Conditions: Non Infectious Uveitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 145
Healthy volunteers: no

Brief summary:
This is a Phase III study to assess the efficacy and safety of DE-109 440 µg every 2 months in subjects with active, non-infectious uveitis of the posterior segment of the eye (NIU-PS).

There is a 6-month, single-arm, open-label period after completion of the 6-month double- masked, controlled period allows the evaluation of the efficacy and safety of intravitreal injection of DE-109 440 µg every 2 months for longer duration than appropriate for a placebo or sham control.

Detailed description:

Arms:
arm 1: Intravitreal injection of DE-109 440 µg in the study eye(s) every 2 months (Day 1, Month 2, and Month 4). arm 2: Sham procedure administered to the study eye(s) every 2 months (Day 1, Month 2, and Month 4). The sham procedure mimics an intravitreal injection without penetrating the eye. arm 3: Dummy Arm: Intravitreal injection of DE-109 at an undisclosed, fixed dose (within the range of 44 µg to 880 µg) in the study eye(s) every 2 months (Day 1, Month 2, and Month 4). arm 4: Subjects completing the Month 6 pre-dose evaluations (the final evaluations in the double-masked period) began the open-label period of the study, in which all subjects received intravitreal injection of DE-109 440 μg in the study eye(s) every 2 months for an additional 6 months of dosing.

Interventions: intervention 1: DE-109 Intravitreal Injections intervention 2: Sham Procedure intervention 3: DE-109 Intravitreal Injections intervention 4: DE-109 Intravitreal Injections (Open Label)
Intervention descriptions: intervention 1: 440 ug of DE-109 Injectable Solution intervention 2: The sham procedure mimics an intravitreal injection without penetrating the eye. intervention 3: Undisclosed Fixed Dose of DE-109 Injectable Solution (range of 44 ug to 880 ug) intervention 4: After double-masked treatment period (injections every 2 months), eligible subjects would enter the open-labeled period and had DE-109 440 ug injections every 2 months (Month 6, Month 8, and Month 10)

Protocol document:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:  
LUMINA: A Phase III, Multicenter, Sham-Controlled, Randomized, 
Double-Masked Study Assessing the Efficacy and Safety of Intravitreal 
Injections of 440 μg DE-109 for the Treatment of Active, Non-Infectious 
Uveitis of the Posterior Segment of the Eye. 
 
NCT Number:  
NCT03711929 
 
Date of the document:
 14 JUL 2021
 
 
 
 


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DE-109 
Protocol 010906IN 
 
TITLE:  LUMINA: A Phase III, Multicenter, Sham-Controlled, Randomized, Double-
Masked Study Assessing the Efficacy and Safety of Intravitreal Injections of 440 μg  
DE-109 for the Treatment of Active, Non-Infectious Uveitis of the Posterior Segment of 
the Eye.  
PROTOCOL NUMBER: 010906IN 
COMPOUND NUMBER: DE-109 injectable solution 
STUDY PHASE: Phase III  
SPONSOR: SANTEN INCORPORATED 
LEGAL REGISTERED ADDRESS: 6401 Hollis Street, Suite 125, Emeryville, CA 94608  
REGULATORY AGENCY IDENTIFIER NUMBER(S): IND Number: 070496 
PROTOCOL VERSION/DATE:  ORIGINAL: 10SEP2018 
AMENDMENT 1: 26MAR2019 
AMENDMENT 2: 29SEP2020 
AMENDMENT 3: 14JUL2021 
I have read the 010906IN 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 Council for Harmonisation (ICH) 
guidelines, and the Declaration of Helsinki. 


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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ............................................................................................9 
1.1. 
Synopsis ........................................................................................................................9 
1.2. 
Schema ........................................................................................................................14 
1.3. 
Schedule of Activities (SoA) ......................................................................................14 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Study Rationale ...........................................................................................................18 
2.2. 
Background .................................................................................................................18 
2.3. 
Benefit/Risk Assessment ............................................................................................19 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................21 
4. 
STUDY DESIGN .......................................................................................................24 
4.1. 
Overall Design ............................................................................................................24 
4.2. 
Scientific Rationale for Study Design ........................................................................27 
4.3. 
Justification for Dose ..................................................................................................28 
4.4. 
End of Study Definition ..............................................................................................28 
5. 
STUDY POPULATION .............................................................................................29 
5.1. 
Inclusion Criteria ........................................................................................................29 
5.2. 
Exclusion Criteria .......................................................................................................30 
5.3. 
Lifestyle Considerations .............................................................................................33 
5.3.1. 
Contraception Requirements ......................................................................................33 
5.3.2. 
Fasting Prior to Blood Draws for Hematology and Chemistry Laboratory 
Tests ............................................................................................................................33 
5.4. 
Screen Failures and Rescreening ................................................................................33 
6. 
STUDY INTERVENTION ........................................................................................34 
6.1. 
Investigational Product Administered, Formulation, Packaging, and 
Labelling .....................................................................................................................34 
6.2. 
Investigational Product Storage, Preparation, Administration, 
Accountability, Handling, and Disposal .....................................................................36 
6.2.1. 
Investigational Product Storage ..................................................................................36 
6.2.2. 
Investigational Product Preparation ............................................................................36 
6.2.3. 
Investigational Product Administration ......................................................................37 
6.2.4. 
Investigational Product Accountability ......................................................................39 
6.2.5. 
Investigational Product Handling and Disposal .........................................................39 


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6.3. 
Measures to Minimize Bias: Randomization and Masking ........................................40 
6.4. 
Investigational Product Compliance ...........................................................................41 
6.5. 
Concomitant Therapy .................................................................................................41 
6.5.1. 
Collection of Prior and Concomitant Medication Information ...................................41 
6.5.2. 
Subjects with Glaucoma: Continuation of Ocular Hypotensive Medication ..............41 
6.5.3. 
Tapering of Systemic Corticosteroid Therapy ............................................................41 
6.5.4. 
Continuation of Stable Doses of Topical Ocular Corticosteroid Medication, 
Topical Ocular Non-Steroidal Anti-Inflammatory Medication, or Selected 
Immunosuppressants ...................................................................................................42 
6.5.5. 
Protocol-Specified Medications Pre and Post Investigational Product 
Administration ............................................................................................................42 
6.5.6. 
Rescue Therapy ..........................................................................................................43 
6.5.7. 
Protocol-Allowed or Specified Medications not Considered Rescue Therapy ..........44 
6.5.8. 
Prohibited Concomitant Medications or Treatments ..................................................44 
6.6. 
Dose Modification ......................................................................................................44 
6.7. 
Intervention after the End of the Study .......................................................................44 
7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL FROM STUDY ......................45 
7.1. 
Discontinuation of Investigational Product ................................................................45 
7.2. 
Subject Early Discontinuation/Withdrawal from the Study .......................................45 
7.3. 
Lost to Follow-up .......................................................................................................45 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................47 
8.1. 
Visit Details and Efficacy Assessments .....................................................................47 
8.1.1. 
Visit Details ................................................................................................................47 
8.1.2. 
Screening Visit, Day -30 to Day -1 ............................................................................47 
8.1.3. 
Double-Masked Treatment Period, Day 1 ..................................................................48 
8.1.4. 
Double-Masked Treatment Period, Day 14 ................................................................49 
8.1.5. 
Double-Masked Treatment Period, Month 1 ..............................................................50 
8.1.6. 
Double-Masked Treatment Period, Month 2 ..............................................................50 
8.1.7. 
Double-Masked Treatment Period, Month 3 ..............................................................52 
8.1.8. 
Double-Masked Treatment Period, Month 4 ..............................................................52 
8.1.9. 
Double-Masked Treatment Period, Month 5 ..............................................................52 
8.1.10. 
Double-Masked Treatment Period, Month 6 ..............................................................53 
8.1.11. 
Open-Label Treatment Period, Month 7 .....................................................................53 


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8.1.12. 
Open-Label Treatment Period, Month 8 .....................................................................53 
8.1.13. 
Open-Label Treatment Period, Month 9 .....................................................................53 
8.1.14. 
Open-Label Treatment Period, Month 10 ...................................................................54 
8.1.15. 
Open-Label Treatment Period, Month 11 ...................................................................54 
8.1.16. 
Month 12/Exit/Early Termination Visit ......................................................................54 
8.1.17. 
Unscheduled Visits .....................................................................................................55 
8.1.18. 
Efficacy Assessments .................................................................................................55 
8.1.19. 
Vitreous Haze .............................................................................................................55 
8.1.20. 
Best-Corrected Visual Acuity .....................................................................................55 
8.1.21. 
Optical Coherence Tomography .................................................................................56 
8.1.22. 
Use of Systemic Corticosteroids .................................................................................56 
8.1.23. 
National Eye Institute Visual Functioning Questionnaire – 25 (VFQ-25) .................56 
8.2. 
Safety Assessments .....................................................................................................56 
8.2.1. 
Slit-Lamp Biomicroscopy ...........................................................................................56 
8.2.2. 
Vitreous Cells .............................................................................................................56 
8.2.3. 
Anterior Chamber Cells ..............................................................................................57 
8.2.4. 
Anterior Chamber Flare ..............................................................................................57 
8.2.5. 
Terminology for Biomicroscopy Findings .................................................................57 
8.2.6. 
Indirect Ophthalmoscopy ............................................................................................58 
8.2.7. 
Intraocular Pressure ....................................................................................................58 
8.2.8. 
Fundus Photography ...................................................................................................58 
8.2.9. 
Fluorescein Angiography ............................................................................................58 
8.2.10. 
Clinical Safety Laboratory Assessments ....................................................................58 
8.2.11. 
Physical Examination .................................................................................................59 
8.2.12. 
Vital Signs ..................................................................................................................59 
8.2.13. 
Events of Special Interest ...........................................................................................59 
8.2.14. 
Pregnancy Testing, Monitoring, and Reporting .........................................................61 
8.2.15. 
Pregnancy Testing ......................................................................................................61 
8.2.16. 
Pregnancy Monitoring and Reporting Procedures ......................................................61 
8.3. 
Adverse Events and Serious Adverse Events .............................................................62 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................62 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................62 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................63 


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8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................63 
8.4. 
Pharmacogenomics .....................................................................................................63 
9. 
STATISTICAL CONSIDERATIONS .......................................................................65 
9.1. 
Estimands ....................................................................................................................65 
9.2. 
Statistical Hypotheses .................................................................................................66 
9.3. 
Sample Size Determination ........................................................................................66 
9.4. 
Populations for Analyses ............................................................................................66 
9.5. 
Statistical Analyses .....................................................................................................67 
9.5.1. 
Handling of Missing Values .......................................................................................67 
9.5.2. 
Efficacy Analyses .......................................................................................................68 
9.5.3. 
Subpopulation Analyses .............................................................................................70 
9.5.4. 
Safety Analyses ..........................................................................................................70 
9.6. 
Interim Analyses, Primary Analysis, and Analysis of Open-Label Period of 
Study ...........................................................................................................................71 
9.6.1. 
Data Monitoring Committee (DMC) ..........................................................................71 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................72 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................72 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................72 
10.1.2. 
Obligations of Investigators ........................................................................................72 
10.1.3. 
Financial Disclosure ...................................................................................................74 
10.1.4. 
Informed Consent Process ..........................................................................................74 
10.1.5. 
Data Protection ...........................................................................................................76 
10.1.6. 
Source Documents ......................................................................................................76 
10.1.7. 
Data Quality Assurance ..............................................................................................77 
10.1.8. 
Sponsor’s Direct Access to Source Data/Documents and IRB/IEC Materials 
for Monitoring and Audit ............................................................................................78 
10.1.9. 
Study and Site Closure................................................................................................79 
10.1.10. 
Confidentiality and Publication Policy .......................................................................79 
10.2. 
Clinical Laboratory Tests ...........................................................................................80 
10.3. 
Estimated Amount of Blood Collected from Each Subject ........................................80 
10.4. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................81 
10.5. 
List of Abbreviations and Specialist Terms ................................................................86 


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11. 
LIST OF REFERENCES ............................................................................................89 
12. 
APPENDICES ............................................................................................................91 
12.1. 
Appendix 1: National Eye Institute Visual Functioning Questionnaire – 25 
(VFQ-25) ....................................................................................................................91 
12.2. 
Appendix 2: ETDRS Visual Acuity Chart Procedure ..............................................108 
12.2.1. 
Procedures for Refraction and Vision Testing ..........................................................108 
12.3. 
Appendix 3: Adverse Event Case Report Form Items and Terms............................116 
12.4. 
Appendix 4: Protocol Amendment 3 Summary of Changes ....................................118 
 
 
LIST OF TABLES 
Table 2: 
Study Objectives, Estimands, and Endpoints ...............................................................9 
Table 3: 
Schedule of Activities .................................................................................................15 
Table 4: 
Study Objectives, Estimands, and Endpoints .............................................................21 
Table 5: 
Investigational Product Descriptions ..........................................................................34 
Table 6: 
Investigational Product Administration Procedure .....................................................38 
Table 7: 
Vitreous Haze (VH), Modified SUN Scale ................................................................55 
Table 8: 
Endpoint Statistical Analysis ......................................................................................68 
Table 9: 
Serum Chemistry and Hematology .............................................................................80 
Table 10: Definition of AE .........................................................................................................81 
Table 11: Definition of SAE .......................................................................................................82 
Table 12: Recording and Follow-Up of AE and/or SAE ............................................................83 
Table 13: Reporting of SAEs ......................................................................................................85 
Table 14: List of Abbreviations and Specialist Terms ................................................................86 
Table 15: 4M Refraction Protocol Summary ............................................................................114 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................14 
Figure 2: 
0.2 mL fill in a 2 mL vial ............................................................................................36 
Figure 3: 
Alignment of the Syringe ............................................................................................37 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: LUMINA: A Phase III, Multicenter, Sham-Controlled, Randomized, Double-
Masked Study Assessing the Efficacy and Safety of Intravitreal Injections of 440 μg DE-109 for 
the Treatment of Active, Non-Infectious Uveitis of the Posterior Segment of the Eye. 
Table 2: 
Study Objectives, Estimands, and Endpoints 
Study Objectives and Estimands 
Corresponding Study Endpoints 
Primary objective (efficacy vs. sham): The 
primary objective of this study is to evaluate the 
efficacy of intravitreal injection of 440 μg DE-
109 every 2 months as compared with sham for 
the treatment of active, non-infectious uveitis of 
the posterior segment of the eye. 
Primary estimand: Vitreous haze 0 (VH0) 
response rate in DE-109 440 µg group vs. Sham 
group at Month 5 in all study eyes that received 
at least one dose of the study treatment where all 
eyes that were rescued due to worsening of 
uveitis or discontinued from the study due to lack 
of efficacy or due to adverse event before Month 
5 will be treated as non-responders. For study 
eyes that were rescued for any other reasons or 
had missing data due to other reasons, imputation 
by the multiple imputation-based approach will 
be used.  
Treatment policy estimand: VH0 response rate 
in DE-109 440 µg group vs. Sham group at 
Month 5 in all study eyes that received at least 
one dose of the study treatment regardless of 
whether subjects have received rescue therapy or 
discontinued from the study due to lack of 
efficacy or due to adverse event. For study eyes 
that had missing data due to any reason, 
imputation by the multiple imputation-based 
approach will be used. 
Composite estimand: Mean composite score in 
DE-109 440 µg group vs. Sham group at Month 
3 and at Month 5 in all study eyes that received 
at least one dose of study treatment. Each study 
eye will be assigned one of the following scores: 
 
Score = 3 if a study eye achieved VH 
score of 0 at the specified visit without 
taking any rescue therapies that could 
affect VH score prior to the specified 
visit  
Primary efficacy endpoint:  
 
VH 0 responsea at Month 5 
Key secondary efficacy endpoints:  
 
Composite endpointb at Month 5 
 
VH 0 response at Month 3 
 
Composite endpoint at Month 3 
Note: Overall Type I error rate will be maintained 
at 0.05 (two-sided) across primary and key 
secondary efficacy endpoint treatment 
comparisons.  
Other secondary efficacy endpoints: 
 
VH 0 or 2-unit responsec at Month 5 
 
VH 0 or 2-unit response at Month 3 
 
VH 0 or 0.5+ responsed at Month 5 
 
VH 0 or 0.5+ response at Month 3 
 
Corticosteroid tapering successe with 
resolution at Month 5 
 
Corticosteroid tapering success with 
resolution at Month 3 
 
BCVA (Best-Corrected Visual Acuity) 
3-line responsef at Month 5 
 
BCVA 3-line response at Month 3 
 
Change from baseline in central subfield 
thickness (CST) at Month 5 as measured 
by OCT 
 
Change from baseline in CST at Month 3 
as measured by OCT 
 
Use of rescue therapy before Month 5 
 
Use of rescue therapy before Month 3 
Note:  Additional secondary and exploratory 
efficacy endpoints will be specified in the 
Statistical Analysis Plan.  


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Table 2: 
Study Objectives, Estimands, and Endpoints (Continued) 
Study Objectives and Estimands 
Corresponding Study Endpoints 
 
Score = 2 if a study eye had at least 
improved by 2 units in VH (compared to 
baseline) at the specified visit without 
taking any rescue therapies that could 
affect VH score prior to the specified 
visit   
 
Score = 1 if a study eye achieved VH 
score of 0.5+ at the specified visit 
without taking any rescue therapies that 
could affect VH score prior to the 
specified visit   
 
Score = -1 if a study eye got rescued due 
to worsening of uveitis or discontinued 
from the study due to lack of efficacy or 
due to adverse event prior to the 
specified visit  
Score = 0 if otherwise 
 
Secondary (long-term efficacy): A secondary 
objective of this study is to evaluate the long-
term efficacy (> 6 months and up to one year) of 
intravitreal injection of 440 μg DE-109 every 2 
months for the treatment of active, non-infectious 
uveitis of the posterior segment of the eye. 
Secondary efficacy endpoints assessing long-term 
efficacy will include the following:  
VH 0 response at each visit after Month 6 
VH 0 or 2-unit response at each visit after Month 6 
VH 0 or 0.5+ response at each visit after Month 6 
Additional secondary and exploratory endpoints 
assessing long-term efficacy will be specified in 
the Statistical Analysis Plan.  
Secondary (safety): A secondary objective of 
this study is to evaluate the safety of intravitreal 
injection of 440 μg DE-109 every 2 months for 
up to one year of dosing for the treatment of 
active, non-infectious uveitis of the posterior 
segment of the eye.  
Safety of DE-109 will be assessed by adverse 
events (AEs), slit-lamp biomicroscopy, indirect 
ophthalmoscopy, BCVA, optical coherence 
tomography (OCT), fundus photography (FP), 
fluorescein angiography (FA), intraocular pressure 
(IOP), laboratory tests (serum chemistry, 
hematology, and urinalysis), physical 
examinations, and vital signs.  
Note: Vitreous haze (VH) will be scored using the modified Standardized Uveitis Nomenclature (SUN) scale.  
a VH 0 response (resolution of inflammation) is defined as a VH score of 0 in the study eye at a specified follow up 
visit based on the modified SUN scale.  
b  Refer to composite score scales defined in the composite estimand in this table.  
c VH 0 or 2-unit response is defined as having a VH score of 0 or a decrease (improvement) of at least 2 units  
(i.e., 2+ to 0, 3+ to 1+, or 4+ to 2+) from baseline in the study eye in VH score at a specified follow up visit based 
on the modified SUN scale.   
d VH 0 or 0.5+ response (remission of inflammation) is defined as a VH score of 0 or 0.5+ in the study eye at a 
specified follow-up visit based on the modified SUN scale.  
e Corticosteroid tapering success with resolution is defined as achievement of a prednisone-equivalent oral dose of 
0 mg/day and a VH score of 0 in the study eye at a specified follow-up visit. This endpoint is assessed based on 
the Intent-to-Taper population (study eyes of subjects who received systemic [oral] corticosteroids at a stable 
prednisone-equivalent dose between ≥15 mg/day and ≤40 mg/day that has remained stable for at least 1 week  


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[7 days] prior to and including on Day 1). 
f BCVA 3-line response is defined as an increase (improvement) of at least 3 lines (15 ETDRS letters) from 
baseline in BCVA at a specified follow-up visit. This endpoint is assessed based on eyes with a baseline best-
corrected visual acuity (BCVA) ≤ 70 ETDRS letters (Snellen equivalent of 20/40 or worse). 
Overall Design: 
This is a Phase III study to assess the efficacy and safety of DE-109 440 µg every 2 months in 
subjects with active, non-infectious uveitis of the posterior segment of the eye (NIU-PS). The 
12-month study consists of a 6-month, randomized, double-masked, parallel design, sham-
controlled evaluation of DE-109 440 µg every 2 months followed by a 6-month, open-label 
period in which all subjects will receive DE-109 440 µg every 2 months.  
The study will begin with a 30 days screening period (Day -30 to Day -1) which will be followed 
by the 6-month double-masked treatment period. In the double-masked period, approximately 
200 eligible subjects will be randomized in a 2:2:1 ratio to three arms: 
1. Test arm: Intravitreal injection of DE-109 440 µg in the study eye(s) every 2 months 
(Day 1, Month 2, and Month 4) (approximately 80 subjects). 
2. Control arm: Sham procedure administered to the study eye(s) every 2 months (Day 1, 
Month 2, and Month 4) (approximately 80 subjects). The sham procedure mimics an 
intravitreal injection without penetrating the eye (the blunt end of an empty syringe is 
pressed against an anesthetized eye).  
3. Dummy arm: Intravitreal injection of DE-109 at an undisclosed, fixed dose (within the 
range of 44 µg to 880 µg) in the study eye(s) every 2 months (Day 1, Month 2, and 
Month 4) (approximately 40 subjects). This study arm (which has the same route of 
administration and frequency as the test arm) is included in the study to help ensure 
masking of treatment assignments. The dose used in this arm will be chosen from a range 
of DE-109 doses (44 µg to 880 µg) previously demonstrated to have an acceptable safety 
profile. The dose in this arm will not vary between participating sites or subjects 
randomized to this arm.  
The hypothesis of the double-masked period is that the test arm (DE-109 440 µg dose every 
2 months) will demonstrate superior efficacy versus the sham control arm. To preserve the 
masking of treatment assignments, there will be separate, unmasked and masked investigators 
(and designated staff) during the double-masked period. At visits at which investigational 
product (IP) is being administered, the unmasked investigator (and designated staff) will 
administer the IP (DE-109 intravitreal injection and sham procedure) and conduct the post-
administration assessments; the masked investigator (and designated staff) will conduct the 
assessments prior to IP administration.  
Open-label period: Subjects completing the Month 6 pre-dose evaluations (the final evaluations 
in the double-masked period) will begin the open-label period of the study, in which all subjects 
will receive intravitreal injection of DE-109 440 µg in the study eye(s) every 2 months for an 
additional 6 months of dosing (i.e., IP injections at Month 6, Month 8, and Month 10 with a final 
follow-up evaluation at Month 12). The same study eye(s) treated during the double-masked 
period will be treated during the open-label period. The open-label period of the study will allow 
evaluation of the long-term (> 6 months and up to one year) efficacy and safety of DE-109 
440 µg every 2 months in subjects with NIU-PS.  


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Study Population: 
For study eligibility, active uveitis is defined as having a vitreous haze (VH) score of at least 
1.5+ based on the modified SUN scale. If anterior segment inflammation is present, it must be 
less severe than the posterior component. Subjects receiving systemic (oral) corticosteroid 
therapy will be eligible to enroll in the study; these subjects will be required to have received a 
prednisone-equivalent dose between ≥15 mg/day and ≤40 mg/day that has remained stable for at 
least 1 week (7 days) prior to and including on the first day of dosing (Day 1). Similarly, subjects 
receiving topical corticosteroid eye drops (other than difluprednate ophthalmic emulsion), topical 
non-steroidal anti-inflammatory eye drops, or certain immunosuppressants will be eligible and 
will be required to have received a stable dose/frequency of the therapy for at least 1 week  
(7 days) prior to Day 1 (Inclusion criteria Section 5.1, #6 and #8; Exclusion criteria Section 5.2, 
#14). 
If both of an eligible subject’s eyes meet all eligibility criteria, both eyes can be randomized into 
the study (i.e., both eyes can be study eyes) and will be assigned to the same treatment arm. The 
investigator will determine whether to enroll both eyes into the study after eligibility has been 
confirmed. The study randomization will include stratification by number of eyes enrolled (one 
eye or two eyes) as well as baseline systemic (oral) corticosteroid use (yes/no) and region (US or 
non-US). There will be separate drug supplies, records, and assessments for each study eye. 
If a fellow eye (non-study eye of a subject in the study) has uveitis at baseline or develops active 
uveitis during the study, the investigator should treat the eye with standard of care local 
therapies; systemically administered therapies should not be used to treat the fellow eye unless 
deemed to be medically necessary. DE-109 may not be administered to a fellow eye.  
Study Assessments: 
Study assessments will include fundus photography (FP), slit-lamp biomicroscopy, indirect 
ophthalmoscopy, optical coherence tomography (OCT), intraocular pressure (IOP), best-
corrected visual acuity (BCVA), fluorescein angiography (FA), the National Eye Institute Visual 
Functioning Questionnaire - 25 (VFQ-25), assessment of adverse events, laboratory tests (serum 
chemistry, hematology, and urinalysis), physical examination, vital signs, and pregnancy testing 
(serum and urine pregnancy tests for women of childbearing potential).  
Tapering of Systemic (Oral) Corticosteroid Use: 
Starting on Day 1, subjects receiving systemic (oral) corticosteroids at a stable prednisone-
equivalent dose between ≥15 mg/day and ≤40 mg/day will taper over a  maximum of 8 weeks to 
a prednisolone-equivalent dose of 0 mg/day. Corticosteroid tapering success with resolution of 
VH will be assessed in these subjects. The study randomization will include stratification by 
baseline systemic (oral) corticosteroid use (yes/no) as well as the number of eyes enrolled (one 
eye or two eyes) and region (US or non-US).  
Protocol-Specified Rescue Therapy Criteria: 
Rescue therapy is defined as any treatment that would have a therapeutic effect on NIU-PS. 
Rescue therapy is prohibited during the study unless there is worsening of uveitis as 
demonstrated by one or more of the following three rescue criteria: 
 


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1. Worsening of uveitis in the study eye as indicated by at least a 2-step increase in VH 
score (i.e., 0 to ≥ 2+, 0.5+ to ≥ 3+, 1+ to ≥ 3+, 1.5+ to ≥ 4+, or 2+ to ≥ 4+) as 
compared to the baseline (Day 1) VH score or the best achieved VH score post 
baseline. 
2. Severe deterioration of vision in the study eye due to worsening of uveitis that is 
indicated by at least doubling of the visual angle (BCVA loss of 3 or more lines 
[≥15 ETDRS letters]) as compared to baseline (Day 1) BCVA. 
3. New or worsening retinal or choroidal uveitic lesion(s) in the study eye determined 
by clinical examination, as compared to baseline. 
When deemed medically necessary, rescue therapy may be administered at the discretion of the 
investigator, even if none of the protocol-specified rescue criteria noted above are satisfied. The 
investigator should contact the medical monitor to discuss the rescue treatment plan prior to the 
administration of rescue therapy. If the investigator is unable to reach the medical monitor, 
rescue treatment should be administered per the investigator’s clinical judgment and the medical 
monitor should be notified as soon as possible to discuss future on-study treatment plans for the 
subject. 
Interim Analyses, Primary Analysis, and Analysis of Open-Label Period: 
An interim analysis is planned when the first 100 subjects complete their Month 5 Visit.  There 
are two goals for this interim analysis (1) to assess for futility; and (2) to re-assess the sample 
size. Sample size re-assessment will be performed with the “promising zone” approach as 
follows (Mehta et al., 2011). If the conditional power at the interim analysis is between 50% and 
80%, the suggested sample size increase may be up to 100 subjects (i.e., 50% of the original 
sample size). If, on the other hand, the conditional power is > 80% or < 50%, no change to the 
sample size will take place. If the conditional power is <30%, then the Data Monitoring 
Committee (DMC) would recommend stopping the trial due to futility.  The DMC could 
recommend stopping the trial due to safety concerns at any of the DMC meetings and the interim 
analysis. An independent statistical and programming team will be used to perform this interim 
analysis of unmasked data and the DMC will review the results and make recommendations 
based on the findings. The planned interim analysis will be specified in greater detail in the SAP 
and in the DMC charter. 
The primary analysis of this study is the analysis of the data from the 6-month, double-masked 
period. These data will be quality-checked, soft-locked, and the primary analysis will be 
conducted after all subjects have completed the Month 6 visit or prematurely discontinued from 
the study prior to Month 6. An interim clinical study report will be written documenting the 
primary analysis results.  
Analysis of the open-label period of the study will be performed after the end of the study and 
documented in the final clinical study report.  
Data Monitoring Committee: 
An independent Data Monitoring Committee (DMC) whose members will not be participating in 
the LUMINA study conduct will serve as an advisory board to the Santen senior management 
team. The DMC will periodically review and make recommendations based on interim data; 
unmasked data will only be reviewed in closed DMC sessions without participation of Santen 


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personnel. The organization, responsibilities, and procedures of the DMC will be specified in a 
governing charter. 
1.2. 
Schema 
Figure 1 provides an overview of the study design. 
 
Figure 1: 
Study Schema 
 
 
1.3. 
Schedule of Activities (SoA) 
The schedule of activities (SoA) is provided in Table 3. 
 


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Table 3: 
Schedule of Activities 
 
Screening 
Double-Masked Period Visits 
Open-Label Period Visits 
 
Screening 
(Within 
30 days 
prior to 
D1; i.e.,  
D -30 to 
D -1) 
D1 
(Baseline) 
D14 
M1 
M2, 
M4 
M3 
M5 
M6 a 
M7, 
M9, 
M11 
M8, 
M10 
M12/ 
Exit/ 
Early 
Termina- 
tion 
Study day 
 
D1 
D14 
D30 
D60,  
D120 
D90 
D150 
D180 
D210, 
D270, 
D330 
D240, 
D300 
M12: D360 
Visit window in days 
NA 
NA 
±2 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
M12: ±7 
IP (DE-109, Sham, Dummy) 
administration 
 
x b 
 
 
x b 
 
 
x 
 
x 
 
Time relative to IP 
administration 
 
pre 
post 
 
 
pre 
post 
 
 
pre a 
post a 
 
pre 
post 
 
Signed and dated informed 
consent  
x c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history, 
history of NIU-PS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination and 
vital signs 
x 
 
 
 
 
 
 
 
xd 
 
 
 
 
 
x 
VFQ-25 
 
x 
 
 
 
 
 
 
xd 
 
 
 
 
 
x  
Serum pregnancy test e 
x e 
 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Urine pregnancy test e 
 
x e 
 
 
 
x e 
 
 
 
x e 
 
 
x e 
 
 
Laboratory safety tests 
(hematology, chemistry, 
urinalysis) f 
x f 
 
 
 
 
 
 
 
x d, f 
 
 
 
 
 
x f 


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Table 3: 
Schedule of Activities (Continued) 
 
Screening 
Double-Masked Period Visits 
Open-Label Period Visits 
 
Screening 
(Within 
30 days 
prior to 
D1; i.e.,  
D -30 to 
D -1) 
D1 
(Baseline) 
D14 
M1 
M2, 
M4 
M3 
M5 
M6 a 
M7, 
M9, 
M11 
M8, 
M10 
M12/ 
Exit/ 
Early 
Termina- 
tion 
Blood sample for 
pharmacogenomics g 
 
 
 
x g 
 
 
 
 
 
 
 
 
 
 
 
Time relative to IP 
administration 
 
pre 
post 
 
 
pre 
post 
 
 
pre a 
post a 
 
pre 
post 
 
Randomization h 
 
x h 
 
 
 
 
 
 
 
 
 
 
 
 
 
Best-corrected visual acuity 
(ETDRS) 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
Slit-lamp biomicroscopy 
x 
x 
x i 
x 
x 
x 
x i 
x 
x 
x 
x i 
x 
x 
x i 
x 
Intraocular pressure 
x 
x 
x j 
x 
x 
x 
x j 
x 
x 
x 
x j 
x 
x 
x j 
x 
Indirect ophthalmoscopy 
x 
x 
x i 
x 
x 
x 
x i 
x 
x 
x 
x i 
x 
x 
x i 
x 
Optical Coherence 
Tomography 
 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
Fundus photography 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
Fluorescein angiography k 
 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
Systemic corticosteroid 
medication status 
x l 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
Other prior or concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prednisolone acetate eye 
drops m 
 
 
x m 
 
 
 
x m 
 
 
 
x m 
 
 
x m 
 
Adverse events n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 


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Table 3: 
Schedule of Activities (Continued) 
IP = Investigational product; NA = not applicable; M=Month; D=Day; pre=prior to IP administration; post = after IP administration. 
a The double-masked period ends with the pre-dose evaluations at Month 6; the first open-label dose of DE-109 is at Month 6. 
b On study visits during the double-masked period at which IP is administered, the unmasked investigator will perform the IP preparation and administration.  
c Signed and dated informed consent form must be obtained prior to conducting any study-related activities. 
d If physical examination and vital signs, VFQ-25 and/or laboratory safety tests were performed at Month 3 under a previous version of the protocol these 
assessments do not need to be performed at Month 5. 
e Serum and urine pregnancy tests are to be performed on all females of child-bearing potential. Urine pregnancy test (hCG) is to be performed prior to each IP 
administration. A positive pregnancy test at screening or Day 1 (Baseline) requires exclusion from the study. At subsequent visits, a positive urine pregnancy test 
requires immediate discontinuation from the study. Pregnancy is an event of special interest and requires follow-up by Santen until the outcome is known.  
f At Month 5 subjects must fast 8 hours prior to the blood draw for hematology and chemistry laboratory tests. At Screening, and Month 12/Exit/Early 
termination visit, lipid may be obtained in the fasting or non-fasting state. 
g This is only applicable if the subject has consented to collection of blood for pharmacogenomics (approximately 10 mL of blood). This sample should be 
collected at the Day 14 visit, but may be collected at any time during the study or at a separate post study visit, if necessary. 
h Refer to Section 8.1.3 for assessments and requirements prior to randomization.  
i After IP administration, slit-lamp biomicroscopy is performed first and then indirect ophthalmoscopy, in both eyes within 30 minutes of IP administration. 
j Intraocular pressure (IOP) is measured in both eyes at approximately 40 ± 10 minutes after IP administration. If IOP is increased ≥10 mmHg 40±10 minutes 
after IP administration compared to prior to IP administration, administer topical IOP lowering medication for use until the subject returns for follow-up per the 
investigator’s discretion. (An unscheduled visit may apply). IOP increase of ≥10 mmHg at any visit compare to the Baseline (Day 1) assessment should be 
reported as an AE.  
k Any required blood or urine sample is to be collected before injection of fluorescein. 
l Subjects receiving systemic (oral) corticosteroid therapy will be required to titrate the dose as needed such that they remain on a stable prednisone-equivalent 
dose between ≥15 mg/day and ≤40 mg/day that has remained stable for at least 1 week (7 days) prior to and including on Day 1. 
m Prednisolone acetate eye drops are to be started after each IP administration and continued for 8 days, according to the following schedule: 4 times per day for 
4 days (including the day of IP administration) followed by 2 times per day for 4 days, then stop. 
n Adverse events (AE) will be recorded starting after the signing of the informed consent form. During the double-masked period, regardless of the source of the 
reported occurrence of an AE in a subject, the masked investigator will assess the causality of the AE. 


