Clinical trial NCT02251938
Conditions: Non-Infectious Uveitis of the Posterior Segment of the Eye
Sponsor: Santen Inc.
Start date: 2014-09-29; Completion date: 2017-11-27
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this extension study is to evaluate the long-term safety of treatment with DE-109 (440 μg) in subjects with non-infectious uveitis of the posterior segment of the eye who have participated in the SAKURA development program.

Detailed description:
This is a multicenter, open-label, extension study of intravitreal injections of the 440 μg dose of DE-109 in subjects with non-infectious uveitis of the posterior segment who received any dose of DE-109 and exited the SAKURA program under Santen Protocol 32-007, Amendment 05.

Subjects who were randomized and received at least two injections of DE-109 during the first five months of the SAKURA program and obtained clinical benefit from the study medication, as determined by the Investigator, may be considered for entry in this 12-month extension study. The minimum time lag from last injection in the SAKURA program to entry into the current protocol is 60 days.

Arms: arm 1: DE-109 440 μg
Interventions: intervention 1: DE-109 440 μg
Intervention descriptions: intervention 1: Medium Dose

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
 
Official Study Title:   
A Phase lllb, Multinational, Multicenter, Open-Label Extension 
Study Assessing the Long-Term Safety of PRN Intravitreal 
Injections of DE-109 in Subjects with Non-Infectious Uveitis of the 
Posterior Segment of the Eye Who Have Participated in the 
SAKURA Development Program 
 
NCT Number:  
NCT02251938 
 
Date of the document: 
June 30, 2014  
 
 


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DE-109
Protocol 32-009
Original
TITLE:  A Phase IIIb, Multinational, Multicenter, Open-Label Extension Study Assessing the 
Long-Term Safety of PRN Intravitreal Injections of DE-109 in Subjects with Non-Infectious 
Uveitis of the Posterior Segment of the Eye Who Have Participated in the SAKURA 
Development Program
SPONSOR:
SANTEN INCORPORATED
2100 Powell Street, 16th Floor
Emeryville, CA  94608
STUDY DRUG:
2.0% DE-109 injectable solution (440 µg of sirolimus)
I have read the 32-009 protocol and agree to conduct the study as outlined. I agree to maintain 
the confidentiality of all information received or developed in connection with this protocol.
INVESTIGATOR:
Date:            
_________________________________
Signature:
_________________________________
Name:              _________________________________
Address:           _________________________________
_________________________________
Phone:
_________________________________
This study will be conducted in accordance with applicable Good Clinical Practices (GCP), 
United States Code of Federal Regulations, International Conference on Harmonization (ICH) 
guidelines, and the Declaration of Helsinki.


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COMPANY/SPONSORAPPROVERS 
Company/Sponsor Address 
Santen, Incorporated 
21 00 Powell Street, 16th Floor 
Emeryville, CA 94608 
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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-109 injectable solution
Name of Active Ingredient: Sirolimus
Title of Study: A Phase IIIb, Multinational, Multicenter, Open-Label Extension Study Assessing the 
Long-Term Safety of PRN Intravitreal Injections of DE-109 in Subjects with Non-Infectious Uveitis of 
the Posterior Segment of the Eye Who Have Participated in the SAKURA Development Program
Study Period (years):  
Estimated date first subject enrolled:  August 2014
Estimated date last subject completed:  November 2017
Phase of Development: 
Phase IIIb Safety Study
Objective: 
The objective of this extension study is to evaluate the long-term safety of treatment with DE-109 (440 
μg) in subjects with non-infectious uveitis of the posterior segment of the eye who have participated in 
the SAKURA development program.
Methodology: 
This is a multicenter, open-label, extension study of intravitreal injections of the 440 μg dose of DE-
109 in subjects with non-infectious uveitis of the posterior segment who received any dose of DE-109 
and exited the SAKURA program under Santen Protocol 32-007, Amendment 05.
Subjects who were randomized and received at least two injections of DE-109 during the first five 
months of the SAKURA program and obtained clinical benefit from the study medication, as 
determined by the Investigator, may be considered for entry in this 12-month extension study. The 
minimum time lag from last injection in the SAKURA program to entry into the current protocol is 60 
days.
The study eye to be treated in this extension study will be the same as the eye treated during the 
SAKURA program.
Study assessments will be conducted for all subjects at Day 1 (Baseline) and Month 12. Each subject
will be followed according to the Investigator’s standard clinical practice at non-study visits. DE-109 
treatment may be administered in the study eye at the Investigator’s discretion during the 12-month
study period but no more frequently than every 60 days.
If the Investigator administers a DE-109 injection to the subject, the visit will be considered a Post-
Baseline PRN Treatment Visit and procedures will be performed and recorded as specified in this 
protocol.
All subjects will exit the study at Month 12, unless terminated early.  Adverse events will be recorded
and collected throughout this extension study, up to the Month 12 exit visit.
Administration of DE-109:

The study eye will be the eye treated in the SAKURA program. 

DE-109 should NOT be administered to the fellow eye.
Rescue therapy:
During the study, rescue therapy may be used at the discretion of the Investigator.  


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Masking:  This is an open-label extension study. All subjects in this unmasked study will receive the 
440 µg dose of DE-109.  
Number of Subjects (planned):  The number of subjects to be enrolled in the study will be 
approximately 200.  
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria:
At Day 1, a subject from the SAKURA program must meet all of the following inclusion criteria:
1.
Have a subject number from participation in the SAKURA program
2.
Exited the SAKURA program under Amendment 05
3.
Have received at least two injections of DE-109 in the first five months of the SAKURA 
program
4.
Received clinical benefit from treatment with DE-109 as determined by the Investigator
5.
Female participants of childbearing potential must not be pregnant or breast-feeding, have a 
negative pregnancy test at Day 1 and must be willing to undergo pregnancy tests throughout 
the study
6.
Both female participants of childbearing potential and male participants able to father children 
must have (or have a partner who has) had a hysterectomy or vasectomy, must abstain from 
intercourse or must agree to practice acceptable methods of contraception throughout the 
course of the study
7.
Ability to give informed consent and attend all study visits
Exclusion Criteria:
A subject from the SAKURA program with any of the following conditions is not eligible to participate 
in the study:
Ocular:
1.
Active infectious uveitis.  However, if the uveitis is the consequence of a previous infectious 
disease, such as tuberculosis, the previous infectious disease must be confirmed as no longer 
active.
2.
Any implantable corticosteroid-eluting device (e.g. Ozurdex, I-vation, Iluvien, fluocinolone 
acetonide [FA] intravitreal implant) in the study eye:
a.
If the Investigator confirms the device has no demonstrable efficacy as indicated in the 
package insert, the subject will be eligible
b.
If a Medidur implant, Iluvien or Retisert has been implanted no less than 3 years and 
90 days prior to Day 1, the subject will be eligible
c.
If a Ozurdex implant has been implanted no less than 180 days prior to Day 1, the 
subject will be eligible
3.
Clinically suspected or confirmed central nervous system or ocular lymphoma
4.
Progressive glaucoma which is unresponsive to treatment.  
5.
Intraocular pressure of  > 21 mmHg while on medical therapy, or chronic hypotony (< 6 
mmHg) 
6.
Any significant ocular disease that could compromise vision in the study eye. These include, 
but are not limited to: 
a.
Diabetic retinopathy: proliferative diabetic retinopathy (PDR) or non-proliferative 
diabetic retinopathy (NPDR) that compromises vision. Subjects with NPDR or PDR 


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that does not compromise vision are not excluded from the study;
b.
Wet age-related macular degeneration;
c.
Myopic degeneration with active subfoveal choroidal neovascularization 
7.
Any of the following treatments to the study eye:
a.
Intravitreal injections in the past 14 days
b.
Intravitreal injections of DE-109 in the past 60 days
8.
Ocular surgery within the past 30 days
9.
Ocular or periocular infection in either eye
10. History of or active herpetic infection in the study eye or adnexa
11. Presence of known active, inactive  toxoplasmosis or toxoplasmosis scar in either eye
12. Presence of any form of ocular malignancy in the either eye including choroidal melanoma
13. History of vitrectomy in the study eye
Non-Ocular:
14. Allergy or hypersensitivity to study drug product or other study related procedures/medications
15. Participation in other investigational drug (SAKURA is an exception) or device clinical trials 
within 30 days prior to Day 1, or planning to participate in other investigational drug or device 
clinical trials for the entire duration of the study.  This includes both ocular and non-ocular 
clinical trials.
16. Any recent systemic infection within 30 days of Day 1 
17. Known to be immunocompromised
18. History of cytomegalovirus infection or clinical evidence of active cytomegalovirus infection 
at Day 1
19. 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
20. Malignancy in remission for less than 5 years prior to study participation (except basal cell or 
squamous cell skin cancer, or treated melanoma of the skin less than 24 months since last 
treatment)
21. Females who are pregnant or lactating and females of child-bearing potential who are not using 
adequate contraceptive precautions (i.e., intrauterine device, oral contraceptives, barrier 
method, or other contraception deemed adequate by the Investigator)
22. Use of medically prescribed marijuana or other illegal medication
23. Active systemic sarcoidosis within the last 30 months (i.e. subjects with uveitis secondary to 
sarcoidosis will be eligible as long as systemic sarcoidosis is not active and systemic 
immunosuppressive therapy has not been given in the last 30 months)
24. Therapeutic radiation to the head or neck within 90 days prior to Day 1 and throughout the 
study
In addition, the Investigator or Santen Medical Monitor may declare a subject ineligible for any sound 
reason.
Investigational product, dosage and mode of administration: 
Investigational product:  DE-109 injectable solution, 440 µg.
Subjects will be treated at the discretion of the Investigator, but no more frequently than every 60 days.  


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Route of Administration: 20 μL intravitreal injection in the study eye.
Duration of the Study: 12 months or commercial availability of DE-109, whichever comes first.
Criteria for Evaluation:
Safety: The long-term safety of DE-109 440 µg will be assessed based on adverse events, visual 
acuity, intraocular pressure, indirect ophthalmoscopy variables, vitreous haze and the use of rescue 
therapy.
Efficacy: Efficacy is not the main objective of this extension study. The long-term efficacy of DE-109 
440 µg may be explored by vitreous haze.
Safety Parameters:

Adverse event incidence rate

Change in best-corrected visual acuity

Change in intraocular pressure

Change in indirect ophthalmoscopy findings

Change in vitreous haze

Proportion of safety subjects who were rescued
Statistical Methods:
This extension study is implemented to provide subjects with access to DE-109 to benefit those who 
have received at least two injections of DE-109 during the first 5-month treatment of the SAKURA 
development program and to evaluate the long-term safety of DE-109 440 μg in subjects with non-
infectious uveitis of the posterior segment of the eye.
No statistical hypotheses will be tested in this study.
The safety data will be summarized descriptively. The Safety population will include all enrolled 
subjects with any safety data collected during the study, whether or not they ever receive any injection 
of DE-109 (440 µg). It will be the analysis population for safety summaries.
The formal definition of rescue therapy will be adequately documented based on clinical data review of 
this extension study prior to database lock.


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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS
1.
PROCEDURES IN CASE OF EMERGENCY .........................................................3
2.
SYNOPSIS...............................................................................................................4
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES................8
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................14
5.
INTRODUCTION..................................................................................................15
6.
OBJECTIVES ........................................................................................................18
7.
INVESTIGATIONAL PLAN .................................................................................19
7.1.
Overall Study Design and Plan ...............................................................................19
7.1.1.
Discussion of Study Design ....................................................................................19
7.2.
Number of Subjects ................................................................................................20
7.3.
Treatment Assignment............................................................................................20
7.4.
Criteria for Study Termination................................................................................20
7.5.
Study Procedures....................................................................................................20
7.5.1.
Visit 1 - Day 1 - Screening/Baseline .......................................................................22
7.5.2.
Visit 2 - Month 12 or Early Termination.................................................................22
7.5.3.
Post-Baseline PRN Treatment Visit ........................................................................23
8.
SELECTION AND WITHDRAWAL OF SUBJECTS............................................24
8.1.
Inclusion criteria.....................................................................................................24
8.2.
Exclusion criteria....................................................................................................24
8.3.
Subject Withdrawal Criteria....................................................................................26
9.
TREATMENT OF SUBJECTS ..............................................................................27
9.1.
Description of Study Drug......................................................................................27
9.2.
Concomitant Medications .......................................................................................27
9.2.1.
Prohibited Medications or Treatments.....................................................................27
9.2.2.
Rescue Therapy......................................................................................................28
9.3.
Treatment Compliance............................................................................................28
9.4.
Randomization and Masking...................................................................................28
10.
STUDY DRUG MATERIALS AND MANAGEMENT .........................................29


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10.1.
Study Drug .............................................................................................................29
10.1.1.
Test Article.............................................................................................................29
10.1.2.
Study Drug Complaint Reporting............................................................................29
10.2.
Study Drug Packaging and Labeling.......................................................................29
10.3.
Study Drug Storage ................................................................................................29
10.4.
DE-109 Preparation ................................................................................................29
10.6.
Study Drug Accountability .....................................................................................32
10.7.
Study Drug Handling and Disposal.........................................................................33
11.
ASSESSMENT OF EFFICACY.............................................................................34
12.
ASSESSMENT OF SAFETY.................................................................................35
12.1.
Adverse Events, Serious Adverse Events and Events of Special Interest .................35
12.1.1.
Definition of Adverse Events..................................................................................35
12.1.1.1.
Assessment of Adverse Events ...............................................................................35
12.1.1.2.
Reporting Adverse Events ......................................................................................36
12.1.2.
Serious Adverse Events ..........................................................................................37
12.1.3.
Sight Threatening Events........................................................................................38
12.1.3.1.
Reporting Serious Adverse Events..........................................................................38
12.1.3.2.
Expedited Reporting of Serious Adverse Events .....................................................38
12.1.4.
Events of Special Interest........................................................................................38
12.1.5.
Follow-up of Adverse Events..................................................................................39
12.1.6.
Manual Back-Up Reporting Procedures..................................................................39
12.2.
Safety Parameters ...................................................................................................39
12.2.1.
Adverse Events.......................................................................................................39
12.2.2.
Visual Acuity..........................................................................................................40
12.2.3.
Intraocular Pressure ................................................................................................40
12.2.4.
Indirect ophthalmoscopy.........................................................................................40
12.2.5.
Vitreous Haze.........................................................................................................40
12.2.6.
New Treatments with Rescue Therapy....................................................................40
12.2.7.
Pregnancy Test .......................................................................................................40
13.
OTHER ASSESSMENTS.......................................................................................41
13.1.
Demographics and Baseline Characteristics ............................................................41
13.2.
Other Assessments..................................................................................................41
14.
STATISTICAL METHODS...................................................................................42


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14.1.
General Considerations...........................................................................................42
14.1.1.
Analysis Parameters ...............................................................................................42
14.1.2.
Sample Size............................................................................................................42
14.1.3.
Statistical Hypotheses and Level of Significance ....................................................42
14.1.4.
Randomization........................................................................................................42
14.1.5.
Study Eye ...............................................................................................................43
14.2.
Study Populations...................................................................................................43
14.3.
Interim Analyses.....................................................................................................43
14.4.
Handling of Missing Values....................................................................................43
14.5.
Demographics and Baseline Characteristics ............................................................43
14.6.
Safety Analysis.......................................................................................................43
15.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................44
15.1.
Study Monitoring....................................................................................................44
15.2.
Audits and Inspections............................................................................................44
15.3.
Institutional Review Board .....................................................................................45
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................46
16.1.
Quality Control.......................................................................................................46
16.2.
Quality Assurance ..................................................................................................46
17.
ETHICS..................................................................................................................47
17.1.
Ethics Review.........................................................................................................47
17.2.
Ethical Conduct of the Study ..................................................................................47
17.3.
Written Informed Consent ......................................................................................47
18.
DATA HANDLING AND RECORDKEEPING.....................................................48
18.1.
Inspection of Records .............................................................................................48
18.2.
Retention of Records ..............................................................................................48
18.2.1.
Source Documents..................................................................................................48
18.2.2.
Data Collection.......................................................................................................49
19.
PUBLICATION POLICY.......................................................................................50
20.
REFERENCES.......................................................................................................51
21.
APPENDICES........................................................................................................54
21.1.
Appendix A - Obligations of Investigators..............................................................54
21.2.
Appendix B - Elements of Informed Consent..........................................................56
21.3.
Appendix C - Declaration of Helsinki.....................................................................58


