Conditions: Macular Edema Retinal Vein Occlusion
Keywords: RVO ME Microneedle Microinjection Triamcinolone Choroid Choroid injection Suprachoroidal Anti-VEGF Subretinal Fluid Cystoid Macular Edema Optical Coherence Tomography OCT Central Subfield Thickness Lucentis Avastin Ranibizumab Bevacizumab Triamcinolone acetonide
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 325
Healthy volunteers: no

Brief summary:
This Phase 3, multicenter, randomized, masked, controlled, parallel group study is designed to demonstrate that suprachoroidal (SC) CLS-TA administered with intravitreal (IVT) anti-VEGF agent in subjects with treatment naive RVO is superior to IVT anti-VEGF agent used alone.

Detailed description:
A Randomized, Masked, Controlled Trial to Study the Safety and Efficacy of Suprachoroidal CLS-TA With Intravitreal Anti-VEGF Agent in Subjects With Retinal Vein Occlusion

Arms:
arm 1: Lucentis (0.5 mg/0.05 mL), IVT injection + CLS-TA (4 mg/0.10 mL), SC injection or Avastin (1.25 mg/0.05 mL), IVT injection + CLS-TA (4 mg/0.10 mL), SC injection arm 2: Lucentis (0.5 mg/0.05 mL), IVT injection + sham SC procedure or Avastin (1.25 mg/0.05 mL), IVT injection + sham SC procedure

Interventions: intervention 1: suprachoroidal CLS-TA intervention 2: suprachoroidal sham intervention 3: Lucentis or Avastin
Intervention descriptions: intervention 1: suprachoroidal injection of CLS-TA intervention 2: sham suprachoroidal procedure intervention 3: IVT anti-VEGF agent. Either a 0.5 mg intravitreal injection of Lucentis or 1.25 mg intravitreal injection of Avastin

Protocol document:
Prot_SAP_000.pdf: 
Compound Name: 
CLS-TA, triamcinolone acetonide injectable suspension 
Protocol Number: 
CLS1003-302 
IND Number: 
115683 
NCT Number:  
NCT03203447 
Protocol Title 
TOPAZ: A Randomized, Masked, Controlled Trial To 
Study The Safety And Efficacy Of Suprachoroidal CLS-TA 
In Combination With An Intravitreal Anti-VEGF Agent In 
Subjects With Retinal Vein Occlusion 
Sponsor: 
Clearside Biomedical, Inc. 
900 North Point Parkway, Suite 200 
Alpharetta, GA 30005 
Issue Date: 
Protocol Amendment 1 Date: 
21 June 2017 
25 January 2018 
 


Clinical Study Report 
CLS1003-302 
16.1 Study Information 
Page 1 of 1 
Confidential 
1.
PROTOCOL AND AMENDMENTS
Table 1: 
Protocol CLS1003-302 
Original Protocol / 
Amendment 
Date 
Protocol Revision 
Amendment 1.1 
25 Jan 2018 
Protocol with Amendment 1.1 
Original Protocol 
21 Jun 2017 
Original 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-302 
 
 
Summary of Changes 
Amendment 1.1 
25 Jan 2018 
Page 1 of 6 
CONFIDENTIAL 
SUMMARY OF CHANGES 
Protocol Amendment 1.1 
 
Protocol Title: 
A RANDOMIZED, MASKED, CONTROLLED TRIAL TO STUDY 
THE SAFETY AND EFFICACY OF SUPRACHOROIDAL CLS-TA IN 
COMBINATION WITH AN INTRAVITREAL ANTI-VEGF AGENT 
IN SUBJECTS WITH RETINAL VEIN OCCLUSION 
Protocol Number: 
IND: 
CLS1003-302 
115683 
Original Version Date: 
21 Jun 2017 
Amendment Number: 
1.1 
Version Date: 
25 Jan 2018 
 
 
 
 
 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension
 Clearside Biomedical, Inc 
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Summary of Changes 
Amendment 1.1 
25 Jan 2018 
Page 2 of 6 
CONFIDENTIAL 
Amendment 1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
Title Page and Footer 
Updated protocol title and 
document version and date 
Protocol versioning 
None 
Investigator’s Agreement 
I have received and read the 
Investigator’s Brochure for CLS-
TA. 
I have received and read the 
Investigator’s Brochure for CLS-
TA and the Investigator’s Brochure 
for bevacizumab. 
Addition of bevacizumab 
Investigator’s Brochure 
None 
2. Synopsis
Removed references to EYLEA as 
study drug  
Added reference to AVASTIN and 
LUCENTIS as study drug 
Added text to describe study 
treatment arms, including endpoints 
Modified statistical analysis 
information  
Comparator drug 
modification 
Describe changes to study 
treatment arms 
Comparator drug 
modification 
None 
None 
IWRS – Interactive web response 
system 
IRT – Interactive response 
technology 
System update 
None 
4. List of 
Abbreviations
5. Introduction 
Provide background and describe 
rationale for use of Avastin and 
Lucentis in conjunction with CLS-
TA 
Comparator drug 
modification 
None 
Section 6.4 
Exploratory Objectives 
Added ‘To evaluate changes from 
baseline based on disease type, 
BRVO and CRVO.  Subjects with 
HRVO data will be included with 
the CRVO group based on 
randomization.’ 
Addition of exploratory 
objective 
None 
Section 7.2.3 
Exploratory Efficacy 
Endpoints 
Added ‘Changes from Baseline on 
visual and anatomic outcomes 
based on disease diagnosis of 
BRVO and CRVO.  HRVO 
Addition of exploratory 
efficacy endpoint 
None 


CLS-TA, triamcinolone acetonide injectable suspension
 Clearside Biomedical, Inc 
CLS1003-302 
Summary of Changes 
Amendment 1.1 
25 Jan 2018 
Page 3 of 6 
CONFIDENTIAL 
Amendment 1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
subjects will be included with the 
CRVO for analyses.’ 
Approximately 460 subjects with 
RVO who are naïve to treatment 
will be enrolled into one of two 
treatment groups. 
Approximately 460 subjects with 
RVO who are naïve to treatment 
will be enrolled into one of four 
treatment groups. 
Update treatment groups 
None 
Section 7.3 Number 
of Subjects 
Section 7.4 Treatment 
Assignment 
After Screening (Day -30 to Day -
1) and Baseline assessments on
Day 0, subjects will be randomly
assigned 1:1 to one of two
treatment groups stratified by
disease type (BRVO, CRVO).
Randomization will proceed as
described until either strata reaches
55% of the total number patients to
be enrolled at which time only
patients from the other strata will
be enrolled.
After Screening (Day -30 to Day -
1) and Baseline assessments on
Day 0, subjects will be randomly
assigned 1:1:1:1 to one of four
treatment groups stratified by
disease type (BRVO, CRVO).
Randomization will proceed as
described until either strata within a
group reaches at least 50% of the
total number patients to be enrolled
in that group at which time only
patients from the other strata will
be enrolled.
Treatment group changes 
None 
Table 3. Subject 
Randomization 
Remove reference to IVT 
aflibercept 
Change treatments arms to include 
IVT Avastin and Lucentis 
Comparator drug 
modification and number of 
subjects per treatment group 
None 
Removed previous table 
Insert new table 
Updates to table 
None 
To determine the safety and 
performance of the SCS 
microinjector when delivering SC 
CLS-TA 
Endpoint added to capture 
microinjector exploratory 
objective 
None 
Figure 2. Study Treatment 
Schedule 
Section 6.3. Exploratory 
Objectives 
Section 7.2.5 Endpoints 
Related to SCS microinjector 
Performance of the SCS 
microinjector, evidenced by 
injection parameters (location, eye 
quadrant, needle length, injection 
Section added for 
microinjector endpoints 
None 


CLS-TA, triamcinolone acetonide injectable suspension
 Clearside Biomedical, Inc 
CLS1003-302 
Summary of Changes 
Amendment 1.1 
25 Jan 2018 
Page 4 of 6 
CONFIDENTIAL 
Amendment 1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
completion, and product 
complaints) at each SC injection 
visit (Visits 2, 5, 8) 
Incidence of TEAEs and SAEs 
related to the SCS microinjector 
Added text for subject withdrawal 
criteria 
Update withdrawal criteria 
None 
Section 8.3. Subject 
Withdrawal Criteria 
Section 8.4. Visit 
Procedure Descriptions 
PRN therapy will be aflibercept for 
all subjects, regardless of 
randomization group. 
Removed slit lamp 
ophthalmoscopy assessment post 
injections 
Identify PRN treatment 
Update to reflect common 
clinic procedures 
None 
None 
Section 9.1. Treatments to be 
Administered 
Section 9.4. Rescue Treatment 
Adjusted to include Avastin and 
Lucentis 
Updated section 9.4.1 title from 
Rescue Therapy Criteria to 
Supplemental Therapy Criteria 
Updated rescue to supplemental 
throughout the protocol 
Clarify treatment 
administration 
Clarify definition of rescue 
versus supplemental therapy 
None 
None 
Updated to include preparation for 
additional anti-VEGF agents 
Comparator drug 
modification 
None 
Section 10.4 Study Drug 
Preparation 
Section 12.2. Adverse 
and Serious Adverse 
Events 
Updates throughout to clarify 
adverse events and reporting 
Clarification of reporting 
procedures 
None 


CLS-TA, triamcinolone acetonide injectable suspension
 Clearside Biomedical, Inc 
CLS1003-302 
Summary of Changes 
Amendment 1.1 
25 Jan 2018 
Page 5 of 6 
CONFIDENTIAL 
Amendment 1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
Addition of new section 
Addition of new section 
None 
Updates throughout the statistical 
analysis section 
Comparator drug 
modification 
None 
Addition of references 
Comparator drug 
modification 
None 
Various formatting changes 
Replaced ‘aflibercept’ with 
‘intravitreal anti-VEGF agent’ or 
‘IVT anti-VEGF agent’ inclusive of 
LUCENTIS and AVASTIN 
Formatting updates 
Change in comparator agents 
None 
Section 12.2.4. Exposure 
In Utero 
Section 13. Statistical 
Considerations 
References 
Throughout protocol 
Appendix A 
Removed post injection slit lamp 
ophthalmoscopy assessment 
Removed serum pregnancy test at 
Visit 8 
Update to reflect common 
clinic procedures 
Urine pregnancy test will be 
done at Visit 8 
None 
None 


CLS-TA, triamcinolone acetonide injectable suspension
 Clearside Biomedical, Inc 
CLS1003-302 
Summary of Changes 
Amendment 1.1 
25 Jan 2018 
Page 6 of 6 
CONFIDENTIAL 
Amendment 1.1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
Section 8 Headers 
Section Header Numbers added 
for ease in navigating document 
Formatting updates 
None 
Section 12.2.4 Intensity 
It is important to distinguish 
between serious and severe AEs. 
Severity is a measure of intensity 
whereas seriousness is defined by 
the criteria under Section 
12.2.1.2. 
It is important to distinguish 
between serious and severe AEs. 
Severity is a measure of intensity 
whereas seriousness is defined by 
the criteria under Section 12.2.1. 
Section reference corrected 
None 
Section 12 Headers 
Section Header Numbers updated 
to remove duplicate 
Formatting updates 
None 


CLS-TA, triamcinolone acetonide injectable suspension
  Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date:25 January 2018 
Page 1 of 79 
CONFIDENTIAL 
Clinical Protocol CLS1003-302 
Project: 
1003 
Compound Number/Name: 
CLS-TA (triamcinolone acetonide injectable suspension) 40 
mg/mL 
Protocol Number: 
CLS1003-302 
IND Number: 
115683 
EudraCT Number: 
2017-002089-37 
Phase: 
3 
Protocol Title: 
TOPAZ: A RANDOMIZED, MASKED, CONTROLLED 
TRIAL TO STUDY THE SAFETY AND EFFICACY OF 
SUPRACHOROIDAL CLS-TA IN COMBINATION 
WITH AN INTRAVITREAL ANTI-VEGF AGENT IN 
SUBJECTS WITH RETINAL VEIN OCCLUSION 
Sponsor: 
Clearside Biomedical, Inc. 
 900 North Point Parkway, Suite 200 
Alpharetta, GA  30005 
Primary Medical Monitor: 
Peter Nicholas, MD 
Telephone: (919) 259-9521 
Global Principal Investigator: 
To be appointed before the end of the study 
Protocol Amendment 1.1 
25 January 2018 
Protocol Amendment 1: 
14 December 2017 
Issue Date: 
21 June 2017 
Sponsor Signatory: 
Jennifer Kissner, PhD 
CONFIDENTIAL 
This protocol contains confidential information about a product provided by Clearside Biomedical, Inc.  
This information is provided for the exclusive use of the Investigators participating in this study.  Any 
and all confidential information contained herein may not be disclosed to any other person or party 
without the prior written consent of Clearside Biomedical, Inc.  


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
CLS1003-302 
 
Clinical Protocol 
 
Version Date:25 January 2018 
Page 2 of 79 
CONFIDENTIAL 
SIGNATURE PAGE 
This study protocol amendment has been reviewed and approved by the undersigned persons. 
It is confirmed that the information and guidance given in this protocol amendment complies 
with scientific principles, the guidelines of Good Clinical Practices, the Declaration of 
Helsinki in the latest relevant version and the applicable legal and regulatory requirements. 
 
Sponsor Signatory: 
Jennifer Kissner, Ph.D. 
Vice President, Clinical Development 
Clearside Biomedical, Inc. 
ELECTRONIC SIGNATURE 
ON FILE 
25 Jan 2018 
 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
CLS1003-302 
 
Clinical Protocol 
 
Version Date: 25 January 2018 
Page 3 of 79 
 
 
CONFIDENTIAL 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for CLS-TA and the Investigator’s 
Brochure for bevacizumab. I have read the Lucentis Prescribing Information and Summary of 
Product Characteristics. I have read the CLS1003-302 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
CLS1003-302 
 
Clinical Protocol 
 
Version Date: 25 January 2018 
Page 4 of 79 
 
 
CONFIDENTIAL 
 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Telephone number 
Primary Medical Monitor 
(24-Hour emergency contact) 
Peter Nicholas, MD 
(919) 259-9521 
Sponsor Clinical Lead 
Kathleen Billman 
(678) 894-0703 
Principal Investigator 
The Global Coordinating Principal Investigator will be appointed 
by the Sponsor before the end of the study.  As part of his or her 
responsibilities, the Global Coordinating Principal Investigator 
will review the final Clinical Study Report and will sign the report 
to confirm that it accurately describes the conduct and results of 
the study. 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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CONFIDENTIAL 
 
2. 
SYNOPSIS 
Name of Company:  
Clearside Biomedical, Inc. 
Name of Study Drug:  
CLS-TA, (triamcinolone acetonide injectable suspension) 40 mg/mL  
LUCENTIS® (ranibizumab injection) for intravitreal injection 
AVASTIN® (bevacizumab) injection  
Name of Active Ingredient 
Triamcinolone Acetonide  
Ranibizumab 
Bevacizumab 
Title of Study: TOPAZ: A randomized, masked, controlled trial to study the safety and efficacy of 
suprachoroidal CLS-TA in combination with an intravitreal anti-VEGF agent in subjects with retinal 
vein occlusion   
Study center(s): Approximately 150 sites globally 
Protocol Number: CLS1003-302 
Study Duration: 12 Months 
Estimated date first subject enrolled: 1Q2018 
Estimated date last subject completed: 3Q2020 
Study Phase: 3 
Objectives:  
Primary: 
• 
To demonstrate that suprachoroidally injected CLS-TA in combination with an intravitreally 
injected anti-VEGF agent is superior to an intravitreally injected anti-VEGF agent alone using a 
best corrected visual acuity (BCVA) outcome measure.  
Secondary: 
• 
To determine the effect of suprachoroidally injected CLS-TA in combination with an intravitreally 
injected anti-VEGF agent on mean change from Baseline in BCVA 
• 
To determine the effect of suprachoroidally injected CLS-TA in combination with an intravitreally 
injected anti-VEGF agent on mean change from Baseline in central subfield thickness  
Safety: 
• 
To evaluate the safety and tolerability of suprachoroidally injected CLS-TA used in combination 
with an intravitreally injected anti-VEGF as measured by reported adverse events and safety 
parameters 
Number of Subjects: Approximately 460 (approximately 230 subjects per arm) randomly assigned 
1:1:1:1 to one of four treatment groups stratified by disease (BRVO, CRVO). Subjects with HRVO 
will be included in this study in the CRVO group. Randomization will proceed as described until 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
CLS1003-302 
 
Clinical Protocol 
 
Version Date: 25 January 2018 
Page 6 of 79 
 
 
CONFIDENTIAL 
 
either stratum within a group reaches approximately 50% of the total number patients to be enrolled 
in that group at which time only patients from the other stratum will be enrolled. 
Diagnosis and main criteria for inclusion:  
Treatment naïve patients diagnosed with macular edema secondary to retinal vein occlusion 
Investigational product, dosage and mode of administration:  
CLS-TA, triamcinolone acetonide injectable suspension, 4 mg in 0.10 mL, suprachoroidal (SC) 
injection  
Lucentis (ranibizumab) Injection, 0.5 mg in 0.05 mL, intravitreal (IVT) Injection 
Avastin (bevacizumab) Injection, 1.25 mg in 0.05 mL, IVT Injection (supplied in single use 
container)  
Reference therapy, dosage and mode of administration: 
Lucentis (ranibizumab) Injection 0.5 mg in 0.05 mL, IVT injection  
Avastin (bevacizumab) Injection 1.25 mg in 0.05 mL, IVT Injection (supplied in single use container) 
Standard of care therapy (PRN period): 
EYLEA® (aflibercept) Injection 2 mg in 0.05 mL, IVT injection 
Treatment Groups: 
ACTIVE ARM:  
Lucentis (0.5 mg/0.05 mL), IVT injection + CLS-TA (4 mg/0.10 mL), SC injection  
Avastin (1.25 mg/0.05 mL), IVT injection + CLS-TA (4 mg/0.10 mL), SC injection 
CONTROL ARM:  
Lucentis (0.5 mg/0.05 mL), IVT injection + sham SC procedure  
Avastin (1.25 mg/0.05 mL), IVT injection + sham SC procedure 
Criteria for Evaluation: 
The approximately 460 subjects (approximately 230 subjects per arm) will be randomly assigned 
1:1:1:1 to one of four treatment groups. Of the four groups, two groups each will receive the 
combination of a suprachoroidal injection of CLS-TA and an intravitreal injection of an anti-VEGF 
agent (bevacizumab or ranibizumab) as the active (combination) arm; and two groups each will 
receive an intravitreal injection of an anti-VEGF agent alone, either bevacizumab or ranibizumab, 
used as a control (monotherapy) arm. 
In terms of analysis, the consideration will be that there are two arms, an active (combination) arm 
and a control (anti-VEGF only) arm: the two active (combination) groups with CLS-TA and an anti-
VEGF agent will be pooled as the active (combination) arm; and the two anti-VEGF only groups will 
be pooled as the control (monotherapy) arm. The primary outcome will be based on comparing best 
corrected visual acuity data from the active (combination) arm to that from the control (monotherapy) 
arm. Specifically, the primary endpoint is the proportion of subjects demonstrating ≥ 15 Early 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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CONFIDENTIAL 
 
Treatment of Diabetic Retinopathy Study letter improvement from Baseline in BCVA at Week 8 
(Month 2). 
 
