHg from pre-injection IOP, the subject 
should be prescribed a topical IOP-lowering medication, and the IOP elevation will be reported 
as an AE. Per the Clinical Investigator’s discretion, the subject can return for follow-up.  If post-
injection IOP at 60 (±10) minutes is > 21 mmHg AND < 30 mmHg, the subject will be managed 
according to the Clinical Investigator’s discretion. 
The applanation tonometer must be calibrated for accuracy before the first subject undergoes 
screening, and periodically until the last subject has exited the study.  For checking calibration, 
follow the manufacturer’s instructions.  
The following IOP measurement procedure is in accordance with the procedure used in the 
Ocular Hypertension Treatment Study (Gordon et al., 2001) at each visit: 
At least two, and sometimes three, consecutive measurements are made to obtain a determination 
of intraocular pressure.  Each IOP measurement should be recorded in the subject’s source 
document and in the eCRFs. 
 If the first 2 measurements differ by less than 3 mmHg, report the mean of the first  
2 measurements.  For example, if the two measurements are 22 and 23, then 22.5 is 
the final recorded IOP. 
 However, if the first 2 measurements differ by greater than or equal to 3 mmHg, take 
a third measurement and report the median IOP (the median is the middle 
measurement after arraying the measurements from low to high).  For example, if the 
three measurements are 15, 19, and 16, then 16 is the final recorded IOP. 
23.4.9. 
Indirect Ophthalmoscopy 
Indirect ophthalmoscopy will be performed for each eye at each visit except Visit 2 (Day 3), 
Visit 9 (Week 20 + 2 days) and Visit10 (Week 20 + 7 days) with pupil dilation. 
Indirect ophthalmoscopy will be used to examine the retina at each study visit.  Indirect 
ophthalmoscopy will be performed prior to and within 30 minutes after each DE-122 or Sham 
injection.  Areas to be assessed include cup to disc ratio, retina, macula and choroid, and 
vitreous.  This will be also applied for the post IVT injection of Rescue treatment. 
Cup/Disc Ratio 
The cup/disc ratio will be determined by the examiner and recorded using two decimal places 
(e.g., 0.80). 
 
 


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Retina, Macula and Choroid 
The retina, macula and choroid will be evaluated for the presence of any clinically significant 
abnormalities, and graded as either normal (within normal limits) or abnormal (clinically 
significant abnormality present).  A description of any abnormalities will be noted. 
Vitreous 
The following National Eye Institute Grading Scheme will be used to measure vitreous haze 
and opacification (Nussenblatt et al., 1985). 
Vitreous Haze Scale 
Step  
Description  
(0)  
Clear 
(Trace or 0.5+)  
Trace 
(1+)  
Few opacities, mild blurring 
(2+)  
Significant blurring but still visible 
(3+)  
Optic nerve visible, no vessels seen 
(4+)  
Dense opacity obscures the optic nerve head 
23.4.10. 
Spectral Domain Optical Coherence Tomography 
Spectralis, Cirrus or 3D OCT will be utilized to take optical images at each study visit except 
Visit 2 (Day 3), Visit 9 (Week 20 + 2 days) and Visit 10 (Week 20 + 7 days).  The images will 
be sent to the central reading center. 
23.4.11. 
Swept Source Optical Coherence Tomography Angiography 
Swept Source OCT angiography will be taken at each study visit except Visit 2 (Day 3), Visit 9 
(Week 20 + 2 days) and Visit 10 (Week 20 + 7 days).  
23.4.12. 
Fundus Photography 
Digital color fundus photography will be taken at Visit 0/Screening (Day -14 to Day -1), Visit 4 
(Week 4), Visit 6 (Week 12), Visit 11 (Week 24) and Visit 13/Exit (Week 32). The images will 
be sent to the central reading center. 
23.4.13. 
Fluorescein Angiography  
Fundus fluorescein angiography will be taken at Visit 0/Screening (Day -14 to Day -1), Visit 4 
(Week 4), Visit 6 (Week 12), Visit 11 (Week 24) and Visit 13/Exit (Week 32). The images will 
be sent to the central reading center.  
23.4.14. 
Urine Pregnancy Test  
A urine pregnancy test will be conducted before IVT injection at Visit 1 (Day 1) for all females 
of childbearing potential.  A female is considered of childbearing potential unless she is post-
menopausal (at least 24 months since last menses occurred), has had her uterus and/or both 


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ovaries removed, or has had a bilateral tubal ligation.  To obtain the pregnancy test, the subject 
should follow instructions provided by the manufacturer of the urine pregnancy test kit.  
23.4.15. 
Serum Pregnancy Test 
A serum pregnancy test will be conducted at Screening (Day -14 to Day -1), Visit 11 (Week 24) 
and Visit 13/Exit (Week 32) for all females of childbearing potential.  A female is considered of 
childbearing potential unless she is post-menopausal (at least 24 months since last menses 
occurred), has had her uterus and/or both ovaries removed, or has had a bilateral tubal ligation.  
To perform the pregnancy test, Human chorionic gonadotropin (hCG) will be contained into 
serum parameters that will be measured.  
23.4.16. 
Hematology, Chemistry and Urinalysis 
Approximately 10 mL of fasting blood and urine samples will be obtained at Visit 0/Screening 
(Day -14 to Day -1), Visit 4 (Week 4), Visit 6 (Week 12), Visit 11 (Week 24) and Visit 13/Exit 
(Week 32).  The subjects will be asked to fast for a minimum of 8 hours prior to each blood and 
urine collection.  Samples will be sent to a central laboratory for analysis. 
There will be up to approximately 5 blood draws for immunogenicity.  Approximately 10 mL or 
2 teaspoons will be collected for each blood draw.  The total amount of blood collected from 
each subject during this study will be up to approximately 50 mL 
Serum Chemistry, Hematology 
The following is a list of the minimum parameters that will be measured.  Other additional 
parameters may also be reported. 
Chemistry  
Hematology 
Albumin 
red blood cells (RBC) 
Creatinine 
white blood cells (WBC) 
lactate dehydrogenase (LDH) 
differential WBC 
glucose 
platelets (PLT) 
calcium 
hemoglobin (HGB) 
potassium 
hematocrit (HCT) 
sodium 
mean corpuscular volume (MCV) 
cholesterol (total, HDL and LDL) 
mean corpuscular hemoglobin (MCH) 
triglycerides 
mean corpuscular hemoglobin conc. (MCHC) 
urea nitrogen 
 
bilirubin (total, direct, indirect) 
 
alkaline phosphatase (ALP) 
 
alanine aminotransferase (ALT) 
 
aspartate aminotransferase (AST) 
 
gamma glutamyl transferase (GGT) 
 
Human chorionic gonadotropin (hCG)* 
 


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Prior to enrolling a subject, the Clinical Investigator will indicate on the source document if any 
screening laboratory values exclude the subject from participating in the study (e.g., serum 
creatinine  1.3 mg/dL). 
*Conduct only at Visit 0/Screening (Day -14 to Day -1), Visit 11 (Week 24) and Visit 13/Exit 
(Week 32). 
Urinalysis 
The following is a list of the minimum urine parameters that will be measured.  Other additional 
urine parameters may also be reported. 
Urinalysis 
PH 
Protein 
Erythrocytes 
Ketones 
Glucose 
Prior to enrolling a subject, the Clinical Investigator will indicate on the source document if any 
screening laboratory values exclude the subject from participating in the study. 
23.4.17. 
Procedures for Pharmacokinetic Serum Sample Collection, Storage and 
Shipment   
Approximately 5 mL of blood sample for assessment of DE-122 levels in serum will be collected 
pre Lucentis® injection at Visit 1 (Day 1), 3 hrs (±10 mins) post DE-122 or Sham injection at 
Visit 1 (Day 1), Visit 2 (Day 3), Visit 3 (Week 1), Visit 4 (Week 4), pre Lucentis® injection at 
Visit 8 (Week 20), 3 hrs (±10 mins) post DE-122 or Sham injection at Visit 8 (Week 20), Visit 9 
(Week 20 + 2 days), Visit10 (Week 20 + 7 days) and Visit11 (Week 24) for all subjects.  The 
actual time of dosing and sampling will be recorded on the eCRF.  After each serum sample is 
taken from the subject, the sample is to be stored on ice until processed for the collection of the 
serum fraction.  The blood sample should be processed for serum within approximately 1 hour 
after blood collection from the subject.  
There will be up to approximately 10 blood draws for PK.  Approximately 5 mL or 1 teaspoon 
will be collected for each blood draw.  The total amount of blood collected from each subject 
during this study will be up to approximately 50 mL. 
Please refer to the separate procedure manual for sample handling, storage, and shipment.  
This procedure is applicable for the subjects who have consented under the protocol prior to 
Version 4.0. 
23.4.18. 
Procedure for Immunogenicity Serum Sample 
Approximately 2 mL of blood sample will be collected for immunogenicity analysis from the 
subject at Visit 1 (Day 1) and Visit 11 (Week 24). 
There will be up to approximately 2 blood draws for immunogenicity.  The total amount of blood 
collected from each subject during this study will be up to approximately 4 mL. 