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2. 
INTRODUCTION 
DE-109 is a formulation of sirolimus administered by intravitreal injection that is being 
developed for the treatment of non-infectious uveitis of the posterior segment of the eye 
(intermediate, posterior, and panuveitis). Sirolimus is an inhibitor of the mammalian target of 
rapamycin (mTOR) and acts as an immunoregulator.  
2.1. 
Study Rationale 
Phase III study 010906IN (LUMINA) will evaluate the efficacy and safety of intravitreal 
injection of DE-109 440 µg administered every 2 months for the treatment of active, 
non-infectious uveitis of the posterior segment of the eye (NIU-PS). In two Phase III studies 
conducted previously in this indication, three doses of DE-109 were evaluated (44 µg, 440 µg, 
and 880 µg, each administered every 2 months); the 440 µg dose demonstrated the optimal 
benefit-risk profile. The 6-month, double-masked period of Phase III study LUMINA is being 
conducted to confirm the efficacy and safety of DE-109 440 µg administered every 2 months 
when compared to a sham control. The 6-month, open-label period of the study will allow 
evaluation of the long-term (> 6 months and up to one year) efficacy and safety of DE-109 
440 µg every 2 months in subjects with NIU-PS. 
2.2. 
Background 
Non-infectious uveitis of the posterior segment of the eye (NIU-PS) is a heterogeneous group of 
intraocular inflammation disorders with both exogenous (infection, trauma) and endogenous 
(autoimmune, idiopathic) etiologies that affects up to 730 people per 100,000 (Durrani et al., 
2004; Jabs et al., 2005). In chronic uveitis, cumulative structural damage and loss of vision result 
from recurrent episodes of inflammation. Thus, active uveitis requires urgent treatment to control 
inflammation.  
Historically, the primary treatment for NIU-PS has been systemic corticosteroid therapy. More 
recently, ocular implants that deliver corticosteroid locally have become available. Systemic 
corticosteroid therapy is associated with known comorbidities (e.g., osteoporosis, hypertension, 
and diabetes, as well as cataracts and glaucoma) that may escalate with dose and frequency of 
use. The available corticosteroid ocular implants are associated with a high rate of increased 
intraocular pressure (IOP), the attendant risk of glaucoma, and with increased risk of cataract 
development. Other systemic immunosuppressive therapies (antimetabolites, T-cell inhibitors, 
alkylating agents, and biologics) may be appropriate as monotherapy in certain patients, or these 
agents may be used to lower the corticosteroid dose, however close monitoring is required due to 
potentially serious side effects such as hepatotoxicity, myelosuppression, or malignancy. Given 
the treatment-limiting side effects of current therapies, there remains an unmet medical need in 
NIU-PS for therapies that can be used on a long-term basis to address the chronicity of the 
disease.  
Sirolimus (also known as rapamycin) is a macrolide antibiotic that inhibits the mammalian target 
of rapamycin (mTOR), a multifunctional kinase. Inhibition of mTOR and its downstream 
signaling molecules by sirolimus results in immunosuppression, primarily by interrupting the 
inflammatory cascade that leads to T-cell activation and proliferation. Emerging evidence 


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suggests that sirolimus also promotes immune tolerance by inducing regulatory T-cells (Tregs), 
which may contribute to the treatment of non-infectious uveitis because of the potential 
dysfunction of Tregs in autoimmune diseases. Sirolimus received initial US regulatory approval 
in 1999 (as Rapamune®) for the prophylaxis of organ rejection in renal transplant patients; 
sirolimus is also the active ingredient in a drug-eluting stent (the CYPHER® Sirolimus-eluting 
Coronary Stent) marketed for improving coronary luminal diameter in patients with symptomatic 
ischemic disease. Evidence of the efficacy of sirolimus in treating uveitis was first obtained in an 
investigator-sponsored study, the SAVE study (Ibrahim et al., 2015; Nguyen et al., 2013). In this 
study of 30 subjects with non-infectious uveitis, sirolimus administered by either intravitreal or 
subconjunctival injection was generally well tolerated and showed bioactivity in reducing 
vitreous haze and cells, in improving visual acuity, and in decreasing the need for systemic 
corticosteroids.  
DE-109 is a formulation of sirolimus that forms a depot which localizes in the inferior portion of 
the vitreous humor, providing sirolimus exposure to the retina/choroid for approximately two 
months. Santen has conducted a nonclinical and clinical development program of DE-109 
through Phase III to demonstrate the efficacy and safety of DE-109 in the treatment of NIU-PS. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of DE-109 is 
provided in the DE-109 Investigational Brochure.  
2.3. 
Benefit/Risk Assessment 
Two Phase III studies have been completed (SAKURA Program: SAKURA Study 1 and 
SAKURA Study 2) which evaluated three doses of DE-109 (44 μg, 440 μg, and 880 μg, each 
administered every 2 months) in subjects with active NIU-PS. A total of 590 randomized, treated 
study eyes (590 subject IDs, 589 subjects) received at least one injection of DE-109 (i.e., 
integrated Safety population).  In the integrated Safety population of the two studies, 459 treated 
study eyes were exposed to the 440 or 880 μg dose of DE-109 for at least 6 months (defined as 
staying in study under either dose for at least 173 days after the first 440 or 880 μg dose) and 318 
treated study eyes were exposed to the 440 or 880 μg dose for at least 1 year (defined as staying 
in study for at least 346 days after the first 440 or 880 μg dose). The DE-109 440 μg dose 
exhibited the optimal benefit/risk profile in Study 1 and performed similarly in Study 2. The 
efficacy and safety data in these large Phase III studies support the 440 μg dose as the most 
appropriate dose of DE-109 for treating active NIU-PS. For the primary endpoint (VH score of 0 
at Month 5), the response rate in the 440 μg dose group was appreciable and consistent across the 
two studies (22.8% and 19.1% in Study 1 and Study 2, respectively).  
The safety data from the SAKURA program demonstrated a reasonable safety profile of the 
440 µg dose of DE-109, with few risks directly related to its use. Risks associated with the use of 
DE-109 are non-infectious endophthalmitis, which was observed mostly with the 880 µg dose 
and successfully treated with corticosteroids and surgical intervention, and the presence of drug 
depot in the visual axis, which, if it occurs, is a self-limiting event that may resolve as the drug 
depot dissolves and moves out of the visual axis. At all three doses (44 μg, 440 μg, and 880 μg, 
each administered every 2 months), DE-109 had minimal effect on IOP with repeat dosing and 
the systemic exposures after intravitreal dosing were well below the levels required for 
immunosuppression, thereby minimizing the possibility of systemic side effects.  


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The undisclosed, fixed dose of DE-109 in the Dummy arm will be within the range of doses 
evaluated in the previous Phase III studies (44 μg to 880 μg), all of which have demonstrated an 
acceptable safety profile.  
The control arm for the 6-month, double-masked period of this study is a sham procedure, which 
mimics an intravitreal injection without penetrating the eye. The protocol allows for the 
administration of rescue therapy for any subject in the study who experiences a worsening of 
uveitis.  
Refer to the DE-109 Investigational Brochure for detailed descriptions of completed studies of 
DE-109 and the safety and efficacy data relevant to the clinical use of DE-109 in NIU-PS. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Table 4: 
Study Objectives, Estimands, and Endpoints 
Study Objectives and Estimands 
Corresponding Study Endpoints 
Primary objective (efficacy vs. sham): The 
primary objective of this study is to evaluate 
the efficacy of intravitreal injection of 440 
μg DE-109 every 2 months as compared with 
sham for the treatment of active, 
non-infectious uveitis of the posterior 
segment of the eye. 
Primary estimand: Vitreous haze 0 (VH0) 
response rate in DE-109 440 µg group vs. 
Sham group at Month 5 in all study eyes that 
received at least one dose of the study 
treatment where all eyes that were rescued 
due to worsening of uveitis or discontinued 
from the study due to lack of efficacy or due 
to adverse event before Month 5 will be 
treated as non-responders. For study eyes 
that were rescued for any other reasons or 
had missing data due to other reasons, 
imputation by the multiple imputation-based 
approach will be used.  
Treatment policy estimand: VH0 response 
rate in DE-109 440 µg group vs. Sham group 
at Month 5 in all study eyes that received at 
least one dose of the study treatment 
regardless of whether subjects have received 
rescue therapy or discontinued from the 
study due to lack of efficacy or due to 
adverse event. For study eyes that had 
missing data due to any reason, imputation 
by the multiple imputation-based approach 
will be used. 
 
Primary efficacy endpoint:  
 
VH 0 responsea at Month 5 
Key secondary efficacy endpoints:  
 
Composite endpointb at Month 5 
 
VH 0 response at Month 3 
 
Composite endpoint at Month 3 
Note: Overall Type I error rate will be maintained at 
0.05 (two-sided) across primary and key secondary 
efficacy endpoint treatment comparisons.  
Other secondary efficacy endpoints: 
 
VH 0 or 2-unit responsec at Month 5 
 
VH 0 or 2-unit response at Month 3 
 
VH 0 or 0.5+ responsed at Month 5 
 
VH 0 or 0.5+ response at Month 3 
 
Corticosteroid tapering successe with resolution at 
Month 5 
 
Corticosteroid tapering success with resolution at 
Month 3 
 
BCVA (Best-Corrected Visual Acuity) 3-line 
responsef at Month 5 
 
BCVA 3-line response at Month 3 
 
Change from baseline in central subfield thickness 
(CST) at Month 5 as measured by OCT 
 
Change from baseline in CST at Month 3 as 
measured by OCT 
 
Use of rescue therapy before Month 5 
 
Use of rescue therapy before Month 3 
Note:  Additional secondary and exploratory 
efficacy endpoints will be specified in the Statistical 
Analysis Plan. 
 
 
 
 
 


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Table 4: 
Study Objectives, Estimands, and Endpoints (Continued) 
Study Objectives and Estimands 
Corresponding Study Endpoints 
Composite estimand: Mean composite score 
in DE-109 440 µg group vs. Sham group at 
Month 3 and at Month 5 in all study eyes that 
received at least one dose of study treatment. 
Each study eye will be assigned one of the 
following scores: 
 
Score = 3 if a study eye achieved VH 
score of 0 at the specified visit 
without taking any rescue therapies 
that could affect VH score prior to 
the specified visit  
 
Score = 2 if a study eye had at least 
improved by 2 units in VH 
(compared to baseline) at the 
specified visit without taking any 
rescue therapies that could affect VH 
score prior to the specified visit   
 
Score = 1 if a study eye achieved VH 
score of 0.5+ at the specified visit 
without taking any rescue therapies 
that could affect VH score prior to 
the specified visit   
 
Score = -1 if a study eye got rescued 
due to worsening of uveitis or 
discontinued from the study due to 
lack of efficacy or due to adverse 
event prior to the specified visit 
 
Score = 0 if otherwise 
 
Secondary (long-term efficacy): A 
secondary objective of this study is to 
evaluate the long-term efficacy (> 6 months 
and up to one year) of intravitreal injection 
of 440 μg DE-109 every 2 months for the 
treatment of active, non-infectious uveitis of 
the posterior segment of the eye. 
Secondary efficacy endpoints assessing long-term 
efficacy will include the following:  
 
VH 0 response at each visit after Month 6 
 
VH 0 or 2-unit response at each visit after Month 6 
 
VH 0 or 0.5+ response at each visit after Month 6 
Additional secondary and exploratory endpoints 
assessing long-term efficacy will be specified in the 
Statistical Analysis Plan. 
 
 
 
 


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Table 4: 
Study Objectives, Estimands, and Endpoints (Continued) 
Study Objectives and Estimands 
Corresponding Study Endpoints 
Secondary (safety): A secondary objective 
of this study is to evaluate the safety of 
intravitreal injection of 440 μg DE-109 every 
2 months for up to one year of dosing for the 
treatment of active, non-infectious uveitis of 
the posterior segment of the eye.  
Safety of DE-109 will be assessed by adverse events 
(AEs), slit-lamp biomicroscopy, indirect 
ophthalmoscopy, BCVA, optical coherence 
tomography (OCT), fundus photography (FP), 
fluorescein angiography (FA), intraocular pressure 
(IOP), laboratory tests (serum chemistry, hematology, 
and urinalysis), physical examinations, and vital signs.  
Note: Vitreous haze (VH) will be scored using the modified Standardized Uveitis Nomenclature (SUN) scale.  
a VH 0 response (resolution of inflammation) is defined as a VH score of 0 in the study eye at a specified follow up 
visit based on the modified SUN scale. 
b  Refer to composite score scales defined in the composite estimand in this table.  
c VH 0 or 2-unit response is defined as having a VH score of 0 or a decrease (improvement) of at least 2 units  
(i.e., 2+ to 0, 3+ to 1+, or 4+ to 2+) from baseline in the study eye in VH score at a specified follow up visit based 
on the modified SUN scale.   
d VH 0 or 0.5+ response (remission of inflammation) is defined as a VH score of 0 or 0.5+ in the study eye at a 
specified follow-up visit based on the modified SUN scale.  
e Corticosteroid tapering success with resolution is defined as achievement of a prednisone-equivalent oral dose of 
0 mg/day and a VH score of 0 in the study eye at a specified follow-up visit. This endpoint is assessed based on 
the Intent-to-Taper population (study eyes of subjects who received systemic [oral] corticosteroids at a stable 
prednisone-equivalent dose between ≥15 mg/day and ≤40 mg/day that has remained stable for at least 1 week  
[7 days] prior to and including on Day 1). 
f BCVA 3-line response is defined as an increase (improvement) of at least 3 lines (15 ETDRS letters) from 
baseline in BCVA at a specified follow-up visit. This endpoint is assessed based on eyes with a baseline best-
corrected visual acuity (BCVA) ≤ 70 ETDRS letters (Snellen equivalent of 20/40 or worse). 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase III study to assess the efficacy and safety of DE-109 440 µg every 2 months in 
subjects with active, non-infectious uveitis of the posterior segment of the eye (NIU-PS). The 
12-month study consists of a 6-month, randomized, double-masked, parallel design, sham-
controlled evaluation of DE-109 440 µg every 2 months followed by a 6-month, open-label 
period in which all subjects will receive DE-109 440 µg every 2 months.  
The study will begin with a 30 days screening period (Day -30 to Day -1) which will be followed 
by the 6-month, double-masked treatment period. In the double-masked period, approximately 
200 eligible subjects will be randomized in a 2:2:1 ratio to three arms: 
1. Test arm: Intravitreal injection of DE-109 440 µg in the study eye(s) every 2 months 
(Day 1, Month 2, and Month 4) (approximately 80 subjects). 
2. Control arm: Sham procedure administered to the study eye(s) every 2 months (Day 1, 
Month 2, and Month 4) (approximately 80 subjects). The sham procedure mimics an 
intravitreal injection without penetrating the eye (the blunt end of an empty syringe is 
pressed against an anesthetized eye).  
3. Dummy arm: Intravitreal injection of DE-109 at an undisclosed, fixed dose (within the 
range of 44 µg to 880 µg) in the study eye(s) every 2 months (Day 1, Month 2, and 
Month 4) (approximately 40 subjects). This study arm (which has the same route of 
administration and frequency as the test arm) is included in the study to help ensure 
masking of treatment assignments. The dose used in this arm will be chosen from a range 
of DE-109 doses (44 µg to 880 µg) previously demonstrated to have an acceptable safety 
profile. The dose in this arm will not vary between participating sites or subjects 
randomized to this arm. 
The study objectives and endpoints are provided in Section 3.  The hypothesis of the double-
masked period is that the test arm (DE-109 440 µg dose every 2 months) will demonstrate 
superior efficacy versus the sham control arm. To preserve the masking of treatment 
assignments, there will be separate, unmasked and masked investigators (and designated staff) 
during the double-masked period. At visits at which IP is being administered, the unmasked 
investigator (and designated staff) will administer the IP (DE-109 intravitreal injection and sham 
procedure) and conduct the post-administration assessments; the masked investigator (and 
designated staff) will conduct the assessments prior to IP administration.  
Open-label period: Subjects completing the Month 6 pre-dose evaluations (the final evaluations 
of the double-masked period) will begin the open-label period of the study in which all subjects 
will receive intravitreal injection of DE-109 440 µg in the study eye(s) every 2 months for an 
additional 6 months of dosing (i.e., IP injections at Month 6, Month 8, and Month 10 with a final 
follow-up evaluation at Month 12). The same study eye(s) treated during the double-masked 
period will be treated during the open-label period. The open-label period of the study will allow 
evaluation of the long-term (> 6 months and up to one year) efficacy and safety of DE-109 
440 µg every 2 months in subjects with NIU-PS. 
 


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Study Population: 
For study eligibility, active uveitis is defined as having a vitreous haze (VH) score of at least 
1.5+ based on the modified SUN scale. If anterior segment inflammation is present, it must be 
less severe than the posterior component. Subjects receiving systemic (oral) corticosteroid 
therapy will be eligible to enroll in the study; these subjects will be required to have received a 
stable prednisone-equivalent dose between ≥15 mg/day and ≤40 mg/day that has remained stable 
for at least 1week (7 days) prior to and including on Day 1. Similarly, subjects receiving topical 
corticosteroid eye drops (other than difluprednate ophthalmic emulsion), topical non-steroidal 
anti-inflammatory eye drops, or certain immunosuppressants will be eligible and will be required 
to have received a stable dose/frequency of the therapy for a specified duration prior to Day 1 
(inclusion criteria Section 5.1, #6 and #8; exclusion criteria Section 5.2, #14). 
If both of an eligible subject’s eyes meet all eligibility criteria, both eyes can be randomized into 
the study (i.e., both eyes can be study eyes) and will be assigned to the same treatment arm. The 
investigator will determine whether both eyes are eligible for randomization into the study. 
Additional guidance regarding the enrollment of both or one of two eligible eyes is provided in 
Section 5. The study randomization will include stratification by number of eyes enrolled (one 
eye or two eyes) as well as baseline systemic (oral) corticorsteroid use (yes/no) and region (US 
or non-US). There will be separate drug supplies, records, and assessments for each study eye. 
If a fellow eye (non-study eye of a subject in the study) has uveitis at baseline or develops active 
uveitis during the study, the investigator should treat the eye with standard of care local 
therapies; systemically administered therapies should not be used to treat the fellow eye unless 
deemed to be medically necessary. DE-109 may not be administered to a fellow eye.  
Overview of Study Assessments: 
Study assessments will include fundus photography (FP), slit-lamp biomicroscopy, indirect 
ophthalmoscopy, optical coherence tomography (OCT), intraocular pressure (IOP), best-
corrected visual acuity (BCVA), fluorescein angiography (FA), the National Eye Institute Visual 
Functioning Questionnaire - 25 (VFQ-25), assessment of adverse events, laboratory tests (serum 
chemistry, hematology, and urinalysis), physical examination, vital signs, and pregnancy testing 
(serum and urine pregnancy tests for women of childbearing potential).  
Tapering of Systemic (Oral) Corticosteroid:  
Starting on Day 1, subjects receiving systemic (oral) corticosteroids at a stable prednisolone-
equivalent dose between ≥15 mg/day and ≤40 mg/day will taper over a maximum of 8 weeks to 
a prednisolone-equivalent dose of 0 mg/day according to the tapering regimen described in 
Section 6.5.3 (the dose of corticosteroid must remain stable for 1 week [7 days] prior to and 
including on Day 1). Corticosteroid tapering success with resolution of VH will be assessed in 
these subjects. The study randomization will include stratification by baseline systemic (oral) 
corticosteroid use (yes/no) as well as the number of eyes enrolled (one eye or two eyes) and 
region (US or non-US).  
 
 
 


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Protocol-Specified Rescue Therapy Criteria: 
Rescue therapy is defined as any treatment that would have a therapeutic effect on NIU-PS 
(detailed definition in Section 6.5.6). Rescue therapy is prohibited during the study unless there 
is worsening of uveitis as demonstrated by one or more of the following three rescue criteria:  
1. Worsening of uveitis in the study eye as indicated by at least a 2-step increase in VH 
score (i.e., 0 to ≥ 2+, 0.5+ to ≥ 3+, 1+ to ≥ 3+, 1.5+ to ≥ 4+, or 2+ to ≥ 4+)  as compared 
to the baseline (Day 1) VH score or best achieved VH score post baseline. 
2. Severe deterioration of vision in the study eye due to worsening of uveitis that is 
indicated by at least doubling of the visual angle (BCVA loss of 3 or more lines 
[≥15 ETDRS letters]) as compared to baseline (Day 1) BCVA. 
3. New or worsening retinal or choroidal uveitic lesion(s) in the study eye determined by 
clinical examination, as compared to baseline. 
When deemed medically necessary, rescue therapy may be administered at the discretion of the 
investigator, even if none of the protocol-specified rescue criteria noted above are satisfied. The 
investigator should contact the medical monitor to discuss the rescue treatment plan prior to the 
administration of rescue therapy. If the investigator is unable to reach the medical monitor, 
rescue treatment should be administered per the investigator’s clinical judgment and the medical 
monitor should be notified as soon as possible to discuss future on-study treatment plans for the 
subject. 
Interim Analyses, Primary Analysis, and Analysis of Open-Label Period: 
An interim analysis is planned when the first 100 subjects complete their Month 5 Visit.  There 
are two goals for this interim analysis (1) to assess for futility; and (2) to re-assess the sample 
size. Sample size re-assessment will be performed with the “promising zone” approach as 
follows (Mehta et al., 2011). If the conditional power at the interim analysis is between 50% and 
80%, the suggested sample size increase may be up to 100 subjects (i.e., 50% of the original 
sample size). If, on the other hand, the conditional power is > 80% or < 50%, no change to the 
sample size will take place. If the conditional power is <30%, then the Data Monitoring 
Committee (DMC) would recommend stopping the trial due to futility.  The DMC could 
recommend stopping the trial due to safety concerns at any of the DMC meetings and the interim 
analysis. An independent statistical and programming team will be used to perform this interim 
analysis of unmasked data and the DMC will review the results and make recommendations 
based on the findings. The planned interim analysis will be specified in greater detail in the SAP 
and in the DMC charter. 
The primary analysis of this study is the analysis of the data from the 6-month, double-masked 
period. These data will be quality-checked, soft-locked, and the primary analysis will be 
conducted after all subjects have completed the Month 6 visit or prematurely discontinued from 
the study prior to Month 6. An interim clinical study report will be written documenting the 
primary analysis results.  
Analysis of the open-label period of the study will be performed after the end of the study and 
documented in the final clinical study report.  
 


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Data Monitoring Committee: 
An independent data monitoring committee (DMC) whose members will not be participating in 
the LUMINA study conduct will serve as an advisory board to the Santen senior management 
team. The DMC will periodically review and make recommendations based on interim data; 
unmasked data will only be reviewed in closed DMC sessions without participation of Santen 
personnel. The organization, responsibilities, and procedures of the DMC will be specified in a 
governing charter.  
4.2. 
Scientific Rationale for Study Design 
The double-masked, randomized, parallel design of the 6-month, comparative period of this 
study is a recognized standard in the evaluation of experimental drug therapies. A subsequent 
single-arm, open-label period, as used in this study, is also a frequently chosen strategy to allow 
evaluation of longer-term efficacy and safety of an experimental drug regimen without requiring 
long-term treatment with a placebo/sham control.  
Given the potential risks associated with intravitreal injections, a sham administration procedure 
is used as a control during the study’s double-masked period rather than an intravitreal injection 
of placebo medication. Sham administration has been routinely used as a control arm in Phase III 
studies of other intravitreally administered therapies for ocular diseases, including uveitis. To 
preserve the masking of the investigator conducting the study assessments, a separate, unmasked 
investigator (and designated staff) will administer the IP (intravitreal injection of DE-109 or 
sham procedure) during the double-masked period. Inclusion of an additional arm (the dummy 
arm), in which subjects receive intravitreal injections of DE-109 at a single, undisclosed fixed 
dose every 2 months, will help to ensure masking in this sham-controlled study. The dose in this 
arm will not vary between participating sites or subjects randomized to this arm. 
Vitreous haze has been previously used as a primary efficacy endpoint in the clinical 
development of other medicinal products for uveitis. Vitreous haze (VH) is a descriptive term for 
the obscuration of fundus details by vitreous cells and protein exudation and was selected as the 
primary efficacy measure because it is strongly linked to inflammation. An assessment of the 
amount of haze is used as a surrogate marker for the degree of inflammation. A six-step scale of 
VH was created at the National Eye Institute in 1985 (Nussenblatt et al., 1985). This scale was 
approved by the Standardization of Uveitis Nomenclature (SUN) Working Group in 2005 as an 
acceptable method of grading VH in clinical research (Sun Working, 2005). 
The primary efficacy endpoint is defined as a VH score of 0 (resolution of inflammation) at 
Month 5; a VH score of 0 at Month 3, composite score at Month 3 and at Month 5 are key 
secondary efficacy endpoints. Month 5 (one month after the Month 4 injection) and Month 3 
(one month after the Month 2 injection) were selected as pre-specified endpoints for evaluating 
VH based on tissue distribution studies which demonstrated that peak levels of sirolimus are 
maintained at the target tissue for up to two months after intravitreal injection of DE-109.  
Secondary efficacy assessments include benefit as measured by the ability to taper from 
corticosteroids and achieve resolution of VH, which is evaluated in the subgroup of subjects 
receiving systemic (oral) corticosteroids at baseline. Accordingly, to help ensure balance across 
the treatment arms within this subgroup, the study randomization will be stratified by subject’s 


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systemic (oral) corticosteroid use at baseline (yes/no) as well as the number of eyes enrolled (one 
eye or two eyes) and region (US or non-US).  
In this study which includes a sham control during the double-masked period, rescue therapy is 
allowed for subjects who experience worsening of disease or vision per protocol-specified 
criteria, or at the investigator’s judgement. In the analysis of VH endpoints including the primary 
endpoint, the use of rescue therapy prior to the evaluation of a VH endpoint will be accounted for 
by considering the subject to be a non-responder.  
An independent Data Monitoring Committee (DMC) will periodically review unmasked 
aggregated and individual-level data during the conduct of the trial to help ensure safety and data 
integrity. An independent statistical and programming team will be used to perform these interim 
analyses of unmasked data.  
Use of the 6-month, single-arm, open-label period after completion of the 6-month double-
masked, controlled period allows the evaluation of the efficacy and safety of intravitreal injection 
of DE-109 440 µg every 2 months for longer duration than appropriate for a placebo or sham 
control.  
4.3. 
Justification for Dose 
The first evidence of the favorable benefit-risk profile of intravitreal injection of sirolimus in 
treating non-infectious uveitis was provided by the SAVE study (Ibrahim et al., 2015; Nguyen et 
al., 2013). In SAVE, 30 subjects with active or quiescent non-infectious uveitis were randomized 
to receive intravitreal or subconjunctival injections of sirolimus every 60 days through day 120 
and at dosing intervals ≥ 2 months from month 6 up to month 12. The SAVE study indicated that 
local administration of sirolimus, including an intravitreal dose of 352 µg every 60 days, was 
generally well tolerated and showed bioactivity in reducing vitreous haze, in improving visual 
acuity, and in decreasing the need for systemic corticosteroids.  
In the two Phase III clinical trials conducted previously by Santen (SAKURA 1 and SAKURA 
2), the efficacy and safety of three doses of DE-109 (44 μg, 440 μg, and 880 μg) administered 
every 2 months were evaluated for the treatment of NIU-PS. The primary efficacy endpoint 
evaluation was at Month 5. A total of 590 randomized, treated study eyes (590 subject IDs, 
589 subjects) received at least one injection of DE-109. The 440 μg dose of DE-109 
(administered to a total of 208 study eyes) demonstrated the optimal benefit-risk profile. The  
6-month, double-masked period of Phase III study LUMINA is being conducted to confirm the 
efficacy and safety of DE-109 440 µg administered every 2 months when compared to a sham 
control.  
4.4. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed all periods of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities 
(Section 1.3). The end of the study is defined as the date of the last visit of the last subject in the 
study.  


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5. 
STUDY POPULATION 
The study will be conducted at up to approximately 100 investigative sites globally.  
The study inclusion and exclusion criteria are specified below. Prospective approval of protocol 
deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, 
will not be permitted.  
Guidance regarding enrollment of both eyes:  
If both of an eligible subject’s eyes meet all eligibility criteria, both eyes can be randomized into 
the study (i.e., both eyes can be study eyes). The investigator will determine whether to enroll 
both eyes into the study after eligibility has been confirmed.  
 Both eyes eligible, enrolling both of the subject’s eyes:   
 Both eyes should be enrolled on a single Day 1 (Baseline) visit.  
 The IWRS will assign both eyes to the same treatment arm.  
 There will be separate drug supplies, records, and assessments for each study eye.  
 Both eyes eligible, enrolling only one of the subject’s two eligible eyes:   
 The eye with the higher Day 1 (Baseline) VH score should be enrolled.  
 If the VH scores are the same, the right eye should be enrolled.  
5.1. 
Inclusion Criteria 
1. Ability to give informed consent and attend all study visits. 
2. Males or females of at least 18 years of age. 
3. Have diagnosis of active uveitis of the posterior segment determined by the investigator 
to be non-infectious based on the subject’s medical history, history of present illness, 
ocular examination, review of systems, physical examination, and any relevant, pertinent 
laboratory evaluations. If anterior segment inflammation is present, it must be less severe 
than the posterior component.  
4. Have active uveitis at the Day 1 visit defined as a ≥ 1.5+ VH score (modified SUN scale) 
in the study eye(s), as assessed by the investigator and confirmed by a central reading 
center. 
5. Have a BCVA ≥ 20 ETDRS letters (20/400 Snellen equivalent or better) and 
≤ 75 ETDRS letters (20/32 Snellen equivalent or worse) in the study eye(s) at the Day 1 
visit. 
6. Subjects being treated with one of the following: methotrexate, azathioprine and 
mycophenolate mofetil (or an equivalent drug, e.g., mycophenolic acid) may be enrolled 
if the dose has remained stable for at least 30 days prior to Day 1 and is anticipated to 
remain stable until the end of the trial. Subject that satisfy this Inclusion criteria may not 
be treated with any other systemic immunosuppressant therapy and consequently cannot 
also satisfy the criteria described in Inclusion criteria #7. 


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7. Subjects being treated with systemic (oral) corticosteroids must have received a stable 
oral prednisone-equivalent dose between ≥15 mg/day and ≤40 mg/day that has remained 
stable for at least 1 week (7 days) prior to and including on Day 1. These subjects will 
comprise the Intent-to-Taper population and will be required to taper from oral 
corticosteroids starting on Day 1. Subject that satisfy this Inclusion criteria may not be 
treated with any other systemic immunosuppressant therapy and consequently cannot also 
satisfy the criteria described in Inclusion criteria #6. 
8. Subjects being treated with topical corticosteroid eye drops (excluding difluprednate 
ophthalmic emulsion) or topical non-steroidal anti-inflammatory eye drops must have 
received stable dosing (same medication type and frequency of use) for at least 7 days 
prior to Day 1 in the study eye(s). Decreases and termination of dose are allowed during 
the study. 
9. Female subjects of childbearing potential must not be pregnant or breast-feeding, must 
have a negative serum pregnancy test at screening, and must be willing to undergo 
pregnancy tests throughout the study.  
10. Female subjects of childbearing potential and male subjects able to father children must 
(a) have (or have a partner who has) had a hysterectomy or vasectomy, (b) abstain from 
intercourse throughout the course of the study, or (c) agree to practice acceptable 
methods of contraception throughout the course of the study (i.e., intrauterine device, oral 
contraceptives, barrier method, or other contraception deemed adequate by the 
investigator).  
5.2. 
Exclusion Criteria 
Ocular Infections:  
1. Confirmed or suspected infectious uveitis in either eye. 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 and not latent. 
2. Ocular or periocular infection in either eye including (but not limited to). 
a. History of herpetic infection in the study eye(s) or adnexa.  
b. Presence of known active or inactive toxoplasmosis or toxoplasmosis scar in 
either eye. 
c. History of cytomegalovirus infection or clinical evidence of active 
cytomegalovirus infection at screening and/or Day 1.  
Ocular Conditions: 
3. Primary diagnosis of anterior uveitis in the study eye(s). 
4. The following ocular inflammatory conditions in the study eye(s): 
a. Ocular inflammation associated with Behcet’s Disease 
b. Serpiginous Choroiditis 
c. Punctate Inner Choroidopathy (PIC) 
d. Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE) 


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5. Pupillary dilation inadequate for quality stereoscopic fundus photography in the study 
eye(s). 
6. Media opacity (other than vitreous haze) that would limit clinical visualization or OCT 
evaluation in the study eye(s). 
7. Any existing lens opacity in the study eye(s) that, in the opinion of the investigator, 
could: 
a. require surgical intervention during the 5-month study period to prevent or treat 
visual loss, or, 
b. interfere with the grading of vitreous haze, or, 
c. preclude evaluation of the posterior pole via fundus photography or OCT 
assessment. 
8. Corneal opacity in the study eye(s) that would preclude reliable assessment of the 
posterior segment. 
9. Uncontrolled glaucoma in the study eye(s) on Day 1, evidenced by an intraocular 
pressure (IOP) > 21 mmHg while on medical therapy, or chronic hypotony  
(IOP < 6 mmHg). 
10. Any active ocular disease other than uveitis that could compromise vision in the study 
eye(s).  These include, but are not limited to: 
a. Diabetic retinopathy 
b. Wet age-related macular degeneration 
c. Myopic degeneration with active subfoveal choroidal neovascularization 
11. History of vitrectomy in the study eye(s). 
12. Presence of epiretinal membrane that according to investigator’s judgement is significant 
enough to limit improvement of macular edema. 
13. Any ocular condition in the study eye(s) that would prevent improvement in visual 
acuity.  
Concomitant Medications: 
14. Use of difluprednate ophthalmic emulsion eye drops in the study eye(s) within 7 days 
prior to Day 1. Difluprednate ophthalmic emulsion eye drops are prohibited throughout 
the duration of the study. 
15. Any of the following treatments prior to Day 1 or anticipated use of any of the following 
treatments to the study eye(s): 
a. Intravitreal injections of anti-vascular endothelial growth factors (bevacizumab, 
aflibercept, ranibizumab, pegaptanib, etc.) within 30 days of Day 1. 
b. Intravitreal or posterior subtenon steroids within 90 days of Day 1. 
16. Any implantable corticosteroid-eluting device (e.g. Ozurdex, Iluvien or equivalent, 
triamcinolone acetonide [TA] intravitreal implant) in the study eye(s) with the following 
exceptions: 
a. Ozurdex implanted at least 6 months prior to Day 1 will be allowed. 


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b. Fluocinolone acetonide implant (Iluvien, Retisert, Yutiq) implanted at least 3 
years prior to Day 1 will be allowed.  
17. Immunosuppressive therapy (e.g., cyclophosphamide, chlorambucil, tacrolimus or 
colchicine) within 30 days of Day 1, other than prednisone or equivalent or permitted 
immunosuppressants described in Inclusion Criteria #6.  
18. Treatment with a monoclonal antibody or any other biologic therapy (i.e. etanercept, 
tocilizumab, adalimumab, rituximab, etc.) within 90 days prior to Day 1.  
19. Use of topical ocular application of marijuana and marijuana derivatives including, but 
not limited to, cannabidiol topical eye drops.  
Surgical: 
20. Any intraocular surgery (excluding eyelid surgery and refractive laser surgery) in the 
study eye(s) within 90 days prior to Day 1.  
21. Capsulotomy in the study eye(s) within 30 days prior to Day 1. 
Malignancies: 
22. Clinically suspected or confirmed central nervous system or ocular lymphoma in either 
eye. 
23. Presence of any form of ocular malignancy in the either eye including choroidal 
melanoma. 
24. 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). 
Non-Ocular Conditions: 
25. Allergy or hypersensitivity to investigational product or other study related 
procedures/medications. 
26. Any recent systemic infection within 30 days of Day 1.  
27. Known to be immunocompromised. 
28. Active systemic sarcoidosis. Subjects with uveitis secondary to sarcoidosis will be 
eligible if either of the following conditions are met:  
a. Systemic sarcoidosis is not active and systemic immunosuppressive therapy has 
not been given in the last 6 months.  
b. Systemic sarcoidosis has remained inactive for at least 6 months and  the subject 
isbeing treated with permitted immunosuppressants as described in Inclusion 
Criteria #6. 
29. 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. 
30. Any uncontrolled systemic disease. 
Pregnancy: 
31. 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). 
 


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Participation in Other Clinical Trials: 
32. Participation in other investigational drug (oral or topical therapy) or device clinical trials 
within 30 days prior to Day 1 and/or participation in other investigational drug 
(intravitreal injection therapy) within 3 months or 5 half-lives (whichever is longer) prior 
to Day 1, or planning to participate in other investigational drug or device clinical trials 
during a time which would overlap with the duration of the study. This includes both 
ocular and non-ocular clinical trials. Exposure to investigational biologics should be 
discussed with medical monitor. 
In addition, the investigator or Santen medical monitor may declare a subject ineligible for any 
sound reason.  
5.3. 
Lifestyle Considerations 
5.3.1. 
Contraception Requirements 
There are no controlled data with the IP in human pregnancy. It is required that females of 
childbearing potential and male subjects able to father children abstain from intercourse or agree 
to practice acceptable methods of contraception throughout the course of the study (i.e., 
intrauterine device, oral contraceptives, barrier method, or other contraception deemed adequate 
by the investigator).  
5.3.2. 
Fasting Prior to Blood Draws for Hematology and Chemistry Laboratory Tests 
Requirements for fasting 8 hours prior to the blood draw for hematology and chemistry 
laboratory tests taken at visits is specified in the SoA (Table 3). 
5.4. 
Screen Failures and Rescreening 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to IP. The following screen failure information is required to 
ensure transparent reporting of screen failure subjects, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities: demography, screen failure details, eligibility criteria, and any SAEs 
reported during screening. The final study report will include screen failure information in 
support of these requirements.  
In this study, a subject who fails screening may be considered for rescreening in consultation 
with the Sponsor or its designee and providing that the subject undergoes re-consent. In no case 
will a subject be allowed to be rescreened more than once. If a subject is to be rescreened after 
failing screening, a new screening period will begin, and all study eligibility criteria will need to 
be re-assessed and confirmed prior to randomization into the study. Rescreened subjects will be 
assigned a new subject number.  


