Clinical trial NCT03126786
Conditions: Diabetic Macular Edema
Keywords: Diabetes Mellitus Diabetic Retinopathy Microneedle Mircoinjection Triamcinolone Choroid Choroid Injection Aflibercept Suprachoroidal Triamcinolone acetonide
Sponsor: Clearside Biomedical, Inc.
Start date: 2017-07-11; Completion date: 2018-04-17
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to evaluate the safety and efficacy of suprachoroidal CLS-TA used with intravitreal aflibercept in subjects with DME.

Detailed description:
This is a Phase 2, multicenter, randomized, double-masked, controlled, parallel-group study of 6 months duration in treatment-naïve subjects with DME. This study is projected to enroll approximately 60 subjects, randomly assigned 1:1 to one of two treatment groups.

The study design includes up to 8 clinic visits over approximately 24 weeks. Subjects will attend visits for Screening (Visit 1, Days -30 to 0); Randomization and Baseline (Visit 2, Day 0 before dosing); Dosing and Evaluation (Visit 2 after dosing to Visit 5, Day 0 through Week 12); As-needed (PRN) Dosing and Follow up (Visit 6 through Visit 7, Week 16 through Week 20), and End of Study (Visit 8, Week 24).

Arms: arm 1: Treatment will consist of IVT injection of Aflibercept followed by an SC injection of CLS-TA arm 2: Treatment will consist of IVT aflibercept injection followed by a sham SC procedure
Interventions: intervention 1: IVT aflibercept intervention 2: Sham SC intervention 3: SC CLS-TA
Intervention descriptions: intervention 1: IVT aflibercept \[2 mg/0.05 mL\] intervention 2: sham SC intervention 3: CLS-TA \[4 mg/100 μL\] SC injection

Protocol documents:
Prot_SAP_000.pdf: 
Compound Name: 
CLS-TA, triamcinolone acetonide injectable suspension 
Protocol Number: 
CLS1004-201 
IND Number: 
115683 
NCT Number:  
NCT03126786 
Protocol Title 
TYBEE: Randomized, Double Masked, Controlled Study 
Comparing the Safety and Efficacy of Suprachoroidal 
CLSTA with Intravitreal Aflibercept versus Aflibercept 
Alone in Subjects with Diabetic Macular Edema 
Sponsor: 
Clearside Biomedical, Inc. 
900 North Point Parkway, Suite 200 
Alpharetta, GA 30005 
Issue Date: 
Protocol Amendment 1 Date: 
14 April 2017 
19 January 2018 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Clinical Protocol CLS1004-201  
Project: 
1004 
Compound Number/Name:  
CLS-TA (triamcinolone acetonide injectable suspension) 
40 mg/mL 
Protocol Number: 
CLS1004-201 
IND Number: 
115683 
Phase: 
2 
Protocol Title: 
TYBEE: Randomized, Double Masked, Controlled Study 
Comparing the Safety and Efficacy of Suprachoroidal CLS-
TA with Intravitreal Aflibercept versus Aflibercept Alone in 
Subjects with Diabetic Macular Edema 
 
Sponsor: 
Clearside Biomedical, Inc. 
 
900 North Point Parkway, Suite 200 
 
Alpharetta, GA 30005 
 
Primary Medical Monitor: 
Peter Nicholas, MD 
 
Telephone: (919) 259-9521 
 
Principal Investigator: 
To be appointed before the end of the study 
Amendment 1.0 Issue Date: 
19 January 2018 
Issue Date: 
14 April 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  
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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 
19 Jan 2018 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for CLS- TA (triamcinolone acetonide 
injectable suspension) 40 mg/mL. I have read the CLS1004-201 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  
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone 
Number 
Clinical Lead, Sponsor 
Kathleen Billman 
kathleen.billman@clearsidebio.com  
678.894.0703 
Medical Monitor 
Peter Nicholas, MD 
919.259.9521 
Principal Investigator 
The Coordinating Principal Investigator will be appointed 
by the Sponsor before the end of the study.  As part of his 
or her responsibilities, the 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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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Clearside Biomedical, Inc. 
Name of Investigational Product: 
CLS-TA (triamcinolone acetonide injectable suspension) 40 mg/mL 
EYLEA® (aflibercept) Injection 
Name of Active Ingredient: 
Triamcinolone Acetonide  
Aflibercept 
Title of Study:  
Randomized, Double Masked, Controlled Study Comparing the Safety and Efficacy of 
Suprachoroidal CLS-TA with Intravitreal Aflibercept versus Aflibercept alone in Subjects with 
Diabetic Macular Edema 
Study centers:  Approximately 30 sites  
Principal Investigator: Multicenter 
Studied period (years):  
Estimated date first subject enrolled: 2Q2017 
Estimated date last subject completed: 3Q2018 
Phase of development: 2 
 