Statistical Methods:  
The primary endpoint is the proportion of subjects demonstrating ≥ 15 letter improvement from 
Baseline in ETDRS BCVA at Week 8 (Month 2).   
The primary analysis is a test of superiority of CLS-TA (TA) administered suprachoroidally in 
combination with an anti-VEGF agent (IA) administered intravitreally vs an intravitreally 
administered anti-VEGF agent used alone. Tests will be conducted using two-sided alpha = 0.05. The 
formal hypothesis is: 
 
H0: IA + TA = IA 
H1: IA + TA ≠ IA 
 
The primary analysis will use the Cochran-Mantel-Haenszel test to evaluate differences in the 
proportion of subjects in the two arms who show 15 or more letters improvement in BCVA at the 
Month 2 visit after adjusting for effects for disease type. Subjects who either receive rescue treatment 
or withdraw from the study prior to the Month 2 visit will be considered as treatment failures for the 
primary endpoint analysis. 
In this trial since the primary comparison will be at Month 2, and as this is a single test, there are no 
multiplicity issues for the primary comparison. The model will include an interaction for adjunctive 
treatment by anti-VEGF agent type. This will be used in sensitivity testing to see if there is a similar 
response to the adjunct CLS-TA therapy between the two types of VEGF inhibitors in the two active 
(combination) groups (CLS-TA with ranibizumab, or CLS-TA with bevacizumab) that comprise the 
active (combination) arm. 
Additional safety and descriptive efficacy data will be collected through approximately 12 months. 
Treatment codes will be broken at Month 2, and the final efficacy analysis will be conducted at this 
time. A descriptive follow-up safety and efficacy analysis will be performed at 6 months to allow 
filing for marketing authorization. Investigators, subjects, and study personnel who have contact with 
the Investigators or subjects will remain masked throughout the study. No adjustment for the follow-
up analysis at Month 6 is required because the final analysis of efficacy is at Month 2 and data from 
all subsequent visits will be descriptive only. 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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CONFIDENTIAL 
 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................8 
4. 
LIST OF ABBREVIATIONS.....................................................................................14 
5. 
INTRODUCTION ......................................................................................................16 
5.1. 
Disease Background and Scientific Rationale ............................................................17 
5.2. 
Description of Investigational Product .......................................................................20 
5.3. 
Summary of Clinical Experience and Justification for Dose Selection ......................21 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
6.1. 
Primary Objective .......................................................................................................25 
6.2. 
Secondary Objectives .................................................................................................25 
6.3. 
Safety Objective ..........................................................................................................25 
6.4. 
Exploratory Objectives ...............................................................................................25 
7. 
INVESTIGATIONAL PLAN .....................................................................................26 
7.1. 
Overall Study Design ..................................................................................................26 
7.2. 
Endpoints ....................................................................................................................26 
7.2.1. 
Primary Efficacy Endpoint .........................................................................................26 
7.2.2. 
Secondary Efficacy Endpoints ....................................................................................26 
7.2.3. 
Exploratory Efficacy Endpoints .................................................................................26 
7.2.4. 
Safety Endpoints .........................................................................................................27 
7.2.5. 
Endpoints Related to SCS microinjector ....................................................................27 
7.3. 
Number of Subjects ....................................................................................................27 
7.4. 
Treatment Assignment ................................................................................................27 
7.5. 
Criteria for Study Termination ...................................................................................29 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................30 
8.1. 
Inclusion Criteria ........................................................................................................30 
8.2. 
Exclusion Criteria .......................................................................................................30 
8.2.1. 
Ophthalmic Exclusion Criteria ...................................................................................30 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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CONFIDENTIAL 
 
8.2.2. 
General Exclusion Criteria .........................................................................................31 
8.2.3. 
Randomization Criteria ...............................................................................................32 
8.3. 
Subject Withdrawal Criteria .......................................................................................32 
8.4. 
Visit Procedure Descriptions ......................................................................................33 
8.4.1. 
General Procedures .....................................................................................................33 
8.4.2. 
Re-Screening Procedures ............................................................................................34 
8.4.3. 
Visit 1 – Screening (Day -30 to -1) ............................................................................34 
8.4.4. 
Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24) .........................................35 
8.4.4.1. 
Pre-dose Procedures: Visit 2, Visit 5 and Visit 8 (Day 0, Week 12 and Week 
24) ...............................................................................................................................35 
8.4.4.2. 
Injection Procedures: Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 
24) ...............................................................................................................................36 
8.4.4.2.1. 
IVT Injection of anti-VEGF agent: .............................................................................36 
8.4.4.2.2    SC Injection of CLS-TA (ACTIVE) OR sham procedure (CONTROL): ...................36 
8.4.5. 
Post-Dose Procedures: Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 
24) ...............................................................................................................................37 
8.4.6. 
Visits 3, 4, 6, and 7 (Weeks 4, 8, 16, and 20) .............................................................37 
8.4.6.1. 
Pre-dose Procedures: Visit 3 (Week 4), Visit 4 (Week 8), Visit 6 (Week 16), 
and Visit 7 (Week 20) .................................................................................................37 
8.4.6.2. 
Injection Procedure: Visit 3 (Week 4), Visit 4 (Week 8), Visit 6 (Week 16), 
and Visit 7 (Week 20) .................................................................................................37 
8.4.6.3. 
Post-Dose Procedures: Visit 3 (Week 4), Visit 4 (Week 8), Visit 6 (Week 
16), and Visit 7 (Week 20) .........................................................................................38 
8.4.7. 
Visits 9, 10, and 11 (Weeks 30, 36, and 42) ...............................................................38 
8.4.7.1. 
Pre-dose Procedures: Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 
(Week 42) ...................................................................................................................38 
8.4.7.2. 
PRN Injection procedure: Visit 9 (Week 30), Visit 10 (Week 36), and Visit 
11 (Week 42) ..............................................................................................................39 
8.4.7.2.1.    IVT Injection of aflibercept: .......................................................................................39 
8.4.7.2.2.    Post-Dose Procedures: Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 
(Week 42) ...................................................................................................................39 
8.4.8. 
Visit 12 (Week 48) End of Study/Early Termination .................................................39 
8.4.9. 
Unscheduled Visits .....................................................................................................40 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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CONFIDENTIAL 
 
9. 
TREATMENT OF SUBJECTS ..................................................................................41 
9.1. 
Treatments to be Administered ...................................................................................41 
9.2. 
Study Eye Determination ............................................................................................42 
9.3. 
Fellow Eye Treatment .................................................................................................42 
9.4. 
Additional Treatment ..................................................................................................42 
9.4.1. 
Supplemental Therapy Criteria ...................................................................................42 
9.4.2. 
PRN Criteria ...............................................................................................................43 
9.5. 
Concomitant Treatments .............................................................................................43 
9.6. 
Treatment Compliance ................................................................................................44 
9.7. 
Randomization and Masking ......................................................................................44 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................46 
10.1. 
Study Drug ..................................................................................................................46 
10.2. 
Study Drug Packaging and Labeling ..........................................................................46 
10.3. 
Study Drug Storage .....................................................................................................46 
10.4. 
Study Drug Preparation ..............................................................................................47 
10.5. 
Administration ............................................................................................................47 
10.6. 
Study Drug Accountability .........................................................................................47 
10.7. 
Study Drug Handling and Disposal ............................................................................47 
11. 
ASSESSMENTS OF EFFICACY ..............................................................................49 
11.1. 
Best Corrected Visual Acuity (BCVA) ......................................................................49 
11.2. 
Central Subfield Thickness as Measured by Spectral Domain Optical 
Coherence Tomography ..............................................................................................49 
11.3. 
Visual Function Questionnaire ...................................................................................49 
11.4. 
EuroQol 5 Dimensions Questionnaire ........................................................................49 
12. 
ASSESSMENTS OF SAFETY ..................................................................................50 
12.1. 
Safety Parameters .......................................................................................................50 
12.1.1. 
Intraocular Pressure ....................................................................................................50 
12.1.2. 
Slit-lamp Biomicroscopy ............................................................................................50 
12.1.2.1. 
Cataract Lens Grading ................................................................................................50 
12.1.3. 
Indirect Ophthalmoscopy ............................................................................................50 


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12.1.4. 
Fluorescein Angiography ............................................................................................50 
12.1.5. 
Fundus Photography ...................................................................................................51 
12.1.6. 
Resting Heart Rate and Blood Pressure ......................................................................51 
12.1.7. 
Pregnancy Test ............................................................................................................51 
12.1.8. 
Central Laboratory Tests ............................................................................................51 
12.1.9. 
Review of Body Systems ............................................................................................51 
12.2. 
Adverse and Serious Adverse Events .........................................................................51 
12.2.1. 
Definition of Adverse Events .....................................................................................51 
12.2.1.1. 
Adverse Event .............................................................................................................51 
12.2.1.2. 
Serious Adverse Event ................................................................................................52 
12.2.2. 
Relationship to Study Drug ........................................................................................53 
12.2.3. 
Recording Adverse Events .........................................................................................54 
12.2.4. 
Intensity ......................................................................................................................54 
12.2.5. 
Exposure In Utero .......................................................................................................55 
12.2.6. 
Reporting Adverse Events ..........................................................................................55 
12.2.7. 
Follow-up of AEs and SAEs .......................................................................................55 
12.2.8. 
End of Trial .................................................................................................................56 
13. 
STATISTICAL CONSIDERATIONS .......................................................................57 
13.1. 
Randomization ............................................................................................................57 
13.2. 
Determination of Sample Size and Level of Significance ..........................................57 
13.3. 
Subject Disposition and Demographic and Baseline Characteristics .........................57 
13.4. 
Analysis Populations ..................................................................................................58 
13.4.1. 
Safety Population ........................................................................................................58 
13.4.2. 
Intent-to-Treat Population ..........................................................................................58 
13.4.3. 
Per Protocol Population ..............................................................................................58 
13.5. 
Analysis Methods .......................................................................................................58 
13.5.1. 
Primary Efficacy Analysis ..........................................................................................58 
13.5.1.1. 
13.5.1.1 Sensitivity Analyses of Primary Efficacy Endpoint .....................................59 
13.5.2. 
Secondary Efficacy Analysis ......................................................................................59 
13.5.2.1. 
Secondary Efficacy Endpoint .....................................................................................59 


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13.5.2.2. 
Exploratory Endpoints ................................................................................................59 
13.5.3. 
Subgroup Analysis ......................................................................................................59 
13.5.4. 
Safety Analysis ...........................................................................................................59 
13.5.4.1. 
Extent of Exposure .....................................................................................................59 
13.5.4.2. 
Safety Endpoints .........................................................................................................60 
13.5.5. 
Schedule of Analyses ..................................................................................................60 
13.5.6. 
Procedure for Accounting for Missing, Unused, or Spurious Data ............................60 
14. 
DIRECT ACCESS TO SOURCE DOCUMENTS .....................................................61 
14.1. 
Study Monitoring ........................................................................................................61 
14.2. 
Audits and Inspections ................................................................................................61 
14.3. 
Institutional Review Board/Independent Ethics Committee ......................................62 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................63 
16. 
ETHICS ......................................................................................................................64 
16.1. 
Ethics Review .............................................................................................................64 
16.2. 
Ethical Conduct of the Study ......................................................................................64 
16.3. 
Written Informed Consent ..........................................................................................64 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................65 
17.1. 
Inspection of Records .................................................................................................65 
17.2. 
Retention of Records ..................................................................................................65 
18. 
PUBLICATION POLICY ..........................................................................................66 
19. 
REFERENCES ...........................................................................................................67 
20. 
APPENDICES ............................................................................................................71 
APPENDIX A:  Study Design and Schedule of Assessments, Visits 1-12.................................72 
APPENDIX B:  Summary of Changes for Amendments ..............................................................74 
 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................14 
Table 3: 
 Subject Randomization ...............................................................................................27 
LIST OF FIGURES 
Figure 1: 
Anatomy of the eye highlighting the suprachoroidal space (SCS) between 
the sclera and choroid .................................................................................................20 
Figure 2: 
Study Treatment Schedule ..........................................................................................29 


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4. 
LIST OF ABBREVIATIONS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
AMD 
Age-related macular degeneration 
BCVA 
Best corrected visual acuity 
BRB 
Blood-retinal barrier 
BRVO 
Branch retinal vein occlusion 
CNV 
Choroidal neovascularization 
CRC 
Central reading center 
CRF 
Case report form 
CRVO 
Central retinal vein occlusion 
CST 
Central subfield thickness 
EDC 
Electronic data capture 
EQ-5D 
EuroQol 5 Dimensions Questionnaire 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FA 
Fluorescein angiography/angiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HRVO 
Hemiretinal vein occlusion 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVT 
Intravitreal 
IRT 
Interactive response technology 


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ME 
Macular edema 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
Non-steroidal anti-inflammatory drug 
OCT 
Optical coherence tomography 
PHI 
Protected health information 
PRN 
Pro re nata; As needed 
RVO 
Retinal vein occlusion 
SAE 
Serious adverse event 
SC 
Suprachoroidal 
SCS 
Suprachoroidal space 
SD-OCT 
Spectral-domain optical coherence tomography 
TA 
Triamcinolone acetonide 
TEAEs 
Treatment-emergent adverse events 
VEGF 
Vascular endothelial growth factor 
VA 
Visual acuity 
VFQ-25 
Visual Function Questionnaire 


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5.
INTRODUCTION
Clearside Biomedical, Inc., is developing CLS-TA, a proprietary ophthalmic formulation of 
triamcinolone acetonide (TA) to be used adjunctively (in “combination”) with an anti-VEGF 
agent to treat subjects with retinal vein occlusion (RVO).  
A phase 3 trial, SAPPHIRE, in treatment naïve RVO subjects is currently ongoing. SAPPHIRE 
is a multicenter, randomized, masked, controlled, parallel group study and is designed to show 
that suprachoroidally injected CLS-TA in combination with the intravitreally injected anti-VEGF 
agent, aflibercept (EYLEA®), is superior to intravitreally injected aflibercept, the anti-VEGF 
agent alone, using best corrected visual acuity (BCVA) as an outcome measure.  
This protocol, for the second phase 3 trial (“TOPAZ”), also in pharmacologic treatment naïve 
RVO subjects, will evaluate a similar concept to the one being studied in SAPPHIRE. TOPAZ 
will evaluate the potential to combine suprachoroidally injected CLS-TA with an intravitreally 
injected anti-VEGF agent. Specifically, the trial will evaluate ranibizumab and bevacizumab, the 
other two most commonly used anti-VEGF agents, each in combination with CLS-TA and 
compare these data to the monotherapy agents, ranibizumab and bevacizumab, used alone. 
TOPAZ is a multicenter, randomized, masked, controlled, parallel group study and is designed to 
show that suprachoroidally injected CLS-TA in combination with an intravitreally injected anti-
VEGF agent is superior to an intravitreally injected anti-VEGF agent (ranibizumab, 
bevacizumab) used alone, using BCVA as outcome measure. 
Suprachoroidal (SC) administration is a novel approach being evaluated for the treatment of 
posterior segment eye diseases; drugs can be delivered to the suprachoroidal space (SCS) with 
access to the retina and choroid via a minimally invasive procedure, a suprachoroidal injection. 
Data from animal models show distribution of triamcinolone acetonide (TA) dominantly in 
posterior segment ocular tissues (sclera, choroid, retinal pigmented epithelial (RPE) cells, retina) 
while limiting exposure to anterior structures including the lens in the eye following 
suprachoroidal injection of TA, thereby providing the rationale for improved efficacy (high drug 
exposure to the choroid, RPE and retina) and the potential for an enhanced safety profile (sparing 
of the anterior chamber and lens) in the case of TA.  
In terms of the three commonly used anti-VEGF agents (aflibercept, ranibizumab and 
bevacizumab) in treatments of posterior segment eye diseases, data are available from several 
level 1 type studies in subjects with neovascular age related macular degeneration (neovascular 
AMD) where ranibizumab and bevacizumab have been compared and bevacizumab has been 
shown to be non-inferior to ranibizumab in improvement in visual acuity at the 12 month 
primary endpoint; the first of these studies was the Comparison of Age-Related Macular 
Degeneration Treatments Trial (CATT) (CATT Research Group 2011). All three agents have 
been evaluated in the Protocol T trial in subjects with diabetic macular edema (Wells, 2016). In 
subjects with RVO, comparative data between these anti-VEGF agents are limited to the one 
clinical trial with level 1 evidence, where aflibercept and bevacizumab were evaluated in 
subjects with central RVO (CRVO) and hemi RVO (HRVO), the SCORE2 study. Based on a 
comparison of mean change in visual acuity from baseline, bevacizumab was non-inferior to 


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aflibercept at the 6-month primary endpoint following six monthly injections of these agents in 
this parallel arm trial (Scott, 2017). Further, in a level 2 study comparing ranibizumab and 
bevacizumab, both agents were shown to be effective for the treatment of BRVO and produced 
similar visual and anatomic outcomes at 6 months (Son, 2017). 
Corticosteroids exert effects in part by tackling multiple cytokines upregulated by inflammatory 
and ischemic insults and by restoring damaged blood-retinal barrier, are different from the anti-
VEGF agents in their molecular targeting (their primary mechanism does not involve reversibly 
binding VEGF even though they can downregulate VEGF), and have been shown to be effective 
for the treatment of subjects with RVO (Ip, 2009; Scott, 2009; Ozurdex Prescribing Information 
2014). More specifically, the corticosteroid, TA, has been shown to improve the visual acuity of 
subjects with RVO in the SCORE BRVO and SCORE CRVO trials conducted by the National 
Eye Institute (NEI) (https://nei.nih.gov/score/score_background). Further, CLS-TA, the 
ophthalmic formulation of TA from the Sponsor, has been validated in its ability to provide a 
significantly better early (month 2; p<0.05) visual acuity outcome in combination with the 
intravitreal agent aflibercept, when compared to intravitreal aflibercept when used alone, in a 
controlled, masked, randomized phase 2 trial, TANZANITE. Detailed data from TANZANITE 
are provided in the Investigator Brochure and in Section 5.3 of this protocol. 
While CLS-TA, the Sponsor’s proprietary aqueous, preservative-free, terminally-sterilized, 
injectable, suspension formulation of TA (40 mg/mL) is being evaluated in combination with 
aflibercept in the phase 3, SAPPHIRE trial, it is likely that combining CLS-TA with ranibizumab 
or combining CLS-TA with bevacizumab will show similar outcomes in terms of visual acuity 
improvements to the outcomes seen from combining CLS-TA with aflibercept. These three anti-
VEGF agents have similar mechanisms of action in that their primary role is to reversibly bind 
and sequester VEGF, and these three agents have provided similar outcomes in improvements in 
visual acuity at the primary endpoints in adequately powered, well-controlled clinical trials in 
subjects with RVO (EYLEA Prescribing Information, 2017; EYLEA Summary of Product 
Characteristics, 2017; LUCENTIS Prescribing Information, 2017; LUCENTIS Summary of 
Product Characteristics, 2016; Scott, 2017). 
The purpose of this phase 3, TOPAZ study, is to demonstrate the efficacy of CLS-TA when used 
in combination with an anti-VEGF agent (ranibizumab, bevacizumab) when compared to these 
anti-VEGF agents (ranibizumab, bevacizumab) alone using a BCVA outcome measure, in 
subjects who are pharmacologic treatment naïve for their RVO.  
5.1. 
Disease Background and Scientific Rationale 
Retinal vein occlusion is the second most common cause of vision loss due to retinal vascular 
disease with a worldwide prevalence of 16.4 million affecting mostly those over the age of 40. 
Data pooled from 15 population studies in the United States (US), Europe, Asia, and Australia 
suggest that there are approximately 520 new cases of RVO per million population. These 
include 442 and 80 cases per million, respectively, of BRVO and CRVO (Rogers, 2010).  


