Clinical trial NCT02555306
Conditions: Age-Related Macular Degeneration
Keywords: Macular Degeneration
Sponsor: Santen Inc.
Start date: 2015-09-16; Completion date: 2017-08-01
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to evaluate the safety, tolerability, immunogenicity, and bioactivity of a single intravitreal (IVT) administration of DE-122 in subjects with refractory exudative age-related macular degeneration (AMD).

Detailed description:

Arms: arm 1: Single intravitreal injection of DE-122 Low Dose Injectable Solution arm 2: Single intravitreal injection of DE-122 Medium-Low Dose Injectable Solution arm 3: Single intravitreal injection of DE-122 Medium-High Dose Injectable Solution arm 4: Single intravitreal injection of DE-122 High Dose Injectable Solution
Interventions: intervention 1: 0.5 mg of DE-122 intervention 2: 1.0 mg of DE-122 intervention 3: 2.0 mg of DE-122 intervention 4: 4.0 mg of DE-122
Intervention descriptions: intervention 1: DE-122 Injectable Solution intervention 2: DE-122 Injectable Solution intervention 3: DE-122 Injectable Solution intervention 4: DE-122 Injectable Solution

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
A Phase I/II, Open-label, Dose-escalating, Sequential-cohort Study 
Assessing the Safety, Tolerability, Immunogenicity, and Bioactivity of a 
Single Intravitreal Injection of DE-122 Injectable Solution for the 
Treatment of Refractory Exudative Age-related Macular 
Degeneration- PAVE Study 
 
NCT Number:  
NCT02555306 
 
Date of the document: 
30 June 2016 
 
 
 


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DE-122
Protocol 36-001
Amendment 03
TITLE:  A Phase I/II, Open-label, Dose-escalating, Sequential-cohort Study Assessing the 
Safety, Tolerability, Immunogenicity, and Bioactivity of a Single Intravitreal Injection of 
DE-122 Injectable Solution for the Treatment of Refractory Exudative Age-related Macular 
Degeneration- PAVE Study
SPONSOR:
SANTEN INCORPORATED
2100 Powell Street,
16th Floor, 
Emeryville, CA  94608
STUDY DRUG:
0.5 mg (20µL of 25 mg/mL) DE-122 injectable solution 
1.0 mg (40µL of 25 mg/mL) DE-122 injectable solution 
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 36-001 protocol and agree to conduct the study as outlined and in accordance 
with 21CFR Parts 11, 50, 54, 56, and 312, 42 USC 282 (j), 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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APPROVERS


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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 Incorporated
2100 Powell Street, 16th Floor
Emeryville, CA  94608
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 Phase I/II, Open-label, Dose-escalating, Sequential-cohort Study Assessing the 
Safety, Tolerability, Immunogenicity, and Bioactivity of a Single Intravitreal Injection of DE-122 
Injectable Solution for the Treatment of Refractory Exudative Age-related Macular Degeneration -
PAVE Study
Study Period:  Approximately 21 months
Estimated date first subject enrolled: August, 2015
Estimated date last subject completed: April, 2017
Phase of Development: 
Phase I/II
Primary Objective: 

To assess the safety and tolerability of a single intravitreal injection of four dose levels of DE-122 
(0.5 mg/eye, 1.0 mg/eye, 2.0 mg/eye and 4.0 mg/eye) in subjects with refractory exudative age-
related macular degeneration.
Secondary Objective: 

To evaluate the bioactivity of four dose levels of DE-122 in subjects with refractory exudative age-
related macular degeneration.
Methodology:
This is an open-label, dose-escalating, sequential-cohort study assessing the safety, tolerability, 
immunogenicity, and bioactivity of a single intravitreal injection of 0.5 mg, 1.0 mg, 2.0 mg and 4.0 mg 
DE-122 administered in approximately 12 subjects with refractory exudative age-related macular 
degeneration (AMD).
The subjects will receive a single intravitreal injection of DE-122 in the study eye.  The number of 
subjects will be approximately 12 subjects (2 or 3 subjects in Cohort 1, 3 subjects each in Cohorts 2, 3 
and 4).  Decisions regarding dose escalation in the next cohort will be based on the recommendations of 
the Safety Review Team consisting of an external Retina Specialist, the Medical Monitor, and the Drug 
Safety Physician.  Dose-Limiting Toxicity response observed in any cohort will result in termination of 
the dose escalation.
To be eligible, subjects with refractory exudative AMD in the study eye must have lesions ≤ 12 disc 
areas, contain ≤ 50% hemorrhage and ≤ 50% fibrosis and ≤ 50% retinal pigment epithelial atrophy. 
Subjects must have received recent Intravitreal Injection of anti-VEGF treatment in the study eye > 30 
days and < 60 days prior to Visit 1 (Day 1) and must satisfy all other inclusion and exclusion criteria.
Subjects must have best corrected visual acuity (BCVA) of 65 to 20 ETDRS letters (20/50 to 20/400
Snellen) in the study eye.
The first eligible subject in Cohort 1 will receive a single intravitreal injection of 0.5 mg DE-122 in the 
study eye and will be evaluated through Visit 3 (Day 8±1).  The Safety Review Team will review the 
safety parameters and determine if the safety and tolerability are acceptable. 
If acceptable, up to two additional eligible subjects in Cohort 1 will each receive a single intravitreal 


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injection of 0.5 mg DE-122 in the study eye before starting Cohort 2.  After the first 2 or 3 subjects in 
Cohort 1 have completed Visit 5 (Day 30±2), the Safety Review Team will review the safety 
parameters of the first 2 or 3 subjects in Cohort 1 and determine if the next dose (1.0 mg) will be 
administered to Cohort 2. 
The same enrollment procedures will be followed for Cohort 2 (1.0 mg of DE-122), Cohort 3 (2.0 mg 
of DE-122) and Cohort 4 (4.0 mg of DE-122), however, 3 subjects will be enrolled in these cohorts.
Rescue therapy with anti-VEGF medication may be allowed at Visit 3 (Day 8±1) and/or at Visit 7 (Day 
60±3) provided the following rescue criteria are met:  < 5 letters gained from baseline BCVA or < 50 
microns reduction from baseline central subfield thickness (CST) as measured by spectral-domain 
optical coherence tomography (SD-OCT).
Subjects who do not receive rescue therapy with anti- VEGF medication at Visit 3 (Day 8±1) will 
receive anti-VEGF treatment at Visit 5 (Day 30±2).
Anti-VEGF treatment at Visit 5 (Day 30±2) and rescue therapy (at Visit 3 and/or Visit 7) should be 
performed using the same anti-VEGF medication received just prior to enrollment in the study. 
Safety assessments will be performed on each subject for up to 90 days.
Number of Subjects (planned):
Approximately 12 subjects (2 or 3 subjects in Cohort 1, 3 subjects each in Cohorts 2, 3 and 4) with 
refractory exudative age related macular degeneration will be enrolled at 5 sites.  The final number of 
subjects enrolled may be adjusted based on the presence of dose limiting toxicities.
Duration of the Study:
The duration of this clinical study includes up to a 7-day screening phase and 90-day treatment/ follow-
up phase. The subject will receive a single drug injection of DE-122 at Visit 1 (Day 1), if rescue
criteria is met, will receive treatment of anti-VEGF medication at Visit 3 (Day 8±1), at Visit 5 (Day 
30±2) if not given at Visit 3, and at Visit 7 (Day 60±3) with follow-up for each subject through Day 90. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria:
At Screening (Day -7 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 subretinal or intraretinal fluid secondary to exudative age-related macular 
degeneration as assessed by SD-OCT in the study eye with a minimum of 300 µm in the 
central subfield.
4.
Prior treatment in the study eye with any intravitreal anti-VEGF medication within the past one 
year prior to Screening visit (at least 3 anti-VEGF treatments within 6 months or 6 anti-VEGF 
treatments within 12 months).
5.
Treatment with intravitreal injection of anti-VEGF > 30 days and < 60 days from Visit 1 
(Day 1).
6.
Clinical examination or imaging shows persistent or increasing lesion activity (intraretinal or 


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subretinal fluid, exudation, or hemorrhage) despite continuous anti-VEGF therapy. 
7.
Total lesion size of ≤ 12 disc areas, contain ≤ 50% hemorrhage and ≤ 50% fibrosis and ≤ 50% 
retinal pigment epithelial atrophy in the study eye.
8.
BCVA of 65 to 20 ETDRS letters (20/50 to 20/400) in the study eye.
9.
Fellow eye must have BCVA equal to or better than the study eye, but not worse than 35 
ETDRS letters (20/200)
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.
BCVA worse than 20/400 in study eye; worse than 20/200 in fellow eye.
2.
Use of any of the following treatments or anticipated use of any of the following treatments to 
the study eye:
o
Intravitreal or periocular corticosteroid, within 90 days prior to Visit 1 (Day 1) and 
throughout the study;
o
Fluocinolone acetonide intravitreal implant, within 12 months prior to Visit 1 (Day 1) and 
throughout the study;  
o
Visudyne photodynamic therapy, within 90 days prior to Visit 1 (Day 1) and throughout 
the study;
3.
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.
4.
Evidence of any other ocular disease other than exudative age related macular degeneration 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).
5.
History of vitrectomy in the study eye.
6.
Need for ocular surgery in the study eye during the course of the study.
7.
YAG laser capsulotomy within 30 days prior to Visit 1 (Day 1) in the study eye.
8.
Intraocular surgery, including lens removal or laser, within 90 days prior to Visit 1 (Day 1) in 
the study eye.
9.
Ocular or periocular infection in either eye.
10. Pupillary dilation inadequate for quality stereoscopic fundus photography in the study eye.
11. Media opacity that would limit clinical visualization, intravenous fluorescein angiography, or 
SD-OCT evaluation in the study eye.
12. History of herpetic infection in the study eye or adnexa.
13. Presence of known active toxoplasmosis, inactive toxoplasmosis or toxoplasmosis scar in 


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either eye.
14. Presence of any form of ocular malignancy including choroidal melanoma in either eye.
Non-Ocular:
15. Prior treatment with any agent targeting the endoglin pathway (including a fusion protein that 
binds bone morphogenic protein).
16. Prior treatment with DE-122 injectable solution.
17. Use of any of the following treatments or anticipated use of any of the following treatments 
during the study:
a.
Systemic treatment with anti-VEGF agents (e.g., bevacizumab) 
b.
Agents targeting the endoglin pathway
18. Allergy or hypersensitivity to study drug product, fluorescein dye, or other study related 
procedures/medications.  
19. Inadequate renal function: serum creatinine > 1.3 mg/dL and BUN > 2 x the upper limit of 
normal (ULN).
20. Inadequate hematologic function: hemoglobin < 10 g/dL; platelet count < 130 x 109 /L; WBC 
< 3.8 X 109 /L or > 10.9 X 109 /L.
21. Inadequate liver function: serum bilirubin > 1.5 mg/dL, GGT, SGOT/ALT, SGPT/AST, and 
alkaline phosphatase outside 2 x ULN. 
22. History of bone marrow suppression.
23. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g., hereditary 
hemorrhagic telangiectasia).
24. History of hemorrhage, epistaxis, hemoptysis (> ½ teaspoon bright red blood), or treatment 
with anticoagulants within 90 days prior to Visit 1 (Day 1).
25. Myocardial infarction, stroke or history of transient ischemic attacks within 180 days prior to 
Visit 1 (Day 1).
26. 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.
27. Therapeutic radiation to the head or neck within 90 days prior to Visit 1 (Day 1).
28. 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.
29. 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).
30. Atrial fibrillation not controlled by the subject’s primary care physician or cardiologist within 


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30 days prior to Visit 1 (Day 1).
31. Clinically significant concurrent illness, laboratory or EKG abnormality.
32. 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.
33. Any systemic infection within 30 days prior to Visit 1 (Day 1).
34. 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.
35. Use of marijuana or illegal medication within 30 days prior to Visit 1 (Day 1) and throughout 
the study.
36. 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 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 one of the following four dose levels of the investigational product, DE-122 
injectable solution by intravitreal injection:

0.5 mg (20µL of 25 mg/mL) DE-122 injectable solution

1.0 mg (40µL of 25 mg/mL) DE-122 injectable solution

2.0 mg (20µL of 100 mg/mL) DE-122 injectable solution

4.0 mg (40µL of 100 mg/mL) DE-122 injectable solution
Route of Administration of Investigational product: 
Single intravitreal injection in the study eye
Criteria for Evaluation:
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 exam, EKG and pregnancy.
Bioactivity: The bioactivity of DE-122 on resolution of fluid will be assessed using the change in CST 
based on SD-OCT at each visit post DE-122 treatment as compared to baseline (change in response to 
anti-VEGF treatment given before Visit 1 (Day 1)).
Statistical Methods:
In addition to data listings, descriptive summaries will be provided for safety and bioactivity parameters 
by dose level.