Objectives:  
The primary objective of this Phase 2 study is to compare the effects of suprachoroidal (SC) CLS-TA 
administered with intravitreal (IVT) aflibercept versus IVT aflibercept alone as measured by best 
corrected visual acuity (BCVA) change from baseline at Week 24 in subjects with treatment-naïve 
diabetic macular edema (DME) 
Secondary: 
 
To compare the effect of SC CLS-TA administered with IVT aflibercept versus IVT aflibercept 
alone in central subfield thickness (CST) as measured by change from baseline at Week 24. 
 
To compare the effect of SC CLS-TA administered with IVT aflibercept every 3 months versus 
IVT aflibercept alone as measured by the number of additional IVT aflibercept injections required over 
24 weeks through visit 5 (Week 12) and from Visit 5 (Week 12) through Visit 8 (Week 24).  
 
To evaluate monthly mean changes from baseline in BCVA as measured by ETDRS letters read 
 
To evaluate monthly mean changes from baseline in CST as measured by SD-OCT 
 
To evaluate mean monthly changes in excess retinal thickness from baseline excess retinal 
thickness in CST 
Safety: 
 
To evaluate the incidence of treatment-emergent adverse events and serious adverse events, 
grouped by organ system, relatedness to study treatment, and intensity 
 
To evaluate the effect of study therapy on intraocular pressure and on the incidence of adverse 
event 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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 
To evaluate the effect of study therapy on the incidence of and progression of potential 
cataractous changes to the lens 
Number of subjects (planned): Approximately 70 subjects 
Diagnosis and main criteria for inclusion:  
Treatment-naïve subjects diagnosed with DME  
Investigational product, dosage, and mode of administration:  
CLS-TA (triamcinolone acetonide injectable suspension) 40 mg/mL injected suprachoroidally; 
EYLEA (aflibercept) 2 mg/0.05 mL, injected intravitreally 
Reference therapy, dosage and mode of administration:  
EYLEA (aflibercept) 2 mg/0.05 mL, intravitreal injection 
Criteria for evaluation: 
Efficacy Endpoint: 
The efficacy endpoint is the mean change from baseline in BCVA using Early Treatment of Diabetic 
Retinopathy Study (ETDRS) letters read at Week 24 (Month 6). 
Secondary Endpoints: 
 
Mean change from baseline in CST at Visit 8 (Week 24) 
 
Mean monthly changes in BCVA using ETDRS letters read 
 
Mean monthly changes in excess retinal thickness from baseline excess retinal 
thickness in CST 
 
Mean number of additional intravitreal aflibercept injections administered through Visit 8 
(Week 24), through visit 5 (week 12) and from Visit 5 (week 12) through visit 8 (week 
24) 
 Number and percentage of subjects gaining ≥5, ≥10, and ≥15 ETDRS letters at Visit 8 
(Week 24) 
Safety Endpoints: 
 
Incidence of treatment-emergent adverse events and serious adverse events, grouped by organ 
system, relatedness to study treatment, and intensity 
 
Mean change from baseline in IOP at each follow-up visit 
 
Percentage of subjects exhibiting an IOP change from baseline of 6-10mm Hg, 11-15 mm Hg, 
16-20 mm Hg, and > 20 mm Hg at each visit 
 
Number/percentage of subjects requiring institution of IOP lowering medications 
 
Number/percentage of subjects experiencing an IOP ≥ 30 mm Hg 
 
Number /percentage of subjects experiencing a ≥ 10 mm increase from baseline in IOP at any 
visit 
 