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6. 
STUDY INTERVENTION 
Study intervention is a general term that refers to any investigational intervention(s), marketed 
product(s), placebo, sham, or medical device(s) intended to be administered to a study subject 
according to a study protocol. In this protocol, the term Investigational Product (IP) is generally 
used to refer to the study interventions, which are the following three DE-109/sham regimens, 
one of which is randomly assigned to each subject’s study eye(s) during the double-masked 
period: (1) DE-109 440 µg administered by intravitreal injection every 2 months, (2) sham 
procedure administered every 2 months, and (3) dummy (DE-109 at an undisclosed fixed dose of 
44 µg to 880 µg) administered by intravitreal injection every 2 months (at the Day 1, Month 2, 
and Month 4 visits). During the open-label period, the IP received will be the same for all 
subjects: DE-109 440 µg administered by intravitreal injection every 2 months (at the Month 6, 
Month 8, and Month 10 visits).  
6.1. 
Investigational Product Administered, Formulation, Packaging, and 
Labelling 
Investigational product descriptions are provided in Table 5, including formulation, packaging, 
and labelling. 
Table 5: 
Investigational Product Descriptions 
Arm Abbreviated 
Name: 
Description 
DE-109: 
DE-109 440 µg 
every 2 months 
Sham: 
Sham procedure 
every 2 months 
Dummy: 
DE-109 at an undisclosed, 
fixed dose of 44 µg to 880 µg 
every 2 months 
Intervention Name 
DE-109 
Sham 
DE-109 
Investigational 
Medicinal Product 
Sirolimus intravitreal 
injection, 22 mg/mL 
Not applicable 
(empty vial) 
Sirolimus intravitreal injection, 
2.2 mg/mL to 44 mg/mL 
Type  
Drug  
Other 
Drug 
Use 
Experimental 
Sham comparator 
To help ensure masking of 
treatment assignments 
Dose Formulation 
Solution for injection 
Not applicable 
Solution for injection 
Unit Dose 
440 µg 
Not applicable 
44 µg to 880 µg 
Frequency of 
administration 
every 2 months 
every 2 months 
every 2 months 
Number of 
administrations 
during the 6-month 
double-masked 
period 
3 (Day 1, Month 2, 
Month 4) 
3 (Day 1, Month 2, 
Month 4) 
3 (Day 1, Month 2, Month 4) 


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Table 5: 
Investigational Product Descriptions (Continued) 
Arm Abbreviated 
Name: 
Description 
DE-109: 
DE-109 440 µg every 
2 months 
Sham: 
Sham procedure 
every 2 months 
Dummy: 
DE-109 at an undisclosed, 
fixed dose of 44 µg to 880 µg 
every 2 months 
Number of 
administrations 
during the 
subsequent, 6-
month open-label 
period 
During the open-label period, all subjects will receive DE-109 440 µg every  
2 months for a total of 3 administrations (Month 6, Month 8, Month 10).  
Route of 
Administration 
Intravitreal injection 
Not applicable 
Intravitreal injection 
Sourcing 
Provided centrally by 
the Sponsor or designee 
Provided centrally by 
the Sponsor or 
designee 
Provided centrally by the 
Sponsor or designee 
Packaging and 
Labeling 
DE-109 solution is 
filled (0.2 mL) in 2 mL 
Type 1 glass vial, with 
13 mm gray butyl 
stopper with B2-40 
coating, and sealed 
with 13 mm colored 
Flip-Off Truedge. One 
vial will be placed in a 
unit carton. The vial 
and unit carton labeling 
will include protocol 
number, kit number, 
and storage conditions. 
A sterile, single-use 
250 μL syringe custom 
marked at 20 µL as 
well as two needles 
(21G and 30G) will be 
placed in a carton and 
provided as a kit for 
injection use.  
The vial and carton for 
Sham is the same as  
DE-109 except no  
DE-109 solution is 
filled in the Sham vial. 
The empty vial and 
unit carton labeling 
will include protocol 
number, kit number, 
and storage 
conditions.  
The same kit including 
syringe and needles 
will be provided for 
Sham as for DE-109. 
(Note: The sham 
procedure mimics an 
intravitreal injection 
without penetrating 
the eye [the blunt end 
of an empty syringe is 
pressed against an 
anesthetized eye]).  
DE-109 solution is filled 
(0.2 mL) in 2 mL Type 1 
glass vial, with 13 mm gray 
butyl stopper with B2-40 
coating, and sealed with 
13 mm colored Flip-Off 
Truedge. One vial will be 
placed in a unit carton. The 
vial and unit carton labeling 
will include protocol number, 
kit number, and storage 
conditions.  
A sterile, single-use 250 μL 
syringe custom marked at 
20 µL as well as two needles 
(21G and 30G) will be placed 
in a carton and provided as a 
kit for injection use. 
 


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6.2. 
Investigational Product Storage, Preparation, Administration, 
Accountability, Handling, and Disposal 
Refer to the Investigational Product Manual for detailed instructions regarding receipt, handling, 
management, storage, administration, and return/disposal of IP, as well as information regarding 
other clinical supplies provided by Santen.  
6.2.1. 
Investigational Product Storage 
Investigational product will be received frozen and should remain frozen in a secure, locked, 
dark, temperature-controlled freezer at -20°C ± 5°C (with allowable temperature excursions up 
to -35°C). Investigational product must be stored with access limited to the authorized site staff 
until the time of use.  
6.2.2. 
Investigational Product Preparation 
On study visits during the double-masked period at which IP is administered (see SoA, Table 3), 
the unmasked investigator or designee will perform the IP preparation and administration. 
IP Preparation for Test Arm (DE-109 440 µg) and Dummy Arm (DE-109 at an undisclosed, 
fixed dose of 44 µg to 880 µg):  
The vial of IP (unique vial number is assigned to a subject’s specific study eye by IWRS) will be 
removed from the freezer and thawed by rotating the vial between the palms of the hands for a 
minimum of approximately 5 minutes, or by setting the vial at room temperature for a minimum 
of approximately 30 minutes. Care should be taken to protect the product from light. After the 
product is thawed, mix the product by gently inverting the vial a few times. Investigational 
product should be drawn into the provided single-use plastic syringe within 60 minutes after 
removing the vial from the freezer. Investigational product should be injected within 2 hours of 
being drawn up into the single-use syringe. 
DE-109 drug product is dispensed from a 2 mL vial. Each vial contains enough IP to inject one 
study eye. Each vial will be used one time only.  
A sterile, single-use 250 μL syringe custom marked at 20 µL as well as two needles (21G and 
30G) will be provided as a kit. Each dose of DE-109 should be administered within 2 hours of 
being drawn up into the single-use plastic syringe. 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. Attach a 21-gauge x 1 ½  inch needle to the syringe.  
Figure 2: 
          


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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. Replace the needle with a 30-gauge x 0.5 inch needle in preparation for the DE-109 
intravitreal injection.   
a. Ensure that the 30-gauge by 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 3). 
c. PLEASE ENSURE THAT THERE ARE NO AIR BUBBLES WITHIN THE 
SYRINGE OR THE NEEDLE HUB PRIOR TO INJECTION.   
Figure 3: 
 
IP Preparation for Control Arm (Sham):  
Removal and thawing procedures are the same for Sham as for DE-109. A syringe loading 
procedure similar to DE-109 should be performed; no drug product will be drawn up into the 
syringe.  
6.2.3. 
Investigational Product Administration 
During the double-masked period, the unmasked investigator will perform all IP administrations 
(DE-109 440 µg, Sham, and Dummy [an undisclosed, fixed dose of DE-109 in the range of  
44 µg to 880 µg]).  
The procedures for IP administration to a single study eye are shown in Table 6. Note that the 
subjects’ pupils will already have been dilated by the masked investigator/staff prior to the 
conduct of the pre IP administration assessments. Detailed guidance regarding IP administration, 
including administration to both eyes, is provided in the Investigational Product Manual.  


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Table 6: 
Investigational Product Administration Procedure 
Notes 
DE-109 440 µg and Dummy  
(an undisclosed, fixed DE-109 dose in the 
range of 44 µg to 880 µg) 
Sham 
Note: The unmasked investigator or designee should ensure that the subject’s pupils are dilated prior to 
IP administration. The use of sterile gloves and face mask by the unmasked study staff is 
recommended. 
 
1. Administer at least 1 drop of topical 
anesthetic (topical 0.5% proparacaine 
hydrochloride ophthalmic solution or an 
equivalent topical ophthalmic anesthetic is 
recommended. Adjunctive administration of 
subconjunctival anesthesia is permitted at the 
discretion of the unmasked Investigator. 
Same as DE-109 
 
2. Administer 5% povidone iodine to the study 
eye. 
Same as DE-109 
 
3. Use a sterile cotton-tipped applicator to 
remove excess fluid from the lower 
conjunctival sac. 
Same as DE-109 
Step #4 may 
be omitted per 
the unmasked 
investigator’s 
discretion. 
4. Take 2 sterile cotton tipped applicators and 
thoroughly soak with 0.5% proparacaine 
topical anesthetic eye drops or an equivalent 
topical ophthalmic anesthetic.  Place the 
soaked applicators, side by side, gently but 
firmly on the conjunctival surface at the area 
of the entry site described below in Step 10 
and hold in place for approximately 1 
minute.  
Same as DE-109 
 
5. Insert sterile eyelid speculum. 
Same as DE-109 
 
6. Place sterile eye drape over study eye. 
Same as DE-109 
 
7. Prior to starting the injection procedure,  
DE-109 should have been prepared as 
described in Section 6.2.2, with the 
appropriate dose of IP drawn into a 250 µL 
single-use plastic syringe. ENSURE THAT 
THERE ARE NO AIR BUBBLES IN THE 
SYRINGE OR NEEDLE HUB. 
Removal and thawing procedures 
are the same for Sham as for  
DE-109 (Section 6.2.2). A syringe 
loading procedure similar to  
DE-109 should be performed; no 
drug product will be drawn up 
into the syringe. 
 
8. If the subject is phakic, the entry site is 
recommended to be 3.5 mm to 4.0 mm 
peripheral to the 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 limbus. An inferior 
injection site is recommended. A caliper may 
be used to identify the needle entry site.  The 
intravitreal injection site may be modified at 
the unmasked investigator’s discretion. 
Not applicable 


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Table 6: 
Investigational Product Administration Procedure (Continued) 
Notes 
DE-109 440 µg and Dummy  
(DE-109 44 µg to 880 µg) 
Sham 
 
9. Insert the needle perpendicular to the eye 
wall at the location specified in Step 10.    
The needle shaft should be inserted deep 
enough into the eye so as to ensure that the 
study drug enters into the vitreous body.  
Press the blunt end of the empty 
syringe against the anesthetized 
eye and hold for approximately  
10 seconds.  
 
10. Very slowly, inject the entire IP 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. 
 
11. Briefly apply pressure for approximately 1 
minute to the needle entry site with a sterile 
cotton tipped applicator. 
Briefly apply pressure for 
approximately 1 minute to the 
recommended entry site (as 
described in this step for DE-109) 
with a sterile cotton tipped 
applicator. 
 
12. Remove the eyelid speculum. 
Same as DE-109 
 
13. Patch the study eye at the unmasked 
investigator’s discretion. 
Same as DE-109 
Immediately after each IP administration, the unmasked investigator or designee will conduct a safety 
check (finger count, hand motion, and light perception).  
Prednisolone acetate eye drops are to be started after each IP administration and continued for 8 days, 
according to the following schedule:  4 times per day for 4 days (including the day of IP 
administration) followed by 2 times per day for 4 days, then stop. 
6.2.4. 
Investigational Product Accountability 
The investigator or designee is responsible for ensuring that an inventory is conducted upon 
receipt of the clinical supplies. The form documenting receipt of clinical supplies should be 
completed, signed, and returned as directed. A copy must be maintained at the site for the 
investigator’s records.   
The investigator or designee is responsible for ensuring that a current record is kept of the 
inventory and dispensing of all IP.  This record will be made available to the study monitor (or 
designee) to account for all clinical supplies. Any significant discrepancy and/or deficiency must 
be recorded with an explanation. 
All supplies sent to the investigator site must be accounted for and in no case will IP be used in 
any unauthorized situation. It is the responsibility of the investigator to return any used and 
unused supplies to the Santen (or designee) at the end of the study. 
6.2.5. 
Investigational Product Handling and Disposal 
All used/un-used vials of IP supplied by Santen must be fully accounted for by the study 
monitor. Accountability will be documented by use of drug accountability forms. During the 


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study as directed by Santen and/or when the trial is completed, used/un-used vials will be 
returned to Santen or designee, or destroyed at the site at the direction of Santen.  
6.3. 
Measures to Minimize Bias: Randomization and Masking 
For the double-masked period, eligible subjects (total sample size of approximately 200 subjects) 
will be randomized in a 2:2:1 ratio to the DE-109 440 µg arm (80 subjects), the Sham arm  
(80 subjects), and the Dummy arm (40 subjects). The randomization will be stratified by baseline 
systemic (oral) corticosteroid use (yes /no), number of subject’s enrolled eyes (1 eye/2 eyes), and 
region (US/non-US). A separate permuted-block randomization with a fixed block size will be 
generated for each stratum. A computer algorithm for random number generation will be used to 
generate the randomization and an IWRS will be used to administer the randomized assignment 
of subject eyes to treatment arms. Subjects with both eyes enrolled will be assigned to the same 
treatment arm in both eyes. 
The 6-month, comparative period of the study is double-masked and sham-controlled. The sham 
procedure mimics an intravitreal injection (the blunt end of an empty syringe is pressed against 
an anesthetized eye). To retain the masking of the investigator, a separate, unmasked investigator 
will be responsible for administering the IP (DE-109 intravitreal injections and sham). The 
masked investigator will conduct assessments prior to IP administration; the unmasked 
investigator will administer the IP and conduct the post-administration assessments. Thus, the 
treatment assignments will be masked to Santen (except Clinical Supply and Quality Assurance 
personnel, as required), study subjects, and masked investigators.  
The dummy arm is included in the double-masked period of the study to help ensure masking of 
treatment assignment given the use of a sham control. All subjects randomized to the dummy 
arm receive intravitreal injections of DE-109 every 2 months at an undisclosed fixed dose of 
44 µg to 880 µg (doses of DE-109 in this range have previously been shown to have an 
acceptable safety profile). The dose in this arm will not vary between participating sites or 
subjects randomized to this arm. Except for a limited number of Santen employees in Clinical 
Supply and Quality Assurance as required, the dose of DE-109 in the dummy arm will remain 
undisclosed to investigators, CROs, and Santen employees involved in the study conduct.  
Separate IP supplies will be assigned to each study eye. At each visit at which IP is to be 
administered, if one eye is enrolled, the IWRS will assign one specific IP vial for administration 
to the subject’s study eye; if both eyes are enrolled, the IWRS will assign one specific IP vial for 
administration to the subject’s left study eye and one specific IP vial for administration to the 
subject’s right study eye. 
A central Reading Center will be used for the fluorescein angiography, fundus photography, and 
OCT assessments. All central readers will be masked to each subject’s IP assignment.  
In case of an emergency, the investigator has the sole responsibility for determining if 
unmasking of a subject’s treatment assignment is warranted. If the investigator decides that 
unmasking is warranted, the investigator should make every effort to contact the medical monitor 
(Table 1) prior to unmasking a subject’s treatment assignment unless this could delay emergency 
treatment of the subject. Santen must be notified as soon as possible if the IP masking of a 
subject is broken. The date, time, and reason for the unmasking must be recorded in the source 


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documents. For unmasking, the randomized treatment assignment of a subject can be obtained 
from the IWRS by designated individuals following a specific IWRS unmasking procedure.  
An independent statistical and programming team will be used to perform the planned interim 
analysis of unmasked data and the Data Monitoring Committee (DMC) will review the results 
and make recommendations based on the findings. To unmask the data for the analysis, a 
designee from the independent statistical and programming team will obtain the randomization 
codes directly from the external randomizer, without involvement of Santen. Review of 
unmasked data by the DMC will only occur in closed DMC sessions without participation of 
Santen personnel. The planned interim analysis will be specified in greater detail in the SAP and 
in the DMC charter.  
6.4. 
Investigational Product Compliance 
Compliance with the dosing schedule specified in this protocol is critical to obtain reliable 
efficacy and safety data. The administration of each dose of IP to each subject’s study eye(s) will 
be documented by the investigator/staff and recorded in the electronic Case Report Forms 
(eCRFs). The study monitors will verify eCRFs and other pertinent data to confirm each subject 
is attending visits, undergoing procedures, and receiving treatment with IP per protocol. 
6.5. 
Concomitant Therapy 
6.5.1. 
Collection of Prior and Concomitant Medication Information 
At Screening, information on prior and concomitant medications taken within the previous 
90 days will be collected. At each study visit, subjects should be questioned concerning any new 
medications or changes in their current medications since their previous study visit and the 
information should be recorded in the eCRF. Medications given specifically for antiseptic 
preparation of the study eye should be recorded as concomitant medications.  
For all medications, the generic name, indication, route of administration, frequency, dose, start 
date, and stop date (if applicable) will be collected; for combination products, the brand name 
will also be documented.  
6.5.2. 
Subjects with Glaucoma: Continuation of Ocular Hypotensive Medication 
Subjects with glaucoma are permitted to continue their prescribed ocular hypotensive medication 
during the study. Any required changes to prescribed ocular hypotensive medications and/or 
discontinuation of ocular hypotensive medications are allowed during the study, per the 
investigator’s judgement. 
6.5.3. 
Tapering of Systemic Corticosteroid Therapy 
For study eligibility, subjects receiving systemic (oral) corticosteroid therapy will be required to 
titrate the dose as needed such that they remain on a stable oral prednisone-equivalent dose 
between ≥15 mg/day and ≤40 mg/day that has remained stable for at least 1 week (7 days) prior 
to and including Day 1. The Intent-to-Taper population is defined as those subjects who are 
receiving oral corticosteroid therapy on Day 1. Starting on Day 1, the corticosteroid dose of these 
subjects should be reduced weekly over a maximum of 8 weeks to discontinuation (0 mg/day) 
according to the following tapering schedule: 


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 Reduce by 10 mg weekly until a dose of 20 mg is reached 
 Then reduce by 5 mg weekly until a dose of 10 mg is reached 
 Then reduce by 2.5 mg weekly until reaching 0 mg 
If the above-suggested tapering scheme needs to be amended significantly, the investigator must 
consult with the study medical monitor. 
6.5.4. 
Continuation of Stable Doses of Topical Ocular Corticosteroid Medication, 
Topical Ocular Non-Steroidal Anti-Inflammatory Medication, or Selected 
Immunosuppressants 
Use of difluprednate ophthalmic emulsion eye drops in the study eye(s) within 7 days prior to 
Day 1 is prohibited. Difluprednate ophthalmic emulsion eye drops are prohibited throughout the 
duration of the study. Subjects being treated with other topical corticosteroid eye drops or with 
topical non-steroidal anti-inflammatory eye drops must have received stable dosing (same 
medication type and frequency of use) for at least 7 days prior to Day 1 in order to be eligible for 
enrollment in the study. These subjects will be allowed to continue the therapy at stable dosing 
during the study (same medication type and frequency of use). Decreases and termination of 
dose are allowed during the study. Similarly, subjects being treated with one of the following: 
methotrexate, azathioprine, or mycophenolate mofetil must have received a stable dose for at 
least 30 days prior to Day 1 with the expectation that the dose will remain stable until the end of 
the trial. These subjects should continue the therapy at a stable dose during the study.  
6.5.5. 
Protocol-Specified Medications Pre and Post Investigational Product 
Administration 
Below are medications to be administered pre and post IP administration.  
Pre IP administration: 
 Pupil dilation: 1% Mydriacyl and 2.5% phenylephrine or equivalent 
 Ocular antisepsis: 5% povidone iodine (also see Table 6, IP administration 
procedure) 
 Topical anesthetic: recommended 0.5% proparacaine hydrochloride or equivalent 
(also see Table 6, IP administration procedure).  
Adjunctive administration of subconjunctival anesthesia is permitted at the discretion of the 
unmasked Investigator. 
Post IP administration: 
 Topical corticosteroid: Prednisolone acetate eye drops are to be started after each IP 
administration and continued for 8 days, according to the following schedule: 4 times 
per day for 4 days (including the day of IP administration) followed by 2 times per 
day for 4 days, then stop. Subjects that are already receiving a stable dose of 
prednisolone acetate eye drops as concomitant therapy should contact the medical 
monitor prior to IP administration to discuss adjusting of the dosing frequency.   
 


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6.5.6. 
Rescue Therapy 
Rescue therapy is defined as any treatment that would have a therapeutic effect on NIU-PS, other 
than intravitreal DE-109. Other protocol-allowed or specified medications that are not considered 
rescue therapy are listed in Section 6.5.7. 
The following are examples of rescue therapies: 
 Systemic corticosteroid therapy (except as described in Section 6.5.7) 
 New systemic treatment with an immunosuppressant agent 
 Increase in dose of ongoing therapy with methotrexate, azathioprine, or 
mycophenolate mofetil (see inclusion criteria Section 5.1, #6) 
 Anti-vascular endothelial growth factor therapy (anti-VEGF) 
 New or increased dose/frequency of topical ocular corticosteroid to the study eye (see 
inclusion criteria Section 5.1, #8) 
 New or increased dose/frequency of topical ocular nonsteroidal anti-inflammatory 
agent to the study eye (see inclusion criteria Section 5.1, #8) 
 Ocular or periocular corticosteroid injection to the study eye 
 Use of difluprednate ophthalmic emulsion eye drops in the study eye 
 Vitrectomy in the study eye 
Because rescue therapies such as those noted above may or will have a therapeutic effect on the 
uveitis in the posterior segment, they are prohibited unless worsening of uveitis in the study eye 
is observed satisfying one or more of the following three rescue criteria:  
1. Worsening of uveitis in the study eye as indicated by at least a 2-step increase in VH 
score (i.e., 0 to ≥ 2+, 0.5+ to ≥ 3+, 1+ to ≥ 3+, 1.5+ to ≥ 4+, or 2+ to ≥ 4+)  as compared 
to the baseline (Day 1) VH score or the best achieved VH score post baseline. 
2. Severe deterioration of vision in the study eye due to worsening of uveitis that is 
indicated by at least doubling of the visual angle (BCVA loss of 3 or more lines 
[≥15 ETDRS letters]) as compared to baseline (Day 1) BCVA. 
3. New or worsening retinal or choroidal uveitic lesion(s) in the study eye determined by 
clinical examination, as compared to baseline. 
When deemed medically necessary, rescue therapy may be administered at the discretion of the 
investigator, even if none of the protocol-specified rescue criteria noted above are satisfied. The 
investigator should contact the study medical monitor to discuss the rescue treatment plan prior 
to the administration of rescue therapy. If the investigator is unable to reach the medical monitor, 
rescue treatment should be administered per the investigator’s clinical judgment and the medical 
monitor should be notified as soon as possible to discuss future on-study treatment plans for the 
subject.  
If both eyes are enrolled and rescue therapy for one of the two enrolled study eyes is required, 
local rather than systemic therapy is encouraged, if appropriate, because systemic therapies will 
affect the response in the other study eye. 


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If rescue therapy is administered, the generic name, indication, route of administration, 
frequency, dose, start date, and stop date (if applicable) will be recorded in the eCRF.  
Satisfaction of any of the protocol-specified rescue criteria noted above also satisfies the 
definition of an ESI of clinically significant new or worsening of uveitis, requiring reporting 
within 24 hours of knowledge of the event as described in Section 8.2.13. 
6.5.7. 
Protocol-Allowed or Specified Medications not Considered Rescue Therapy 
Protocol-allowed or specified medications NOT considered rescue therapy are as follows:  
 Investigational product (DE-109, Sham, Dummy). 
 Oral corticosteroids administered in accordance with the protocol-specified tapering 
schedule (Section 6.5.3).  
 Ongoing stable dose/frequency of corticosteroid eye drops is permitted, non-steroidal 
anti-inflammatory eye drops, methotrexate, azathioprine, or mycophenolate mofetil, 
as allowed by the protocol.  
 The protocol-specified administration of prednisolone acetate eye drops following 
each IP administration.  
6.5.8. 
Prohibited Concomitant Medications or Treatments 
Any treatment that would have a therapeutic effect on the uveitis in the posterior segment is 
prohibited, as described in Section 6.5.6.  
Refer to the inclusion and exclusion criteria (Section 5.1 and Section 5.2) for other specific 
prohibited concomitant medications or treatments.  
6.6. 
Dose Modification 
In this study, the IP dose/regimen is assigned by randomization. Dose titration or modification is 
not allowed. Rescue therapy is allowed for worsening of uveitis as described in Section 6.5.6.  
6.7. 
Intervention after the End of the Study 
No subsequent intervention is currently planned for subjects completing this 12-month study.  


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7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL FROM STUDY 
7.1. 
Discontinuation of Investigational Product 
Subjects may be discontinued from IP administration for adverse events, non-compliance with 
study drug, protocol deviation, lack of efficacy, withdrawal by subject, lost to follow-up, study 
termination, or other reasons. The investigator or Santen medical monitor may discontinue a 
subject from further IP administration for reasons related to the best interest of the subject. If a 
subject is discontinued from IP administration at any point during the study, he or she will be 
encouraged to remain in the study and attend all scheduled visits for safety follow up, including 
ocular procedures other than IP administration, through Month 12. If a subject decides not to 
enter into the open-label period, the investigator should discuss the option of early termination 
with the medical monitor. Subjects that have received at least one open-label treatment are 
encouraged to remain in the study and attend all scheduled visits for safety follow up through 
Month 12. 
7.2. 
Subject Early Discontinuation/Withdrawal from the Study 
A subject may withdraw from the study at any time at his/her own request, or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. At the time of discontinuing from the 
study, if possible, an early termination visit will be conducted to collect the data as shown in the 
SoA (Table 3); the subject will be permanently discontinued both from the IP and from the study 
at that time. 
If the subject withdraws consent for disclosure of future information, Santen may retain and 
continue to use any data collected before such a withdrawal of consent. If a subject withdraws 
from the study, he/she may request destruction of any samples taken and not tested, and the 
investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. The following actions must be taken if a 
subject fails to return to the clinic for a required study visit: 
 The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
 Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 


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 Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or discontinuation of the study is handled as indicated in 
Section 10.1.9. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Table 3). Protocol waivers or 
exemptions from study inclusion/exclusion criteria are not allowed. Adherence to the study 
design requirements, including those specified in the SoA, is essential and required for study 
conduct.  
8.1. 
Visit Details and Efficacy Assessments 
8.1.1. 
Visit Details 
The SoA (Table 3) provides a high-level overview of the visits. The sections below provide visit 
guidance/details by visit. 
8.1.2. 
Screening Visit, Day -30 to Day -1 
Subjects taking oral corticosteroids: To be randomized into the study, subjects being treated 
with systemic (oral) corticosteroids must be on a stable oral prednisone-equivalent dose between 
≥15 mg/day and ≤40 mg/day for at least 1 week (7 days) prior to and including on Day 1. 
Tapering of oral corticosteroids will begin on Day 1 according to the tapering regimen described 
in Section 6.5.3  
Visit details: 
 Explain the purpose and details of the study to the subject and obtain written 
informed consent prior to performing any study-related procedures.  
 Obtain the subject’s demographic information, medical and surgical history 
(including history of NIU-PS), current ocular and systemic conditions, and 
medication history (including systemic corticosteroid status).  
 Perform physical examination. 
 Record vital signs. 
 If the subject is a woman of child-bearing potential, collect blood for serum 
pregnancy test. 
 Collect fasting or non-fasting blood for serum chemistry and hematology tests for 
laboratory analysis as described in the SoA (Table 3). 
 Obtain urine sample for urinalysis. 
 Assess BCVA using ETDRS charts. 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography for submission to reading center. 
 Assess for adverse events (occurring after the signing of the informed consent). 


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 Record concomitant medications (including systemic corticosteroid medication 
status).  
 Review the inclusion and exclusion criteria. Do not continue with screening 
procedures in any subject who does not meet the screening eligibility 
requirements.  
 Enter the subject information into the EDC system (Medidata) for the Screening visit 
to obtain the Subject ID.  
Rescreening after screen failure: Depending on the reason(s) for screen failure, rescreening of 
a subject may be allowed; see Section 5.4.  
8.1.3. 
Double-Masked Treatment Period, Day 1 
At all study visits at which masked IP is administered:   
 The masked investigator or designee performs assessments in both eyes that are prior 
to IP administration.  
 The unmasked investigator or designee performs IP administration (DE-109 
intravitreal injection / sham procedure), the safety check immediately after IP 
administration (finger count, hand motion, and light perception), and the post-
administration assessments.  
Visit details:  
Verify that central laboratory results from blood and urine collected at screening have been 
obtained and reviewed.  
Perform the following assessments prior to randomization and prior to administration of IP: 
 If the subject is a woman of child-bearing potential, conduct urine pregnancy test.  
A positive pregnancy test requires exclusion from the study. 
 Assess BCVA using ETDRS charts to confirm study eye(s) eligibility (inclusion 
Section 5.1, #5) 
 Administer dilation eye drops (1% Mydriacyl and 2.5% phenylephrine or equivalent 
applied topically). 
 Administer the VFQ-25. 
 Obtain fundus photography for immediate submission to reading center.  
 Measure IOP. 
 Perform slit-lamp biomicroscopy. Assess intended study eye(s) eligibility with 
respect to VH score (≥ 1.5+ in each intended study eye). 
 Perform indirect ophthalmoscopy. 
 Perform OCT. 
 Perform fluorescein angiography (recommended post investigator eligibility 
confirmation). 


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 Assess for adverse events. 
 Record concomitant medications (including systemic corticosteroid medication 
status). 
Confirm qualifying VH score for each of the subject’s intended study eyes has been obtained 
from the Reading Center based on fundus photography at Day 1. Perform final review of 
inclusion/exclusion criteria. If the subject and the subject’s intended study eye(s) meet all 
eligibility criteria, randomize the eye(s) into the study using the EDC system (Medidata, 
including IWRS component) to obtain the assigned vial number(s) to be dispensed to the study 
eye(s).  
The unmasked investigator or designee performs IP preparation and administration as specified 
in Section 6.2.2 and Section 6.2.3.  
Perform the following post IP administration assessments in both eyes: 
 Within 30 minutes after the administration of IP: 
 Perform slit-lamp biomicroscopy 
 Perform indirect ophthalmoscopy 
 Measure IOP as follows: At approximately 40 (±10) minutes following administration 
of IP, measure IOP by applanation tonometry. If there is an increase of ≥ 10 mmHg at 
40 (±10) minutes post IP administration compared to prior to IP administration, 
administer topical IOP-lowering drops until the subject returns for follow-up, per the 
investigator’s discretion. (An unscheduled visit may apply). Note that IOP increase of 
≥ 10 mmHg should be reported as an adverse event. 
 Initiate administration of prednisolone acetate eye drops, for 8 days following each IP 
administration, according to the following schedule:  4 times per day for 4 days 
(including the day of IP administration) followed by 2 times per day for 4 days, then 
stop.  
 Assess for adverse events. 
 Record concomitant medications. 
8.1.4. 
Double-Masked Treatment Period, Day 14 
Allowable visit window:  Day 14 ± 2 days 
Visit details: 
If the subject has consented to the pharmacogenomics sampling protocol, collect blood for 
pharmacogenomics. Pharmcogenomic sample should be collected at the Day 14 visit, but may be 
collected at any time during the study or at a separate post study visit, if necessary. 
Perform the following assessments in both eyes: 
 Assess BCVA using ETDRS charts. 
 Administer dilation eye drops (1% Mydriacyl and 2.5% phenylephrine or equivalent 
applied topically). 


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 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic corticosteroid medication 
status). 
Record the study visit in the EDC system (Medidata) for Day 14. 
8.1.5. 
Double-Masked Treatment Period, Month 1 
Allowable visit window:  Day 30 ± 3 days 
Visit details: 
Perform the following assessments in both eyes: 
 Assess BCVA using ETDRS charts. 
 Administer dilation eye drops (1% Mydriacyl and 2.5% phenylephrine or equivalent 
applied topically). 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic corticosteroid medication 
status). 
Record the study visit in the EDC system (Medidata) for Month 1.  
8.1.6. 
Double-Masked Treatment Period, Month 2 
At all study visits at which masked IP is administered:   
 The masked investigator or designee performs assessments in both eyes that are prior 
to IP administration.  
 The unmasked investigator or designee performs IP administration (DE-109 
intravitreal injection / sham procedure), the safety check immediately after IP 
administration (finger count, hand motion, and light perception), and the post-
administration assessments.   


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Allowable visit window:  Day 60 ± 3 days 
Visit details:  
Perform the following assessments/procedures in both eyes prior to administration of IP:  
 If the subject is a woman of child-bearing potential, conduct urine pregnancy test. A 
positive pregnancy test requires immediate discontinuation from the study. Pregnancy 
is an event of special interest and requires follow-up by Santen until the outcome is 
known. 
 Assess BCVA using ETDRS charts.  
 Administer dilation eye drops (1% Mydriacyl and 2.5% phenylephrine or equivalent 
applied topically). 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic corticosteroid medication 
status). 
Use the EDC System (Medidata, including IWRS component) to record the Month 2 visit and 
obtain the vial number(s) assigned to the subject’s study eye(s). 
The unmasked investigator or designee performs IP preparation and administration as specified 
in Section 6.2.2 and Section 6.2.3.  
Perform the following post IP administration assessments in both eyes: 
 Within 30 minutes after the administration of IP: 
 Perform slit-lamp biomicroscopy 
 Perform indirect ophthalmoscopy 
 Measure IOP as follows: At approximately 40 (±10) minutes following administration 
of IP, measure IOP by applanation tonometry. If there is an increase of ≥ 10 mmHg at 
40 (±10) minutes post IP administration compared to prior to IP administration, 
administer topical IOP-lowering drops until the subject returns for follow-up, per the 
investigator’s discretion. (An unscheduled visit may apply). Note that IOP increase of 
≥ 10 mmHg should be reported as an adverse event. 
 Initiate administration of prednisolone acetate eye drops, for 8 days following each IP 
administration, according to the following schedule:  4 times per day for 4 days 
(including the day of IP administration) followed by 2 times per day for 4 days.  
 Assess for adverse events. 


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 Record concomitant medications. 
8.1.7. 
Double-Masked Treatment Period, Month 3 
Allowable visit window:  Day 90 ± 3 days 
Visit details: 
Perform the following assessments in both eyes: 
 Assess BCVA using ETDRS charts. 
 Administer dilation eye drops (1% Mydriacyl and 2.5% phenylephrine or equivalent 
applied topically). 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform fluorescein angiography. 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic corticosteroid medication 
status). 
Record the study visit in the EDC system (Medidata) for Month 3.  
8.1.8. 
Double-Masked Treatment Period, Month 4 
Allowable visit window: Day 120 ± 3 days; other procedures/details are the same as for Month 2 
(Section 8.1.6).  
8.1.9. 
Double-Masked Treatment Period, Month 5 
Note: Subjects must fast 8 hours prior to the blood draw for hematology and chemistry 
laboratory tests taken at Month 5. 
 
Allowable visit window:  Day 150 ± 3 days 
 
Visit details: 
Perform the following assessments in both eyes: 
 Perform physical examination. Note: if this was performed at Month 3 under a 
previous version of the protocol it does not need to be repeated. 
 Record vital signs. Note: if this was performed at Month 3 under a previous version 
of the protocol it does not need to be repeated. 