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21.4.
Appendix D - Procedures for Examinations ............................................................63
21.4.1.
Demographics, Medical History and Medication.....................................................63
21.4.2.
Pregnancy Test .......................................................................................................63
21.4.3.
Visual Acuity..........................................................................................................63
21.4.3.1.
Procedures for Refraction and Vision Testing .........................................................63
21.4.4.
Intraocular Pressure (IOP) ......................................................................................70
21.4.5.
Indirect ophthalmoscopy.........................................................................................71
21.4.6.
Vitreous Haze.........................................................................................................71
21.5.
Appendix E – Manual SAE Reporting Process........................................................71


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LIST OF TABLES
Table 1:
Emergency Contact Information ...............................................................................3
Table 2:
Abbreviations and Specialist Terms........................................................................14
Table 3:
Schedule of Events .................................................................................................21
Table 4:
DE-109 Dosing.......................................................................................................29
Table 5:
SAE Manual Reporting Fax numbers......................................................................72


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LIST OF FIGURES
Figure 1:
DE-109 Chemical Structure....................................................................................27
Figure 2:
0.3 mL fill in a 0.5 mL vial.....................................................................................30
Figure 3:
0.3 mL fill in a 2 mL vial........................................................................................30
Figure 4:
The alignment of the syringe...................................................................................31


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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
AE
Adverse Event
Baseline
Earliest Assessment of Each Measure on Day 1
BCVA
Best-Corrected Visual Acuity
DE-109
Sirolimus Injectable Solution
eCRF
Electronic Case Report Form
ETDRS
Early Treatment of Diabetic Retinopathy Study
FDA
Food and Drug Administration
FKBP-12
FK binding protein 12
EDC 
Electronic Data Capture
GCP
Good Clinical Practice
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IL
Interleukin
IOP
Intraocular Pressure
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MHC
Major Histocompatibility Complex
mTOR
Mammalian Target of Rapamycin
NEI
National Eye Institute
NPDR
Non-Proliferative Diabetic Retinopathy
PDR
Proliferative Diabetic Retinopathy
SAE
Serious Adverse Event
SAKURA
Santen Protocol 32-007
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SUN
Standardized Uveitis Nomenclature Photographic Scale
USA
United States of America
VH
Vitreous Haze


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5.
INTRODUCTION
Uveitis is a heterogenous group of intraocular inflammation disorders with both exogenous 
(infection, trauma) and endogenous (autoimmune disorders, idiopathic) etiologies.  The most 
widely used classification of uveitis is based on the anatomical location of the inflammation
within the eye.  Anterior uveitis is the most common type and can involve the cornea, iris, and/or 
ciliary body.  Intermediate uveitis affects the middle portion of the eye, such as the ciliary body, 
anterior vitreous and peripheral retina.  Posterior uveitis can involve the vitreous, choroid, retina, 
and/or optic nerve.  Panuveitis, also referred to as diffuse, involves the anterior and posterior 
segments.
Uveitis is responsible for approximately 10% of the visual handicap in Western countries 
(Nussenblatt, 1990).  The prevalence of posterior uveitis and its associated ocular morbidity is 
not well characterized.  However, one study of an Israeli population and another of a Netherlands 
population approximated that 15 to 22% of uveitis affect the posterior segment (Rothova et al., 
1996; Weiner et al., 1991), while the study of Veterans Affairs patients estimated 10% with 
posterior uveitis (Suhler et al., 2008).  The study of the Netherlands population also found that in 
patients with posterior uveitis, 46% experienced visual loss of <20/40 or greater and 28% 
experienced macular edema (Rothova et al., 1996).  In chronic uveitis, cumulative structural 
damage and loss of vision result from recurrent episodes of inflammation. T-cell infiltration is 
primarily responsible for the inflammation (Barton et al., 1995).  T-cells release cytokines 
including various interleukins (IL-2, IL-4, and IL-10) and interferon gamma (Barton et al., 
1995).  Major histocompatibility complex molecules (MHC Class I and II) and adhesion 
molecules are upregulated by the cytokine release (Charteris et al., 1992; George et al., 1997; 
Whitcup et al., 1992a).  In experimental uveitis models, adhesion molecules have been found on 
ocular resident cells before leukocytes reach the inside of the eye (Whitcup et al., 1993; Whitcup 
et al., 1992b).  Thus, adhesion molecules enable leukocytes to migrate to the site of 
inflammation, contributing to the inflammatory cascade that occurs with active uveitis.
Corticosteroids are the mainstay of treatment for active, non-infectious uveitis.  Corticosteroids 
are administered topically, by periocular injection, via intravitreal injection and implant, or 
systemically.  Topical corticosteroids are useful for the management of anterior uveitis. In 
general, periocular corticosteroid injections are appropriate for intermediate uveitis. Retisert™ is 
a fluocinolone acetonide intravitreal implant which releases drug slowly over a period of months.  
This product was approved by the Food and Drug Administration (FDA) in 2005 for the 
treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.  Long-term 
data shows that subjects who receive fluocinolone acetonide implants sometimes require cataract 
extraction and a significant percentage require treatment to reduce IOP (Callanan et al., 2008).  
Even though this newer treatment approach is now available, many patients with chronic, 
posterior uveitis are more difficult to manage and require systemic corticosteroids due to 
recurring inflammation.  Co-morbidities from systemic corticosteroid use are well known, such 
as Cushingoid syndrome, diabetes, osteoporotic bones, and metabolic disturbances (Anglade et 
al., 2007).  Systemic immunosuppressive agents, although they require close monitoring, are 
therefore sometimes utilized for their steroid-sparing capabilities.  Immunosuppressive agents 
can be categorized into three (3) main classes: T-cell inhibitors (cyclosporine, tacrolimus), 
antimetabolites (azathioprine, methotrexate, mycophenolate mofetil, leflunomide), and alkylating 


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agents (cyclophosphamide, chlorambucil).  More recently, biologic agents have been explored 
for use in uveitis, including tumor necrosis factor-α inhibitors (infliximab, etanercept, and 
adalimumab), anti-lymphocyte agents (rituximab and alemtuzumab), and an interleukin-2 
receptor blocker (daclizumab).
Currently corticosteroids are the only approved drug class in the United States for non-infectious 
uveitis. Systemic cyclosporine which blocks T-cell activation and inhibits the production of 
cytokines has been approved in Germany and a few other countries for treatment-refractory 
uveitis but is not approved in the United States.  Although a variety of treatment options are 
available, the co-morbidities associated with corticosteroids and the inconvenience of close 
monitoring required with systemic immunosuppressive and biologic agents warrant more 
treatment options.
Sirolimus for ocular administration is being tested with a proprietary formulation, DE-109 for the 
treatment of non-infectious, posterior uveitis.  This proprietary formulation was originally 
developed by MacuSight, Inc. and in June 2010, Santen, Inc. acquired the worldwide rights to 
the formulation.  The formulation provides drug exposure to the retina/choroid for up to 
approximately 2 months, and is amenable to delivery by the intravitreal route of administration.  
The active pharmaceutical ingredient in the formulation is sirolimus. Sirolimus, also known as 
rapamycin, was isolated in the 1970’s from Streptomyces hygroscopicus in soil samples from 
Easter Island (Napoli et al., 2001).  Sirolimus is the active pharmaceutical ingredient in 2 
products approved by the FDA, specifically Rapamune®, an immunosuppressive agent used in 
renal transplant patients, and the CYPHER® sirolimus-eluting Coronary Stent approved for 
improving coronary luminal diameter in patients with symptomatic ischemic disease.
The mechanism of action of sirolimus in inmmunoregulation has been described extensively in 
the literature (Kahan, 2001; Napoli et al., 2001; Sehgal, 1998; Sehgal, 2003).  Sirolimus blocks 
T-lymphocyte activation and smooth muscle and endothelial cell proliferation that occurs in 
response to antigenic and cytokine (IL-2, IL-4 and IL-15) stimulation employing either 
Ca2+-dependent or Ca2+-independent pathways (Rapamune, 2009; Sehgal, 1995; Sehgal, 1998).  
Sirolimus arrests cell cycle progression by direct interaction with 2 intracellular proteins, 
specifically the immunophilin FK binding protein 12 (FKBP-12) and the mammalian target of 
rapamycin (mTOR), a multifunctional serine-threonine kinase (Napoli et al., 2001).  In cells, 
sirolimus binds to FKBP-12, and the resulting sirolimus: FKBP-12 complex then binds to and 
inhibits mTOR.  The inhibition of mTOR blocks IL-2 mediated signal transduction pathways that 
prevent cell cycle progression from G1 to S phase in T cells, endothelial cells, osteosarcoma 
cells, myogenic cell lines and smooth muscle cells (Kwon et al., 2005; Sehgal, 1998).  In 
addition, sirolimus inhibits the production of antibodies (Sehgal, 1995; Sehgal, 1998).  Sirolimus 
has also been shown to down-regulate the expression of many genes related to inflammation 
such as interleukin-8, endothelial-monocyte activating polypeptide II, granulocyte chemotactic 
protein 2, cyclooxygenase 1 and 2, and inducible nitric oxide synthas (Adamis, 2002; Attur et al., 
2000; Joussen et al., 2004; Nuhrenberg et al., 2005).
Similar to cyclosporine, sirolimus blocks T-cell activation and inhibits the production of 
inflammatory cytokines.  Moreover, tacrolimus, another immunomodulatory agent closely 
related to sirolimus, has shown effectiveness in uveitis refractory to cyclosporine (Kilmartin et 
al., 1998; Sloper et al., 1999).  Since sirolimus provides an inhibitory effect on inflammation, it 
may be beneficial in the treatment of active, non-infectious uveitis.


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Sirolimus has been administered to patients with non-infectious intermediate, posterior uveitis, 
or panuveitis in an investigator-sponsored protocol trial known as the SAVE study (Nguyen et 
al., 2013).  This was an initial Phase I study evaluating intravitreal and subconjunctival 
administration of sirolimus and the results of the study supported the continued development of 
DE-109.
The SAKURA development program is a multinational, multicenter, randomized, double-
masked protocol (Santen Protocol 32-007) assessing the safety and efficacy of three doses of 
DE-109 (44 µg, 440 µg and 880 µg) administered every 2 months in subjects with active, non-
infectious uveitis of the posterior segment of the eye. A planned unmasked analysis of 6-month 
data of 347 subjects has been completed. In the analysis, both the 440 µg and 880 µg doses of 
DE-109 demonstrated efficacy in the treatment of non-infectious uveitis affecting the posterior 
segment of the eye. The 440 µg dose demonstrated statistically significant differences for the 
primary and key secondary endpoints when compared to the 44 µg dose. Efficacy results for the 
880 µg dose regimen were not as significant compared to the 44 µg dose. Additionally, there was 
a tendency towards increased reporting of AEs associated with intraocular inflammation 
following intravitreal administration with the 880 µg dose. In the overall analysis, the 440 µg 
dose demonstrated a more favorable Benefit-Risk profile than the 880 µg dose.  The SAKURA 
development program is on-going and continues to enroll.
This study (Santen, Protocol 32-009) is being initiated to allow subjects continued access to
DE-109 (440 µg) following participation in the SAKURA program and to obtain additional
long-term safety data on the to be developed dose.


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6.
OBJECTIVES
The objective of this extension study is to evaluate the long-term safety of treatment with
DE-109 (440 μg) in subjects with non-infectious uveitis of the posterior segment of the eye.


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7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design and Plan
This is a multicenter, open-label, extension study of intravitreal injections of the 440 μg dose of 
DE-109 in subjects with non-infectious uveitis of the posterior segment who received any dose 
of DE-109 and exited the SAKURA program under Santen Protocol 32-007, Amendment 05.
Subjects who were randomized and received at least two injections of DE-109 during the first 
five months of the SAKURA study and obtained clinical benefit from the study medication, as 
determined by the Investigator, may be considered for entry in this 12-month extension study.
The minimum time lag from last injection in the SAKURA program to entry into the current 
protocol is 60 days.
The study eye to be treated in this extension study will be the same as the eye treated during the 
SAKURA program.The study eye must meet all eligibility criteria of the extension study.
DE-109 should NOT be administered to the fellow eye. If the fellow eye requires treatment 
during the study, alternative local therapies (e.g., intravitreal or periocular injection of 
triamcinolone acetonide, Ozurdex, Iluvien, anti-VEGF treatments or photodynamic therapy, etc) 
may be administered to that eye.  The regimen and frequency of treatments for the fellow eye 
will be at the Investigator’s discretion.
Study assessments will be conducted for all subjects at Day 1 (Baseline) and Month 12. Each
subject will be followed according to the Investigator’s standard clinical practice at non-study 
visits. DE-109 treatment may be administered in the study eye at the Investigator’s discretion 
during the 12-month study period but no more frequently than every 60 days.
If the Investigator administers a DE-109 injection to the subject, the visit will be considered a 
Post-Baseline PRN Treatment Visit and procedures will be performed and recorded as specified 
in this protocol (See Table 3).
All subjects will exit the study at Month 12, unless terminated early.  Adverse events (AEs) will 
be recorded and collected throughout this extension study, up to the Month 12 exit visit.
It is anticipated that approximately 200 subjects from the SAKURA program may be enrolled in 
this study. Subjects will be screened for eligibility and written informed consent will be obtained 
before any study related procedures are performed.
7.1.1. Discussion of Study Design
This study is designed to provide access to DE-109 (440 µg) for those subjects who received 
treatment during the SAKURA program.  In addition the study will evaluate the long-term safety
of DE-109.
The 440 μg dose of DE-109 will be the only dose utilized in this open-label study.  Subjects will 
be evaluated for treatment with DE-109 as needed, but may not receive an injection of DE-109 
more frequently than every 60 days.  DE-109 may only be administered to the study eye.
Rescue treatment for the study eye and all treatments for the non-study eye are to be 
administered at the discretion of the Investigator. The long-term safety of DE-109 (440 µg) will 


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be assessed based on adverse events (AEs), best-corrected visual acuity (BCVA), intraocular 
pressure (IOP), indirect ophthalmoscopy variables, VH and the use of rescue therapy.
The final safety data evaluation will be assessed at Month 12.  Interim analyses may be 
performed by the Sponsor at various times during the study.
7.2.
Number of Subjects
The number of subjects to be enrolled in the study will be approximately 200 subjects.  
7.3.
Treatment Assignment
This is an open-label study and all subjects will receive the 440 μg dose of DE-109. 
7.4.
Criteria for Study Termination
This study may be stopped by Santen at any time following appropriate notification.
7.5.
Study Procedures
All subjects must sign a written informed consent form (ICF) before undergoing any study-
related procedure. Each subject will be assigned the same patient number assigned to them in the 
SAKURA program.
A Schedule of Events is provided in Table 3 and detailed procedures for examinations can be 
found in Section 21.4.  


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Table 3:
Schedule of Events
Visit 1
Day 1
Screening/Baseline
Post-Baseline
PRN Treatment 
Visits
Visit 2
Month 12 or
Early Terminationd
Assessment Window (Days)
-
≥60 days since last 
injection
±14
Informed Consenta
X
Demographics
X
Medical/Surgical history 
X
Medications
X
x
x
Urine pregnancy test, if 
appropriate
xb
xb
xb
Inclusion/exclusion criteria
X
Best-Corrected Visual Acuity 
X
x
x
Intraocular pressure
xc
xc
x
Indirect ophthalmoscopye
X
x
x
Vitreous haze
X
x
x
DE-109 administration, if 
needed 
x
x
Adverse events
xf
xf
x
a. Informed consent will be obtained prior to conducting any study-related activities.
b. Urine pregnancy tests are to be performed on all women of child-bearing potential.
c. On days when DE-109 injections are administered perform IOP before and 40 ( ±10) minutes after DE-109 
injection.
d. For Early Termination Visits please complete the procedures for the Month 12 visit.
e. Indirect ophthalmoscopy will be performed prior to each study drug injection and then again within 30 minutes 
after study drug injection
f. On days when DE-109 injections are administered AEs will be elicited before and after DE-109 injection.


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7.5.1. Visit 1 - Day 1 - Screening/Baseline

Explain the purpose and details of the study to the subject and obtain written informed 
consent prior to the subject’s participation in any extension study related activity.

Determine if the subject has:
o
A subject number from participation in the SAKURA program, Amendment 05
o
Received at least two treatments of DE-109 in the first five months of the SAKURA 
program
o
Received clinical benefit from treatment with DE-109 as determined by the 
Investigator.

Record subject’s demographics, medical and surgical history and medications.

If the subject is a woman of child-bearing potential, perform a urine pregnancy test.

Review the inclusion and exclusion criteria. If the subject has met the inclusion/exclusion 
criteria, the subject may continue in the study. 