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Refer to the separate procedure manual for sample handling, storage, and shipment. 
23.4.19. 
Procedures for Pharmacogenomics/genomics Blood Sample Collection, Storage 
and Shipment 
Approximately 10 mL of blood will be collected for future genetic analysis from the subject and 
stored in a refrigerator until shipment.  It can be drawn once at any visit during the study after 
Visit 1(Day 1).  Please refer to the separate procedure manual for sample handling, storage, and 
shipment.  The samples will be coded to protect the participant’s private information.  Individual 
subjects’ results from the research testing on their samples will not be communicated to them.  
23.4.20. 
Procedure for Biomarker Serum Sample 
Approximately 10 mL of blood sample will be collected for biomarker analysis from the subject 
pre Lucentis® injection at Visit 1 (Day 1), 3 hrs (±10 mins) post DE-122 or Sham injection at 
Visit 1 (Day 1), Visit 2 (Day 3) if applicable, Visit 3 (Week 1), Visit 4 (Week 4), pre Lucentis® 
injection at Visit 8 (Week 20), 3 hrs (±10 mins) post DE-122 or Sham injection at Visit 8  
(Week 20), Visit 9 (Week 20 + 2 days) if applicable, Visit 10 (Week 20 + 7 days) and Visit 11 
(Week 24). 
There will be up to approximately 10 blood draws for Biomarker.  The total amount of blood 
collected from each subject during this study will be up to approximately 100 mL. 
Refer to the separate procedure manual for sample handling, storage, and shipment. 
23.4.21. 
Procedure for Biomarker Aqueous Humor Sample 
Approximately 50~120 µL of aqueous humor sample will be collected for biomarker analysis 
from the subject at Visit 1 (Day 1), Visit 4 (Week 4) and Visit 8 (Week 20). 
Refer to the separate procedure manual for sample handling, storage, and shipment. 
 
 


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SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
A Multi-Center, Randomized, Double Masked and Active 
Controlled Phase II Study Assessing the Efficacy and Safety of 
Intravitreal Injections of DE-122 in combination with Lucentis® 
Compared to Lucentis® Monotherapy in Subjects with Wet Age-
related Macular Degeneration - AVANTE study 
 
NCT Number:  
NCT03211234 
 
 
Date of the document: 
11 Oct 2019  
 
 
 


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STATISTICAL ANALYSIS PLAN 
DE-122 Study 36-002 
 
Protocol Title: 
A Multi-Center, Randomized, Double Masked and Active Controlled Phase II Study 
Assessing the Efficacy and Safety of Intravitreal Injections of DE-122 in combination 
with Lucentis® Compared to Lucentis® Monotherapy in Subjects with Wet Age-
related Macular Degeneration – AVANTE study 
 
Product: 
2.0 mg (20µL of 100 mg/mL) 
DE-122 injectable solution  
4.0 mg (40µL of 100 mg/mL)  
DE-122 injectable solution 
 
Protocol 
Number:  
36-002 Amendment 07 
Sponsor: 
Santen Inc. 
 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
U.S.A. 
Date:  
October 11, 2019 
 
Status:  
Version 1.0 
 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen Inc. and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by Federal and State Laws.  Persons to 
whom this information is disclosed must be informed that this information is privileged and 
confidential and that it should not be further disclosed. 
 


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APPROVAL SIGN-OFF SHEET 
A Multi-Center, Randomized, Double Masked and Active Controlled Phase II Study 
Assessing the Efficacy and Safety of Intravitreal Injections of DE-122 in Combination with 
Lucentis® Compared to Lucentis® Monotherapy in Subjects with Wet Age-related Macular 
Degeneration – AVANTE Study 
DE-122 Study 36-002 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
ABBREVIATIONS .........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
2.1. 
Objectives ...................................................................................................................10 
2.2. 
Endpoints ....................................................................................................................10 
2.2.1. 
Primary Efficacy Endpoint .........................................................................................10 
2.2.2. 
Secondary Efficacy Endpoint .....................................................................................10 
2.2.3. 
Safety Endpoint ..........................................................................................................10 
2.2.4. 
Pharmacokinetics Endpoint ........................................................................................11 
2.2.5. 
Immunogenicity Endpoint ..........................................................................................11 
2.2.6. 
Biomarker Endpoint ....................................................................................................11 
2.2.7. 
Exploratory Endpoints ................................................................................................11 
2.2.7.1. 
M-CHARTS™ .............................................................................................................11 
2.2.7.2. 
Swept Source OCT Angiography ...............................................................................11 
2.2.7.3. 
Subretinal Hyper-Reflective Material and Retinal Pigment Epithelium 
Elevation .....................................................................................................................11 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
General Study Design .................................................................................................12 
3.2. 
Randomization and Masking ......................................................................................13 
3.3. 
Sample Size Planning .................................................................................................14 
3.4. 
Visits and Assessments ...............................................................................................14 
4. 
DEFINTIONS .............................................................................................................18 
4.1. 
Time-Related Terms ...................................................................................................18 
4.1.1. 
Screening Visit ............................................................................................................18 
4.1.2. 
Baseline Visit ..............................................................................................................18 
4.1.3. 
Study Day ...................................................................................................................18 
4.1.4. 
Analysis Periods .........................................................................................................18 
4.1.5. 
Out-of-Window Measurements, Analysis Window and Analysis Visit .....................18 
4.1.6. 
Days on Treatment ......................................................................................................19 


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4.2. 
Efficacy-Related Definitions ......................................................................................19 
4.2.1. 
Study Eye and Fellow Eye ..........................................................................................19 
4.2.2. 
Baseline Score ............................................................................................................19 
4.2.3. 
Change and Percent Change from Baseline ................................................................20 
4.2.4. 
Efficacy Measures ......................................................................................................20 
4.3. 
Safety-Related Definitions ..........................................................................................21 
4.3.1. 
Adverse Event .............................................................................................................21 
4.3.1.1. 
Severity of Adverse Event ..........................................................................................21 
4.3.1.2. 
Serious Adverse Event ................................................................................................21 
4.3.1.3. 
Ocular Adverse Event .................................................................................................21 
4.3.1.4. 
Suspected Adverse Reaction .......................................................................................21 
4.3.1.5. 
Events of Special Interest ...........................................................................................22 
4.3.2. 
Safety Measures ..........................................................................................................22 
4.3.3. 
Rescue Therapy ..........................................................................................................22 
4.3.4. 
Baseline Score ............................................................................................................22 
4.3.5. 
Change and Percent Change from Baseline ................................................................22 
4.3.6. 
Change after Injection .................................................................................................22 
4.4. 
Other Definitions ........................................................................................................25 
4.4.1. 
Prior and Concomitant Medications ...........................................................................25 
4.4.2. 
Pharmacokinetic Measures .........................................................................................25 
4.4.3. 
M-CHARTS™ .............................................................................................................26 
4.4.4. 
Subretinal Hyper-Reflective Material and Retinal Pigment Epithelium 
Elevation .....................................................................................................................26 
5. 
STUDY POPULATION .............................................................................................27 
5.1. 
Intention-to-Treat Population .....................................................................................27 
5.2. 
Safety Population ........................................................................................................27 
5.3. 
Full Analysis Set .........................................................................................................27 
5.4. 
Per-Protocol Set ..........................................................................................................27 
5.5. 
PK Population .............................................................................................................27 
5.6. 
Biomarker Population .................................................................................................27 
6. 
GENERAL CONSIDERATIONS ..............................................................................28 
6.1. 
Adjustments for Covariates ........................................................................................28 
6.2. 
Handling of Missing Data ...........................................................................................28 