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 Collect fasting blood for serum chemistry and hematology tests for laboratory 
analysis. Note: if these samples were collected at Month 3 under a previous version of 
the protocol they do not need to be repeated. 
 Obtain urine sample for urinalysis. Note: if this sample was collected at Month 3 
under a previous version of the protocol it does not need to be repeated.  
 Assess BCVA using ETDRS charts. 
 Administer dilation eye drops (1% Mydriacyl and 2.5% phenylephrine or equivalent 
applied topically). 
 Administer the VFQ-25. Note: if this was performed at Month 3 under a previous 
version of the protocol it does not need to be repeated. 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform fluorescein angiography. 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic corticosteroid medication 
status). 
Record the study visit in the EDC system (Medidata) for Month 5.  
8.1.10. 
Double-Masked Treatment Period, Month 6 
Allowable visit window:  Day 180 ± 7 days; other procedures/details are the same as for Month 2 
8.1.11. 
Open-Label Treatment Period, Month 7 
Allowable visit window:  Day 210 ± 7 days; other procedures/details are the same as for Month 1 
(Section 8.1.5).  
8.1.12. 
Open-Label Treatment Period, Month 8 
Allowable visit window:  Day 240 ± 7 days; other visit procedures/details are the same as for 
Month 2 (Section 8.1.6). 
8.1.13. 
Open-Label Treatment Period, Month 9 
Allowable visit window:  Day 270 ± 7 days; other visit procedures/details are the same as for 
Month 1 (Section 8.1.5).  


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8.1.14. 
Open-Label Treatment Period, Month 10 
Allowable visit window:  Day 300 ± 7 days; other visit procedures/details are the same as for 
Month 2 (Section 8.1.6). 
8.1.15. 
Open-Label Treatment Period, Month 11 
Allowable visit window:  Day 330 ± 7 days; other visit procedures/details are the same as for 
Month 1 (Section 8.1.5).  
8.1.16. 
Month 12/Exit/Early Termination Visit 
Allowable visit window for Month 12 visit: Day 360 ± 7 days 
Visit details: 
Perform the following procedures/assessments in both eyes at Month 12 or at early termination 
from study if a subject discontinues both study participation and IP after Day 1 and before the 
Month 12 visit:  
 Perform physical examination. 
 Record vital signs. 
 If the subject is a woman of child-bearing potential, collect blood for serum 
pregnancy test. 
 Collect fasting or non-fasting blood for serum chemistry and hematology tests for 
laboratory analysis as described in the SoA (Table 3). 
 Obtain urine sample for urinalysis. 
 Assess BCVA using ETDRS charts. 
 Administer dilation eye drops (1% Mydriacyl and 2.5% phenylephrine or equivalent 
applied topically). 
 Administer the VFQ-25. 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform fluorescein angiography 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic corticosteroid medication 
status). 
Record the study visit in the EDC system (Medidata) for the Month 12/Exit/Early Termination 
visit.  


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8.1.17. 
Unscheduled Visits 
If a subject requires evaluation between scheduled visits, applicable study procedures may be 
performed as specified in the protocol (e.g., if performed, assessment in both eyes for visual 
acuity must follow protocol-specified BCVA evaluation using ETDRS chart). At a minimum, 
unscheduled visits should include (1) assessment for adverse events and (2) recording of 
concomitant medications. DE-109 will not be administered at an unscheduled visit.  
8.1.18. 
Efficacy Assessments 
These sections provide descriptions of assessments from which one or more efficacy endpoints 
are determined (VH, BCVA, OCT, and use of systemic corticosteroids) as well as the patient 
reported outcome (VFQ-25). Note that BCVA and OCT are also assessments of safety. Planned 
time points for all assessments are provided in the SoA (Table 3) and details by visit are 
provided in Section 8.1.1. 
8.1.19. 
Vitreous Haze 
Vitreous haze (VH) will be assessed using the modified SUN scale, as follows: 
Table 7: 
Vitreous Haze (VH), Modified SUN Scale 
Step 
Description 
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  
A VH score of 1.5+ will be used to categorize subjects with a VH score of greater than 1+ but less 
than 2+ 
 
VH scores will be recorded during slit-lamp biomicroscopy evaluations. Study eligibility with 
respect to VH will be confirmed by central reading of fundus photographs; the reading center 
procedures are detailed in a procedure manual.  
8.1.20. 
Best-Corrected Visual Acuity 
The best-corrected visual acuity (BCVA) will be recorded (for both eyes) using ETDRS charts 
and the total number of letters at 4 meters and 1 meter will be recorded.  If a subject’s visual 
acuity is so poor that he/she cannot read any chart letters when tested at 1 meter, then the 
subject’s ability to count fingers, detect hand motion, or have light perception should be 
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8.1.21. 
Optical Coherence Tomography  
Optical Coherence Tomography (OCT) will be performed for both eyes. Central subfield 
thickness will be recorded. OCT will be performed using reading center certified photographers, 
equipment, and standardized protocols. Refer to the reading center procedure manuals for the 
complete protocol.  
8.1.22. 
Use of Systemic Corticosteroids 
Subjects use of systemic corticosteroids will be collected and this information will be used in 
determining efficacy endpoints assessing corticosteroid tapering success.  
8.1.23. 
National Eye Institute Visual Functioning Questionnaire – 25 (VFQ-25) 
The National Eye Institute Visual Functioning Questionnaire - 25 (VFQ-25), version 2000, 
including the appendix questions, will be administered (National_Eye_Institute, 2000). The 
VFQ-25 is a patient reported outcome that was designed to measure the dimensions of self-
reported vision-targeted health status that are most important for persons who have chronic eye 
diseases. The VFQ-25 is provided in Section 12.1.  
8.2. 
Safety Assessments 
This section describes the following safety assessments: slit-lamp biomicroscopy, indirect 
ophthalmoscopy, IOP, fundus photography, fluorescein angiography, laboratory tests (serum 
chemistry, hematology, and urinalysis), pregnancy testing, physical examination, and vital signs. 
Assessment of AEs and SAEs is described in Section 8.3. Assessment of BCVA and OCT are 
described in Section 8.1.20 and Section 8.1.21, respectively. Planned time points for all 
assessments are provided in the SoA (Table 3) and details by visit are provided in Section 8.1.1. 
8.2.1. 
Slit-Lamp Biomicroscopy 
Slit-lamp biomicroscopy will be used to examine eye structures for both eyes during screening 
and at each follow-up study visit. At visits when IP is administered, slit-lamp biomicroscopy will 
be performed prior to IP administration and then again within 30 minutes after IP administration. 
Areas to be assessed include vitreous, lids, conjunctiva, cornea, anterior chamber cells and flare, 
iris, pupil, lashes, ocular motility, lens, and cataract status.  
8.2.2. 
Vitreous Cells 
Slit-lamp biomicroscopy will be used to assess vitreous cells. The following SUN scale for 
vitreous cell count will be used to measure vitreous cells: 


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Vitreous Cell Count Scale 
(1 mm x 3 mm beam in anterior vitreous) 
0 
0 cells 
0.5+ 
1-10 cells 
1+ 
11-20 cells 
2+ 
21-30 cells 
3+ 
31-100 cells 
4+ 
>100 cells 
8.2.3. 
Anterior Chamber Cells 
Slit-lamp biomicroscopy will be used to assess anterior chamber cells. The following scale will 
be used to measure anterior chamber cells:   
Anterior Chamber Cells 
(1 mm x 1 mm slit beam) 
0 
0 cells 
0.5+ 
1-5 cells 
1+ 
6-15 cells 
2+ 
16-25 cells 
3+ 
26-50 cells 
4+ 
>50 cells 
8.2.4. 
Anterior Chamber Flare 
Slit-lamp biomicroscopy will be used to assess anterior chamber flare. The following scale will 
be used to measure anterior chamber flare:   
Anterior Chamber Flare 
0    None  
1+  Faint  
2+  Moderate (iris and lens details clear)  
3+  Marked (iris and lens details hazy) 
4+  Intense (fibrin or plastic aqueous) 
8.2.5. 
Terminology for Biomicroscopy Findings 
Consistency in the recording of biomicroscopy findings will be facilitated by providing a 
selection of possible terms on the eCRF for each area to be assessed; additional terms may be 
recorded as needed. Whenever possible, consistency should be maintained in the use of terms 
between examinations.  


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8.2.6. 
Indirect Ophthalmoscopy 
Indirect ophthalmoscopy will be used to examine the retina of each eye during screening and at 
each follow-up study visit, and will be performed with pupil dilation. At visits when IP is 
administered, indirect ophthalmoscopy will be performed prior to IP administration and then 
again within 30 minutes after IP administration. Areas to be assessed include retina vessels, 
macula, fovea, periphery, optic nerve, and vitreous. Consistency in the recording of findings will 
be facilitated by providing a selection of possible terms on the eCRF for each area to be 
assessed; additional terms may be recorded as needed. 
8.2.7. 
Intraocular Pressure 
Intraocular Pressure (IOP) will be measured during screening and at each follow-up study visit. 
The examiner will measure IOP in each eye and record results in mmHg (e.g., 24). A single 
measurement is made to obtain a determination of IOP. The same contact tonometer employing 
the investigator’s standard technique will be used throughout the study.  
At visits when IP is administered, IOP will be measured prior to IP administration and at 
approximately 40 (±10) minutes after IP administration. See the visit details of dosing visits 
(e.g., Day 1 visit details, Section 8.1.3). 
Tonometer calibration: The tonometer must be calibrated for accuracy before the first subject 
undergoes screening, and periodically according to manufacturer’s instructions 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.  
8.2.8. 
Fundus Photography 
At each visit, digital color fundus photography will be taken of both eyes using reading center 
certified photographers, equipment, and standardized protocols. Fundus photographs will be 
submitted to a central reading center. The procedures are detailed in the reading center procedure 
manual.  
8.2.9. 
Fluorescein Angiography 
Wide field fundus fluorescein angiography (FA) will be taken of both eyes using reading center 
certified photographers (Day 1), equipment and a standardized protocol at the visits as specified 
in the SoA (Table 3). Refer to the reading center procedure manual for the complete protocol.  
8.2.10. 
Clinical Safety Laboratory Assessments 
 Fasting or non-fasting blood samples and urine samples will be obtained for 
laboratory assessments according to the SoA (Table 3). Samples will be sent for 
analysis to the designated central laboratory. Note: Blood and urine samples should 
be collected before injection of fluorescein. 


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 See Section 10.2 for the clinical laboratory tests to be performed.  
 The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease (uveitis), unless judged by the investigator to be more severe than 
expected for the subject's condition. Lab shifts within the range of normal should 
generally not be considered AEs.  
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 60 days after the last IP administration should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or Santen medical monitor. 
 If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and Santen 
notified. 
 All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Table 3). 
 If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the investigator (e.g., SAE 
or AE or dose modification), then the results must be recorded in the eCRF. 
A retest of screening laboratory tests is permitted only if there is reason to believe the initial 
value was either due to a sample processing error or an extenuating circumstance. 
8.2.11. 
Physical Examination 
A full body systematic physical examination will be conducted by the investigator/designee.  
8.2.12. 
Vital Signs 
Systolic and diastolic blood pressure should be measured only after the subject has been in a 
sitting position for at least 5 minutes, and will be recorded in millimeters of mercury (mmHg). 
Measurement with an automated sphygmomanometer is acceptable.  
Heart rate should be measured only after the subject has been in a sitting position for at least 2 
minutes, and will be recorded in beats per minute (bpm). 
Temperature should be measured.  
8.2.13. 
Events of Special Interest 
Events of Special Interest (ESIs) are medical events both anticipated and unanticipated that may 
have particular impact on the benefit/risk profile of DE-109 and therefore may require more 
detailed characterization. The DE-109 Investigational Brochure is the source for defining the 
DE-109 ESIs and should be consulted for further information.  
 


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The DE-109 ESIs are specific to the study eye only and are as follows:  
 Clinically significant new or worsening of uveitis, defined as satisfaction of any of 
the following:  
 Worsening of uveitis in the study eye as indicated by at least a 2-step increase in 
VH score (i.e., 0 to ≥ 2+, 0.5+ to ≥ 3+, 1+ to ≥ 3+, 1.5+ to ≥ 4+, or 2+ to ≥ 4+) as 
compared to the baseline (Day 1) VH score or the best achieved VH score post-
baseline. 
 Severe deterioration of vision in the study eye due to worsening of uveitis that is 
indicated by at least doubling of the visual angle (loss of 3 or more lines [≥15 
ETDRS letters]) as compared to baseline (Day 1) BCVA. 
 New or worsening retinal or choroidal uveitic lesion(s) in the study eye as 
compared to baseline (Day 1). 
 New or worsening uveitis otherwise deemed clinically significant by the 
investigator in the study eye as compared to the baseline (Day 1). 
Note: When documenting clinically significant new or worsening uveitis, the anatomic 
location (e.g., anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis ) 
should be specified.  
 Endophthalmitis / Sterile Endophthalmitis in the study eye – A guided questionnaire 
is provided as part of the eCRFs to facilitate the documentation of endophthalmitis 
and sterile endophthalmitis. Endophthalmitis is also to be reported as an SAE 
(Section 10.4). 
 Traumatic cataract in the study eye 
 Vitreoretinal hemorrhage in the study eye 
 Drug depot in visual axis in the study eye 
 Retinal detachment (also to be reported as an SAE, Section 10.4) in the study eye 
 Increased IOP (> 10 mmHg as compared to baseline). Note that certain instances of 
increased IOP are to be reported as an SAE (IOP >35 mmHg that persists for at least 
7 days despite pharmacologic therapy, Section 10.4) in the study eye.  
 Cataract (new or worsening from baseline) in the study eye 
 Investigational product administration error considered to be significant by the 
investigator (examples include administration of IP from an incorrect kit and IP 
administration error attributed to some aspect of the instructions provided) 
 Pregnancy (see Section 8.2.14) 
Additionaly below are the two (pregnancy and medication error) ESIs that need to be reported 
regardless of the study eye involvement:  
Most ESIs are AEs, some ESIs may also be SAEs, and some ESIs may not be AEs (e.g., an IP 
administration error may not be an AE; pregnancies are not AEs). However, all ESIs should be 
reported within 24 hours of knowledge of the event using applicable eCRFs and recording as 


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much information as available. ESIs should be followed by the investigator to the same extent as 
SAEs, that is, until the event is determined to be resolved, irreversible, chronic, stable, the 
subject withdraws consent, or no further information can be reasonably obtained. Monitoring for 
pregnancy and follow-up of pregnancy is described in Section 8.2.14. 
8.2.14. 
Pregnancy Testing, Monitoring, and Reporting 
8.2.15. 
Pregnancy Testing 
If the subject is a woman of child-bearing potential, a blood sample will be obtained during 
screening for a serum pregnancy test. Samples will be sent for analysis to the central laboratory. 
Urine samples will be collected for pregnancy tests prior to IP administrations as specified in the 
SoA (Table 3). Urine samples will be analyzed at the site with results available prior to 
administration of IP. 
8.2.16. 
Pregnancy Monitoring and Reporting Procedures 
Pregnancy in female subjects and female partners of male subjects will be monitored starting 
from screening through the Month 12/Exit/Early Termination visit.  
Although not considered an AE or SAE, pregnancy is an ESI and requires careful monitoring and 
follow up. If a pregnancy is reported by a study subject (or in the partner of a study subject), the 
investigator must:  
 Inform Santen within 24 hours of learning of the pregnancy. 
 If the pregnancy has occurred in a study subject, discontinue further IP administration 
and/or withdraw the subject from the study. 
 Report pregnancy information on the eCRF following instructions. 
 Follow the pregnancy until outcome is known.  Santen will request specific follow-up 
on a case-by-case basis.  
Additional details regarding collection, reporting, and follow-up of pregnancy is provided below: 
Female subjects who become pregnant: The investigator will collect pregnancy information on 
any female subject who becomes pregnant while participating in this study. Information will be 
recorded on the appropriate form and submitted to Santen within 24 hours of learning of a 
subject's pregnancy. The subject will be followed to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to Santen. Generally, follow-up will not be required for longer 
than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an Event of Special 
Interest (ESI). Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. Any 
post-study pregnancy-related SAE considered reasonably related to the IP by the investigator 
will be reported to Santen. While the investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through spontaneous 


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reporting. Any female subject who becomes pregnant while participating in the study will 
discontinue IP and be withdrawn from the study.  
Male subjects with partners who become pregnant: The investigator will attempt to collect 
pregnancy information on any male subject’s female partner who becomes pregnant while the 
male subject is in this study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to Santen within 24 hours of learning of the partner’s pregnancy. 
The female partner will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to Santen. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AE and SAE are provided in Section 10.4. 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally authorized representative) to the masked or unmasked investigator. 
The masked and unmasked investigator and any qualified designees are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE and 
following up on-going AEs and SAEs as specified below.  
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse events and SAEs will be monitored for and collected at the time points specified in the 
SoA (Table 3), from the signing of the Informed Consent Form (ICF) until the subject 
withdrawal or the scheduled exit visit. (Note: Although AEs will be monitored for and collected 
prior to IP administration, the statistical data analysis will determine and summarize treatment-
emergent AEs, i.e., those AEs that began or worsened in severity after the first IP 
administration.) 
All SAEs will be recorded and reported to Santen or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.4. The investigator will 
submit any updated SAE data to Santen within 24 hours of it being available.  
Investigators are not obligated to monitor for new AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the IP or study participation, the investigator must promptly notify Santen. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.4. During the 
double-masked period, regardless of the source of the reported occurrence of an AE in a subject, 
the masked investigator will assess the causality of the AE. 


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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
All reported AEs should be followed by the investigator until resolution or until the subject’s 
participation in the study ends.  
More extensive follow-up is required for (1) SAEs and (2) IP related AEs that lead to or cause 
early withdrawal of a subject from the study. Both of these types of events should be followed by 
the investigator until the event is determined to be resolved, irreversible, chronic, stable, the 
subject withdraws consent, or no further information can be reasonably obtained. As described in 
Section 8.2.13, ESIs are followed up to this same extent.  
In addition to the above, Santen (or designee) may request, on a case-by-case basis, follow up of 
events/subjects beyond the scheduled exit visit.  
Prior to database lock, follow-up information on an individual SAE or AE (or ESI) will be 
entered into the eCRF. When database lock has already been completed, or if information 
requested by Santen is not part of the eCRF, the site’s response to follow-up requests should be 
emailed or documented on paper and faxed to Santen Global Pharmacovigilance (see Table 1).  
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to Santen of an SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a study intervention 
under clinical investigation are met. 
Santen has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a study intervention under clinical investigation. Santen will comply 
with country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
Santen will prepare investigator safety reports for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Santen policy and forward 
them to investigators as necessary. An investigator who receives an investigator safety report 
describing an SAE or other specific safety information (e.g., summary or listing of SAEs) from 
Santen will review and then file it along with the Investigational Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.4. 
Pharmacogenomics 
All subjects participating in the study will have the option to participate in blood sampling for 
pharmacogenomics and this will be consented to collect this optional test. Subjects who do not 
wish to participate in the pharmacogenomic sampling may still participate in the study. 
on Day 14 visit, but may be collected 
at any time during the study or at a separate post study visit, if necessary, as shown in the SoA 
(Table 3). 


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separate procedure manual.  
investigator and 
participants.  


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9. 
STATISTICAL CONSIDERATIONS 
Unless specified otherwise, efficacy measures will be summarized by planned (i.e., randomized) 
treatment and based on the FAS population, and safety measures will be summarized by actual 
treatment received and based on the Safety population. All efficacy endpoint analyses will be 
performed on eyes enrolled in the study (referred to as study eyes). Safety assessments that 
pertain to the eye will be analyzed by the study eye and fellow eye separately. Safety 
assessments that pertain to the subject will be analyzed at the subject level. 
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 (%). 
Statistical testing is planned for the analysis of efficacy endpoints of the double-masked period 
only (not safety endpoints) and will assess for superiority of efficacy observed in the test arm 
(440 µg DE-109 every 2 months) compared to the sham control. Statistical testing will not 
involve the dummy arm, which is included in the study to help ensure masking of treatment 
assignments. Unless specified otherwise, the statistical testing will be conducted at a significance 
level of 0.05 (two-sided). Additional details of the statistical methods will be described in the 
Statistical Analysis Plan (SAP). 
All data manipulations, descriptive summaries, and statistical hypothesis testing will be 
performed using SAS Version 9.4 or later. FDA guidance regarding case report tabulations 
(annotated eCRFs, SAS datasets, metadata, and SAS programs) in electronic submissions will be 
followed. Data definition tables will be created for SDTM and ADaM datasets separately.  
9.1. 
Estimands 
 The primary estimand is: Vitreous haze 0 (VH0) response rate in DE-109 440 µg group 
vs. Sham group at Month 5 in all study eyes that received at least one dose of the study 
treatment where all eyes that were rescued due to worsening of uveitis or discontinued 
from the study due to lack of efficacy or due to adverse event before Month 5 will be 
treated as non-responders. For study eyes that were rescued for any other reasons or had 
missing data due to other reasons, imputation by the multiple imputation-based approach 
will be used. 
 The treatment policy estimand is: VH0 response rate in DE-109 440 µg group vs. Sham 
group at Month 5 in all study eyes that received at least one dose of the study treatment 
regardless of whether subjects have received rescue therapy or discontinued from the 
study due to lack of efficacy or due to adverse event. For study eyes that had missing data 
due to any reason, imputation by the multiple imputation-based approach will be used. 
 The composite estimand is: Mean composite score in DE-109 440 µg group vs. Sham 
group at Month 3 and at Month 5 in all study eyes that received at least one dose of study 
treatment. Each study eye will be assigned one of the following scores: 
o Score = 3 if a study eye achieved VH score of 0 at the specified visit without taking 
any rescue therapies that could affect VH score prior to the specified visit  
o Score = 2 if a study eye had at least improved by 2 units in VH (compared to 
baseline) at the specified visit without taking any rescue therapies that could affect 
VH score prior to the specified visit   


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o Score = 1 if a study eye achieved VH score of 0.5+ at the specified visit without 
taking any rescue therapies that could affect VH score prior to the specified visit   
o Score = -1 if a study eye got rescued due to worsening of uveitis or discontinued from 
the study due to lack of efficacy or due to adverse event prior to the specified visit 
o Score = 0 if otherwise 
9.2. 
Statistical Hypotheses  
The primary efficacy endpoint (VH 0 response at Month 5) will be analyzed using the Cochran-
Mantel-Haenszel (CMH) test with Row Mean Scores statistic, stratified by the number of 
enrolled eyes from a subject (one eye or two eyes), baseline systemic (oral) corticosteroid use 
(yes or no), and region (US or non-US). The null (H0) and alternative (H1) hypotheses are as 
follows:  
H0: πsham = π440 
H1: πsham ≠ π440 
where πsham and π440 denote the response rate for sham and 440 μg DE-109, respectively.   
9.3. 
Sample Size Determination 
Assuming a 30% VH 0 response rate for DE-109 440 µg group and a 12% response rate for the 
sham treatment group, 160 subjects (80 subjects per arm) is required to achieve 80% power to 
detect such a difference in response rate between the DE-109 440 µg group and the sham 
treatment group using the Pearson’s Chi-square test (two-sided, α = 0.05). Including 
approximately 40 subjects in the dummy arm, a total of approximately 200 subjects with active 
NIU-PS will be randomized in a 2:2:1 ratio to DE-109 440 µg, sham, and dummy arms.  
9.4. 
Populations for Analyses 
The following analysis populations for study analyses are defined: Full Analysis Set (FAS), 
Safety, Per-Protocol (PP), Intent-to-Taper, Macular Edema, Vision 20/40 or Worse: 
 The FAS population will consist of all study eyes that are randomized and received 
at least one administration of study treatment. The FAS population will be the 
analysis population for the primary analysis and will use treatment as randomized.  
 For analyses of ocular AEs and safety parameters assessed per eye, the Safety 
population will consist of all study eyes which received at least one administration of 
IP. For analyses of non-ocular AEs and safety parameters assessed per subject, the 
Safety population will consist of all subjects who received at least one 
administration of IP. 
 The PP population will be a subset of the FAS population. The PP population will be 
the analysis population for sensitivity analyses and will use treatment as randomized. 
Any study eye affected by a significant protocol deviation (such that the outcome to 
treatment could be altered) will be excluded from the PP population. In addition, any 
study eye without the Month 5 VH score will be excluded from the PP population. 
Eyes to be excluded from the PP population will be identified before the unmasking 
of treatment assignments. 


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 The Intent-to-Taper population will be a subset of the FAS population, consisting 
of study eyes from subjects who were taking systemic (oral) corticosteroids at a stable 
prednisone-equivalent dose between ≥15 mg/day and ≤40 mg/day for at least 1 week 
(7 days) prior to and including on Day 1. The Intent-to-Taper population will be used 
for the analysis of tapering success performed using eyes as randomized.  
 The Macular Edema population will be a subset of the FAS population and will 
consist of study eyes with CST ≥ 300 microns at baseline. 
 The Vision 20/40 or Worse population will be a subset of the FAS population and 
will consist of study eyes with BCVA ≤ 70 ETDRS letters (Snellen equivalent of 
20/40 or worse) at baseline. 
9.5. 
Statistical Analyses 
Details of statistical analyses will be described in the SAP, which will be developed and finalized 
before database lock. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints (see Table 4). 
9.5.1. 
Handling of Missing Values 
In the analysis of VH 0, VH 0 or 2-unit decrease (improvement), and VH 0 or 0.5+ responses: 
 Subjects who (a) receive rescue therapy for conditions other than worsening of uveitis 
or (b) are rescued due to the worsening of uveitis but do not meet the protocol-
defined rescue criteria, missing VH scores subsequent to receiving rescue therapy will 
be imputed using a multiple imputation-based approach before receiving rescue 
therapy.  
 Missing VH scores of subjects not rescued before Month 5/Month 3 visit will be 
imputed using a multiple imputation-based approach.   
The multiple imputation model will include vitreous haze measures at preceding visits and 
baseline characteristics. The response status will then be determined based on the observed or 
imputed VH scores. 
No imputation is needed for composite score analysis as eyes with missing VH scores will be 
assigned a score of zero, unless they are rescued due to the worsening of uveitis or discontinued 
from the study due to lack of efficacy or adverse event (which will be assigned with a score of    
-1).  
For medical events including AEs, completely or partially missing onset and resolution dates will 
be imputed in a conservative fashion to be detailed in the SAP.  The same rules will be followed 
to impute completely or partially missing start and end dates of non-study medications. 
Unless specified otherwise, descriptive summaries will be based on observed cases.  No 
imputation of missing scores will be implemented. 
Additional details on handling of missing data and sensitivity analyses on imputation methods  
will be provided in the SAP. 


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9.5.2. 
Efficacy Analyses 
Rescue therapy is defined in Section 6.5.6 and is essentially any treatment that would have a 
therapeutic effect on NIU-PS other than intravitreal DE-109. Rescue therapy is permitted in the 
case of worsening of uveitis that satisfies protocol-defined rescue criteria. The use of rescue 
therapy is considered in assessing the VH response endpoints (VH 0 response, VH 0 or 2-unit 
improvement, and VH 0 or 0.5+ response). In the analysis of these endpoints at a specific follow-
up visit (e.g., Month 5 or Month 3), subjects who met one of the protocol-defined rescue criteria 
will be assessed as non-responders regardless of whether the subjects were rescued or not. 
 
Table 8: 
Endpoint Statistical Analysis 
Endpoint 
Statistical Analysis Methods 
Primary endpoint: 
VH 0 responsea at Month 5 
For the primary analysis of VH 0 response at Month 5, 
the Cochran-Mantel-Haenszel (CMH) test with Row 
Mean Scores statistic stratified by number of enrolled 
eyes from a subject (one eye or two eyes), baseline 
systemic (oral) corticosteroid use (yes or no), and region 
(US or non-US) will be conducted.  
Logistic generalized estimating equation (GEE) model, 
treatment policy strategy, last-observation-carried-
forward (LOCF) imputation, and multiple imputation 
with tipping point analysis will be used as a sensitivity 
analysis. 
Secondary endpoints: 
Key secondary efficacy endpoints:  
 
Composite endpointb at Month 5 
 
VH 0 response at Month 3 
 
Composite endpoint at Month 3 
A hierarchical approach will be used to control the 
overall Type I error rate associated with the multiple 
comparisons across the primary and the key secondary 
efficacy endpoints.  
If the hypothesis testing for the primary endpoint 
successfully rejects the null hypothesis, the first key 
secondary efficacy endpoint will be tested, and so on.  
All the other secondary efficacy endpoints are 
supportive in nature. Therefore, no formal hypothesis 
testing will be performed on secondary efficacy 
endpoints. Two-sided 95% confidence intervals and 
nominal p-values may be reported for them, and such 
results will be interpreted descriptively in terms of the 
support they provide to the treatment comparisons for 
the primary and the key secondary efficacy endpoints in 
the sense of logical consistency.  
 
 


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Table 8: 
Endpoint Statistical Analysis (Continued) 
Endpoint 
Statistical Analysis Methods 
Other secondary efficacy endpoints 
(double-masked period of study): 
 
VH 0 or 2-unit responsec at Month 
5 
 
VH 0 or 2-unit response at Month 3 
 
VH 0 or 0.5+ responsed at Month 5 
 
VH 0 or 0.5+ response at Month 3 
 
Corticosteroid tapering success with 
resolutione at Month 5 
 
Corticosteroid tapering success with 
resolution at Month 3 
 
BCVA 3-line responsef at Month 5 
 
BCVA 3-line response at Month 3 
 
Change from baseline in central 
subfield thickness (CST) at Month 
5 as measured by OCT 
 
Change from baseline in CST at 
Month 3 as measured by OCT 
 
Use of rescue therapy before Month 
5 
 
Use of rescue therapy before Month 
3 
Other secondary efficacy endpoints 
(open-label period of study): 
 VH 0 response at each visit after 
Month 6 
 VH 0 or 2-unit response at each 
visit after Month 6 
 VH 0 or 0.5+ response at each 
visit after Month 6 
Note:  Additional secondary/exploratory 
efficacy endpoints will be specified in the 
Statistical Analysis Plan. 
For secondary efficacy endpoints during double-
masked period: 
All binary secondary endpoints will be analyzed using 
the Cochran-Mantel-Haenszel (CMH) test with Row 
Mean Scores statistic stratified by number of enrolled 
eyes from a subject (one eye or two eyes), baseline 
systemic (oral) corticosteroid use (yes or no), and region 
(US vs. non-US). Change-from-baseline endpoints will 
be analyzed by a mixed-effects model for repeated 
measures (MMRM) using observed cases. The statistical 
model for the analysis of each continuous secondary 
endpoint may be adjusted if it fails to converge. More 
details regarding model specifications will be provided 
in the SAP. 
 
For secondary efficacy endpoints during open-label 
period: 
No formal inferential analysis will be performed. 
Summary statistics will be provided. 
 
 
 
 


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Table 8: 
Endpoint Statistical Analysis (Continued) 
Endpoint 
Statistical Analysis Methods 
Exploratory 
Will be described in the statistical analysis plan 
finalized before database lock. 
Note: Vitreous haze (VH) will be scored using the modified Standardized Uveitis Nomenclature (SUN) scale.  
a VH 0 response (resolution of inflammation) is defined as a VH score of 0 in the study eye at a specified follow up 
visit based on the modified SUN scale. 
b  Refer to composite score scales defined in the composite estimand in this table.   
cVH 0 or 2-unit response is defined as having a VH score of 0 or a decrease (improvement) of at least 2 units (i.e., 
2+ to 0, 3+ to 1+, or 4+ to 2+) from baseline in the study eye in VH score at a specified follow up visit based on 
the modified SUN scale. 
d VH 0 or 0.5+ response (remission of inflammation) is defined as a VH score of 0 or 0.5+ in the study eye at a 
specified follow-up visit based on the modified SUN scale.  
e Corticosteroid tapering success with resolution is defined as achievement of a prednisone-equivalent oral dose of 
0 mg/day and a VH score of 0 in the study eye at a specified follow-up visit. This endpoint is assessed based on 
the Intent-to-Taper population (study eyes of subjects who received systemic [oral] corticosteroids at a stable 
prednisone-equivalent dose of between ≥15 mg/day and ≤40 mg/day that has remained stable for at least 1 week 
[7days] prior to and including on Day 1). 
f BCVA 3-line response is defined as an increase (improvement) of at least 3 lines (15 ETDRS letters) from baseline 
in BCVA at a specified follow-up visit. This endpoint is assessed based on eyes with a baseline best-corrected 
visual acuity (BCVA) ≤70 ETDRS letters (Snellen equivalent of 20/40 or worse).  
9.5.3. 
Subpopulation Analyses  
All the analyses listed in Section 9.5.2 will be repeated on the PP, Intent-to-Taper, Macular 
Edema, and Vision 20/40 or Worse sub-populations. 
9.5.4. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
Safety of DE-109 will be assessed by AEs and evaluation with slit-lamp biomicroscopy, indirect 
ophthalmoscopy, BCVA, intraocular pressure (IOP), fundus photography, fluorescein 
angiography, laboratory tests (serum chemistry, hematology, and urinalysis), physical 
examinations and vital signs. 
Besides the overall summary of AEs, subjects with any AE(s) will be tabulated by system organ 
class (SOC) and preferred term specified in MedDRA dictionary. They will also be tabulated by 
SOC, preferred term, and maximum severity. For 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. SAEs will be tabulated similarly.  Separate summaries for ocular AEs 
and non-ocular AEs will also be performed. Ocular AEs will be summarized for study eyes and 
fellow eyes separately.  Any ocular AE that occurred simultaneously to both eyes will be counted 
once for both the study eye and the fellow eye.  Injection-procedure related AEs will be tabulated 
by SOC and preferred term. 
AEs leading to death, SAEs, and AEs leading to discontinuation, if any, will be listed separately. 
Events of special interest will be listed by type of event. For other safety variables, descriptive 
summaries of observed score or status, change or shift from baseline, and/or change after 
injection, whichever applicable, will be performed. 


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9.6. 
Interim Analyses, Primary Analysis, and Analysis of Open-Label 
Period of Study 
An interim analysis is planned when the first 100 subjects complete their Month 5 Visit. There 
are two goals for this interim analysis (1) to assess for futility; and (2) to re-assess the sample 
size. Sample size re-assessment will be performed with the “promising zone” approach as 
follows (Mehta et al., 2011). If the conditional power at the interim analysis is between 50% and 
80%, the suggested sample size increase may be up to 100 subjects (i.e., 50% of the original 
sample size). If, on the other hand, the conditional power is > 80% or < 50%, no change to the 
sample size will take place. If the conditional power is <30%, then the Data Monitoring 
Committee (DMC) would recommend stopping the trial due to futility.  The DMC could 
recommend stopping the trial due to safety concerns at any of the DMC meetings and the interim 
analysis. An independent statistical and programming team will be used to perform this interim 
analysis of unmasked data and the DMC will review the results and make recommendations 
based on the findings. The planned interim analysis will be specified in greater detail in the SAP 
and in the DMC charter.  
The primary analysis of this study is the analysis of the data from the 6-month, double-masked 
period. These data will be quality-checked, soft-locked, and the primary analysis will be 
conducted after all subjects have completed the Month 6 visit or prematurely discontinued from 
the study prior to Month 6. An interim clinical study report will be written documenting the 
primary analysis results.  
Analysis of the open-label period of the study will be performed after the end of the study and 
documented in the final clinical study report.  
9.6.1. 
Data Monitoring Committee (DMC) 
An independent data monitoring committee (DMC) whose members will not be participating in 
the LUMINA study conduct will serve as an advisory board to the Santen senior management 
team. The DMC will periodically review and make recommendations based on interim data; 
unmasked data will only be reviewed in closed DMC sessions without participation of Santen 
personnel. The organization, responsibilities, and procedures of the DMC will be specified in a 
governing charter. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki (Declaration_of_Helsinki, 2008) and Council for 
International Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines (CIOMS_Ethical_Guidelines, 2016).  
 Applicable ICH Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
10.1.2. 
Obligations of Investigators 
In summary, the clinical investigator has agreed to the following obligations: 
 Obtaining signed and dated 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 Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) and ensuring a copy of the letter indicating IRB/IEC approval 
is available at the investigational site before involving any subject in any study 
related activity; submitting verification of the approval to the Sponsor. Providing 
written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC. Submitting the final report to IRB/IEC 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/IEC of all protocol amendments/modifications and obtaining 
approval for the amendment/modification from the IRB/IEC in accordance with local 
requirements before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study subjects; sending the 
Sponsor a copy of the letter from the IRB/IEC approving the 
amendment/modification. 
 Reporting to the Sponsor and the IRB/IEC any SAEs or other significant safety 
findings that occur in the course of the investigation.  
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, and all other applicable local 
regulations.  