Perform the following assessments:
For subjects exiting the SAKURA program at this visit, the following assessments 
will be obtained from the SAKURA Termination Visit.  Please skip to “Evaluation 
of Need for Treatment.”
o
BCVA
o
IOP 
o
Indirect ophthalmoscopy
o
VH.

Evaluation of Need for Treatment - If in the judgment of the investigator, the subject needs 
DE-109 treatment, it has been at least 60 days since the last treatment, and the results of the 
urine pregnancy test were negative (for women of child-bearing potential), perform the study 
drug administration procedures as described in Section 10.4 and 10.5.

The following assessments must be performed after the administration of study drug:
o
Indirect ophthalmoscopy within 30 minutes following injection
o
IOP 40 (±10) minutes following injection
o
AEs
7.5.2. Visit 2 - Month 12 or Early Termination

At Day 360 (±14) or if the subject is exiting the study early, perform the following 
assessments:
o
Update medications
o
Urine pregnancy test for women of child-bearing potential  


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o
BCVA
o
IOP
o
Indirect ophthalmoscopy
o
VH
o
AEs.

Exit the subject from the study.
7.5.3.
Post-Baseline PRN Treatment Visit
The subject may receive DE-109 treatments at the discretion of the Investigator, but no more 
frequently than every 60 days. If a subject receives treatment with DE-109 between scheduled 
study assessments, the following procedures will be performed:
o
Update medications
o
If the subject is a woman of child-bearing potential, perform a urine pregnancy test
o
BCVA
o
IOP
o
Indirect ophthalmoscopy
o
VH
o
AE.

If in the judgment of the Investigator, the subject needs DE-109 treatment, it has been at least 
60 days since the last treatment, and the results of the urine pregnancy test were negative (for 
women of child-bearing potential), perform the study drug administration procedures as 
described in Section 10.4 and Section 10.5.

The following assessments must be performed after the administration of study drug:
o
Indirect ophthalmoscopy within 30 minutes following injection
o
IOP 40 (±10) minutes following injection
o
AEs.


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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.
Inclusion criteria
At Day 1, a subject from the SAKURA program must meet all of the following inclusion criteria:
1. Have a subject number from participation in the SAKURA program 
2. Exited the SAKURA program under Amendment 05
3. Have received at least two injections of DE-109 in the first five months of the SAKURA 
program
4. Received clinical benefit from treatment with DE-109 as determined by the Investigator
5. Female participants of childbearing potential must not be pregnant or breast-feeding, 
have a negative pregnancy test at screening and must be willing to undergo pregnancy 
tests throughout the study
6. Both female participants of childbearing potential and male participants able to father 
children must have (or have a partner who has) had a hysterectomy or vasectomy, must 
abstain from intercourse or must agree to practice acceptable methods of contraception 
throughout the course of the study.
7. Ability to give informed consent and attend all study visits
8.2.
Exclusion criteria
A subject from the SAKURA program with any of the following conditions if not eligible to 
participate in the study:
Ocular:
1. Active infectious uveitis.  However, if the uveitis is the consequence of a previous 
infectious disease, such as tuberculosis, the previous infectious disease must be 
confirmed as no longer active.
2. Any implantable corticosteroid-eluting device (e.g. Ozurdex, I-vation, Iluvien, 
fluocinolone acetonide [FA] intravitreal implant) in the study eye:
a.
If the Investigator confirms the device has no demonstrable efficacy as indicated 
in the package insert, the subject will be eligible
b. If a Medidur implant, Iluvien or Retisert has been implanted no less than 3 years 
and 90 days prior to Day 1, the subject will be eligible
c.
If a Ozurdex implant, has been implanted no less than 180 days prior to Day 1, the 
subject will be eligible
3. Clinically suspected or confirmed central nervous system or ocular lymphoma
4. Progressive glaucoma which is unresponsive to treatment  


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5. Intraocular pressure of  > 21 mmHg while on medical therapy, or chronic hypotony
(<6 mmHg) 
6. Any significant ocular disease that could compromise vision in the study eye. These 
include,  but are not limited to: 
a.
Diabetic retinopathy: proliferative diabetic retinopathy (PDR) or non-proliferative 
diabetic retinopathy (NPDR) that compromise vision. Subjects with NPDR or 
PDR that does not compromise vision are not excluded from the study;
b. Wet age-related macular degeneration;
c.
Myopic degeneration with active subfoveal choroidal neovascularization 
7. Any of the following treatments to the study eye:
a.
Intravitreal injections in the past 14 days
b. Intravitreal injections of DE-109 in the past 60 days
8. Ocular surgery within the past 30 days
9. Ocular or periocular infection in either eye
10. History of herpetic infection in the study eye or adnexa
11. Presence of known active, inactive  toxoplasmosis or toxoplasmosis scar in either eye
12. Presence of any form of ocular malignancy in the either eye including choroidal 
melanoma
13. History of vitrectomy in the study eye
Non-Ocular:
14. Allergy or hypersensitivity to study drug product or other study related procedures/
medications
15. Participation in other investigational drug (SAKURA is an exception) or device clinical 
trials within 30 days prior to Day 1, or planning to participate in other investigational 
drug or device clinical trials for the entire duration of the study.  This includes both 
ocular and non-ocular clinical trials.
16. Any recent systemic infection within 30 days of Day 1
17. Known to be immunocompromised
18. History of or active cytomegalovirus infection or clinical evidence of active 
cytomegalovirus infection at Day 1
19. 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


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20. Malignancy in remission for less than 5 years prior to study participation (except basal 
cell or squamous cell skin cancer, or treated melanoma of the skin less than 24 months 
since last treatment)
21. Females who are pregnant or lactating and females of child-bearing potential who are not 
using adequate contraceptive precautions (i.e., intrauterine device, oral contraceptives, 
barrier method, or other contraception deemed adequate by the Investigator)
22. Use of medically prescribed marijuana or other illegal medication
23. Active systemic sarcoidosis within the last 30 months (i.e. subjects with uveitis secondary 
to sarcoidosis will be eligible as long as systemic sarcoidosis is not active and systemic 
immunosuppressive therapy has not been given in the last 30 months).
24. Therapeutic radiation to the head or neck within 90 days prior to Day 1 and throughout 
the study.
In addition, the 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 
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 will not be
replaced.  Subjects may be terminated from the study due to any of the following reasons:

Non-compliance

Lack of efficacy

Lost to follow-up

Protocol violation

Withdrawal by subject

AE

Death

Other
If a subject is discontinued from the study before completing Month 12, then to the extent 
possible, all assessments, including safety, that are scheduled to be performed at Month 12
should be performed on the day of discontinuation.
Subjects who discontinue prematurely will not be replaced.


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9.
TREATMENT OF SUBJECTS
9.1.
Description of Study Drug
DE-109 is a depot formulation of sirolimus, an immunomodulatory agent which inhibits the 
mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell 
growth, proliferation, motility and survival through changes in transcription and protein 
synthesis.
Figure 1:
DE-109 Chemical Structure
Investigational Product: 2.0% DE-109 injectable solution (440 µg)
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 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
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. There may be 
prohibited therapies not mentioned below.
The following medications or treatments are prohibited:

Participation in other investigational drug (SAKURA is an exception) or device clinical 
trials within 30 days prior to 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.

Therapeutic radiation to the head or neck within 90 days prior to Day 1 and throughout 
the study.

Use of medically prescribed marijuana or other illegal medication within 30 days prior to 
Day 1 and throughout the study.


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9.2.2.
Rescue Therapy
Rescue therapy may be used at the discretion of the Investigator.
9.3.
Treatment Compliance
The Investigator is not required to administer DE-109 at any visit. DE-109 treatments may be 
given, as needed, at the discretion of the Investigator; however, DE-109 treatments may not be 
given more frequently than every 60 days.
The Investigator is responsible for scheduling the subject for follow-up visits based on the 
Investigator’s standard clinical procedures and these visits are not study visits. If a subject 
receives treatment with DE-109 (440 µg) between scheduled study assessments, the visit will be 
a Post-Baseline PRN Treatment Visit and procedures will be performed and recorded as 
specified in this protocol (See Table 3).
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. The decision to administer study drug on any 
given study day is at the discretion of the Investigator.  All subjects who are dosed will receive 
the same open-label dose of DE-109 (440 µg). Study drug will contain a unique number and 
should be dispensed in sequential, ascending order by each center.


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10.
STUDY DRUG MATERIALS AND MANAGEMENT
10.1.
Study Drug
10.1.1.
Test Article
DE-109 (440 µg) is formulated as clear, non-aqueous solutions of the drug substance, sirolimus, 
in a vehicle composed of polyethylene glycol 400 (PEG 400) and ethanol. Both PEG 400 and 
ethanol are widely used as solubilizing excipients in injectable formulations (Strickley, 2004).
The dosage of sirolimus to be administered in this extension study will be 440 µg DE-109 as
shown in Table 4.
Table 4:
DE-109 Dosing
Injection Volume of:
Will deliver
approximately:
20 µL of 22 µg/µL (2.0%)
intravitreally
440 µg of sirolimus
DE-109 (440 µg) will be supplied frozen either as 0.3 mL of sterile injectable solution in 0.5 mL 
vials or 0.3 mL of sterile injectable solution in 2 mL vials. Investigator must use the syringes 
and needles supplied by the sponsor.
10.1.2.
Study Drug Complaint Reporting
Complaints regarding the study drug should be reported to Santen Product Complaint at 
415-268-9100 or the study monitor.
10.2.
Study Drug Packaging and Labeling
DE-109 (440 µg) injectable solutions are filled in 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, unique kit number, and storage conditions.
10.3.
Study Drug Storage
DE-109 (440 µg) will be received frozen. DE-109 (440 µg) must be stored and should remain
frozen in a secure, locked, dark, temperature controlled,  -20ºC ± 5ºC (with allowable 
temperature excursions up to -35º C) freezer with restricted access until the time of use.  
10.4.
DE-109 Preparation
The vial of study drug will be removed from the freezer and thawed by rotating the vial between 
the palms of the hands for a minimum of 5 minutes, or by setting the vial at room temperature for 
a minimum of 30 minutes. Care should be taken to protect the product from light. Study drug 
should be drawn into the provided single-use plastic syringe within 60 minutes after removing 


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the vial from the freezer. Study drug should be injected within 2 hours of being drawn up into the 
single-use syringe.
Each vial contains enough study drug to inject one subject.  Each vial will be used one time only. 
A sterile, single-use 250 μL syringe custom marked at 20 µL will be provided separately for
intravitreal injection use.  These will be used for intravitreal injections of DE-109. Instructions 
for filling the syringe are as follows:
1. Remove the sterile, single-use 250 μL syringe custom marked at 20 µL from the 
packaging.
a.
If the drug product is dispensed from a 0.5 mL vial, attach a 23-gauge x 1 inch or 
25-gauge x 5/8 inch needle to the syringe.
Figure 2:
0.3 mL fill in a 0.5 mL vial
b. If the drug product is dispensed from a 2 mL vial, attach a 21-gauge x 1 ½  inch
needle to the syringe.
Figure 3:
0.3 mL fill in a 2 mL vial
2. Using sterile technique, carefully draw up more than 20 µL of DE-109 into the plastic 
syringe.  It should be noted that due to the slight viscosity drawing up DE-109 will be slow.  
3. For DE-109 (440 µg) preparation, replace the needle with a 30-gauge x 0.5 inch needle for 
the intravitreal 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 BLACK MARK ON THE SYRINGE (See Figure 4).
c.
PLEASE ENSURE THAT THERE ARE NO AIR BUBBLES WITHIN THE 
SYRINGE OR THE NEEDLE HUB PRIOR TO INJECTION.  


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Figure 4:
The alignment of the syringe
10.5.
Administration
10.5.1.
Instructions for Intravitreal Injection of DE-109
10.5.1.1.
Eye Preparation
The subject may receive DE-109 (440 µg) treatments at the discretion of the Investigator, but no 
more frequently than every 60 days.  Instructions for ocular antisepsis are provided below.
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 5% povidone iodine to the study eye immediately prior to injection.
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 superotemporal conjunctival 
surface at the area of the entry site described below in Step 10 and hold in place for 
approximately 1 minute;
6. Administer a subconjunctival injection of 0.25 mL of 2% lidocaine without epinephrine 
or equivalent to the superotemporal quadrant to the area of the entry site described below 
in Step 10 (Steps #5 and 6 may be omitted per the Investigator’s discretion);


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7. Insert sterile eyelid speculum;
8. Place sterile eye drape over study eye;
9. Prior to starting the injection procedure, DE-109 should have been prepared as described 
in Section 10.4, with the appropriate dose of study drug drawn into a 250 µL single-use 
plastic syringe. ENSURE THAT THERE ARE NO AIR BUBBLES IN THE 
SYRINGE OR NEEDLE HUB;
10. If the subject is phakic, the entry site is recommended to be 3.5 mm to 4.0 mm peripheral 
to the inferotemporal limbus.  If the subject is aphakic or pseudophakic, the entry site is 
recommended to be 3.0 mm to 3.5 mm peripheral to the inferotemporal limbus. A caliper 
may be used to identify the needle entry site.  The intravitreal injection site may be 
modified at the Investigator’s discretion.
11. Insert the needle perpendicular to the eye wall at the location specified in Step 10.
12. Very slowly, inject the entire study drug volume and hold for 5 seconds prior to slowly 
withdrawing the needle. Do not pull back on the plunger at any time prior to withdrawing 
the needle;
13. Briefly apply pressure for approximately 1 minute to the needle entry site with a sterile 
cotton tipped applicator;
14. Remove the eyelid speculum;
15. Patch the study eye at the Investigator’s discretion;
Prescribe fluoroquinolone equivalent antibiotic eye drops 3 times per day for 2 days following 
each injection (Aiello et al., 2004).
10.6.
Study Drug Accountability
The 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 -20°C or lower 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 Investigator’s records. 
The 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 Investigator must be accounted for and in no case will study drugs be 
used in any unauthorized situation.  It is the responsibility of the Investigator to ensure that any 
used and unused supplies are available to Santen (or designee) throughout the study.


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10.7.
Study Drug Handling and Disposal
All investigational products including unused vials of study drug supplied by Santen will be 
returned to Santen or designee and be fully accounted for by the monitor with the help of the 
person responsible for dispensing the study drug. Accountability will be documented by use of 
drug accountability forms.
The used vials of study drug will be stored at the investigational site upon completion of 
accountability procedures and returned to Santen or designee, or destroyed at the site at the 
direction of Santen, after the trial is completed.


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11.
ASSESSMENT OF EFFICACY
The long-term efficacy of DE-109 (440 µg) may be explored by VH.


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12.
ASSESSMENT OF SAFETY
12.1.
Adverse Events, Serious Adverse Events and Events of Special 
Interest
12.1.1.
Definition of Adverse Events
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with study drug. An AE therefore can 
be an unintended sign (including an abnormal laboratory finding), symptom, or disease 
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 
wash-out period, may be recorded as an AE even if no study drug has been administered.
Any significant 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.
Lack of efficacy of the study drug for the condition being investigated is not considered an AE
unless a clinically significant change is assessed by the Investigator.  In addition, any elective 
surgical procedure scheduled or planned prior to study entry is not considered an AE and the 
underlying diagnosis for which surgery is to be performed should be captured in the medical 
history as a pre-existing condition.
For this protocol, an AE is any on-study untoward medical occurrence (e.g. sign, symptom, 
disease, syndrome, intercurrent illness) that occurs in a study subject, regardless of the suspected 
cause and regardless of timing of DE-109 (440 µg) administration. An on-study AE can occur 
anytime after the date of informed consent through the last study visit. An AE will be considered 
as treatment-emergent if the AE occurred on or after the date of the first DE-109 (440 µg) 
treatment up to the last study visit.  Treatment-emergent AEs are a subset of on-study AEs.  Both 
on-study and treatment-emergent AEs will be reported.
12.1.1.1.
Assessment of Adverse Events
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 or well-
being. Direct questioning and examination should then be performed as appropriate.
Severity of the AE should be assessed according to the following criteria:
Mild: Aware or unaware of event, but easily tolerated
Moderate: Discomfort enough to cause interference with usual activities
Severe: Incapacitating; unable to work or perform usual activity.
Regardless of severity, some AEs may also meet regulatory serious criteria.  Refer to definitions 
and reporting of serious adverse events (SAEs) in Section 12.1.2.


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An Investigator who is qualified in medicine must make the determination of relationship to the 
study drug for each AE (related or not related).  The Investigator should decide whether, in his or 
her medical judgment, there is a reasonable possibility that the study drug caused the AE/SAE 
based on facts, evidence, science-based rationales, and clinical judgment.  When assessing 
causality, the Investigator may consider the following information when determining the 
relationship to the study drug 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.