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RVO is a prevalent ischemic retinopathy, second only to diabetic retinopathy (Mitchell, 1996; 
Koh, 2016). The blockage of a retinal vein leads to hypoperfusion and ischemia accompanied by 
inflammation of the vasculature and edema in the area drained by the affected vein (Ehlers, 
2011). The severity and prognosis depend on the location of the blockage. CRVO occurs when 
there is thrombosis that occludes the main outflow vessel of the eye and BRVO results from 
occlusion of a proximal branch of the central vein. After CRVO, venous return from the entire 
retina is compromised and after BRVO it is compromised from ≤50% of the retina. Thus, on 
average, CRVO tends to be more severe than BRVO. The retinal circulation is a closed system 
with little or no opportunity for collateral flow. Consequently, all blood that enters the retina 
through the central retinal artery must exit through the central retinal vein; therefore, obstruction 
of the central retinal vein or one of its main branches compromises perfusion to all of the retina 
(CRVO) or ≤50% of the retina (BRVO) resulting in retinal ischemia and upregulation of 
hypoxia-stimulated genes. 
The major cause of decreased vision in patients with RVO is macular edema. A small clinical 
trial demonstrated that the hypoxia-regulated gene product VEGF is a particularly important 
stimulator of macular edema in RVO (Campochiaro, 2008), and this has since been confirmed in 
multicenter phase 3 trials. Intravitreal injection of VEGF-neutralizing proteins is now first line 
therapy for patients with macular edema due to retinal vein occlusion (Campochiaro, 2010; 
Brown, 2010; Brown, 2011; Campochiaro, 2011; Holz, 2013; Brown, 2013). In most patients, 
early visual outcomes show improvements in vision, but there are some patients who have a 
suboptimal response to VEGF suppression, probably because other hypoxia-stimulated pro-
permeability factors play a role (Campochiaro, 2015). Patients who have a good response to 
VEGF suppression often require intraocular injections for many years; after 4 years of treatment, 
50% of BRVO and 46% of CRVO patients have not had resolution of edema and still require 
intravitreal injections of a VEGF-neutralizing protein to control edema (Campochiaro, 2014). 
Therefore, additional treatment approaches are needed. 
Corticosteroids provide an alternative approach that has theoretical appeal because they cause 
transcriptional repression of a large number of genes whose products participate in inflammation, 
vascular leakage, and angiogenesis (Yang-Yen, 1990; Schule, 1990; Heck, 1994) Intravitreal 
injection of triamcinolone acetonide, no more frequently than every 4 months, provided 
improvements in visual acuity in subjects with CRVO and in subjects with BRVO, but also 
induced cataract in many patients and increased intraocular pressure (IOP) in a substantial 
number of patients (Aref, 2015). Intravitreal injection of a dexamethasone implant reduces edema 
and improves vision in patients with RVO, but is also complicated by cataract in almost all 
patients and increased IOP in some patients (Boyer, 2014). In a level 1 study comparing 
ranibizumab with dexamethasone implant evaluated according to the European label, no 
difference was observed in BCVA between ranibizumab and dexamethasone at months 1 and 2. 
From month 3 to month 6, there was signiﬁcant difference in BCVA gains in favor of 
ranibizumab (Hoerauf, 2016). Therefore, with efficacy appearing to favor the anti-VEGF agents, 
and because of the additional ocular side effects seen from intravitreal corticosteroids compared 
to those seen with intravitreal anti-VEGF agents, intravitreal corticosteroids are generally used as 


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second line treatment in patients with RVO who despite a long course of injections of a VEGF-
neutralizing protein have residual edema or who cannot substantially extend the period between 
injections without recurrent edema. 
Suprachoroidal injection provides a new route of local administration of drug to the eye, and that 
may have advantages for administration of corticosteroids. Data from animal models show 
distribution of TA dominantly in posterior segment ocular tissues (sclera, choroid, retinal 
pigmented epithelial (RPE) cells, retina) while limiting exposure to anterior structures including 
the lens in the eye following suprachoroidal injection of TA, thereby providing the rationale for 
improved efficacy (high drug exposure to the choroid, RPE and retina) and the potential for an 
enhanced safety profile because of sparing of the anterior chamber and lens by reducing the 
stimuli for cataract or increases in intraocular pressure. 
Therefore, Clearside is approaching the treatment of RVO by adopting a dual strategy to 
optimize treatment for the patient. The use of an anti-VEGF agent adjunctively with a 
corticosteroid, might be particularly useful since these two agents tackle different complications 
of RVO through different mechanistic pathways. The anti-VEGF agent, reduces excess fluid 
through reversible VEGF binding and clearance, and is required frequently, often monthly. The 
other agent, a corticosteroid, causes transcriptional repression of a large number of genes whose 
products participate in inflammation, vascular leakage, and angiogenesis (Yang-Yen, 1990; 
Schule, 1990; Heck, 1994), reduces VEGF levels in addition to that of other cytokines and 
restores damaged blood-retinal barrier, and is usually used less often, about once every three to 
four months. Using the two types of agents together provides the potential advantage of tackling 
different aspects of the disease in parallel and, therefore, offers the potential for both a more 
rapid and a better outcome in terms of best corrected visual acuity (BCVA) improvement. 
Further, if each agent is able to contribute and sustain reduction in macular edema in addition to 
sustaining improvement in visual acuity, there is the potential to reduce the frequency of 
administration of therapy. Data supporting this hypothesis of using an anti-VEGF agent in 
combination with CLS-TA are available from the phase 2, TANZANITE, trial that Clearside, the 
Sponsor, conducted in treatment naïve RVO subjects. Data from TANZANITE showed that 
giving an intravitreal injection of aflibercept along with a suprachoroidal injection of CLS-TA 
(combination arm) at baseline provided improved visual acuity and macular edema reduction 
outcomes at all 3 months of the study compared with a control intravitreal injection of aflibercept 
only (control arm), and with the requirement for significantly fewer additional aflibercept 
injections based on the as needed criteria used in the three month follow-up period in that trial. 
More specifically, an early improvement in BCVA from the combination of aflibercept and CLS-
TA in subjects with RVO was statistically significantly (p<0.05) better than the mean increase in 
BCVA from baseline seen from the monotherapy anti-VEGF (aflibercept) only arm. Further, the 
proportion of subjects gaining 15 or more ETDRS letters of BCVA was approximately 61% at 
month 2 in the combination arm in this trial; this kind of result is seen usually after 3-6 monthly 
anti-VEGF injections in subjects with RVO (EYLEA Prescribing Information, 2017; 
LUCENTIS Prescribing Information, 2017; Scott, 2017). Details regarding this phase 2 


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TANZANITE trial and the data can be found in Section 5.3 of this Protocol, and in the CLS-TA 
Investigator’s Brochure. 
While CLS-TA is being evaluated in combination with aflibercept in the phase 3, SAPPHIRE 
trial, it is likely that combining CLS-TA with ranibizumab or combining CLS-TA with 
bevacizumab will show similar outcomes in terms of visual acuity improvements to the visual 
acuity outcomes seen from combining CLS-TA with aflibercept. These three anti-VEGF agents 
have similar mechanisms of action in that their primary role is to reversibly bind and sequester 
VEGF, and these three agents have provided similar outcomes in improvements in visual acuity 
at the primary endpoints in adequately powered, well-controlled clinical trials in subjects with 
RVO. 
5.2. 
Description of Investigational Product 
CLS-TA, triamcinolone acetonide injectable suspension, is a preservative-free, terminally 
sterilized, aqueous suspension, formulated for administration into the eye. It will be administered 
as a suprachoroidal injection of 4 mg in 0.10 mL (40 mg/mL).  
Figure 1: 
Anatomy of the eye highlighting the suprachoroidal space (SCS) between the 
sclera and choroid 
Additional information regarding CLS-TA, triamcinolone acetonide injectable suspension, 40 
mg/mL is available in its Investigator’s Brochure.  
Ranibizumab (Lucentis) is approved for the treatment of patients with Wet Age-related Macular 
Degeneration (AMD), macular edema following Retinal Vein Occlusion (RVO), Diabetic 
Macular Edema (DME) and Diabetic Retinopathy (DR), and Myopic Choroidal 
Neovascularization (mCNV) in multiple regions, including the United States and Europe. Full 
prescribing information for ranibizumab can be found in the LUCENTIS Prescribing 
Information, 2017, and Summary of Product Characteristics, 2016. In this study, ranibizumab 
will be administered as an IVT injection of 0.5 mg in 0.05 mL.  


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Bevacizumab (Avastin) is a full-length recombinant humanized monoclonal antibody that blocks 
all isoforms of VEGF-A. It shares a similar molecular structure with ranibizumab, which was 
designed as a monocolonal antibody fragment from the same parent murine antibody. It is 
approved by the Food and Drug Administration (FDA) and other health authorities as a systemic 
therapy for the treatment of metastatic colorectal cancer, treatment of non-squamous non-small 
cell lung cancer, glioblastoma, and metastatic renal cell carcinoma (Avastin Prescribing 
Information, 2016, and Summary of Product Characteristics, 2017). However, bevacizumab is 
not approved for ophthalmic use in any jurisdiction, therefore additional information is available 
in its Investigator’s Brochure. Bevacizumab will be supplied for this trial in single use containers 
and administered as an IVT injection of 1.25 mg in 0.05 mL. 
5.3. 
Summary of Clinical Experience and Justification for Dose Selection 
Triamcinolone acetonide (TA) has been used safely and effectively in human ocular therapeutics 
to treat conditions involving inflammation for over 50 years. The initial recommended dose of 
the TA formulation approved by the FDA for ocular indications is 4 mg in 0.10 mL 
(TRIESENCE® (triamcinolone acetonide injection, suspension)). The dose of CLS-TA 
administered as a single suprachoroidal injection is similar (4 mg in 0.10 mL). TRIESENCE and 
CLS-TA contain the same active and inactive ingredients at approximately the same 
concentrations (Triesence Prescribing Information, 2016). Both formulations are aqueous 
suspensions that are preservative-free, have been terminally sterilized and designed for 
ophthalmic use.  
Clearside has completed 2 clinical trials in patients with non-infectious uveitis and one clinical 
trial in patients with RVO. 
The completed clinical study, CLS1001-101 (NCT01789320), was a phase 1/2, open-label, 
safety and tolerability study in subjects with intermediate, posterior, or pan non-infectious 
uveitis. Each subject received a single SC injection of TA (4 mg in 100 µL; TRIESENCE). Nine 
of the 11 subjects in the safety analysis set (82%) completed the 26-week study. All subjects had 
at least one adverse event (AE), with a total of 37 AEs reported. One serious adverse event 
(unrelated pulmonary emboli; SAE) occurred. No deaths were reported. No significant increases 
in intraocular pressure (IOP) were reported. The most commonly reported AE, eye pain, was 
reported in 5 subjects. Subjects in the per-protocol analysis set (n=8) showed improvements in 
mean improvements in best corrected visual acuity (BCVA) from baseline, and in mean 
reductions in macular edema from baseline in this study. 
The completed clinical study, CLS1001-201 (NCT02255032), was a phase 2, randomized, 
masked safety and efficacy study in subjects with ME associated with non-infectious uveitis. 
Twenty-two subjects were randomly assigned to receive either a single SC injection of CLS-TA, 
4 mg in 100 µL or 0.8 mg in 100 µL in a 4:1 randomization. Subjects in the 4.0 mg treatment 
group were observed to have a mean reduction in central subfield thickness (CST) of 164 
microns (p=0.002) when measured from Baseline at 2 months. Mean improvement in BCVA was 
9.2 ETDRS letters (p=0.0004) when measured from Baseline at 2 months. One SAE (unrelated 
atrial fibrillation) occurred. No subjects discontinued due to an AE, and there were no 


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Investigator-reported increases in IOP at follow-up visits; no subject was treated with IOP 
lowering medication. 
The completed clinical study, CLS1003-201 (CT02303184), was a phase 2, randomized, masked 
safety and efficacy study in subjects with ME secondary to RVO. Forty-six subjects were 
randomly assigned 1:1 to either a SC injection of CLS-TA administered in combination with an 
IVT injection of aflibercept (ACTIVE), or an IVT injection of aflibercept alone (CONTROL). 
Subjects were evaluated over the three-month study period with monthly visits; additional 
intravitreal aflibercept treatments were determined using as needed (PRN) criteria that included 
the presence of central retinal fluid or losses in visual acuity. Since a key goal of the study was to 
determine if suprachoroidal CLS-TA affected the requirement for additional treatment when 
administered along with intravitreal aflibercept, a count of the requirement for additional 
intravitreal aflibercept injections over the 3-month trial served as the primary outcome measure. 
The study met the primary endpoint with sixty percent fewer additional IVT aflibercept 
injections (p=0.013) required in the ACTIVE group receiving the combination of SC CLS-TA 
and IVT aflibercept compared with subjects in the CONTROL arm who only received 
aflibercept at baseline. In terms of secondary endpoints, mean improvements from baseline in 
BCVA were 16, 20, and 19 ETDRS letters in the ACTIVE group and 11, 12, and 11 letters in the 
CONTROL group at Months 1, 2, and 3 respectively. Subjects were observed to have a mean 
reduction in CST of 446 µm in the ACTIVE (combination) group, and a 405 µm reduction in the 
CONTROL group when measured from Baseline at Month 1. Further, the approximately 450 µm 
reduction in CST in the ACTIVE (combination) group was maintained through the 3 months of 
the study while the CONTROL group showed only approximately 350 µm reductions in CST at 
both months 2 and 3. No subjects discontinued due to an AE and no SAEs were reported. A total 
of 4 subjects in the active group reported AEs pertaining to elevated IOP: 2 events each of ocular 
hypertension and IOP increase. All events were mild or moderate in intensity and considered to 
be related to study drug. 
Safety profiles have been similar in all three studies with eye pain being the most commonly 
reported AE. Additional information regarding clinical experience with TA administered to the 
SCS is available in the Investigator’s Brochure. 
Current clinical practice worldwide involves the use of one of the three anti VEGF agents, 
aflibercept, ranibizumab, and bevacizumab, for the treatment of subjects with RVO, almost 
exclusively as the initial therapy. Several level 1 types of clinical trials have been conducted in 
the US, in Europe and in the other parts of the world, where each of these anti-VEGF agents 
have been evaluated for the treatment of subjects with various posterior segment ocular 
conditions, including subjects with RVO.  
The three anti-VEGF agents used most commonly to treat subjects with RVO have similar 
mechanisms of action in that their primary role is to reversibly bind, sequester and enhance the 
clearance of VEGF. While there are finer mechanistic differences between aflibercept (binds 
VEGF-A, VEGF-B and placental growth factor) and the other two anti-VEGF agents 
(ranibizumab and bevacizumab only bind VEGF-A), these three agents have all provided similar 
outcomes in improvements in visual acuity at the primary endpoints in adequately powered, 