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6.3. 
Handling of Special Measurement Values .................................................................28 
6.4. 
Multi-Center Studies ...................................................................................................29 
6.5. 
Multiple Comparisons / Multiplicity ..........................................................................29 
6.6. 
Interim Analysis ..........................................................................................................29 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................30 
7.1. 
Subject Disposition .....................................................................................................30 
7.2. 
Demographics and Baseline Characteristics ...............................................................30 
7.3. 
Medical and Surgical History .....................................................................................31 
7.4. 
Protocol Deviations ....................................................................................................31 
7.5. 
Prior and Concomitant Medications ...........................................................................31 
7.6. 
Exposure to Study Medication ....................................................................................32 
7.7. 
Treatment Compliance ................................................................................................32 
8. 
EFFICACY ANALYSES ...........................................................................................33 
8.1. 
Primary Endpoint ........................................................................................................33 
8.1.1. 
Primary Analysis ........................................................................................................33 
8.1.2. 
Sensitivity Analysis ....................................................................................................33 
8.2. 
Analyses of Secondary Endpoints ..............................................................................33 
8.2.1. 
Primary Analysis ........................................................................................................33 
8.2.2. 
Sensitivity Analysis ....................................................................................................34 
8.3. 
Subgroup Analyses .....................................................................................................34 
9. 
SAFETY ANALYSES ...............................................................................................35 
9.1. 
Adverse Event .............................................................................................................35 
9.2. 
Slit-lamp Biomicroscopy ............................................................................................35 
9.3. 
Ophthalmoscopy .........................................................................................................35 
9.4. 
Intraocular Pressure ....................................................................................................36 
9.5. 
Rescue Therapy ..........................................................................................................36 
9.6. 
Electrocardiogram (EKG) ...........................................................................................36 
9.7. 
Vital Signs ..................................................................................................................36 
9.8. 
Laboratory Assessments .............................................................................................36 
10. 
PHARMACOKINETIC ANALYSES ........................................................................37 
11. 
IMMUNOGENICITY ANALYSIS ............................................................................37 
12. 
BIOMARKER ANALYSIS........................................................................................37 
13. 
OTHER ANALYSES .................................................................................................37 


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13.1. 
M-CHARTS™ .............................................................................................................37 
13.2. 
SS-OCT Angiography ................................................................................................37 
13.3. 
Subretinal Hyper-Reflective Material and Retinal Pigment Epithelium 
Elevation .....................................................................................................................37 
14. 
REFERENCES ...........................................................................................................37 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................15 
Table 2: 
Analysis Periods .........................................................................................................18 
Table 3: 
Post-Baseline Analysis Visit and Analysis Window ..................................................19 
Table 4: 
Efficacy Measures ......................................................................................................20 
Table 5: 
Safety Measures ..........................................................................................................23 
Table 6: 
Pharmacokinetic Measures .........................................................................................25 
 
LIST OF FIGURES 
Figure 1: 
Study Design Diagram ................................................................................................13 
 
 


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ABBREVIATIONS 
Abbreviation 
Explanation 
ADaM 
Analysis Data Model  
ADR(s) 
Adverse Drug Reaction(s) 
AE(s) 
adverse event(s) 
AMD 
age-related macular degeneration 
ATC 
Anatomical-Therapeutic-Chemical  
AUC 
area under the curve 
BCVA 
best corrected visual acuity 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CNV 
Choroidal neovascularization  
CRLT 
Central retinal lesion thickness 
CSR 
clinical study report 
CST 
central subfield thickness 
eCRF 
electronic Case Report Form 
EKG 
electrocardiogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ESI(s) 
event(s) of special interest 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
HM 
horizontal metamorphopsia 
IOP 
intraocular pressure 
ITT 
intention-to-treat 
IVT 
intravitreal 
LOCF 
last-observation-carried-forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
μg/mL 
microgram per milliliter 
mm 
millimeter 
mmHg 
millimeters of mercury 
μm 
micrometer 
 


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ABBREVIATIONS (Continued) 
Abbreviation 
Explanation 
OD 
oculus dexter (right eye) 
OS 
oculus sinister (left eye) 
OU 
oculus uterque (both eyes) 
PK 
pharmacokinetic/pharmacokinetics 
PPS 
per-protocol set 
RPE 
retinal pigment epithelium 
SAE(s) 
serious adverse event(s) 
SADR(s) 
serious adverse drug reaction 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SD-OCT 
spectral-domain optical coherence tomography 
SDTM 
study data tabulation model 
SHRM 
subretinal hyper-reflective material 
SOC 
system organ classification 
US 
United States 
VEGF 
vascular endothelial growth factor 
VM 
vertical metamorphopsia 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the 
analysis of data collected within the scope of Santen’s Protocol 36-002, Amendment 07, “A 
Multi-Center, Randomized, Double Masked and Active Controlled Phase II Study Assessing the 
Efficacy and Safety of Intravitreal Injections of DE-122 in Combination with Lucentis® 
Compared to Lucentis® Monotherapy in Subjects with Wet Age-related Macular Degeneration - 
AVANTE Study”.  It applies to the study protocol dated 08 January 2019 and provides detailed 
instructions as to how each analysis will be performed. 
Results obtained from the analyses specified in the final approved version of the SAP will 
become the basis of the clinical study report (CSR) for this protocol.  Any deviations from the 
final approved version of the SAP must be substantiated by sound statistical reasoning and 
documented in the CSR. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective is: 
 To assess the safety and efficacy of repeated intravitreal injections of DE-122 (2.0 mg 
per eye and 4.0 mg per eye) given in combination with Lucentis® in subjects with 
wet age-related macular degeneration (AMD) compared with Lucentis® alone. 
The secondary objectives are 
 To evaluate the pharmacokinetics and immunogenicity of DE-122 following repeated 
IVT injections of DE-122 in subjects with wet AMD in serum samples. 
 To evaluate biomarker candidates of DE-122 following repeated IVT injections of 
DE-122 in subjects with wet AMD in both serum and aqueous humor samples. 
2.2. 
Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is mean change from baseline in Best Corrected Visual Acuity 
(BCVA) at Week 24. 
2.2.2. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoints are: 
 The proportions of subjects with ≥ 15 Early Treatment Diabetic Retinopathy Study 
(ETDRS) letters (3 line gainers) of BCVA improvement, < 15 letter change (stable), 
and ≥ 15 letter loss from baseline to week 24. 
 Change from baseline in central subfield thickness (CST), macular volume (MV) and 
central retinal lesion thickness (CRLT) as measured by spectral-domain optical 
coherence tomography (SD-OCT) assessed at Week 24. 
 Change from baseline in total lesion area and total area of choroidal 
neovascularization (CNV), greatest linear dimension of the total lesion area (GLD) by 
fluorescein angiogram (FA), as determined by a central reading center at Week 24. 
2.2.3. 
Safety Endpoint 
The safety of DE-122 will be evaluated by: 
 Adverse events (AEs) 
 Slit lamp biomicroscopy 
 IOP 
 Indirect ophthalmoscopy 


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 Laboratory assessment including serum chemistry, hematology, and urinalysis 
 Vital signs 
 Electrocardiogram (EKG) 
2.2.4. 
Pharmacokinetics Endpoint 
Pharmacokinetic profile will be assessed by pharmacokinetic parameters including AUC, Cmax, 
tmax, and t1/2. 
2.2.5. 
Immunogenicity Endpoint 
Immunogenicity will be assessed by the incidence of DE-122 antibody development in serum. 
2.2.6. 
Biomarker Endpoint 
For biomarker investigation, serum samples and aqueous humor samples from the study eye will 
be measured for levels of angiogenesis-related proteins. 
2.2.7. 
Exploratory Endpoints 
2.2.7.1. 
M-CHARTS™ 
The degree of metamorphopsia will be explored by vertical metamorphopsia score (VM) and 
horizontal metamorphopsia score (HM) from the M-CHARTS™. 
2.2.7.2. 
Swept Source OCT Angiography 
Swept Source OCT (SS-OCT) angiography will be evaluated for future exploratory research.  
This exploratory evaluation will be a collaboration between Santen and a third party, and is out 
of the scope of this document. 
2.2.7.3. 
Subretinal Hyper-Reflective Material and Retinal Pigment Epithelium Elevation 
Subretinal hyper-reflective material (SHRM) and retinal pigment epithelium elevation (RPEE) 
by SD-OCT will be evaluated for future exploratory research. 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is a randomized, double masked and active controlled study assessing the safety and 
efficacy of repeated intravitreal injections of DE-122 (2.0 mg or 4.0 mg) in combination with 
Lucentis® compared to Lucentis® monotherapy in subjects with wet AMD.  Seventy-six (76) 
subjects wet AMD were randomly assigned to one of three treatment arms in two stages:  
 Arm 1: Sham + Lucentis® 0.5 mg (N=17) 
 Arm 2: DE-122, 2.0 mg + Lucentis® 0.5 mg (N=31) 
 Arm 3: DE-122, 4.0 mg + Lucentis® 0.5 mg (N=28) 
As shown in the Study Design Diagram (Figure 1), this study will consist of two stages.  In 
Stage 1, the first 6 subjects will be randomized to either Arm 1 or Arm 2 in a 1:1 ratio.  After all 
the 6 subjects have completed the Week 4 visit, the Safety Review Team will review the data to 
determine whether or not the safety and tolerability is acceptable.  Subsequently in Stage 2, 
approximately 70 subjects will be randomized in a 1:2:2 ratios among the three arms. 
Subjects will receive, in combination with Lucentis®, either 6 monthly intravitreal injections of 
DE-122 (2.0 mg), DE-122 (4.0 mg), or Sham in the study eye.  The Primary Analysis is planned 
when all subjects complete the Week 24 visit.  The Follow-up Analysis is planned at Week 32 to 
assess the number of anti-VEGF injections used for Rescue in addition to efficacy and safety 
data. 
To be eligible, a subject must have been previously treated (i.e., At least 3 IVT injections of 
Anti-VEGF for treatment naïve eyes or eyes adequately maintained on continuous intravitreal 
anti-VEGF therapy).  This condition was not required for subjects who enrolled before Protocol 
Amendment 06. 