The AE may be recorded as Related to study drug if there is a plausible temporal 
relationship between the onset of the AE and administration of the study drug, and the 
AE cannot be readily explained by the subject’s clinical state, inter-current illness, or 
concomitant therapies; and/or the AE follows a known pattern of response to the study 
drug; and/or the AE abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.

Reporting the AE as Not Related to study drug may be considered if, for example, there 
is good evidence that the AE has an etiology other than the study drug (e.g., pre-existing 
medical condition, underlying disease, inter-current illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to administration of the study drug
(e.g., cancer diagnosed 2 days after first dose of study drug).
12.1.1.2.
Reporting Adverse Events 
AEs, whether spontaneously reported by the subject or noted by authorized study personnel, will 
be recorded in the subject’s medical record and on the appropriate AE eCRF. Each recorded AE 
will be described by its duration (i.e., start and end dates), severity, regulatory seriousness 
criteria if applicable, suspected relationship to the study drug, and actions taken.
AEs that occur after any subject has provided written informed consent up to Month 12 must be 
recorded. If an adverse event is ongoing at the time of study exit, then the Investigator should 
perform reasonable follow-up efforts as necessary (e.g. telephone contact, post-study office visit) 
to determine the outcome of the event.  To improve the quality and precision of acquired AE 
data, 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 (e.g., record congestive heart failure rather than dyspnea, rales, and cyanosis).  
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).

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.


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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.

For intermittent events (e.g., intermittent headache) and events that occur with each 
instillation (e.g., eyes burn for 5 minutes after every dose), the event start date should be 
recorded as the date the subject first started to experience the event.  The end date should 
reflect when the last occurrence resolved or stopped. For example, if a subject had an 
intermittent headache from 14 MAY 2014 until 21 MAY 2014 and each individual headache 
lasts 3 hours a day, then the date of resolution is 21 MAY 2014 (not 14 MAY 2014).

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.

If an event occurs with each instillation (e.g., eyes burn mild to moderate for 5 minutes after 
every dose), record the maximum severity of the individual incident. In the example above, 
the severity is moderate.
12.1.2.
Serious Adverse Events
SAEs are defined as any findings that suggest a significant hazard, contraindication, side effect, 
or precaution. Any adverse event is considered a serious adverse event if it results in any of the 
following outcomes:

Death

Life threatening:
A life-threatening event is any event that places the subject at immediate risk of death 
from the event as it occurred; it does not refer to an event that hypothetically might have 
caused death if it were more severe.

In-subject hospitalization and/or prolonged hospitalization

A persistent or significant disability/incapacity

A congenital anomaly/birth defect

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 (See Section 12.1.3).

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.


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12.1.3.
Sight Threatening Events
For the purposes of this study the following ocular adverse events will be reported as serious 
adverse events:

Loss of 6 or more lines of vision (≥30 letters) from Baseline;

Endophthalmitis;

Purulent, infectious conjunctivitis;

Retinal detachment;

IOP > 35 mmHg that persists for at least 7 days despite pharmacologic therapy;

Other significant ocular events per Investigator’s discretion
12.1.3.1.
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, 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 Medical/Surgical History eCRF and 
be mentioned as part of the action taken in response to the illness.
When new significant information (including the outcome of the event) is obtained, the 
Investigator should enter the information directly into the eCRF within 24 hours or as soon as 
possible after knowledge of the information.
Depending on the nature and seriousness of the AE, Santen may request additional 
documentation, for example, copies of the ophthalmic and medical record of the subject as well 
as results of laboratory tests. If the subject was hospitalized, the site should summarize the 
hospital discharge summary and provide to Santen upon request.
12.1.3.2.
Expedited Reporting of Serious Adverse Events
Santen (or designee) will provide the Investigator with a reporting cover letter and an 
anonymized MedWatch 3500A for expedited reporting of SAEs to the Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC). The 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.
12.1.4.
Events of Special Interest
Events of Special Interest (ESIs) are events that may require special attention for the purposes of 
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be reported on the appropriate eCRF with as much information as available within 24 hours of 
knowledge of the event:

Study medication administration error – Study medication administration errors 
determined to be significant by the 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.
12.1.5.
Follow-up of Adverse Events
All reported AEs at study exit will be followed by the 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 Santen Drug Safety requests follow-up on an individual SAE or designated ESI, site response 
to follow-up requests should be faxed to Santen Drug Safety: 415-276-5882 (fax) or 
drugsafety@santeninc.com.
12.1.6.
Manual Back-Up Reporting Procedures
This study is utilizing an electronic data capture (EDC) system for data entry.  In the event that 
the EDC system is unavailable for electronic reporting, the manual back-up reporting procedures
found in Section 21.5 should be followed.
12.2.
Safety Parameters
The safety assessments will include the incidence of AEs and SAEs and treatment with rescue
therapy. Changes in BCVA, IOP, indirect ophthalmoscopy variables and VH will also be used to 
evaluate the long-term safety of DE-109.
12.2.1.
Adverse Events
AEs will be elicited from the subjects following the signing of informed consent through the end 
of the study.  The information will include at least a description of the event, whether or not it is 
serious, onset and duration, severity, relation to study drug, 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 16.0, 
2013).  Ocular and non-ocular AEs will be summarized separately.  See Section 12.1 for 
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12.2.2.
Visual Acuity
BCVA will be measured for each eye at Day 1, Month 12 and Post-Baseline PRN Treatment 
Visits using an ETDRS chart.
12.2.3.
Intraocular Pressure
IOP will be measured for each eye using applanation tomometry at Day 1, Month 12 and Post-
Baseline PRN Treatment Visits prior to evaluation of need for treatment.  If DE-109 (440 µg) is 
administered, a second assessment will be made 40 (±10) minutes after injection.
12.2.4.
Indirect ophthalmoscopy
An indirect ophthalmoscopy will be performed at Day 1, Month 12 and Post-Baseline PRN 
Treatment Visits to examine the retina of each eye.  Indirect ophthalmoscopy will be performed 
prior to each study drug injection and then again within 30 minutes after study drug injection. 
Assessments include lens, retina, macula, choroid, and optic nerve.  Lens will be assessed for the 
presence or absence of cataract.  All other assessments will be noted as normal or abnormal.
12.2.5.
Vitreous Haze 
VH will be assessed for each eye at each visit using the modified SUN scale scores of: 0, 0.5+, 
1+, 1.5+, 2+, 3+, 4+.
12.2.6.
New Treatments with Rescue Therapy
Concomitant medications will be assessed according to the Investigator’s standard practice for 
the incidence of new treatment with rescue therapy, among those subjects not previously treated 
with rescue therapy in the SAKURA program.
12.2.7.
Pregnancy Test
A urine pregnancy test will be conducted at Day 1, Month 12 and Post-Baseline PRN Treatment 
Visits for all women of childbearing potential.


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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 BCVA, IOP, indirect ophthalmoscopy 
findings, VH and pregnancy test.
13.2.
Other Assessments
Other assessments include concomitant medications and exposure to study drug.  The number of 
DE-109 (440 µg) treatments between Day 1 and Month 12 will be evaluated.


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14.
STATISTICAL METHODS
14.1.
General Considerations
This protocol is implemented to evaluate the long-term safety of treatment with DE-109 (440 µg)
in subjects with non-infectious uveitis of the posterior segment of the eye among those subjects 
who received at least two treatments of DE-109 during the first five months of the SAKURA
program and received clinical benefit, as determined by the Investigator. The minimum time lag 
from last injection during the SAKURA program to entry into the current protocol is 60 days. 
Study visits for assessment are scheduled at Day 1 and Month 12.  At the discretion of the 
investigator, dosing of DE-109 (440 µg) may take place at Day 1 or at any Post-Baseline PRN 
Treatment Visit prior to the Month 12 assessment visit.
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.  No statistical hypothesis testing will be conducted on any parameter.
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.
Analysis Parameters

AE incidence rate 

Change in BCVA

Change in IOP

Change in indirect ophthalmoscopy findings

Change in VH

Proportion of safety subjects who were rescued who were not previously rescued in the 
SAKURA program.
14.1.2.
Sample Size
The sample size will not be determined 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 
Randomization is not employed in this study. The decision to administer study drug on any  
study day is at the discretion of the Investigator.  All subjects who are dosed will receive the 
same open-label dose (440 µg) of DE-109.


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14.1.5.
Study Eye
The study eye must meet all eligibility criteria. For analysis purposes, the study eye will be the 
eye actually treated in this extension study. If a subject receives no injection of DE-109 (440 µg)
in this extension study, then the eye designated as the study eye in the SAKURA program is the 
study eye.
14.2.
Study Populations
The Safety population will include all enrolled subjects with any safety data collected during the 
study, whether or not they ever receive any injection of DE-109 (440 µg). It will be the analysis 
population for safety summaries.
14.3.
Interim Analyses
No formal interim analysis is planned for this study; however, the Sponsor may perform interim 
analyses throughout the study.
14.4.
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.
14.5.
Demographics and Baseline Characteristics
Age, sex, race, ethnicity, and baseline assessments will be summarized descriptively.
14.6.
Safety Analysis
The safety assessments will include the incidence of AEs and SAEs and treatment with rescue 
therapy.  Changes in BCVA, IOP, indirect ophthalmoscopy variables and VH will also be used to 
evaluate the long-term safety of DE-109. Safety data from both eyes will be included.
Each AE will be classified into a system organ classification (SOC) and coded to a preferred 
term using the most updated version of MedDRA (MedDRA 16.0, 2013). Subjects with any 
AE(s) will be tabulated by SOC and preferred term.  They will also be tabulated by SOC, 
preferred term, and maximum severity.  In these AE tables, a subject who experienced multiple 
AEs 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 will be presented first to be separated from non-
ocular AEs.  Study-medication-related and injection-procedure-related AEs will be summarized 
similarly. In addition, AEs, SAEs, and AEs leading to discontinuation and death, if any, will be 
listed. ESIs, if any, will also be listed by event type.
Ocular safety outcome measures will be summarized using descriptive statistics.  Specifically for 
BCVA, IOP, indirect ophthalmoscopy findings, and VH, scores and changes from baseline will 
be summarized descriptively; in addition, clinically significant changes from baseline, if any,
will be listed.


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15.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The 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, 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 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 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 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 Investigator will allow Santen (or designee), the governing IRB or EC, 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 medical 
records at any time during the study.  These study records must be retained at the study site and 


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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 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 Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB or IEC
approval, and all materials approved by the IRB or IEC for this study including the subject 
consent form and recruitment materials must be maintained by the 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 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 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 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 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 (Section 15.2).


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18.
DATA HANDLING AND RECORDKEEPING
18.1.
Inspection of Records
The 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, 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 Investigator until 
notified by Santen (or designee) that the records may be destroyed.
18.2.1.
Source Documents
The Investigator must maintain detailed source documents on all study subjects who provide 
informed consent. Source documents include subject medical records, hospital charts, clinic 
charts, study files, as well as the results of diagnostic tests (e.g., laboratory tests, visual field test 
printouts).
The following minimum information should be entered into the subject’s medical record:

The date the subject entered the study and the subject number

The study protocol number and the name of Santen Inc.

The date that informed consent was obtained

Evidence that the subject meets study eligibility requirements (e.g., medical history, study 
procedures and/or evaluations)

The dates of all study-related subject visits

Evidence that required procedures and/or evaluations were completed

Use of any concomitant medications

Documentation of study drug accountability

Occurrence and status of any AEs

The date the subject exited the study and a notation as to whether the subject completed or 
terminated early from the study, including the reason for early termination


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18.2.2.
Data Collection
The Investigator must maintain detailed records on all subjects who provide informed consent.  
Data for screened and eligible 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 Investigator agrees to the release of the data from this study and 
acknowledges the above publication policy.


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20.
REFERENCES
1. Adamis, A. (2002).  Is diabetic retinopathy an inflammatory disease?  British Journal of 
Ophthalmology 86(4):363-5.
2. Aiello, L., Brucker, A., Chang, S., Cunningham, E., D'Amico, D., Flynn, H., Grillone, L., 
Hutcherson, S., Liebmann, J., O'Brien, T., Scott, I., Spaide, R., Ta, C., Trese, M. (2004).  
Evolving Guidelines for Intravitreous Injections.  Retina 24(5):S3-S19.
3. Anglade, E., Yatscoff, R., Foster, R., Grau, U. (2007).  Next-generation calcineurin 
inhibitors for ophthalmic indications.  Expert opin. Investig. Drugs 16(10):1525-40.
4. Attur, M., Patel, R., Thakker, G., Vyas, P., Levartovsky, D., Patel, P., Naqvi, S., Raza, R., 
Patel, K., Abramson, D., Bruno, G., Abramson, S., Amin, A. (2000).  Differential anti-
inflammatory effects of immunosuppressive drugs:  Cyclosporin, rapamycin and FK-506 
on inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and PGE2 production.  
Inflammation Research 49:20-6.
5. Barton, K., McLauchlan, M., Calder, V., Lightman, S. (1995).  The Kinetics of Cytokine 
mRNA Expression in the Retina during Experimental Autoimmune Uveoretinitis.  Cellular 
Immunology 164:133-40.
6. Callanan D., Jaffe, G., Martin, D., Pearson, A., Comstock, T. Treatment of Posterior 
Uveitis With a Fluocinolone Acetonide Implant  Three-Year Clinical Trial Results. (2008). 
Arch Ophthalmol 126(9):1191-1201
7. Charteris, D., Barton, K., McCartney, A., Lightman, S. (1992).  CD4+ Lymphocyte 
Involvement in Ocular Behcet's Disease.  Autoimmunity 12(3):201-6.
8. George, R., Chan, C., Whitcup, S., Nussenblatt, R. (1997).  Ocular Immunopathyology of 
Behcet's Disease.  Survey of Ophthalmology 42(2):157-62.
9. Joussen, A., Poulaki, V., Le, M., Koizumi, K., Esser, C., Janicki, H., Schraermeyer, U., 
Kociok, N., Fauser, S., Kirchhof, B., Kern, T., Adamis, A. (2004).  A central role for 
inflammation in the pathogenesis of diabetic retinopathy.  The FASEB Journal 
18(12):1450-2.
10. Kahan, B. (2001).  Sirolimus: a comprehensive review.  Expert Opin Pharmacother 
2(11):1903-17.
11. Kilmartin, D., Forrester, J., Dick, A. (1998).  Tacrolimus (FK506) in failed cyclosporin A 
therapy in endogenous posterior uveitis.  Ocul Immunol Inflamm 6(2):101-9.
12. Kwon, Y., Hong, H., Kim, J., Shin, J., Son, Y. (2005).  Inhibitory Effect of Rapamycin on 
Corneal Neovascularization In Vitro and In Vivo.  Investigative Ophthalmology & Visual 
Science 46(2):454-60.


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13. MedDRA 16.0. MedDRA MSSO, Medical Dictionary for Regulatory Activities, Version 
16.0.  
14. Napoli, K., Taylor, P. (2001).  From Beach to Bedside: History of the Development of 
Sirolimus.  Therapeutic Drug Monitoring 23(5):559-86.
15. Nguyen, Q., Ibrahim, M., Watters, A., Bittencourt, M., Yohannan, J., Sepah, Y., Dunn, J., 
Naor, J., Shams, N., Shaikh, O., Leder, H., Do, D. (2013).  Ocular tolerability and efficacy 
of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious 
uveitis: primary 6-month results of the SAVE Study.  Journal of Ophthalmic Inflammation 
and Infection 3(32):1-15.
16. Nuhrenberg, T., Voisard, R., Fahlisch, F., Rudelius, M., Braun, J., Gschwed, J., Kountides, 
M., Herter, T., Bauer, R., Hombach, V., Baeuerle, P., Zohlnhofer, D. (2005).  Rapamycin 
attenuates vascular wall inflammation and progenitor cell promoters after angioplasty.  
Faseb J 19(2):246-8.
17. Nussenblatt, R. (1990).  The natural history of uveitis.  International Ophthalmology 
14:303-8.
18. Rapamune. Rapamune (sirolimus) Oral Solution and Tables - Package Insert. (2009). 
19. Rothova, A., Suttorp-van Schulten, M., Treffers, W., Kijlstra, A. (1996).  Causes and 
frequency of blindness in patients with intraocular inflammatory disease.  British Journal of 
Ophthalmology 80:332-6.
20. Sehgal, S. (1995).  Rapamune (Sirolimus, Rapamycin): An Overview and Mechanism of 
Action.  Therapeutic Drug Monitoring 17(6):660-5.
21. Sehgal, S. (1998).  Rapamune (RAPA, rapamycin, sirolimus): Mechanism of Action 
Immunosuppressive Effect Results From Blockage of Signal Transduction and Inhibition 
of Cell Cycle Progression.  Clinical Biochemistry 31(5):335-40.
22. Sehgal, S. (2003).  Sirolimus: Its Discovery, Biolgical Properties, and Mechanism of 
Action.  Transplantation Procedings 35(Suppl 3A):S7-S14.
23. Sloper, C., Powell, R., Dua, H. (1999).  Tacrolimus (FK506) in the treatment of posterior 
uveitis refractory to cyclosporine.  Ophthalmology 106(4):723-8.
24. Strickley, R. (2004).  Solubilizing Excipients in Oral and Injectable Formulations.  
Pharmaceutical Research 21(2):201-30.
25. Suhler, E., Lloyd, M., Choi, D., Rosenbaum, J., Austin, D. (2008).  Incidence and 
Prevalence of Uveitis in Veterans Affairs Medical Centers of the Pacific Northwest.  
American Journal of Ophthalmology 146(6):890-6.
26. Weiner, A., BenEzra, D. (1991).  Clinical Patterns and Associated Conditions in Chronic 
Uveitis.  American Journal of Ophthalmology 112(2):151-8.