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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1.
PROCEDURES IN CASE OF EMERGENCY .........................................................3
2.
SYNOPSIS...............................................................................................................4
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES................9
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................14
5.
INTRODUCTION..................................................................................................16
6.
OBJECTIVES ........................................................................................................18
7.
INVESTIGATIONAL PLAN .................................................................................19
7.1.
Overall Study Design and Plan ...............................................................................19
7.1.1.
Selection of Concentrations in the Study.................................................................21
7.2.
Number of Subjects ................................................................................................21
7.3.
Treatment Assignment............................................................................................21
7.4.
Dose Adjustment Criteria .......................................................................................22
7.4.1.
Safety Criteria for Adjusting or Stopping Doses......................................................22
7.5.
Criteria for Study Termination................................................................................23
7.6.
Study Procedures....................................................................................................23
7.6.1.
Screening Phase......................................................................................................25
7.6.1.1.
Visit 0/Screening (Day -7 to Day -1).......................................................................25
7.6.2.
Treatment/follow-up phase .....................................................................................25
7.6.2.1.
Visit 1 (Day 1)........................................................................................................25
7.6.2.2.
Visit 2 (Day 2)........................................................................................................27
7.6.2.3.
Visit 3 (Day 8±1)....................................................................................................27
7.6.2.4.
Visit 4 (Day 15±2)..................................................................................................28
7.6.2.5.
Visit 5 (Day 30±2)..................................................................................................29
7.6.2.6.
Visit 6 (Day 45±3)..................................................................................................30
7.6.2.7.
Visit 7 (Day 60±3)..................................................................................................30
7.6.3.
Study Exit...............................................................................................................31
7.6.3.1.
Visit 8/Exit (Day 90±3) ..........................................................................................31
7.6.4.
Unscheduled Visits.................................................................................................32
8.
SELECTION AND WITHDRAWAL OF SUBJECTS............................................33


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8.1.
Subject Inclusion Criteria .......................................................................................33
8.2.
Subject Exclusion Criteria ......................................................................................33
8.3.
Subject Withdrawal Criteria....................................................................................36
9.
TREATMENT OF SUBJECTS ..............................................................................37
9.1.
Description of Study Drug......................................................................................37
9.2.
Concomitant Medications .......................................................................................37
9.2.1.
Prohibited Medications or Treatments.....................................................................37
9.2.2.
Rescue Therapy at Visit 3 (Day 8±1) and/or at Visit 7 (Day 60±3)..........................37
9.2.3.
Anti-VEGF treatment at Visit 5 (Day 30±2)............................................................37
9.3.
Treatment Compliance............................................................................................38
9.4.
Randomization and Masking...................................................................................38
10.
STUDY DRUG MATERIALS AND MANAGEMENT .........................................39
10.1.
Study Drug .............................................................................................................39
10.1.1.
Investigational Drug ...............................................................................................39
10.1.2.
Study Drug Complaint Reporting............................................................................39
10.1.3.
Other Study Supplies..............................................................................................39
10.2.
Study Drug Packaging and Labeling.......................................................................39
10.3.
Study Drug Storage ................................................................................................39
10.4.
Study Drug Preparation ..........................................................................................39
10.5.
Loading the Syringe................................................................................................40
10.6.
Eye Preparation ......................................................................................................41
10.7.
Study Drug Administration.....................................................................................41
10.8.
Study Drug Accountability .....................................................................................42
10.9.
Study Drug Handling and Disposal.........................................................................42
11.
ASSESSMENT OF SAFETY.................................................................................43
11.1.
Adverse Events.......................................................................................................43
11.1.1.
Definition of Adverse Events..................................................................................43
11.1.1.1.
Assessment of Adverse Events ...............................................................................43
11.1.1.2.
Reporting Adverse Events ......................................................................................44
11.1.2.
Serious Adverse Events ..........................................................................................45
11.1.2.1.
Reporting Serious Adverse Events..........................................................................46
11.1.2.2.
Expedited Reporting of Serious Adverse Events .....................................................46
11.1.3.
Events of Special Interest........................................................................................46


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11.1.4.
Follow-up of Adverse Events..................................................................................47
11.1.5.
Manual Back-Up Reporting Procedures..................................................................47
11.2.
Safety Parameters ...................................................................................................48
11.2.1.
Physical Examination .............................................................................................48
11.2.2.
Electrocardiogram (EKG).......................................................................................48
11.2.3.
Vital Signs..............................................................................................................48
11.2.4.
Best Corrected Visual Acuity..................................................................................48
11.2.5.
Slit-lamp Biomicroscopy ........................................................................................48
11.2.6.
Intraocular Pressure ................................................................................................48
11.2.7.
Indirect Ophthalmoscopy........................................................................................48
11.2.8.
Urine Pregnancy Test .............................................................................................49
11.2.9.
Serum Pregnancy Test ............................................................................................49
11.2.10.
Serum Chemistry, Hematology and Urinalysis........................................................49
11.2.11.
Fundus Photography...............................................................................................49
11.2.12.
Fluorescein Angiography........................................................................................49
11.2.13.
Adverse Events.......................................................................................................49
12.
ASSESSMENT OF BIOACTIVITY.......................................................................50
13.
OTHER ASSESSMENTS.......................................................................................51
13.1.
Demographics and Baseline Characteristics ............................................................51
13.2.
Immunogenicity......................................................................................................51
13.3.
Biomarker...............................................................................................................51
13.4.
Other Assessments..................................................................................................51
14.
STATISTICAL METHODS...................................................................................52
14.1.
General Considerations...........................................................................................52
14.1.1.
Study Endpoints .....................................................................................................52
14.1.2.
Sample Size............................................................................................................52
14.1.3.
Statistical Hypotheses and Level of Significance ....................................................52
14.1.4.
Randomization........................................................................................................52
14.1.5.
Study Eye ...............................................................................................................52
14.2.
Study Populations...................................................................................................52
14.3.
Handling of Missing Values....................................................................................53
14.5.
Demographics and Baseline Characteristics ............................................................53
14.6.
Bioactivity Analyses...............................................................................................53


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14.7.
Safety Analysis.......................................................................................................53
14.8.
Other Analysis........................................................................................................54
14.8.1.
Immunogenicity Analysis .......................................................................................54
14.8.2.
Biomarker Analysis ................................................................................................54
15.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................55
15.1.
Study Monitoring....................................................................................................55
15.2.
Audits and Inspections............................................................................................55
15.3.
Institutional Review Board .....................................................................................56
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................57
16.1.
Quality Control.......................................................................................................57
16.2.
Quality Assurance ..................................................................................................57
17.
ETHICS..................................................................................................................58
17.1.
Ethics Review.........................................................................................................58
17.2.
Ethical Conduct of the Study ..................................................................................58
17.3.
Written Informed Consent ......................................................................................58
18.
DATA HANDLING AND RECORDKEEPING.....................................................59
18.1.
Inspection of Records .............................................................................................59
18.2.
Retention of Records ..............................................................................................59
18.2.1.
Source Documents..................................................................................................59
18.2.2.
Data Collection.......................................................................................................60
19.
PUBLICATION POLICY.......................................................................................61
20.
REFERENCES.......................................................................................................62
21.
APPENDICES........................................................................................................64
21.1.
Appendix A - Obligations of Investigators..............................................................64
21.2.
Appendix B - Elements of Informed Consent..........................................................66
21.3.
Appendix C - Declaration of Helsinki.....................................................................68
21.4.
Appendix D - Procedures for Examinations ............................................................74
21.4.1.
Demographics/Eligibility, Medical/Surgical History and Concomitant 
Medication .............................................................................................................74
21.4.2.
Physical Examination .............................................................................................74
21.4.3.
Vital Signs..............................................................................................................74
21.4.4.
EKG .......................................................................................................................75
21.4.5.
Best Corrected Visual Acuity..................................................................................75


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21.4.6.
Slit-Lamp Biomicroscopy.......................................................................................75
21.4.7.
Intraocular Pressure ................................................................................................77
21.4.8.
Indirect Ophthalmoscopy........................................................................................78
21.4.9.
Spectral Domain Optical Coherence Tomography...................................................78
21.4.10.
Fundus Photography...............................................................................................78
21.4.11.
Fluorescein Angiography........................................................................................79
21.4.12.
Urine Pregnancy Test .............................................................................................79
21.4.13.
Serum Pregnancy Test ............................................................................................79
21.4.14.
Hematology, Chemistry and Urinalysis...................................................................79
21.4.15.
Procedure for Immunogenicity Serum Sample ........................................................81
21.4.16.
Procedure for Biomarker Serum Sample .................................................................81
LIST OF TABLES
Table 1:
Emergency Contact Information ...............................................................................3
Table 2:
Abbreviations and Specialist Terms........................................................................14
Table 3:
Dose Groups and Associated DE-122 Concentration...............................................21
Table 4:
Schedule of Events .................................................................................................24
Table 5:
DE-122 Dosing.......................................................................................................39
Table 6:
Protocol Amendment 03 Summary of Changes.......................................................82
LIST OF FIGURES
Figure 1:
Study Schematic .....................................................................................................20
Figure 2:
0.3 mL fill in a 2 mL vial........................................................................................40
Figure 3:
Alignment of the syringe (20 µL example)..............................................................41


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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)
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
DE-122
a chimeric anti-CD105 (endoglin) IgG1 antibody consisting of human Cκ and 
Cγ1 constant regions with murine Vκ and VH regions
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
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
independent ethics committee
IOP
intraocular pressure
IRB
institutional review board


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Table 2:
Abbreviations and Specialist Terms (Continued)
Abbreviation/Term
Definition
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
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
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 exudative 
AMD.  Although Eylea®, which is the most recently approved anti-VEGF medication for 
exudative AMD, showed more than 95% of the subjects maintained vision defined as losing 
< 15 ETDRS letters for 12 months; however, 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 exudative 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 to induce 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 exudative 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 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 being conducted by TRACON 
Pharmaceuticals, Inc.  As of 06 December 2014, over 300 patients had been treated with 
TRC105.  The majority of the patients have been Caucasian with ages ranging from 18-87 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 exudative AMD.
Santen is opening the IND with this Phase I/II study (Protocol 36-001), 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 exudative AMD.  Four dose levels of DE-122 will 
be assessed in the 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 results from the nonclinical studies.  
Additional information regarding the nonclinical studies is provided in the Investigator’s 
Brochure.
As of June 2016, 2 subjects in Cohort 1 have been enrolled and completed the study with no 
adverse events, and no safety and tolerability concerns.


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6.
OBJECTIVES
Primary Objective: 

To assess the safety and tolerability of a single intravitreal injection of four dose 
levels of DE-122 (0.5 mg/eye, 1.0 mg/eye, 2.0 mg/eye and 4.0 mg/eye) in subjects 
with refractory exudative age-related macular degeneration.
Secondary Objective: 

To evaluate the bioactivity of four dose levels of DE-122 in subjects with refractory 
exudative age-related macular degeneration.


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7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design and Plan
This is an open-label, dose-escalating, sequential-cohort study assessing the safety, tolerability, 
immunogenicity, and bioactivity of a single IVT injection of 0.5 mg, 1.0 mg, 2.0 mg and 4.0 mg 
DE-122 injection administered in a total of approximately 12 subjects with refractory exudative 
AMD.
Approximately 12 subjects in four cohorts (2 or 3 subjects in Cohort 1, 3 subjects each in 
Cohorts 2, 3 and 4) will receive a single IVT injection of DE-122 in the study eye. Decisions 
regarding dose escalation will be based on the recommendations of the Safety Review Team 
consisting of an external Retina Specialist, the Medical Monitor, and the Drug Safety Physician.  
Dose-Limiting Toxicity response observed in any cohort will result in termination of the dose 
escalation.
The study is designed to include up to a 7-day screening phase and 90-day treatment/follow-up
phase for each subject. 
The first eligible subject in Cohort 1 will receive a single intravitreal injection of 0.5 mg DE-122 
in the study eye and will be evaluated through Visit 3 (Day 8±1).  The Safety Review Team will 
review the safety parameters and determine if the safety and tolerability are acceptable. 
If acceptable, up to two additional eligible subjects in Cohort 1 will each receive a single 
intravitreal injection of 0.5 mg DE-122 in the study eye before starting Cohort 2.  After the first
2 or 3 subjects in Cohort 1 have completed Visit 5 (Day 30±2), the Safety Review Team will 
review the safety parameters of the first 2 subjects in Cohort 1 and determine if the next dose 
(1.0 mg) will be administered to Cohort 2. 
The same enrollment procedures will be followed for Cohort 2 (1.0 mg of DE-122), Cohort 3 
(2.0 mg of DE-122) and Cohort 4 (4.0 mg of DE-122), however 3 subjects must be enrolled in 
these cohorts.
Rescue therapy with anti-VEGF medication may be allowed at Visit 3 (Day 8±1) and/or at 
Visit 7 (Day 60±3) provided the following rescue criteria are met:  < 5 letters gained from 
baseline BCVA or < 50 microns reduction from baseline CST as measured by SD-OCT.
All subjects will receive IVT anti-VEGF treatment at Visit 5 (Day 30±2) after DE-122 IVT 
injection, in order to avoid a prolonged period without treatment, if no rescue therapy was given 
at Visit 3 (Day 8±1), regardless of the visual acuity and CST outcomes.
All anti-VEGF treatment should be performed using the same anti-VEGF medication received 
just prior to enrollment in the study. 
Safety assessments will be performed on each subject for up to 90 days.
All subjects will be closely monitored at Days 8 and/or 30 for dose limiting toxicities by the 
Safety Review team (Section 7.4.1).
Randomization is not employed in this study due to the small sample size and the dose-escalating 
design.  Refer to Figure 1 for a pictorial representation of the study design.