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well-controlled clinical trials in subjects with RVO (Eylea Prescribing Information, 2017; Eylea 
Summary of Product Characteristics, 2017,  Lucentis Prescribing Information, 2017; Lucentis 
Summary of Product Characteristics, 2016 and Scott, 2017). Further, in subjects with 
neovascular AMD, bevacizumab has been shown to be non-inferior to ranibizumab in multiple 
independent level 1 studies; these include the CATT sponsored by the NEI in the US (CATT 
Research Group 2011), the Alternative Treatments to Inhibit VEGF in Age-related Choroidal 
Neovascularization (IVAN) Trial, sponsored by the National Institute for Health Research 
programme (United Kingdom) (Chakravarthy 2012) and the French Evaluation Group Avastin 
Versus Lucentis (GEFAL) Trial, sponsored by the Hospices Civils de Lyon (Kodijkian 2013). 
All three agents have also been evaluated in the Protocol T trial in subjects with diabetic 
macular edema (Wells, 2016) where subjects with good incoming vision (better than 
approximately 75 ETDRS letters read) showed similar visual acuity outcomes at evaluations at 
12 and 24 months from baseline. In subjects with RVO, comparative data between these anti-
VEGF agents are limited to the one clinical trial with level 1 evidence, where aflibercept and 
bevacizumab were evaluated in subjects with central RVO (CRVO) and hemi RVO (HRVO), the 
SCORE2 study. Based on a comparison of mean change in visual acuity from baseline, 
bevacizumab was non-inferior to aflibercept at the 6-month primary endpoint following six 
monthly injections of each agent in this parallel arm trial (Scott, 2017). Further, in a level 2 
study comparing ranibizumab and bevacizumab, both agents were shown to be effective for the 
treatment of BRVO and produced similar visual and anatomic outcomes at 6 months (Son, 
2017). These data show that in subjects with RVO, these two anti-VEGF agents provide similar 
visual acuity outcomes at month 6 when given monthly for 6 months. Further, the data from 
aflibercept or ranibizumab from five level 1 phase 3 clinical trials, with 3 in subjects with CRVO 
and 2 in subjects with BRVO (Eylea Prescribing Information, 2017; Lucentis Prescribing 
Information, 2017) show comparable gains of between 15 and 18 ETDRS letters in terms of 
change from baseline in BCVA. Therefore, the data from SCORE2 along with that from the five 
phase 3 trials from aflibercept and ranibizumab suggest that all three commonly used anti-VEGF 
agents, when given monthly for 6 months, lead to similar visual acuity outcomes in subjects with 
RVO. 
Although intravitreal corticosteroid therapy is a readily available treatment option for macular 
edema secondary to RVO, initial first-line treatment is with intravitreal anti-VEGF therapy, and 
is used most commonly in almost every case for treatment naïve RVO subjects, except for rare 
exceptions. This is due to the perception that anti-VEGF treatments are more efficacious and 
safer than corticosteroid therapy. In the one adequately powered, well controlled randomized, 
masked comparative, COMRADE C trial, where ranibizumab and dexamethasone implant were 
compared in CRVO subjects, the perception that the anti-VEGF agent provides better outcomes 
than the corticosteroid was validated because, although at month 1 and month 2 the visual acuity 
data were comparable, ranibizumab was significantly better than dexamethasone implant from 
month 3 through month 6 when each agent was administered according to the European label 
(Hoerauf, 2016). It has become common that corticosteroid therapy is typically used as a rescue 
therapy for eyes that have an unsuccessful result with initial anti-VEGF therapy. Aflibercept is 
generally perceived to be best anti-VEGF therapy for posterior segment eye diseases in part 


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because of the superior visual outcomes seen in diabetic macular edema (DME) subjects with 
vision 20/50 or worse in the Protocol T trial (Wells, 2016).  
This study aims to consider the safety and efficacy of SC CLS-TA combined with IVT 
ranibizumab, and SC CLS-TA combined with IVT bevacizumab for the treatment of eyes of 
subjects with RVO. While CLS-TA, is being evaluated in combination with aflibercept in the 
phase 3, SAPPHIRE trial, it is likely that combining CLS-TA with ranibizumab or combining 
CLS-TA with bevacizumab will show similar outcomes in terms of visual acuity improvements 
to combining CLS-TA with aflibercept. CLS-TA itself has been validated in its ability to provide 
a significantly better early (month 2; p<0.05) visual acuity outcome in combination with the IVT 
agent aflibercept, when compared to IVT aflibercept when used alone, in a controlled, masked, 
randomized phase 2 trial, TANZANITE. Since these three anti-VEGF agents have similar 
mechanisms of action in that their primary role is to reversibly bind and sequester VEGF, and 
these three agents have provided similar outcomes in improvements in visual acuity at the 
primary endpoints in adequately powered, well-controlled clinical trials, this phase 3, TOPAZ, 
trial is designed to evaluate whether suprachoroidally injected CLS-TA in combination with an 
intravitreally injected anti-VEGF agent (ranibizumab, bevacizumab) is superior to intravitreally 
injected anti-VEGF agent (ranibizumab, bevacizumab) used alone, using BCVA as outcome 
measure at month 2.  
With the first phase 3, SAPPHIRE trial, which evaluates the use of CLS-TA combined with 
aflibercept for the treatment of RVO, and this phase 3, TOPAZ trial, which will evaluate CLS-
TA combined with either bevacizumab or ranibizumab for the treatment of RVO, the outcome 
will provide understanding of the safety and efficacy of CLS-TA with all commonly utilized 
anti-VEGF agents for the treatment of RVO. 


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6.
STUDY OBJECTIVES AND PURPOSE
The purpose of this study is to demonstrate the safety and efficacy of suprachoroidally injected 
CLS-TA (“suprachoroidal CLS-TA”) used in combination with an intravitreally injected anti-
VEGF agent (“intravitreal anti-VEGF agent”) in subjects with RVO. 
6.1. 
Primary Objective 
To demonstrate that in pharmacologic treatment naïve subjects with RVO, suprachoroidal (SC) 
CLS-TA administered with an intravitreal (IVT) anti-VEGF agent is superior to IVT anti-VEGF 
agent alone using a best corrected visual acuity (BCVA) outcome. 
6.2. 
Secondary Objectives 
The secondary objectives of the study are: 
•
To determine the effect of SC CLS-TA administered in conjunction with an IVT anti-
VEGF agent on mean change from Baseline in BCVA
•
To determine the effect of SC CLS-TA administered in conjunction with an IVT anti-
VEGF agent on mean change from Baseline in CST
6.3. 
Safety Objective 
The safety objectives of the study are: 
•
To evaluate the safety and tolerability of SC CLS-TA administered with an IVT anti-VEGF
agent as measured by reported adverse events and safety parameters
6.4. 
Exploratory Objectives 
The exploratory objectives of the study are: 
•
To determine the effect of SC CLS-TA administered with an IVT anti-VEGF agent on
change from Baseline in subject-reported outcomes.
•
To determine the effect of SC CLS-TA administered with an IVT anti-VEGF agent on
changes from Baseline in complications associated with RVO; these evaluations will
include changes in neovascularization and perfusion status, and analyses based on whether
or not these complications were present at baseline.
•
To evaluate changes from baseline based on disease type, BRVO and CRVO. Subjects with
HRVO data will be included with the CRVO group based on randomization.
•
To determine the safety and performance of the SCS microinjector when used to inject SC
CLS-TA


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7. INVESTIGATIONAL PLAN 
7.1. Overall Study Design 
This is a phase 3, multicenter, randomized, masked, controlled, parallel group study of 
approximately 12 months duration in pharmacologic treatment-naïve subjects with RVO. This 
study is projected to enroll approximately 460 subjects, randomly assigned 1:1:1:1 to one of four 
treatment groups stratified by disease (BRVO, CRVO). Subjects with HRVO will be included in 
this study. Randomization will proceed as described until either stratum within a group reaches 
approximately 50% of the total number patients to be enrolled in that group at which time only 
patients from the other stratum will be enrolled.  
The study design includes 12 clinic visits over approximately 50 weeks. Subjects will participate 
in 5 periods: Screening (Visit 1, Days -30 to -1); Randomization and Baseline (Visit 2, Day 0 
before dosing); Dosing and Evaluation (Visit 2 [after dosing] to Visit 8, Day 0 through Week 
24); PRN Dosing and Follow-up (Visit 9 to 11; Weeks 30 through 42); and End of Study (Visit 
12; Week 48). 
7.2. Endpoints 
7.2.1. Primary Efficacy Endpoint 
The primary endpoint is the proportion of subjects demonstrating ≥ 15 letter improvement from 
Baseline in Early Treatment of Diabetic Retinopathy Study (ETDRS) BCVA at Visit 4 
(Month 2). 
7.2.2. Secondary Efficacy Endpoints 
• Mean change from Baseline (Visit 2, Day 0) in BCVA at Visit 4 (Week 8) and 
Visit 8 (Week 24) 
• Mean change from Baseline (Visit 2, Day 0) in CST at Visit 4 (Week 8) and Visit 
8 (Week 24) 
7.2.3. Exploratory Efficacy Endpoints 
• Change from Baseline (Visit 2, Day 0) in subject-reported outcomes at Visit 8 
(Week 24) as measured by the Visual Function Questionnaire (VFQ-25) and the 
EuroQol 5 Dimensions Questionnaire (EQ-5D)   
• Change from Baseline in signs and complications of RVO (eg, 
neovascularization, perfusion) at Visit 8 (Week 24) and Visit 12 (Week 48) 
• Changes from Baseline on visual and anatomic outcomes based on disease 
diagnosis of BRVO and CRVO. HRVO subjects will be included with the CRVO 
for analyses. 


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7.2.4. Safety Endpoints 
• Incidence of treatment-emergent adverse events (TEAEs) and SAEs, grouped by 
organ system, relatedness to study drug, and intensity  
• Incidence of changes in safety parameters including: IOP, slit-lamp 
biomicroscopy, indirect ophthalmoscopy, imaging parameters, and vital signs  
7.2.5. Endpoints Related to SCS microinjector 
• Performance of the SCS microinjector, evidenced by injection parameters 
(location, eye quadrant, needle length, injection completion, and product 
complaints) at each SC injection visit (Visits 2, 5, 8)  
• Incidence of TEAEs and SAEs related to the SCS microinjector   
7.3. Number of Subjects 
Approximately 460 subjects with RVO who are naïve to treatment will be enrolled into one of 
four treatment groups. 
7.4. Treatment Assignment 
Subjects enrolled in this study will be eligible upon a finding of RVO in the study eye. After 
Screening (Day -30 to Day -1) and Baseline assessments on Day 0, subjects will be randomly 
assigned 1:1:1:1 to one of four treatment groups stratified by disease type (BRVO, CRVO). 
Randomization will proceed as described until either stratum within a group reaches at least 50% 
of the total number patients to be enrolled in that group at which time only patients from the 
other strata will be enrolled.  
 
Table 3:  
Subject Randomization 
TREATMENT ARM 
Number of 
Subjects 
ACTIVE:  
IVT injection of Lucentis (0.5 mg/0.05 mL) + SC injection of CLS-TA (4 
mg/0.10 mL)   
OR 
IVT injection of Avastin (1.25 mg/0.05 mL) + SC injection of CLS-TA (4 mg/ 
0.10 mL) 
 
~115 
 
~115 
CONTROL:  
IVT injection of Lucentis (0.5 mg/0.05 mL) + sham SC procedure 
OR 
IVT injection of Avastin (1.25 mg/0.05 mL) + sham SC procedure 
 
~115 
 
~115 


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Dosing and Evaluation Period: After randomization, subjects will receive treatment as follows: 
ACTIVE (combination): IVT injection of anti-VEGF agent + suprachoroidal injection of CLS-
TA (4 mg/100 µL) SC injections: 
Subjects randomly assigned at Baseline to the ACTIVE group will receive an IVT injection of 
anti-VEGF agent followed by a SC injection of CLS-TA on Visit 2 (Day 0), Visit 5 (Week 12) 
and Visit 8 (Week 24). Subjects will receive an intravitreal injection of anti-VEGF agent only at 
Visit 3 (Week 4). 
After the Baseline visit, subjects will return for 6 monthly (every 4 weeks) visits through Visit 8 
(Week 24) to assess safety and efficacy. Evaluation for, and determination of the requirement for 
additional therapy based on established criteria will take place at Visit 4 (Week 8) and from Visit 
6 (Week 16) through end of study. To maintain masking, subjects not receiving additional 
therapy on Week 8, and Weeks 16 and 20 will receive sham IVT injections. 
CONTROL (anti-VEGF): IVT injection of anti-VEGF agent + sham SC procedure 
Subjects randomly assigned at Baseline to the CONTROL group will receive monthly IVT anti-
VEGF agent injections beginning at Visit 2 (Day 0) and continuing through Visit 8 (Week 24). 
To maintain masking, subjects in the CONTROL group will also receive a sham SC procedure 
on Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24). 
Subjects will return for 6 monthly (every 4 weeks) visits through Visit 8 (Week 24) to assess 
safety and efficacy and to determine whether additional therapy is needed based on established 
criteria. 
PRN Dosing and Follow-up Period: 
At the conclusion of the dosing and evaluation period (Day 0 through Week 24), subjects will be 
followed for safety through Visit 12 (Week 48). Subjects will be treated, as needed (PRN), with 
an intravitreal injection of aflibercept.  
 
 


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Figure 2:  
Study Treatment Schedule 
 
 
 
7.5. Criteria for Study Termination 
The study or parts of the study may be discontinued by the Sponsor, or at the recommendation of 
an Investigator after consultation with Sponsor, at any time.   
If the clinical study is prematurely terminated or suspended, the Sponsor will inform the 
Investigators and the regulatory authorities of the termination/suspension and the reason(s) for 
the termination/suspension. The Investigator should promptly notify the Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC) of the termination or suspension and of the 
reasons. 


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8. SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. Inclusion Criteria 
Individuals are eligible for participation in this study if he/she meets the following criteria: 
1. Has a clinical diagnosis of RVO in the study eye within ≤ 6 months screening; 
2. Has a CST of ≥ 300 µm in the study eye as measured by spectral-domain optical 
coherence tomography (SD-OCT) with intraretinal or subretinal fluid and confirmed by 
the central reading center (CRC); 
3. Has an ETDRS BCVA score of ≥ 20 letters read and ≤ 70 letters read in the study eye; at 
least 20 letters in the non-study eye; 
4. Is naïve to local pharmacologic treatment for RVO in the study eye; 
5. Is at least 18 years of age, understands the language of the informed consent and is 
willing and able to provide written informed consent before any study procedures, and is 
willing to comply with the instructions and attend all scheduled study visits. 
8.2. Exclusion Criteria 
8.2.1. Ophthalmic Exclusion Criteria 
An individual is ineligible for participation in this study if he/she meets any of the following 
criteria: 
1. Has ME with etiology other than RVO; 
2. Has, in the study eye, used any topical ocular corticosteroid in the 10 days before 
treatment at Visit 2 (Day 0); has at any time received any intraocular or periocular 
corticosteroid injection, an OZURDEX® implant, a RETISERT® implant, or an 
ILUVIEN® implant; 
3. Has evidence of or history of any ophthalmic condition in the study eye that may have an 
associated neovascularization or edema component including, but not limited to, 
age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema 
(DME), retinal detachment, central serous chorioretinopathy, scleritis, optic neuropathy, 
or retinitis pigmentosa;  
4. Has a history of rubeosis irides or other neovascularization in the study eye; any active 
vitreous hemorrhage in the study eye within the last 90 days; 
5. Has a history of any vitreoretinal surgery (scleral buckle placement, pars plana 
vitrectomy, retrieval of dropped nucleus or intraocular lens, sheathotomy) ever in the 
study eye or any ocular surgery in the 3 months before randomization. Prior cataract 
extraction or Yttrium-Aluminum-Garnet (YAG) laser capsulotomy is allowed but must 
have been performed at least 3 months before Visit 2 (Day 0);  


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6. Has a history of an ocular procedure or condition in the study eye within the 3 months 
before randomization that, in the Investigator’s opinion, could compromise globe or 
retinal integrity (eg, staphyloma, high myopia, predisposition to scleral thinning); 
7. An ocular condition in the study eye that, in the opinion of the Investigator, would put the 
subject at risk due to study treatment or procedures (eg, active ocular infection, history of 
a SC hemorrhage, chalazion, significant blepharitis); 
8. Has scarring from laser photocoagulation or from other cause in the study eye that would 
compromise visual acuity; has an epiretinal membrane that is a major contributor to 
reduced visual acuity 
9. Has had >3 macular laser photocoagulation treatments; or has had photocoagulation or 
cryotherapy in the study eye within the 6 months before Visit 2 (Day 0);  
10. Has significant media opacity precluding evaluation of retina and vitreous in the study 
eye. This includes cataract that is felt to be a major contributor to reduced visual acuity 
and/or likely to undergo surgical repair within 3 months of randomization;  
11. History of glaucoma, optic nerve head change consistent with glaucoma damage; or 
ocular hypertension in the study eye requiring more than one medication; 
12. Has a IOP > 21 mmHg in the study eye at Visit 1 (Day -30 to -1); subjects are not 
excluded if IOP is < 22 mmHg in the study eye with no more than 1 IOP-lowering 
medication as long as there is no history of glaucoma and the subject has a normal optic 
nerve and no evidence of visual field loss; 
13. Has a history of glaucoma surgery (filtration surgery/trabeculectomy or tube shunt) in the 
study eye; has a history of laser trabeculoplasty or MIGs surgery in the study eye; 
14. Has a history of clinically significant IOP elevation in response to corticosteroid 
treatment (“steroid responder”);  
8.2.2. General Exclusion Criteria 
Individuals are ineligible for participation in this study if he/she meet the following criteria: 
15. Is a female subject who is pregnant, lactating or planning a pregnancy or is a female 
subject of childbearing potential who does not agree to submit to a pregnancy test at 
Screening; Females of childbearing potential must agree to use an acceptable method of 
contraception throughout participation in the study. Acceptable methods of contraception 
include double barrier methods (condom with spermicide or diaphragm with spermicide), 
hormonal methods (oral contraceptives; implantable, transdermal, or injectable 
contraceptives), or an intrauterine contraceptive device with a documented failure rate of 
less than 1% per year. Abstinence may be considered an acceptable method of 
contraception at the discretion of the Investigator, but the subject must agree to use one of 
the acceptable birth control methods if she becomes sexually active; 