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27. Whitcup, S., Chan, C., Li, Q., Nussenblatt, R. (1992a).  Expression of Cell Adhesion 
Molecules in Posterior Uveitis.  Arch Ophthalmol 110(5):662-6.
28. Whitcup, S., DeBarge, L., Caspi, R., Harning, R., Nussenblatt, R., Chan, C. (1993).  
Monoclonal Antibodies against ICAM-1 (CD54) and LFA-1 (CD11a/CD18) Inhibit 
Experimental Autoimmune Uveitis.  Clinical Immunology and Immunopathology 
67(2):143-50.
29. Whitcup, S., Wakefield, D., Li, Q., Nussenblatt, R., Chan, C. (1992b).  Endothelial 
Leukocyte Adhesion Molecule-1 in Endotoxin-Induced Uvetis.  Investigative 
Ophthalmology & Visual Science 33(9):2626-30.


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21.
APPENDICES
21.1.
Appendix A - Obligations of Investigators
In summary, the 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 (Santen) 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.
II.
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
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.
State the expected DURATION of the subject’s participation.
C.
Describe the PROCEDURES to be followed.
D.
Identify any EXPERIMENTAL procedures.
2. Describe any reasonably foreseeable RISKS OR DISCOMFORTS to the subject.
3. Describe any BENEFITS to 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, and
C.
The subject MAY DISCONTINUE participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
II.
Additional Elements of Informed Consent
When appropriate, one or more of the following elements of information shall also be provided 
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1. A statement that particular treatment or procedure may involve risks to the subject (or to 
the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable.
2. Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent.
3. Any additional costs to the subject that may result from participation in the research.
4. The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject.
5. A statement that significant new findings developed during the course of the research, 
which may relate to the subject’s willingness to continue participation, will be provided 
to the subject.
6. The approximate number of subjects involved in the study.
The informed consent requirements in this protocol are not intended to preempt any applicable 
Federal, State, or local laws which require additional information to be disclosed for informed 
consent to be legally effective.
Nothing in this protocol is intended to limit the authority of a physician to provide emergency 
medical care to the extent the physician is permitted to do so under applicable Federal, State, or 
local law.
REFERENCE: 21 CFR, Part 50.25 – PROTECTION OF HUMAN SUBJECTS, Elements of 
Informed Consent.


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21.3.
Appendix C - Declaration of Helsinki


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9. 
Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cmmot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue 
influence. 
10. 
Physicians should consider the ethical, legal and regulatory norn1s 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. 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. 
It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-deternunation, privacy, and confidentiality of personal 
infonnation of research subjects. 
12. Medical research involving human subjects must confonn 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. 
13. 
Appropriate caution must be exercised in the conduct of medical research that may 
harm the environment. 
14. 
The design and perforn1ance of each research study involving human subjects must be 
clearly described 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 infonnation regarding 
funding, sponsors, institutional affiliations, other potential conflicts of interest, 
incentives for subjects and provisions for treating and/or compensating subjects who are 
harn1ed as a consequence of participation in the research study. The protocol should 
describe arrangements for post-study access by study subjects to interventions identified 
as beneficial in the study or access to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, connnent, guidance and 
approval to a research ethics connnittee before the study begins. This connnittee must 
be independent of the researcher, the sponsor and any other undue influence. It must 
take into consideration the laws and regulations of the country or countries in which the 
research is to be perforn1ed as well as applicable international noons 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 connnittee must have the right to monitor 
ongoing studies. The researcher must provide monitoring inforn1ation to the connnittee, 
especially infonnation about any serious adverse events. No change to the protocol may 
be made without consideration and approval by the committee. 
16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
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volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. The responsibility for the protection of research 
subjects must always rest with the physician or other health care professional and never 
the research subjects, even though they have given consent. 
17. 
Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
conununity stands to benefit from the results of the research. 
18. 
Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and commtmities 
involved in the research in comparison with foreseeable benefits to them and to other 
individuals or commtmities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first subject. 
20. 
Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive 
and beneficial results. 
21. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
22. 
Participation by competent individuals as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or cormnunity 
leaders, no competent individual may be enrolled in a research study unless he or she 
freely agrees. 
23. 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal infom1ation and to minimize the impact of the study on 
their physical, mental and social integrity. 
24. 
In medical research involving competent human subjects, each potential subject must be 
adequately infonned 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, 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 infonnation 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 infom1ation, the physician or another 
appropriately qualified individual must then seek the potential subject's freely-given 
infonned consent, preferably in writing. If the consent cannot be expressed in writing, 
the non-written consent must be fom1ally documented and witnessed. 
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25. For medical research using identifiable human material or data, physicians must 
normally seek consent for the collection, analysis, storage and/or reuse. There may be 
situations where consent would be impossible or impractical to obtain for such research 
or would pose a threat to the validity of the research. In such situations the research may 
be done only after consideration and approval of a research ethics conunittee. 
26. 
When seeking informed consent for participation in a research study the physician 
should be particularly cautious if the potential subject is in a dependent relationship 
with the physician or may consent tmder duress. In such situations the infonned consent 
should be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
27. For a potential research subject who is incompetent, 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 population represented by the potential subject, 
the research cannot instead be performed with competent persons, and the research 
entails only tninimal risk and minimal burden. 
28. 
When a potential research subject who is deemed incompetent 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. 
29. 
Research involving subjects who are physically or mentally incapable of giving 
consent, for example, tmconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the 
research population. In such circumstances the physician should seek infom1ed consent 
from the legally authorized representative. If no such representative is available and if 
the research cannot be delayed, the study may proceed without informed consent 
provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the 
research should be obtained as soon as possible from the subject or a legally authorized 
representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the 
publication of the results of research. Authors 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. They should adhere to accepted guidelines for ethical 
reporting. Negative and inconclusive as well as positive results should be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in 
accordance with the principles of tlus Declaration should not be accepted for 
publication. 
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C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that 
the research 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 setve as research subjects. 
32. 
The benefits, risks, burdens and effectiveness of a new intetvention must be tested 
against those of the best cunent proven intetvention, except in the following 
circumstances: 
• 
The use of placebo, or no u·eatment, is acceptable in studies where no cunent 
proven intetvention exists: or 
• 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessmy to detennine the efficacy or safety of an intetvention and the 
patients who receive placebo or no treatment will not be subject to any risk of 
serious or ineversible hann. ExtTeme care must be taken to avoid abuse of this 
option. 
33. At the conclusion of the study, patients entered into the study are entitled to be 
infonned about the outcome of the study and to share any benefits that result from it, for 
example, access to intetventions identified as beneficial in the study or to other 
appropriate care or benefits. 
34. 
The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to pmticipate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
35. 
In the treatment of a patient, where proven intetventions do not exist or have been 
ineffective, the physician, after seeking expe11 advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intetvemion if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intetvention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available. 
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21.4.
Appendix D - Procedures for Examinations
21.4.1.
Demographics, Medical History and Medication
Demographics, medical and surgical history, medications, current ocular and systemic conditions
will be obtained through subject interviews at Day 1.  Medications will be updated at each visit, 
as appropriate.
21.4.2.
Pregnancy Test 
A urine pregnancy test will be conducted at Day 1, Month 12 and Post-Baseline PRN Treatment 
Visits for all women of childbearing potential. Samples will be analyzed at the site with results 
available prior to administration of study drug.
21.4.3.
Visual Acuity
BCVA will be measured for each eye at Day 1, Month 12 and Post-Baseline PRN Treatment 
Visits under normal room illumination using an ETDRS chart.
21.4.3.1.
Procedures for Refraction and Vision Testing
Refraction and visual acuity measurements will be performed for all subjects by trained vision 
examiners only. Refraction should be conducted prior to visual acuity testing to obtain best-
corrected vision as described below. Best-corrected visual acuity is measured at all trial visits 
using standard charts, lighting, and procedures. Best correction is determined by careful 
refraction at that visit according to the standard protocol for refraction described below.
21.4.3.1.1. Equipment
Refraction equipment required includes:
1. Retro illuminated light box and ETDRS 4 meter distance acuity chart set
2. Trial lens frames
3. Trial lens set with plus or minus cylinder lenses
4. Jackson cross-cylinder of 0.25, 0.50, and 1.00 diopters
5. Pinhole occluder
6. Tissues or eye pads and tape
7. A 1 meter rigid measuring stick
21.4.3.1.2. Visual Acuity charts
Chart 1 is used for testing the visual acuity of the RIGHT eye; Chart 2 for testing the LEFT eye; 
and Chart R (or 3) for refraction only. Subjects should not be allowed to see any of the charts 
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21.4.3.1.3. Visual Acuity Lane and Visual Acuity Box
A distance of 4 meters is required between the subject’s eyes and the visual acuity charts. With 
the box light off, not more than 15 foot-candles of light (161.4 Lux) should fall on the center of 
the chart. To measure the amount of light, the room is set up for visual acuity testing, but with 
the box light off. The light meter is placed at the fourth line from the top of the chart, with its 
back against the chart and the reading is taken. If more than one lane is available for testing 
visual acuity, the visual acuity of individual subjects should be measured in the same lane at each 
visit, if possible. If different lanes are used to test visual acuity, they must each meet the same 
standards.
Retro illuminated ETDRS charts are used in this trial. The illuminator box will be either wall-
mounted or mounted on the stand. The light box should be mounted at a height such that top of 
third row letter is 49±2 inches from floor.
The visual acuity light box is equipped with two General Electric 20-watt fluorescent tubes and 
ballast. Each tube is partly covered a 14-inch fenestrated sleeve, which is centered on the tube 
and open in the back. This serves as a “baffle” to produce even illumination over the testing 
chart. Because of the illumination of the fluorescent tube diminishes by 5 percent during the first 
100 hours and by another 5 percent during the next 2000 hours, new tubes should be kept on for 
4 days (96 hours) continuously, and should be replaced once a year.
A sticker should be placed on the back of the light box, indicating the date on which the present 
tubes were installed. A spare set of burned in bulbs should be available on sight.
21.4.3.1.4. Beginning Approximate Refraction
At the baseline visit, the subject’s beginning refraction is determined by one of the following 
ways:
a.
If the subject’s visual acuity is 20/100 or better and the subject does not require 
glasses for distance vision, then the beginning approximate refraction should be no 
lens correction or plano.
b. If the subject’s visual acuity is 20/100 or better and the subject requires glasses for 
distance viewing, the glasses should be measured using a lensometer, and these 
measurements are used for the beginning refraction.
c.
If the subject’s visual acuity is less than 20/100 with or without correction, then 
retinoscopy or auto-refraction should be performed to determine the beginning 
approximate refraction.
d. If the subject wears contact lenses for refraction, a notation should be made that the 
refraction was over contact lenses. It is suggested that the subject wear the contact 
lenses for future examinations. If the subject is not a regular contact lens wearer and 
wore the lens by mistake, they should be removed and you should wait at least 30 
minutes before beginning the refraction. The subject should be reminded not to wear 
contact lenses at subsequent visits.
Refractions are performed with either plus or minus cylinder power. Whichever cylinder type is 
used at baseline (minus or plus) must be used for all subsequent visits. Best correction results 
should be recorded on the sponsor-provided worksheet which will be included in the source 


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documents. At each follow-up visits, the results of the protocol refraction from the previous 
visits are used as the beginning approximate refraction. If the previous refraction is not 
available for some reason, the procedure described immediately above should be used.
The charts used for measuring distance visual acuity must NOT be used for refraction.  
Refraction for each eye should be performed at 4 meters unless the subject’s visual acuity at 4 
meters on the refraction charts (Chart R or Chart 3) is worse than 20/160. If visual acuity is 
worse than 20/160 the eye is refracted at 1.0 meter. If during the refraction process at 1 meter, 
the subject is reading letters on the eighth line or lower line of the chart, the refraction should be 
continue at 4 meters. Whenever a subject cannot read any letters on the top line of Chart R or 
Chart 3 at 1.0 meter the vision should be checked with a pinhole to see whether reduced vision is 
due, at least in part, to a larger refractive error. If there is no improvement with the pinhole, then 
the eye is exempt from refraction.
21.4.3.1.5. Subjective Refraction
Subjective refraction allows one to determine the best correction for a subject to perform the 
visual acuity tests.  The “push plus” approach is used. Add minus diopter spherical corrections 
only when the subject is able to read at least one more letter on a line or a letter on a smaller 
line.
21.4.3.1.5.1.Procedure
1. Measure and record the distance vision of the eye being tested using Chart R while 
occluding the fellow eye. The fellow eye should be lightly patched with an eye pad or 
tissue and tape. Subjects should be reminded to blink and encouraged to use eccentric 
fixation, or their side vision, when necessary.
2. All refraction and vision testing must be done at 4 meters or 1 meter. Distance for 4 
meters is 13 feet and 1.5 inches or 157.5 inches. The one meter distance is 39 and 3/8 
inches.
3. All subjects should be seated for testing. A rigid measuring device should be used to 
measure the distance from the subject to the chart if testing is done at 1 meter. The 
distance is measured from the outer canthus to the center of the second letter (left eye) or 
fourth letter (right eye) of the third line of the chart. For 4 meter testing, clear and 
permanent floor markings should be used to mark the distance for consistency.
4. Place and adjust the trial frame on the subject’s face so that the lens cells are parallel to 
the anterior plane of the orbits and centered in front of the pupils. Adjust the lens cells for 
the proper distance from the cornea. Be sure the trial frame is comfortable on the 
subject’s face.
5. Occlude the left eye by lightly patching with the eye pad or tissue and tape.
a.
Place the spherical lens correction in the compartment closest to the eye.
b. The cylindrical lens correction, if present, is placed in the compartment in front of 
the spherical correction.  Adjust the axis.
6. Spherical Correction: To determine the highest plus or least minus sphere, refract the 
right eye. The following refraction steps are recommended for visual acuities of 


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20/10 to 20/80 with the beginning approximate refraction. For visual acuities less 
than 20/80, refer to the refraction table for the appropriate sphere and cylinder 
powers and testing distance and follow a similar procedure.  Note: Whenever visual 
acuity is improved to a higher range, refraction should be performed with the smaller 
sphere and cylinder powers given for the better visual acuity level.  
a.
Hold a +0.50 sphere in front of the subject’s right eye. The subject should be looking 
at the smallest legible line on the visual acuity chart. In these exact words, ask the 
subject, “Is this better, worse, or no change?”
b. If the subject responds that the vision is worse or blurred, remove the +0.50 sphere 
from in front of the trial frame and go to Step 6d.
c.
If the subject responds better or no change, remove the +0.50 sphere from in front of 
the trial frame and replace the spherical lens in the trial frame with a spherical lens 
that is one-half diopter more positive. Continue this procedure by returning to Step 6a 
and repeating this process until a +0.50 makes the vision worse or blurred and then 
go to Step 6d.  
d. Hold a -0.50 sphere in front of the subject’s right eye. In these exact words, ask the 
subject, “Is this better, worse, or no change?” If the subject replies “worse” or “no 
change,” go to Step 6f. If they reply “better” go to step 6e.
e.
Hold the -0.50 sphere in front of the eye. If the subject responds that the vision is 
better, ask the subject to read the visual acuity chart. Only when the visual acuity is 
improved, by at least one letter, may you increase the minus by 0.50 (or decrease 
the plus) and repeat Step 6d. Whenever visual acuity is not improved, go to Step 6f.  
f.
Remove the -0.50 sphere from in front of the eye and hold a +0.50 sphere in front of 
the right eye. In these exact words, ask the subject, “Is this better, worse, or no 
change?” If the subject responds that the vision is better or unchanged, then return to 
Step 6c. Otherwise, go to Step 7. Spherical testing should always end with a plus 
lens.  
7. Cylinder Axis: To determine and refine the cylinder axis for PLUS cylinder, proceed as 
follows; (if minus cylinders are used, the appropriate technique using minus cylinders 
must be employed and minus cylinder must be used throughout the trial.)
a. Have the subject look at a line which is either one or two lines larger than the 
smallest line the subject is able to read.  Ask the subject to focus on a rounded 
letter such as, “C”, “D”, or “O”.  The subject should focus on the same letter 
throughout this procedure.  
b. If a cylinder is present in the beginning approximate refraction, then go to Step 
7c.  Otherwise, follow the option listed below to determine if cylinder may be 
needed.  
Testing for cylinder when there is none in the beginning approximate 
refraction:
Place a +0.50 diopter cylinder with a positive axis first at 90°, then compare this 
to no cylinder; repeat this procedure for 180°, then 45°, and 135° always 