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Figure 1: 
Study Design Diagram 
 
3.2. 
Randomization and Masking 
In Stage 1, the first 6 subjects will be randomized to either Arm 1 or Arm 2 in a 1:1 ratio.  A 
blocked randomization with a fixed block size of 2 will be employed. 
In Stage 2, approximately 70 subjects will be randomized to all three Arms in a 1:2:2 ratios.  A 
blocked randomization with a fixed block size of 5 stratified by lesion type (polypoidal choroidal 
vasculopathy [PCV] vs. non-PCV) will be employed.  Approximately one third (1/3) of the 
subjects in each arm are expected to have PCV in Stage 2. 
This is a double-masked study, where the subjects and the examiners including the Principal 
Investigator (PI), are masked to the treatment regimen.  However, the designated injecting 
physician (who is not the PI) will not be masked to the treatment regimen. 
The Sponsor will have masked and unmasked data review teams.  The designated Safety Review 
Team will review the safety data of the 6 subjects in Stage 1 to determine if the safety and 
tolerability of the doses at Week 4 are acceptable.  In case of a medical emergency, the Principal 


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Investigator or site staff may reveal the treatment information by unmasking in the Interactive 
Web Response Systems (IWRS). 
3.3. 
Sample Size Planning 
Approximately 76 subjects (Arm 1: 17, Arm 2: 31, Arm 3: 28) with wet AMD will be enrolled at 
approximately 14 sites.  The sample size is not based upon any statistical considerations. 
3.4. 
Visits and Assessments 
Assessments at each visit and visit windows are specified in the Schedule of Event (Table 1). 
 


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Table 1: 
Schedule of Events 
*Only the subjects who have consented under the protocol prior to Amendment 07 require the grayed-out examinations in the 
table.  
Visit Number 
Visit 0 
(SCRN) 
Visit 
1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 
8 
Visit 9 
Visit 10 
Visit 
11 
Visit 
12 
Visit 
13 
/Exit 
Visit Schedule 
(Time window; days) 
D-14 
to -1 
D1 
D3 
W1 
W4 
W8 
W12 
W16 
W20 
W20 
+ 2 days 
W20 
+ 7 
days 
W24 
W28 
W32 
D3 
D8 
(±1) 
D29 
(±3) 
D57 
(±3) 
D85 
(±4) 
D113 
(±4) 
D141 
(±4) 
W20 
 + 2 
days 
W20 
+ 7(±1) 
days 
D169 
(±5) 
D197 
(±5) 
D225 
(±5) 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history, 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EKG 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
BCVA (ETDRS) 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
M-CHARTS™ 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Slit-lamp 
biomicroscopyb 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Intraocular pressure 
(IOP)c 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Indirect 
ophthalmoscopyb 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SD-OCT 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SS-OCT angiographyd 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 


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Table 1: 
Schedule of Events (Continued) 
Visit Number 
Visit 0 
(SCRN) 
Visit 
1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 
8 
Visit 9 
Visit 10 
Visit 
11 
Visit 
12 
Visit 
13 
/Exit 
Visit Schedule 
(Time window; days) 
D-14 
to -1 
D1 
D3 
W1 
W4 
W8 
W12 
W16 
W20 
W20 
+ 2 days 
W20 
+ 7 
days 
W24 
W28 
W32 
D3 
D8 
(±1) 
D29 
(±3) 
D57 
(±3) 
D85 
(±4) 
D113 
(±4) 
D141 
(±4) 
W20 
 + 2 
days 
W20 
+ 7(±1) 
days 
D169 
(±5) 
D197 
(±5) 
D225 
(±5) 
Fundus photography 
(FP) 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
Fluorescein angiography 
(FA) 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
Urine pregnancy teste 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisf 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
Serum pregnancy teste 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hematology, chemistry 
serum samplef 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
PK serum sampleg 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
Biomarker serum 
sampleg 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
Immunogenicity serum 
sample 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacogenomics/geno
mics blood samplea, h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker aqueous 
humor samplea 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 


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Table 1: 
Schedule of Events (Continued) 
Visit Number 
Visit 0 
(SCRN) 
Visit 
1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 
8 
Visit 9 
Visit 10 
Visit 
11 
Visit 
12 
Visit 
13 
/Exit 
Visit Schedule 
(Time window; days) 
D-14 
to -1 
D1 
D3 
W1 
W4 
W8 
W12 
W16 
W20 
W20 
+ 2 days 
W20 
+ 7 
days 
W24 
W28 
W32 
D3 
D8 
(±1) 
D29 
(±3) 
D57 
(±3) 
D85 
(±4) 
D113 
(±4) 
D141 
(±4) 
W20 
 + 2 
days 
W20 
+ 7(±1) 
days 
D169 
(±5) 
D197 
(±5) 
D225 
(±5) 
Lucentis® IVT injectioni 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
DE-122 or Sham IVT 
Injectioni 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse event 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SCRN= Screening; D=Day; W=Week; PK=Pharmacokinetic 
 
a. Collection and Pharmacogenomics/genomics blood sample collection. 
b. On days when either Lucentis®/DE-122 or Lucentis®/Sham IVT injections are administered, slit lamp biomicroscopy and indirect ophthalmoscopy will be 
performed prior to injection and within 30 minutes after DE-122 or Sham injection.  This will be also applied for the post IVT injection of Rescue treatment. 
c. On days when either Lucentis®/DE-122or Lucentis® /Sham IVT injections are administered, IOP will be performed before and after Lucentis® IVT injection.  
In addition, after DE-122 or Sham injection, IOP will be performed again.  This will be also applied for the post injection of Rescue treatment. 
d. Selected sites will conduct. 
e. Serum and urine pregnancy tests are to be performed on all females of child-bearing potential. 
f. Subjects should fast for a minimum of 8 hours prior to urine specimen and blood draw for serum chemistry tests. 
g. At baseline (Day 1, Visit 1), serum sample for DE-122 concentration (if applicable) and biomarker will be collected  
1) 
prior to the Lucentis® injection;  
2) 
post DE-122 or Sham injection: 3 hours, 48 hours, 1 week and 4 weeks (prior to the Lucentis® injection).  
 At Week 20, serum sample for DE-122 concentration (if applicable) and biomarker will also be collected 
1) 
prior to the Lucentis® injection;  
2) 
post DE-122 or Sham injection: 3 hours, 48 hours, 1 week and 4 weeks. 
h. Pharmacogenomics/genomics blood sample can be drawn once at Day 1 or any visit after Visit 1(Day 1) during the study.  
i. Lucentis® will be administered first, and then DE-122 or Sham will be injected.  Rescue treatment with any anti-VEGF IVT injection can be performed during 
the Week 24 and Week 28 visits. 


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4. 
DEFINTIONS 
4.1. 
Time-Related Terms 
4.1.1. 
Screening Visit 
The screening visit is Visit 0 when the subject provided written informed consent. 
4.1.2. 
Baseline Visit  
The baseline visit is Visit 1 (Day 1) visit when the subject is randomized. 
4.1.3. 
Study Day  
The study day variable is the relative day of the observation with respect to the reference date, 
which is set to Day 1.  In this study, the reference date is the baseline visit date, and the study 
day will be defined as: 
 For days prior to the injection date, study day = date – baseline visit date  
 For days on/after the injection date, study day = date – baseline visit date + 1 
Note that there is no study day 0. 
4.1.4. 
Analysis Periods 
Analysis periods for the efficacy and safety analysis are defined in Table 2. 
Table 2: 
Analysis Periods 
Analysis Period 
Analysis Period Start Date  
Analysis Period End Date 
On-treatment Period 
The date of the first Lucentis® injection  
The date of the Week 24 visit, 
or the Study Exit date, 
whichever came first 
Follow-up Period 
The date of the first day after Week 24 visit 
The Study Exit date 
Entire Study 
Efficacy: the date of randomization; 
Safety: the date of the first Lucentis® injection 
The Study Exit date 
4.1.5. 
Out-of-Window Measurements, Analysis Window and Analysis Visit 
A measurement collected at a visit is an out-of-window measurement if the study day of the visit 
falls outside of a visit window specified in Table 1, or a within-window measurement otherwise. 
Analysis visit is a timing variable which will be used for all analyses involving visits.  For each 
analysis visit, an analysis window is provided in order to determine which of the analysis visit a 
measurement should be mapped to.  The analysis visit of a measurement will be determined by 
the study day of the measurement and the specified analysis windows.  The study visit, assigned 
when the measurement was collected, will not necessarily agree with the analysis visit. 