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 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/IEC study including the 
subject consent form and recruitment materials; maintaining records of all actions by 
the IRB/IEC regarding the study. 
 Making study records available for inspection by the Sponsor (Santen) and 
representatives of the FDA 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: 
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 Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) indicating that the protocol was approved, including the name and address 
of the IRB/IEC.  
 A copy of the consent form approved by IRB/IEC.  
 A list of current members of the IRB/IEC. 
 Financial disclosure (Section 10.1.3). 
II. While the Study Is in Progress 
 Acknowledgment of receipt of the test and control articles; documentation of 
disposition of all test and control articles. 
 Original Case Report Forms for each subject enrolled in the study. 
 Information regarding all deviations from the protocol. 
 Information regarding all adverse medical events occurring to a subject while 
enrolled in the study. 
 Annual progress report (if study is ongoing for more than one year). Letter from the 
IRB/IEC 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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10.1.3. 
Financial Disclosure 
Investigators and sub-investigators will provide Santen with sufficient, accurate financial 
information as requested to allow Santen to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for one year 
after completion of the study.  
10.1.4. 
Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding 
the study. Each subject should be allowed time to consider the information provided.  
 Subjects must be informed that their participation is voluntary and that they are free 
to discontinue from the study at any time. Subjects or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center.  
 The Informed Consent Form must be approved by the governing IRB/IEC. 
 The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The subject’s signed and dated informed consent must be obtained 
before any protocol-directed procedures are performed. 
 The subject’s signature must be witnessed by the authorized person obtaining the 
informed consent. If the investigator obtains informed consent, then the subject’s 
signature must be witnessed by another individual (e.g., member of the site staff).   
 The investigator or authorized person obtaining the informed consent must also sign 
and date the IRB/IEC-approved Informed Consent Form where designated. 
 Subjects must be re-consented to the most current version of the IRB/IEC-approved 
ICF(s) during their participation in the study.  
 The Principal Investigator(s) must maintain the original, signed Informed Consent 
Form with the study records.  A copy of the ICF(s) must be provided to the subject or 
the subject’s legally authorized representative.  
 A subject who is rescreened is not required to sign another ICF if the rescreening 
occurs within 30 days from the previous ICF signature date. 
 The ICF will contain a separate section that addresses blood samples collected and 
stored for subsequent pharmacogenomics analysis by Santen. The investigator or 
authorized designee will explain to each subject the objectives of this exploratory 
research. Subjects will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. 
See Section 10.1.4.1 for further details on the content of informed consent. 


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10.1.4.1. 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 Informed Consent Form.  
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. Describe the extent, if any, to which CONFIDENTIALITY of records identifying the 
subject will be maintained. Note that regulatory agencies 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 what they consist of, 
OR where further information may be obtained. 
7. Tell whom to contact for ANSWERS to pertinent questions about the research, and 
research subjects’ rights and whom to contact in the event of a research-related INJURY 
to the subject. 
8. State that participation is VOLUNTARY, refusal to participate will involve NO 
PENALTY or loss of benefits to which the subject is otherwise entitled, and the subject 
MAY DISCONTINUE participation at any time without penalty or loss of benefits to 
which the subject is otherwise entitled. 
II. Additional Elements of Informed Consent 
When appropriate, one or more of the following elements of information shall also be provided 
to each subject:  
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. 


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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. 
10.1.5. 
Data Protection 
 Subjects will be assigned a unique identifier by Santen. Any subject records or 
datasets that are transferred to Santen will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
 The subject must be informed that his/her personal study-related data will be used by 
Santen in accordance with local data protection law. The level of disclosure must also 
be explained to the subject.  
 The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
Santen, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.6. 
Source Documents 
The investigator must maintain detailed source documents on all study subjects who are enrolled 
in the study or who undergo screening. Source documents include subject medical records, 
hospital charts, clinic charts, investigator subject study files, as well as the results of diagnostic 
tests (e.g., laboratory tests, OCT). Data for enrolled subjects will be transcribed on to eCRFs 
provided by the Sponsor.  All data should be transcribed completely, promptly, and legibly on 
the eCRFs. Data transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained. Exit forms are to be completed for all 
enrolled subjects, regardless if they did or did not complete the study (e.g., subject 
discontinuation, study termination). 
The investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. The following minimum information 
should be entered into the subject’s medical record: 
 The date the subject entered the study and the subject number   


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 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 concurrent medications 
 Documentation of IP accountability 
 Occurrence and status of any AEs 
 The date the subject exited the study, and a notation as to whether the subject 
completed the study or was discontinued, including the reason for discontinuation 
10.1.7. 
Data Quality Assurance 
 All subject data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to Santen or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
 The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.  
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Trial sites, facilities, laboratories and all data (including sources) and documentation 
must be available for GCP audit by Santen or inspection by competent authorities.  
 Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan and contracts. 
 Santen or designee is responsible for the data management of this study including 
quality checking of the data.  
 Santen assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
 Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  


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 Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator until notified by Santen that the records 
may be destroyed. No records may be transferred to another location or party without 
written notification to Santen.  
10.1.8. 
Sponsor’s Direct Access to Source Data/Documents and IRB/IEC Materials for 
Monitoring and Audit 
10.1.8.1. Study Monitoring 
Santen or Santen’s designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The investigator agrees to allow the 
monitor to inspect the drug storage area, investigational product stocks, drug accountability 
records, subject charts and study source documents, and other records relative to study conduct. 
Before an investigational site can enter a subject into the study, a representative of the Sponsor 
will visit the investigational study site to: 
 Determine the adequacy of the facilities 
 Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Santen or its representatives.  This 
will be documented in a Clinical Study Agreement between Santen or its designee 
and the investigator. 
During the study, a monitor from Santen or representative will have regular contacts with the 
investigational site, for the following: 
 Provide information and support to the investigator(s) 
 Confirm that facilities remain acceptable 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
 Perform source data verification.  This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, 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 non-serious AEs and SAEs have been properly documented on CRFs and 
confirm any safety information requiring expedited reporting to Santen Inc PVU 
(including SAEs, ESIs and Pregnancies) have been forwarded to Santen and those 
SAEs that met criteria for reporting have been forwarded to the IRB/IEC. 
The monitor will be available between visits if the investigator(s) or other staff need information 
or advice. 


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10.1.8.2. Audits and Inspections 
Authorized representatives of Santen, a regulatory authority (national or foreign), an Independent 
Ethics Committee or an Institutional Review Board may visit the site to perform audits or 
inspections, including source data verification.  The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Council for Harmonisation, and any applicable regulatory requirements.  The 
investigator should contact Santen immediately if contacted by a regulatory agency about an 
inspection. 
10.1.9. 
Study and Site Closure 
Santen’s designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of Santen. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Santen or investigator may include but are not 
limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Santen's procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the investigator 
 Discontinuation of further development of the investigational product 
10.1.10. 
Confidentiality and 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 to the investigator that is indicated as confidential. 
The data generated by this clinical study are the property of Santen, Incorporated (the Sponsor) 
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. 
This study will be registered at ClinicalTrials.gov, and results information from this study will be 
submitted to ClinicalTrials.gov. 


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In signing this protocol, the investigator agrees to the release to Santen of the data from this 
study, and acknowledges the above publication policy.  
10.2. 
Clinical Laboratory Tests 
Serum Chemistry and Hematology 
The following is a list of the minimum parameters that will be measured. Other additional 
parameters may also be reported. 
Table 9: 
Serum Chemistry and Hematology 
Chemistry  
Hematology 
Albumin 
red blood cells (RBC) 
Creatinine 
white blood cells (WBC) 
lactate dehydrogenase (LDH) 
differential WBC 
Glucose 
platelets (PLT) 
Calcium 
hemoglobin (HGB) 
Potassium 
hematocrit (HCT) 
Sodium 
mean corpuscular volume (MCV) 
cholesterol (total, HDL and LDL) 
mean corpuscular hemoglobin (MCH) 
Triglycerides 
mean corpuscular hemoglobin conc. (MCHC) 
urea nitrogen 
 
bilirubin (total, direct, indirect) 
 
alkaline phosphatase (ALP) 
 
alanine aminotransferase (ALT) 
 
aspartate aminotransferase (AST) 
 
gamma glutamyl transferase (GGT) 
 
Urinalysis 
The following is a list of the minimum urine parameters that will be measured. Other additional 
urine parameters may also be reported. 
PH 
Protein  
Erythrocytes  
Ketones 
Glucose 
10.3. 
Estimated Amount of Blood Collected from Each Subject 


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10.4. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Table 10: 
Definition of AE 
AE Definition 
 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
Events Meeting the AE Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator (and not related to progression of underlying disease [uveitis], unless judged by the 
investigator to be more severe than expected for the subject's condition). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfil the definition of an AE or SAE.  
Events NOT Meeting the AE Definition  
 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which 
are associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition. 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 


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Table 11: 
Definition of SAE 
A SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it 
were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
4. Results in persistent disability/incapacity 
 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
 
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.  
 
Ocular AEs required to be reported as SAEs: For the purposes of this study, the following ocular AEs will 
be reported as SAEs: 
 
Loss of 6 or more lines of vision (≥30 letters) from baseline 
 
Endophthalmitis (also to be reported as an ESI, Section 8.2.13) 
 
Purulent, infectious conjunctivitis 
 
Retinal detachment (also to be reported as an ESI, Section 8.2.13) 
 
IOP >35 mmHg that persists for at least 7 days despite pharmacologic therapy (also to be 
reported as an ESI, Section 8.2.13) 
 
Other significant ocular events per Investigator’s discretion 
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in 
other situations such as important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should usually be considered 
serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 


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Table 12: 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant AE/SAE information in the CRF. 
 
It is not acceptable for the investigator to send photocopies of the participant’s medical records to 
Santen in lieu of completion of the Santen/AE/SAE CRF page. 
 
There may be instances when copies of medical records for certain cases are requested by Santen. 
In this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission to Santen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will assess intensity for each AE and SAE reported during the study and assign it to 1 
of the following categories:  
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should 
not be confused with an SAE. Severe is a category utilized for rating the intensity of an event; and 
both AEs and SAEs can be assessed as severe. 
 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe. 


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Table 12: 
Recording and Follow-Up of AE and/or SAE (Continued) 
AE and SAE Recording 
Assessment of Causality  Note: During the double-masked period, regardless of the source of the 
reported occurrence of an AE in a subject, the masked investigator will assess the causality of the AE. 
 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 
The following criterial can be used to make a causality judgment: 
 
Related (possibly or probably) 
o There is a clinically plausible time sequence between onset of the AE and 
investigational product administration/protocol procedure; and/or  
o There is a biologically plausible mechanism for investigational product causing or 
contributing to the AE; and 
o The AE may or may not be attributed to concurrent/underlying illness, other drugs, or 
protocol procedures. 
 
Not Related 
o A clinically plausible temporal sequence is inconsistent with the onset of the AE and 
Investigational product administration/protocol procedure; and/or 
o A causal relationship is considered biologically implausible. The investigator will use 
clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
 
The investigator will also consult the Investigational Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
 
For each AE/SAE, the investigator must document in the medical records that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Santen. However, it is very important that the 
investigator always assess causality for every event before the initial transmission of the SAE 
data to Santen. 
 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 


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Table 12: 
Recording and Follow-Up of AE and/or SAE (Continued) 
AE and SAE Recording 
Procedures for Follow-up of AEs and SAEs 
 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Santen to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
 
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide Santen with a copy of any post--mortem findings including 
histopathology.  
 
New or updated information will be recorded in the originally completed CRF. 
 
The investigator will submit any updated SAE data to Santen within 24 hours of receipt of the 
information. 
Table 13: 
Reporting of SAEs 
SAE Reporting to Santen via an Electronic Data Collection Tool 
 
The primary mechanism for reporting an SAE to Santen will be the electronic data collection 
tool. 
 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool 
(see next section) in order to report the event within 24 hours. 
 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
 
After the study is completed at a given site, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then the 
site can report this information on a paper SAE form (see next section) or to Santen Global 
Pharmacovigilance (Table 1). 
 
Contacts for SAE reporting can be found in Table 1. 
 
For SAE supporting information (i.e. X-ray reports, hospital summaries, etc.) that are not 
included in the EDC format, follow a procedure analogous to the manual SAE reporting process 
(see next section).  
SAE Reporting to Santen via Paper CRF (If Electronic Data Collection Tool is Unavailable) 
 
Complete both the paper AE and SAE Forms (located in your site regulatory binder) 
 
Attach a Fax Cover Sheet with your contact information and fax to Santen Global 
Pharmacovigilance (Table 1).  
 
In the rare circumstance of the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the paper AE and SAE forms sent by overnight mail or courier service. 
 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames. 
 
Contacts for SAE reporting can be found in Table 1. 


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10.5. 
List of Abbreviations and Specialist Terms 
The following abbreviations and specialist terms are used in this study protocol. 
Table 14: 
List of Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
µg 
Micrograms 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ADaM 
Analysis Data Model 
ANCOVA 
Analysis of covariance 
AST 
aspartate aminotransferase 
BCVA 
Best-Corrected Visual Acuity 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CMH 
Cochran–Mantel–Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form (paper or electronic) 
CRO 
Contract Research Organization 
CST 
Central subfield thickness 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ESI 
Event of Special Interest 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FP 
Fundus photography 
GCP 
Good Clinical Practice 
GEE 
General estimating equation 
GGT 
Gamma glutamyl transferase 
hCG 
Human chorionic gonadotropin 
HCT 
Hematocrit 


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Table 14: 
List of Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Explanation 
HDL 
High-density lipoproteins 
HGB 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoproteins 
LOCF 
Last Observation Carried Forward 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mL 
Milliliters 
MMRM 
Mixed-effects model for repeated measures 
mTOR 
Mammalian target of rapamycin 
NIU-PS 
Non-infectious uveitis of the posterior segment of the eye 
NPDR 
Non-proliferative diabetic retinopathy 
OCT 
Optical coherence tomography 
PDR 
Proliferative diabetic retinopathy 
PGx 
Pharmacogenomic 
PLT 
Platelets 
PP 
Per-protocol 
PVU 
Pharmacovigilance Unit 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Activities 


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Table 14: 
List of Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Explanation 
SOC 
System Organ Class 
SDTM 
Study Data Tabulation Model 
SUN 
Standardization of Uveitis Nomenclature 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
VA 
Visual Acuity 
VFQ-25 
Visual Functioning Questionnaire 
VH 
Vitreous haze 
WBC 
White blood cell 


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11. 
LIST OF REFERENCES 
1. 
CIOMS_Ethical_Guidelines. (2016).  International Ethical Guidelines for Health-related 
Research Involving Humans Prepared by the Council for International Organizations of 
Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO). 
CIOMS Ethical Guidelines. 
 
2. 
Declaration_of_Helsinki. (2008).  World Medical Association Declaration of Helsinki 
Ethical Principals for Medical Research Involving Human Subjects. Declaration of 
Helsinki. 
 
3. 
Durrani, O., Tehrani, N., Marr, J., Moradi, P., Stavrou, P., Murray, P. (2004).  Degree, 
duration, and causes of visual loss in uveitis. Br J Ophthalmology. 88:1159-62. 
 
4. 
Ibrahim, M., Sepah, Y., Watters, A., Bittencourt, M., Vigil, E., Do, D., Nguyen, Q. 
(2015).  One-Year Outcomes of the SAVE Study: Sirolimus as a Therapeutic Approach 
for UVEitis. Transl Vis Sci Technol. 4:1-13. 
 
5. 
Jabs, D., Nussenblatt, R., Rosenbaum, J. (2005).  Standarization of Uveitis Nomenclature 
for Reporting Clinical Data. Results of the First International Workshop. American 
Journal of Ophthalmology. 140(3):509-16. 
 
6. 
Mehta, C. R., Pocock, S. J. (2011).  Adaptive increase in sample size when interim results 
are promising: a practical guide with examples. Stat Med. 30(28):3267-84. doi: 
10.1002/sim.4102. PubMed PMID: 22105690. 
 
7. 
National_Eye_Institute. (2000).  National Eye Institute Visual Functioning 
Questionnaire-25 (VFQ-25), Version 2000, Interviewer Administered Format. RAND 
under Sponsorship of National Eye Institute, NIH. 
 
8. 
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. 
 
9. 
Nussenblatt, R., Palestine, A., Chan, C., Roberge, F. (1985).  Standardization of Vitreal 
Inflammatory Activity in Intermediate and Posterior Uveitis. Ophthalmology. 92(4):467-
71. 
 
10. 
Sun Working, G. (2005).  PERSPECTIVES Standardization of Uveitis Nomenclature or 
Reporting Clinical Data. Results of the First International Workshop. American Journal 
of Ophthalmology. 140(3):509-16. 
 


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12. 
APPENDICES 
12.1. 
Appendix 1: National Eye Institute Visual Functioning 
Questionnaire – 25 (VFQ-25) 
National Eye Institute Visual Functioning Questionnaire - 25 (VFQ-25) version 2000 
(Interviewer Administered Format) plus appendix is provided below.  


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12.2. 
Appendix 2: ETDRS Visual Acuity Chart Procedure 
Tumbling “E” chart is available for subjects who cannot read alphabet. 
12.2.1. 
Procedures for Refraction and Vision Testing 
Refraction and visual acuity measurements will be performed for all subjects by trained vision 
examiners only. The name and certification number of the vision examiner should be 
documented in the subject’s source document at each visit. When possible, visual acuity 
examiners should not have access to the subject’s chart or previous visual acuity testing results. 
Only the previous refraction should be made available. 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.   
12.2.1.1. 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 
12.2.1.2. 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 
before the examination. 
12.2.1.3. 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. 


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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. 
12.2.1.4. 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 Santen-provided worksheet which will be included in the source 
documents. At each follow-up visit, 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 
continued 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. 


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12.2.1.5. 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.   
12.2.1.5.1. 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 
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 


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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 
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. 


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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. 
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 
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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. 
12.2.1.6. 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 
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 
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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.   
12.2.1.7. 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. 
12.2.1.7.1. 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.   
12.2.1.7.2. 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 
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. 
12.2.1.7.3. 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. 
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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.” 
Table 15: 
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 
 


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12.3. 
Appendix 3: Adverse Event Case Report Form Items and Terms 
Concise Description of Event: 
A concise description of the signs, symptoms, complaints, or 
diagnosis of the subject’s problem (e.g., nasal congestion). Complete 
one AE form for related symptoms that can be grouped as one 
condition (e.g., If a subject complains of sneezing, nasal congestion, 
watery eyes, the AE is described as cold symptoms). If two 
independent events occur at the same time, separate AE forms must 
be completed for each event. 
Affected Eye(s): 
Indicate if ocular event is OD, OS, or OU. Non-ocular events should 
be recorded as N/A. 
Adverse Event Serious?: 
If AE is serious or an Event of Special Interest, Santen must be 
notified immediately (within 24 hours). Complete both the AE and 
the SAE eCRFs in the EDC system. In the event the EDC system is 
unavailable, and your site needs to report an SAE, please follow the 
manual process described in the body of the protocol under 
“Reporting of SAEs.”   
Date of Event Onset: 
The date the event started. 
Maximum Severity of Event: 
Record the severity of the AE according to the following definitions: 
Mild: Aware or unaware of event, but easily tolerated 
Moderate: Discomfort enough to cause interference with usual 
activity 
Severe: Incapacitating; unable to work or perform usual activity 
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. Record 
that the severity of the headaches ranged from mild to moderate in 
the comment section of the form.  
If an event occurs with each injection (e.g., eyes burn mild to 
moderate for 5 minutes after every injection), record the maximum 
severity of the individual incident. In the example above, the severity 
is moderate. Record that the severity of the event ranged from mild 
to moderate in the comment section of the form.  
Action Taken as Related to 
this AE:  
Indicate the action taken as a result of the AE. If the frequency of 
Investigational product administration was changed or discontinued 
temporarily or if surgery was required, provide more detailed 
explanation in the comment section of the form. If “Other” is 
indicated, specify the action taken. 


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Outcome of Event: 
Indicate the outcome of the AE and provide resolution date or date 
of death.   
For intermittent events (e.g., intermittent headache) and events that 
occur with each injection (e.g., eyes burn for 5 minutes after every 
injection), the date should reflect when the last occurrence resolved 
or stopped. For example, if a subject has an intermittent headache 
from 12/14/2010 until 12/21/2010 and each individual headache lasts 
3 hours a day, then the date of resolution is 12/21/2010 (NOT 
12/14/2010). 
If treatment was initiated, then include the treatment and duration in 
the comments section (e.g., subject took acetaminophen for 
headache on 12/14/2010, 12/17/2010 and 12/20/2010). 
Relationship to Study 
Drug/Investigational 
Product: 
Indicate if there is a reasonable possibility that the AE may have 
been caused by the study drug/investigational product with a Yes or 
No response. A “reasonable possibility” means there is evidence to 
suggest a causal relationship between the study drug/investigational 
product and the AE.  
If response is No, select the possible alternative explanation of the 
event from the list provided. 
Relationship to Injection 
Procedure: 
The event cannot be attributed to the subject’s underlying medical 
condition or other concomitant therapy and there is a compelling 
temporal relationship between the onset of the event and the 
injection procedure that leads the investigator to believe there is 
evidence of a reasonable causal relationship. 
 
For SAE supporting information (i.e., X-ray 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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12.4. 
Appendix 4: 
Protocol Amendment 3 Summary of Changes 
Global Changes: 
Herein is a summary of changes made to protocol amendment 2 
dated 29 Septemeber 2020 and reflected in Amendment 3 dated 
14JUL2021. New text is identified in bold and italicized and deleted 
text with bold/strikethrough. 
 Updated Company/Sponsor Approver(s) 
 Updated Contact Information.  
 Updated changes per FDA comments  
In addition to the changes included in this document, there are 
administrative updates made throughout the protocol, including 
clarifications, changes in wording, punctuation, abbreviations, date, 
number or format for clarity and consistency; these changes are not 
listed in this document for conciseness. 
 
 
Section: 
Table 2, Table 4, Footnotes, Section 9.1  
Original Text: 
Table 2: Study Objectives and Endpoints  
Study Objectives  
Primary (efficacy vs. sham): The primary objective of this study is to 
evaluate the efficacy of intravitreal injection of 440 μg DE-109 every 2 
months as compared with sham for the treatment of active, non-infectious 
uveitis of the posterior segment of the eye. 
Corresponding Study Endpoints 
Primary efficacy endpoint: 
 
VH 0 responsea at Month 5 
Key secondary efficacy endpoints: 
 
VH 0 or 2-unit responseb at Month 5 
 
VH 0 response at Month 3 
 VH 0 or 2-unit response at Month 3 
Note: Overall Type I error rate will be maintained at 0.05 (two-sided) across 
primary and key secondary efficacy endpoint treatment comparisons.  
Other secondary efficacy endpoints:  
 
VH 0 or 0.5+ responsec at Month 5 
 
VH 0 or 0.5+ response at Month 3 
 
Corticosteroid tapering successd with resolution at Month 5 


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 
Corticosteroid tapering success with resolution at Month 3 
 
BCVA (Best-Corrected Visual Acuity) 3-line responsee at Month 5 
 
BCVA 3-line response at Month 3 
 
Change from baseline in central subfield thickness (CST) at Month 5 as 
measured by OCT 
 
Change from baseline in CST at Month 3 as measured by OCT 
 
Use of rescue therapy before Month 5 
 
Use of rescue therapy before Month 3 
Note:  Additional secondary and exploratory efficacy endpoints will be specified 
in the Statistical Analysis Plan. 
Footnotes 
Note: Vitreous haze (VH) will be scored using the modified Standardized Uveitis 
Nomenclature (SUN) scale.  
aVH 0 response (resolution of inflammation) is defined as a VH score of 0 in the study eye 
at a specified follow up visit based on the modified SUN scale.  
b  VH 0 or 2-unit response is defined as having a VH score of 0 or a decrease 
(improvement) of at least 2 units (i.e., 2+ to 0, 3+ to 1+, or 4+ to 2+) from baseline in the 
study eye in VH score at a specified follow up visit based on the modified SUN scale.   
c VH 0 or 0.5+ response (remission of inflammation) is defined as a VH score of 0 or 
0.5+ in the study eye at a specified follow-up visit based on the modified SUN scale.  
d Corticosteroid tapering success with resolution is defined as achievement of a 
prednisone-equivalent oral dose of 0 mg/day and a VH score of 0 in the study eye at a 
specified follow-up visit. This endpoint is assessed based on the Intent-to-Taper 
population (study eyes of subjects who received systemic [oral] corticosteroids at a 
stable prednisone-equivalent dose between ≥15 mg/day and ≤40 mg/day that has 
remained stable for at least 1 week [7 days] prior to and including on Day 1). 
e BCVA 3-line response is defined as an increase (improvement) of at least 3 lines (15 
ETDRS letters) from baseline in BCVA at a specified follow-up visit. This endpoint is 
assessed based on eyes with a baseline best-corrected visual acuity (BCVA) ≤ 70 
ETDRS letters (Snellen equivalent of 20/40 or worse). 
Revised Text: 
Table 2: Study Objectives, Estimands, and Endpoints 
Study Objectives and Estimands 
Primary objective (efficacy vs. sham): The primary objective of this study 
is to evaluate the efficacy of intravitreal injection of 440 μg DE-109 every 
2 months as compared with sham for the treatment of active, 
non-infectious uveitis of the posterior segment of the eye. 
Primary estimand: Vitreous haze 0 (VH0) response rate in DE-109 440 
µg group vs. Sham group at Month 5 in all study eyes that received at 
least one dose of the study treatment where all eyes that were rescued due 
to worsening of uveitis or discontinued from the study due to lack of 
efficacy or due to adverse event before Month 5 will be treated as non-
responders. For study eyes that were rescued for any other reasons or 
had missing data due to other reasons, imputation by the multiple 
imputation-based approach will be used.  
Treatment policy estimand: VH0 response rate in DE-109 440 µg group 
vs. Sham group at Month 5 in all study eyes that received at least one 


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dose of the study treatment regardless of whether subjects have received 
rescue therapy or discontinued from the study due to lack of efficacy or 
due to adverse event. For study eyes that had missing data due to any 
reason, imputation by the multiple imputation-based approach will be 
used. 
Composite estimand: Mean composite score in DE-109 440 µg group vs. 
Sham group at Month 3 and at Month 5 in all study eyes that received at 
least one dose of study treatment. Each study eye will be assigned one of 
the following scores: 
 Score = 3 if a study eye achieved VH score of 0 at the specified 
visit without taking any rescue therapies that could affect VH 
score prior to the specified visit  
 Score = 2 if a study eye had at least improved by 2 units in VH 
(compared to baseline) at the specified visit without taking any 
rescue therapies that could affect VH score prior to the specified 
visit   
 Score = 1 if a study eye achieved VH score of 0.5+ at the specified 
visit without taking any rescue therapies that could affect VH 
score prior to the specified visit   
 Score = -1 if a study eye got rescued due to worsening of uveitis or 
discontinued from the study due to lack of efficacy or due to 
adverse event prior to the specified visit  
 Score = 0 if otherwise 
Corresponding Study Endpoints  
Primary efficacy endpoint:  
 VH 0 responsea at Month 5 
Key secondary efficacy endpoints:  
 VH 0 or 2-unit responseComposite endpointb at Month 5 
 VH 0 response at Month 3 
 VH 0 or 2-unit responseComposite endpoint at Month 3 
Note: Overall Type I error rate will be maintained at 0.05 (two-sided) 
across primary and key secondary efficacy endpoint treatment 
comparisons.  
Other secondary efficacy endpoints: 
 VH 0 or 2-unit responsec at Month 5 
 VH 0 or 2-unit response at Month 3 
 VH 0 or 0.5+ responsecresponsed at Month 5 
 VH 0 or 0.5+ response at Month 3 
 Corticosteroid tapering successdsuccesse with resolution at Month 5 
 Corticosteroid tapering success with resolution at Month 3 


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 BCVA (Best-Corrected Visual Acuity) 3-line responseeresponsef at 
Month 5 
 BCVA 3-line response at Month 3 
Footnotes: 
Note: Vitreous haze (VH) will be scored using the modified Standardized 
Uveitis Nomenclature (SUN) scale.  
a VH 0 response (resolution of inflammation) is defined as a VH score of 0 
in the study eye at a specified follow up visit based on the modified SUN 
scale. 
b  Refer to composite score scales defined in the composite estimand in 
this table.  
cb VH 0 or 2-unit response is defined as having a VH score of 0 or a 
decrease (improvement) of at least 2 units  
(i.e., 2+ to 0, 3+ to 1+, or 4+ to 2+) from baseline in the study eye in VH 
score at a specified follow up visit based on the modified SUN scale.   
dc VH 0 or 0.5+ response (remission of inflammation) is defined as a VH 
score of 0 or 0.5+ in the study eye at a specified follow-up visit based on 
the modified SUN scale.  
ed Corticosteroid tapering success with resolution is defined as 
achievement of a prednisone-equivalent oral dose of 0 mg/day and a VH 
score of 0 in the study eye at a specified follow-up visit. This endpoint is 
assessed based on the Intent-to-Taper population (study eyes of subjects 
who received systemic [oral] corticosteroids at a stable prednisone-
equivalent dose between ≥15 mg/day and ≤40 mg/day that has remained 
stable for at least 1 week  
[7 days] prior to and including on Day 1). 
fe BCVA 3-line response is defined as an increase (improvement) of at least 
3 lines (15 ETDRS letters) from baseline in BCVA at a specified follow-
up visit. This endpoint is assessed based on eyes with a baseline best-
corrected visual acuity (BCVA) ≤ 70 ETDRS letters (Snellen equivalent 
of 20/40 or worse). 
Rationale: 
This change is in accordance with the ICH E9 (R1) addendum, to define 
the primary estimand and other estimands of the study. Key secondary 
endpoints are modified to be aligned with study estimands.  
 
 
Section: 
Section 1.1, Section 4.1, Section 6.5.6, and Section 8.2.13 
Original Text: 
Protocol-Specified Rescue Therapy Criteria: 
Rescue therapy is defined as any treatment that would have a therapeutic 
effect on NIU-PS. Rescue therapy is prohibited during the study unless 


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there is worsening of uveitis as demonstrated by one or more of the 
following three rescue criteria:  
1. Worsening of uveitis in the study eye as indicated by at least a 
2-step increase in VH score (i.e., 0 to ≥ 1+, 0.5+ to ≥ 1.5+, 1+ 
to ≥ 2+, 1.5+ to ≥ 3+, or 2+ to 4+) post baseline as compared to 
the baseline (Day 1) VH score. 
 
 
The DE-109 ESIs are specific to the study eye only and are as follows:  
 Clinically significant new or worsening of uveitis, defined as 
satisfaction of any of the following:  
 Worsening of uveitis in the study eye as indicated by at 
least a 2-step increase in VH score (i.e., 0 to ≥ 1+, 0.5+ to 
≥ 1.5+, 1+ to ≥ 2+, 1.5+ to ≥ 3+, or 2+ to 4+) as compared 
to the baseline (Day 1) VH score or the best achieved VH 
score post-baseline. 
Revised Text: 
Protocol-Specified Rescue Therapy Criteria: 
Rescue therapy is defined as any treatment that would have a therapeutic 
effect on NIU-PS. Rescue therapy is prohibited during the study unless 
there is worsening of uveitis as demonstrated by one or more of the 
following three rescue criteria:  
11. Worsening of uveitis in the study eye as indicated by at least a 2-
step increase in VH score (i.e., 0 to ≥ 1+2+, 0.5+ to ≥ 1.5+3+, 1+ to 
≥ 2+3+, 1.5+ to ≥ 4+3+, or 2+ to ≥ 4+) post baseline as compared 
to the baseline (Day 1) VH score or best achieved VH score post 
baseline. 
 
 
The DE-109 ESIs are specific to the study eye only and are as follows:  
 Clinically significant new or worsening of uveitis, defined as 
satisfaction of any of the following:  
Worsening of uveitis in the study eye as indicated by at least a 2-step 
increase in VH score (i.e., 0 to ≥ 1+2+, 0.5+ to ≥ 1.5+3+, 1+ to ≥ 2+3+, 
1.5+ to ≥ 4+3+, or 2+ to ≥ 4+) as compared to the baseline (Day 1) VH 
score or the best achieved VH score post-baseline. 
Rationale: 
Updated to reflect that a ½ unit is not recognized as a step change in the 
vitreous haze, so only whole unit increases in the vitreous haze are used in 
the rescue criteria and Events of Special Interest definitions. 


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Section: 
Section 1.1, Section 4.1, Section 9.6 
Original Text: 
Interim Analyses, Primary Analysis, and Analysis of Open-Label 
Period: 
An interim analysis is planned when the first 100 subjects complete their 
Month 5 Visit.  There are two goals for this interim analysis (1) to assess 
for futility; and (2) to re-assess the sample size. Alpha spending for this 
interim analysis will be 0.00001. Sample size re-assessment will be 
performed with the “promising zone” approach as follows (Mehta et al., 
2011). If the conditional power at the interim analysis is between 50% and 
80%, the suggested sample size increase would be 100 subjects (i.e., 50% 
of the original sample size). If, on the other hand, the conditional power is 
> 80% or < 50%, no change to the sample size will take place. If the 
conditional power is <10%, then the Data Monitoring Committee (DMC) 
would recommend stopping the trial due to futility.  The DMC could 
recommend stopping the trial due to safety concerns at any of the DMC 
meetings and the interim analysis. An independent statistical and 
programming team will be used to perform this interim analysis of 
unmasked data and the DMC will review the results and make 
recommendations based on the findings. The planned interim analysis will 
be specified in greater detail in the SAP and in the DMC charter. 
Revised Text: 
Interim Analyses, Primary Analysis, and Analysis of Open-Label 
Period: 
An interim analysis is planned when the first 100 subjects complete their 
Month 5 Visit.  There are two goals for this interim analysis (1) to assess 
for futility; and (2) to re-assess the sample size. Alpha spending for this 
interim analysis will be 0.00001. Sample size re-assessment will be 
performed with the “promising zone” approach as follows (Mehta et al., 
2011). If the conditional power at the interim analysis is between 50% and 
80%, the suggested sample size increase would be may be up to 100 
subjects (i.e., 50% of the original sample size). If, on the other hand, the 
conditional power is > 80% or < 50%, no change to the sample size will 
take place. If the conditional power is <10%30%, then the Data 
Monitoring Committee (DMC) would recommend stopping the trial due to 
futility.  The DMC could recommend stopping the trial due to safety 
concerns at any of the DMC meetings and the interim analysis. An 
independent statistical and programming team will be used to perform this 
interim analysis of unmasked data and the DMC will review the results and 
make recommendations based on the findings. The planned interim 
analysis will be specified in greater detail in the SAP and in the DMC 
charter. 


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Rationale: 
Change in the futility threshold to allow trial to stop earlier if the treatment 
does not show enough evidence to provide benefits to the subjects. 
 
Section: 
Section 8.1.7 
Original Text: 
Double-Masked Treatment Period, Month 3 
Note: Subjects must fast 8 hours prior to the blood draw for hematology 
and chemistry laboratory tests taken at Month 3. 
Allowable visit window:  Day 90 ± 3 days 
Visit details: 
Perform the following assessments in both eyes: 
 Perform physical examination. 
 Record vital signs. 
 Collect fasting blood for serum chemistry and hematology tests 
for laboratory analysis. 
 Obtain urine sample for urinalysis. 
 Assess BCVA using ETDRS charts. 
 Administer dilation eye drops (1% Mydriacyl and 2.5% 
phenylephrine or equivalent applied topically). 
 Administer the VFQ-25. 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform fluorescein angiography. 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic 
corticosteroid medication status). 
Record the study visit in the EDC system (Medidata) for Month 3. 


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Revised Text: 
Double-Masked Treatment Period, Month 3 
Note: Subjects must fast 8 hours prior to the blood draw for 
hematology and chemistry laboratory tests taken at Month 3. 
Allowable visit window:  Day 90 ± 3 days 
Visit details: 
Perform the following assessments in both eyes: 
 Perform physical examination. 
 Record vital signs. 
 Collect fasting blood for serum chemistry and hematology 
tests for laboratory analysis.  
 Obtain urine sample for urinalysis. 
 Assess BCVA using ETDRS charts. 
 Administer dilation eye drops (1% Mydriacyl and 2.5% 
phenylephrine or equivalent applied topically). 
 Adminster the VFQ-25 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform fluorescein angiography. 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic 
corticosteroid medication status). 
Record the study visit in the EDC system (Medidata) for Month 3. 
Rationale: 
Our primary endpoint has changed from Month 3 to Month 5.  Physical 
exam and vital signs, laboratory safety tests, and VFQ-25 have been 
moved to align these safety assessments and the patient-reported outcomes 
with the primary endpoint. 
 
Section: 
Section 8.1.9.  