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comparing to no cylinder after each axis position.  If the subject says that the 
vision is improved at any one of the four axis positions, place a +0.50 cylindrical 
lens in the trial frame at the preferred axis and go to Step 7c.  If the subject prefers 
no cylinder at all four axis positions, then go to Step 9.
c. Place the +0.25 diopter hand held cross-cylinder (for VA 20/10 – 20/80) first with 
the positive axis 45° to the right of the preferred cylinder axis (as determined 
above), and second with the positive axis 45° to the left of the preferred cylinder 
axis.  Ask the subject, “Which do you like better, position one or position two?”  
Also, tell the subject that both positions may blur their vision.  The subject must 
choose the least blurred position, either one or two.  “Neither” is allowed only if 
both positions are equally blurred or equally good.
d. If “neither” position is better and this was the first test of axis position, move the 
axis of the cylinder in the trial frame 15° to the right or left and return to Step 7c.  
Otherwise, proceed to Step 7e.  
e. When one position is preferred over another, move the cylinder to the preferred 
positive axis position in the step sizes noted below and return to Step 7c.  If no 
single position is better than another then go to Step 8.
Cylinder Refinement
Cylinder Power
suggested axis step 
sizes
Axis Step Sizes
     <1.00D
15º
     1.00 - <2.00D
10º
     2.00 - <3.00D
5º
     3.00 - <5.00D
3º
     5.0 - <8.00D
2º
8. Cylinder Power: Cylinder power is refined by following the step:
a.
Ask the subject to look at the smallest line that can be read on the visual acuity chart.  
b. Test the cylinder power by placing 0.25 diopter cross-cylinder (for vision of 20/10 –
20/80) first with the positive axis and second with the negative axis coincident with 
the cylinder axis. Ask the subject, “Which is better, position one or position two?” Do 
not give the subject the choice of neither.
c.
If the subject prefers the minus axis coincident with the cylinder axis, the total power 
of the correcting plus cylinder is reduced by 0.25 diopter. Repeat the process until the 
subject cannot choose one of the cross cylinder positions over the other. If the subject 
indicates a change that would introduce negative cylinder power, remove all cylinder 
power and continue testing for positive cylinder power at an axis 90° away from the 
previous axis. Otherwise, go to Step 8d.
d. If the subject prefers the plus axis coincident with the cylinder axis, increase the 
power of the cylinder by 0.25 diopter and return to Step 8b. Otherwise, proceed to 
Step 8e.


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e.
When the subject feels that both positions are equally bad or good, and the cylinder 
power in the trial frame has changed by more than 0.50 diopter, return to Step 7c and 
re-check the axis if necessary. Otherwise, proceed to Step 9.
Note: If the cylinder is changed by more than 0.50 diopter, the spherical equivalent 
should be maintained. (For each 0.50 plus CX increase, add -0.25 to the sphere, for each 
0.50 minus CX increase, add +0.25 to the sphere).
9. Spherical Correction Refinement: Recheck, or “refine” the power of the sphere by 
adding +0.25 and -0.25 spheres and changing the spherical power by 0.25 diopter 
increments of the appropriate sign until the subject cannot detect any improvement in 
vision. As a reminder, minus sphere should only be added if the subject can read 
additional letters and spherical testing should always begin and end with a plus lens.  
10. Record the lens corrections obtained by subjective refraction for the right eye on the 
examination form in the section for visual acuity measurements as the correction obtained 
by protocol refraction for the right eye.
11. Repeat the entire process (Steps 1-10) for the left eye and record the refraction results on 
the VAE worksheet.
21.4.3.1.6. Best Corrected Visual Acuity Measures
1. As a reminder, Charts 1, 2, and R (or 3) are used for testing the right eye, left eye, and 
refraction, respectively. Subjects should not see the charts until the test begins.
2. The lens correction from the subjective refraction should be in the trial frame worn by the 
subject.  
3. All eyes must be tested at 4 meters first, even if the refraction was performed at 1 
meter.
4. The subject should be seated comfortably directly in front of the chart so that the eyes 
remain at the 4 meter distance. Testing always begins with the right eye. The fellow eye 
should be occluded with a folded tissue or eye pad lightly taped over the eye behind the 
trial frame serves as an effective occlude that allows eccentric fixation without 
inadvertent use of the covered eye. After testing the right eye, occlusion of the right eye 
should be done BEFORE Chart 2 is put up for testing the left eye.  
5. The subject is asked to read the letters slowly, approximately one letter per second. The 
subject should be told that only one chance is given to read each letter, but may change 
their mind before moving to the next letter. If the subject is unsure about the identity of 
the letter, then the subject should be encouraged to guess.  
6. The subject should begin by reading the top line of the chart and continue reading 
every letter on each smaller line, from left to right on each line. The subject should 
be encouraged to continue reading even if making mistakes. Each letter read is 
counted. The examiner circles every correct letter read and totals each line and the whole 
column (0 if no letters are correct) on the data collection form. An X is put through letters 
read incorrectly. Letters, for which no guess was attempted, are not marked. When a 
subject reaches a level where he/she cannot guess, the examiner may stop the test 


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provided that the subject has made errors on previous guesses, which is a clear indication 
that the best visual acuity has been obtained.
7. When a subject cannot read at least 20 letters on the chart at 4.0 meters, the subject 
is tested at 1.0 meter. The distance from the subject to the chart should be measured 
again using the rigid one meter stick. The distance is measured from the outer canthus 
to the center of the fourth letter (right eye) or the second letter (left eye) of the third 
line of the chart. The spherical correction in the trial frame should be changed by 
adding +0.75 to correct for the closer test distance. The subject may fixate eccentrically 
or turn or shake his/her head to improve visual acuity. Particular care should be taken to 
make sure the subject does not move forward when testing at 1 meter. The subject should 
be reminded to blink.
8. The examiner should not tell the subject if a letter was identified correctly. The subject 
may be encouraged by neutral comments, such as “good”, “next”, and “OK.”
9. The examiner should not stand close to the chart during testing. Attention should be 
focused on the subject and data collection form. If the subject has difficulty locating the 
next line to read, the examiner may go up to the chart and point briefly to the next line to 
be read, but then must move away from the chart.
10. When 20 or more letters are read at 4 meters the visual acuity score for that eye is 
recorded as the number of letters correct at 4 meters plus 30. The subject gets credit 
for the thirty 1 meter letters even though they did not have to read them. Otherwise, the 
visual acuity score is the number of letters read correctly at 1.0 meter plus the number, if 
any, read at 4 meters. If no letters are read correctly at either 4 meters or 1 meter, then the 
visual acuity score is recorded as 0.  
21.4.3.1.7. Testing for Count Finger Vision, Hand Motion Vision and Light Perception/No 
Light Perception Vision
If the subject’s visual acuity is so poor that he/she cannot read any chart letters when tested at 
one meter then the subject’s ability to count fingers, detect hand motion, or have light perception 
should be evaluated.
21.4.3.1.7.1.Testing for Count Fingers Vision
In testing for count fingers vision, the examiner’s hand holding 1, 2, or 5 fingers is held steady at 
a distance of two feet directly in front of the eye being examined. The fellow eye is completely 
occluded with a patch on the face. A light should be shone directly on the hand from behind the 
subject. The examiner’s fingers should be presented in random order and repeated five times.  
Eccentric fixation, if present, should be encouraged. If the subject correctly identifies three of the 
five presentations, then count fingers vision is noted. If not, then the subject must be tested for 
hand motion vision.  
21.4.3.1.7.2.Testing for Hand Motion Vision
The examiner’s hand with all fingers spread out should be extended two feet directly in front of 
the eye being examined. The fellow eye should be occluded with a patch on the subject’s face.  A
light should be shown directly on the examiner’s hand from behind the subject. The examiner’s 


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hand should be moved in an up-and-down direction (vertically) or in a side-to-side direction 
(horizontally) at a constant speed of approximately one back and forth presentation per second. 
The subject is instructed that the examiner’s hand will be presented and they will have to respond 
to the question: “What am I doing with my hand?” This should be repeated five times. Three out 
of five correct responses indicate that hand motion vision is present. If the subject does not 
correctly identify three of five presentations, then you must test for light perception.
21.4.3.1.7.3.Testing for Light Perception/No Light Perception Vision
Light perception should be tested with an indirect ophthalmoscope in a darkened room. The 
fellow eye should be completely patched and covered by the subject’s hand. The indirect 
ophthalmoscope light should be in focus at 1 meter with the rheostat set at maximum voltage. 
From that distance the beam should be directed in and out of the subject’s eye at least four times, 
and the subject should be asked to respond when he/she sees the light. If the examiner is 
convinced that the subject perceives the light, vision should be recorded as “light perception,” if 
not, vision should be recorded as “no light perception.”
4M Refraction Protocol Summary
Refraction Distance
       Check Sphere First              Check Cylinder Axis 
then Power
Sphere “Refinement”
If VA on “R” chart is 
between:
Power
(a)
Increment
Axis
(b)
Power
(c)
Increment
Power
(d)
Increment
20/10 – 20/80
(4 meters)
+.50
-.50
+.50
-.50
.25
JCC
.25
JCC
+.25
-.25
+.25
-.25
+.25
-.25
20/100 – 20/160
(4 meters)
+1.00
-1.00
+1.00
-1.00
.50
JCC
.50
JCC
+.50
-.50
+.50
-.50
+.50
-.50
20/200 – 20/400
(1 meter)
+2.00
-2.00
+2.00
-2.00
1.00
JCC
1.00
JCC
+1.00
-1.00
+1.00
-1.00
+1.00
-1.00
<20/400
(1.0 meters)
sequence refraction a-d
+2.00
-2.00
+2.00
-2.00
No cylinder test required
No refinement required
21.4.4.
Intraocular Pressure (IOP)
IOP will be measured for each eye using applanation tomometry at Day 1, Month 12 and Post-
Baseline PRN Treatment Visits prior to evaluation of need for treatment.  If DE-109 is 
administered, a second assessment will be made 40 (±10) minutes after injection.
The examiner will measure IOP and record results in mmHg with one decimal place (e.g., 24.0). 
A single measurement is made to obtain a determination of intraocular pressure. The same 
contact tonometer employing the Investigator’s standard technique, will be used throughout the
study. In addition, all reasonable efforts should be made to have the same examiner obtain all 
IOP measurements for a given subject.


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The tonometer must be calibrated for accuracy before the first subject undergoes screening, and 
at least once every 30 days thereafter, until the last subject has exited the study. For checking 
calibration, follow the manufacturer’s instructions. If when checked, the variation is within ±2 
mmHg, the tonometer is considered adequately calibrated. However, if the variation exceeds this 
amount, the tonometer should be sent for repair and a different, adequately calibrated instrument 
should be used for IOP measurement. The date of each calibration, along with the name and 
signature (or initials) of the person who performed the calibration, must be documented. The 
tonometer calibration record will be retained as a part of the study record.
21.4.5.
Indirect ophthalmoscopy
An indirect ophthalmoscopy will be performed at Day 1, Month 12 and Post-Baseline PRN 
Treatment Visits to examine the retina of each eye.  Indirect ophthalmoscopy will be performed 
prior to each study drug injection and then again within 30 minutes after study drug injection. 
Assessments include lens, retina, macula, choroid, and optic nerve.  Lens will be assessed for the
presence or absence of cataract prior to study drug administration. All other assessments will be 
noted as normal or abnormal.
21.4.6.
Vitreous Haze 
VH will be assessed for each eye according to the Investigator’s standard practice at Day 1, 
Month 12 and Post-Baseline PRN Treatment Visits using the modified SUN scale:
0 
No inflammation 
0.5+ 
Trace Inflammation (slight blurring of the optic 
disc margins and or loss of nerve fiber layer reflex)
1+ 
Mild blurring of the retinal vessels and optic nerve 
1.5+ 
Optic nerve head and posterior retina view 
obstruction greater than 1+ but less than 2+ 
2+ 
Moderate blurring of the optic nerve head 
3+ 
Marked blurring of the optic nerve head 
4+ 
Optic Nerve head not visible 
21.5.
Appendix E – Manual SAE Reporting Process
In the event the EDC system is unavailable and your site needs to report a SAE, please follow 
the manual process described below. 
Complete both the paper AE and SAE forms (located in your site regulatory binder)
Attach a Fax Cover Sheet with your contact information and address to Santen Drug Safety
Fax the Cover Sheet, AE form and SAE form to Santen at the appropriate fax number 
identified below. 
For SAE supporting information (i.e. xray reports, hospital summaries etc.) that are not included 
in the EDC format, follow the same reporting process as for manual SAE reporting. 


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Table 5:
SAE Manual Reporting Fax numbers

SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
A Phase lllb, Multinational, Multicenter, Open-Label Extension 
Study Assessing the Long-Term Safety of PRN Intravitreal 
Injections of DE-109 in Subjects with Non-Infectious Uveitis of the 
Posterior Segment of the Eye Who Have Participated in the 
SAKURA Development Program 
 
NCT Number:  
NCT02251938 
 
Date of the document: 
November 15, 2017  
 
 
 


Protocol Title: 
Product: 
Protocol Number: 
Sponsor: 
Date: 
Status: 
§ anb!ll 
STATISTICAL ANALYSIS PLAN 
SPRING STUDY 
A Phase lllb, Multinational, Multicenter, Open-Label Extension 
Study Assessing the Long-Term Safety ofPRN Intravitreal 
Injections ofDE-109 in Subjects with Non-Infectious Uveitis of the 
Posterior Segment of the Eye Who Have Participated in the 
SAKURA Development Program 
2.0% DE-l 09 injectable solution ( 440 J.lg of sirolimus) 
32-009 
Santen Inc. 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
U.S.A. 
November 15,2017 
Version 1.0 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Santen Inc., and may not be disclosed to others 
except to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by Federal 
and State Laws. Persons to whom this information is disclosed must be informed that this information is privileged and 
confidential and that it should not be further disclosed. 