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The following analysis windows for post-baseline visits will be applied to minimize the amount 
of missing data for analysis purposes: 
Table 3: 
Post-Baseline Analysis Visit and Analysis Window 
Post-Baseline Analysis Visit 
(Target Assessment Date) 
Visit Window 
Analysis Window 
Week 1 (Day 8) 
[7, 9] 
[2, 18] 
Week 4 (Day 29) 
[26, 32] 
[19, 43] 
Week 8 (Day 57) 
[54, 60] 
[44, 71] 
Week 12 (Day 85) 
[81, 89] 
[72, 99] 
Week 16 (Day 113) 
[109, 117] 
[100, 127] 
Week 20 (Day 141) 
[137, 145] 
[128, 155] 
Week 24 (Day 169) 
[164, 174] 
[156, 183] 
Week 28 (Day 197) 
[192, 202] 
[184, 211] 
Week 32 (Day 225) 
[220, 230] 
[212, 253] 
For analyses involving post-baseline visits, if there are two or more measurements that fall into 
the same analysis window of a post-baseline visit, then the measurement at visit with any 
injection will be selected.  If there is no visit with any injection, then the measurement closest to 
the target assessment day will be selected for that visit.  In the case that two measurements are 
equidistant to the target assessment day, i.e., one is before and one is after the target assessment 
day, the later one will be selected for that visit. 
4.1.6. 
Days on Treatment  
Days on treatment measures the duration of exposure to a study medication received during the 
study.  For this study, the days on treatment is defined as: 
 Days on treatment = (date of last dose – date of first dose) + 1 
4.2. 
Efficacy-Related Definitions 
4.2.1. 
Study Eye and Fellow Eye 
The study eye of a randomized, treated subject is the eye that was injected with study medication 
at baseline (Day 1).  For subjects who were randomized but not treated, the study eye is the eye 
determined to be injected by the Clinical Investigator at baseline (Day 1).  The Clinical 
Investigator selected “OD” or “OS” for “Study Eye” on the Primary Diagnosis eCRF. 
Fellow eye is the non-study eye. 
4.2.2. 
Baseline Score 
For any measure, the baseline score is the last observed measurement prior to the initial injection 
of study medication at the baseline visit. 


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4.2.3. 
Change and Percent Change from Baseline 
The change and the percent change from baseline in a measure at a post-baseline visit will be 
defined as: 
 Change = score at the post-baseline visit – baseline score. 
 Percent change from baseline = 100 × change / (baseline score). 
4.2.4. 
Efficacy Measures 
Table 4 lists all the efficacy measures to be evaluated for this study. 
Table 4: 
Efficacy Measures 
Efficacy Measures 
Note 
Best corrected visual acuity 
(BCVA) 
BCVA measures the acuteness or clearness of the best-corrected vision, 
with a range of [0, 110] in ETDRS letters.  The total number of 
corrected letters will be measured at both 4 meters and 1 meter.  The 
sum of the total number of corrected letters at both 4 meters and 1 
meter will be used for analysis.  If a subject cannot read the ETDRS 
chart, Finger Counts, Hand Motion, Light Perception, or No Light 
Perception will be recorded.  BCVA will be 0 for these situations in any 
analysis.  
An increase in BCVA indicates improvement in the best-corrected 
vision.  A 5-letter difference in visual acuity is equivalent to one 
Snellen line.  A BCVA score of 85 ETDRS letters is equivalent to 
20/20 vision, which is considered normal vision. 
Central subfield thickness 
(CST) 
CST, also known as foveal thickness, measures the central portion of 
macular in micrometer (μm), with a range of [0, 2000] without 
decimals.  CST is defined as the average retinal thickness in the central 
1 millimeter (mm) diameter of the macular.  ‘Ungradable’ may be 
selected when the SD-OCT image is unable to measure for any reason. 
Macular volume (MV) 
Macular volume measures the sum of the volumes of the neural retina 
in the central 6 mm of the macula in mm3 (one to four digits with two 
digits to the right of the decimals).  ‘Ungradable’ may be selected when 
the SD-OCT image is unable to measure for any reason. 
Central retinal lesion 
thickness (CRLT) 
CRLT is the distance between the inner limiting membrane of the retina 
and the Bruch’s membrane.  In this study, CRLT will be measured at 
the sum of the neurosensory retinal thickness (RET) at the foveal 
centerpoint, subretinal fluid thickness (SRF) at the foveal centerpoint, 
SHRM at the foveal centerpoint, and RPE+RPEE thickness at the 
foveal centerpoint.  Each of the four individual thickness components 
will be measured in μm with a range of [0, 2000] without decimals. 
If “Ungradable” was selected for RPE + RPEE and SHRM 
measurement, for example the RPE is absent or disrupted, measurement 
from Bruch’s membrane to the inner border of SHRM and enter that 
value will be used together with the RET and SRF measurement for 
CRLT. 
CRLT is determined by FA. 


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Table 4: 
Efficacy Measures (Continued) 
Efficacy Measures 
Note 
Total lesion area 
Total lesion area is defined as the entire complex of lesion components 
(mm2), which is the sum of total CNV area and the areas of each of the 
non-CNV lesion components.  Total lesion area will be determined by 
FA. 
Total area of choroidal 
neovascularization (CNV) 
The total area of CNV measures the total area of new blood vessels that 
originate from the choroid and extend through Bruch's membrane into 
the subretinal pigment epithelium (sub-RPE).  
The total area of CNV will be measured in mm2.  ‘Ungradable’ may be 
selected when the FA image is unable to measure for any reason. 
Greatest linear dimension of 
the total lesion area (GLD) 
GLD of the total lesion area is measured from the total lesion area 
(mm) determined by FA. 
4.3. 
Safety-Related Definitions 
4.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with the study drug(s). 
An on-study AE can occur at any time after the date of informed consent through the last study 
visit.  An AE will be considered as treatment-emergent if the AE onset occurs on or after the 
analysis period start date and prior to or on the on-treatment analysis period end date as defined 
in Section 4.1.4.  Treatment-emergent AEs are a subset of on-study AEs.  Both on-study and 
treatment-emergent AEs are to be recorded, but only treatment-emergent AEs will be tabulated. 
Each AE will be classified into a system organ class (SOC) and coded to a preferred term (PT) 
using Medical Dictionary for Regulatory Activities (MedDRA), version 20.0 published in 2017. 
4.3.1.1. 
Severity of Adverse Event 
Each AE will be graded by the Clinical Investigator as Mild, Moderate, or Severe based on the 
criteria specified in Section 12.1.1.1 of the protocol. 
4.3.1.2. 
Serious Adverse Event 
An AE will be counted as a serious adverse event (SAE) if the Clinical Investigator answered 
“Yes” to the AE eCRF question “Is the adverse event serious?” 
4.3.1.3. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected “OD”, “OS”, or 
“OU” for “Event Location” on the AE eCRF. 
4.3.1.4. 
Suspected Adverse Reaction 
An AE will be counted as a suspected adverse reaction (SAR) if the Clinical Investigator 
answered “Related” to the AE eCRF question “Relationship to study drug”. 