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Figure 1:
Study Schematic


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7.1.1.
Selection of Concentrations in the Study
In this clinical study, four dose levels of DE-122 (0.5 mg, 1.0 mg, 2.0 mg or 4.0 mg) are being 
tested in subjects with refractory exudative AMD.  Systemic exposure of DE-122 in this study 
given by a single IVT injection at dose levels up to 4.0 mg/eye is anticipated to be significantly 
lower than the systemic exposure in over 300 cancer 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/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.
The starting IVT dose of 0.5 mg utilized in this clinical study is only 1/10 (10%) of the 5 mg 
dose determined as safe in the single dose toxicity study in cynomolgus monkeys by IVT 
injection (and 1/20, or 5%, of the safe 5 mg dose taking into account differences in monkey and 
human vitreous volumes).  The highest 4.0 mg dose tested in this clinical study is only 80% of 
the safe dose in monkeys (and 40% of that dose with differences in vitreous volume considered).
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 
lowest effective dose was 0.5 μg/eye.  Considering the vitreous volume difference between 
human and mouse (~1000:1 ratio), 0.5 mg/eye is considered a logical starting dose level for this
initial clinical study.  In addition, the 0.5 mg DE-122 IVT dose is 10 times lower than the 
tolerated dose of 5.0 mg/eye utilized in the single dose toxicity study in cynomolgus monkeys,
aside from the margin of safety conferred by the difference in vitreous volume between monkey 
and human eyes described above.
7.2.
Number of Subjects
Approximately 12 subjects (2 or 3 subjects in Cohort 1, 3 subjects each in Cohorts 2, 3 and 4) 
with refractory exudative age related macular degeneration will be enrolled at 5 sites.  The final 
number of subjects enrolled may be adjusted based on the presence of dose limiting toxicities.
7.3.
Treatment Assignment
Four dose levels of DE-122 will be administered by a single IVT injection in the study eye as 
noted in Table 3.
Table 3:
Dose Groups and Associated DE-122 Concentration
Dose Group
DE-122 Concentration
Cohort 1: 0.5mg
20 microliters of 25 mg/mL DE-122
Cohort 2: 1.0mg
40 microliters of 25 mg/mL DE-122
Cohort 3: 2.0mg
20 microliters of 100 mg/mL DE-122
Cohort 4: 4.0mg
40 microliters of 100 mg/mL DE-122


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7.4.
Dose Adjustment Criteria
The Safety Review Team will review safety parameters after the first subject in a given cohort 
has completed Visit 3 (Day 8±1).  The remaining subjects in the cohort will receive the same 
dose if neither the safety criteria for adjusting or stopping doses (Section 7.4.1) nor the criteria 
for study termination (Section 7.5) preclude their treatment.
When the first 2 or 3 subjects in Cohort 1 and 3 subjects in other Cohorts have completed Visit 5
(Day 30±2), the Safety Review Team will again evaluate the safety parameters.  If the safety 
criteria for adjusting or stopping doses and the criteria for study termination are not met, the first 
subject in the next cohort will receive the next higher DE-122 dose level.
The same safety evaluations will be performed for each cohort.
7.4.1.
Safety Criteria for Adjusting or Stopping Doses
If more than one of the following dose limiting toxicities is observed in any one cohort, planned 
doses may be adjusted or stopped by the Safety Review Team.
Visual acuity loss from baseline defined as:
o
Loss of best corrected visual acuity (BCVA) of 30 or more letters not due to 
vitreous hemorrhage or injection procedure OR 
o
Transition to no light perception (NLP) not due to injection procedure
Clinically significant inflammation defined as: 
o
> 3+ vitreous haze as measured by the National Eye Institute Grading Scheme 
(Nussenblatt et al., 1985) OR
o
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):
o
> 35 mmHg OR
o
Increase of > 15 mmHg from baseline
If any of the following adverse events (AEs) occur in any one subject in any cohort, planned 
doses will be adjusted by treating additional subjects at the same or lower dose level (the 
occurrence of a second adverse event in either the same or different subjects in one cohort will
qualify for study termination, Section 7.5):
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 a given cohort at any time, the Safety Review Team 
may determine to treat additional subjects within that cohort before moving to the next cohort.


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7.5.
Criteria for Study Termination
Unacceptable safety signals that prevent moving to the next higher dose cohort or result in 
stopping the study may include any of the following, if deemed to be related to study drug 
DE-122 (not DE-122 administration procedures):
Pattern of systemic AEs
Any of the following AEs in any 2 subjects in any cohort:
o
Retinal Non-perfusion of the study eye/vascular occlusion
o
Vasculitis 
o
Retinitis 
o
> 2+ disc edema
o
> 2 quadrants of retinal hemorrhage
7.6.
Study Procedures
All subjects must sign a written ICF before participating in any study-related activity.  
Enrollment will occur at Visit 1 (Day 1) after a subject meets all eligibility requirements at 
Screening (Day -7 to Day -1) and Visit 1 (Day 1).  Each enrolled 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 21.4, Appendix D – Procedures for Examinations. 


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Table 4:
Schedule of Events
Visit Number
Visit 0
(SCRN)
Visit 1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
/Exit
Visit Schedule
(Time window; days)
D-7
to -1
D1
D2
D8
(±1)
D15
(±2)
D30 
(±2)
D45
(±3)
D60
(±3)
D90
(±3)
Pre
Post
Informed consenta
X
Demographics/Eligibility
X
X
Medical/surgical history, 
Concomitant medication 
X
X
X
X
X
X
X
X
X
Physical exam
X
X
Vital signs
X
X
X
X
X
X
X
X
X
EKG 
X
X
X
X
BCVA (ETDRS)
X
X
X
X
X
X
X
X
X
Slit-lamp biomicroscopyb
X
X
X
X
X
X
X
X
X
X
Intraocular pressurec
X
X
X
X
X
X
X
X
X
X
Indirect ophthalmoscopyb
X
X
X
X
X
X
X
X
X
X
SD-OCT 
X
X
X
X
X
X
X
X
X
Fundus photography
X
X
X
X
Fluorescein angiography
X
X
X
X
Urine pregnancy testd
X
X
Urinalysise
X
X
X
X
Serum pregnancy testd
X
X
Hematology, chemistry serum 
samplee
X
X
X
X
Immunogenicity serum sample
X
X
Biomarker serum samplef
X
X
X
X
X
DE-122 IVT Injection
X
Rescue with anti-VEGF 
Injectiong
(X)
(X)
Anti-VEGF Injectionh
X
Adverse events
X
X
X
X
X
X
X
X
X
a. Informed Consent Form - obtain prior to conducting any study-related activities. 
b. Slit-lamp biomicroscopy and indirect ophthalmoscopy will be performed prior to DE-122 or anti-VEGF intravitreal injection 
and within 30 minutes after injection.
c.
IOP will be performed before DE-122 or anti-VEGF Intravitreal injection and 40±10 minutes after injection.  If IOP is 
increased ≥ 10 mmHg, repeat IOP measurement 60±10 minutes after the injection. 
d. Serum and urine pregnancy tests are to be performed on all women of child-bearing potential.
e. Collect fasting urine and blood specimen.
f.
Biomarker serum sample will be collected from the subjects in Cohorts 3 and 4. 
g. If subjects meet the following rescue criteria at Visit 3 (Day 8±1) and/or at Visit 7 (Day 60±3):  <5 letters gained from 
baseline BCVA or < 50 microns reduction from baseline CST as measured by SD-OCT.
h. Subjects who do not receive rescue therapy with anti-VEGF medication at Visit 3 (Day 8±1) will receive anti-VEGF 
treatment at Visit 5 (Day 30±2).


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7.6.1.
Screening Phase
7.6.1.1.
Visit 0/Screening (Day -7 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 subject’s demographic information, medical, surgical and medication history.

Perform the following assessments: (all ophthalmic procedures to be performed OU)

Physical examination (if not performed by external internist)

Vital signs 

EKG

BCVA (ETDRS)

Slit-lamp biomicroscopy

IOP

Indirect ophthalmoscopy

SD-OCT

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.

Upload all collected images (SD-OCT, fundus photograph and fluorescein 
angiogram) to sponsor.

Schedule the subject to return for Visit 1 (Day 1).
7.6.2.
Treatment/follow-up phase
7.6.2.1.
Visit 1 (Day 1)

Review results of the following procedures performed at Screening (Day -7 to 
Day -1) to determine continuation in the study:


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
Physical exam

EKG

Urinalysis

Blood chemistry and hematology tests

Serum pregnancy test (for females of child-bearing potential)

If the subject continues to be eligible for the study, the following assessments must be 
performed prior to administration of DE-122 to confirm eligibility and obtain baseline 
characteristics:

Query for AEs

Update medical history and medications

Vital signs 

BCVA (ETDRS)

Slit-lamp biomicroscopy

IOP

Indirect ophthalmoscopy

SD-OCT

Immunogenicity serum sample

Biomarker serum sample (in Cohorts 3 and 4)

Perform final review of inclusion/exclusion criteria. If the subject meets all eligibility 
criteria, determine the study eye (Section 14.1.5), and then perform DE-122 
administration.

The following procedures must be performed for DE-122 administration (Section 10):

Prepare the DE-122 (Section 10.4)

Load the syringe (Section 10.5)

Prepare the eye including ocular antisepsis of study eye (Section 10.6)

Administer DE-122 (Section 10.7)

The following assessments must be performed after the administration of DE-122:

Within 30 minutes following DE-122 injection 

Slit-lamp biomicroscopy  

Indirect ophthalmoscopy

IOP 40 (±10) minutes following DE-122 injection

If post-injection IOP is increased ≥ 10 mmHg from pre-injection IOP, the 
IOP will be measured again 60 (±10) minutes following injection.  If there 


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is an increase of ≥ 10 mmHg at 60 (±10) minutes post-injection compared 
to pre-injection IOP, the subject should be prescribed a topical IOP-
lowering medication and monitored for resolution of the event by the 
Clinical Investigator.  An IOP increase of ≥ 10 mmHg shall be reported as 
an AE.

AE assessments must be performed after the DE-122 administration

Upload all collected images (SD-OCT) to sponsor.

Schedule the subject to return for Visit 2 (Day 2). 
7.6.2.2.
Visit 2 (Day 2)

Perform the following assessments:

Query for AEs

Update medical history and medications

Vital signs 

BCVA (ETDRS)

Slit-lamp biomicroscopy

IOP

Indirect ophthalmoscopy

SD-OCT

Biomarker serum sample (in Cohorts 3 and 4)

Upload all collected images (SD-OCT) to sponsor.

Instruct the subject to fast for a minimum of 8 hours prior to next visit.

Schedule the subject to return for the Visit 3 (Day 8±1).
7.6.2.3.
Visit 3 (Day 8±1)

Perform the following assessments:

Query for AEs

Update medical history and medications

Vital signs 

EKG

BCVA (ETDRS)

Slit-lamp biomicroscopy

IOP

Indirect ophthalmoscopy


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
SD-OCT

Urinalysis

Hematology, chemistry serum sample

Biomarker serum sample (in Cohorts 3 and 4)

Upload all collected images (SD-OCT) to sponsor.

Rescue therapy with anti-VEGF medication may be allowed at Visit 3 (Day 8±1) 
provided the following rescue criteria are met: 

< 5 letters gained from baseline BCVA OR

< 50 microns reduction from baseline CST as measured by SD-OCT.

Rescue therapy should be performed using the same anti-VEGF medication 
administered just prior to enrollment in the study.  (Section 9.2.2)

If rescue is performed, the following assessments must be performed after the 
administration of anti-VEGF treatment:

Within 30 minutes following anti-VEGF treatment

Slit-lamp biomicroscopy  

Indirect ophthalmoscopy

IOP: 40 (±10) minutes following injection

If post-injection IOP is 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 subject should be prescribed a topical IOP-
lowering medication and monitored for resolution of the event by the 
Clinical Investigator.  An IOP increase of ≥ 10 mmHg shall be reported as 
an AE.