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16. Has any uncontrolled systemic disease that, in the opinion of the Investigator, would 
preclude participation in the study (eg, infection, uncontrolled elevated blood pressure, 
cardiovascular disease, poor glycemic control) or put the subject at risk due to study 
treatment or procedures; NOTE: Uncontrolled BP at screening may be treated before 
Visit 2;  
17. Has a myocardial infarction or stroke within 90 days of treatment; 
18. Has a likely need for hospitalization or surgery within the study period, including planned 
elective surgery or hospitalization; 
19. Has a known hypersensitivity to any component of the formulation of TA, ranibizumab, 
bevacizumab, aflibercept, fluorescein, topical anesthetics, or the antiseptic used to 
prepare the eye for injection according to the Investigator’s standard practice; 
20. Is currently enrolled in an investigational drug or device study or has used an 
investigational drug within 30 days of entry into this study or participated in an ocular 
device study in the last 90 days. 
21. History of any inflammatory or other medical condition that the investigator might 
reasonably anticipate will require treatment with high-dose corticosteroids (more than 
10mg/day oral prednisone or the equivalent) for more than 14 days. 
8.2.3. Randomization Criteria 
Subjects are eligible for randomization at Visit 2 if the following criteria are met: 
1. The CRC confirms ME by SD-OCT (from Visit 1 SD-OCT data), with intraretinal, sub-
RPE, or subretinal fluid; 
2. The CRC confirms a retinal thickness of ≥ 300 μm in the central subfield from the Visit 1 
SD-OCT data;                                                                                                                          
3. The subject gains no more than 10 letters of vision in BCVA between the Screening visit 
and Randomization (Visit 2) in the study eye; 
4. The subject continues to meet all of the inclusion and none of the exclusion criteria. 
8.3. Subject Withdrawal Criteria 
Subjects may withdraw from the study at any time and for any reason without obligation. 
Subjects may be removed from the study at the Investigator’s discretion. Investigators may 
withdraw a subject from the study because a new health condition appears or an existing 
condition worsens that requires care or medication prohibited by the protocol and it is in the 
subject’s best interest to exit the study, according to the Investigator’s clinical judgement.  In the 
event that a subject develops a medical condition that requires treatment with a medication 
prohibited by this protocol (i.e. if the treating physician determines, using best medical 
judgment, that such medications are medically necessary for the subject’s welfare), then a 
protocol deviation will be recorded.  In such cases, provided the investigator determines that it is 


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in the subject’s best interest to continue in the study, the Sponsor’s preference is to retain such 
subjects in the study. For a list of prohibited medications, please see Section 9.5. 
Subjects who withdraw prematurely from the study will be asked to complete study assessments 
at the Early Termination Visit. If an SAE is unresolved at the time of the subject’s final study 
visit, the Investigator should make every attempt to follow up until the SAE is resolved or 
stabilized, the subject is lost to follow-up, or there is some other resolution of the event.  
8.4. Visit Procedure Descriptions 
8.4.1. General Procedures 
The study will consist of 12 study visits over approximately 50 weeks. Subjects are expected to 
attend all study visits. All ocular assessments at Visit 1 (Screening) and Visit 12 (Week 48) will 
be performed on both eyes. IOP will be collected in both eyes at all visits. Data from all other 
ocular assessments at all other visits will be collected for the study eye only.  
Subjects will be screened for entry at Visit 1 (Days -30 to -1) and the study eye identified. Each 
eligible subject will return to the clinic within 30 days to be randomly assigned and treated at 
Visit 2 (Day 0). After baseline assessments and randomization on Day 0, subjects will receive an 
IVT injection of an anti-VEGF agent (following the Investigator’s standard practice for IVT 
injections) in the study eye, followed by either a sham SC injection or an active SC dose of CLS-
TA in the study eye, depending on the group assigned at randomization. Subjects will be 
assessed after injection for safety. 
Additional safety follow-up visits will occur approximately every 4 weeks through Month 6 
(Visits 3 through 8; Weeks 4, 8, 12, 16, 20 and 24). Subjects in the CONTROL group will 
receive IVT injections of an anti-VEGF agent at each of these visits. Subjects in the ACTIVE 
group will receive an IVT injection of an anti-VEGF agent at Visit 3 (Week 4); a sham IVT 
injection will be performed at Visit 4, 6 and 7 (Weeks 8, 16 and 20) to ensure masking is 
maintained. The subject will receive the same anti-VEGF agent per the protocol schedule, 
throughout the first 24 weeks of the study. 
At Visit 5 (Week 12) and Visit 8 (Week 24) subjects will receive another IVT injection of anti-
VEGF agent (following the Investigator’s standard practice for IVT injections) in the study eye, 
followed by either a sham SC injection or an active SC dose of CLS-TA in the study eye), 
depending on the group assigned at Visit 2 (Day 0).  
After the completion of the Dosing and Evaluation Period (6 months), subjects will enter the 
PRN Dosing and Follow-up Period of the study to be observed and receive PRN treatment every 
6 weeks at Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 (Week 42). PRN therapy will be 
aflibercept for all subjects, regardless of randomization group. 
The final visit of the study occurs at Visit 12 (Week 48). 


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8.4.2. Re-Screening Procedures 
Subjects may be re-screened if the reason for their initial screening failure has changed. A 
subject who is designated as a screen failure before being randomly assigned at Visit 2 (Day 0) 
may be re-screened up to 2 additional times, for a total of 3 screenings, upon Sponsor approval.  
Subjects who are re-screened are required to sign a new consent form. Screening assessments 
must be repeated if timings for the assessments fall outside of the specified study windows.  
8.4.3. Visit 1 – Screening (Day -30 to -1) 
At Visit 1, subjects will be screened for eligibility. Written informed consent will be obtained for 
each subject before any study-specific assessments are performed. During Visit 1, the following 
procedures will be performed: 
1. Obtain written informed consent 
2. Assign subject number 
3. Collect demographic data and medical and ocular history  
4. Review concomitant medications  
5. Perform resting heart rate (resting 5 mins) and blood pressure measurements 
6. Collect blood and urine for central laboratory tests before fluorescein angiogram (FA), 
including serum pregnancy test on females of childbearing potential 
7. Perform a review of body systems 
8. Perform ophthalmic assessments on both eyes:  
a. ETDRS BCVA  
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP  
d. Dilated indirect ophthalmoscopy 
e. SD-OCT*  
9. Perform photographic evaluations:* 
a. FA  
b. Fundus photograph 
10. Assess AEs 
11. Determine study eye based upon eligibility criteria 
12. Schedule subject to return for Visit 2, Randomization/Treatment  
 


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NOTE:  
* All images (SD-OCT, fundus photographs, and FA) should be uploaded to the CRC.  
8.4.4. Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24) 
Visit 2 must occur within 30 days of Visit 1 (Screening) and may only occur once subject is 
determined to be eligible for treatment, which includes central laboratory results and 
confirmation of eligibility based on SD-OCT reading by the CRC being received and reviewed 
by the Investigator. No subject may be treated without CRC confirmation of eligibility. 
The Visit 2 randomization procedures should not be conducted until the subject is deemed 
eligible based on meeting all of the inclusion and none of the exclusion criteria. Once randomly 
assigned, subjects will remain in the same treatment group for the duration of participation in the 
study. 
8.4.4.1. 
Pre-dose Procedures: Visit 2, Visit 5 and Visit 8 (Day 0, Week 12 and Week 24)  
The following procedures must be performed before the injection (the same day as the injection): 
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform resting heart rate (resting 5 mins) and blood pressure 
4. Administer VFQ-25 and EQ-5D (Visit 2 and Visit 8 only) 
5. Collect urine for pregnancy test in females of child-bearing potential 
6. Collect blood and urine for central lab tests before FA, (Visit 8 only) 
7. Perform ophthalmic assessments on the study eye only, unless otherwise designated:  
a. ETDRS BCVA (both eyes) 
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP (both eyes)  
d. Dilated indirect ophthalmoscopy 
e. SD-OCT  
8. Perform photographic evaluations (Visit 8 only): 
a. Fluorescein angiogram (FA)  
b. Fundus photograph 
9. Review eligibility criteria (Visit 2 only)  
If subject continues to be eligible for randomization based on results from screening 
and Visit 2 assessments, and subject meets all randomization criteria in 8.2.3, subjects 


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will be randomly assigned via the interactive response technology (IRT) to receive an 
IVT injection of an assigned anti-VEGF agent in conjunction with either sham or 
active SC injection of CLS-TA in the study eye. 
10. Log onto the IRT and randomly assign subject to treatment 
8.4.4.2. 
Injection Procedures: Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24)  
Injections should be performed the same day as the pre-injection procedures. For details on the 
injection procedure, please see the Investigator Site File. The subject, non-injecting physician, 
Sponsor, study coordinator, visual acuity technician, and the CRC will be masked to treatment. 
The injecting physician and supporting study staff who are present during the injection procedure 
must be designated as unmasked for the study. Unmasked personnel should not perform efficacy 
assessments at any visit. 
1. Confirm the study eye 
2. Retrieve study drug kit number assigned by IRT 
3. Prepare eye for injection according to the Investigator’s standard practice 
4. The UNMASKED injecting Investigator should perform IVT injection of assigned anti-
VEGF agent, SC injection of CLS-TA, and all sham procedures to the study eye 
8.4.4.2.1. IVT Injection of anti-VEGF agent: 
1. Prepare study eye for IVT injection of assigned anti-VEGF agent 
2. Administer anti-VEGF agent IVT injection following the Investigator’s standard practice 
for IVT injections. The location of the IVT injection and the SC injection should be 
approximately 2 or more clock hours apart on the globe. A temporal quadrant is the 
recommended location for SC injections. 
3. Assess study eye by indirect ophthalmoscopy immediately after the injection,  
4. Measure IOP after injection 
8.4.4.2.2    SC Injection of CLS-TA (ACTIVE) OR sham procedure (CONTROL): 
1. When the study eye IOP is < 30 mm Hg, either spontaneously or by treatment, as 
determined by the Investigator, prepare study eye for SC injection according to the 
Investigator’s standard practice.  NOTE: This is a separate, additional preparation prior to 
the second injection. 
2. Administer SC injection of 0.10 mL of CLS-TA or sham procedure approximately 2 or 
more clock hours on the globe from the location of the IVT injection 
3. Assess study eye by indirect ophthalmoscopy immediately after the injection,  


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8.4.5. Post-Dose Procedures: Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24)  
The following assessments must occur after the IVT injection, SC injection or sham procedures: 
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform ophthalmic assessments on the study eye only:  
a. Evaluate IOP 10 to 30 minutes after injection 
b. If IOP remains elevated, subject must remain on site until IOP is under control 
according to the Investigator’s best medical judgment. 
c. If IOP is < 30 mmHg, the subject may leave the clinic 
4. 
Schedule time for subject to return for next visit  
8.4.6. Visits 3, 4, 6, and 7 (Weeks 4, 8, 16, and 20)  
8.4.6.1. Pre-dose Procedures: Visit 3 (Week 4), Visit 4 (Week 8), Visit 6 (Week 16), and Visit 7 
(Week 20)  
The following procedures must be performed before the injection (the same day as the injection): 
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform resting heart rate (seated 5 mins) and blood pressure measurements 
4. Perform ophthalmic assessments on the study eye only, unless otherwise designated:  
a. ETDRS BCVA 
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP (both eyes)  
d. Dilated indirect ophthalmoscopy 
e. SD-OCT  
8.4.6.2. Injection Procedure: Visit 3 (Week 4), Visit 4 (Week 8), Visit 6 (Week 16), and Visit 7 
(Week 20)  
1. Confirm the study eye 
2. Retrieve assigned anti-VEGF agent  
3. Prepare eye for injection according to the Investigator’s standard practice 


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4. The UNMASKED injecting Investigator should administer IVT injection of anti-VEGF 
agent OR sham IVT procedure to the study eye. (All subjects receive an IVT injection of 
anti-VEGF agent at Visit 3 (Week 4)).  
5. Assess study eye by indirect ophthalmoscopy immediately after the injection,  
6. Measure IOP after injection 
8.4.6.3. Post-Dose Procedures: Visit 3 (Week 4), Visit 4 (Week 8), Visit 6 (Week 16), and Visit 7 
(Week 20)  
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform ophthalmic assessments on the study eye only:  
a. Evaluate IOP 10 to 30 minutes after injection 
b. If IOP remains elevated, subject must remain on site until IOP is under control 
according to the Investigator’s best medical judgment. 
c. If IOP is < 30 mmHg, the subject may leave the clinic 
4. Schedule time for subject to return for next visit  
8.4.7. Visits 9, 10, and 11 (Weeks 30, 36, and 42)  
Beginning at Visit 9 (Week 30) through Visit 11(Week 42), study treatments will be 
administered PRN. Investigators, subjects, and study personnel will remain masked during the 
PRN Dosing and Follow-up Period. 
8.4.7.1. Pre-dose Procedures: Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 (Week 42)  
The following assessments must be performed; however, dosing is PRN: 
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform resting heart rate (seated 5 mins) and blood pressure measurements 
4. Perform ophthalmic assessments on the study eye only, unless otherwise designated:  
a. ETDRS BCVA 
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP (both eyes) 
d. Dilated indirect ophthalmoscopy 
e. SD-OCT  
f. Confirm study eye 


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8.4.7.2. PRN Injection procedure: Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 (Week 42) 
If subject qualifies for PRN therapy according to the Additional Therapy Criteria listed in Section 
9.4.1, the following injection and post-dose procedures should be performed, consistent with the 
subject’s treatment group: 
1. Confirm the study eye
2. Retrieve study drug kit number assigned by IRT
3. Prepare eye for injection according to the Investigator’s standard practice
4. The UNMASKED injecting Investigator should perform IVT injection of aflibercept
8.4.7.2.1.  IVT Injection of aflibercept: 
1. Prepare study eye for IVT injection of aflibercept
2. Administer aflibercept IVT injection according to the instructions in the approved label.
3. Assess study eye by indirect ophthalmoscopy immediately after the injection,
4. Measure IOP after injection
8.4.7.2.2.  Post-Dose Procedures: Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 (Week 42) 
The following assessments must occur after the IVT injection: 
1. Assess AEs
2. Review changes to concomitant medications
3. Perform ophthalmic assessments on the study eye only:
a.
Evaluate IOP 10 to 30 minutes after injection
b. If IOP remains elevated, subject must remain on site until IOP is under control
according to the Investigator’s best medical judgment.
c.
If IOP is < 30 mmHg, the subject may leave the clinic
4.
Schedule time for subject to return for next visit
8.4.8. Visit 12 (Week 48) End of Study/Early Termination 
Visit 12 is the final study visit. Subjects who terminate early should complete all Visit 12 
assessments.  
1. Assess AEs
2. Review changes to concomitant medications
3. Perform resting heart rate (seated 5 mins) and blood pressure measurements


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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4. Collect blood and urine for central laboratory tests, including serum pregnancy test on 
females of child-bearing potential  
5. Perform a review of body systems 
6. Perform ophthalmic assessments on both eyes: 
a. ETDRS BCVA 
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP  
d. Dilated indirect ophthalmoscopy 
e. SD-OCT  
7. Administer VFQ-25 and EQ-5D  
8. Perform photographic evaluations: 
a. FA  
b. Fundus photograph  
8.4.9. Unscheduled Visits 
To ensure subject safety during the study, any subject who requires additional follow-up or 
treatment for any reason at any time during the study that does not fall on a scheduled study visit 
should have that visit recorded as an Unscheduled Visit.  


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9. TREATMENT OF SUBJECTS
9.1. Treatments to be Administered 
Subjects will be assigned to one of four treatment groups in the study based upon randomization 
assignment.  
Treatment in each of the two groups in the ACTIVE (combination) arm will consist of three 
unilateral SC injections of 4 mg of CLS-TA in 0.10 mL administered 12 weeks apart (Visits 2, 5, 
and 8), along with 4 IVT injections of an anti-VEGF agent (bevacizumab or ranibizumab) in to 
the study eye over 24 weeks according to the study schedule.  Subjects in the ACTIVE arm will 
also receive sham IVT procedures to maintain masking at visits where the SC CLS-TA injection 
is not being administered (Visit 4, 6, and 7). Beginning with Visit 9 (Week 30), subjects will be 
assessed for PRN treatment that will consist of IVT aflibercept based on PRN criteria (Section 
9.4.2). 
Treatment in each of the two groups in the CONTROL (monotherapy) arm of the study will 
consist of 7 unilateral IVT injections of an anti-VEGF agent (bevacizumab or ranibizumab) 
administered 4 weeks apart (Visits 2 through 8) along with three sham SC procedures 
administered 12 weeks apart (Visits 2, 5, and 8) in to the study eye according to the study 
schedule. Beginning with Visit 9 (Week 30), subjects will be assessed for PRN treatment that 
will consist of an IVT injection of aflibercept based on PRN criteria (Section 9.4.2). These 
subjects would have received either ranibizumab or bevacizumab (control) only up to week 24, 
but will now receive an IVT injection of aflibercept when needed in the latter 24 weeks of the 
study, similar to the treatment that the subjects receive in the other arm during this period of the 
trial. In this manner, there is consistency of evaluation in this latter portion of the study. 
Subjects will be assigned to either of the following arms: 
1. ACTIVE: IVT anti-VEGF agent [Lucentis (0.5 mg/0.05 mL) or Avastin (1.25 mg/0.05
mL)] + SC CLS-TA [4 mg /0.10 mL]
2. CONTROL: IVT anti-VEGF agent [Lucentis (0.5 mg/0.05 mL) or Avastin (1.25
mg/0.05 mL)] + SC sham procedure
Approximately 460 subjects will be randomly assigned to a group in a 1:1:1:1 ratio where 
approximately 230 subjects will be assigned to the ACTIVE (combination) treatment (115 to 
each group) and approximately 230 subjects will be assigned to the CONTROL treatment (115 to 
each group).  
Sham IVT and sham SC procedures will be performed using needleless hubs attached to the 
appropriate syringe to maintain masking. This is a non-invasive procedure. 
All SC injections may only be performed by trained Investigators. Training will be documented 
by the Sponsor in writing. Training documentation will be maintained at the site as well as with 
the Sponsor.  


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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Detailed instructions on the SC injection procedure can be found in the Investigative Site File. 
9.2. Study Eye Determination 
The study eye will be the eye receiving the IVT anti-VEGF agent, SC CLS-TA injection, or the 
sham procedures depending upon the group to which the subject is randomly assigned. The 
determination of the study eye will be based on Screening/Baseline information and will be 
determined before randomization. 
If both eyes meet study criteria, the eye with the better chance of achieving an improvement in 
BCVA, in the Investigator’s opinion, should be used as the study eye. If both eyes qualify for the 
study and appear similar in their chance of improvement, the right eye should be designated as 
the study eye. The eye that is not designated as the study eye will be denoted as the fellow eye. 
9.3. Fellow Eye Treatment 
Only one study eye of each subject may be treated in the study.  
Ocular therapy for the fellow eye is not subject to the requirements of this protocol. Local 
medications are permitted for the fellow eye during the course of this study. Medications used in 
the fellow eye will be recorded in the subject’s medical chart and the case report form (CRF).  
9.4. Additional Treatment 
If, at any time during the study, a subject is considered at immediate risk for a vision-threatening 
event, the Investigator should immediately follow best medical practice in the Investigator’s 
judgment for treating the subject. All additional therapy will be recorded in the subject’s source 
document and the CRF. 
9.4.1. Supplemental Therapy Criteria 
Beginning at Week 8 (Visit 4) through and including Week 20 (Visit 8), if any of the following 
criteria are met in the study eye, the intravitreal anti-VEGF agent the subject is randomized to 
will be administered. 
• Macular edema (ME), defined as intraretinal, subretinal or sub-RPE fluid (new or 
persistent), in conjunction with a CST ≥ 340 µm as measured by SD-OCT. 
• A decrease in BCVA of 6 letters or greater between the current visit and the BCVA 
reading from the previous visit with an increase in CST of > 50 µm from the previous 
visit, associated with new fluid.  
• A decrease in BCVA of 10 letters or greater from the best measurement (during the 
study) with an increase in CST of > 50 µm from the previous visit, associated with new 
fluid. 