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4.3.1.5. 
Events of Special Interest 
Events of special interest (ESI) such as pregnancy, study medication administration error, ocular 
telangiectasia and bleeding events will be identified throughout the study.  An event will be 
counted as ESI if the Clinical Investigator selected “Yes” to the AE eCRF question “Is it a 
protocol defined Event of Special Interest (ESI)?” 
4.3.2. 
Safety Measures  
Table 5 lists the safety measures to be evaluated in this study. 
4.3.3. 
Rescue Therapy  
Subjects are eligible for rescue with any anti-VEGF IVT injection during the Week 24 and Week 
28 if one of the following rescue criteria is met:  
 BCVA decrease of ≥ 5 letters from the last visit score 
 CST increase from the last visit of ≥ 50µm 
 The discretion of investigator 
4.3.4. 
Baseline Score 
For any measure, the baseline score is the last observed measurement prior to the initial injection 
of study medication at the baseline visit. 
4.3.5. 
Change and Percent Change from Baseline 
The change and the percent change from baseline in a measure at a post-baseline visit will be 
defined as: 
 Change = score at the post-baseline visit – baseline score. 
 Percent change from baseline = 100 × change / (baseline score) 
For any measure assessed pre and post injection at visits with injection(s), only the pre-injection 
scores at the visit will be used to derive the change-from-baseline variable. 
4.3.6. 
Change after Injection 
For any measure assessed pre and post injection, the change after injection is defined as: 
 Change after injection = post-injection score at the visit – pre-injection score at the 
visit. 
If multiple post-injection scores are available at the visit, then the first observation will be used 
to derive the change after injection. 
If more than one injection were given to the subject at the same visit, change after injection in 
IOP will be performed for each injection.  


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Table 5: 
Safety Measures 
Safety Measure 
Note 
Intraocular pressure (IOP) 
IOP will be measured by applanation tonometry and reported in 
millimeters of mercury (mmHg).  The IOP of an eye is derived 
as the mean/median of two or three consecutive IOP 
measurements. 
IOP will be measured before Lucentis® and 40 (±10) minutes 
after Lucentis® injection.  If applicable, IOP will be measured 
again 60 (±10) minutes following Lucentis® injection.  Any 
increase of ≥ 10 mmHg in IOP at 60 (±10) minutes post-
injection will be reported as an AE.  
The procedure will be also applied for DE-122 or Sham 
injection, and any post IVT injection of rescue treatment. 
Slit-lamp biomicroscopy findings: 
lid Redness 
lid edema 
conjunctival hyperemia 
conjunctival edema 
corneal edema 
anterior chamber cells 
anterior chamber flare 
iris 
pupil 
lens 
phakic lens severity 
Slit-lamp biomicroscopy will be performed prior to Lucentis® 
injection and within 30 minutes after DE-122 or Sham injection, 
and any post IVT injection of rescue treatment. 
 
Anterior Chamber Cells will be graded as 0 = No cells, 0.5 = 1-5 
cells, 1 = 6-15 cells, 2 = 16-25 cells, 3 = 26-50 cells, or 4 = >50 
cells. 
 
Anterior Chamber Flare will be graded as 0 = None, 1 = Faint, 2 
= Moderate, 3 = Marked, or 4 = Intense. 
 
The iris and pupil status of an eye will be graded as either 
normal or abnormal. 
 
The lens of an eye will be classified as phakic, aphakic, or 
pseudophakic. 
 
The rest biomicroscopy parameters will be graded as 0 = None, 
1 = Mild, 2 = Moderate, or 3 = Severe. 


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Table 5: 
Safety Measures (Continued) 
Safety Measure 
Note 
Ophthalmoscopy findings:  
cup/disc ratio 
retina 
macula 
choroid 
vitreous 
Indirect ophthalmoscopy will be performed prior to Lucentis® 
injection and within 30 minutes after DE-122 or Sham injection, 
and any post IVT injection of rescue treatment. 
 
Cup/disc ratio will be recorded with two decimal points (e.g., 
0.80). 
 
The retina, macula and choroid will be graded as either normal 
or abnormal. 
 
Vitreous haze and opacification will be graded as:  
0 = Clear 
Trace or 0.5+ = Trace 
1+ = Few opacities, mild blurring 
2+ = Significant blurring but still visible 
3+  = Optic nerve visible, no vessels seen 
4+ = Dense opacity obscures the optic nerve head.  
Laboratory test: 
urinalysis 
hematology 
serum chemistry 
Laboratory test results will be graded as: 
1 = Normal 
2 = Not Clinically Significant Abnormality 
3 = Clinically Significant Abnormality 
4 = No Results/Invalid Results 
5 = Sample Not Collected 
 
Refer to Section 23.4.16 of the protocol for the list of the 
minimum blood parameters and urine parameters. 
Vital signs: 
systolic blood pressure 
diastolic blood pressure 
heart rate 
Systolic blood pressure and diastolic blood pressure will be 
measured in mmHg.  Heart rate will be measured by 
beats/minute.  The average of two or three readings will be used. 


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Table 5: 
Safety Measures (Continued) 
Safety Measure 
Note 
EKG 
EKG report will be reviewed by the Clinical Investigator and 
will be graded as: 
1 = Normal 
2 = Abnormal, Clinically Insignificant 
3 = Abnormal, Potentially Clinically Insignificant 
4 = Abnormal, Potentially Clinically Significant 
5 = Abnormal, Potentially Exclusionary 
6 = Abnormal, Clinically Significant 
7 = Unable to Evaluate 
8 = Unable to evaluate but measurements provided are 
correct 
 
4.4. 
Other Definitions 
4.4.1. 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications.  
Specifically, a prior medication is defined as any non-study medication taken that ended prior to 
the treatment start date.  A concomitant medication is defined as any non-study medication taken 
concurrently while on the study medication, i.e., the treatment period of a concomitant 
medication taken by a subject’s needs to overlap with his/her treatment period of the study 
medication. 
4.4.2. 
Pharmacokinetic Measures 
Table 6 lists all the PK measures to be estimated. 
Table 6: 
Pharmacokinetic Measures 
Pharmacokinetic Measure 
Note 
Area under the curve 
(AUC) 
AUC (μg/mL × day) reflects the extent of exposure to DE-109 
after injection.  It equals the integral of the concentration-time 
curve. 
Cmax 
Cmax denotes the peak plasma concentration of DE-109 observed 
after injection. 
tmax 
tmax denotes the time to reach Cmax. 
Elimination half-life (t1/2) 
t1/2 is the time required for the concentration of DE-109 to reach 
half of its original value. 
PK parameters will be estimated for each of the following time intervals based on plasma 
concentrations collected during the corresponding time interval:  


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 Day 1 to Week 4 visit 
 Week 20 to Week 24 visit 
4.4.3. 
M-CHARTS™ 
Narrow Dotted Lines with one line (Type I) and Bold Dotted Lines with one line (Type B) are 
used in this study to measure the severity of metamorphopsia in macular lesions.  VM and HM of 
Type I and Type B in each eye will be examined three times.  The median from the 3 
measurements will be used.  The VM and HM of Type I range from 0 to 2 while 0 to 2.4 for 
Type B.  The VM and HM scores in normal eyes without metamorphopsia are 0.  A large score 
indicates more sever metamorphopsia. 
4.4.4. 
Subretinal Hyper-Reflective Material and Retinal Pigment Epithelium Elevation 
SHRM is a morphological change seen on OCT as hyper-reflective material located external to 
the retina, or subretinal fluid if it is present, and internal to the RPE.  SHRM will be graded as 
“Yes” if there is any SHRM, “No” if there is no SHRM, “Ungradable” if there is any reason it 
would be unable to grade because of pathology or reasons unrelated to quality of the image, and 
“Ungradable/Quality” if there are quality reasons that it is indeterminable that SHRM is present.  
An RPEE refers to RPE that is separated from Bruch’s membrane.  The material external to the 
elevated RPE may be hypo-reflective, or have reflective material that could be pigment, blood, 
or CNV.  The RPE may also be elevated by drusen.  RPEE will be graded as “Yes” if there is 
any RPEE on any scan, “No” if there is no RPEE on any scan, “Ungradable” if there is any 
reason that it would be unable to grade because of pathology or reasons unrelated to quality of 
the image, and “Ungradable/Quality” if there are quality reasons that it is indeterminable that 
RPEE is present. 


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5. 
STUDY POPULATION 
5.1. 
Intention-to-Treat Population 
The Intention-to-Treat (ITT) Population will include all randomized subjects in the study. 
5.2. 
Safety Population 
The Safety Population will include all subjects who received at least one injection of the study 
medication.  It will be the study population for safety analyses performed with subjects as 
treated. 
5.3. 
Full Analysis Set  
The Full Analysis Set (FAS) will include all subjects who received at least one injection of the 
study medication (DE-122 or Lucentis®) and provided at least one post-baseline BCVA 
measurement of the study eye during the study.  It will be the population used for efficacy 
analyses performed with subjects as randomized. 
5.4. 
Per-Protocol Set 
The Per-Protocol Set (PPS) is a subset of the FAS.  It includes all FAS subjects without protocol 
violations that could affect the primary efficacy endpoint.  It will be the analysis population for 
some sensitivity analyses performed with subjects as randomized. 
Before the unmasking of treatment assignment, Santen’s study team will review all protocol 
deviations, identify subjects with any protocol deviation that could impact the efficacy outcome, 
and determine whether or not to exclude the subject from the PPS. 
5.5. 
PK Population 
The Pharmacokinetic (PK) Population will include all subjects who receive at least one DE-122 
and have at least one quantifiable post-injection PK serum assessment.  It will be the study 
population for PK analyses.  
5.6. 
Biomarker Population 
The Biomarker Population will include all subjects who receive at least one DE-122 and have at 
least one quantifiable post-injection biomarker serum assessment.  It will be the study population 
for biomarker analyses. 