DE-109 2.0% 
32-009 Statistical Analysis Plan 
APPROVAL SIGN-OFF SHEET 
A Phase Illb, Multinational, Multicenter, Open-label Extension Study Assessing the Long-
term Safety of PRN Intravitreal Injections of DE-109 in Subjects with Non-Infectious 
Uveitis of the Posterior Segment of the Eye Who Have Participated in the SAKURA 
Development Program 
DE-109 Study 32-009 
Confidential 
Page 2 of 20 


DE-1092.0% 
32-009 Statistical Analysis Plan 
TABLE OF CONTENTS 
ABBREVIATIONS ......................................................................................................................... 6 
1. 
INTRODUCTION ........................................................................................................ 7 
2. 
3. 
3.1. 
3.2. 
3.3. 
3.4. 
4. 
4.1. 
4.1.1. 
4.1.2. 
4.1.3. 
4.1.4. 
4.1.5. 
4.2. 
4.2.1. 
4.2.2. 
4.2.3. 
4.2.4. 
4.3. 
4.4. 
4.4.1. 
4.4.1.1. 
4.4.1.2. 
4.4.1.3. 
4.4.1.4. 
4.4.2. 
4.5. 
4.5.1. 
4.5.2. 
Confidential 
STUDY OBJECTIVE ................................................................................................... ? 
STUDY DESIGN ......................................................................................................... 7 
General Study Design ................................................................................................... 7 
Randomization and Masking ........................................................................................ 8 
Sample Size Planning ................................................................................................... 8 
Visits and Assessments ................................................................................................. 8 
DEFINITIONS ............................................................................................................. 9 
Time-Related Terms ..................................................................................................... 9 
Baseline Visit ................................................................................................................ 9 
Study Exit Visit. ............................................................................................................ 9 
Study Day I Days on Study I Days on Treatment ...................................................... ! 0 
Post-baseline PRN Treatment Visit ............................................................................ 1 0 
Analysis Visit and Analysis Window ......................................................................... 1 0 
Safety- Related Defmitions ......................................................................................... 11 
Study Eye and Fellow Eye .......................................................................................... ll 
Baseline Score ............................................................................................................ 11 
Change from Baseline ................................................................................................. 11 
Change after Injection ................................................................................................. 11 
Efficacy Related Defmitions ....................................................................................... 11 
Safety Related Definitions .......................................................................................... 12 
Adverse Event ............................................................................................................. 12 
Ocular Adverse Event ................................................................................................. 12 
Serious Adverse Event ................................................................................................ 12 
Suspected Adverse Reaction ....................................................................................... 13 
Events of Special Interest ........................................................................................... 13 
Other Safety Assessments ........................................................................................... 13 
Other Defmitions ........................................................................................................ 15 
Rescue Therapy and Rescue Rate ............................................................................... 15 
Prior and Concomitant Medications ........................................................................... 15 
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DE-109 2.0% 
32-009 Statistical Analysis Plan 
5. 
5.1. 
6. 
6.1. 
6.2. 
6.2.1. 
6.2.2. 
6.3. 
6.4. 
6.5. 
7. 
7.1. 
7.2. 
7.3. 
7.4. 
7.5. 
7.6. 
8. 
8.1. 
8.2. 
8.3. 
8.4. 
8.5. 
8.6. 
8.7. 
8.8. 
8.9. 
9. 
Confidential 
STUDY POPULATION ............................................................................................. 15 
Safety Population ........................................................................................................ 15 
GENERAL CONSIDERATIONS ............................................................................. 15 
Adjustments for covariates ......................................................................................... 16 
Handling of Missing Data ........................................................................................... 16 
Safety Measures .......................................................................................................... 16 
Dates for Medical Events and Medications ............................................................... .16 
Multi-Center Studies ................................................................................................... 16 
Multiple Comparisons I Multiplicity .......................................................................... 16 
Interim Analysis .......................................................................................................... 17 
SUMMARY OF STUDY POPULATION DATA .................................................... .17 
Subject Disposition ..................................................................................................... 17 
Demographics and Baseline Characteristics ............................................................... 17 
Medical and Surgical History ..................................................................................... 17 
Protocol Deviations .................................................................................................... 18 
Prior and Concomitant Medications ........................................................................... 18 
Treatment Exposure .................................................................................................... 18 
SAFETY ANALYSES ............................................................................................... 18 
Adverse Event ............................................................................................................. 18 
Vitreous Haze (VH) .................................................................................................... 19 
Best-Corrected Visual Acuity (BCV A) ...................................................................... 19 
Intraocular Pressure (IOP) .......................................................................................... 19 
Indirect Ophthalmoscopy ............................................................................................ 20 
Use of Rescue Therapy ............................................................................................... 20 
Treatment Exposure .................................................................................................... 20 
Slit-lamp Biomicroscopy ............................................................................................ 20 
Central Retinal Thickness ........................................................................................... 20 
REFERENCE ............................................................................................................. 20 
Page 4 of 20 


DE-1092.0% 
32-009 Statistical Analysis Plan 
LIST OFT ABLES 
Table 1 Assessment Schedule .......................................................................................................... 8 
Table 2 Analysis Visit and Analysis Window ............................................................................... ! 0 
Table 3 Other Safety Assessments ................................................................................................. 13 
Table 4 Handling of Missing Date ................................................................................................. 16 
Confidential 
Page 5 of20 


DE-109 2.0% 
32-009 Statistical Analysis Plan 
ABBREVIATIONS 
AE(s) 
Adverse Event(s) 
ATC 
Anatomical-Therapeutic-Chemical 
BCVA 
Best-Corrected Visual Acuity 
CDISC 
Clinical Data Interchange Standards Consortium 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
EMEA 
Europe, the Middle East and Africa 
ESI(s) 
Event( s) of Special Interest 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
lOP 
Intraocular Pressure 
MedORA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimeter of Mercury 
OCT 
Optical Coherence Tomography 
OD 
Oculus Dexter (right eye) 
OS 
Oculus Sinister (left eye) 
ou 
Oculus Uterque (both eyes) 
PRN 
Pro ReNata (as needed) 
SAE(s) 
Serious Adverse Event(s) 
SAKURA 
Santen Protocol 32-007 
SAP 
Statistical Analysis Plan 
SAR(s) 
Suspected Adverse Reaction(s) 
SAS 
Statistical Analysis System 
soc 
System Organ Classification 
SUN 
Standardized Uveitis Nomenclature 
us 
United States 
VH 
Vitreous Haze 
WHO-DOE 
World Health Organization Drug Dictionary Enhanced 
Confidential 
Page 6 of 20 