Mean change in lens grading at each visit 
 
Statistical methods: 
The primary efficacy analysis comparing outcomes from the ACTIVE treatment group with 
CONTROL treatment using the mean change from baseline (Visit 2, Day 0) BCVA at Week 24 will 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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be performed using a Mixed Model for Repeated Measurements (MMRM). This model will include 
treatment (Active or Control), visit (Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 12), Visit 6 
(Week 16), Visit 7 (Week 20), and Visit 8 (Week 24) and the 2-way interactions of treatment and 
visit, and the BCVA baseline will be included as the covariate. The dependent variable is the mean 
change from baseline BCVA at each time point. Taking into account the correlation of the BCVA 
measurements at each visit, the covariance structure may be assumed to be unstructured. The two-
sided 90% confidence interval for the difference in the mean change from baseline in the ACTIVE 
and CONTROL treatment groups will be presented. The p-values for testing the treatment difference 
will also be reported based on MMRM model.  
The primary analysis will be performed on the ITT population, with a supportive analysis conducted 
on the PP analysis set. 
Treatment groups in secondary endpoints will be compared using a similar MMRM as used for the 
primary efficacy endpoint analysis, if appropriate. A descriptive analysis will be performed for all 
secondary endpoints. Additional analyses, for example, Kaplan-Meier method for time to first 
additional IVT aflibercept injection) will be added if appropriate, and these analyses will be detailed 
in the SAP and finalized before the study database lock.  
For safety endpoints, incidence of TEAEs and SAEs, grouped by organ system, relatedness to study 
drug, and intensity will be summarized. Also the incidence of changes in safety parameters including: 
IOP, slit-lamp biomicroscopy, indirect ophthalmoscopy, imaging parameters, and vital sign 
measurements will be summarized. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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 AND DEFINITIONS OF TERMS.............................12 
5. 
INTRODUCTION ......................................................................................................14 
5.1. 
Disease Background and Scientific Rationale ............................................................14 
5.2. 
Description of Investigational Product .......................................................................15 
5.3. 
Summary of Clinical Experience and Justification for Dose Selection ......................16 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................18 
6.1. 
Primary Efficacy Objective ........................................................................................18 
6.2. 
Secondary Efficacy Objectives ...................................................................................18 
6.3. 
Safety Objectives ........................................................................................................18 
7. 
INVESTIGATIONAL PLAN .....................................................................................19 
7.1. 
Overall Study Design ..................................................................................................19 
7.2. 
Endpoints ....................................................................................................................19 
7.2.1. 
Primary Efficacy Endpoint .........................................................................................19 
7.2.2. 
Secondary Efficacy Endpoints ....................................................................................20 
7.2.3. 
Safety Endpoints .........................................................................................................20 
7.3. 
Number of Subjects ....................................................................................................20 
7.4. 
Treatment Assignment ................................................................................................20 
7.5. 
Criteria for Study Termination ...................................................................................21 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................22 
8.1. 
Inclusion Criteria ........................................................................................................22 
8.2. 
Exclusion Criteria .......................................................................................................22 
8.2.1. 
Ophthalmic Exclusion Criteria ...................................................................................22 
8.2.2. 
General Exclusion Criteria .........................................................................................23 
8.3. 
Subject Withdrawal Criteria .......................................................................................24 
8.4. 
Visit Procedure Descriptions ......................................................................................24 
8.4.1. 
General Procedures .....................................................................................................24 
8.4.2. 
Re-Screening Procedures ............................................................................................25 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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8.4.3. 
Visit 1 – Screening (Day -30 to -1) ............................................................................25 
8.4.4. 
Visit 2 (Day 0) and Visit 5 (Week 12) ........................................................................26 
8.4.4.1. 
Pre-dose Procedures: Visit 2 (Day 0) and Visit 5 (Week 12) .....................................26 
8.4.4.2. 
Injection Procedures: Visit 2 (Day 0) and Visit 5 (Week 12) .....................................27 
8.4.4.3. 
Post-Dose Procedures: Visit 2 (Day 0) and Visit 5 (Week 12) ..................................27 
8.4.5. 
Visit 3 (Week 4) and Visit 4 (Week 8) .......................................................................28 
8.4.5.1. 
Injection Procedure: Visit 3 (Week 4) and Visit 4 (Week 8) .....................................28 
8.4.6. 
Visit 6 (Week 16) and Visit 7 (Week 20) ...................................................................28 
8.4.6.1. 
Injection Procedure: Visit 6 (Week 16) and Visit 7 (Week 20) .................................29 
8.4.7. 
Visit 8 (Week 24) End of Study/Early Termination ...................................................29 
8.4.8. 
Unscheduled Visits .....................................................................................................30 
9. 
TREATMENT OF SUBJECTS ..................................................................................31 
9.1. 
Treatments to be Administered ...................................................................................31 
9.2. 
Study Eye Determination ............................................................................................31 
9.3. 
Fellow Eye Treatment .................................................................................................31 
9.4. 
Additional Treatment ..................................................................................................32 
9.4.1. 
Additional Therapy Criteria ........................................................................................32 
9.4.2. 
PRN Period Treatment Criteria ..................................................................................32 
9.5. 
Concomitant Treatments .............................................................................................32 
9.6. 
Treatment Compliance ................................................................................................33 
9.7. 
Randomization and Masking ......................................................................................33 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................35 
10.1. 
Study Drug ..................................................................................................................35 
10.2. 
Study Drug Packaging and Labeling ..........................................................................35 
10.3. 
Study Drug Storage .....................................................................................................35 