AE assessments must be performed after the anti-VEGF medication 
administration

Schedule the subject to return for Visit 4 (Day 15±2).
7.6.2.4.
Visit 4 (Day 15±2)

Perform the following assessments.

Query for AEs

Update medical history and medications

Vital signs 

BCVA (ETDRS)

Slit-lamp biomicroscopy


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
IOP

Indirect ophthalmoscopy

SD-OCT

Instruct the subject to fast for a minimum of 8 hours prior to next visit. 

Schedule the subject to return for Visit 5 (Day 30±2).
7.6.2.5.
Visit 5 (Day 30±2)

The following assessments must be performed prior to administration of anti-VEGF 
medication

Query for AEs

Update medical history and medications

Vital signs 

EKG

BCVA (ETDRS)

Slit-lamp biomicroscopy

IOP

Indirect ophthalmoscopy

SD-OCT

Fundus photography

Fluorescein angiography

Urinalysis

Urine pregnancy test

Hematology, chemistry serum sample

Immunogenicity serum sample

Biomarker serum sample (in Cohorts 3 and 4)

Upload all collected images (SD-OCT, fundus photograph and fluorescein 
angiogram) to sponsor.

Subjects who did not receive rescue therapy with anti-VEGF medication at Visit 3 
(Day 8±1) will receive anti-VEGF treatment. The anti-VEGF medication should be 
performed using the same drug received just prior to enrollment in the study 
(Section 9.2.3). If the subject received rescue therapy at Visit 3 (Day 8±1), anti-
VEGF treatment and post-injection assessments are not necessary. 

The following assessments must be performed after the administration of anti-VEGF 
treatment:


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Within 30 minutes following anti-VEGF treatment

Slit-lamp biomicroscopy  

Indirect ophthalmoscopy

IOP: 40 (±10) minutes following injection

If post-injection IOP is 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 subject should be prescribed a topical IOP-
lowering medication and monitored for resolution of the event by the 
Clinical Investigator. An IOP increase of ≥ 10 mmHg shall be reported as 
an AE.

AE assessments must be performed after the anti-VEGF treatment.

Schedule the subject to return for Visit 6 (Day 45±3).
7.6.2.6.
Visit 6 (Day 45±3)

Perform the following assessments:

Query for AEs

Update medical history and medications

Vital signs 

BCVA (ETDRS)

Slit-lamp biomicroscopy

IOP

Indirect ophthalmoscopy

SD-OCT

Upload all collected images (SD-OCT) to sponsor.

Schedule the subject to return for Visit 7 (Day 60±3).
7.6.2.7.
Visit 7 (Day 60±3)

Perform the following assessments:

Query for AEs

Update medical history and medications

Vital signs 

BCVA (ETDRS)

Slit-lamp biomicroscopy

IOP


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
Indirect ophthalmoscopy

SD-OCT

Fundus photography

Fluorescein angiography

Urine pregnancy test

Upload all collected images (SD-OCT, fundus photograph and fluorescein 
angiogram) to sponsor.

Rescue therapy with anti-VEGF medication may be allowed at Visit 7 (Day 60±3) 
provided the following rescue criteria are met: 

< 5 letters gained from baseline BCVA   OR

< 50 microns reduction from baseline CST as measured by SD-OCT.

Rescue therapy should be performed using the same anti-VEGF medication 
administered just prior to enrollment in the study (Section 9.2.2).

If rescue is performed, the following assessments must be performed after the 
administration of anti-VEGF treatment:

Within 30 minutes following anti-VEGF treatment

Slit-lamp biomicroscopy

Indirect ophthalmoscopy

IOP:  40 (±10) minutes following injection

If post-injection IOP is 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 subject should be prescribed a topical IOP-
lowering medication and monitored for resolution of the event by the 
Clinical Investigator.  An IOP increase of ≥ 10 mmHg shall be reported as 
an AE.

AE assessments must be performed after the anti-VEGF treatment

Instruct the subject to fast for a minimum of 8 hours prior to next visit. 

Schedule the subject to return for Visit 8/Exit (Day 90±3).
7.6.3.
Study Exit
7.6.3.1.
Visit 8/Exit (Day 90±3)

Perform the following assessments:

Query for AEs

Update medical history and medications


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Physical exam (if not performed by external internist)

Vital signs 

EKG

BCVA (ETDRS)

Slit-lamp biomicroscopy

IOP

Indirect ophthalmoscopy

SD-OCT

Fundus photography

Fluorescein angiography

Urinalysis

Serum pregnancy test (for females of child-bearing potential) 

Hematology, chemistry serum sample

Biomarker serum sample (in Cohorts 3 and 4)

Upload all collected images (SD-OCT, fundus photograph and fluorescein 
angiogram) to sponsor.

Exit subject from study.
7.6.4.
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.


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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 -7 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 subretinal or intraretinal fluid secondary to exudative AMD as assessed by 
SD-OCT in the study eye with a minimum of 300 µm in the central subfield.
4. Prior treatment in the study eye with any intravitreal anti-VEGF medication within the 
past one year prior to Screening visit (at least 3 anti-VEGF treatments within 6 months or 
6 anti-VEGF treatments within 12 months).
5. Treatment with intravitreal injection of anti-VEGF > 30 days and < 60 days from Visit 1 
(Day 1).
6. Clinical examination or imaging shows persistent or increasing lesion activity 
(intraretinal or subretinal fluid, exudation, or hemorrhage) despite continuous anti-VEGF 
therapy.
7. Total lesion size of ≤ 12 disc areas, contain ≤ 50% hemorrhage and ≤ 50% fibrosis and
≤ 50% retinal pigment epithelial atrophy in the study eye.
8. BCVA of 65 to 20 ETDRS letters (20/50 to 20/400) in the study eye.
9. Fellow eye must have BCVA equal to or better than the study eye, but not worse than 
35 ETDRS letters (20/200)
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. BCVA worse than 20/400 in study eye; worse than 20/200 in fellow eye.
2. Use of any of the following treatments or anticipated use of any of the following 
treatments to the study eye:
o
Intravitreal or periocular corticosteroid, within 90 days prior to Visit 1 (Day 1) and 
throughout the study;


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o
Fluocinolone acetonide intravitreal implant, within 12 months prior to Visit 1 (Day 1) 
and throughout the study;
o
Visudyne photodynamic therapy, within 90 days prior to Visit 1 (Day 1) and 
throughout the study;
3. 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.
4. Evidence of any other ocular disease other than exudative 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).
5. History of vitrectomy in the study eye.
6. Need for ocular surgery in the study eye during the course of the study.
7. YAG laser capsulotomy within 30 days prior to Visit 1 (Day 1) in the study eye.
8. Intraocular surgery, including lens removal or laser, within 90 days prior to Visit 1 
(Day 1) in the study eye.
9. Ocular or periocular infection in either eye.
10. Pupillary dilation inadequate for quality stereoscopic fundus photography in the study 
eye.
11. Media opacity that would limit clinical visualization, intravenous fluorescein 
angiography, or SD-OCT evaluation in the study eye.
12. History of herpetic infection in the study eye or adnexa.
13. Presence of known active toxoplasmosis, inactive toxoplasmosis or toxoplasmosis scar in 
either eye.
14. Presence of any form of ocular malignancy including choroidal melanoma in either eye.
Non-Ocular:
15. Prior treatment with any agent targeting the endoglin pathway (including a fusion protein 
that binds bone morphogenic protein).
16. Prior treatment with DE-122 injectable solution.
17. Use of any of the following treatments or anticipated use of any of the following 
treatments during the study :
a.
Systemic treatment with anti-VEGF agents (e.g., bevacizumab) 
b. Agents targeting the endoglin pathway
18. Allergy or hypersensitivity to study drug product, fluorescein dye, or other study related 
procedures/medications.  
19. Inadequate renal function: serum creatinine > 1.3 mg/dL and BUN > 2 x the ULN.
20. Inadequate hematologic function: hemoglobin < 10 g/dL; platelet count < 130 x 109 /L; 
WBC < 3.8 X 109 /L or > 10.9 X 109 /L. 


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21. Inadequate liver function: serum bilirubin > 1.5 mg/dL, GGT, SGOT/ALT, SGPT/AST, 
and alkaline phosphatase outside 2 x ULN.
22. History of bone marrow suppression.
23. Active bleeding or pathologic condition that carries a high risk of bleeding 
(e.g., hereditary hemorrhagic telangiectasia).
24. History of hemorrhage, epistaxis, hemoptysis (> ½ teaspoon bright red blood), or 
treatment with anticoagulants within 90 days prior to Visit 1 (Day 1).
25. Myocardial infarction, stroke or history of transient ischemic attacks within 180 days 
prior to Visit 1 (Day 1).
26. 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. 
27. Therapeutic radiation to the head or neck within 90 days prior to Visit 1 (Day 1).
28. 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.
29. 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).
30. Atrial fibrillation not controlled by the subject’s primary care physician or cardiologist 
within 30 days prior to Visit 1 (Day 1).
31. Clinically significant concurrent illness, laboratory or EKG abnormality.
32. 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.
33. Any systemic infection within 30 days prior to Visit 1 (Day 1).
34. 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.
35. Use of marijuana or illegal medication within 30 days prior to Visit 1 (Day 1) and 
throughout the study.
36. Unable to comply with study procedures or follow-up visits.


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In addition, the Clinical Investigator or Santen Medical Monitor may declare a subject 
ineligible for any sound reason.
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 8/Exit (Day 90±3), then to 
the extent possible, all assessments, including safety, that are scheduled to be performed at 
Visit 8/Exit should be performed on the day of discontinuation.
Subjects who discontinue prematurely may be replaced.


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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 exudative AMD in the study eye other than DE-122 are prohibited during the 
study, except anti-VEGF treatment as a rescue therapy at Visit 3 (Day 8±1) and/or at Visit 7 
(Day 60 ±3), and anti-VEGF treatment at Visit 5 (Day 30±2) as described in Section 9.2.2 and 
Section 9.2.3.
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 at Visit 3 (Day 8±1) and/or at Visit 7 (Day 60±3)
Rescue therapy is defined as IVT injection of anti-VEGF medication which is the same 
medication administered just prior to the enrollment in the study. Rescue therapy with anti-
VEGF medication may be allowed at Visit 3 (Day 8±1) and/or at Visit 7 (Day 60±3) provided 
the following rescue criteria are met:  < 5 letters gained from baseline BCVA or < 50 microns 
reduction from baseline CST as measured by SD-OCT.
9.2.3.
Anti-VEGF treatment at Visit 5 (Day 30±2)
Subjects who did not receive rescue therapy with anti-VEGF medication at Visit 3 (Day 8±1) 
will receive anti-VEGF treatment at Visit 5 (Day 30±2).  The anti-VEGF injection should be 
performed using the same anti-VEGF medication administered just prior to the enrollment in the 
study.


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9.3.
Treatment Compliance
In order to obtain reliable safety and bioactivity 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 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
Randomization is not employed in this study due to the small sample size and the open-label, 
dose-escalating design.


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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 at two
concentrations.  The 4 dose levels of DE-122 to be administered in the study eye are shown in 
Table 5.
Table 5:
DE-122 Dosing
Injection Volume of:
Will deliver
approximately:
20 microliters of 25 mg/mL DE-122
0.5 mg DE-122
40 microliters of 25 mg/mL DE-122
1.0 mg DE-122
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.
Study Drug Complaint Reporting
Complaints regarding the DE-122 for IVT injection should be reported to Santen/Representative
Product Complaint at 415-268-9100.
10.1.3.
Other Study Supplies
Laboratory supplies for obtaining blood and urine specimens will be supplied by the central 
laboratory.  Santen/Representative will supply a fluoroquinolone equivalent antibiotic eye drop, 
10% povidone iodine, needles, and syringes.
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.
10.3.
Study Drug Storage
DE-122 injectable solutions will be provided by Santen/Representative and will be stored in an 
appropriate secure area at the investigational site.  DE-122 vials should be protected from light, 
stored upright, and kept refrigerated at 2° to 8°C (36° to 46°F).
10.4.
Study Drug Preparation
<Investigational drug: DE-122>


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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.
Each vial contains enough DE-122 to inject one subject.  Each vial will be used one time only. 
10.5.
Loading the Syringe
<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:
37. Remove the sterile, single-use 250 μL syringe, custom marked at 20 µL or 40 µL, from 
the packaging.
38. 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 2mL vial.  See Figure 2.
39. 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).
40. 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 40µL black 
mark on the syringe, expelling the excess fluid drawn up.  See Figure 3.
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


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Figure 3:
Alignment of the syringe (20 µL example)
10.6.
Eye Preparation
<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.
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.
<Rescue with anti-VEGF medication at Visit 3/Visit 7 or anti-VEGF treatment at Visit 5>
Eye preparation for anti-VEGF administration to be done as per anti-VEGF drug 
labeling or standard manner in the clinical site.
10.7.
Study Drug Administration
<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 
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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. 
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 prior 
to 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.
<Rescue with anti-VEGF medication at Visit 3/Visit 7 or anti-VEGF treatment at Visit 5>
The administration procedure for anti-VEGF medication should follow the anti-VEGF drug 
labeling or standard practice at the clinical site.
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 clinical supplies shipment form should be completed, signed, and returned as 
directed.  A copy must be maintained at the site for the Principal Investigator’s records. 
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 Disposal
All investigational products including unused vials of DE-122 supplied by Santen/Representative 
will be fully accounted for by the monitor with the help of the 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.
The used vials of DE-122 will be stored at the investigational site upon completion of 
accountability procedures and returned to Santen or designee after the trial is completed.