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6. 
GENERAL CONSIDERATIONS 
Besides data listings, all measures will be summarized by randomized arm and/or overall.  
Continuous variables will be summarized using descriptive statistics such as number of 
observations (n), mean, standard deviation, minimum, and maximum.  Categorical variables will 
be tabulated using frequency (n), sometimes along with percentage (%). 
All data manipulations and descriptive summaries will be implemented using SAS®, Version 9.4 
or later. 
6.1. 
Adjustments for Covariates 
Covariate adjustments are not applicable to this study. 
6.2. 
Handling of Missing Data 
For safety measures, missing scores will not be imputed for data summaries.   
For efficacy measures, the last-observation-carried-forward (LOCF) approach may be used to 
impute missing post-baseline values in sensitivity analysis.  Baseline scores will not be carried 
forward. 
Completely or partially missing onset and resolution dates of medical events, i.e., medical 
history events and AEs will be imputed in a conservative fashion as follows. 
Date 
Type of Missing Date 
Handling of Missing Date 
Event onset date 
(e.g., YYYY-
MM-DD) 
Completely missing 
No imputation will be applied. 
Only YYYY is available 
Use the first day of YYYY to impute the missing 
month and day of the onset date 
YYYY and MM are 
available but DD is missing 
Use the first day of MM to impute the missing day 
of the onset date 
Event resolution 
date 
(e.g., YYYY-
MM-DD) 
Completely missing 
No imputation will be applied 
Only YYYY is available 
Use the last day of YYYY to impute the missing 
month and day of the resolution date  
YYYY and MM are 
available but DD is missing 
Use the last day of MM to impute the missing day 
of the resolution date 
Same rules will be followed to impute completely or partially missing start and end dates of non-
study medications.  
6.3. 
Handling of Special Measurement Values  
For BCVA, Finger Counts, Hand Motion, Light Perception, or No Light Perception will be set 
to 0 letter in the analysis.  
For measures determined by SD-OCT and FA, “Ungradable” will be treated as missing data. 


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For M-CHARTS™, any VM and HM with “Unmeasurable” in Type I and Type B will be set to 2 
and 2.4, respectively. 
6.4. 
Multi-Center Studies 
This is a multi-center study enrolling subjects from up to 14 sites.  No pooling algorithm will be 
applied. 
6.5. 
Multiple Comparisons / Multiplicity 
Multiplicity adjustment is not applicable to this study. 
6.6. 
Interim Analysis 
An interim analysis was planned in Protocols Amendment 06 and previous versions but was 
removed from Protocol Amendment 07.  Therefore, no formal interim analysis will be 
conducted. 


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7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The subject disposition will be summarized by treatment arm and overall for all randomized 
subjects.  The summary will include the number of subjects in the ITT Population, the numbers 
and percentages of subjects in the Safety Population, FAS, PPS, PK Population and Biomarker 
Population.  The summary will also include the numbers and percentages of completers and non-
completers at Week 24 (Visit 11) and Week 32 (Visit 13), as well as the number and percentage 
of non-completers by primary discontinuation reason.  The number of percentages of subjects 
enrolled prior to Protocol Amendment 06 and on/after Protocol Amendment 06 will also be 
provided. 
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for the FAS 
Population by planned treatment arm and overall, safety population by actual treatment and 
overall.  Specifically, for subject demographics, the following variables will be summarized:  
 Age at randomization (continuous and categorical: < 65 years or ≥ 65 years) 
 Sex (categorical: Male or Female) 
 Race (categorical: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, or Other/Multiracial) 
 Ethnicity (categorical: Hispanic/Latino or Not) 
 Country (categorical: Philippine or US) 
For baseline characteristics, the following variables will be summarized for study eye: 
 Lesion type (PCV or non-PCV) 
 Prior anti-VEGF treatment in the study eye (Yes or No) 
 If yes, refractory to anti-VEGF treatment or not (Yes or No) 
 And, how long since the first anti-VEGF treatment 
 And, the type of most recent prior anti-VEGF treatment (type 1: Lucentis or 
Ranibizumab; type 2: Avastin or Bevacizumab; type 3: Eylea or Aflibercept) 
 Baseline BCVA 
 Baseline FA readings including total lesion area, total area of CNV, and greatest 
linear dimension of the total lesion area 
 Baseline CST, MV and CRLT 
 Baseline IOP 
 Baseline lens status (aphakic, pseudophakic or phakic) 


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Summaries of demographic and baseline characteristics will be repeated on the following 
subgroups: 
 Country 
 Lesion type (PCV or non-PCV) 
 Prior anti-VEGF treatment in the study eye (Yes or No) 
 Protocol version (before Amendment 06 or on/after Amendment 06) 
7.3. 
Medical and Surgical History 
For this study, medical and surgical history (i.e., medical events) will be coded using 
MedDRA 20.0, 2017.  Each medical event will be classified into a SOC and mapped to a PT. 
The medical and surgical history will be summarized for the FAS population.  Subjects reporting 
any medical and surgical history at baseline will be tabulated by SOC and PT for each planned 
treatment and overall. 
7.4. 
Protocol Deviations 
In this study, protocol deviations are categorized as follows: 
 Safety issues 
 Consent issues 
 Enrollment issues 
 Protocol implementation issues 
 Other deviations 
A protocol deviation is considered major if it may affect the subject’s rights, safety, or well-
being and/or the completeness, accuracy, and reliability of the study data.  Santen’s study team 
will review all protocol deviations and determine the list of major protocol deviations prior to 
database lock.  All randomized subjects with any major protocol deviation(s) will be tabulated by 
deviation category for each planned treatment and overall.  In addition, all protocol deviations 
will also be listed. 
7.5. 
Prior and Concomitant Medications 
For this study, non-study medications, including prior and concomitant medications, will be 
coded using World Health Organization Drug Dictionary Enhanced (WHO-DDE) (March 2017).  
Each non-study medication will be classified using the Anatomical-Therapeutic-Chemical (ATC) 
classification system and mapped to a WHO-DDE preferred drug name. 
Non-study medications will be summarized for the Safety population.  Subjects taking any prior 
medications will be tabulated by ATC level 3, level 4 and preferred drug name for each actual 
treatment received and overall.  A subject will be counted at most once for each prior 
medication, even if the subject took the same prior medication on multiple occasions.  Subjects 
taking any concomitant medications will be tabulated similarly.  In addition, prior medications 
and concomitant medications will also be listed, separately. 


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Any prior medications taken for target disease will be summarized and listed. 
7.6. 
Exposure to Study Medication 
The treatment exposure to DE-122 will be reflected by the number of DE-122 injections received 
(1 to 6).  For Safety subjects, the exposure will be summarized by frequency and percentage for 
actual treatment received and overall. 
7.7. 
Treatment Compliance 
A subject will be considered fully compliant if the study eye was injected with the planned 
treatment at each visit when the injection is scheduled per protocol.  If the subject skipped the 
injection of DE-122 at the investigator’s decision with the corresponding AE reported, then this 
subject will still be considered as treatment compliant.  Treatment compliance will be 
summarized for the FAS population by planned treatment and overall.  The treatment compliance 
statuses will also be listed by planned treatment, subject ID, and injection visit. 