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• If vision is worse than approximately 70 letters read and there is new or persistent 
intraretinal or sub-retinal fluid or sub-RPE fluid, that in the opinion of the investigator is 
affecting vision, even if CST <340 µm. 
9.4.2. PRN Criteria 
During the PRN Dosing and Follow-up Period (Visits 9 through 11 [Weeks 30 through 42]), 
study arm will remain masked and additional dosing is limited to the criteria above. PRN 
treatment will consist of an IVT injection of aflibercept for all subjects regardless of 
randomization. All subjects will continue to be assessed for safety during the PRN Dosing and 
Follow-up Period. 
9.5. Concomitant Treatments  
The list of prohibited treatments provided below is not intended to be comprehensive, but rather 
to help guide the Investigator’s medical judgment. In cases where a subject presents with a 
treatment not included on the following list, or should there be any question on the part of the 
Investigator, Investigators are encouraged to confer with the Medical Monitor for any 
clarification. 
Use of the following treatments is prohibited at any time during the study: 
• Increases to topical ophthalmic non-steroidal anti-inflammatory drugs in the study eye  
• Any corticosteroid implant (ie, OZURDEX®, ILUVIEN® or RETISERT®) in the study 
eye 
• Topical, periocular, or IVT corticosteroids in the study eye  
• High dose systemic corticosteroids (>10 mg/day of prednisone or equivalent) for more 
than 14 days 
• Any IVT agents except those specified in the study protocol 
• Systemic anti-angiogenic drugs (anti-VEGF) including, for example, bevacizumab 
• Macular (grid/focal) laser 
• Any investigational drug or device 
In cases where there is anticipated need for any of the treatments listed here during the study, or 
if a subject presents to the Investigator having initiated treatment during the study with one of 
these treatments, it is the responsibility of the Investigator to notify the Sponsor immediately. If 
additional therapy is necessary to treat worsening of RVO in the study eye and normal standard 
of care requires additional intervention, the treatment(s) should be recorded in the subject’s CRF 
and should follow the guidelines presented for supplemental therapy criteria. Subjects will not be 
discontinued from the study because of initiation of or change in a prohibited medication. 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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9.6. Treatment Compliance 
Study drug will only be administered by trained study Investigators (principal Investigator or 
sub-Investigator) in the office. No study drug will be dispensed to subjects; therefore, subject 
treatment compliance is not applicable.  
9.7. Randomization and Masking 
Subjects’ randomized treatment assignments will be protected using a masked allocation 
schedule created by a clinical allocation schedule system. Subjects, non-injecting physicians, site 
technicians measuring BCVA, and the CRC for images will be masked to treatment assignments. 
The randomization code will not be available to these individuals until after the study is 
completed and the database is locked. 
In the event of a medical need, the injecting physician and supporting study staff who are present 
during the injection procedure are unmasked, thus immediate emergency unmasking is not 
necessary. Emergency unmasking of subjects by other Investigators or authorized clinical site 
personnel will occur via the IRT. 
Site technicians, CRC personnel, and designated readers and graders should not unmask the 
subject’s randomized treatment assignment without the Sponsor’s approval unless immediately 
required in response to an SAE. If the Sponsor is not notified before the unmasking event, the 
Investigator must immediately contact the Sponsor informing them of the specific details of the 
occurrence. The Sponsor personnel involved in the collection, interpretation, analysis, review, or 
any decision-making stemming from the study data will remain masked to subject status for the 
duration of the study unless otherwise warranted. 
The subject will be masked to treatment throughout the study. The subject shall not discuss the 
study drug with any masked study personnel. All designated readers and graders, the subjects, 
the Sponsor’s masked personnel, and masked monitors involved in reporting, obtaining, and 
reviewing the clinical evaluations for subjects will not be aware of the specific randomized 
treatment assignment for any subject.  
Only study staff who are designated by the Investigator to prepare and administer study drug and 
conduct test article accountability may know the randomized treatment assignment. The 
unmasked Investigator and staff may not participate in efficacy assessments. The unmasked 
Investigator may participate in ophthalmic examinations before and after injection for safety.  
Designee(s) will not discuss the test article with other site personnel or the Sponsor monitors and 
will instruct subjects not to discuss the study drug or appearance of the packaging with the 
Investigator, sub-Investigator(s) or any other study staff while the study is ongoing. This level of 
masking will be maintained throughout the conduct of the study. 
The external packaging for the test article and sham control will be identical.  
If masking is compromised, any masked personnel who become unmasked will not conduct any 
further masked clinical evaluations with the subject whose treatment has been unmasked. In the 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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case of unmasking, the site will notify the IRB and Sponsor/designee; follow-up training may be 
required. 
In cases where subjects meet supplemental therapy criteria, the masking of the subject, non-
injecting physician, and site technician measuring BCVA should be maintained.  The masked 
physician will perform pre-injection exam procedures in accordance with standard subject 
visits.  If the masked physician determines the subject meets supplemental therapy criteria, the 
masked physician will provide written confirmation to the injecting physician informing them of 
the need to administer supplemental therapy. As the injecting physician is unmasked, and has 
knowledge of the treatment to be administered, the injecting physician should utilize written 
information from the masked physician in conjunction with their knowledge of subject treatment, 
to determine the appropriate therapy to be administered, if any.  
 


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10. STUDY DRUG MATERIALS AND MANAGEMENT
10.1. Study Drug 
CLS-TA is a sterile, preservative-free, aqueous suspension formulated for administration into the 
eye. The drug product is terminally sterilized and is intended for single use. CLS-TA is supplied 
as a 40 mg/mL sterile suspension in a 2-mL/13-mm TopLyo® single-use vial with a rubber 
stopper and an aluminum seal. 
Additional information regarding CLS-TA is available in the CLS-TA Investigator’s Brochure. 
Avastin is a preservative-free, clear to slightly opalescent, colorless to pale brown, sterile 
solution. Each carton is for single eye use only. 
Additional information regarding Avastin is available in the bevacizumab Investigator’s 
Brochure. 
Lucentis is a sterile, colorless to pale yellow solution. Each carton is for single eye use only. 
Additional information regarding Lucentis is available in the LUCENTIS Prescribing 
Information, 2017 and Summary of Product Characteristics, 2016. 
Eylea is a sterile, clear, colorless to pale yellow solution. Each carton is for single eye use only. 
Additional information regarding Eylea is available in the EYLEA Prescribing Information, 2017 
and Summary of Product Characteristics, 2017. 
10.2. Study Drug Packaging and Labeling 
The study drug kits for SC injection of CLS-TA (active SC kit and sham SC kit) will be supplied 
to each site by the Sponsor and will be labeled indicating the product is for investigational use 
only. 
Commercially available Lucentis, Avastin and Eylea, needles, and syringes necessary for IVT 
administration and sham IVT administration will be provided by the Sponsor. 
10.3. Study Drug Storage 
CLS-TA will be stored at ambient temperatures between 15°C and 25°C (59°F-77°F) in an area 
with limited, controlled access and temperature monitoring; do not freeze. CLS-TA should be 
protected from light by storing in the carton provided. 
The anti-VEGF agent should be stored according to the label for the agent in the trial. 


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10.4. Study Drug Preparation 
Shake the vial of CLS-TA vigorously for 10 seconds to ensure a uniform suspension before 
withdrawing the product from the vial.  
Preparation of the anti-VEGF agent will be performed according to the details for ranibizumab, 
bevacizumab, and aflibercept as described in the Investigative Site File. The same technique is 
followed for the initial treatments, additional treatments through week 24, and the PRN portion 
through the end of the trial. 
10.5. Administration 
CLS-TA will be administered as a single SC injection of 4 mg in 0.10 mL. 
All CLS-TA injections may only be performed by trained Investigators. Training will be 
documented by the Sponsor in writing. Training documentation will be maintained at the site as 
well as with the Sponsor. Investigators will be trained by Clearside Biomedical, Inc. staff or their 
designees. SC injection procedure training will consist of a video, instructional training and 
hands on training utilizing the microinjector. 
Detailed instructions on the CLS-TA injection procedure can be found in the Investigative Site 
File. 
The date and time of the injection will be recorded in the subject’s medical chart and the CRF. 
All needles used and the needle length used for injection will also be recorded. 
Administration of all anti-VEGF agents will be per the Investigator’s standard practice for IVT 
injections. 
10.6. Study Drug Accountability 
Accountability of study drug kits will be conducted by either designated study staff and/or the 
study monitor. Accountability will be ascertained by performing reconciliation between the 
number of study drug cartons (kits and components) sent to the site and the number used and 
unused at the time of reconciliation.   
Study drug shipment records will be verified and accountability performed by comparing the 
shipment inventory sheet to the actual quantity of drug and injectors received at the site. 
Accurate records of receipt and disposition of the study drug and injectors (eg, dates, quantity, 
subject number, kits used, kits unused) must be maintained by the Investigator or his/her 
designee.  
10.7. Study Drug Handling and Disposal 
At the end of the study and after study drug kit accountability has been verified, all study drug 
(used and unused vials) and unused microinjector components will be returned to the Sponsor (or 
designee) or destroyed at the site and documented according to the site’s standard process. Any 
used injectors and vials of study drug involved in a product complaint must be maintained and 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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return to the Sponsor (or designee). All study drug and injector accounting procedures must be 
completed before the study is considered complete. 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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11. ASSESSMENTS OF EFFICACY 
For additional information on an assessment, see the Investigative Site File. 
11.1. Best Corrected Visual Acuity (BCVA)  
Best corrected visual acuity (BCVA) will be evaluated by ETDRS using standardized lighting 
and standardized lanes. The results shall be reported as the number of letters read. Visual acuity 
testing should precede any examination requiring contact with the eye.  
In order to provide standardization and well-controlled assessments of BCVA during the study, 
all BCVA assessments must be performed by trained staff who are certified on the study 
procedure using certified VA equipment/lanes. 
11.2. Central Subfield Thickness as Measured by Spectral Domain Optical 
Coherence Tomography 
Retinal thickness and disease characterization will be assessed via SD-OCT. The SD-OCT 
instrument and technician must be certified before screening any subjects. The technician is 
encouraged to use the same certified equipment throughout the subject’s study participation. All 
images should be taken by the same technician, whenever possible, on each subject per research 
site. Images will be sent to the CRC for analysis and interpretation in a masked fashion. 
11.3. Visual Function Questionnaire  
The VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related 
constructs, plus an additional single-item general health rating question. The VFQ-25 takes 
approximately 10 minutes on average to administer in the interviewer format. A trained 
technician will administer this questionnaire to the subject.  
11.4. EuroQol 5 Dimensions Questionnaire 
The EQ-5D is a standardized measure of health status developed to provide a simple, generic 
measure of health for clinical and economic appraisal. The EQ-5D is designed for self-
completion by respondents. It is cognitively undemanding, taking only a few minutes to 
complete. Instructions to respondents are included in the questionnaire. Subjects unable to read 
may have the EQ-5D read to them. 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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12. ASSESSMENTS OF SAFETY  
For additional information on an assessment, see the Investigative Site File. 
12.1. Safety Parameters 
12.1.1. Intraocular Pressure  
Intraocular pressure will be measured by applanation tonometry and results will be recorded in 
mmHg. Where available, Goldmann applanation tonometry should be used at all visits. 
Tonopens may be used for post-injection pressure checks and in cases where no Goldmann is 
available. The technician is encouraged to use the same tonometry method throughout the 
subject’s study participation. At any visit where both IVT anti-VEGF agent/sham and SC CLS-
TA/sham injections are to be administered, IOP will be measured 3 times: before IVT anti-
VEGF agent injection, after IVT anti-VEGF agent injection but before SC CLS-TA injection, 
and after SC CLS-TA injection. Tonometers must be calibrated for accuracy before the first 
subject screening at that site and according to the manufacturer specifications during the study, 
until the last subject has exited the study at that site. 
12.1.2. Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy, including magnification, will be performed consistent with standard 
clinical practice. This procedure should be conducted in the same manner for all subjects and 
will include an assessment of each of the following as normal or abnormal: eyelids, sclera and 
conjunctiva, cornea, anterior chamber, iris, and lens. All abnormal findings will be described. 
Slit lamp examination of the iris is to rule out neovascularization of the iris (NVI). 
12.1.2.1. Cataract Lens Grading  
If an abnormal finding of cataract is noted during the slit-lamp examination, the cataract should 
be graded for nuclear opalescence, cortical opacity, and posterior subcapsular opacity. Graders 
must verify training on the grading procedures. 
12.1.3. Indirect Ophthalmoscopy  
Indirect ophthalmoscopy should be performed according to the Investigator’s standard clinical 
practice. This procedure should be the same for all subjects observed at the Investigator’s site. 
The fundus will be examined thoroughly and the following variables will be assessed as normal 
or abnormal (including but not limited to): vitreous, retina, choroid, and optic nerve/disc, 
appearance of vessels, absence of neovascularization.  
12.1.4. Fluorescein Angiography  
Fluorescein angiography will be performed for anatomic assessments and will include the area of 
fluorescein leakage, area of capillary nonperfusion, the presence of retinal vascular and optic 
nerve head staining, and retinal pigment epithelium abnormalities. Digital equipment will be 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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registered and photographers certified for the imaging procedures. De-identified images will be 
uploaded to the CRC.  
12.1.5. Fundus Photography 
Color fundus photographs will be obtained. It is recommended that when both fundus 
photographs and FA are conducted in the same visit, the fundus photographs should be taken 
first. All photographs should be taken by the same photographer, whenever possible, on all 
subjects per research site. Digital equipment will be registered and photographers certified for 
the imaging procedures. De-identified images will be uploaded to the CRC.  
12.1.6. Resting Heart Rate and Blood Pressure 
Resting heart rate and resting blood pressure (systolic and diastolic, preferably on the same arm 
each time) will be measured at every visit after the subject has rested for about 5 minutes.  
12.1.7. Pregnancy Test 
Pregnancy tests will be performed on all females of childbearing potential. Urine pregnancy tests 
will be performed at Visits 2, 5 and 8. Serum tests will be performed at Visits 1 and 12. 
12.1.8. Central Laboratory Tests 
Non-fasting clinical laboratory tests will be performed at Visits 1, 8 and 12. These laboratory 
tests include serum chemistry, hematology, and urinalysis and are to rule out any underlying 
disease that may exclude the subject from participation.  
12.1.9. Review of Body Systems 
A review of body systems will include an assessment of each of the following as normal or 
abnormal: skin, cardiovascular, respiratory, neurological, and musculoskeletal systems. All 
abnormal findings will be described. This exam may be performed by any medical doctor or 
legally qualified personnel according to local laws/regulations.  
12.2. Adverse and Serious Adverse Events 
12.2.1. Definition of Adverse Events 
12.2.1.1. Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition after or during exposure to a pharmaceutical product, whether or 
not considered causally related to the product. In clinical studies, an AE can include an 
undesirable medical condition occurring at any time, including baseline or washout periods, even 
if no study treatment has been administered. This should be considered when a subject requires 
new or additional treatment for a pre-existing illness, or other medical condition. Lack of, or 
insufficient clinical response should not be recorded as an adverse event. 


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In addition, clinically significant changes in objective findings (e.g., laboratory, ECG, X-ray, 
Physical examination) should also be considered as to whether these are adverse events. The 
criteria for determining whether an objective finding should be reported as an adverse event are 
as follows: 
1. Associated with accompanying symptoms; and/or 
2. Requires medical/surgical intervention; and/or 
3. Leads to a change in trial dosing, or discontinuation from the trial, significant additional 
concomitant drug treatment, or other therapy; and/or 
4. Leads to any of the outcomes included in the definition of serious adverse event; and/or 
5. Is considered to be an adverse event as determined by the investigator, or Sponsor. 
Any abnormal test result that is determined to be an error, does not require reporting as an 
adverse event, provided the result has been validated by a repeat test result. 
All AEs that occur after any subject has signed consent, before treatment, during treatment, or 
during the study participation, whether or not they are related to the study, must be recorded on 
the forms provided. 
12.2.1.2. Serious Adverse Event 
An SAE is an AE occurring during any study phase (ie, baseline, treatment, washout, or follow-
up), and at any dose of the investigational product, comparator, or placebo, that fulfils one or 
more of the following: 
• Results in death 
• Is immediately life-threatening* 
• Requires in-patient hospitalization or prolongation of existing hospitalization** 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above*** 
All SAEs that occur after any subject has signed consent, before treatment, during treatment, or 
during study participation, whether or not they are related to the study, must be recorded. 
 
*A life-threatening event is one that places the subject at immediate risk of death from the event 
as it occurred; not hypothetically that had the reaction occurred in a more severe form, it may 
have caused, or could cause death. 
 


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**Hospitalization is defined as any “formal in-patient admission” (even if less than 24 hours). 
For chronic, or long-term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
In-patient admission does not include: 
• 
Emergency Room visits 
• 
Outpatient/same-day/ambulatory procedures and observation 
• 
Hospice facilities and respite care 
• 
Rehabilitation facilities, skilled nursing facilities, nursing homes 
• 
Admission for treatment of a pre-existing condition, not associated with an adverse event, 
or worsening of the condition. 
• 
Social admission (e.g. subject needs a place to sleep) 
• 
Optional admission not associated with a precipitating clinical adverse event (e.g. 
elective cosmetic surgery) 
***Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered serious when, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such events include: allergic bronchospasm 
requiring intensive treatment in an emergency room, or at home, blood dyscrasias, or 
convulsions that do not result in inpatient admission. 
12.2.2. Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Not related or Related). Adverse events are assessed as 
either related to the injection procedure, or to the study drug (CLS-TA, bevacizumab, 
ranibizumab, aflibercept). The relationship to trial treatment will be assessed utilizing the 
following definitions: 
Not Related: There is not a reasonable possibility (no valid reason) that the adverse event is 
related to the injection procedure, or to the trial study drug. 
Related:  
There is a reasonable possibility (even if undetermined) that the adverse event is 
related to the injection procedure or to the trial study drug. 
 