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Original Text: 
Double-Masked Treatment Period, Month 5 
Allowable visit window:  Day 150 ± 3 days 
Visit details: 
Perform the following assessments in both eyes: 
 Assess BCVA using ETDRS charts. 
 Administer dilation eye drops (1% Mydriacyl and 2.5% 
phenylephrine or equivalent applied topically). 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform fluorescein angiography. 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic 
corticosteroid medication status).  
Record the study visit in the EDC system (Medidata) for Month 5. 
Revised Text: 
Double-Masked Treatment Period, Month 5 
Note: Subjects must fast 8 hours prior to the blood draw for hematology 
and chemistry laboratory tests taken at Month 5. 
Allowable visit window:  Day 150 ± 3 days 
Visit details: 
Perform the following assessments in both eyes: 
 Perform physical examination. Note: if this was performed at 
Month 3 under a previous version of the protocol it does not 
need to be repeated. 
 Record vital signs. Note: if this was performed at Month 3 
under a previous version of the protocol it does not need to be 
repeated. 
 Collect fasting blood for serum chemistry and hematology 
tests for laboratory analysis. Note: if these samples were 
collected at Month 3 under a previous version of the protocol 
they do not need to be repeated. 


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 Obtain urine sample for urinalysis. Note: if this sample was 
collected at Month 3 under a previous version of the protocol 
it does not need to be repeated. 
 Assess BCVA using ETDRS charts. 
 Administer dilation eye drops (1% Mydriacyl and 2.5% 
phenylephrine or equivalent applied topically). 
 Administer the VFQ-25. Note: if this was performed at Month 
3 under a previous version of the protocol it does not need to 
be repeated. 
 Measure IOP. 
 Perform slit-lamp biomicroscopy. 
 Perform indirect ophthalmoscopy. 
 Obtain fundus photography. 
 Perform fluorescein angiography. 
 Perform OCT. 
 Assess for adverse events. 
 Record concomitant medications (including systemic 
corticosteroid medication status). 
Record the study visit in the EDC system (Medidata) for Month 5. 
Rationale: 
Our primary endpoint has changed from Month 3 to Month 5.  Physical 
exam and vital signs, laboratory safety tests, and VFQ-25 have been 
moved to align these safety assessments and patient-reported outcomes 
with the primary endpoint. 
 
Section: 
Section 8.2.3 
Original Text: 
8.2.3.. Anterior Chamber Cells 
Slit-lamp biomicroscopy will be used to assess anterior chamber cells. The 
following scale will be used to measure anterior chamber cells:   


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Anterior Chamber Cells 
(1 mm x 1 mm slit beam) 
0 
<1 cells 
0.5+ 
1-5 cells 
1+ 
6-15 cells 
2+ 
16-25 cells 
3+ 
26-50 cells 
4+ 
>50 cells 
 
Revised Text: 
8.2.3.. Anterior Chamber Cells 
Slit-lamp biomicroscopy will be used to assess anterior chamber cells. The 
following scale will be used to measure anterior chamber cells:   
Anterior Chamber Cells 
(1 mm x 1 mm slit beam) 
0 
0 <1 cells 
0.5+ 
1-5 cells 
1+ 
6-15 cells 
2+ 
16-25 cells 
3+ 
26-50 cells 
4+ 
>50 cells 
 
Rationale: 
Updated to provide clarity. 
 
 
Section: 
Section 9.2  
Original Text: 
9.1 Statistical Hypotheses  
The primary efficacy endpoint (VH 0 response at Month 5) will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test with Row Mean 
Scores statistic, stratified by the number of enrolled eyes from a subject 
(one eye or two eyes) and region (US or non-US). The null (H0) and 
alternative (H1) hypotheses are as follows:  
Revised Text: 
9.2 Statistical Hypotheses  


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The primary efficacy endpoint (VH 0 response at Month 5) will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test with Row Mean 
Scores statistic, stratified by the number of enrolled eyes from a subject 
(one eye or two eyes), baseline systemic (oral) corticosteroid use (yes or 
no), and region (US or non-US). The null (H0) and alternative (H1) 
hypotheses are as follows:  
Rationale: 
This is addition of language to reflect that subjects are stratified based on 
baseline systemic (oral) corticosteroid use in addition to number of eyes 
and region, and that analysis will account for all stratifying factors. 
 
Section: 
Section 9.4 
Original Text: 
9.3 Population for Analyses 
The following analysis populations for study analyses are defined: Intent-
to-Treat (ITT), Safety, Per-Protocol (PP), Intent-to-Taper, Macular Edema, 
Vision 20/40 or Worse: 
 The ITT population will consist of all study eyes. The ITT 
population will be the analysis population for the primary 
analysis and will use treatment as randomized.  
 For analyses of ocular AEs and safety parameters assessed per 
eye, the Safety population will consist of all study eyes which 
received at least one administration of IP. For analyses of non-
ocular AEs and safety parameters assessed per subject, the 
Safety population will consist of all subjects who received at 
least one administration of IP. 
Revised Text: 
9.4 Population for Analyses  
The following analysis populations for study analyses are defined: Intent-
to-Treat (ITT)Full Analysis Set (FAS), Safety, Per-Protocol (PP), Intent-
to-Taper, Macular Edema, Vision 20/40 or Worse: 
 The ITTFAS population will consist of all study eyes that are 
randomized and received at least one administration of study 
treatment. The ITT FAS population will be the analysis 
population for the primary analysis and will use treatment as 
randomized.  
Rationale: 
Change in the definition of the analysis population from Intent-to-treat 
(ITT) to Full Analysis Set (FAS) to align the analysis population with the 
study estimands, as deemed acceptable by FDA review comments. 
  
 


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Section: 
Section 9.5.1 
Original Text: 
Section 9.4.1 Handling of Missing Values 
In the analysis of VH 0, VH 0 or 2-unit decrease (improvement), and VH 0 
or 0.5+ responses: 
 Subjects who (a) receive rescue therapy for conditions other 
than worsening of uveitis or (b) are rescued due to the 
worsening of uveitis but do not meet the protocol-defined 
rescue criteria, missing VH scores subsequent to receiving 
rescue therapy will be imputed using the last observed VH 
score before receiving rescue therapy.  
 Missing VH scores of subjects not rescued before Month 
5/Month 3 visit will be imputed using a last-observation-carried 
forward (LOCF) approach.   
The response status will then be determined based on the observed or 
imputed VH scores. Sensitivity analyses using other imputation methods 
will be performed. 
For medical events including AEs, completely or partially missing onset 
and resolution dates will be imputed in a conservative fashion to be 
detailed in the SAP.  The same rules will be followed to impute completely 
or partially missing start and end dates of non-study medications. 
Unless specified otherwise, descriptive summaries will be based on 
observed cases.  No imputation of missing scores will be implemented. 
Additional details on handling of missing data will be provided in the SAP. 
Revised Text: 
Section 9.5.1 Handling of Missing Values  
In the analysis of VH 0, VH 0 or 2-unit decrease (improvement), and VH 0 
or 0.5+ responses: 
 Subjects who (a) receive rescue therapy for conditions other 
than worsening of uveitis or (b) are rescued due to the 
worsening of uveitis but do not meet the protocol-defined 
rescue criteria, missing VH scores subsequent to receiving 
rescue therapy will be imputed using a the last observed VH 
scoremultiple imputation-based approach before receiving 
rescue therapy.  
 Missing VH scores of subjects not rescued before Month 
5/Month 3 visit will be imputed using a multiple imputation-
based approachlast-observation-carried forward (LOCF) 
approach.   


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The multiple imputation model will include vitreous haze measures at 
preceding visits and baseline characteristics. The response status will then 
be determined based on the observed or imputed VH scores. 
No imputation is needed for composite score analysis as eyes with 
missing VH scores will be assigned a score of zero, unless they are 
rescued due to the worsening of uveitis or discontinued from the study 
due to lack of efficacy or adverse event (which will be assigned with a 
score of -1).  
For medical events including AEs, completely or partially missing onset 
and resolution dates will be imputed in a conservative fashion to be 
detailed in the SAP.  The same rules will be followed to impute completely 
or partially missing start and end dates of non-study medications. 
Unless specified otherwise, descriptive summaries will be based on 
observed cases.  No imputation of missing scores will be implemented. 
Additional details on handling of missing data and sensitivity analyses on 
imputation methods  will be provided in the SAP. 
Rationale: 
The approach to missing data will be changed from LOCF to multiple 
imputation to be aligned with the study estimands.   
 
Section: 
Table 8, Footnotes  
Original Text: 
Endpoint Statistical Analysis Secondary endpoints 
Key secondary efficacy endpoints:  
 
VH 0 or 2-unit responseb at Month 5 
 
VH 0 response at Month 3 
 
VH 0 or 2-unit response at Month 3 
 
Other secondary efficacy endpoints  
(double-masked period of study):  
 
VH 0 or 0.5+ responsec at Month 5 
 
VH 0 or 0.5+ response at Month 3 
 
Corticosteroid tapering success with resolutiond at Month 5 
 
Corticosteroid tapering success with resolution at Month 3 
 
BCVA 3-line responsee at Month 5 
 
BCVA 3-line response at Month 3 
 
Change from baseline in central subfield thickness (CST) at Month 5 as 
measured by OCT 
 
Change from baseline in CST at Month 3 as measured by OCT 
 
Use of rescue therapy before Month 5 


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 
Use of rescue therapy before Month 3 
 
Statistical Analysis Methods 
For the primary analysis of VH 0 response at Month 5, the Cochran-Mantel-
Haenszel (CMH) test with Row Mean Scores statistic stratified by number of 
enrolled eyes from a subject (one eye or two eyes) and region (US or non-US) 
will be conducted. Logistic generalized estimating equation (GEE) model will be 
used as a sensitivity analysis. 
A hierarchical approach will be used to control the overall Type I error rate 
associated with the multiple comparisons across the primary and the key 
secondary efficacy endpoints at the 0.04999 level (two-sided) .  
If the hypothesis testing for the primary endpoint successfully rejects the null 
hypothesis, the first key secondary efficacy endpoint will be tested, and so on.  
For the other secondary endpoints, no multiplicity adjustment will be made. 
For secondary efficacy endpoints during double-masked period: 
All binary secondary endpoints will be analyzed using the Cochran-Mantel-
Haenszel (CMH) test with Row Mean Scores statistic stratified by number of 
enrolled eyes from a subject (one eye or two eyes) and region (US vs. non-US). 
Change-from-baseline endpoints will be analyzed by a mixed-effects model for 
repeated measures (MMRM) using observed cases. The statistical model for the 
analysis of each continuous secondary endpoint may be adjusted if it fails to 
converge. More details regarding model specifications will be provided in the 
SAP. 
 
Footnotes:  
Note: Vitreous haze (VH) will be scored using the modified Standardized Uveitis 
Nomenclature (SUN) scale.  
a VH 0 response (resolution of inflammation) is defined as a VH score of 0 in the study 
eye at a specified follow up visit based on the modified SUN scale.  
b  VH 0 or 2-unit response is defined as having a VH score of 0 or a decrease 
(improvement) of at least 2 units (i.e., 2+ to 0, 3+ to 1+, or 4+ to 2+) from baseline in the 
study eye in VH score at a specified follow up visit based on the modified SUN scale.   
c VH 0 or 0.5+ response (remission of inflammation) is defined as a VH score of 0 or 
0.5+ in the study eye at a specified follow-up visit based on the modified SUN scale.  
d Corticosteroid tapering success with resolution is defined as achievement of a 
prednisone-equivalent oral dose of 0 mg/day and a VH score of 0 in the study eye at a 
specified follow-up visit. This endpoint is assessed based on the Intent-to-Taper 
population (study eyes of subjects who received systemic [oral] corticosteroids at a 
stable prednisone-equivalent dose of between ≥15 mg/day and ≤40 mg/day that has 
remained stable for at least 1 week [7 days] prior to and including on Day 1). 
e BCVA 3-line response is defined as an increase (improvement) of at least 3 lines (15 
ETDRS letters) from baseline in BCVA at a specified follow-up visit. This endpoint is 
assessed based on eyes with a baseline best-corrected visual acuity (BCVA) ≤ 70 ETDRS 
letters (Snellen equivalent of 20/40 or worse). 
Revised Text: 
Secondary endpoints: 
Key secondary efficacy endpoints:  
 
VH 0 or 2-unit responseComposite endpointb at Month 5 
 
VH 0 response at Month 3 


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 
VH 0 or 2-unit responseComposite endpoint at Month 3 
 
Other secondary efficacy endpoints (double-masked period of study): 
 
VH 0 or 2-unit responsec at Month 5 
 
VH 0 or 2-unit response at Month 3 
 
VH 0 or 0.5+ responsecresponsed at Month 5 
 
VH 0 or 0.5+ response at Month 3 
 
Corticosteroid tapering success with resolutiond resolutione at Month 5 
 
Corticosteroid tapering success with resolution at Month 3 
 
BCVA 3-line responseeresponsef at Month 5 
 
BCVA 3-line response at Month 3 
 
Change from baseline in central subfield thickness (CST) at Month 5 as 
measured by OCT 
 
Change from baseline in CST at Month 3 as measured by OCT 
 
Use of rescue therapy before Month 5 
 
Use of rescue therapy before Month 3 
Statistical Analysis  
For the primary analysis of VH 0 response at Month 5, the Cochran-Mantel-
Haenszel (CMH) test with Row Mean Scores statistic stratified by number of 
enrolled eyes from a subject (one eye or two eyes), baseline systemic (oral) 
corticosteroid use (yes or no), and region (US or non-US) will be conducted.  
Logistic generalized estimating equation (GEE) model, treatment policy strategy, 
last-observation-carried-forward (LOCF) imputation, and multiple imputation 
with tipping point analysis will be used as a sensitivity analysis. 
A hierarchical approach will be used to control the overall Type I error rate 
associated with the multiple comparisons across the primary and the key 
secondary efficacy endpoints at the 0.04999 level (two-sided).  
If the hypothesis testing for the primary endpoint successfully rejects the null 
hypothesis, the first key secondary efficacy endpoint will be tested, and so on.  
All the other secondary efficacy endpoints are supportive in nature. Therefore, 
no formal hypothesis testing will be performed on secondary efficacy endpoints. 
Two-sided 95% confidence intervals and nominal p-values may be reported for 
them, and such results will be interpreted descriptively in terms of the support 
they provide to the treatment comparisons for the primary and the key 
secondary efficacy endpoints in the sense of logical consistency. For the other 
secondary endpoints, no multiplicity adjustment will be made. 
For secondary efficacy endpoints during double-masked period: 
All binary secondary endpoints will be analyzed using the Cochran-Mantel-
Haenszel (CMH) test with Row Mean Scores statistic stratified by number of 
enrolled eyes from a subject (one eye or two eyes), baseline systemic (oral) 
corticosteroid use (yes or no), and region (US vs. non-US). Change-from-


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baseline endpoints will be analyzed by a mixed-effects model for repeated 
measures (MMRM) using observed cases. The statistical model for the analysis of 
each continuous secondary endpoint may be adjusted if it fails to converge. More 
details regarding model specifications will be provided in the SAP. 
 
Footnotes: 
Note: Vitreous haze (VH) will be scored using the modified Standardized Uveitis 
Nomenclature (SUN) scale.  
a VH 0 response (resolution of inflammation) is defined as a VH score of 0 in the 
study eye at a specified follow up visit based on the modified SUN scale. 
b  Refer to composite score scales defined in the composite estimand in this 
table.   
cb VH 0 or 2-unit response is defined as having a VH score of 0 or a decrease 
(improvement) of at least 2 units  
(i.e., 2+ to 0, 3+ to 1+, or 4+ to 2+) from baseline in the study eye in VH score 
at a specified follow up visit based on the modified SUN scale.   
dc VH 0 or 0.5+ response (remission of inflammation) is defined as a VH score of 
0 or 0.5+ in the study eye at a specified follow-up visit based on the modified 
SUN scale.  
ed Corticosteroid tapering success with resolution is defined as achievement of a 
prednisone-equivalent oral dose of 0 mg/day and a VH score of 0 in the study 
eye at a specified follow-up visit. This endpoint is assessed based on the Intent-
to-Taper population (study eyes of subjects who received systemic [oral] 
corticosteroids at a stable prednisone-equivalent of dose between ≥15 mg/day 
and ≤40 mg/day that has remained stable for at least 1 week  
[7 days] prior to and including on Day 1). 
fe BCVA 3-line response is defined as an increase (improvement) of at least 3 
lines (15 ETDRS letters) from baseline in BCVA at a specified follow-up visit. 
This endpoint is assessed based on eyes with a baseline best-corrected visual 
acuity (BCVA) ≤ 70 ETDRS letters (Snellen equivalent of 20/40 or worse). 
Rationale: 
Added the clarification in the analysis of the primary endpoint regarding 
the stratification factors. Sensitivity analysis strategy is changed to be 
aligned with the study estimands. Clarification on the multiplicity 
adjustment for other secondary endpoints is also added. 
 
 



SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:  
LUMINA: A Phase III, Multicenter, Sham-Controlled, Randomized, 
Double-Masked Study Assessing the Efficacy and Safety of Intravitreal 
Injections of 440 μg DE-109 for the Treatment of Active, Non-Infectious 
Uveitis of the Posterior Segment of the Eye. 
 
 
NCT Number:  
NCT03711929
 
Date of the document:
16 Aug 2022 
 
 
 


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STATISTICAL ANALYSIS PLAN 
DE-109 LUMINA 
 
 
 
Protocol Title: 
LUMINA: A Phase III, Multicenter, Sham-Controlled, Randomized, Double-
Masked Study Assessing the Efficacy and Safety of Intravitreal Injections of 
440 μg DE-109 for the Treatment of Active, Non-Infectious Uveitis of the 
Posterior Segment of the Eye 
 
 
Product: 
DE-109 
 
 
Protocol Number:  
010906IN 
 
 
Sponsor: 
Santen Incorporated 
 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
USA. 
 
 
Date:  
August 16, 2022 
 
 
Status:  
Version 2.0 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen Inc. and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by Federal and State Laws.  Persons to 
whom this information is disclosed must be informed that this information is privileged and 
confidential and that it should not be further disclosed. 
 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................9 
2. 
OBJECTIVES, ESTIMANDS, AND ENDPOINTS ..................................................10 
2.1. 
Objectives ...................................................................................................................10 
2.1.1. 
Primary Objective .......................................................................................................10 
2.1.2. 
Secondary Objectives .................................................................................................10 
2.1.2.1. 
Long-term Efficacy Objective ....................................................................................10 
2.1.2.2. 
Safety Objective ..........................................................................................................10 
2.2. 
Estimands ....................................................................................................................10 
2.2.1. 
Primary estimand ........................................................................................................10 
2.2.2. 
Treatment policy estimand .........................................................................................10 
2.2.3. 
Composite estimands ..................................................................................................10 
2.3. 
Endpoints ....................................................................................................................11 
2.3.1. 
Primary Efficacy Endpoint .........................................................................................11 
2.3.2. 
Key Secondary Efficacy Endpoints ............................................................................11 
2.3.3. 
Secondary Efficacy Endpoints ....................................................................................11 
2.3.4. 
Safety Endpoints .........................................................................................................12 
2.3.5. 
Exploratory Endpoints ................................................................................................12 
3. 
STUDY DESIGN .......................................................................................................13 
3.1. 
General Study Design .................................................................................................13 
3.2. 
Randomization and Masking ......................................................................................14 
3.3. 
Sample Size Planning .................................................................................................14 
3.4. 
Visits and Assessments ...............................................................................................15 
4. 
TIME-RELATED TERMS .........................................................................................19 
4.1. 
Baseline Visit ..............................................................................................................19 
4.2. 
Injection Visit .............................................................................................................19 
4.3. 
Study Day and Analysis Visit .....................................................................................19 
4.4. 
Treatment Period, Treatment Start Date, and Treatment End Date ............................19 
4.5. 
Treatment Exposure ....................................................................................................19 
5. 
GENERAL CONSIDERATIONS ..............................................................................20 
5.1. 
Adjustments for Covariates ........................................................................................20 
5.2. 
Handling of Missing Data ...........................................................................................20 


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5.2.1. 
Efficacy Measures ......................................................................................................20 
5.2.2. 
Safety Measures ..........................................................................................................21 
5.2.3. 
Dates for Medical Events and Medications ................................................................21 
5.3. 
Multi-Center Studies ...................................................................................................23 
5.4. 
Multiple Comparisons / Multiplicity ..........................................................................23 
5.5. 
Interim Analysis and Data monitoring Committee .....................................................23 
5.5.1. 
Interim Analysis ..........................................................................................................24 
6. 
STUDY POPULATION .............................................................................................25 
6.1. 
Safety Population ........................................................................................................25 
6.2. 
Full Analysis Set .........................................................................................................25 
6.3. 
Per-Protocol Population ..............................................................................................25 
6.4. 
Intent-to-Taper Population ..........................................................................................25 
6.5. 
Macular Edema Population .........................................................................................26 
6.6. 
Vision 20/40 or Worse Population .............................................................................26 
6.7. 
Open-Label Safety Population ....................................................................................26 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................27 
7.1. 
Subject and Study Eye Disposition .............................................................................27 
7.2. 
Demographics and Baseline Characteristics ...............................................................27 
7.3. 
Medical and Surgical History .....................................................................................28 
7.4. 
Protocol Deviations ....................................................................................................28 
7.5. 
Impact of the COVID-19 Pandemic ...........................................................................28 
7.6. 
Prior and Concomitant Medications ...........................................................................29 
7.7. 
Treatment Compliance ................................................................................................29 
7.8. 
Treatment Exposure ....................................................................................................29 
8. 
EFFICACY ANALYSES ...........................................................................................30 
8.1. 
Efficacy-Related Definitions ......................................................................................30 
8.1.1. 
Study Eye and Fellow Eye ..........................................................................................30 
8.1.2. 
Baseline Score ............................................................................................................30 
8.1.3. 
Change and Percent Change from Baseline ................................................................30 
8.1.4. 
Change after Injection .................................................................................................30 
8.1.5. 
Efficacy Measures ......................................................................................................30 
8.1.6. 
Rescue Therapy ..........................................................................................................31 
8.1.7. 
Response Endpoint and Response Rate ......................................................................32 


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8.1.8. 
Intent-to-Taper Subject and Corticosteroid Tapering Success ...................................33 
8.1.9. 
Best-corrected Visual Acuity Response .....................................................................33 
8.1.10. 
Central Subfield Thickness Response ........................................................................33 
8.2. 
Analyses of Primary Endpoint and Secondary Endpoints ..........................................33 
8.2.1. 
Primary Analyses ........................................................................................................33 
8.2.2. 
Sensitivity Analyses ....................................................................................................35 
8.2.3. 
Analyses of Key Secondary Efficacy Endpoints ........................................................36 
8.2.4. 
Analyses of Secondary Efficacy Endpoints ................................................................36 
8.2.4.1. 
Analyses of Binary Secondary Endpoints ..................................................................36 
8.2.4.2. 
Analyses of Continuous Secondary Endpoints ...........................................................36 
8.3. 
Subgroup Analyses .....................................................................................................38 
8.4. 
Exploratory Analyses ..................................................................................................38 
8.4.1. 
Analysis of combined total drug group ......................................................................38 
8.4.2. 
Analysis of exploratory endpoints ..............................................................................38 
8.4.3. 
Bayesian analysis of the primary endpoint .................................................................38 
8.4.3.1. 
Prior Data ....................................................................................................................38 
8.4.3.2. 
Bayesian Analysis .......................................................................................................39 
9. 
SAFETY ANALYSES ...............................................................................................40 
9.1. 
Safety-Related Definitions ..........................................................................................40 
9.1.1. 
Adverse Event .............................................................................................................40 
9.1.1.1. 
Ocular Adverse Event .................................................................................................40 
9.1.1.2. 
Adverse Drug Reaction ...............................................................................................40 
9.1.1.3. 
Serious Adverse Event ................................................................................................40 
9.1.1.4. 
Sight-Threatening Adverse Event...............................................................................41 
9.1.1.5. 
Events of Special Interest ...........................................................................................41 
9.1.2. 
Safety Measures ..........................................................................................................42 
9.2. 
Adverse Events ...........................................................................................................43 
9.3. 
Intraocular Pressure ....................................................................................................44 
9.4. 
Slit-lamp Biomicroscopy ............................................................................................44 
9.4.1. 
Lens .............................................................................................................................44 
9.5. 
Ophthalmoscopy .........................................................................................................44 
9.6. 
Physical Examination and Vital Signs ........................................................................45 
9.7. 
Laboratory Tests .........................................................................................................45 


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10. 
SUMMARY OF CHANGES TO THE PROTOCOL ................................................45 
10.1. 
Adding Exploratory Endpoints ...................................................................................45 
10.2. 
Adding Exploratory Analyses .....................................................................................45 
11. 
REFERENCE .............................................................................................................46 
APPENDIX A. VFQ-25 COMPOSITE SCORE AND SUBSCALES .......................................47 
APPENDIX B. CLINICAL LABORATORY PARAMETERS .................................................49 
 
LIST OF TABLES 
Table 1: 
 Table of Activities .....................................................................................................16 
Table 2: 
 Efficacy Measures .....................................................................................................31 
Table 3: 
 Safety Assessments ....................................................................................................42 
Table 4: 
 Serum Chemistry and Hematology ............................................................................49 
 
LIST OF FIGURES 
Figure 1: 
Study Design Diagram ................................................................................................13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Explanation 
ADR 
Adverse Drug Reaction 
AE(s) 
Adverse Event(s) 
ANCOVA 
analysis of covariance 
AR(1) 
autoregressive (covariance structure) 
ARH(1) 
heterogeneous autoregressive (covariance structure) 
ATC 
Anatomical-Therapeutic-Chemical 
BCVA 
Best-Corrected Visual Acuity 
CI 
Confidence Interval 
CM 
Concomitant Medications 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
CST 
Central Subfield Thickness 
DM 
Double-Masked 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
ESI(s) 
Event(s) of Special Interest 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EXCH 
exchangeable (correlation structure) 
ET 
Early Termination 
FAS 
Full Analysis Set 
GEE 
Generalized Estimating Equation 
IOP 
Intraocular Pressure 
IP 
Investigational product 
LOCF 
Last-observation-carried-forward 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
LS 
least squares 
MAR 
Missing at random 
MCMC 
Monte Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Medical History 
mmHg 
Millimeter of Mercury 
 


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ABBREVIATIONS (Continued) 
Abbreviation 
Explanation 
MMRM 
mixed-effects model for repeated measures 
NEI 
National Eye Institute 
NIU-PS 
non-infectious uveitis of the posterior segment of the eye 
OCT 
Optical Coherence Tomography 
OHT 
Ocular Hypertension 
OD 
Oculus Dexter (right eye) 
OL 
Open-Labeled 
OS 
Oculus Sinister (left eye) 
OU 
Oculus Uterque (both eyes) 
PP 
Per-Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOC 
System Organ Class 
SUN 
Standardized Uveitis Nomenclature 
TOEP 
Toeplitz (covariance) 
TOEPH 
heterogeneous Toeplitz (covariance) 
UN 
unstructured (correlation structure) 
US 
United States 
VEGF 
Vascular endothelial growth factor 
VH 
Vitreous haze 
VFQ 
Visual Functioning Questionnaire 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the 
analysis of data collected from the LUMINA study within the scope of Santen’s Protocol 
010906IN, “LUMINA: A Phase III, Multicenter, Sham-Controlled, Randomized, Double-
Masked Study Assessing the Efficacy and Safety of Intravitreal Injections of 440 μg DE-109 for 
the Treatment of Active, Non-Infectious Uveitis of the Posterior Segment of the Eye.” It applies 
to the study protocol Amendment 3, dated 14 JUL 2021, and provides detailed instructions as to 
how each analysis will be performed. 
Results obtained from the analyses specified in the final approved version of the SAP will 
become the basis of the clinical study report (CSR) for this study.  Any deviations from the final 
approved version of the SAP must be substantiated by sound statistical reasoning and 
documented in the CSR. 


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2. 
OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of intravitreal injection of  DE-109 
440 μg every 2 months as compared with Sham for the treatment of active, non-infectious uveitis 
of the posterior segment of the eye. 
2.1.2. 
Secondary Objectives 
2.1.2.1. 
Long-term Efficacy Objective 
To evaluate the long-term efficacy (>6 months and up to one year) of intravitreal injection of 
DE-109 440 µg every 2 months for the treatment of active, non-infectious uveitis of the posterior 
segment of the eye. 
2.1.2.2. 
Safety Objective 
To evaluate the safety of intravitreal injection of DE-109 440 µg every 2 months for up to one 
year of dosing for the treatment of active, non-infectious uveitis of the posterior segment of the 
eye. 
2.2. 
Estimands 
2.2.1. 
Primary estimand 
Vitreous haze (VH) 0 response rate in DE-109 440 µg group vs. Sham group at Month 5 in all 
study eyes that received at least one dose of the study treatment where all eyes that were rescued 
due to worsening of uveitis or discontinued from the study due to lack of efficacy or due to 
adverse events before Month 5 will be treated as non-responders. For study eyes that were 
rescued for any other reasons or had missing data due to other reasons, imputation by the 
multiple imputation-based approach will be used. 
2.2.2. 
Treatment policy estimand  
Vitreous haze (VH) 0 response rate in DE-109 440 µg group vs. Sham group at Month 5 in all 
study eyes that received at least one dose of the study treatment regardless of whether subjects 
have received rescue therapy or discontinued from the study due to lack of efficacy or due to 
adverse events. For study eyes that had missing data due to any reason, imputation by the 
multiple imputation-based approach will be used. 
2.2.3. 
Composite estimands  
Mean composite score in DE-109 440 µg group vs. Sham group at Month 3 and at Month 5 in all 
study eyes that received at least one dose of study treatment. Each study eye will be assigned one 
of the following scores: 
 Score = 3 if a study eye achieved VH score of 0 at the specified visit without taking 
any rescue therapies that could affect VH score prior to the specified visit  


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 Score = 2 if a study eye had at least improved by 2 units in VH (compared to 
baseline) at the specified visit without taking any rescue therapies that could affect 
VH score prior to the specified visit   
 Score = 1 if a study eye achieved VH score of 0.5+ at the specified visit without 
taking any rescue therapies that could affect VH score prior to the specified visit   
 Score = -1 if a study eye got rescued due to worsening of uveitis or discontinued from 
the study due to lack of efficacy or due to adverse events prior to the specified visit  
 Score = 0 if otherwise 
2.3. 
Endpoints 
2.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint, vitreous haze (VH) 0 response, is defined as having a VH score 
of 0 at Month 5 based on the modified Standardized Uveitis Nomenclature (SUN) scale. 
2.3.2. 
Key Secondary Efficacy Endpoints 
The following key secondary endpoints will be assessed: 
 Mean composite score at Month 5: mean of composite scores of all study eyes by the 
composite scoring system (defined in Section 2.2.3) 
 VH 0 response at Month 3: having a VH score of 0 at Month 3 (modified SUN scale) 
 Mean composite score at Month 3: mean of composite scores of all study eyes by the 
composite scoring system (defined in Section 2.2.3) 
2.3.3. 
Secondary Efficacy Endpoints 
The secondary endpoints to be assessed for the Double-Masked analysis period include: 
 VH 0 or 2-unit response at Month 5: having a VH score of 0 or a decrease 
(improvement) of at least 2 units (i.e., 2+ to 0, 3+ to 1+, or 4+ to 2+) from baseline in 
VH score at Month 5 (modified SUN scale) 
 VH 0 or 2-unit response at Month 3: having a VH score of 0 or a decrease 
(improvement) of at least 2 units from baseline in VH score at Month 3 (modified 
SUN scale) 
 VH 0 or 0.5+ response at Month 5: having a VH score of 0 or 0.5+ at Month 5 
(modified SUN scale) 
 VH 0 or 0.5+ response at Month 3: having a VH score of 0 or 0.5+ at Month 3 
(modified SUN scale) 
 Change from baseline in VH score at post-baseline visits up to Month 6 
 Corticosteroid tapering success with resolution at Month 5 (for the Intent-to-Taper 
population as defined in Section 6.4):  having a prednisone-equivalent oral dose of  


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0 mg/day and a VH score of 0 at Month 5 without taking any rescue therapies that 
could affect VH score 
 Corticosteroid tapering success with resolution at Month 3 (for the Intent-to-Taper 
population as defined in Section 6.4):  having a prednisone-equivalent oral dose of 0 
mg/day and a VH score of 0 at Month 3 without taking any rescue therapies that 
could affect VH score 
 BCVA (Best-Corrected Visual Acuity) 3-line response at Month 5 (for the Vision 
20/40 or Worse population as defined in Section 6.6): having an increase 
(improvement) of at least 3 lines (15 ETDRS letters) from baseline in BCVA 
 Change from baseline in BCVA at post-baseline visits up to Month 6 
 Central subfield thickness (CST) 50-micron response at Month 5 (for the Macular 
Edema population as defined in Section 6.5): having a decrease (improvement) of at 
least 50 microns from baseline in CST at Month 5 
 Change from baseline in central subfield thickness (CST) at Month 5 as measured by 
optical coherence tomography (OCT) 
 Change from baseline in CST at Month 3 as measured by OCT 
 Change from baseline in the National Eye Institute (NEI) Visual Functioning 
Questionnaire-25 (VFQ-25) composite score at Month 5 
 Use of rescue therapy before Month 5 
 Use of rescue therapy before Month 3 
Secondary endpoints assessing long-term efficacy will include the following: 
 VH 0 response at each visit after Month 6 
 VH 0 or 2-unit response at each visit after Month 6 
 VH 0 or 0.5+ response at each visit after Month 6 
2.3.4. 
Safety Endpoints 
Safety of DE-109 will be assessed by adverse events (AEs), slit-lamp biomicroscopy, indirect 
ophthalmoscopy, best-corrected visual acuity (BCVA), optical coherence tomography (OCT), 
fundus photography (FP), fluorescein angiography (FA), intraocular pressure (IOP), laboratory 
tests (serum chemistry, hematology, and urinalysis), physical examinations, and vital signs. 
2.3.5. 
Exploratory Endpoints 
Binary endpoints for best-corrected visual acuity (BCVA) at Month 3 and Month 5 for the 
Macular Edema population as defined in Section 6.5: 
 BCVA x-line response: having an increase (improvement) of at least 5x ETDRS 
letters, where x = 1 to 3; 
 BCVA x-line worsening: having a decrease (worsening of at least 5x ETDRS letters, 
where x = 1 to 3; 
 BCVA maintaining: have a change of > -5 and < 5 EDTRS letters 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is a Phase III study to assess the efficacy and safety of DE-109 440 µg every 2 months in 
subjects with active, non-infectious uveitis of the posterior segment of the eye (NIU-PS). The 
12-month study consists of a 6-month, randomized, double-masked, parallel design, sham-
controlled evaluation of DE-109 440 µg every 2 months followed by a 6-month, open-label 
period in which all subjects will receive DE-109 440 µg every 2 months (Figure 1). 
 
Figure 1: 
Study Design Diagram 
  
 
The study will begin with a 30-day screening period (Day -30 to Day -1) which will be followed 
by the 6-month double-masked treatment period. In the double-masked period, approximately 
200 eligible subjects will be randomized in a 2:2:1 ratio to three arms: 
1. Test arm: Intravitreal injection of DE-109 440 µg in the study eye(s) every 2 months 
(Day 1, Month 2, and Month 4) (approximately 80 subjects). 
2. Control arm: Sham procedure administered to the study eye(s) every 2 months (Day 1, 
Month 2, and Month 4) (approximately 80 subjects). The sham procedure mimics an 
intravitreal injection without penetrating the eye (the blunt end of an empty syringe is 
pressed against an anesthetized eye).  
3. Dummy arm: Intravitreal injection of DE-109 at an undisclosed, fixed dose (within the 
range of 44 µg to 880 µg) in the study eye(s) every 2 months (Day 1, Month 2, and 
Month 4) (approximately 40 subjects). This study arm (which has the same route of 
administration and frequency as the test arm) is included in the study to help ensure 
masking of treatment assignments. The dose used in this arm will be chosen from a range 
of DE-109 doses (44 µg to 880 µg) previously demonstrated to have an acceptable safety 
profile. The dose in this arm will not vary between participating sites or subjects 
randomized to this arm.  