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11.
ASSESSMENT OF SAFETY
11.1.
Adverse Events
11.1.1.
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 DE-122.  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 DE-122 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 IVT DE-122 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. 
11.1.1.1.
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 11.1.2.
A Clinical Investigator who is qualified in medicine must make the determination of the 
relationship of the investigational drug, DE-122 to each AE (related or not related).  The Clinical 


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Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the DE-122 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 DE-122 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 DE-122 if there is a plausible temporal 
relationship between the onset of the AE and administration of the DE-122, 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 
DE-122; and/or the AE abates or resolves upon discontinuation of the DE-122. 

Reporting the AE as Not Related to DE-122 may be considered if, for example, there 
is good evidence that the AE has an etiology other than the DE-122 (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 DE-122 (e.g., cancer diagnosed 2 days after dose of DE-122).
11.1.1.2.
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), severity, regulatory seriousness 
criteria if applicable, suspected relationship to the DE-122, actions taken and outcome.
AEs that occur after any subject has provided written informed consent, before treatment, during 
treatment, or within 30 days following the cessation of treatment, 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 
(e.g., record suspected or probable myocardial infarction); this has to be updated in 
the clinical database once the diagnosis is confirmed. 


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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.
11.1.2.
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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
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. 
11.1.2.1.
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.
11.1.2.2.
Expedited Reporting of Serious Adverse Events
Santen (or designee) will provide the Principal Investigator with a reporting cover letter and an 
anonymized MedWatch 3500A for expedited reporting of SAEs to the IRB or IEC.  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.
11.1.3.
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:


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
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 women 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 – 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 
following IVT injection of DE-122.  Any ocular telangiectasia or bleeding (both extra 
and intraocular) occurring during study treatment should be reported and the subject 
followed until the end of the study or resolution of the event. 
11.1.4.
Follow-up of Adverse Events
All reported AEs at study exit will be followed by the Clinical Investigator (or his/her designee) 
until the event is resolved or determined to be irreversible, chronic, or stable.
In addition, on a case-by-case basis, Santen (or designee) may request follow up beyond the end 
of the study.
If the Santen Pharmacovigilance Department requests follow-up on an individual SAE or 
designated ESI, site response to follow-up requests should be faxed to Santen 
Pharmacovigilance:  415-276-5882 (fax) or drugsafety@santeninc.com.
11.1.5.
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.

Attach a fax cover sheet with your contact information and address to Santen 
Pharmacovigilance.

Fax the cover sheet and the AE and SAE form to Santen Pharmacovigilance at 
When the EDC system becomes available, update the EDC system with all previously reported 
information.


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11.2.
Safety Parameters
The safety assessments will include adverse events (AEs), BCVA, slit-lamp biomicroscopy, 
indirect ophthalmoscopy, intraocular pressure (IOP), serum chemistry, hematology, urinalysis, 
vital signs, physical exam, fundus photography, fluorescein angiography, EKG, pregnancy.
11.2.1.
Physical Examination
A full body systematic physical exam will be conducted by the Clinical Investigator or an 
external internist during Screening (Day -7 to Day -1) and Visit 8/Exit (Day 90±3).
11.2.2.
Electrocardiogram (EKG)
EKGs will be performed at Screening (Day -7 to Day -1), Visit 3 (Day 8±1), Visit 5 (Day 30±2) 
and at Visit 8/Exit (Day 90±3).  The Clinical Investigator will review the EKG report for 
abnormalities.
11.2.3.
Vital Signs
Blood pressure and heart rate will be measured at each visit 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).
11.2.4.
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 at each visit.  If a subject could not read ETDRS chart, Finger Counts, 
Hand Motion, Light Perception, or No Light Perception will be recorded.
11.2.5.
Slit-lamp Biomicroscopy
Slit-lamp biomicroscopy will be performed at each visit.  On the visit of DE-122 or anti-VEGF 
injection, a biomicroscopy examination will be performed prior to DE-122 or anti-VEGF 
injection and a second one within 30 minutes after injection.
11.2.6.
Intraocular Pressure
IOP will be measured by applanation tonometry and reported in millimeters of mercury (mmHg) 
at each study visit.  On the visit of DE-122 or anti-VEGF injection, IOP will be measured before 
DE-122 or anti-VEGF injection and 40 (±10) minutes after injection.  If post-injection IOP is 
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 subject will 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 IOP increase of ≥ 10 mmHg shall be reported as an AE.
11.2.7.
Indirect Ophthalmoscopy
Indirect ophthalmoscopy will be performed at each visit.  On the visit of DE-122 or anti-VEGF 
injection, an ophthalmoscopy examination will be performed prior to DE-122 or anti-VEGF 
injection and a second one within 30 minutes after injection.


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11.2.8.
Urine Pregnancy Test 
A urine pregnancy test will be conducted at Visit 5 (Day 30±2) and Visit 7 (Day 60±3) for all 
women of childbearing potential.  It should be conducted prior to anti-VEGF IVT injection.
11.2.9.
Serum Pregnancy Test 
A serum pregnancy test will be conducted at Screening (Day -7 to Day -1) and Visit 8/Exit 
(Day 90±3) for all women of childbearing potential.
11.2.10.
Serum Chemistry, Hematology and Urinalysis
A fasting blood sample and urine sample will be taken at Screening (Day -7 to Day -1), Visit 3 
(Day 8±1), Visit 5 (Day 30±2), and Visit 8/Exit (Day 90±3).
11.2.11.
Fundus Photography
Digital color fundus photography will be taken at Screening (Day -7 to Day -1), Visit 5 
(Day 30±2), Visit 7 (Day 60±3) and Visit 8/Exit (Day 90±3) in both eyes.  At Visit 5 
(Day 30±2), it will be performed prior to anti-VEGF injection. Required fields to be captured 
are:  Nasal to macula (The image is centered on the optic nerve), Posterior pole (The image is 
centered on the macula).
11.2.12.
Fluorescein Angiography 
Fundus fluorescein angiography will be taken at Screening (Day -7 to Day -1), Visit 5 
(Day 30±2), Visit 7 (Day 60±3) and Visit 8/Exit (Day 90±3) in both eyes. At Visit 5 
(Day 30±2), it will be performed prior to anti-VEGF injection. Required fields to be captured 
are:  Nasal to macula (The image is centered on the optic nerve), Posterior pole (The image is 
centered on the macula).
11.2.13.
Adverse Events
AEs will be elicited from the subjects starting at the Screening (Day -7 to Day -1) through Visit 
8/Exit (Day 90±3).  The information will include at least a description of the event, whether or 
not it is serious, onset and duration, frequency, severity, relation to DE-122, 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 11.1
for complete information regarding AE reporting.


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12.
ASSESSMENT OF BIOACTIVITY
Measures to assess bioactivity include subretinal fluid and macular volume.  The effects of 
DE-122 on resolution of subretinal fluid will be assessed using the change in CST and the 
macular volume based on SD-OCT.
SD-OCT will be performed for both eyes at each visit. CST, an average of central subfield
thickness, will be recorded.  In addition, macular volume will be determined.


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13.
OTHER ASSESSMENTS
13.1.
Demographics and Baseline Characteristics
Subject demographics include age, race, sex, and ethnicity.  Baseline characteristics include
medical history, prior medications, and baseline results of physical exam, 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 injection of IVT DE-122, the 
last pre-injection value will be used as the baseline value.
13.2.
Immunogenicity
ADA titer will be measured in serum samples collected at Visit 1 (Day 1) and Visit 5 
(Day 30±2).
13.3.
Biomarker 
For the biomarker finding, serum samples will be collected according examination schedule from 
the subjects in Cohorts 3 and 4, and measured for levels of endoglin-related proteins. The 
remaining serum samples will be stored for future exploratory research to identify possible other 
biomarkers associated with the study drug(s) and/or ophthalmologic disease conditions.
13.4.
Other Assessments
Other assessments include concomitant medications and exposure to study drug.


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14.
STATISTICAL METHODS
14.1.
General Considerations
All study parameters will be listed and a selected list of parameters will be summarized
descriptively by dose level and overall. 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.
14.1.1.
Study Endpoints
Safety:

Incidence and severity of adverse events (AEs), slit-lamp biomicroscopy, indirect 
ophthalmoscopy, BCVA, IOP, fundus photography, fluorescein angiography, serum 
chemistry, hematology, urinalysis, vital signs, physical exam, EKG and pregnancy
Bioactivity:

Change in CST and macular volume based on SD-OCT at each visit post DE-122 
treatment
14.1.2.
Sample Size
Approximately twelve subjects (2 or 3 subjects in Cohort 1; 3 subjects in Cohorts 2, 3, and 4) 
with refractory exudative age related macular degeneration will be enrolled at 5 sites.  The final 
number of subjects enrolled may be adjusted based on the presence of dose limiting toxicities.
This sample size is not planned based on statistical considerations. 
14.1.3.
Statistical Hypotheses and Level of Significance
No statistical hypothesis is defined for this study. 
14.1.4.
Randomization 
This is an open-label, non-randomized study.
14.1.5.
Study Eye
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.
14.2.
Study Populations
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ITT Population:  The ITT population will include all subjects in the study.  It will be the
primary study population for bioactivity analyses, where subjects are grouped by planned
dose level unless specified otherwise.
Safety Population:  The Safety population will include all subjects who receive the 
injection of IVT DE-122. It will be the study population for safety analyses performed 
with subjects as treated.
14.3.
Handling of Missing Values
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.
For Bioactivity endpoints, missing post-injection values will be imputed using the last-
observation-carried-forward (LOCF) approach.
14.5.
Demographics and Baseline Characteristics
Age, sex, race, ethnicity, and baseline assessments will be summarized descriptively by dose 
level. 
Subjects with abnormal medical history will be tabulated by treatment arm and body system.
Subjects using any prior medications will be tabulated by dose level, Anatomical Therapeutic 
Chemical levels, and preferred term specified in the World Health Organization Drug Dictionary 
Enhanced  (World Health Organization Drug Dictionary Enhanced, 2011). 
14.6.
Bioactivity Analyses
Changes from baseline in BCVA, retinal thickness (CST), and macular volume will be 
summarized descriptively by dose level of DE-122.  Change in retinal thickness after anti-VEGF 
injection will also be provided.
14.7.
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 exam, 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.


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14.8.
Other Analysis
14.8.1.
Immunogenicity Analysis
To assess immunogenicity, the incidence of DE-122 antibody development in each cohort will be 
summarized by frequency counts and percentages.
14.8.2.
Biomarker Analysis
Changes from baseline in levels of biomarkers will be summarized descriptively by dose level of 
DE-122.


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15.
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 FDA, 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 FDA or other regulatory agency regulations.
15.1.
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.
15.2.
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 
records, eCRFs, recruitment materials, and corresponding portions of the subject’s charts and 


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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.
15.3.
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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16.
QUALITY CONTROL AND QUALITY ASSURANCE
16.1.
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.
16.2.
Quality Assurance
Santen (or designee) may conduct a quality assurance audit at any time.


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17.
ETHICS
17.1.
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 21.1 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. 
17.2.
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, and Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).
17.3.
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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18.
DATA HANDLING AND RECORDKEEPING
18.1.
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.
18.2.
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.
18.2.1.
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 
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18.2.2.
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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19.
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 as required by the Food and Drug Administration (FDA).
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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20.
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-b 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. (2008).  Choroidal Neovascularization.  In: Lim J, editor. Age-
Related Macular Degeneration. 2nd ed. Chapter 5; 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-b/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. (2008).  Exudative (Neovascular) Age-Related Macular Degeneration.  
In: Lim J, editor. Age-Related Macular Degeneration. 2nd ed. Chapter 8; p. 125-57.
9. MedDRA. MedDRA MSSO, Medical Dictionary for Regulatory Activities, Version 16.1.   
Available from http://www.meddra.org/
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.