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “unrelated.” If there is 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship 
between the investigational product and the occurrence of the AE, then the AE should be 
considered “related.” 
12.2.3. Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes in laboratory values, blood pressure, and pulse 
need not be reported as AEs. However, abnormal values that constitute an SAE or lead to 
discontinuation of administration of study drug must be reported and recorded as an AE.  
Information about AEs will be collected from the signing of the consent form until the end of the 
study. Serious adverse event information will be collected from signing of the consent form until 
the end of study participation. The AE term should be reported in standard medical terminology 
when possible. For each AE, the Investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, seriousness outcome (if applicable), 
and whether or not it caused the subject to discontinue the study. 
12.2.4. Intensity 
The intensity of each AE will be graded using National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v 4.03. The criteria can be accessed at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
The term “severe” is a measure of intensity. A severe AE is not necessarily an SAE. 
Grade refers to the intensity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of intensity for each AE based on this general guideline: 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention 
indicated; limiting age-appropriate instrumental activities of 
daily living (ADL) 
Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of the 
hospitalization indicated; disabling; limiting self-care ADL 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 


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It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1. An AE of severe intensity 
may not be considered serious. 
12.2.5. Exposure In Utero 
Should a pregnancy occur, it must be reported and recorded on the provided pregnancy form.  
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
12.2.6. Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from the signing of the consent form until the 
end of study participation. Any SAEs considered related to the investigational product and 
discovered by the Investigator at any time after the study should be reported. All SAEs must be 
reported to Clearside Biomedical, or its designee, within 24 hours of the first awareness of the 
event. The Investigator must complete, sign, and date the SAE pages, verify the accuracy of the 
information recorded on the SAE pages with the corresponding source documents, and send a 
copy by fax to Clearside Biomedical, or its designee.   
Additional follow-up information, if required or available, should be faxed to Clearside 
Biomedical, or its designee, within one business day of receipt. The information should be 
recorded on a follow-up SAE form and placed with the original SAE information and kept with 
the appropriate section of the CRF and/or study file. 
The investigator or Clearside Biomedical (or third parties if applicable), if appropriate, is 
responsible for reporting suspected serious unexpected adverse reactions to the competent 
authorities in all the Member States and/or countries concerned, and to the Ethics Committee in 
compliance with current legislation. 
12.2.7. Follow-up of AEs and SAEs 
All AEs and SAEs reported during study conduct must be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or the subject is lost to follow-up.  
Subjects will be followed for any treatment-related SAEs reported at the end of participation 
until the condition stabilizes, the event is otherwise explained, the subject is lost to follow-up, or 
the subject withdraws consent.   


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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NOTE: “Resolution” means the subject has returned to baseline state of health, or the 
Investigator does not expect any further improvement in the subject’s condition or does not 
expect worsening of the AE. 
For a non-serious AE that is first identified on the last scheduled contact, the event must be 
recorded on the AE CRF with the current status noted, but no further follow-up needs to be 
performed. 
Post-Study SAEs:  Investigators are not obligated to actively seek SAE information in former 
study participants; however, any new SAE reported by the subject to the Investigator that occurs 
after the last scheduled contact and is determined by the Investigator to be associated with the 
use of study drug, should be reported to the Sponsor. The Investigator should follow related 
SAEs identified after the last scheduled contact until the event has resolved or stabilized or the 
subject is lost to follow-up.  
12.2.8. End of Trial 
The end of the trial is defined as the last subject’s last visit (Visit 12), as this will be the final 
date that data is collected from a trial participant. 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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13. 
STATISTICAL CONSIDERATIONS 
A detailed statistical analysis plan will be prepared for this study. The plan will contain a 
discussion of the statistical methods, a description of the computational algorithms and data 
handling conventions, and specifications for the data summaries and listings. It will be finalized 
before database lock. This study will be analyzed by comparing the combination (active) arm, 
with an anti-VEGF agent and CLS-TA, to the anti-VEGF monotherapy (control) arm. The active 
arm will consist of two active groups: one group will receive anti-VEGF (ranibizumab) and 
corticosteroid (CLS-TA) and the other group will receive anti-VEGF (bevacizumab) and 
corticosteroid (CLS-TA) at randomization. The control arm will likewise consist of two groups: 
one group will receive anti-VEGF (ranibizumab only) and the other group will receive anti-
VEGF (bevacizumab only) at randomization. 
13.1. Randomization 
There will be approximately 460 subjects randomly assigned 1:1:1:1 to one of the four treatment 
groups described above, each stratified by disease (BRVO, CRVO). HRVO subjects will be 
enrolled in this study and analyzed in the CRVO arm. Randomization will proceed as described 
until either stratum within a group reaches at least 50% of the total number patients to be 
enrolled in that group at which time only patients from the other stratum will be enrolled. 
Assignment of subjects to treatment groups will be performed via the IRT. 
13.2. Determination of Sample Size and Level of Significance 
With a total sample size of 460 subjects in a 1:1:1:1 randomization, this study will have 90% 
power to detect a difference of 15% between treatments if the actual proportion of subjects 
showing improvement of 15 letters is 0.50 for the control anti-VEGF agent arm at 2 months.  
Power was based on a Pearson chi-squared difference in proportions of subjects showing 
improvement in BCVA at Month 2. The estimate for the IVT anti-VEGF agent proportion was 
set at 0.5, which is a worst-case scenario analysis because the variance of the proportion was 
maximal at 0.5. This, in turn, makes the power estimate robust with regard to the actual value of 
the IVT anti-VEGF agent proportion. The proportion for SC injection of CLS-TA adjunctive to 
anti-VEGF agent (combination) was estimated over a range of values. A minimal clinical effect 
of 15% greater improvement was selected. For 90% power, this will require 227 subjects/group.  
13.3. Subject Disposition and Demographic and Baseline Characteristics 
Subject disposition and demographic, and baseline characteristics will be summarized 
descriptively by treatment group, treatment arm, and overall. 


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13.4. Analysis Populations 
13.4.1. Safety Population 
The Safety Population will include all randomly assigned subjects who are administered at least 
one dose of the study drug. All safety analyses will be based on the Safety Population. 
13.4.2. Intent-to-Treat Population 
The Intent-to-treat (ITT) Population will include all randomized subjects. Subjects will be 
analyzed as originally allocated after randomization. The ITT Population will be used for 
efficacy analyses. Missing data will be imputed using the last observation carried forward 
(LOCF) method. If a subject receives rescue therapy, LOCF will be used for the primary analysis 
using last available data from prior to administration of the rescue therapy. 
13.4.3. Per Protocol Population 
The Per-protocol (PP) Population will include all subjects in the ITT population who do not have 
significant protocol deviations. The rules for determining exclusions from the PP Population will 
be finalized after a clinical review of the data and resolution of all queries but before unmasking 
of treatment assignments. Missing data will not be imputed in the PP population. There will also 
not be any imputations of data for subjects who receive rescue therapy in the PP population. 
13.5. Analysis Methods 
Efficacy and safety endpoints are provided in Section 7.2. 
13.5.1. Primary Efficacy Analysis 
The primary endpoint is the proportion of subjects demonstrating ≥ 15 letter improvement from 
Baseline in ETDRS BCVA at Week 8 (Month 2).  
The primary analysis is a test of superiority of suprachoroidally injected CLS-TA when used 
adjunctively (in “combination”) with intravitreally injected anti-VEGF agent. The primary 
analysis will use the Cochran-Mantel-Haenszel test to evaluate differences in the proportion of 
subjects in the two arms who show 15 or more letters improvement in BCVA at the 2-month 
visit after adjusting for effects for disease type. Subjects who either receive rescue therapy or 
withdraw from the study prior to the 2-month visit will be considered as treatment failures for the 
primary endpoint analysis. 
Tests to evaluate the treatment superiority of suprachoroidally injected CLS-TA (TA) in 
combination with intravitreally injected anti-VEGF agent (IA) compared with IVT anti-VEGF 
agent alone will be conducted using a two-sided alpha = 0.05 
The formal hypothesis is: 
H0: IA + TA = IA 
H1: IA + TA ≠ IA 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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The Breslow-Day test will be used to assess homogeneity of results across Investigators. 
These methods were chosen because the subjects are stratified by RVO disease type, that is, 
CRVO and BRVO. For measures such as BCVA, differences across strata may be large enough 
to have impact on the overall results. 
The Cochran-Mantel-Haenszel test adjusts for differences in results between disease types and 
the Breslow-Day test assesses homogeneity of results across Investigators. 
13.5.1.1. 13.5.1.1 Sensitivity Analyses of Primary Efficacy Endpoint 
To evaluate the robustness of the analysis of the primary efficacy endpoint, sensitivity analyses 
will be performed using a placebo-based multiple imputation Pattern Mixture Model (PMM) and 
a tipping point analysis of the PMM in the ITT population. These sensitivity analyses will be 
detailed in the statistical analysis plan (SAP) and finalized prior to the study database lock. 
13.5.2. Secondary Efficacy Analysis 
13.5.2.1. Secondary Efficacy Endpoint 
• Mean change from Baseline (Visit 2, Day 0) in BCVA at Visit 4 (Week 8) and Visit 8 
(Week 24) 
• Mean change from Baseline (Visit 2, Day 0) in CST at Visit 4 (Week 8) and Visit 8 
(Week 24) 
13.5.2.2. Exploratory Endpoints 
• Change from Baseline (Visit 2, Day 0) in subject-reported outcomes at Visit 8 (Week 
24) as measured by the VFQ-25 and the EQ-5D 
• Change from Baseline in signs and complications of RVO (eg, neovascularization, 
perfusion) at Visit 8 (Week 24) 
• Changes from Baseline based on disease type, CRVO or BRVO. 
13.5.3. Subgroup Analysis 
Subgroup analyses, if any, will be detailed in the statistical analysis plan. All these analyses will 
be considered as exploratory. 
13.5.4. Safety Analysis  
13.5.4.1. Extent of Exposure 
The extent of exposure (ie, whether a subject received the injection and whether it was a 
complete or partial injection) will be listed. 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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13.5.4.2. Safety Endpoints 
• Incidence of TEAEs and SAEs, grouped by organ system, relatedness to study drug, and 
intensity  
• Incidence of changes in safety parameters including: IOP, slit-lamp biomicroscopy, 
indirect ophthalmoscopy, imaging parameters, and vital signs  
13.5.5. Schedule of Analyses 
Additional safety and descriptive efficacy data will be collected through approximately one year, 
the end of the study. Treatment codes will be broken at Month 2, and the final efficacy analysis 
will be conducted at this time. A descriptive follow-up safety and efficacy analysis will be 
performed at 6 months to allow filing the marketing authorization. Investigators, subjects, and 
study personnel who have contact with the Investigators or subjects will remain masked 
throughout the study. No adjustment for the analysis at Month 6 or at Month 12 are required 
because the final analysis of efficacy is at Month 2 and data from all subsequent visits will be 
descriptive only.  
13.5.6. Procedure for Accounting for Missing, Unused, or Spurious Data 
Any missing, unused, or spurious data will be noted in the final clinical study report. 
The Last Observation Carried Forward (LOCF) method will be used if visits are missed in the 
ITT Population. No imputation for missed visits will be used in the PP Population. This provides 
an indication of the sensitivity of the data to missing observations.  
Likewise, the LOCF method will be used if a subject requires rescue therapy. The last recorded 
data before the rescue will be carried forward to all subsequent visits for the ITT Population. No 
imputation for rescue medications will be used in the PP Population. All data points will be set to 
missing after a subject’s receipt of a rescue medication in the PP Population only. 
Details of the methodology for handling missing or partial dates will be addressed in the 
Statistical Analysis Plan. 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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14. DIRECT ACCESS TO SOURCE DOCUMENTS 
14.1. Study Monitoring 
Before an investigator can enter a subject into the study, a representative of Clearside 
Biomedical, Inc. will visit the 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 Clearside Biomedical, Inc. or its 
representatives. This will be documented in a Clinical Study Agreement between 
Clearside Biomedical, Inc. and the Investigator. 
During the study, a monitor from Clearside Biomedical, Inc. or its representative will have 
regular contacts with the study site to: 
• 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 CRFs, and that investigational product accountability checks 
are being performed 
• Perform source data verification. This includes a comparison of the data in the CRFs 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 (eg, clinic 
charts). 
• Record and report any protocol deviations not previously sent to Clearside Biomedical, 
Inc. or designee. 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to Clearside Biomedical, Inc. or designee 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 needs 
information or advice. 
14.2. Audits and Inspections 
Authorized representatives of Clearside Biomedical, Inc. a regulatory authority, an Independent 
Ethics Committee or an Institutional Review Board may visit the study site to perform audits or 
inspections, including source data verification. The purpose of a Clearside Biomedical 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 Conference on Harmonization, and any applicable regulatory requirements.  


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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The Investigator should contact Clearside Biomedical immediately if contacted by a regulatory 
agency about an inspection. 
14.3. Institutional Review Board/Independent Ethics Committee 
The Principal Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC 
approval and all materials approved by the IRB/IEC for this study, including the subject consent 
form and recruitment materials, must be maintained by the Investigator and made available for 
inspection. 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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15. QUALITY CONTROL AND QUALITY ASSURANCE 
The progress of the study will be monitored by onsite, written, e-mail, and telephone 
communications between personnel at the study site and the Sponsor. The Investigator will allow 
Sponsor monitors, or designee(s), to inspect all CRFs; subject records (source documents); 
signed Informed Consent Forms; records of study drug receipt, storage, and disposition; and 
regulatory files related to the study. 
At the time of database lock, the clinical database will be audited to ensure accuracy of the data, 
as well as to provide an estimated error rate for the final, locked database. The audit will involve 
a comparison of CRF values with values from data listings generated from the clinical database. 
Values identified as critical safety and efficacy variables will be confirmed for 100% of the 
subjects. In addition, a random sample of subjects will be selected for which all data values, 
excluding comment fields, will be checked. The number of subjects whose data will be randomly 
reviewed will be determined to provide sufficient accuracy for the estimated error rate of the 
clinical database.  
 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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16. ETHICS 
16.1. Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
Investigator must submit written approval to Clearside Biomedical, Inc, or designee, before he or 
she can enroll any subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Clearside Biomedical, Inc. will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the International Council for Harmonisation 
Guideline for Good Clinical Practice, and applicable regulatory requirements. 
16.3. Written Informed Consent 
The Principal Investigator(s) at each site will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, and possible risk and benefit of the study.  
Subjects must also be notified that they are free to discontinue from the study at any time. The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form. A copy 
of the signed Informed Consent Form must be given to the subject. 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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17. DATA HANDLING AND RECORDKEEPING 
17.1. Inspection of Records 
Clearside Biomedical, Inc., and designees, 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, study drug stocks, drug 
accountability records, subject charts and study source documents, and other records relative to 
study conduct. 
17.2. Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or if not approved, 2 years after the 
discontinuance of the test article for investigation or according to local regulation. If it becomes 
necessary for Clearside Biomedical, Inc. or the Regulatory Authority to review any 
documentation relating to the study, the Investigator must permit access to such records. 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
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Page 66 of 79 
 
 
CONFIDENTIAL 
 
18. PUBLICATION POLICY 
The institutions and Investigators participating in this study shall have no right to publish or 
present the results of this study without the prior written consent of Clearside Biomedical, Inc. 
 
 


CLS-TA, triamcinolone acetonide injectable suspension
  Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date: 25 January 2018 
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CONFIDENTIAL 
19.
REFERENCES
Avastin® [Prescribing Information]. South San Francisco, CA. Genentech, Inc. 2016 
Avastin® [Summary of Product Characteristics]. Welwyn Garden City, United Kingdom.  
Roche Registration Limited. 2017 
Aref AA, Scott IU, Oden NL, Ip MS, Blodi BA, VanVeldhuisen PC; SCORE Study Investigator 
Group. Incidence, risk factors, and timing of elevated intraocular pressure after intravitreal 
triamcinolone acetonide injection for macular edema secondary to retinal vein occlusion: 
SCORE study report 15. JAMA Ophthalmol. 2015;133(9):1022-1029. 
Boyer D, Heier J, Brown DM, Clark WL, Vitti R, Berliner AJ, et al. Vascular endothelial growth 
factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results 
of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5):1024-1032. 
Boyer DS, Yoon YH, Belfort RJ, et al. Three-year, randomized, sham-controlled trial of 
dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 
2014;121(10):1904-1914. 
Brown DM, Campochiaro PA, Singh RP, et al. Efficacy and safety of ranibizumab in the 
treatment of macular edema secondary to central retinal vein occlusion:6-month results of the 
phase III CRUISE study. Ophthalmology 2010;117(6):1124-1133. 
Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for 
macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. 
Ophthalmology 2011;118(8):1594-1602. 
Brown DM, Heier JS, Clark WL, Boyer DS, Vitti R, Berliner AJ, et al. Intravitreal aflibercept 
injection for macular edema secondary to central retinal vein occlusion: 1-year results from the 
phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429-437. 
Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein 
occlusions; implication of VEGF as a critical stimulator. Molec Ther 2008;16(4):791-799. 
Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch 
retinal vein occlusion: 6-month primary endpoint results of a phase III study. Ophthalmology 
2010;117(6):1102-1112. 
Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular 
edema following central retinal vein occlusion: 12-month outcomes of a phase III study. 
Ophthalmology 2011;118(10):2041-2049. 
Campochiaro PA, Sophie R, Pearlman J, et al. Long-term outcomes in patients with retinal vein 
occlusion treated with ranibizumab: The RETAIN Study. Ophthalmology. 2014;121(1):209-219. 
Campochiaro PA, Hafiz G, Mir TA, et al. Pro-permeability factors after dexamethasone implant 
in retinal vein occlusion; the Ozurdex for retinal vein occlusion (ORVO) study. Am J 
Ophthalmol 2015;160(2):313-321 


CLS-TA, triamcinolone acetonide injectable suspension
  Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date: 25 January 2018 
Page 68 of 79 
CONFIDENTIAL 
Campochiaro PA, Clark WL, Boyer DS, Heier JS, Brown DM, Vitti R, et al. Intravitreal 
aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the 
VIBRANT study. Ophthalmology. 2015;122(3)538-544. 
CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. 
Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 
2011;364(20):1897-1908. 
Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat 
neovascular age-related macular degeneration: one-year findings from the IVAN randomized 
trial. Ophthalmology. 2012;119:1399–1411. 
Comyn O, Lightman SL, Hykin PG. Corticosteroid intravitreal implants vs. ranibizumab for the 
treatment of vitreoretinal disease. Curr Opin Ophthalmol. 2013;24(3):248-54. 
Cunningham MA, Edelman JL, Kaushal S. Intravitreal steroids for macular edema: the past, the 
present, and the future. Surv Ophthalmol. 2008r;53(2):139-149. 
Ehlers JP, Fekrat S. Retinal vein occlusion: beyond the acute event. Surv Ophthalmol. 
2011;56(4):281-299. 
EYLEA® [Prescribing Information]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc., 2017. 
EYLEA® [Summary of Product Characteristics]. Berlin, Germany: Bayer Pharma AG, 2012 
Felinski EA, Antonetti DA. Glucocorticoid regulation of endothelial cell tight junction gene 
expression: novel treatments for diabetic retinopathy. Curr Eye Res. 2005;30(11):949-957. 
Hahn P, Fekrat S. Best practices for treatment of retinal vein occlusion. Curr Opin Ophthalmol. 
2012;23(3):175-181. 
Heck S, Kullmann M, Gast A, et al. A distinct modulating domain in glucocorticoid receptor 
monomers in the repression of activity of the transcription factor AP1. EMBO J 
1994;13(17):4087-4095. 
Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central 
retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol 
2013;97(3):278-284. 
Hoerauf H, Feltgen N, Weiss C, Paulus EM, Schmitz-Valckenberg S, et al COMRADE-C Study 
Group. Clinical efficacy and safety of ranibizumab versus dexamethasone for central retinal vein 
occlusion (COMRADE C): a European label study. Am J Ophthalmol. 2016;169:258-267. 
Ip MS, Scott IU, VanVeldhuisen PC, Oden NL, Blodi BA, Fisher M, et al; SCORE Study 
Research Group. A randomized trial comparing the efficacy and safety of intravitreal 
triamcinolone with observation to treat vision loss associated with macular edema secondary to 
central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion 
(SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101-1114. 