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Subjects completing the Month 6 pre-dose evaluations (the final evaluations in the double-
masked period) will begin the open-label period of the study, in which all subjects will receive 
intravitreal injection of DE-109 440 µg in the study eye(s) every 2 months for an additional 
6 months of dosing (i.e., investigational product (IP) injections at Month 6, Month 8, and 
Month 10 with a final follow-up evaluation at Month 12). The same study eye(s) treated during 
the double-masked period will be treated during the open-label period. The open-label period of 
the study will allow evaluation of the long-term (> 6 months and up to one year) efficacy and 
safety of DE-109 440 µg every 2 months in subjects with NIU-PS. 
3.2. 
Randomization and Masking 
For the double-masked period, eligible subjects (total sample size of approximately 200 subjects) 
will be randomized in a 2:2:1 ratio to the DE-109 440 μg arm (80 subjects), the Sham arm (80 
subjects), and the Dummy arm (40 subjects). The randomization will be stratified by baseline 
systemic (oral) corticosteroid use (yes/no), number of subject’s enrolled eyes (1 eye/2 eyes), and 
region (US/non-US). A separate permuted-block randomization with a fixed block size will be 
generated for each stratum. A computer algorithm for random number generation will be used to 
generate the randomization and an IWRS will be used to administer the randomized assignment 
of subject eyes to treatment arms. Subjects with both eyes enrolled will be assigned to the same 
treatment arm in both eyes. 
The 6-month, comparative period of the study is double-masked and sham-controlled. The sham 
procedure mimics an intravitreal injection (the blunt end of an empty syringe is pressed against 
an anesthetized eye). To retain the masking of the investigator, a separate, unmasked investigator 
will be responsible for administering the IP (DE-109 intravitreal injections and sham). The 
masked investigator will conduct assessments prior to IP administration; the unmasked 
investigator will administer the IP and conduct the post-administration assessments. Thus, the 
treatment assignments will be masked to Santen (except Clinical Supply and Quality Assurance 
personnel, as required), study subjects, and masked investigators.  
The dummy arm is included in the double-masked period of the study to help ensure masking of 
treatment assignment given the use of a sham control. All subjects randomized to the dummy 
arm receive intravitreal injections of DE-109 every 2 months at an undisclosed fixed dose of 
44μg to 880μg (doses of DE-109 in this range have previously been shown to have an acceptable 
safety profile). The dose in this arm will not vary between participating sites or subjects 
randomized to this arm. Except for a limited number of Santen employees in Clinical Supply and 
Quality Assurance as required, the dose of DE-109 in the dummy arm will remain undisclosed to 
investigators, CROs, and Santen employees involved in the study conduct. 
3.3. 
Sample Size Planning 
Assuming a 30% VH 0 response rate for DE-109 440 μg group and a 12% response rate for the 
sham treatment group, 160 subjects (80 subjects per arm) is required to achieve 80% power to 
detect such a difference in response rate between the DE-109 440 μg group and the sham 
treatment group using the Pearson’s Chi-square test (two-sided, α = 0.05). Including 
approximately 40 subjects in the dummy arm, a total of approximately 200 subjects with active 
NIU-PS will be randomized in a 2:2:1 ratio to DE-109 440 μg, sham, and dummy arms. Because 
some subjects will contribute two study eyes to this study, the planned sample size of 80 subjects 


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in both the test (DE-109 440 μg) and control (sham procedure) arms will achieve more than 80% 
power. 
3.4. 
Visits and Assessments 
The schedule of activities (SoA) is provided in Table 1. 
 


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Table 1: 
Table of Activities 
 
Screening 
Double-Masked Period Visits 
Open-Label Period Visits 
 
Screening 
(Within 
30 days 
prior to 
D1; i.e.,  
D -30 to 
D -1) 
D1 
(Baseline) 
D14 
M1 
M2, 
M4 
M3 
M5 
M6 a 
M7, 
M9, 
M11 
M8, 
M10 
M12/ 
Exit/ 
Early 
Termina- 
tion 
Study day 
 
D1 
D14 
D30 
D60,  
D120 
D90 
D150 
D180 
D210, 
D270, 
D330 
D240, 
D300 
M12: D360 
Visit window in days 
NA 
NA 
±2 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
M12: ±7 
IP (DE-109, Sham, Dummy) 
administration 
 
x b 
 
 
x b 
 
 
x 
 
x 
 
Time relative to IP 
administration 
 
pre 
post 
 
 
pre 
post 
 
 
pre a 
post a 
 
pre 
post 
 
Signed and dated informed 
consent  
x c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history, 
history of NIU-PS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination and 
vital signs 
x 
 
 
 
 
 
 
 
xd 
 
 
 
 
 
x 
VFQ-25 
 
x 
 
 
 
 
 
 
xd 
 
 
 
 
 
x  
Serum pregnancy test e 
x e 
 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Urine pregnancy test e 
 
x e 
 
 
 
x e 
 
 
 
x e 
 
 
x e 
 
 
Laboratory safety tests 
(hematology, chemistry, 
urinalysis) f 
x f 
 
 
 
 
 
 
 
x d, f 
 
 
 
 
 
x f 
Blood sample for 
pharmacogenomics g 
 
 
 
x g 
 
 
 
 
 
 
 
 
 
 
 
Time relative to IP 
administration 
 
pre 
post 
 
 
pre 
post 
 
 
pre a 
post a 
 
pre 
post 
 
Randomization h 
 
x h 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1: 
Table of Activities (Continued) 
 
Screening 
Double-Masked Period Visits 
Open-Label Period Visits 
 
Screening 
(Within 
30 days 
prior to 
D1; i.e.,  
D -30 to 
D -1) 
D1 
(Baseline) 
D14 
M1 
M2, 
M4 
M3 
M5 
M6 a 
M7, 
M9, 
M11 
M8, 
M10 
M12/ 
Exit/ 
Early 
Termina- 
tion 
Best-corrected visual acuity 
(ETDRS) 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
Slit-lamp biomicroscopy 
x 
x 
x i 
x 
x 
x 
x i 
x 
x 
x 
x i 
x 
x 
x i 
x 
Intraocular pressure 
x 
x 
x j 
x 
x 
x 
x j 
x 
x 
x 
x j 
x 
x 
x j 
x 
Indirect ophthalmoscopy 
x 
x 
x i 
x 
x 
x 
x i 
x 
x 
x 
x i 
x 
x 
x i 
x 
Optical Coherence 
Tomography 
 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
Fundus photography 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
Fluorescein angiography k 
 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
Systemic corticosteroid 
medication status 
x l 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
Other prior or concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prednisolone acetate eye 
drops m 
 
 
x m 
 
 
 
x m 
 
 
 
x m 
 
 
x m 
 
Adverse events n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
IP = Investigational product; NA = not applicable; M=Month; D=Day; pre=prior to IP administration; post = after IP administration. 
a The double-masked period ends with the pre-dose evaluations at Month 6; the first open-label dose of DE-109 is at Month 6. 
b On study visits during the double-masked period at which IP is administered, the unmasked investigator will perform the IP preparation and administration.  
c Signed and dated informed consent form must be obtained prior to conducting any study-related activities. 
d If physical examination and vital signs, VFQ-25 and/or laboratory safety tests were performed at Month 3 under a previous version of the protocol these 
assessments do not need to be performed at Month 5. 
e Serum and urine pregnancy tests are to be performed on all females of child-bearing potential. Urine pregnancy test (hCG) is to be performed prior to each IP 
administration. A positive pregnancy test at screening or Day 1 (Baseline) requires exclusion from the study. At subsequent visits, a positive urine pregnancy 
test requires immediate discontinuation from the study. Pregnancy is an event of special interest and requires follow-up by Santen until the outcome is known.  
f At Month 5 subjects must fast 8 hours prior to the blood draw for hematology and chemistry laboratory tests. At Screening, and Month 12/Exit/Early 
termination visit, lipid may be obtained in the fasting or non-fasting state. 


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g This is only applicable if the subject has consented to collection of blood for pharmacogenomics (approximately 10 mL of blood). This sample should be 
collected at the Day 14 visit, but may be collected at any time during the study or at a separate post study visit, if necessary. 
h Refer to Section 8.1.3 of the protocol for assessments and requirements prior to randomization.  
i After IP administration, slit-lamp biomicroscopy is performed first and then indirect ophthalmoscopy, in both eyes within 30 minutes of IP administration. 
j Intraocular pressure (IOP) is measured in both eyes at approximately 40 ± 10 minutes after IP administration. If IOP is increased ≥10 mmHg 40±10 minutes 
after IP administration compared to prior to IP administration, administer topical IOP lowering medication for use until the subject returns for follow-up per the 
investigator’s discretion. (An unscheduled visit may apply). IOP increase of ≥10 mmHg at any visit compare to the Baseline (Day 1) assessment should be 
reported as an AE.  
k Any required blood or urine sample is to be collected before injection of fluorescein. 
l Subjects receiving systemic (oral) corticosteroid therapy will be required to titrate the dose as needed such that they remain on a stable prednisone-equivalent 
dose between ≥15 mg/day and ≤40 mg/day that has remained stable for at least 1 week (7 days) prior to and including on Day 1. 
m Prednisolone acetate eye drops are to be started after each IP administration and continued for 8 days, according to the following schedule: 4 times per day for 
4 days (including the day of IP administration) followed by 2 times per day for 4 days, then stop. 
n Adverse events (AE) will be recorded starting after the signing of the informed consent form. During the double-masked period, regardless of the source of the 
reported occurrence of an AE in a subject, the masked investigator will assess the causality of the AE. 
 


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4. 
TIME-RELATED TERMS 
4.1. 
Baseline Visit 
The Baseline Visit is the visit when a randomized subject receives the first administration of an 
investigational product (IP) (either an injection of DE-109 or a sham procedure). 
4.2. 
Injection Visit 
The injection visit is defined as the visit at which a subject received an investigational product 
(IP) in the study eye. Note that if a subject did not receive any IPs at a visit where an 
administration of IP was scheduled per protocol, the visit will not be considered an injection visit 
for the subject. In the LUMINA study, Day 1, Months 2, 4, 6, 8, and 10 visits may be injection 
visits  
4.3. 
Study Day and Analysis Visit  
The study day describes the relative day of an observation starting with the reference date 
designated as Study Day 1.  In this study, the reference date is the baseline visit date.  Thus, the 
study day will be calculated as: 
 For a pre-baseline date, Study Day = Date – Baseline Visit Date  
 For a post-baseline date, Study Day = Date – Baseline Visit Date + 1 
Analysis visit is a timing variable to be used for analyses involving visits. For this study, the 
analysis visit is the same as the nominal visit. 
4.4. 
Treatment Period, Treatment Start Date, and Treatment End Date 
Treatment start date and treatment end date for each treatment period are defined as follows in  
Treatment Period 
Treatment Start Date 
Treatment End Date 
Double-Masked (DM) 
Treatment Period 
The date at which a randomized subject 
received the first injection of DE-109 or 
the first Sham procedure 
The date of the last double-masked injection 
of DE-109 + 120 days, the date of the first 
injection of the open-label DE-109 440 µg, 
or the Study Exit date, whichever came first 
Open-Label (OL) 
Treatment Period 
The date of the first open-label injection 
of DE-109 440 µg 
The date of the last open-label injection of 
DE-109 440 µg + 120 days, or the Study 
Exit date, whichever came earlier 
Entire Study 
The date at which a randomized subject 
received the first injection of DE-109 or 
the first Sham procedure 
The date of the last open-label injection of 
DE-109 440 µg + 120 days, or the Study 
Exit date, whichever came earlier 
4.5. 
Treatment Exposure  
The treatment exposure to DE-109 will be reflected by the number of injections received. The 
treatment exposure to Sham will be the number of administered Sham procedures. 


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5. 
GENERAL CONSIDERATIONS 
All measures will be summarized descriptively.  Continuous variables will be summarized using 
descriptive statistics such as number of observations (n), mean, standard deviation, standard 
error, median, minimum, and maximum.  Categorical variables will be tabulated using frequency 
(n) and percent (%). 
Unless otherwise specified, the following conventions will be followed in reporting the decimal 
places. 
Reporting Statistics 
Decimal Places 
Range (Low Value, High Value) 
Recorded Decimal Places 
Mean, Median  
Recorded value + 1 Decimal Places 
Confidence Interval, Standard Deviation, Standard Error 
Recorded value + 2 Decimal Places 
P-value 
4 Decimal Places (ex. 0.0021) 
The statistical testing will be conducted at a significance level of 0.05 (two-sided) and the  
95% confidence interval will be shown, unless specified otherwise.  No statistical testing will be 
conducted for safety measures. 
All data manipulations, descriptive summaries, and statistical hypothesis testing will be 
performed using Statistical Analysis System (SAS) Version 9.4 or later. Individual data, 
including relevant derived variables, will be listed. 
Additional analyses not specified in this SAP may be conducted if deemed necessary and will be 
documented in the CSR. 
5.1. 
Adjustments for Covariates 
Details in covariates to be included in the statistical model for each individual statistical analysis 
are provided in Section 8. 
5.2. 
Handling of Missing Data 
5.2.1. 
Efficacy Measures 
For the analysis of VH 0 response at Month 5 (primary endpoint) and at Month 3 (key secondary 
endpoint), study eyes will be treated as non-responders if they meet at least one of the following 
criteria: 
1. A study eye is rescued due to the protocol-specified worsening of uveitis (Section 8.1.6) 
2. A subject discontinued from the study due to lack of efficacy or adverse events 
3. A study eye meets the protocol-specified worsening of uveitis rescue criteria 
(Section 8.1.6) regardless whether the eye received any rescue therapies 
Study eyes which were rescued due to worsening of uveitis specified under previous protocol 
versions but did not meet the rescue criteria under the current version will be treated as rescued 
due to other reasons and censored the data after being rescued. The multiple imputation-based 
approach (Section 8.2.1) will be applied to impute missing VH score data of study eyes which 


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were not rescued and treated as non-responders. The VH 0 response status will then be 
determined based on the observed or imputed VH score. 
The same approach will be applied to the inferential analyses of other VH response endpoints. 
For the analysis of composite score (at Month 3 and at Month 5), study eyes with missing VH 
score at a given visit will be assigned with a score of 0, unless the study eyes got rescued due to 
protocol-specified worsening of uveitis or corresponding subjects discontinued the study due to 
adverse events or lack of efficacy (in this case, the score will be -1).  
For the analysis of corticosteroid tapering success on the Intent-to-Taper population, study eyes 
rescued before Month 5/Month 3 will be treated as corticosteroid tapering failures. The Last-
Observed-Carried-Forward (LOCF) approach will be applied to impute missing data of study 
eyes not rescued before Month 5/Month 3, i.e., the missing overall prednisone-equivalent dose at 
Month 5/Month 3 will be imputed by last derived overall dose. The tapering status at Month 
5/Month 3 will then be determined based on the derived or imputed overall dose. 
No imputation is needed for the analysis of the binary endpoint “use of rescue therapy before 
Month 5/Month 3”. 
To assess the impact of missing data on the primary analysis results for VH 0 response at Month 
5, the following imputation approaches will be applied to some sensitivity analyses: 
 The LOCF approach for any FAS study eyes with missing VH score at Month 5 
 Treatment policy approach: The primary analysis will be performed on FAS study eyes 
regardless whether they get rescued. That is, no censoring of observed VH score after a 
rescue will be implemented. Other missing VH scores will be imputed with multiple 
imputation-based approach. 
For analyses of “change from baseline in central subfield thickness at Month 5 as measured by 
OCT” and “change from baseline in the NEI VFQ-25 composite score at Month 5”, the LOCF 
approach will be applied for any FAS study eyes with missing score at Month 5. 
“Change from baseline in VH score at post-baseline visits up to Month 6” and “change from 
baseline in BCVA at post-baseline up to Month 6” will be analyzed using the mixed-effects 
model for repeated measures (MMRM) on observed cases.  No imputation of missing data will 
be needed. 
Subgroup analyses of all binary endpoints will employ the same imputation approach for the 
primary analysis of that endpoint. Other descriptive efficacy summaries will be based on 
observed data, unless otherwise specified. 
5.2.2. 
Safety Measures 
Descriptive summaries of safety measures will be based on observed data only.  No imputation 
of missing scores will be implemented. 
5.2.3. 
Dates for Medical Events and Medications 
Completely or partially missing onset and resolution dates for AEs, Concomitant Medications 
(CM), and Medical History (MH) will be imputed in a conservative fashion as follows: 


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Incomplete Adverse Event Onset Date 
1. Year imputation 
 If year is missing (or AE onset date is completely missing), then the onset date will 
not be imputed. 
2. Month imputation 
 If year is not missing but month is missing, then:  
 If year = year of first study dose date, then set the month and day to the day and 
month of first study dose 
 Else if year ≠ year of first study dose: set month to January 
3. Day imputation 
 If day is missing (month and year not missing), then: 
 If year = year and month = month of first study dose, then set day to day of first 
study dose 
 Else if year ≠ year or month ≠ month of first study dose, then set day to first day 
of the month in the year 
Incomplete Adverse Event Resolution Date 
 Do not impute if any resolution date is missing  
 If the duration of AE is needed, the following approach may be considered: 
 If year is missing (or AE resolution date is completely missing): do not impute 
 If year is not missing but month and day are missing: impute December 31st for 
missing month and day 
 If year and day are not missing but month is missing: impute December for 
missing month 
 If year and month are not missing but day is missing: impute last day of the month 
for missing day. 
Incomplete CM or MH Onset Date 
1. If year is missing (or CM/MH onset date is completely missing): do not impute 
2. If year is not missing but month and day are missing: impute January 1st for missing 
month and day 
3. If year and day are not missing but month is missing: impute January for missing month 
4. If year and month are not missing but day is missing: impute 01 for missing day 
Incomplete CM or MH Resolution Date 
 Do not impute if any resolution date is missing. 
 If the duration of event is needed, the following approach may be considered: 


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 If year (or resolution date is completely missing): do not impute 
 If year is not missing but month and day are missing: impute the last day of the 
year 
 If year and day are not missing but month is missing: impute the last month of the 
year for the missing month 
 If year and month are not missing but day is missing: impute the last day of the 
month of the year 
5.3. 
Multi-Center Studies 
This is a multicenter study with approximately 72 centers, among which a maximum of 35 
centers are planned to be outside of the United States.  The number of subjects per site might be 
small.  Therefore, there are no analyses adjusting for sites. 
5.4. 
Multiple Comparisons / Multiplicity 
To control the overall Type I error rate associated with the multiple comparisons on the primary 
and the key secondary endpoints at the 0.05 level (two-sided), the following hierarchical testing 
strategy will be employed: 
A. Conduct the statistical testing for the primary comparison between DE-109 440 µg and 
Sham treatment arm on the primary endpoint (VH 0 response) at the significance level of 
0.05 (two-sided) 
B. If the result of the primary comparison on the primary endpoint is positive (i.e., p-value  
< 0.05), then conduct the statistical testing for the primary comparison between DE-109 
440 µg and Sham treatment arm on the following key secondary endpoints in a 
hierarchical fashion: 
1. Mean composite score at Month 5 
2. VH 0 response at Month 3 
3. Mean composite score at Month 3 
The primary comparison on the (i+1)th key secondary endpoint will be performed 
inferentially ONLY IF the result of the primary comparison in the ith key secondary 
endpoint is positive, where i = 1 or 2. 
5.5. 
Interim Analysis and Data monitoring Committee 
An independent data monitoring committee (DMC) whose members will not be participating in 
the LUMINA study conduct will serve as an advisory board to the Santen senior management 
team. The DMC will periodically review and make recommendations based on interim data; 
unmasked data will only be reviewed in closed DMC sessions without participation of Santen 
personnel. The organization, responsibilities, and procedures of the DMC will be specified in a 
governing charter. 
An interim analysis is planned when the first 100 subjects complete their Month 5 Visit. The 
DMC is authorized to evaluate unblinded interim efficacy and safety analyses. Study sites will 


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receive information about interim results only if they need to know for the safety of their 
patients.  
5.5.1. 
Interim Analysis 
The objectives of the interim analysis are to assess for futility and to re-assess the sample size. 
No analyses are planned for the purpose of stopping the study early for efficacy. The futility and 
sample size re-assessment are based on evaluation of conditional power in relationship to pre-
specified decision rules defined by ranges of attainable conditional power values under the 
“promising zone” approach (Mehta et al., 2011). If the conditional power is less than 30%, 
futility will be recommended and the study may stop for futility. If the conditional power is 
between 50% and 80%, the sample size will be increased up to 100 extra subjects. If the 
conditional power between 30% and 50% or greater than 80%, no change to the sample size will 
take place. 
The futility and sample size re-assessment analysis will be evaluated for the primary endpoint, 
vitreous haze (VH) 0 response at Month 5 based on subjects who were randomized, received at 
least one dose of IP at baseline, and reached or completed Month 3 visit of the study. Missing 
VH status at the interim analysis will be handled using the multiple imputation approach in the 
similar manner as specified in Section 8.2.1. However, only number of enrolled eye will be used 
as the stratification factor in the Cochran-Mantel-Haenszel (CMH) test procedure (Yu et al., 
2020). 
The conditional power at the interim analysis, denoted by CP𝛿1
̂(𝑧1, 𝑛2
̃), can be defined by the 
following equation (Mehta et al., 2011): 
CP𝛿1
̂(𝑧1, 𝑛2
̃) = 1 − Φ (
𝑧𝛼/2√𝑛2 −𝑧1√𝑛1
√𝑛2
̃
−𝑧1√𝑛2
̃
√𝑛1
) 
where 𝑛1is the number of evaluable subjects at the interim analysis, 𝑛2 is the total number of 
subjects at the final analysis,  𝑛2
̃ = 𝑛2 −𝑛1, 𝑧𝛼/2 = Φ−1(1 −𝛼/2), and 𝑧1 is the squared root of 
the CMH test statistic as computed at the interim analysis of 𝑛1 evaluable subjects. Define the 
estimated treatment difference,  𝛿1̂ = 𝜋̂440 −𝜋̂sham at interim analysis, where  𝜋̂440 and  𝜋̂sham 
are Mantel-Haenszel weighted response rates of DE-109 440 µg and Sham arms at interim 
analysis, respectively. 
The primary analysis of this study is the analysis of the data from the 6-month, double-masked 
period. These data will be quality-checked, soft-locked, and the analysis for double-masked 
period will be conducted after all subjects have completed the Month 6 visit or prematurely 
discontinued from the study prior to Month 6. 


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6. 
STUDY POPULATION 
6.1. 
Safety Population 
For analyses of ocular adverse events (AEs) and safety parameters assessed per eye, the Safety 
population will consist of all study eyes which received at least one administration of 
investigational product (IP) and study eyes will be classified by the actual treatment received. 
For analyses of non-ocular AEs and safety parameters assessed per subject, the Safety population 
will consist of all subjects which received at least one administration of IP and subjects will be 
classified by the actual treatment received.  
6.2. 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all study eyes that are randomized and received at 
least one administration of study treatment. The efficacy analyses will be performed using the 
FAS and study eyes will be classified by the randomized treatment assignment, irrespective of 
the actual treatment received. For analyses of other parameters assessed per subject, the FAS 
population will consist of all subjects whose study eye(s) are randomized and received at least 
one IP administration and subjects will be classified by the planned treatment assignment. 
6.3. 
Per-Protocol Population 
The Per-Protocol (PP) Population will be a subset of the FAS population. The PP population will 
be the analysis population for sensitivity analyses and will use treatment as randomized. Any 
study eye affected by a significant protocol deviation (such that the outcome to treatment could 
be altered) will be excluded from the PP Population. In addition, any study eye without the 
Month 5 VH score will be excluded from the PP Population.  
Before database lock and the unmasking of treatment assignments, Santen’s study team will 
review all protocol deviations, identify study eyes with any protocol deviation that could impact 
the efficacy outcome, and determine whether or not to exclude the study eye from the PP 
population. 
When data are presented at the subject level, PP Population is referred to subjects who have all 
of their study eyes qualified for the PP Population.  
6.4. 
Intent-to-Taper Population 
The Intent-to-Taper population will be a subset of the FAS population, consisting of study eyes 
from subjects who were taking systemic (oral) corticosteroids at a stable prednisone-equivalent 
dose between ≥15 mg/day and ≤40 mg/day for at least 1 week (7 days) prior to and including on 
Day 1. The Intent-to-Taper population will be used for the analysis of tapering success 
performed using eyes as randomized. 
When data are presented at the subject level, Intent-to-Taper Population is also referred to 
subjects who have their study eye(s) qualified for the Intent-to-Taper Population.  


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6.5. 
Macular Edema Population 
The Macular Edema population will be a subset of the FAS population and will consist of study 
eyes with central subfield thickness (CST) ≥ 300 microns at baseline. It will be the analysis 
population for the analysis of CST 50-micron response to be performed with study eyes 
classified by randomized treatment assignments. 
When data are presented at the subject level, Macular Edema Population is also referred to 
subjects who have at least one of their study eyes qualified for the Macular Edema Population. 
6.6. 
Vision 20/40 or Worse Population 
The Vision 20/40 or Worse population will be a subset of the FAS population and will consist of 
study eyes with BCVA ≤ 70 ETDRS letters (Snellen equivalent of 20/40 or worse) at baseline. It 
will be the analysis population for the analysis of BCVA 3-line response to be performed with 
study eye classified by randomized treatment assignments. 
When data are presented at the subject level, Vision 20/40 or Worse Population is also referred 
to subjects who have at least one of their study eyes qualified for the Vision 20/40 or Worse 
Population. 
6.7. 
Open-Label Safety Population 
The Open-Label Safety population will include all Safety subjects who received at least one 
open-label injection of the DE-109 440 µg. It will be the analysis population for safety analyses 
for the Open-Label analysis period to be performed with subjects as treated. 
 


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7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject and Study Eye Disposition 
The subject and study eye disposition of FAS population will be summarized by treatment period 
(double-masked and open-label) and by planned treatment assignments (for double-masked 
period) and overall.  
The FAS and the FAS subsets including the PP Population, Intent-to-Taper Population, Vision 
20/40 or Worse Population, and Macular Edema Population, Safety Population, subjects who 
were taking systemic corticosteroid at baseline, and subjects who completed vitreous haze (VH) 
assessment at Month 3, Month 5, Month 6, and Month 12 will be tabulated at the subject level. In 
addition, subjects who discontinued the study before Month 3, Month 5, Month 6, and Month 12 
will be tabulated separately by the primary discontinuation reason. Subjects whose study eye(s) 
are in the FAS will also be summarized by country. 
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and subject-level baseline characteristics will be descriptively summarized 
for FAS population.  Specifically, the following variables will be summarized: 
 Age at randomization (continuous and categorical: < 65 years or ≥ 65 years) 
 Sex (categorical: Male or Female) 
 Ethnicity (categorical: Hispanic/Latino or Not) 
 Race (categorical: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, or Other) 
 Study eye (categorical: OD, OS, or OU) 
 Laterality of uveitis (bilateral or unilateral) 
 Overall prednisone-equivalent dose (mg/day) for subjects whose study eye(s) are in 
the Intent-to-Taper population 
Baseline characteristics will also be descriptively summarized for eye-level FAS by number of 
enrolled eyes. The following variables will be summarized: 
 Baseline VH score for the study eye and the fellow eye 
 Anatomic location of uveitis of the study eye (intermediate, posterior, intermediate + 
posterior, or panuveitis) 
 Etiology of uveitis of the study eye 
 Duration of uveitis of the study eye in months derived as [Day 1 Visit Date – Uveitis 
Onset Date (observed or imputed)]/30. Partially missing uveitis onset dates, if any, 
will be imputed using the approach specified in Section 5.2.3. 
 Baseline BCVA of the study eye for 
 FAS population 


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 Vision 20/40 or Worse population 
 Baseline CST of the study eye for  
 FAS population 
 Macular Edema population 
Other baseline characteristic variables may be summarized as suggested by the data. 
7.3. 
Medical and Surgical History 
For this study, medical history (i.e., medical events) will be coded using MedDRA 23.1, 2020 
and summarized for the FAS population. Each medical event will be classified into a system 
organ class (SOC) and mapped to a preferred term (PT).  
Subjects reporting any medical history events will be tabulated by SOC and preferred term 
specified in MedDRA for each planned double-masked treatment assignment and overall. In 
addition, subjects reporting any medical history events ongoing at baseline, any medical history 
events in study eyes that are linked to SOC Eye disorders, and any medical history events 
ongoing at baseline in study eyes that are linked to SOC Eye disorders will also be tabulated. 
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 
In this study, protocol deviations are categorized as follows: 
 Informed Consent 
 Inclusion/Exclusion Criteria 
 Study Drug 
 Protocol Procedures/Safety 
 Endpoint Data 
 Visit Window 
 Prohibited Med/Procedures 
 Other 
A protocol deviation is considered significant if it may affect the subject’s rights, safety, or  
well-being, and/or the completeness, accuracy, or reliability of the study data.  Santen’s study 
team will review all protocol deviations and determine the list of significant protocol deviations 
prior to database lock.  All enrolled subjects with any significant protocol deviation(s) will be 
tabulated by deviation category.  In addition, two listings will be provided: (1) all significant 
protocol deviations and (2) subjects excluded from the per protocol population. 
7.5. 
Impact of the COVID-19 Pandemic 
The impact of the COVID-19 pandemic is defined as any disruption to the study and subject 
participation, such as changes in study visits, missed visits, subject discontinuations, etc. All 


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Safety Population subjects who experienced any of such impact will be summarized and listed 
along with the description of how their participation was altered. 
7.6. 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications.  
Specifically, prior medication is defined as any non-study medication taken and ended prior to 
the first administration of study treatment. Concomitant medication for an analysis period is 
defined as any non-study medication taken concurrently with the study medication during that 
analysis period.  
For this study, non-study medications, including prior and concomitant medications, will be 
coded using World Health Organization (WHO) Drug Global, Version September 2018, format 
B3.  Each non-study medication will be classified using the Anatomical-Therapeutic-Chemical 
(ATC) classification system and mapped to a WHO Drug preferred drug name. 
Non-study medications will be summarized for the Safety population. Subjects taking any prior 
medications, will be tabulated by ATC level 3, level 4, and preferred drug name.  A subject will 
be counted at most once for each prior medication, even if the subject took the same prior 
medication on multiple occasions.  Subjects taking any concomitant medications will be 
tabulated similarly.  In addition, prior medications and concomitant medications will also be 
listed, separately. 
7.7. 
Treatment Compliance 
Treatment compliance will be summarized only for the Double-Masked analysis period. For each 
subject in the Full Analysis Set (FAS), the treatment compliance at Day 1, Month 2, and Month 4 
will be considered achieved if: 1) subject received an administration of study medication in the 
study eye (‘Yes’ to the eCRF question “Has the study eye been injected?”), and 2) the dose 
actually received was the planned dose. A subject will be considered fully compliant with 
double-masked treatment if the treatment compliance was achieved at all scheduled injection 
visits, up to Month 4 or Study Exit, which ever came earlier. 
The treatment compliance will be summarized for the FAS population by planned Double-
Masked treatment and overall. The treatment compliance statuses will also be listed by planned 
Double-Masked treatment, subject ID, and visit. 
7.8. 
Treatment Exposure 
The treatment exposure to DE-109 will be reflected by the number of injections received. The 
treatment exposure to Sham will be the number of administered Sham procedures.  For the 
Double-Masked analysis period, Safety Population study eyes will be tabulated by the number of 
injections (1, 2, and 3) for each actual Double-Masked treatment and overall. The numbers of 
injections received during the Double-Masked, Open-Label, and the Entire Study analysis 
periods will also be listed for the Safety Population. 


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8. 
EFFICACY ANALYSES 
8.1. 
Efficacy-Related Definitions 
8.1.1. 
Study Eye and Fellow Eye 
The study eye of a treated subject will be the eye that received an investigational product (IP) at 
baseline (Day 1). For subjects who enrolled both eyes in the study and both eyes received IPs at 
baseline (Day 1), both of their eyes will be considered as study eyes. Number of enrolled study 
eyes for each subject is defined as the number of eyes that received an IP administration at 
baseline (Day 1). 
For subjects who enrolled one eye in the study, the other eye which did not receive an IP at 
baseline (Day 1) will be the non-study eye, or fellow eye. In a case when a subject enrolled in the 
study with both eyes eligible but only one of his/her eyes received an IP during the Double-
Masked period, the eye which received an IP will be considered study eye, the eye which did not 
received any IPs will be considered fellow eye.  
8.1.2. 
Baseline Score 
For any measure, the baseline score is the last observed measurement prior to the first 
administration of the IP. 
8.1.3. 
Change and Percent Change from Baseline 
For any measure, the change and the percent change from baseline at a post-baseline visit will be 
derived as: 
 Change from Baseline = (Score at the Post-Baseline Visit) – (Baseline Score) 
 Percent Change from Baseline = 100 × Change / (Baseline Score) 
8.1.4. 
Change after Injection 
For any measure assessed pre and post administration of an IP at injection visits, the change after 
injection at an injection visit will be derived as: 
 Change after injection = (Post-Administration score) – (Pre-Administration score)  
If multiple pre-injection or post-injection scores were collected at an injection visit, then the 
score closest to the injection time will be used to derived the change after injection variable. 
8.1.5. 
Efficacy Measures 
Table 2 lists all the efficacy measures that were evaluated in LUMINA study. 
 


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Table 2: 
Efficacy Measures 
Efficacy measure 
Note 
Vitreous haze (VH) 
VH was graded using the modified SUN scale as 0, 
0.5+, 1+, 1.5+, 2+, 3+, or 4+. A decrease in VH score 
indicates improvement in the vitreous inflammation. 
Overall prednisone-equivalent dose 
The overall prednisone-equivalent dose (mg/day) of 
all eligible systemic corticosteroids in each day 
Best-corrected visual acuity (BCVA) 
BCVA measures the acuteness or clearness of best-
corrected vision, with a range of [0, 110] in ETDRS 
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 
BCVA score of 85 ETDRS letters is equivalent to 
20/20 vision, which is considered normal vision. 
Central Subfield Thickness (CST) 
For each eye, the CST was measured using Optical 
Coherence Tomography (OCT). OCT was performed 
using reading center certified photographers, 
equipment, and standardized protocols. 
NEI VFQ-25: Composite score and 12 
subscales (General Health, General Vision, 
Ocular Pain, Near Activities, Distance 
Activities, Vision-Specific Social Functioning, 
Vision-Specific Mental Health, Vision-
Specific Role Difficulties, Vision-Specific 
Dependency, Driving, Color Vision, 
Peripheral Vision) 
As shown in Appendix A, each NEI VFQ item was 
recorded to a 0-100 scale. The composite score and 
subscales will be derived based on the recorded items. 
An increase in the NEI VFQ-25 composite score or 
subscale indicates improvement in certain visual 
function. 
Note that the 39-item NEI VFQ (VFQ-25 + optional 
items) conducted at the US sites will be used to derive 
the VFQ-25 composite score and subscales (double-
check). 
8.1.6. 
Rescue Therapy 
Rescue therapy is defined as any treatment that would have a therapeutic effect on NIU-PS, other 
than intravitreal DE-109.  
 Systemic corticosteroid therapy (except during the tapering window) 
 New systemic treatment with an immunosuppressant agent 
 Increase in dose of ongoing therapy with methotrexate, azathioprine, or 
mycophenolate mofetil (or an equivalent drug, e.g., mycophenolic acid)  
 Anti-vascular endothelial growth factor therapy (anti-VEGF) 
 New or increased dose/frequency of topical ocular corticosteroid to the study eye 
 New or increased dose/frequency of topical ocular nonsteroidal anti-inflammatory 
agent to the study eye 
 Ocular or periocular corticosteroid injection to the study eye 


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 Use of difluprednate ophthalmic emulsion eye drops in the study eye 
 Vitrectomy in the study eye 
Other protocol-allowed or specified medications that are not considered rescue therapy are listed 
as follows: 
 Investigational product (DE-109, Sham, Dummy). 
 Oral corticosteroids administered in accordance with the protocol-specified tapering 
schedule (refer to Protocol Section 6.5.3).  
 Ongoing stable dose/frequency of corticosteroid eye drops is permitted (exception of 
difluprednate), non-steroidal anti-inflammatory eye drops, methotrexate, azathioprine, 
or mycophenolate mofetil are allowed by the protocol.  
 The protocol-specified administration of prednisolone acetate eye drops following 
each IP administration. 
Rescue therapies will be performed when worsening of uveitis in the study eye is observed 
satisfying one or more of the following three rescue criteria: 
1. Worsening of uveitis in the study eye as indicated by at lease a 2-step increase in VH 
score (i.e., 0 to ≥2+, 0.5+ to ≥3+, 1+ to ≥3+, 1.5+ to ≥4+, or 2+ to ≥4+) as compared to 
the baseline (Day 1) VH score or the best achieved VH score post baseline. 
2. Severe deterioration of vision in the study eye due to worsening of uveitis that is 
indicated by at least doubling of the visual angle (BCVA loss of 3 or more lines  
[≥15 ETDRS letters]) as compared to baseline (Day 1) BCVA. 
3. New or worsening retinal or choroidal uveitic lesion(s) in the study eye determined by 
clinical examination, as compared to baseline. 
These three above criteria are generally referred to as protocol-specified rescue criteria.  
When subjects got rescued when deemed medically necessary even if none of the protocol-
specified rescue criteria were satisfied, all of the reasons will be pooled together and referred to 
as Other rescue criterion. Further breakdown of reasons under the “Other” category might be 
performed if deemed necessary. 
8.1.7. 
Response Endpoint and Response Rate 
Three VH response endpoints will be evaluate at Month 3, Month 5, Month 6, and at each visit 
after Month 6 in this study. VH response endpoints are defined as follows: 
 VH 0 response: having a VH score of 0 (modified SUN scale). Study eyes which met 
this criterion are called VH 0 responders. 
 VH 0 response: having a VH score of 0 or 0.5+ (modified SUN scale). Study eyes 
which met this criterion are called VH 0 or 0.5+ responders. 
 VH 0 response: having a VH score of 0 or a decrease (improvement0 of at least  
2 units from baseline in VH score (modified SUN scale). Study eyes which met this 
criterion are called VH 0 or 2-unit responders. 