DE-1092.0% 
32-Q09 Statistical Analysis Plan 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the 
analysis of data collected within the scope ofSanten's Protocol32-009 (SPRING), "A Phase 
Illb, Multinational, Multicenter, Open-Label Extension Study Assessing the Long-Tenn Safety 
ofPRN Intravitreal Injections ofDE-109 in Subjects with Non-Infectious Uveitis ofthe Posterior 
Segment of the Eye Who Have Participated in the SAKURA Development Program". 
This SAP applies to the study protocol32-009 US Amendment 01 dated 02 June 2016 and 
provides details of the descriptive statistical analyses of data collected from this Open-Label 
study. Results from the descriptive statistical analyses will become the basis of the Clinical 
Study Report (CSR) for Protocol32-009. 
2. 
STUDY OBJECTIVE 
The objective of this extension study is to evaluate the long-tenn safety of treatment with 
DE-109 (440 J.Lg) in subjects with non-infectious uveitis ofthe posterior segment ofthe eye. 
3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is a multicenter, open-label, extension study of intravitreal injections of the 440 J.Lg dose of 
DE-109 in subjects with non-infectious uveitis of the posterior segment who received any dose 
ofDE-109 and exited the SAKURA program under Santen Protocol32-007. In addition, 
subjects who were randomized and received at least two injections ofDE-109 during the first 
five months of the SAKURA study and obtained clinical benefit from the study medication, as 
determined by the Investigator, may be considered for entry in this 12-month extension study. 
The minimum time lag from last injection in the SAKURA program to entry into the SPRING 
program is 60 days. Any subjects can enter into protocol32-009 US Amendment 01 if that 
subject is from U.S. and the time lag from exiting the SAKURA program to entry into protocol 
32-009 is no more than 6 months. 
Each subject retains the same subject ID as had been previously assigned in the SAKURA 
program. The study eye to be treated in this extension study is the same as the eye treated during 
the SAK.URA program. 
Study assessments are conducted for all subjects at Day I (Baseline), Month 2, Month 4, Month 
6, Month 8, Month 10 and Month 12. Additional visits may be conducted according to the 
Investigator's standard clinical practice at interim unscheduled visits. DE-l 09 treatment may be 
administered in the study eye at the Investigator's discretion on Day 1 and/or any of the Post-
Baseline PRN Treatment Visits at Month 2-10 but no more frequently than every 60 days. 
Treatment of the fellow eye with alternative local therapies is at the Investigator's discretion. 
However, administration ofDE-109 to the fellow eye is a protocol deviation, and is counted as 
such. 
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3.2. 
Randomization and Masking 
This is an open-label study. Randomization is not employed in this study. At the investigator's 
discretion, an injection ofDE-109 (440 ~g) may be administered. The study drug container has 
a unique number and is dispensed in sequential ascending order by each center. 
3.3. 
Sample Size Planning 
There is no statistical consideration regarding the sample size. The original defmed number of 
subjects for SPRING study was approximately 200 subjects. Due to slow enrolment, the sample 
size has been adjusted to 60 subjects. The enrollment was completed by 18 November 2016. Of 
the 60 subjects, 13 signed the consent of Protocol US Amendment 01. 
3.4. 
Visits and Assessments 
The assessments to be conducted at each visit can be found in Table 1. 
Table 1 Assessment Schedule 
Month 
Day 1 
Post-Baseline 
2/4/6/8/10 
PRN 
Post-Baseline 
Screening! 
Treatment 
PRN 
Baseline 
Visits 
Treatment 
Visitsh 
Assessment window 
±7 
(Days) 
~60 days since 
Note: ~60 days 
-
last injection 
since last 
injection 
Informed consenta 
X 
Demographics 
X 
Medical/surgical history 
X 
Medications 
X 
X 
X 
Urine pregnancy test, if 
xb 
xb 
xb 
appropriate 
Inclusion/exclusion 
X 
criteria 
Best-corrected visual 
X 
X 
X 
acuity 
Intraocular pressure 
Xc 
Xc 
Xc 
Indirect 
X 
X 
X 
ophthalmoscopye 
Vitreous haze 
X 
X 
X 
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Month 12 or 
Early 
Terminationd 
±14 
X 
xb 
X 
Xc 
X 
X 
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Month 
Day 1 
Post-Baseline 
2/4/6/8/10 
Month 12 or 
Post-Baseline 
Screening/ 
PRN 
Early 
Treatment 
PRN 
Baseline 
Visits 
Treatment 
Terminationd 
Visitsh 
Slit lamp 
biomicroscopyh 
X 
X 
X 
X 
DE-l 09 administration, 
X 
X 
X 
if needed (PRN) 
Enodothelial cell count 
X 
X 
X 
X 
(only at selected sites )h 
Adverse events 
xf 
xf 
xf 
xf 
lrnagingh: OCT 
xs 
xs 
xs 
xg 
(including CRT), FA, 
FP .. 
AbbreVIations: 
• Informed consent is be obtained prior to conducting any study-related activities. 
b Urine pregnancy tests are to be performed on all women of childbearing potential. 
c On days when DE-109 injections are administered, perform lOP before and 40 (±10) minutes after DE-109 
injection. 
d For Early Termination Visits please complete the procedures for the Month 12 visit. 
Error! Reference source not found. 
Indirect ophthalmoscopy is performed prior to each study drug 
injection and then again within 30 minutes after study drug injection. 
Error! Reference source not found. 
On days when DE· I 09 injections are administered AEs are elicited 
before and after DE-l 09 injection. 
8 Performed at investigator's discretion. 
h For subjects under Protocol US Amendment 01 only. 
4. 
DEFINITIONS 
4.1. 
Time-Related Terms 
4.1.1. 
Baseline Visit 
The baseline visit of the SPRING study is the first scheduled visit on Day 1. 
4.1.2. 
Study Exit Visit 
The study exit visit of the SPRING study is the Month 12 visit or early termination visit. If both 
are missing, the last visit before exit date will be considered as study exit visit. For subjects who 
don't have any visits after Day 1, Day 1 visit will be considered as both Baseline Visit and Study 
Exit Visit. 
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4.1.3. 
Study Day I Days on Study I Days on Treatment 
The study day variable describes the relative day of the observation starting with Day 1 as the 
reference date. There will be no Day 0. The study day will be calculated as follows: 
• 
For events occurring on or after the reference date 
Study Day = (Date - Baseline Visit Date) + 1 
• 
For events occurring before the reference date 
Study Day= (Date- Baseline Visit Date) 
Days on Study measures the duration each subject remains in the study and will be calculated as 
follows: 
Days on Study = (Study Exit Date - Baseline Visit Date) + 1. 
Days on Treatment measures the duration between the date of first exposure to DE-l 09 and exit 
date of each subject and will be calculated as follows: 
Days on Treatment = (Study Exit Date- Date of First Exposure to Treatment in SPRING 
Study+ I. 
4.1.4. 
Post-baseline PRN Treatment Visit 
A Post-Baseline PRN Treatment visit is defined as any visit at which a subject received an 
intravitreal injection ofDE-109 (440 flg) in the study eye, or the scheduled Post-Baseline PRN 
Treatment Visits at Month 2, Month 4, Month 6, Month 8, and Month 10 for subjects under US 
Amendment 01. Therefore, it is not necessary to receive an injection in a Post-baseline PRN 
Treatment Visits for subjects under US Amendment 01. 
4.1.5. 
Analysis Visit and Analysis Window 
Analysis visit is a timing variable to be used for tables and listings involving visits. In SPRING 
study, possible values of analysis visit include Baseline, Month 2, Month 4, Month 6, Month 8, 
Month 10, and Month 12. The analysis window will be used to determine the analysis visit of an 
assessment based on the study day of the assessment. The analysis window usually is slightly 
wider than the corresponding assessment window specified in the protocol for analysis purposes. 
Table 2 shows the analysis windows for post-baseline visits in SPRING study. Detailed 
defmitions of analysis visit and analysis window will also be provided in the ADaM 
specifications document. 
Table 2 Analysis Visit and Analysis Window 
Analysis Visit 
Visit Window 
Analysis 
Window 
Baseline (Day I) 
1 
I 
Month 2 (Day 60) 
[53, 67] 
[2, 67] 
Month 4 (Day 120) 
[113, 127] 
[68, 127] 
Month 6 (Day 180) 
[173, 187] 
[128, 187] 
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Month 8 (Day 240) 
[233, 247] 
[188, 247] 
Month 10 (Day 300) 
[293, 307] 
[248, 307] 
Month 12 (Day 360) 
[346, 374] 
>=308 
In SPRING study, all Post-Baseline Visits including PRN and Unscheduled visits with any study 
assessments will be mapped to any of the analysis visits according to the table above. For 
example, an assessment collected at an Unscheduled Visit may be mapped to the analysis visit 
"Month 4" if the study day of the Unscheduled Visit is 125. Another example, an assessment 
collected at an Early Termination visit may be mapped to the analysis visit "Month 1 0" if the 
study day of the Early Termination visit is 250. 
A subject may have more than one visit that is mapped to Month 12. However, only the Month 
12 visit with latest date is considered as study exit visit. When summarizing VH and BCV A, 
Month 12 visit refers to this last Month 12 Visit. 
4~2. 
Safety- Related Definitions 
4.2.1. 
Study Eye and Fellow Eye 
The study eye is the eye designated as the study eye in the SAKURA program. 
The fellow eye is the non-study eye. 
4.-2.2. 
Baseline Score 
For each measure, the baseline score of the SPRING study is the observed measurement prior to 
the injection of DE-l 09 ( 440 f.! g) at Day 1 if an injection is given at Day 1, or the observed 
measurement by Day 1 otherwise. 
4.2.3. 
Change from Baseline 
The change from. baseline in a measure 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 before and after injection at visits, only the pre-injection scores will be 
used to derive the change-from-baseline variable. 
4.2.4. 
Change after Injection 
For any measure assessed before and after injection at injection visits, the change after injection 
at an injection visit will be derived as: 
Change after Injection= Post-Injection Score at the Visit- Pre-Injection Score at the Visit. 
4.3. 
Efficacy Related Definitions 
The long-term efficacy ofDE-109 (440 f.lg) may be explored by VH. There are no efficacy-
related endpoints that need to be defmed in this document. 
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4.4. 
Safety Related Definitions 
4.4.1. 
Adverse Event 
Under Protocol32-009, an AE is defined as any on-study untoward medical occurrence 
(e.g. sign, symptom, disease, syndrome, intercurrent illness) that occurs in a study subject, 
regardless of the suspected cause and regardless of timing of DE-l 09 ( 440 j.tg) administration. 
An on-study AE can occur any time after the date of informed consent through the last study 
visit. An AE will be considered as treatment-emergent if the AE occurred on or after the date of 
the first DE-l 09 ( 440 j.tg) treatment in Spring Study up to the last study visit. Treatment-
emergent AEs are a subset of on-study AEs. 
The severity of each AE will be graded by the Clinical Investigator as Mild (aware or unaware of 
event, but easily tolerated), Moderate (discomfort enough to cause interference with usual 
activity), or Severe (incapacitating; unable to work or perform usual activity). Each AE will be 
classified into a system organ classification (SOC) and coded to a preferred term using Medical 
Dictionary for Regulatory Activities (MedORA 16.0). 
4.4.1.1. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected 'OD', 'OS', or 'OU' 
under Item 2 (Eye(s) affected) on the AE eCRF. 
4.4.1.2. 
Serious Adverse Event 
Serious Adverse Events (SAEs) are defined as any fmdings that suggest a significant hazard, 
contraindication, side effect, or precaution. An AE will be counted as a serious adverse event 
(SAE) if the Clinical Investigator selected 'Yes' under Item 5 (Is the adverse event serious?) on 
the AE eCRF. Any adverse event is considered a serious adverse event if it results in any ofthe 
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; 
• 
In-subject hospitalization and/or prolonged hospitalization; 
• 
A persistent or significant disability/incapacity; 
• 
A congenital anomaly/birth defect; 
• 
Sight threatening event 
A sight-threatening AE is defmed as any ocular AE that places the subject at immediate 
risk of permanent vision loss in either the study eye or the fellow eye. See more in 
Section 4.4.1.2.1; 
• 
Other medically significant events: 
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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. 
4.4.1.2.1. Sight-Threatening Adverse Event 
The sight-threatening AE is defmed as any ocular AE that places the subject at immediate risk of 
permanent vision loss in either the study eye or the fellow eye. In this extension study, the 
following serious ocular AEs will be reported as sight-threatening AEs: 
• 
Loss of 6 or more lines of vision (2:30 letters) from Baseline; 
• 
Endophthalmitis; 
• 
Purulent, infectious conjunctivitis; 
• 
Retinal detachment; 
• 
lOP > 35 mmHg that persists for at least 7 days despite pharmacologic therapy; 
• 
Other significant ocular events per Investigator's discretion. 
4.4.1.3. 
Suspected Adverse Reaction 
An AE will be counted as a suspected adverse reaction (SAR) if the Clinical Investigator 
selected either of the two options on the AE eCRF listed in Section 4.4.1.3.1 and Section 
4.4.1.3.2. 
4.4.1.3.1. Study-Medication Related Adverse Event 
• 
"Related" under Item 11 (Relation to Study Drug) 
4.4.1.3.2. Injection-Procedure Related Adverse Event 
• 
"Related to the injection procedure" under Item 12 (Attributable Causes) 
4.4.1.4. 
Events of Special Interest 
Events of Special Interest (ESis) in this study include study drug administration error and 
Pregnancy. 
4.4.2. 
Other Safety Assessments 
All the other safety measures besides AE to be evaluated for the SPRING study are listed in 
Table 3. 
Table 3 Other Safety Assessments 
Safety Measures 
Note 
Slit-lamp Biomicroscopy: 
VH is assessed for each eye using the modified SUN scale as 
Vitreous haze 
0, 0.5+, 1 +, 1.5+, 2+, 3+, or 4+. A decrease in VH score 
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DE-109 2.0% 
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indicates improvement in the vitreous inflammation. 
Best-corrected visual acuity 
BCVA measures the acuteness or clearness of best-corrected 
vision in ETDRS letters (e.g., 75 letters). An increase in 
BCVA indicates improvement in the best-corrected vision. A 
5-letter difference in visual acuity is equivalent to one Snellen 
line. A BCV A score of 85 ETDRS letters is equivalent to 
20/20 vision, which is considered normal vision. 
Intraocular pressure (lOP) 
lOP, the fluid pressure inside the eye, is recorded in mmHg 
with one decimal point (e.g., 24.0 mmHg). IfDE-109 is 
administered, a second assessment of lOP is made after 
injection. 
Indirect ophthalmoscopy: 
The lens of an eye is classified as Phakic, Aphakic, or 
lens and cataract 
Pseudophakic. Phakic lens is assessed for the presence of 
cataract (Yes or No). 
Indirect ophthalmoscopy: 
Retina, macula, choroid, and optic nerve, if able to be 
Retina, 
assessed, are graded as Normal or Abnormal. If DE-l 09 is 
macula, 
administered, these ophthalmoscopy parameters are performed 
choroid, 
again after injection. 
optic nerve 
Slit-lamp biomicroscopy: 
The status of each of these biomicroscopy parameters is rated 
Lid Hyperemia, 
as 0 =None, 1 = Mild, 2 = Moderate, or 3 = Severe. For each 
Lid Edema, 
abnormal record, the clinical significance (Clinically 
Conjunctival Hyperemia, 
Significant or Not Clinically Significant) is also determined. 
Chemosis, 
Corneal Edema, 
Conjunctival Discharge 
Exudate, 
Anterior Chamber Flare 
Slit-lamp biomicroscopy: 
The status of each of these biomicroscopy parameters is 
Pupil, 
determined as Normal or Abnormal. For each abnormal 
Lashes, 
record, the clinical significance (Clinically Significant or Not 
Ocular Motility, 
Clinically Significant) is also determined. 
Iris 
Slit-lamp biomicroscopy: 
This measure is rated as 0 = 0 cells, 0.5+ = l-1 0 cells, 1 + = 11-
Vitreous Cell Count 
20 cells, 2+ = 21-30 cells, 3+ = 31-1 00 cells, or 4+ = ~ 1 00 
cells. 
Slit-lamp biomicroscopy: 
This measure is rated as 0 = <1 cell, 0.5+ = 1-5 cells, 1 + = 6-
Anterior Chamber Cell 
15 cells, 2+ = 16-25 cells, 3+ = 26-50 cells, or 4+ =~50 cells. 
Central retinal thickness 
At investigator's discretion, assessments of both eyes by OCT 
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imaging methods are performed. Measurement of CRT in 
microns is obtained from the OCT reading. Equipment type is 
specified. Images are collected into a central repository 
• For subjects under US Amendment 01 only. 
4.5. 
Other Definitions 
4.5.1. 
Rescue Therapy and Rescue Rate 
Rescue therapy refers to any treatment that would have a therapeutic effect on the uveitis in the 
posterior segment (e.g., systemic treatment with an immunosuppressant agent, or a corticosteroid 
injection in the study eye) other than intravitreal DE-l 09. Topical ocular corticosteroid 
medication is not considered rescue therapy. Data related to rescue therapies will be reviewed 
and documented by the Medical Monitor prior to database lock to make the final determination 
of whether a medication will be classified as rescue therapy. Rescue rate is defined as the 
percentage of subjects who receive rescue therapy during the SPRING study among all subjects. 
4.5.2. 
Prior and Concomitant Medications 
Prior medications are non-study medications started and ended prior to the enrollment (Day 1) of 
the study. Concomitant medications are non-study medication taken during the study, i.e., the 
treatment period of a concomitant medication taken by a subject needs to overlap with the 
observation period from Day 1 to the Study Exit of the subject. 
All medications are coded using the World Health Organization Drug Dictionary Enhanced 
(WHO-DOE) March 2014 version. Each medication will be classified using the Anatomical-
Therapeutic-Chemical (A TC) classification system and mapped to a WHO-DOE preferred drug 
name. 
5. 
STUDYPOPULATION 
5.1. 
Safety Population 
Safety Population will include all enrolled subjects with any safety assessment data (defined in 
Section 4.4) collected during the SPRING study, regardless of receiving an injection ofDE-109 
( 440 J.l.g) or not in this study. It will be the analysis population for descriptive summaries of all 
safety measures. 
6. 
GENERAL CONSIDERATIONS 
All variables will be summarized by the last dose received in SAKURA study and overall. 
Continuous variables will be summarized using descriptive statistics such as number of 
observations (n), mean, standard deviation, medium, minimum, and maximum. Categorical 
variables will be tabulated using frequency (n) and percent (%). 
All data manipulations and descriptive summaries will be performed using SAS Version 9.4 or 
later. 
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DE-109 2.0% 
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6.1. 
Adjustments for covariates 
No inferential analysis is planned for this study. Therefore, no covariate will be adjusted. 
6.2. 
Handling of Missing Data 
6.2.1. 
Safety Measures 
Descriptive summaries of safety measures will be based on observed data only. No imputation 
of missing scores will be implemented. 
6.2.2. 
Dates for Medical Events and Medications 
Completely or partially missing onset and resolution dates for medical events including medical 
history and AEs will be imputed in a conservative fashion as in Table 4. 
Table 4 Handling of Missing Date 
Date 
Type of Missing 
Handling of Missing Date 
Date 
Event onset date 
Completely missing 
No imputation will be applied. 
(e.g., YYYY-MM-
Only YYYY is 
Use the frrst day of YYYY to impute the 
DD) 
available 
missing month and date parts of the onset date 
YYYY and MM are 
Use the fust day ofMM to impute the missing 
available but DD is 
date part of the onset date 
missing 
Event resolution date 
Completely missing 
No imputation will be applied. The event will 
(e.g., YYYY-MM-
be considered ongoing (i.e., not resolved) at 
DD) 
the last visit date. 
OnlyYYYYis 
Use the last day of YYYY to impute the 
available 
missing month and date parts of the resolution 
date 
YYYY and MM are 
Use the last day of MM to impute the missing 
available but DD is 
date part of the resolution date 
missing 
The same rules will be followed to impute completely or partially missing start and end dates of 
concomitant medications. 
6.3. 
Multi-Center Studies 
This is a multi-center study enrolling subjects from sites in multiple countries, including the US, 
India, and Europe. 
6.4. 
Multiple Comparisons I Multiplicity 
Multiplicity adjustment is not applicable to the descriptive summaries of this study. 
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6.5. 
Interim Analysis 
No formal interim analysis is planned for this study. 
7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The subject disposition for all enrolled subjects will be tabulated by Safety population. Safety 
population will be further tabulated by subjects who completed study exit assessment and Month 
12 Visit completers. Non-completers at Month 12 will be tabulated by the primary 
discontinuation reason and will be listed by subject ID. Days to premature discontinuation will 
also be summarized. 
The subject enrollment will be summarized by geographic region and country, if applicable. 
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for the 
Safety Population. Subject demographics collected under Protocol 32-009 include age at entry, 
gender and geographic region. Race and ethnicity for the Safety Population will be carried over 
from the SAK.URA program. 
For baseline characteristics, the baseline scores of the following variables will be summarized: 
• 
Baseline VH score of study eye 
• 
Anatomic location of uveitis of study eye (intermediate, posterior or panuveitis) 
• 
Presence of cataract in the study eye (Phakic lens only) (yes or no) 
• 
Baseline BCV A of study eye 
• 
Use of systemic corticosteroid 
• 
Rescued in SAKURA study 
• 
Entered open-label period in SAKURA study 
Other baseline characteristic variables may be summarized as suggested by the data. 
7.3. 
Medical and Surgical History 
The medical history events will be coded using the MedDRA Version 16.0 and summarized for 
the Safety population. 
Subjects reporting any medical history events will be tabulated by System Organ Class (SOC) 
and preferred term specified in MedDRA. In addition, the following subsets of medical history 
events will be tabulated: 
• 
SOC Eye Disorders medical events in study eye by Preferred Term and Lowest Level 
Term 
• 
Medical events ongoing at baseline by SOC and Preferred Term 
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• 
SOC Eye Disorders medical events ongoing at baseline in study eye by Preferred Term 
and Lowest Level Term 
Any subject with more than one medical and/or surgical term within the same SOC (or mapped 
to the same preferred term) will be counted only once for that SOC (or preferred term). 
7.4. 
Protocol Deviations 
Protocol deviation(s) will be listed by geographic region (US, EMEA, or India) and subject. 
Major protocol deviations will be tabulated by deviation category. 
7.5. 
Prior and Concomitant Medications 
For Safety subjects, all non-study medications will be tabulated by A TC level and WHO-DDE 
preferred drug name. A subject will be counted at most once for each non-study medication, 
even if the subject received the same medication on multiple occasions. Details of those non-
study medication usages will be listed including subject information, start and end date of the 
medication, unit, dose and frequency. 
7.6. 
Treatment Exposure 
The extent of exposure to DE-l 09 ( 440 Jlg) in the SPRING study will be assessed by the number 
ofDE-109 injections (0, 1, 2, 3, 4, 5, or 6) together with days on treatment (<60, ~60 and <120, 
~ 120 and <180, ~180 and <240, ~240 and <300, or ~300). 
8. 
SAFETY ANALYSES 
Safety measures collected in this extension study include: 
• 
On-Study AEs 
• 
VH 
• 
BCVA 
• 
lOP 
• 
Indirect ophthalmoscopy 
• 
Treatment exposure 
• 
Use of rescue therapy 
• 
Slit-lamp Biomicroscopy 
• 
Central Retinal Thickness 
Unless specified otherwise, safety measures collected from both eyes will be summarized for 
study eyes and fellow eyes separately. 
8.1. 
Adverse Event 
All AE(s) will be coded by MedORA 16.0, 2013. All analysis will focus on on-study AEs given 
the PRN nature of this study. The information that whether an AE is treatment emergent or not 
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will be provided in all the AE related listings. All AE tables will be summarized by last dose 
received in SAK.URA study, received injection or not in SPRING study, and overall. 
Besides the overall summary of AEs, subjects with any AE(s) will be tabulated by SOC, 
preferred term, and maximum severity. A subject who experienced multiple AEs within a SOC 
or preferred term will be counted only once for that SOC or preferred term. SAEs, SARs, 
Serious SARs, study-medication related AEs, and injection-procedure related AEs will be 
tabulated similarly. 
Ocular AEs, ocular SARs, serious ocular AEs, and serious ocular SARs will be summarized. 
Any ocular AE that occurred simultaneously to both eyes will be counted once for both the study 
eye and the fellow eye. 
Sight-threatening AEs will be summarized by type of event specified in Section 4.4.1.2.1 . 
Eye disorders AEs may be tabulated using lowest level term and preferred term to provide more 
detailed information. 
Non-ocular AEs and serious non ocular AEs will be presented by SOC and preferred term. 
All AEs reported during the study will be listed. SAEs, SARs, Ocular AEs, study-medication 
related AEs, injection-procedure related AEs, AEs leading to death, AEs leading to 
discontinuation, sight-threatening AEs, and ESis, if any, will be listed separately. 
8.2. 
Vitreous Haze (VH) 
VH score, change from baseline, and shift from baseline in VH at Month 12 visit and Study Exit 
visit will be summarized and listed. 
Subgroup analysis will be performed for change from baseline in study eye at study exit by 
demographics and baseline characteristics in Section 7.2. 
Subjects with any score of 3+ or above in VH after Baseline will be listed. 
8.3. 
Best-Corrected Visual Acuity (BCV A) 
BCV A and change from baseline in BCV A at Month 12 and Study Exit visit will be summarized 
and listed. 
Subjects with improvement or worsening of at least 5 letters, I 0 letters, or 15 letters in study eye 
at Month 12 visit will be tabulated, as well as subjects maintained BCVA within 5 letters of 
change in study eye. 
Subjects with any BCV A score of 0 after baseline will be listed. 
8.4. 
Intraocular Pressure (lOP) 
lOP, change from baseline in lOP at the Study Exit visit, and change after injection in lOP will 
be summarized. 
Subjects with elevated lOP reported as an AE will be tabulated. Subjects with any increase of~ 
10 mmHg in lOP from baseline at any post-baseline visit, or after injection will be tabulated and 
listed. In addition, Subjects with lOP of at least 25, 30, or 35 mmHg at any post-baseline visit 
will be summarized. 
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8.5. 
Indirect Ophthalmoscopy 
For retina, macula, choroid, and optic nerve, shift from baseline in status (Normal or Abnormal) 
will be summarized at study exit visit and shift after injection will be summarized by injection 
visit. Subjects with any change from normal at baseline to abnormal in status after baseline will 
be listed. 
For phakic lens only, shift from baseline in presence of cataract (Yes or No) at study exit visit 
will be summarized. Subjects with no cataract presence at baseline to cataract presence after 
baseline, if any, will be listed. 
8.6. 
Treatment Exposure 
The exposure to DE-l 09 will be evaluated by descriptive summaries of number of injections 
during the study, time to first injection, and study days on the drug. 
8.7. 
Use of Rescue Therapy 
Subjects who take any medication qualified as rescue therapy, or who have vitrectomy 
procedures in study eye will be listed. The rescue rate in SPRJNG study will be calculated. 
Time to first rescue from Day 1 for rescued subjects will be summarized descriptively. 
Subgroup analysis of rescue rate will be performed by rescue status in SAKURA study, and 
received injection or not in SPRlNG study. 
8.8. 
Slit-lamp Biomicroscopy 
Only subjects who are under US Amendment 01 have slit-lamp biomicroscopy assessments. 
However, none of those subjects have slit-lamp biomicroscopy records at baseline since all of 
them entered the amendment after day 1. Taking this fact into consideration, all the slit-lamp 
biomicroscopy parameters (Lid Hyperemia, Lid Edema, Conjunctival Hyperemia, Chemosis, 
Corneal Edema, Conjunctival Discharge Exudate, Anterior Chamber Flare, Pupil, Lashes, Ocular 
Motility, Iris, Vitreous Cell Count and Anterior Chamber Cells) will be presented only in 
listings. 
8.9. 
Central Retinal Thickness 
Since central retinal thickness assessment is at investigator's discretion and is only for subjects 
under US Amendment 0 I, only a few records were collected. Therefore, subjects with central 
retinal thickness records will simply be listed by type of OCT machine. 
9. 
REFERENCE 
None. 
Confidential 
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