CLS-TA, triamcinolone acetonide injectable suspension
  Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date: 25 January 2018 
Page 69 of 79 
CONFIDENTIAL 
Kiernan DF, Mieler WF. The use of intraocular corticosteroids. Expert Opin Pharmacother. 
2009;10(15):2511-2525. 
Kodjikian L1, Souied EH, Mimoun G, Mauget-Faÿsse M, Behar-Cohen F, Decullier E, Huot L, 
Aulagner G; GEFAL Study Group. Ranibizumab versus bevacizumab for neovascular age-
related macular degeneration: results from the GEFAL noninferiority randomized trial. 
Ophthalmology. 2013;120(11):2300-2309. 
Koh V, Cheung CY, Li X, et al. Retinal vein occlusion in a multi-ethnic asian population: the 
Singapore Epidemiology of Eye Disease Study. Ophthalmic Epidemiol. 2016;23(1):6-13].  
LUCENTIS® [Prescribing Information]. South San Francisco, CA. Genentech, Inc. 2017 
LUCENTIS® [Summary of Product Characteristics]. Camberley, United Kingdom. Novartis 
Europharm Limited, 2016 
Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in 
Australia. Arch Ophthalmol 1996;114(10):1243-1247.  
National Eye Institute. SCORE Study Results. Nei.nih.gov. 
https://nei.nih.gov/score/score_background. Published September 14, 2009. Accessed November 
09, 2017.  
OZURDEX® [Prescribing Information]. Irvine, CA: Allergan, Inc., 2014. 
Rogers S, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchell P, et al; International Eye Disease 
Consortium. The prevalence of retinal vein occlusion: pooled data from population studies from 
the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117(2):313-319. 
Schule R, Rangarajan P, Kliewer S, et al. Functional antagonism between oncoprotein c-Jun and 
the glucocorticoid receptor. Cell 1990;62(6):1217-1226.  
Scott IU, Ip MS, VanVeldhuisen PC, Oden NL, Blodi BA, Fisher M, Chan CK, Gonzalez VH, 
Singerman LJ, Tolentino M; SCORE Study Research Group. A randomized trial comparing the 
efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated 
with macular Edema secondary to branch retinal vein occlusion: the Standard Care vs 
Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 
2009;127(9):1115-1128.  
Scott IU, VanVeldhusen PC, Ip MS, Blodi BA, Oden NL, Awh CC, et al; SCORE2 Research 
Group. Effect of bevacizumab vs aflibercept on visual acuity among patients with macular 
edema due to central retinal vein occlusion. JAMA. 2017;317(20):2071-2087. 
Son BK, Kwak HW, Kim ES, Yu SY. Comparison of ranibizumab and bevacizumab for macular 
edema associated with branch retinal vein occlusion. Korean J Ophthalmol. 2017 ;31(3):209-216. 
TRIESENCE® [Prescribing Information]. Fort Worth, TX: Alcon Laboratories, Inc., 2016. 
Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB et al for the Diabetic 
Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic 


CLS-TA, triamcinolone acetonide injectable suspension
  Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date: 25 January 2018 
Page 70 of 79 
CONFIDENTIAL 
Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical 
Trial. Ophthalmology. 2016;123(6):1351-1359. 
Yang-Yen HF, Chambard JC, Sun YL, et al. Transcriptional interference between c-Jun and the 
glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein 
interaction. Cell 1990;62(6):1205-15. 


CLS-TA, triamcinolone acetonide injectable suspension                                                      Clearside Biomedical, Inc.  
CLS1003-302 
 
Clinical Protocol 
 
Version Date: 25 January 2018 
Page 71 of 79 
 
 
CONFIDENTIAL 
 
20. APPENDICES 


CLS-TA, triamcinolone acetonide injectable suspension                                                                                                         Clearside Biomedical, Inc. 
CLS1003-302 
 
 
Clinical Protocol 
 
Version Date:  25 January 2018  
Page 72 of 79 
CONFIDENTIAL 
 
APPENDIX A:  Study Design and Schedule of Assessments, Visits 1-6 
 
Visit # 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit Type 
Screening 
Randomization/Treatment 
Baseline Evaluation 
Dosing and Evaluation 
 
Visit Window 
Day  
-30 to -1 
Day 0 
Week 4 
Day 28 ± 3 
Week 8 
Day 56 ± 5 
Week 12 
Day 84 ± 5 
Week 16 
Day 112 ± 5 
Assessments 
 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
Informed Consent 
● 
 
 
 
 
 
 
 
 
 
 
Assign Subject Number 
● 
 
 
 
 
 
 
 
 
 
 
Assign Randomization Number 
 
● 
 
 
 
 
 
 
 
 
 
Demographics, Medical & Ocular History 
● 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
● 
● 
 
 
 
 
 
 
 
 
 
Assess Adverse Events 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Concomitant Medication Review 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Resting Heart Rate and Blood Pressure 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
Urine Pregnancy Test 
 
● 
 
 
 
 
 
● 
 
 
 
Central Laboratory Tests1 
● 
 
 
 
 
 
 
 
 
 
 
Review of Systems 
● 
 
 
 
 
 
 
 
 
 
 
BCVA 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
Slit-lamp Biomicroscopy2 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
IOP 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Dilated Indirect Ophthalmoscopy 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
Indirect Ophthalmoscopy 
 
 
● 
 
● 
 
● 
 
● 
 
● 
SD-OCT 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
Select Study Eye/Confirm Study Eye 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
VFQ-25 & EQ-5D 
 
● 
 
 
 
 
 
 
 
 
 
Fluorescein Angiogram 
● 
 
 
 
 
 
 
 
 
 
 
Fundus Photos 
● 
 
 
 
 
 
 
 
 
 
 
IRT/Randomize 
 
● 
 
 
 
 
 
 
 
 
 
IVT Anti-VEGF agent or Sham Injection 
 
● 
● 
● 
● 
● 
SC CLS-TA or Sham Injection3,4 
 
● 
 
 
● 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                                                                         Clearside Biomedical, Inc. 
CLS1003-302 
 
 
Clinical Protocol 
 
Version Date:  25 January 2018  
Page 73 of 79 
CONFIDENTIAL 
 
APPENDIX A:  Study Design and Schedule of Assessments, Visits 7-12 
Visit # 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12  
Visit Type 
Dosing and Evaluation 
PRN Dosing and Follow Up 
End of Study 
Visit Window 
Week 20 
Day 140 ± 5 
Week 24 
Day 168 ± 5 
Week 30 
Day 210 ± 5 
Week 36 
Day 252 ± 5 
Week 42 
Day 294 ±5 
Week 48 
Day 336 ± 5 
Assessments 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose  
Pre-dose 
Post-dose 
 
Demographics, Medical & Ocular History 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
 
 
 
 
 
 
 
 
 
 
 
Assess Adverse Events 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Concomitant Medication Review 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Resting Heart Rate and Blood Pressure 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
Urine Pregnancy Test 
 
 
● 
 
 
 
 
 
 
 
 
Central Laboratory Tests1 
 
 
● 
 
 
 
 
 
 
 
● 
Review of Systems 
 
 
 
 
 
 
 
 
 
 
● 
BCVA 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
Slit-lamp Biomicroscopy2 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
IOP 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Dilated Indirect Ophthalmoscopy 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
Indirect Ophthalmoscopy 
 
● 
 
● 
 
● 
 
● 
 
● 
 
SD-OCT 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
Select Study Eye/Confirm Study Eye 
● 
 
● 
 
● 
 
● 
 
● 
 
 
VFQ-25 & EQ-5D 
 
 
● 
 
 
 
 
 
 
 
● 
Fluorescein Angiogram 
 
 
● 
 
 
 
 
 
 
 
● 
Fundus Photos 
 
 
● 
 
 
 
 
 
 
 
● 
IRT/Randomize 
 
 
 
 
 
 
 
 
 
 
 
IVT Anti-VEGF agent or Sham Injection3, 
● 
 
● 
PRN 
PRN 
PRN 
 
SC CLS-TA or Sham Injection3,4 
 
 
● 
 
 
 
 
1. 
Central laboratory test samples should be collected before FA being performed; central laboratory tests include a serum pregnancy test for females of child-bearing 
potential (except Visit 8). 
2. 
Any finding of cataract should be graded. 
3. 
All injection/sham procedures should be administered the same day as the pre-injection assessments.   
4. 
Suprachoroidal or sham injection dependent on study treatment group assigned should be performed after the IVT anti-VEGF agent injection (once IOP is < 30 mmHg). 


CLS-TA, triamcinolone acetonide injectable suspension
    Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date:  25 January 2018 
Page 74 of 79 
CONFIDENTIAL 
APPENDIX B:  Summary of Changes for Amendments 
Amendment 1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
Title Page and Footer 
Updated protocol title and 
document version and date 
Protocol versioning 
None 
Investigator’s Agreement 
I have received and read the 
Investigator’s Brochure for CLS-
TA. 
I have received and read the 
Investigator’s Brochure for CLS-
TA and the Investigator’s 
Brochure for bevacizumab. 
Addition of bevacizumab 
Investigator’s Brochure 
None 
2. Synopsis
Removed references to EYLEA 
as study drug  
Added reference to AVASTIN 
and LUCENTIS as study drug 
Added text to describe study 
treatment arms, including 
endpoints 
Modified statistical analysis 
information  
Comparator drug 
modification 
Describe changes to study 
treatment arms 
Comparator drug 
modification 
None 
None 
IWRS – Interactive web response 
system 
IRT – Interactive response 
technology 
System update 
None 
4. List of 
Abbreviations
5. Introduction 
Provide background and describe 
rationale for use of Avastin and 
Lucentis in conjunction with 
CLS-TA 
Comparator drug 
modification 
None 
Section 6.4 
Exploratory Objectives 
Added ‘To evaluate changes from 
baseline based on disease type, 
BRVO and CRVO.  Subjects with 
HRVO data will be included with 
the CRVO group based on 
randomization.’ 
Addition of exploratory 
objective 
None 


CLS-TA, triamcinolone acetonide injectable suspension
    Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date:  25 January 2018 
Page 75 of 79 
CONFIDENTIAL 
APPENDIX B:  Summary of Changes for Amendments 
Amendment 1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
Section 7.2.3 
Exploratory Efficacy 
Endpoints 
Added ‘Changes from Baseline 
on visual and anatomic outcomes 
based on disease diagnosis of 
BRVO and CRVO.  HRVO 
subjects will be included with the 
CRVO for analyses.’ 
Addition of exploratory 
efficacy endpoint 
None 
Section 7.3 Number 
of Subjects 
Approximately 460 subjects with 
RVO who are naïve to treatment 
will be enrolled into one of two 
treatment groups. 
Approximately 460 subjects with 
RVO who are naïve to treatment 
will be enrolled into one of four 
treatment groups. 
Update treatment groups 
None 
Section 7.4 
Treatment 
Assignment 
After Screening (Day -30 to Day 
-1) and Baseline assessments on
Day 0, subjects will be randomly
assigned 1:1 to one of two
treatment groups stratified by
disease type (BRVO, CRVO).
Randomization will proceed as
described until either strata
reaches 55% of the total number
patients to be enrolled at which
time only patients from the other
strata will be enrolled.
After Screening (Day -30 to Day 
-1) and Baseline assessments on
Day 0, subjects will be randomly
assigned 1:1:1:1 to one of four
treatment groups stratified by
disease type (BRVO, CRVO).
Randomization will proceed as
described until either strata within
a group reaches at least 50% of
the total number patients to be
enrolled in that group at which
time only patients from the other
strata will be enrolled.
Treatment group changes 
None 
Table 3. Subject 
Randomization 
Remove reference to IVT 
aflibercept 
Change treatments arms to
include IVT Avastin and Lucentis
Comparator drug 
modification and number of 
subjects per treatment group 
None 


CLS-TA, triamcinolone acetonide injectable suspension
    Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date:  25 January 2018 
Page 76 of 79 
CONFIDENTIAL 
APPENDIX B:  Summary of Changes for Amendments 
Amendment 1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
Removed previous table 
Insert new table 
Updates to table 
None 
To determine the safety and 
performance of the SCS 
microinjector when delivering SC 
CLS-TA 
Endpoint added to capture 
microinjector exploratory 
objective 
None 
Performance of the SCS 
microinjector, evidenced by 
injection parameters (location, 
eye quadrant, needle length, 
injection completion, and product 
complaints) at each SC injection 
visit (Visits 2, 5, 8) 
Incidence of TEAEs and SAEs 
related to the SCS microinjector 
Section added for 
microinjector endpoints 
None 
Added text for subject withdrawal 
criteria 
Update withdrawal criteria 
None 
Figure 2. Study Treatment 
Schedule 
Section 6.4. Exploratory 
Objectives 
Section 7.2.5 Endpoints 
Related to SCS microinjector 
Section 8.3. Subject 
Withdrawal Criteria 
Section 8.4. Visit Procedure 
Descriptions 
PRN therapy will be aflibercept 
for all subjects, regardless of 
randomization group. 
Removed slit lamp 
ophthalmoscopy assessment post 
injections 
Identify PRN treatment 
Update to reflect common 
clinic procedures 
None 
None 


CLS-TA, triamcinolone acetonide injectable suspension
    Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date:  25 January 2018 
Page 77 of 79 
CONFIDENTIAL 
APPENDIX B:  Summary of Changes for Amendments 
Amendment 1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
Adjusted to include Avastin and 
Lucentis 
Updated section 9.4.1 title from 
Rescue Therapy Criteria to 
Supplemental Therapy Criteria 
Updated rescue to supplemental 
throughout the protocol 
Clarify treatment 
administration 
Clarify definition of rescue 
versus supplemental therapy 
None 
None 
Updated to include preparation 
for additional anti-VEGF agents 
Comparator drug 
modification 
None 
Updates throughout to clarify 
adverse events and reporting 
Clarification of reporting 
procedures 
None 
Addition of new section 
Addition of new section 
None 
Updates throughout the statistical 
analysis section 
Comparator drug 
modification 
None 
Section 9.1. Treatments to be 
Administered 
Section 9.4. Rescue Treatment 
Section 10.4 Study Drug 
Preparation 
Section 12.2. Adverse and 
Serious Adverse Events 
Section 12.2.5. Exposure In 
Utero 
Section 13. Statistical 
Considerations 
References 
Addition of references 
Comparator drug 
modification 
None 


CLS-TA, triamcinolone acetonide injectable suspension
    Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date:  25 January 2018 
Page 78 of 79 
CONFIDENTIAL 
APPENDIX B:  Summary of Changes for Amendments 
Amendment 1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
Throughout protocol 
Various formatting changes 
Replaced ‘aflibercept’ with 
‘intravitreal anti-VEGF agent’ or 
‘IVT anti-VEGF agent’ inclusive 
of LUCENTIS and AVASTIN 
Formatting updates 
Change in comparator 
agents 
None 
Appendix A 
Removed post injection slit lamp 
ophthalmoscopy assessment 
Removed serum pregnancy test at 
Visit 8 
Update to reflect common 
clinic procedures 
Urine pregnancy test will be 
done at Visit 8 
None 
None 


CLS-TA, triamcinolone acetonide injectable suspension
    Clearside Biomedical, Inc. 
CLS1003-302 
Clinical Protocol 
Version Date:  25 January 2018 
Page 79 of 79 
CONFIDENTIAL 
APPENDIX B:  Summary of Changes for Amendments 
Amendment 1.1 
Section Changed 
Previous Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on Subjects 
(Risk/Benefit) 
Section 8 Headers 
Section Header Numbers added 
for ease in navigating document 
Formatting updates 
None 
Section 12.2.4 Intensity 
It is important to distinguish 
between serious and severe AEs. 
Severity is a measure of intensity 
whereas seriousness is defined by 
the criteria under Section 
12.2.1.2. 
It is important to distinguish 
between serious and severe AEs. 
Severity is a measure of intensity 
whereas seriousness is defined by 
the criteria under Section 12.2.1. 
Section reference corrected 
None 
Section 12 Headers 
Section Header Numbers updated 
to remove duplicate 
Formatting updates 
None