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For response endpoints at Month 6 and at visits of the Open-Label analysis period, subjects who 
were rescued before the visit when the endpoint is evaluated will be treated as non-responders. 
The response rate will be estimated as the proportion of responders in the corresponding 
treatment group.  
8.1.8. 
Intent-to-Taper Subject and Corticosteroid Tapering Success 
Subjects who were taking systemic (oral) corticosteroid(s) at baseline (Day 1) with the overall 
prednisone-equivalent dose between 15 mg/day and 40 mg/day are called Intent-to-Taper 
subjects. An Intent-to-Taper study eye will be considered a corticosteroid taper success if the 
corresponding subject’s overall prednisone-equivalent dose was tapered off to 0 mg/day and the 
study eye achieved VH score of 0 at Month 5. Intent-to-Taper study eyes which were rescued 
before Month 5 will be treated as corticosteroid tapering failures.  
The tapering success rate will be estimated as the proportion of corticosteroid tapering successes 
among Intent-to-Taper study eyes in the corresponding treatment group.  
8.1.9. 
Best-corrected Visual Acuity Response 
The BCVA response endpoint is defined as a study eye having an increase (improvement) of at 
least 15 ETDRS letters (i.e., 3 lines) at Month 5. The BCVA response endpoint will be 
summarized for Vision 20/40 or Worse Population. 
8.1.10. 
Central Subfield Thickness Response 
In the study, subjects with the CST in the study eye ≥ 300 microns at baseline (Day 1) are called 
macular edema subjects. CST 50-micron response is defined for macular edema subjects as 
having a decrease (improvement) of at least 50 microns in CST at Month 5. 
8.2. 
Analyses of Primary Endpoint and Secondary Endpoints 
Unless specified otherwise, efficacy analyses will be performed on the study eye, based on the 
FAS, and data on fellow eye will not be used. 
8.2.1. 
Primary Analyses 
The primary efficacy endpoint, VH 0 response, is defined as having a VH score of 0 at Month 5 
(modified SUN scale). For the primary endpoint, the VH 0 response rate will be evaluated in 
accordance with the following null (versus alternative) hypothesis: 
H0: 𝜋sham = 𝜋440  
versus 
HA: 𝜋sham ≠𝜋440 
where 𝜋sham and 𝜋440 denote the response rate for sham and 440 µg DE-109, respectively. 
The Cochran-Mantel-Haenszel (CMH) test with Row Mean Scores statistic (Yu et al., 2020), 
stratified by pooled strata based on the number of enrolled eyes from a subject (one eye or two 
eyes), baseline systemic (oral) corticosteroid use (yes or no), and region (US or non-US). Such 
pooling is needed to avoid the situation where subjects in too small strata might all have the 
same responses (either success or failure); hence, do not contribute to the test. To guarantee that 


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a pooled stratum has at least one success and one failure, the pooling algorithm will be 
performed as follows: 
 Determine the number of subjects in each stratum, defined by crossing the number of 
enrolled eyes, baseline systemic corticosteroid use, and region. 
 Within each combination of number of enrolled eyes and region, if one or both strata, 
stratified by corticosteroid use, have less than 25 subjects, then those strata will be 
pooled. 
 Within each stratification factor level based on number of enrolled eyes, if at least one of 
(pooled/unpooled) strata have less than 25 subjects, then those strata will be pooled 
together. 
The pooling algorithm will be performed based on the available data prior to the unmasking of 
the randomization. At the interim analysis, only number of enrolled eyes will be used as the 
stratification factor.  
Study eyes will be treated as non-responders if they meet at least one of the following criteria: 
1. A study eye is rescued due to the protocol-specified worsening of uveitis (Section 8.1.6) 
2. A subject discontinued from the study due to lack of efficacy or adverse events 
3. A study eye meets the protocol-specified worsening of uveitis rescue criteria 
(Section 8.1.6) regardless whether the eye received any rescue therapies 
Study eyes which were rescued due to worsening of uveitis specified under previous protocol 
version but did not meet the rescue criteria under the current version will be treated as rescued 
due to other reason and censored the data after being rescued. The multiple imputation-based 
approach will be applied to impute missing VH score data of study eyes which were not rescued 
and treated as non-responders. The VH 0 response status will then be determined based on the 
observed or imputed VH score. 
For missing VH score due to any other reasons other than protocol-specified worsening of 
uveitis, the multiple imputation approach will be applied as follows: 
1. Use Markov chain Monte Carlo (MCMC) to create monotone missingness first with VH 
score on the logarithm scale. Then obtain standard multiple imputations under MAR 
assumptions for missing VH scores using monotone regression on the logarithm scale. 
The imputed values will be then converted into an eligible VH score based on the 
absolute distance. The missing data are filled in and 50 complete datasets are created. The 
seed that will be used in the SAS program is 135711.  
2. Each of 50 complete datasets will then be analyzed separately. The CMH test statistic, 
response rate for each treatment group, and the rate difference will be calculated for each 
complete sets. 
3. The final CMH test statistic, obtained from each complete dataset, will be transformed 
using Wilson-Hilferty transformation and combined for inference purposes (O'Kelly et 
al., 2014). Rates and rate differences will also be combined without any transformations. 


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The Mantel-Haenszel weighted response rate (%) of each treatment group, the Mantel-Haenszel 
weighted rate difference, the corresponding asymptotic 95% confidence interval (CI) and the 
CMH’s p-value will be reported. 
The main part of the SAS code for the specified CMH test procedure and the multiple imputation 
are provided in Appendix C, respectively. 
8.2.2. 
Sensitivity Analyses 
The following sensitivity analyses will be performed to assess the robustness of the results from 
the primary analysis: 
 The primary analysis will be repeated on the PP Population. 
 The CHM test stratified by the same pooled strata as in the primary analysis will be 
performed on the FAS population the missing data due to other reasons handled using 
the Last-Observation-Carried-Forward (LOCF) approach. Subjects who were rescued 
due to the protocol-specified worsening of uveitis or discontinued from the study due 
to lack of efficacy or adverse events prior to Month 5 will be treated as non-
responders. 
 Treatment policy strategy: The CHM test stratified by the same pooled strata as in the 
primary analysis will be performed on the FAS population regardless whether study 
eyes get rescued. The missing VH score will be imputed using multiple-imputation 
approach in the similar manner as described in Section 8.2.1. 
 A generalized estimating equation (GEE) method will be used on observed cases up 
to Month 6 using identity link function. The GEE might be applied on the imputed 
data (via the same imputation approach as in primary analysis) if there are 
considerable large amount of missingness. The model will include pooled geographic 
region (US vs non-US), baseline VH score of the study eye (1.5+, 2+, ‘3+ or 4+’), 
treatment, visit, and treatment-by-visit as explanatory variables. An unstructured 
(UN) correlation structure will be used to model the correlation of the responses from 
subjects. For subjects rescued before Month 6, all VH scores of study eye collected 
after the start date of rescue therapy will be excluded from the analysis. 
 If the UN correlation structure fails to converge, then an exchangeable (EXCH) 
correlation structure will be used to model the correlation. If the EXCH model fails to 
converge, then the independent model will be used.  
 Multiple imputation with tipping point analysis will be performed to assess the impact 
of missing data on the primary analysis results. The following steps will be performed 
to generate different possible imputation scenarios: 
 Use Markov chain Monte Carlo (MCMC) to create monotone missingness first 
with VH score on the logarithm scale. Then obtain standard multiple imputations 
under MAR assumptions for missing VH scores using monotone regression on the 
logarithm scale. The missing data are filled in and 50 complete datasets are 
created. The seed that will be used in the SAS program is 135711. 


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 The imputed values for the treatment group will be added a different amount of 
0.05, 0.10, 0.15, 0.20, and 0.25. The newly derived imputed values will be then 
converted into a eligible VH score based on the absolute distance.  
 For each possible imputed scenario (associated with different added amounts), the 
primary analysis will be repeated and the p-values as well as the response rates 
will be obtained to determine whether the outcome under the scenario is positive 
or negative. The larger the added amount that required to reverse the conclusion 
of the primary analysis, the more robust the conclusion is considered to be. 
No multiplicity adjustment will be made to these sensitivity analyses. 
8.2.3. 
Analyses of Key Secondary Efficacy Endpoints 
The following key secondary endpoints will be analyzed: 
 Composite score at Month 5 
 VH 0 response rate at Month 3 
 Composite score at Month 3 
All the key secondary endpoints will be analyzed using CMH test in the similar manner as the 
primary endpoint analysis. Study eyes with missing VH score at a given visit will be assigned 
with a score of 0 in the composite score system. For each composite score analysis, the raw mean 
score, Mantel-Haenszel weighted mean score, corresponding mean difference, its asymptotic 
95% confidence interval, and p-values will be reported. 
8.2.4. 
Analyses of Secondary Efficacy Endpoints 
8.2.4.1. 
Analyses of Binary Secondary Endpoints 
All binary secondary VH response endpoints and use of rescue therapy before Month 5 will be 
analyzed on the FAS using similar approach to the primary analysis.  
For each of these binary endpoints, the frequency (n) and percent (%) of each treatment group 
will be reported. The Mantel-Haenszel weighted rates and rate difference and it 95% CI will also 
be reported. 
BCVA binary endpoint defined in Section 8.1.9 will be descriptively summarized on observed 
cases for the Vision 20/40 or Worse Population. CST binary endpoint defined in Section 8.1.10 
will be descriptively summarized on observed cases for the Macular Edema Population. 
8.2.4.2. 
Analyses of Continuous Secondary Endpoints 
The following secondary endpoints will be analyzed using MMRM on observed cases up to 
Month 6: 
 Change from baseline in VH score at a post-baseline visit up to Month 6 
 Change from baseline in BCVA score at a post-baseline visit up to Month 6 
For the analysis of change from baseline in VH score, the MMRM model will include country 
(US or non-US), baseline systemic (oral) corticosteroid use status, study eye, treatment, visit, and 


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treatment-by-visit as fixed effects, baseline VH score and baseline-by-visit as covariates. 
Correlations of change from baseline in VH score due to eyes and study visits within a subject 
will be modeled using a direct product structure, which is constructed by taking the Kronecker 
product of an unstructured matrix (modeling the correlation across study eyes) and an 
unstructure matrix (modeling the correlation across study visits). For subjects rescued before 
Month 6, all VH scores of the study eye collected after the start date of rescue therapy will be 
excluded from the analysis. 
For the analysis of change from baseline in BCVA score, the MMRM model will include country 
(US or non-US), baseline systemic (oral) corticosteroid use status, baseline VH score of the 
study eye (1.5+, 2+, or ‘3+ or 4+’), study eye, treatment, visit, and treatment-by-visit as fixed 
effects, baseline BCVA score and baseline-by-visit as covariates. Correlations of change from 
baseline in BCVA due to eyes and study visits within a subject will be modeled using a direct 
product structure, which is constructed by taking the Kronecker product of an unstructured 
matrix (modeling the correlation across study eyes) and an unstructure matrix (modeling the 
correlation across study visits). For subjects rescued before Month 6, all BCVA of the study eye 
collected after the start date of rescue therapy will be excluded from the analysis. 
For each MMRM model, the denominator degrees of freedom for fixed effects will be estimated 
using the Kenward-Roger approximation (Kenward et al., 1997). An unstructured (UN) 
covariance matrix will be used to model the within-subject correlation due to study eyes and 
study visits. If the UN model fails to converge, then an autoregressive of order 1 (AR(1)) 
covariance matrix will be used to model the within-subject correlation due to study visits while 
study eye-related within-subject correlation structure remains unchanges. If the AR(1) model 
fails to converge, then the compound symmetry model will be used.  
The following secondary endpoints will be analyzed using the analysis of covariance 
(ANCOVA) with missing data at Month 5 being imputed by the LOCF approach: 
 Change from baseline in CST at Month 5 as measured by OCT 
 Change from baseline in the NEI VFQ-25 composite score and subscales at Month 5 
For the analysis of change from baseline in CST at Month 5, the ANCOVA model will include 
study eye, country (US or non-US), baseline systemic (oral) corticosteroid use status, and 
treatment as factors and baseline CST score as a covariate. Correlations of change from baseline 
in CST within a subject due to eyes will be modeled using UN structure. 
For the analysis of changes from baseline in the NEI VFQ-25 composite score and subscales at 
Month 5, the ANCOVA model will include country (US or non-US), baseline systemic (oral) 
corticosteroid use status, baseline VH score of the study eye (1.5+, 2+, or ‘3+ or 4+’) or the 
worse study eye (i.e., higher VH score) for subjects who enrolled both eyes, number of enrolled 
study eyes, and treatment as factors and baseline VFQ-25 score as a covariate. 
For each of these continuous endpoints, the least squares (LS) mean change from baseline of 
each DE-109 group with its standard error will be reported. For each treatment comparison, the 
LS mean difference with the 95% CI will be reported. 


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8.3. 
Subgroup Analyses 
The homogeneity of treatment effects among prospectively defined subgroups will be assessed 
via descriptive statistics of VH 0 response rate, including Mantel-Haenszel weighted rates and 
rate difference and it 95% CI, by the number of treated eyes for the following subgroups: 
 Age (< 65 or ≥ 65 years) 
 Sex (males or females) 
 Race (White or non-White) 
 Country (US or non-US) 
 Baseline VH score of the study eye (1.5+, 2+, or ‘3+ or 4+’) 
 Anatomic location of uveitis of study eye at baseline (intermediate, posterior, 
intermediate + posterior, or panuveitis) 
 Intent-to-taper status at baseline (yes or no) 
 Mean diurnal IOP at baseline (< 25 or ≥ 25 mmHg) 
 Baseline BCVA score of the study eye (≤70 letters or >70 letters) 
 Baseline BCVA score of the study eye (≤65 letters or >65 letters) 
 Presence of macular edema in the study eye at baseline (yes [CST ≥ 300 microns] or no 
[CST < 300 microns]) 
Similarly, subgroup analyses will also be performed for the composite score. Other subgroup 
analyses may be performed as deemed necessary. 
8.4. 
Exploratory Analyses 
8.4.1. 
Analysis of combined total drug group 
A total drug group consists of all FAS subjects who were randomized into either the DE-109  
440 μg arm or the DE-109 fixed dose (dummy) arm. The analysis of primary endpoint and key 
secondary endpoints will be applied on the total drug study group in comparison to the Sham 
arm. 
8.4.2. 
Analysis of exploratory endpoints 
For the analysis of BCVA-response endpoints based on Macular Edema population, response 
rate of each treatment, rate difference and its 95% confidence interval will be reported. 
8.4.3. 
Bayesian analysis of the primary endpoint 
8.4.3.1. 
Prior Data 
The DE-109 clinical trial program includes Sakura 1 (32-007-S1) and Sakura 2 (32-007-S2), two 
randomized controlled trials in which subjects were randomized to the DE-109 study drug at one 
of three doses: 44 μg, 440 μg and 880 μg. The inclusion/exclusion criteria in Sakura studies are 
very similar to those in LUMINA study, although inclusion criteria in Sakura studies were 


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slightly more liberal. The primary endpoint in the study (i.e., LUMINA study) will be analyzed 
using a Bayesian approach with Sakura data served as prior knowledge.  
To ensure the similarity of data from subjects across trials, only Sakura studies’ Intent-to-treat 
subjects who meet the additional following inclusion criteria will be included in the derivation of 
prior distribution: 
 Having a BCVA ≥ 20 ETDRS letters and ≤ 75 ETDRS letters in the study eye(s) at 
the Day 1 visit. 
 Subject being treated with systemic (oral) corticosteroids must have received a stable 
oral prednisone-equivalent dose between ≥15 mg/day and ≤40 mg/day at Day 1 visit. 
The prior distribution representing the prior knowledge learned from a study will be derived 
based on the number of responders and number of subjects in the study population. If the 
previous study with 𝑁 randomized subjects had 𝑛 responders of the primary endpoint, the prior 
distribution for the response rate 𝜋 will be 
𝜋 ~Beta(𝑤⋅𝑛, 𝑤⋅(𝑁−𝑛)), 
where 𝑤 represents the weight to compensate for possible variability from previous study and 
this study. 
8.4.3.2. 
Bayesian Analysis 
To assess the superiority of DE-109 440 μg compared to Sham, a Bayesian analysis of the 
primary endpoint using Sakura studies data as prior knowledge will be employed. The prior 
distribution for the DE-109 440 μg will be derived from Sakura 1 and Sakura 2 study, separately. 
For this analysis, the weight to account for possible variability across studies is chosen to be 
40%, with other values will be used to assess the robustness of such choice. Prior distribution of 
Sham’s response rate will be Beta (1, 1) as Sham has not been used as a comparator in previous 
studies. The posterior distribution of response rates will be calculated based on data collected 
from subjects who received DE-109 440 μg and Sham in this study and the corresponding prior 
distribution, respectively.  
The efficacy of DE-109 440 μg is determined based on whether the posterior probability of  
DE-109 440 μg superiority is met, that is 
P(𝜋440 −𝜋sham > 0 | Data) > 0.975 
where 𝜋440 and 𝜋sham are the response rate of the DE-109 440 μg and Sham arm, respectively. 
To further assess the robustness of the Bayesian analysis, a sensitivity analysis will be performed 
where different weights (20%, 30%, 40%, 50%, and 60%) in the derivation of prior distribution 
will be used. Another sensitivity analysis with prior data including all Sakura studies’ intent-to-
treat subjects will also be performed. 


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9. 
SAFETY ANALYSES 
9.1. 
Safety-Related Definitions 
9.1.1. 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical participant, 
temporally associated with the use of study intervention, whether or not related to the study 
intervention.  An AE reported on the AE eCRF will be considered as treatment-emergent if the 
AE occurred on or after the treatment start date up to 120 days after treatment end date (or the 
last study visit).  In other words, a reported event will not be counted as a treatment-emergent 
AE if it can be determined that the onset of the event occurred prior to the treatment start date or 
beyond 120 days after treatment end date. For tabulations of AEs during the Double-Masked 
analysis period or the Open-Label analysis period, only treatment-emergent AEs will be 
included. Note that events that occurred before the first administration of investigational product 
(IP) are considered medical history events and will be tabulated separately.  
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). AEs will also be rated by the 
Investigator as to their causality/relationship to the IP. 
Each AE will be classified into a system organ class (SOC) and coded to a preferred term (PT) 
using Medical Dictionary for Regulatory Activities (MedDRA), version 23.1 published in 2020. 
9.1.1.1. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected “OD”, “OS”, or 
“OU” under ‘Event Location’ on the AE eCRF. 
9.1.1.2. 
Adverse Drug Reaction 
An AE will be counted as an adverse drug reaction (ADR) if  
 the AE was considered study medication-related, i.e., the Clinical Investigator 
answered ‘Related’ to the AE eCRF question “Relationship to Study Drug”, OR 
 the AE was considered injection procedure-related, i.e., the Clinical Investigator 
answered ‘Related’ to the AE eCRF question “Relationship to Study Drug injection 
procedure” 
9.1.1.3. 
Serious Adverse Event 
An AE will be counted as a serious adverse event (SAE) if the Clinical Investigator selected 
“Yes” to the question ‘Is the adverse event serious?’ on the AE eCRF.  Any AE is considered a 
SAE if it fulfills one or more of the following criteria: 
 Death (i.e., the AE caused or led to death) 
 Life threatening (i.e., immediately life-threatening) 
 It required or prolonged inpatient hospitalization. 


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 It resulted in a persistent or significant disability/incapacity (i.e., the AE resulted in a 
substantial disruption of the subject’s ability to carry out normal life functions). 
 It resulted in a congenital anomaly/birth defect in the offspring of a study subject who 
was exposed to study therapy prior to conception or during pregnancy. 
 It is a medically significant event(s), which may include “sight-threatening events,” that 
may not meet any of the above serious criteria but may jeopardize the subject or require 
medical or surgical intervention to prevent one of the outcomes listed above. 
9.1.1.4. 
Sight-Threatening Adverse Event 
A sight-threatening AE is any SAE that places the subject at immediate risk of permanently 
losing vision in either eye as a direct result of the event. An AE will be counted as a sight-
threatening AE if the Clinical Investigator checked an ‘Sight-Threatening’ option under ‘Serious 
Criteria/Category’ question on the SAE eCRF. 
9.1.1.5. 
Events of Special Interest 
An event of special interest (ESI) is a medical event both anticipated and unanticipated that may 
have a particular impact on the benefit/risk profile of the study medication. For this study, ESIs 
are specific to the study eye only and are as follows: 
 Clinically significant new or worsening of uveitis, defined as satisfaction of any of 
the following:  
 Worsening of uveitis in the study eye as indicated by at least a 2-step increase in 
VH score (i.e., 0 to ≥ 2+, 0.5+ to ≥ 3+, 1+ to ≥ 3+, 1.5+ to ≥ 4+, or 2+ to ≥ 4+) as 
compared to the baseline (Day 1) VH score or the best achieved VH score post-
baseline. 
 Severe deterioration of vision in the study eye due to worsening of uveitis that  
is indicated by at least doubling of the visual angle (loss of 3 or more lines  
[≥15 ETDRS letters]) as compared to baseline (Day 1) BCVA. 
 New or worsening retinal or choroidal uveitic lesion(s) in the study eye as 
compared to baseline (Day 1). 
 New or worsening uveitis otherwise deemed clinically significant by the 
investigator in the study eye as compared to the baseline (Day 1). 
 Endophthalmitis / Sterile Endophthalmitis in the study eye  
 Traumatic cataract in the study eye 
 Vitreoretinal hemorrhage in the study eye 
 Drug depot in visual axis in the study eye 
 Retinal detachment in the study eye 
 Increased IOP (> 10 mmHg as compared to baseline).  
 Cataract (new or worsening from baseline) in the study eye 


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For regulatory reporting requirement, pregnancy and investigational product administration 
error considered to be significant by the investigator are also considered ESIs for this study 
9.1.2. 
Safety Measures 
Table 3 lists the safety measures to be evaluated for this study. 
Table 3: 
Safety Assessments 
Safety Measures 
Note 
Slit-lamp biomicroscopy:  
vitreous, eyelid, conjunctiva, 
cornea, anterior chamber cells 
and flare, iris and pupil, ocular 
motility 
The status of each of these biomicroscopy parameters was 
determined as Normal or Abnormal. For each abnormal record, the 
parameter was rated as 1 = Mild, 2 = Moderate, or 3 = Severe. 
Slit-lamp Biomicroscopy: 
vitreous cell count 
This measure was rated as 0 = 0 cells, 0.5+ = 1-10 cells, 1+ = 11-20 
cells, 2+ = 21-30 cells, 3+ = 31-100 cells, 4+ = >100 cells 
Slit-lamp Biomicroscopy: 
anterior chamber cells 
This measure was rated as 0 = 0 cells, 0.5+ = 1-5 cells, 1+ = 6-15 
cells, 2+ = 16-25 cells, 3+ = 26-50 cells, 4+ = >50 cells 
Slit-lamp Biomicroscopy: 
anterior chamber flare 
This measure was rated as 0 = None, 1+ = Faint, 2+ = Moderate, 
3+ = Marked, 4+ = Intense 
Slit-lamp Biomicroscopy: 
lens and cataract 
The lens of an eye was classified as Phakic, Aphakic, or 
Pseudophakic. For phakic lens with cataract, the severity was rates 
as 1 = Mild, 2 = Moderate, 3 = Severe. In addition, whether 
cataract affects grading of degree of inflammation (Yes or No) was 
also determined. 
Intraocular pressure 
The IOP, the fluid pressure inside the eye, was recorded in mmHg 
with one decimal point (e.g., 24.0 mmHg). For this study, the 
elevated IOP, depending on the level of elevation, might be 
reported as an AE at Clinical Investigator’s discretion. 
Indirect ophthalmoscopy: 
retina vessels, macula, fovea, 
periphery, optic nerve, cup-to-
disc ratio 
The status of retina vessels, macula, fovea, periphery, and optic 
nerve was determined as Normal or Abnormal. The cup-to-disc 
ratio was recorded with two decimal points (e.g., 0.80) 
Best-corrected visual acuity 
(BCVA) 
BCVA measures the acuteness or clearness of best-corrected 
vision, with a range of [0, 110] in ETDRS 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 BCVA score of 85 ETDRS letters is equivalent to 20/20 vision, 
which is considered normal vision. 
Central Subfield Thickness 
(CST) 
For each eye, the CST was measured using Optical Coherence 
Tomography (OCT). OCT was performed using reading center 
certified photographers, equipment, and standardized protocols. 
 


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Table 3: 
Safety Assessments (Continued) 
Safety Measures 
Note 
Physical examination: 
Height, weight 
The physical exam result was determined as Normal, Abnormal, or 
No Change. The weight and the height were recorded with one 
decimal point in inch/cm and lb/kg, respectively. The conversion 
rules “1 lb = 0.453592 kg” and “1 in = 2.54 cm” will be followed to 
convert lb to kg and into cm, respectively. 
Vital signs:  
Oral temperature, systolic and 
diastolic blood pressure, heart 
rate 
The oral temperature was recorded in °F or °C. The conversion rule 
“°C = 5/9 × (°F – 32)” will be followed to convert °F to °C.  The 
blood pressure (systolic and diastolic) and the heart rate were 
recorded in mmHg and beats per minute (bpm), respectively. 
Laboratory tests:  
Blood chemistry/hematology, 
urinalysis 
The minimum blood and urine parameters collected in the study are 
listed in Appendix B.  
Hematology, chemistry, and urinalysis outcomes were determined 
by the Clinical Investigator as Normal, Not Clinically Significant 
Abnormality, or Clinically Significant Abnormality based on the 
comprehensive review of the relevant laboratory test results. 
The safety-related measures collected in this study include AEs, events of special interest (ESIs), 
slit-lamp biomicroscopy findings, IOP, best-corrected visual acuity, indirect ophthalmoscopy 
findings, central subfield thickness, physical exam results, vital signs, and laboratory test results. 
The Safety population will be used for all summaries. 
All the safety-related measures will be summarized descriptively by actual treatment received. 
Except AEs, the descriptive summary of each ocular safety-related measurement and the change 
from baseline in that measure will be performed for study eyes and fellow eyes separately. 
9.2. 
Adverse Events 
Subjects with any AE(s) will be tabulated by type of AE(s) and number of enrolled eyes for each 
actual treatment received and total drug (i.e., the combination of DE-109 440 µg and DE-109 
fixed dose arm). Study eyes with any ocular AE(s) will be tabulated by type of AE(s) for each 
actual treatment received and total drug. For subject-level summaries, any AEs experienced by 
either eye or both eyes will be counted once for that AE. Unless specified otherwise, ocular AEs 
in study eyes will be summarized at the eye-level, while overall AEs, ocular AEs in fellow eyes, 
and non-ocular AEs will be summarized at the subject-level. 
Besides the overall AE summary, AEs, SAEs, ADRs, serious ADRs will be tabulated by SOC 
and preferred term for all AEs, ocular AEs, and non-ocular AEs separately.  A subject/study eye 
which experienced multiple AEs within a SOC or preferred term will be counted only once for 
that SOC or preferred term for subject-level/eye-level summaries. Non-serious AEs (including 
number of events) will also be summarized by SOC and preferred term. ESIs will be summarized 
descriptively at the eye-level. 
AEs, SAEs, ADRs, serious ADRs, ocular AEs, AEs leading to death, AEs leading to study drug 
discontinuation, and ESIs, if any, will be listed separately. 


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9.3. 
Intraocular Pressure 
IOP and change from baseline in IOP will be summarized by analysis visit. 
Change after injection in IOP will be summarized by injection visit. Subjects with any increase 
of ≥10 mmHg in IOP after injection will be listed. 
9.4. 
Slit-lamp Biomicroscopy 
For each biomicroscopy parameter rated on a 0-3 scale (0=None, 1=Mild, 2=Moderate, 
3=Severe), rating scores and changes from baseline will be summarized by analysis visit for 
study eyes and fellow eyes, separately.  In addition, any worsening (increase) of ≥ 2 units from 
baseline will be listed.  Any clinically significant worsening from baseline in severity will also 
be listed. 
For lid hyperemia, lid edema, conjunctival hyperemia, chemosis, corneal edema, conjunctival 
discharge/exudate, and anterior chamber flare, shift from baseline in severity rating score will be 
summarized by analysis visit and shift after injection will be summarized by injection visit. 
Subjects with any clinically significant abnormality will be listed by biomicroscopic parameter. 
In addition, subjects with any worsening (increase) of 2 units or more from baseline will also be 
listed by biomicroscopic parameter. 
For pupil, lashes, ocular motility, and iris, shift from baseline in status (Normal or Abnormal) 
will be summarized by analysis visit and shift after injection will be summarized by injection 
visit. Subjects with any clinically significant abnormality will be listed by biomicroscopic 
parameter. In addition, subjects with any change from Normal at baseline to Abnormal in status 
will also be listed by biomicroscopic parameter. 
For vitreous cell count and anterior chamber cells, shift from baseline in rating score will be 
summarized by analysis visit and shift after injection will be summarized by injection visit. 
9.4.1. 
Lens 
For phakic lens only, shift from baseline in cataract severity score will be summarized by 
analysis visit and shift after injection will be summarized by injection visit. Subjects with any 
worsening (increase) of 2 units or more from baseline in cataract severity will be listed. In 
addition, subjects with any cataract that affected grading of degree of inflammation will also be 
listed. 
9.5. 
Ophthalmoscopy 
For retina vessels, macula, fovea, periphery, and optic nerve, shift from baseline in status 
(Normal or Abnormal) will be summarized by analysis visit and shift after injection will be 
summarized by injection visit. Subjects with any change from Normal at baseline to Abnormal in 
status will be listed by ophthalmoscopic parameter. 
For vitreous hemorrhage, retinal detachment, and retinal tear, shift from baseline in presence 
status (None or Present) will be summarized by analysis visit and shift after injection will be 
summarized by injection visit. Subjects with any change from None at baseline to Present in 
presence status will be listed by ophthalmoscopic parameter. 


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For cup/disc ratio, score and change-from-baseline score will be summarized by analysis visit. 
Change after injection in cup/disc ratio will be summarized by injection visit. Subjects with any 
worsening (increase) of 0.2 units or more from baseline in cup/disc ratio will be listed. 
9.6. 
Physical Examination and Vital Signs 
For weight, height, oral temperature, blood pressure, and heart rate, score and change from 
baseline score will be summarized by analysis visit. Subjects with any change from Normal at 
baseline to Abnormal in physical exam result will be listed. 
9.7. 
Laboratory Tests 
Hematology results will be summarized by laboratory test and analysis visit. Subjects with any 
clinically significant abnormality in hematology will be listed. 
 
10. 
SUMMARY OF CHANGES TO THE PROTOCOL 
10.1. 
Adding Exploratory Endpoints 
The visual acuity-related endpoints (presented in Section 2.3.5) were added to explore the 
treatment effect of DE-109 440 µg among Macular Edema population subjects. 
10.2. 
Adding Exploratory Analyses  
In previous studies, DE-109 has showed some evidence of efficacy across different doses. To 
further explore the overall efficacy of DE-109, the analysis of primary endpoint and the analyses 
of key secondary endpoints will be repeated on the combined DE-109 µg and DE-109 fixed dose 
arms versus Sham arm. 
Analysis of BCVA-related endpoints was also added in corresponding to the added exploratory 
endpoints. 
 


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11. 
REFERENCE 
 
1. 
Kenward, M. G., Roger, J. H. (1997).  Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood. Biometrics. 53(3):983-97. PubMed PMID: 9333350. 
 
2. 
Mehta, C. R., Pocock, S. J. (2011).  Adaptive increase in sample size when interim results 
are promising: a practical guide with examples. Stat Med. 30(28):3267-84. 
 
3. 
O'Kelly, M., Ratitch, B. Clinical Trials with Missing Data: A Guide for Practitioners: 
John Wiley & Sons; 2014. 
 
4. 
Yu, J., Koch, G. (2020).  Randomization-Based Methods for Treatment Comparisons for 
Dichotomous Outcomes for Multiple Anatomical Regions. Statistics in 
Biopharmaceutical Research. 13(4):1-15. doi: 10.1080/19466315.2020.1750471. 
 


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APPENDIX A. VFQ-25 COMPOSITE SCORE AND SUBSCALES 
Following steps will be taken to derive the VFQ-25 composite score and subscales: 
Step One: Recode Item Scores 
Item Numbers on VFQ-25 
Original Responsea 
Recode Value 
1, 3, 4 
1 
2 
3 
4 
5 
100 
75 
50 
25 
0 
2 
1 
2 
3 
4 
5 
6 
100 
80 
60 
40 
20 
0 
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 16a, A3b, A4b, A5b, A6b, 
A7b, A8b, A9b 
1 
2 
3 
4 
5 
6 
100 
75 
50 
25 
0 
*c 
15cd 
1 
2 
3 
4 
100 
75 
50 
25 
0 
17, 18, 19, 20, 21, 22, 23, 24, 25, A11ab, A11bb, A12b, A13b 
1 
2 
3 
4 
5 
0 
25 
50 
75 
100 
A1b, A2b 
0 
to 
10 
0 
to 
100 
a Original response choices as printed in the questionnaire 
b The letter “A” before the item number indicates that this item is an optional item from the Appendix of VFQ-25 
questionnaire. 
c A response of ‘6’ indicates that the person does not perform the activity because of non-vision related problems. If 
‘6’ is selected, the item will be recoded as missing. 
d Item 15c has 4 levels (1, 2, 3, or 4), but it is recoded to 5 levels by incorporating the response choice for Item 15b: 
if 15b = 1 then 15c is recoded to 0; 
if 15b = 2 or 3 then 15c is recorded to missing. 


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Step Two: Identify Items Needed to Derive VFQ-25 Composite Score and Subscales 
Score or Subscale 
Items to be averaged (after step 1) 
General Health 
General Vision 
Ocular Pain 
Near Activities 
Distance Activities 
Vision Specific Social Functioning 
Vision Specific Mental Health 
Vision Specific Role Difficulties 
Vision Specific Dependency 
Driving 
Color Vision 
Peripheral Vision 
1, A1 
2, A2 
4, 19 
5, 6, 7, A3, A4, A5 
8, 9, 14, A6, A7, A8 
11, 13, A9 
3, 21, 22, 25, A12 
17, 18, A11a, A11b 
20, 23, 24, A13 
15c, 16, 16a 
12 
10 
Composite Score 
All items except Item 1 and A1 
Step Three: Derive VFQ-25 Composite Score and Subscales 
Score = Sum of all items with a non-missing answer / Total number of items with a non-missing 
answer, with a range of [0, 100] (0 = Worst possible score; 100 = Best score) 


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APPENDIX B. CLINICAL LABORATORY PARAMETERS 
Serum Chemistry and Hematology 
The following is a list of the minimum parameters that will be measured. Other additional 
parameters may also be reported. 
Table 4: 
Serum Chemistry and Hematology 
Chemistry  
Hematology 
Albumin 
red blood cells (RBC) 
Creatinine 
white blood cells (WBC) 
lactate dehydrogenase (LDH) 
differential WBC 
Glucose 
platelets (PLT) 
Calcium 
hemoglobin (HGB) 
Potassium 
hematocrit (HCT) 
Sodium 
mean corpuscular volume (MCV) 
cholesterol (total, HDL and LDL) 
mean corpuscular hemoglobin (MCH) 
Triglycerides 
mean corpuscular hemoglobin conc. (MCHC) 
urea nitrogen 
 
bilirubin (total, direct, indirect) 
 
alkaline phosphatase (ALP) 
 
alanine aminotransferase (ALT) 
 
aspartate aminotransferase (AST) 
 
gamma glutamyl transferase (GGT) 
 
Urinalysis 
The following is a list of the minimum urine parameters that will be measured. Other additional 
urine parameters may also be reported. 
PH 
Protein  
Erythrocytes  
Ketones 
Glucose 
 


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