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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.
13. Sun Working Group. (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. U.S.Department of Health and Human Services, National Institutes of Health. (01 Aug 
2004). The Seventh Report of the Joint National Committee on Prevention, Detection, 
Evaluation, and Treatment of High Blood Pressure.
15. Warrington, K., Hillarby, M., Li, C., Letarte, M., Kumar, S. (2005).  Functional Role of 
CD105 in TGF-b1 Signalling in Murine and Human Endothelial Cells.  Anticancer 
Research 25(3B):1851-64.
16. World Health Organization Drug Dictionary Enhanced. World Health Organization Drug 
Dictionary Enhanced (WHO-DDE), September 2011 Version.   Available from 
http://www.umc-products.com/DynPage.aspx?id=73588&mn1=1107&mn2=1139
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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21.
APPENDICES
21.1.
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 21.1).
I.
Prior to the Beginning of the Study

A signed Form FDA-1572, Statement of Investigator.

A current curriculum vitae (CV) if not submitted to Santen previously or if updated.

CVs for all sub-Investigators listed on the 1572.

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.


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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.

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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21.2.
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.


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II.
Additional Elements of Informed Consent
When appropriate, one or more of the following elements of information shall also be provided 
to each subject: 
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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21.3.
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.
7.
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights.


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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.
18.
Physicians may not be involved in a research study involving human subjects unless they 
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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 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.


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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.
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 


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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.
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.


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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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21.4.
Appendix D - Procedures for Examinations
21.4.1.
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 -7 to Day -1).  Medical history and concomitant 
medications will be obtained through subject interviews at each visit. CST before the recent anti-
VEGF medication received at > 30 days and < 60 days from Visit 1 (Day 1) will be collected as 
a Medical History.
21.4.2.
Physical Examination
A full body systematic physical exam will be conducted during Screening (Day -7 to Day -1) and 
Visit 8/Exit (Day 90±3).  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.
21.4.3.
Vital Signs
Blood pressure and heart rate will be measured at each visit 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 (U.S.Department of Health and 
Human Services et al., 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. 
21.4.4.
EKG
EKGs will be recorded at Screening (Day -7 to Day -1) and reviewed for abnormalities by the 
Clinical Investigator prior to enrollment. EKGs will also be performed at Visit 3 (Day 8 ±1), 
Visit 5 (Day 30±2), and Visit 8/Exit (Day 90±3).
21.4.5.
Best Corrected Visual Acuity
ETDRS chart will be used to examine BCVA at each study visit. See Study Procedures manual
for the detailed procedure for measuring visual acuity.
21.4.6.
Slit-Lamp Biomicroscopy
Slit-lamp biomicroscopy will be used to examine eye structures at each study visit.  Slit-lamp 
biomicroscopy will be performed prior to injection and then again within 30 minutes after 
injection on the visit of DE-122 or anti-VEGF injection.
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
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


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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
Mild
(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 Group, 2005).  The iris and the pupil will be evaluated for the presence of clinically 
significant abnormalities.
Anterior Chamber Cells 
(0) = No cells
(0.5) = 1-5 cells
(1) = 6-15 cells
(2) = 16-25 cells
(3) = 26-50 cells


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(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.
21.4.7.
Intraocular Pressure
IOP will be measured by applanation tonometry at each study visit.  At the visit of DE-122 or 
anti-VEGF medication injection, IOP will be measured before DE-122 or anti-VEGF medication
injection and 40 (±10) minutes after injection.  If post-injection IOP is 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 subject will 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 
IOP increase of ≥ 10 mmHg shall be reported as an AE.
IOP should be measured only after the biomicroscopy examination has been completed.
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:
The right eye is always tested first.  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 two measurements differ by 2 mmHg or less, then the average of the two 
measurements becomes the recorded IOP.  For example, if the two measurements are 
22 and 23, then 22.5 is the final recorded IOP.


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
However, if the two measurements differ by 3 mmHg or more, then a third 
measurement is made, and the median of the three measurements becomes the 
recorded 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.

The IOP in the left eye is then measured using the same technique.
21.4.8.
Indirect Ophthalmoscopy
Indirect ophthalmoscopy will be performed for each eye at each visit 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 anti-
VEGF medication injection.  Areas to be assessed include cup to disc ratio, retina, macula and 
choroid, and vitreous.
Cup/Disc Ratio
The cup/disc ratio will be determined by the examiner and recorded using two decimal places 
(e.g., 0.80).
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
21.4.9.
Spectral Domain Optical Coherence Tomography
Spectralis, Cirrus or 3D OCT will be utilized to take optical images of both eyes at each study 
visit.  The same machine must be used consistently throughout the study for any given subject.
21.4.10.
Fundus Photography
Digital color fundus photography will be taken at Screening (Day -7 to Day -1), Visit 5 
(Day 30±2), Visit 7 (Day 60±3) and Visit 8/Exit (Day 90±3) in both eyes. Required fields to be 
captured are:


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
The optic disc, Field 1

The macula, Field 2
21.4.11.
Fluorescein Angiography 
Fundus fluorescein angiography will be taken at Screening (Day -7 to Day -1), Visit 5 
(Day 30±2), Visit 7 (Day 60±3) and Visit 8/Exit (Day 90±3) in both eyes.  Required fields to be 
captured are:

The optic disc, Field 1

The macula, Field 2
21.4.12.
Urine Pregnancy Test 
A urine pregnancy test will be conducted at Visit 5 (Day 30±2) and Visit 7 (Day 60±3) for all 
women 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 obtain the pregnancy test, the subject 
should follow instructions provided by the manufacturer of the urine pregnancy test kit. 
21.4.13.
Serum Pregnancy Test
A serum pregnancy test will be conducted at Screening (Day -7 to Day -1) and Visit 8/Exit 
(Day 90±3) for all women 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. 
21.4.14.
Hematology, Chemistry and Urinalysis
Approximately 10 mL of fasting blood and urine samples will be obtained at Screening (Day -7 
to Day -1), Visit 3(Day 8±1), Visit 5 (Day 30±2) and Visit 8/Exit (Day 90±3).  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.


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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)*
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 Screening (Day -7 to Day -1) and Visit 8/Exit (Day 90±3).
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


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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.
21.4.15.
Procedure for Immunogenicity Serum Sample
Approximately 5 mL of serum sample will be collected for immunogenicity analysis from the 
subject at Visit 1 (Day 1) and Visit 5 (Day 30±2).
Refer to the separate procedure manual for sample handling, storage, and shipment.
21.4.16.
Procedure for Biomarker Serum Sample
Approximately 10 mL of blood sample will be collected for biomarker analysis from the subject 
at Visit 1 (Day 1), Visit 2 (Day 2), Visit 3 (Day 8±1), Visit 5 (Day 30±2) and Visit 8 (Day 90±3).
There will be up to 5 blood draws for Biomarker. The total amount of blood collected from each 
subject in Cohort 3 and Cohort 4 during this study will be approximately 50 mL.
Refer to the separate procedure manual for sample handling, storage, and shipment.


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Table 6:
Protocol Amendment 03 Summary of Changes
Page
Section Number and Title
Description of Change
4-8
2.SYNOPSIS
Modifications were made to reflect the study period and 
the study design changes made throughout the protocol.
16
5. INTRODUCTION
Rationale:  To update the status of the study.
Amendment 02 text:
(None)
Amendment 03 text:
As of June 2016, 2 subjects in Cohort 1 have been 
enrolled and completed the study with no adverse 
events, and no safety and tolerability concerns.
19
7.1. Overall Study Design and 
Plan.
Rationale: To allow the cohort transition from Cohort 1 
to Cohort 2 with 2 subjects safety data at least, 
according to the upadated study status.
Amendment 02 context:
Three subjects will be enrolled in Cohort 1. Three 
subjects safety data is required to make a decision by 
Safety Review Team whether or not the transition to 
Cohort 2 is acceptable.
Amendment 03 context:
Two or Three subjects will be enrolled in Cohort 1. 
Two subjects safety data at least is required to make a 
decision by Safety Review Team whether or not the 
transition to Cohort 2 is acceptable.
20
Figure 1: Study Shematic
Rationale:  Updated in accordance with the change of 
overall study design and plan.
21
7.2. Number of Subjects
Rationale:  In accordance with the change of overall 
study design and plan and change of number of sites.
Amendment 02 text:
Approximately 12 subjects (3 subjects per cohort) with 
refractory exudative age related macular degeneration 
will be enrolled at 3-4 sites.  Amendment 03 text:
Approximately 12 subjects (2 or 3 subjects in Cohort 1, 
3 subjects each in Cohorts 2, 3 and 4) with refractory 
exudative age related macular degeneration will be 
enrolled at 5 sites.  
22
7.4. Dose Adjustment Criteria
Rationale:  In accordance with the change of 
overall study design.
Amendment 02 text:
When all subjects in the cohort have completed 
Visit 5 (Day 30±2), the Safety Review Team will 
again evaluate the safety parameters.
Amendment 03 text:
When the first 2 or 3 subjects in Cohort 1 and 3 
subjects in other Cohorts have completed Visit 5 
(Day 30±2), the Safety Review Team will again 
evaluate the safety parameters.


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Table 6:
Protocol Amendment 03 Summary of Changes (Continued)
Page
Section Number and Title
Description of Change
24
Table 4: Schedule of Events
Rationale: Updated in accordance with the addition 
of blood sample collection for biomarker anaylisis.
25
27
27
29
31
7.6.2.1. Visit 1 (Day 1)
7.6.2.2. Visit 2 (Day 2)
7.6.2.3. Visit 3 (Day 8±1)
7.6.2.5. Visit 5 (Day 30±2)
7.6.3.1. Visit 8/Exit (Day 
90±3)
Rationale:  To add blood sample collection for 
biomarker analysis.
Amendment 02 text:
(None)
Amendment 03 text:
Biomarker serum sample (in Cohorts 3 and 4)
33
8.1. Subjects Inclusion Criteria
Rationale:  To expand the subjects enrollment 
according to the updated status of the study in 
which no safety issue was seen so far.
Amendment 02 text:
8.BCVA of 50 to 20 ETDRS letters (20/100 to 
20/400) in the study eye.
Amendment 03 text:
8.BCVA of 65 to 20 ETDRS letters (20/50 to 
20/400) in the study eye.
51
13. OTHER ASSESSMENTS
Rationale:  To add biomarker analysis.
Amendment 02 text:
13.3  Other Assessments
Other assessments include concomitant 
medications and exposure to study drug.
Amendment 03 text:
13.3 Biomarker 
For the biomarker finding, serum samples will be 
collected according examination schedule from the 
subjects in Cohorts 3 and 4, and measured for 
levels of endoglin-related proteins. The remaining 
serum samples will be stored for future exploratory 
research to identify possible other biomarkers 
associated with the study drug(s) and/or 
ophthalmologic disease conditions.
13.4  Other Assessments
Other assessments include concomitant 
medications and exposure to study drug.


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Table 6:
Protocol Amendment 03 Summary of Changes (Continued)
Page
Section Number and Title
Description of Change
52
14.1.2. Sample Size
Rationale:  In accordance with the change of 
overall study design and plan and change of 
number or sites.
Amendment 02 text:
Approximately 12 subjects (3 subjects per cohort) 
with refractory exudative age related macular 
degeneration will be enrolled at 3-4 sites.  
Amendment 03 text:
Approximately twelve subjects (2 or 3 subjects in 
Cohort 1; 3 subjects in Cohorts 2, 3, and 4) with 
refractory exudative age related macular 
degeneration will be enrolled at 5 sites.  
54
14.8.2. Biomarker Analysis
Rationale:  To add biomarker analysis.
Amendment 02 text:
(None)
Amendment 03 text:
Changes from baseline in levels of biomarkers will 
be summarized descriptively by dose level of DE-
122.
81
24.1.16. Procedure for 
Biomarker Serum Sample
Rationale:  To add biomarker analysis.
Amendment 02 text:
(None)
Amendment 03 text:
Approximately 10 mL of blood sample will be 
collected for biomarker analysis from the subject at 
Visit 1 (Day 1), Visit 2 (Day 2), Visit 3 (Day 8±1), 
Visit 5 (Day 30±2) and Visit 8 (Day 90±3).
There will be up to approximately 5 blood draws 
for Biomarker. The total amount of blood collected 
from each subject in Cohort 3 and Cohort 4 during 
this study will be up to approximately 50 mL.
Refer to the separate procedure manual for sample 
handling, storage, and shipment.

SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
A Phase I/II, Open-label, Dose-escalating, Sequential-cohort Study 
Assessing the Safety, Tolerability, Immunogenicity, and Bioactivity of a 
Single Intravitreal Injection of DE-122 Injectable Solution for the 
Treatment of Refractory Exudative Age-related Macular 
Degeneration- PAVE Study 
 
NCT Number:  
NCT02555306 
 
Date of the document: 
August 09, 2017  
 
 
 


 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol 
Title: 
A Phase I/II, Open-label, Dose-escalating, Sequential-cohort 
Study Assessing the Safety, Tolerability, Immunogenicity, and 
Bioactivity of a Single Intravitreal Injection of DE-122 Injectable 
Solution for the Treatment of Refractory Exudative Age-related 
Macular Degeneration- PAVE Study  
 
Product: 
0.5 mg, 1.0 mg, 2.0 mg and 4.0 mg  DE-122 injectable solutions 
 
 
Protocol 
Number:  
36-001 
 
 
Sponsor: 
Santen Inc. 
 
2100 Powell Street, 16th floor 
Emeryville, CA 94608 
U.S.A. 
 
 
Date:  
August  09, 2017 
 
 
Status:  
Version 2.1 
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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Page ii of 24 
APPROVAL SIGN-OFF SHEET 
A Phase I/II, Open-label, Dose-escalating, Sequential-cohort Study Assessing the 
Safety, Tolerability, Immunogenicity, and Bioactivity of a Single Intravitreal Injection of 
DE-122 Injectable Solution for the Treatment of Refractory Exudative Age-related 
Macular Degeneration- PAVE Study 
 
DE-122 Study 36-001 
 
 
 
 
 


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Version 2.0  
 
 
Page iii of 24 
TABLE OF CONTENTS 
ABBREVIATIONS .........................................................................................................................1 
1. 
INTRODUCTION ........................................................................................................3 
2. 
STUDY OBJECTIVE ...................................................................................................4 
2.1. 
Primary Objective and Endpoints .................................................................................4 
2.2. 
Secondary Objective and Endpoints .............................................................................4 
3. 
STUDY DESIGN .........................................................................................................5 
3.1. 
General Study Design ...................................................................................................5 
3.2. 
Randomization and Masking ........................................................................................5 
3.3. 
Sample Size Planning ...................................................................................................5 
3.4. 
Visits and Assessments .................................................................................................5 
4. 
DEFINTIONS ...............................................................................................................8 
4.1. 
Time-Related Terms .....................................................................................................8 
4.1.1. 
Baseline Visit ................................................................................................................8 
4.1.2. 
Study Day .....................................................................................................................8 
4.1.3. 
Out-of-Window Measurements and Analysis Window ................................................8 
4.1.4. 
Analysis Visit and Analysis Timepoint ........................................................................8 
4.2. 
Endpoint-Related Definitions .......................................................................................8 
4.2.1. 
Study Eye and Fellow Eye ............................................................................................8 
4.2.2. 
Baseline Score ..............................................................................................................9 
4.2.3. 
Change from Baseline ...................................................................................................9 
4.2.4. 
Change after Injection ...................................................................................................9 
4.3. 
Safety-Related Definitions ............................................................................................9 
4.3.1. 
Adverse Event ...............................................................................................................9 
4.3.1.1. 
Severity of Adverse Event ............................................................................................9 
4.3.1.2. 
Serious Adverse Event ..................................................................................................9 
4.3.1.3. 
Ocular Adverse Event .................................................................................................10 
4.3.1.4. 
Adverse Drug Reaction ...............................................................................................10 
4.3.1.5. 
Events of Special Interest ...........................................................................................10 
4.3.2. 
Safety Measures ..........................................................................................................10 
4.4. 
Other Definitions ........................................................................................................11 
4.4.1. 
Bioactivity Measures ..................................................................................................11 


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4.4.2. 
Immunogenicity ..........................................................................................................11 
4.4.3. 
Biomarker ...................................................................................................................11 
5. 
STUDY POPULATION .............................................................................................12 
5.1. 
Intention-to-Treat Population .....................................................................................12 
6. 
GENERAL CONSIDERATIONS ..............................................................................13 
6.1. 
Adjustments for Covariates ........................................................................................13 
6.2. 
Handling of Missing Data ...........................................................................................13 
6.3. 
Multi-Center Studies ...................................................................................................13 
6.4. 
Multiple Comparisons / Multiplicity ..........................................................................14 
6.5. 
Interim Analysis ..........................................................................................................14 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................15 
7.1. 
Subject Disposition .....................................................................................................15 
7.2. 
Demographics and Baseline Characteristics ...............................................................15 
7.3. 
Medical and Surgical History .....................................................................................15 
7.4. 
Protocol Deviations ....................................................................................................15 
7.5. 
Prior and Concomitant Medications ...........................................................................15 
8. 
SAFETY ANALYSES ...............................................................................................17 
8.1. 
Adverse Event .............................................................................................................17 
8.2. 
Best Corrected Visual Acuity .....................................................................................17 
8.3. 
Slit-lamp Biomicroscopy ............................................................................................17 
8.3.1. 
Iris ...............................................................................................................................17 
8.3.2. 
Lens .............................................................................................................................17 
8.4. 
Intraocular Pressure ....................................................................................................17 
8.5. 
Ophthalmoscopy .........................................................................................................18 
8.6. 
Laboratory Assessments .............................................................................................18 
8.7. 
Vital Signs ..................................................................................................................18 
9. 
BIOACTIVITY ANALYSES .....................................................................................19 
10. 
BIOMARKER ANALYSES ......................................................................................19 
11. 
IMMUNOGENICITY ................................................................................................19 
12. 
REFERENCES ...........................................................................................................19 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events .......................................................................................................7 
Table 2: 
Safety Measures ..........................................................................................................10 
 
 
 
LIST OF FIGURES 
Figure 1:  Study Design Diagram ..................................................................................................6 
 


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Page 1 of 24 
ABBREVIATIONS 
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 
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 
FDA 
Food and Drug Administration 
IOP 
intraocular pressure 
ITT 
intention-to-treat 
LOCF 
last-observation-carried-forward 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
μg/mL 
microgram per milliliter 
mm 
millimeter 
mmHg 
millimeters of mercury 
μm 
micrometer 
OD 
oculus dexter (right eye) 
OS 
oculus sinister (left eye) 
OU 
oculus uterque (both eyes) 
PK 
pharmacokinetic/pharmacokinetics 
SADR(s) 
serious adverse drug reactions(s) 
 


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Page 2 of 24 
ABBREVIATIONS (Continued) 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SD-OCT 
spectral-domain optical coherence tomography 
SDTM 
Study Data Tabulation Model 
SOC 
system organ classification 
US 
United States 
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 36-001, “A Phase I/II, Open-
label, Dose-escalating, Sequential-cohort Study Assessing the Safety, Tolerability, 
Immunogenicity, and Bioactivity of a Single Intravitreal Injection of DE-122 Injectable Solution 
for the Treatment of Refractory Exudative Age-related Macular Degeneration- PAVE Study ”. It 
applies to the study protocol dated 30 June 2016 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 OBJECTIVE 
2.1. 
Primary Objective and Endpoints 
The primary objective is: 
• To assess the safety and tolerability of a single intravitreal injection of four dose levels of 
DE-122 (0.5 mg/eye, 1.0 mg/eye, 2.0 mg/eye and 4.0 mg/eye) in subjects with refractory 
exudative age related macular degeneration.  
The safety and tolerability of DE-122 will be assessed by 
• adverse events (AEs) 
• indirect ophthalmoscopy 
• best-corrected visual acuity (BCVA) 
• slit-lamp biomicroscopy  
• intraocular pressure (IOP) 
• fundus photography 
• fluorescein angiography  
• serum chemistry 
• hematology 
• urinalysis  
• physical exam 
• electrocardiogram (EKG)  
• pregnancy test 
• vital signs 
Section 4.3.2 gives a detailed description of the safety measures to be collected in this study. 
2.2. 
Secondary Objective and Endpoints 
The secondary objective is to evaluate the bioactivity of four dose levels of DE-122 in subjects 
with refractory exudative age-related macular degeneration. 
The bioactivity of DE-122 on resolution of fluid will be assessed using the change in CST based 
on SD-OCT at each visit post DE-122 treatment as compared to baseline (change in response to 
anti-VEGF treatment given before Visit 1 (Day 1)). 
 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is an open-label, dose-escalating, sequential-cohort study assessing the safety, tolerability, 
immunogenicity, and bioactivity of a single intravitreal injection of 0.5 mg, 1.0 mg, 2.0 mg and 
4.0 mg DE-122 administered in approximately 12 subjects with refractory exudative age-related 
macular degeneration (AMD). It employs a dose-escalation design to study four cohorts of 
subjects as shown in the Study Design Diagram (Figure 1).   
Four cohorts of  subjects each will receive a single intravitreal injection of DE-122 in the study 
eye. Decisions regarding dose escalation in the next cohort will be based on the 
recommendations of the Safety Review Team consisting of an external Retina Specialist, the 
Medical Monitor, and the Drug Safety specialist. Dose-Limiting Toxicity response observed in 
any cohort will result in termination of the dose escalation. 
3.2. 
Randomization and Masking 
This is an open-label cohort study.  Randomization is not employed in this study due to the dose-
escalation design.   
3.3. 
Sample Size Planning 
Approximately 12 subjects (2 or 3 subjects in Cohort 1; 3 subjects in Cohorts 2, 3, and 4) with 
refractory exudative age related macular degeneration will be enrolled at 5 sites. The final 
number of subjects enrolled may be adjusted based on the presence of dose limiting toxicities 
 
This sample size is not planned based on 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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    Figure 1:  Study Design Diagram  
 


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Table 1: 
Schedule of Events  
Visit Number 
Visit 0 
(SCRN) 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
/Exit 
Visit Schedule 
(Time window; days) 
D-7 
to -1 
D1 
D2 
D8 
(±1) 
D15 
(±2) 
D30 
(±2) 
D45 
(±3) 
D60 
(±3) 
D90 
(±3) 
Pre 
Post 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
Demographics/Eligibility 
X 
X 
 
 
 
 
 
 
 
 
Medical/surgical history, 
Concomitant medication  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
 
 
 
 
 
 
 
 
X 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
EKG  
X 
 
 
 
X 
 
X 
 
 
X 
BCVA (ETDRS) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Slit-lamp biomicroscopyb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intraocular pressurec 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Indirect ophthalmoscopyb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCT  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Fundus photography 
X 
 
 
 
 
 
X 
 
X 
X 
Fluorescein angiography 
X 
 
 
 
 
 
X 
 
X 
X 
Urine pregnancy testd 
 
 
 
 
 
 
X 
 
X 
 
Urinalysise 
X 
 
 
 
X 
 
X 
 
 
X 
Serum pregnancy testd 
X 
 
 
 
 
 
 
 
 
X 
Hematology, chemistry serum 
samplee 
X 
 
 
 
X 
 
X 
 
 
X 
Immunogenicity serum sample 
 
X 
 
 
 
 
X 
 
 
 
Biomarker serum samplef 
 
X 
 
X 
X 
 
X 
 
 
X 
DE-122 IVT Injection 
 
X 
 
 
 
 
 
 
 
Rescue with anti-VEGF 
Injectiong 
 
 
 
 
(X) 
 
 
 
(X) 
 
Anti-VEGF Injectionh 
 
 
 
 
 
 
X 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. Informed Consent Form - obtain prior to conducting any study-related activities.  
b. Slit-lamp biomicroscopy and indirect ophthalmoscopy will be performed prior to DE-122 or anti-VEGF intravitreal injection 
and within 30 minutes after injection. 
c. IOP will be performed before DE-122 or anti-VEGF Intravitreal injection and 40±10 minutes after injection.  If IOP is 
increased ≥ 10 mmHg, repeat IOP measurement 60±10 minutes after the injection.  
d. Serum and urine pregnancy tests are to be performed on all women of child-bearing potential. 
e. Collect fasting urine and blood specimen. 
f. Biomarker serum sample will be collected from the subjects in Cohorts 3 and 4.  
g. If subjects meet the following rescue criteria at Visit 3 (Day 8±1) and/or at Visit 7 (Day 60±3):  <5 letters gained from 
baseline BCVA or < 50 microns reduction from baseline CST as measured by SD-OCT. 
h. Subjects who do not receive rescue therapy with anti-VEGF medication at Visit 3 (Day 8±1) will receive anti-VEGF 
treatment at Visit 5 (Day 30±2). 