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8. 
EFFICACY ANALYSES 
Unless specified otherwise, the efficacy analyses will be performed on the FAS, where subjects 
are classified by planned treatment, irrespective of the actual treatment received. 
Unless specified otherwise, all efficacy analyses will be performed on the study eye, and the data 
on fellow eye will not be used.  
8.1. 
Primary Endpoint 
8.1.1. 
Primary Analysis 
The primary efficacy endpoint is mean change from baseline in BCVA at Week 24.  No formal 
statistical hypothesis testing will be implemented for the primary endpoint.  Descriptive 
summaries will be provided by each planned treatment arm.  The differences in mean change 
between Arm 2 or 3 and Arm 1, as well as the corresponding 95% confidence intervals based on 
t-test without multiplicity adjustment will also be provided.  Descriptive summaries of BCVA 
measured at Week 28 and Week 32 will be provided, in which any records after the rescue 
injection(s) will be censored. 
The primary analyses will be performed on the FAS.  Besides the summary tables, plots of 
BCVA measures versus analysis visit will be provided.  BCVA score, and percent change from 
baseline will also be summarized. 
8.1.2. 
Sensitivity Analysis 
To assess the robustness of the primary analysis results, the same analysis may be repeated on 
the PPS with observed cases, and FAS with missing data imputed by the LOCF approach. 
In addition, if the scheduled injection was skipped at a visit, BCVA measured at the first visit 
after that visit will be censored.  Descriptive summaries will be performed based on the censored 
dataset to assess the impact of missing injection on the primary analysis results. 
8.2. 
Analyses of Secondary Endpoints 
8.2.1. 
Primary Analysis 
Frequency and percentage of subjects with BCVA improvement of ≥ 15 ETDRS letters (3-line 
gainers); within 15 letters change (stable) and loss of ≥ 15 letters from baseline at Week 24 will 
be provided based on FAS.  The differences in proportion between Arm 2 or 3 and Arm 1, as 
well as the corresponding 95% confidence intervals based on t-test without multiplicity 
adjustment will be provided.  Besides the summary table, bar plot will be performed. 
Change from baseline in CST, MV, CRLT, total lesion area, total area of CNV, and GLD of the 
total lesion area at Week 24 will be summarized descriptively by treatment arms based on 
observed data.  The differences in mean change between Arm 2 or 3 and Arm 1, and the 
corresponding 95% confidence intervals based on t-test without multiplicity adjustment will be 
provided.  Scores and percent change from baseline will be provided.  Plots of measurement and 


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change from baseline versus analysis visit will also be provided.  Frequency and percentage of 
subjects with ‘ungradable’ data will be provided. 
8.2.2. 
Sensitivity Analysis 
To assess the robustness of the primary analysis results, the same analysis may be repeated on 
the PPS with observed cases. 
In addition, if the scheduled injection was skipped at a visit, the efficacy data measured at the 
first visit after that visit will be censored.  Descriptive summaries will be performed based on the 
censored dataset to assess the impact of missing injection on the primary analysis results. 
8.3. 
Subgroup Analyses 
To assess the homogeneity of treatment effects among subgroups, primary endpoint will be 
analyzed for the following subgroups: 
 Age group (< 65, or ≥ 65 years) 
 Sex (males or females) 
 Country (Philippine or US) 
 Lesion type (PCV or non-PCV) 
 Prior anti-VEGF treatment in the study eye (yes or no) 
 Type of most recent prior anti-VEGF treatment in the study eye (type 1: Lucentis or 
Ranibizumab; type 2: Avastin or Bevacizumab; type 3: Eylea or Aflibercept) 
 Protocol version (before or on/after Amendment 06) 
 Lens status (phakic or non- phakic). 
Other subgroup analyses may be performed as suggested by the data. 


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9. 
SAFETY ANALYSES 
The safety-related measures collected in this study include AEs, IOP, slit-lamp biomicroscopy 
variables, indirect ophthalmoscopy variables, laboratory tests (hematology, chemistry, and 
urinalysis), vital signs, physical exam, fundus photography, fluorescein angiography, EKG, and 
pregnancy. 
The Safety population will be used for all safety summaries, where subjects will be classified by 
actual treatment received. 
9.1. 
Adverse Event 
Subjects with any AE(s), SAE(s), SAR(s), serious SAR(s) and ESI(s) will be tabulated for each 
actual treatment received.  Besides the overall AE summary, subjects with any AE(s) will be 
tabulated by SOC and PT specified in MedDRA Version 20.0.  Subjects with any AE(s) will also 
be tabulated by SOC, PT and maximum severity.  A subject who experienced multiple AEs 
within a SOC or PT will be counted only once at the maximum severity for that SOC or PT.  
SAEs, SARs, and Serious SARs will be tabulated similarly. 
Summaries for ocular AEs and non-ocular AEs will also be performed.  Ocular AEs, ocular 
SAEs and ocular SARs will be summarized for study eyes and fellow eyes separately.  Any 
ocular AE that occurred simultaneously to both eyes will be counted once for both the study eye 
and the fellow eye. 
All AE tabulations will be performed on the Safety population for the On-treatment period, 
Follow-up period and entire study. 
AEs, AEs leading to death, AEs leading to discontinuation, SAEs, and ESIs, if any, will be listed 
separately. 
9.2. 
Slit-lamp Biomicroscopy 
Frequency and percentage of severity rating score will be summarized by actual treatment 
received and analysis visit for study eyes.  In addition, subjects with any clinically significant 
worsening from baseline, defined as from normal to abnormal for iris and pupil, or worsening 
(increase) of 2 units or more for the rest biomicroscopy parameters, will be summarized and 
listed.  For anterior chamber cells, rating score from 0 to 0.5 is considered as 1 unit of increase, 
and from 0 to 1 is considered as 2 unit of increase.  The summaries of cataract severity score 
apply to phakic lens only. 
For all biomicroscopy parameters, subjects with any worsening of 2 units or more after injection 
will be summarized and listed. 
9.3. 
Ophthalmoscopy 
For cup to disc ratio, scores and changes from baseline will be summarized by actual treatment 
received and analysis visit for study eyes. 


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For binary ophthalmoscopy parameters (retina, macular and choroid), subjects with any change 
from Normal at baseline to Abnormal in status will be tabulated by actual treatment received and 
analysis visit for study eyes.  In addition, a listing will be provided. 
For vitreous haze, frequency and percentage of severity rating score will be summarized by 
actual treatment received and analysis visit for study eyes.  In addition, subjects with worsening 
(increase) of 2 units or more from baseline will be summarized and listed. 
For all ophthalmoscopy parameters, subjects with any worsening of 2 units or more after 
injection will be summarized and listed. 
9.4. 
Intraocular Pressure 
IOP scores, changes from baseline and percent change from baseline in pre-injection IOP will be 
summarized by actual treatment received and analysis visit. 
Change after injection in IOP will be summarized repeatedly at 40 (±10) and 60 (±10) minutes 
following injection.  Subjects with an increase of ≥ 10 mmHg at 60 (±10) minutes post-injection 
in IOP will be listed by treatment arm and subject ID.  These analyses will be performed for the 
injection of Lucentis and DE-122, respectively. 
9.5. 
Rescue Therapy 
Frequency and percentage of subjects who received rescue therapy will be summarized.  Subjects 
who received rescue therapy will be listed. 
9.6. 
Electrocardiogram (EKG) 
Any worsening from normal/not clinically significant abnormality at baseline to clinically 
significant abnormality will be summarized by actual treatment received and analysis visit.  
Subjects with clinically significant abnormality will be listed. 
9.7. 
Vital Signs 
Blood pressures and pulse rate, and changes from baseline will be summarized by actual 
treatment received and analysis visit. 
9.8. 
Laboratory Assessments 
For each type of laboratory assessments (chemistry, hematology, or urinalysis), any worsening 
from normal/not clinically significant abnormality at baseline to clinically significant 
abnormality will be summarized by actual treatment received and analysis visit.  Subjects with 
clinically significant abnormality will be listed. 


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10. 
PHARMACOKINETIC ANALYSES 
All PK analyses will be performed on the PK population, with subjects as treated.  
Pharmacokinetic parameters (AUC, Cmax, tmax, and t1/2) will be summarized descriptively by 
actual treatment arm and analysis interval.   
11. 
IMMUNOGENICITY ANALYSIS 
To assess immunogenicity, the incidence of DE-122 antibody development in each arm will be 
summarized by frequency counts and percentages. 
12. 
BIOMARKER ANALYSIS  
Translational Research will provide the report of biomarker investigation.  Scores, changes from 
baseline and percent change from baseline in levels of potential biomarkers will be summarized 
descriptively by actual treatment received and analysis visit.  Besides the summary tables, plots 
of biomarker measures versus analysis visit will be provided.  Pearson’s correlation between 
change from baseline in BCVA and each biomarker will be analyzed by actual treatment and 
analysis visit.  The 95% confidence interval of the correlation coefficient based on Fisher’s Z 
transformation will be provided. 
13. 
OTHER ANALYSES 
13.1. 
M-CHARTS™ 
Score and change from baseline in VM and HM in study eye will be summarized by planned 
treatment received and analysis visit for Type I and Type B, separately.  The same analysis will 
be repeated using the average of MV and MH, and the worst (larger) of MV and MH. 
13.2. 
SS-OCT Angiography 
The analysis of SS-OCT angiography will be conducted by a third party. 
13.3. 
Subretinal Hyper-Reflective Material and Retinal Pigment 
Epithelium Elevation 
Frequency and percentage of subjects who had the presence of SHRM and RPEE in the study 
eye will be summarized by planned treatment received and analysis visit. 
14. 
REFERENCES 
None.