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4. 
DEFINTIONS 
4.1. 
Time-Related Terms  
4.1.1. 
Baseline Visit  
For this study, the baseline visit is the Day 1 visit when the injection of DE-122 is scheduled.        
4.1.2. 
Study Day  
The study day variable describes the relative day of the observation starting with the reference 
date as Day 1.  In this study, the initial injection date (visit 1data) of the study medication is the 
reference day and the study day will be calculated as: 
• For days prior to the injection date, Study Day = Date – Injection Date  
• For days on/after the injection date, Study Day = Date – Injection Date + 1 
Note that there is no Study Day 0.   
4.1.3. 
Out-of-Window Measurements and Analysis Window 
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. 
If there are many out-of-window measurements for a visit, then a window wider than the 
specified visit window may be defined for analysis purposes to minimize missing data.  Such 
wider windows for analysis (i.e., analysis windows), if needed, will be determined by the 
Medical Monitor and the Study Statistician based on the review of all out-of-window 
measurements before the database lock. 
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 closest to the target 
assessment day will be selected for that visit.  In the case that two measurements are closest and 
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. 
4.1.4. 
Analysis Visit and Analysis Timepoint 
Analysis visit and analysis time point are timing variables to be defined in the ADaM 
specifications document for analyses involving visits.  Possible values of these timing variables 
may vary depending on which assessment is considered. 
4.2. 
Endpoint-Related Definitions 
4.2.1. 
Study Eye and Fellow Eye 
The study eye of a subject is the eye with worse vision.  It will be chosen by the Clinical 
Investigator at Day 1 (Baseline).  
Fellow eye is the non-study eye. 
 


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4.2.2. 
Baseline Score 
For any measure, the baseline score is the last observed measurement prior to the injection of 
study medication. For this study, the baseline score would be the measurement prior to the initial 
injection at baseline visit. 
4.2.3. 
Change from Baseline 
For any measure, the change from baseline at a post-baseline visit will be derived as: 
Change from Baseline at a Post-Baseline Visit = (Score at the Post-Baseline Visit) – (Baseline 
Score). 
For any measure assessed pre- and post-injection at Baseline, only the pre-injection score will be 
used to derive the change-from-baseline variable. 
4.2.4. 
Change after Injection 
For any measure assessed pre- and post-injection at Baseline, the change after injection will be 
derived as: 
Change after Injection = Post-Injection Score – Pre-Injection Score. 
The last pre-injection score and the first post-injection score will be used to derive the change 
after injection variable.  
4.3. 
Safety-Related Definitions 
4.3.1. 
Adverse Event 
As defined in 21 CFR 312.32(a), an AE is any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related.  AEs reported on the AE 
electronic Case Report Form (eCRF) will be assessed according to the recently amended FDA 
regulations 21 CFR Parts 312 and 320.   
An AE will be considered as a treatment-emergent AE if the AE onset date is on or after the 
injection.  In other words, an AE will not be counted as a treatment-emergent AE if it can be 
determined that the AE occurred prior to injection.  For AE summaries, only the treatment-
emergent AEs will be tabulated.  
Each AE will be classified into a system organ classification (SOC) and coded to a preferred 
term using MedDRA Version 18.0.   
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 11.1.1.1 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?” 


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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. 
Adverse Drug Reaction 
An AE will be counted as an ADR if the Clinical Investigator answered “Related” to the AE 
eCRF question “Relationship to Study Drug?”  
4.3.1.5. 
Events of Special Interest 
Events of special interest (ESIs) such as pregnancy, study medication administration error and 
ocular telangiectasia and bleeding will be identified throughout the study.  
4.3.2. 
Safety Measures  
Table 2 below lists the safety measures to be evaluated in this study.   
Table 2: 
Safety Measures 
Safety Measure 
Note 
Best-corrected visual acuity 
BCVA measures the acuteness or clearness of the best-
corrected vision, with a range of [0, 97] in ETDRS letters.  An 
increase in BCVA indicates an improvement in the best-
corrected vision.  
Slit-lamp biomicroscopy findings: 
lid Redness, lid edema, conjunctival 
hyperemia, conjunctival Edema, 
corneal edema, anterior chamber 
cells, anterior chamber flare 
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 other six biomicroscopy parameters will be graded as 0 = 
None, 1 = Mild, 2 = Moderate, or 3 = Severe. 
Iris 
The iris status of an eye will be graded as either Normal or 
Abnormal. 
Lens description 
The lens of an eye will be classified as phakic, aphakic, or 
pseudophakic. 
Phakic lens severity score 
The status of a phakic lens will be graded as 0 = None, 1 = 
Mild, 2 = Moderate, or 3 = Severe. 
Intraocular pressure  
IOP, the fluid pressure inside the eye, is recorded in mmHg.  
The IOP of an eye is derived as the mean/median of two or 
three consecutive IOP measurements.  In this study, the IOP 
increase of ≥ 10 mmHg from baseline needs to be reported as 
an AE. 


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Table 2: 
Safety Measures (Continued) 
Indirect Ophthalmoscopy findings:  
cup/disc ratio, retina, macula and 
choroid, vitreous 
Cup/disc ratio will be recorded with two decimal points (e.g., 
0.80).   
Retina (including macular) and choroid will be graded as either 
Normal or Abnormal. 
Vitreous haze 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, and 4+ = Dense opacity obscures the optic nerve head.  
 
Fundus Photography 
Optic disc, Macula. 
Fluorescein Angiography 
Optic disc, Macula. 
Laboratory assessments: 
hematology, chemistry and 
urinalysis 
Refer to Section 21.4.15 of the protocol for the list of the 
minimum blood parameters and urine parameters.    
Vital signs: 
systolic blood pressure, diastolic 
blood pressure, heart rate 
For systolic blood pressure (mmHg), if two measurements 
collected at a visit differ by 5 mmHg or less, then the average 
of the two will be used as the recorded pressure; otherwise, a 
third measurement will be taken and the average of the three 
will be used as the recorded pressure.  Same rules apply to 
diastolic blood pressure (mmHg).  
The average of the two (or three, if performed) heart rate 
measurements will be used as the recorded heart rate (beats per 
minute). 
4.4. 
Other Definitions 
4.4.1. 
Bioactivity Measures  
Bioactivity measures in this study include CST (μm) and macular volume (mm3) measured by 
SD-OCT.  Bioactivity of DE-122 will be considered evident if a considerable decrease in CST or 
macular volume is observed.  
4.4.2. 
Immunogenicity 
 ADA titer will be measured in serum samples collected at Visit 1 (Day 1) and Visit 5  
(Day 30±2). 
4.4.3. 
Biomarker  
Serum samples will be collected  in Cohorts 3 and 4, and measured for levels of endoglin-related 
proteins. Changes from baseline in levels of biomarkers will be summarized descriptively by 
dose level of DE-122. 
 


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5. 
STUDY POPULATION  
5.1. 
Intention-to-Treat Population 
The Intention-to-Treat (ITT) Population will include all subjects in the study.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6. 
GENERAL CONSIDERATIONS 
Besides data listings, all measures will be summarized by dose level 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 (%). Percentages will not be displayed for 
summaries by dose level due to the small sample size.     
All data manipulations and descriptive summaries will be implemented using SAS®, Version 9.3 
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 bioactivity measures, the last-observation-carried-forward (LOCF) approach may be used to 
impute missing post-injection values. However, baseline scores will not be carried forward.   
Completely or partially missing onset and resolution dates of medical events including AEs will 
be conservatively imputed 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 date parts of the onset date 
YYYY and MM are 
available but DD is 
missing 
Use the first day of MM to impute the missing date 
part 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 date parts of the resolution date  
YYYY and MM are 
available but DD is 
missing 
Use the last day of MM to impute the missing date 
part 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. 
Multi-Center Studies 
This is a multi-center study enrolling subjects from 5 US sites.  No pooling algorithm will be 
applied. 


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6.4. 
Multiple Comparisons / Multiplicity 
Multiplicity adjustment is not applicable to this study. 
6.5. 
Interim Analysis 
No formal interim analysis is planned for this study. 


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7. 
SUMMARY OF STUDY POPULATION DATA 
Percentages will not be displayed for summaries by dose level due to the small sample size.     
7.1. 
Subject Disposition 
The subject disposition will be summarized by dose level and overall.  The summary will include 
the number of subjects in the ITT Population, as well as the numbers and percentages of 
completers and non-completers.  
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for the ITT 
Population by dose level and overall.  Specifically for subject demographics, the following 
variables will be summarized:  
• Age at entry (continuous and categorical: < 65 years or ≥ 65 years) 
• Sex 
• Race 
• Ethnicity 
For baseline characteristics, the following variables will be summarized for study eyes:   
• Baseline BCVA 
• Baseline IOP 
• Baseline CST 
• Baseline macular volume 
7.3. 
Medical and Surgical History 
The medical and surgical history will be summarized for the ITT Population.  Subjects reporting 
any medical and surgical history at baseline will be tabulated by body system for each dose level 
and overall.     
7.4. 
Protocol Deviations 
Subjects with any protocol deviation(s) will be listed by dose level and subject ID.   
7.5. 
Prior and Concomitant Medications 
Prior medications are medications taken and ended prior to injection.  Concomitant medications 
are non-study medications a subject took during the study on or after injection.  For this study, 
all prior and concomitant medications will be coded using WHO-DDE (Enhanced, March 2015 
Version format B2).  Each prior or concomitant medication will be classified using the 
Anatomical-Therapeutic-Chemical (ATC) classification system and mapped to a WHO-DDE 
preferred drug name.     
Subjects taking any prior medication in the Safety Population will be tabulated by ATC level and 
preferred drug name.  A subject will be counted at most once for each prior medication, even if 


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the subject took the same prior medication on multiple occasions.  Subjects taking any 
concomitant medications will be tabulated similarly.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. 
SAFETY ANALYSES 
The safety-related measures collected in this study include AEs, BCVA, slit-lamp biomicroscopy 
variables, IOP, indirect ophthalmoscopy variables, laboratory tests (hematology, chemistry, and 
urinalysis), vital signs, physical exam, and EKG.  The Safety Population will be used for all 
safety summaries performed with subjects as treated.   
8.1. 
Adverse Event 
Subjects with any AE(s) (or ADR(s)) will be tabulated by SOC and preferred term specified in 
MedDRA Version 18.0.  They will also be tabulated by SOC, preferred term, and maximum 
severity.  In these AE tables, a subject who experienced multiple AEs (or ADR(s)) within a SOC 
or preferred term will be counted only once at the maximum severity for that SOC or preferred 
term; in addition, ocular AEs (or ADRs) will be presented first to be separated from non-ocular 
AEs (or ADRs).   
AEs, SAEs, AEs leading to discontinuation, and deaths, if any, will be listed separately by dose 
level, subject ID, and onset time. 
ESI(s) will be listed by event type, dose level, and subject ID.   
8.2. 
Best Corrected Visual Acuity 
BCVA scores and changes from baseline in BCVA score will be summarized by dose level and 
analysis visit.  The overall number and proportion of subjects maintaining vision will be 
obtained. 
8.3. 
Slit-lamp Biomicroscopy 
Rating scores and changes from baseline in rating score will be summarized by dose level, 
biomicroscopy parameter, and analysis visit.  Subjects with any worsening (increase) of ≥ two 
units from baseline will be listed by biomicroscopic parameter, dose level, and subject ID.       
8.3.1. 
Iris 
Iris statuses and changes from baseline in iris status will be summarized by dose level and 
analysis visit.  Subjects with any worsening from Normal at baseline to Abnormal at any post-
baseline visit will be listed by dose level and subject ID. 
8.3.2. 
Lens 
Subjects with any worsening (increase) of ≥ 2 units from baseline in phakic lens severity score 
will be listed by dose level and subject ID.    
8.4. 
Intraocular Pressure 
IOP scores and changes from baseline in IOP will be summarized by dose level and analysis 
visit.  Subjects with an increase of ≥ 10 mmHg from baseline in IOP will be listed by dose level 
and subject ID.   


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8.5. 
Ophthalmoscopy  
The cup/disc ratio, retina, macula and choroid, as well as vitreous scale will be summarized by 
dose level and analysis visit.    
8.6. 
Laboratory Assessments 
For each type of laboratory assessments (chemistry, hematology, or urinalysis), any worsening 
from baseline in laboratory result will be listed by dose level and laboratory test.   
8.7. 
Vital Signs  
Subjects with any worsened vital signs after injection will be listed by dose level for each type of 
vital signs (blood pressure or heart rate).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9. 
BIOACTIVITY ANALYSES 
All bioactivity analyses will be performed on the ITT population.  For BCVA, CST and macular 
volume, scores and changes from baseline will be summarized descriptively by dose level and 
analysis visit.     
10. 
BIOMARKER ANALYSES 
The following descpritive analysis is planned by dose level of DE-122: 
• Individual Patient listing of biomarker level for each visit,  both numeric and graph.  
• Individual  Changes from baseline in levels of biomarkers for each post-baseline visit, 
both numeric and graph. 
• Summary analysis of above two by the two dose levels. 
11. 
IMMUNOGENICITY 
ADA titer will be measured in serum samples collected at Visit 1 (Day 1) and Visit 5 
(Day 30±2). Change from baseline in ADA titer, as well as other related analyses will be 
perfomed per request.  
12. 
REFERENCES 
None.