10.4. 
Study Drug Preparation ..............................................................................................35 
10.5. 
Administration ............................................................................................................35 
10.6. 
Study Drug Accountability .........................................................................................36 
10.7. 
Study Drug Handling and Disposal ............................................................................36 
11. 
ASSESSMENT OF EFFICACY ................................................................................37 
11.1. 
Best Corrected Visual Acuity .....................................................................................37 
11.2. 
Central Subfield Thickness as Measured by Spectral-Domain Optical 
Coherence Tomography ..............................................................................................37 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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12. 
ASSESSMENT OF SAFETY .....................................................................................38 
12.1. 
Safety Parameters .......................................................................................................38 
12.1.1. 
Vital Signs ..................................................................................................................38 
12.1.2. 
Review of Body Systems ............................................................................................38 
12.1.3. 
Laboratory Assessments .............................................................................................38 
12.1.3.1. 
Pregnancy Screen ........................................................................................................38 
12.1.3.2. 
Ophthalmic Screening ................................................................................................38 
12.2. 
Adverse and Serious Adverse Events .........................................................................39 
12.2.1. 
Definition of Adverse Events .....................................................................................39 
12.2.1.1. 
Adverse Event .............................................................................................................39 
12.2.1.2. 
Serious Adverse Event ................................................................................................40 
12.2.2. 
Relationship to Study Drug ........................................................................................40 
12.2.3. 
Recording Adverse Events .........................................................................................40 
12.2.4. 
Intensity ......................................................................................................................40 
12.2.5. 
Reporting Adverse Events ..........................................................................................41 
12.2.6. 
Follow-up of AEs and SAEs .......................................................................................42 
13. 
STATISTICS ..............................................................................................................43 
13.1. 
Randomization ............................................................................................................43 
13.2. 
Determination of Sample Size and Level of Significance ..........................................43 
13.3. 
Subject Disposition and Demographic and Baseline Characteristics .........................43 
13.4. 
Analysis Populations ..................................................................................................43 
13.4.1. 
Safety Population ........................................................................................................43 
13.4.2. 
Intent-to-Treat Population ..........................................................................................43 
13.4.3. 
Per Protocol Population ..............................................................................................43 
13.5. 
Analysis Methods .......................................................................................................44 
13.5.1. 
Primary Efficacy Analysis ..........................................................................................44 
13.5.1.1. 
Sensitivity Analyses of Primary Efficacy Endpoint ...................................................44 
13.5.2. 
Secondary Efficacy Analysis ......................................................................................44 
13.5.2.1. 
Secondary Efficacy Endpoints ....................................................................................44 
13.5.3. 
Subgroup Analysis ......................................................................................................45 
13.5.4. 
Safety Analysis ...........................................................................................................45 
13.5.4.1. 
Extent of Exposure .....................................................................................................45 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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13.5.4.2. 
Safety Endpoints .........................................................................................................45 
13.5.5. 
Schedule of Analyses ..................................................................................................45 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................46 
14.1. 
Study Monitoring ........................................................................................................46 
14.2. 
Audits and Inspections ................................................................................................46 
14.3. 
Institutional Review Board .........................................................................................47 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................48 
16. 
ETHICS ......................................................................................................................49 
16.1. 
Ethics Review .............................................................................................................49 
16.2. 
Ethical Conduct of the Study ......................................................................................49 
16.3. 
Written Informed Consent ..........................................................................................49 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................50 
17.1. 
Inspection of Records .................................................................................................50 
17.2. 
Retention of Records ..................................................................................................50 
18. 
PUBLICATION POLICY ..........................................................................................51 
19. 
LIST OF REFERENCES ............................................................................................52 
20. 
APPENDICES ............................................................................................................54 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................12 
 
 
LIST OF FIGURES 
Figure 1: 
Anatomy of the Eye ....................................................................................................15 
Figure 2: 
Study Design ...............................................................................................................19 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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4. 
 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
AMD 
Age-related macular degeneration 
ANCOVA 
Analysis of covariance 
BCVA 
Best corrected visual acuity 
CRC 
Central reading center 
CRF 
Case report form 
CST 
Central subfield thickness 
DM 
Diabetes mellitus 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FA 
Fluorescein angiography/angiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IA 
IVT aflibercept 
ICH 
International Council for Harmonisation  
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVT 
Intravitreal 
IWRS 
Interactive web response system 
LOCF 
Last observation carried forward 
MAR 
Missing at random 
ME 
Macular edema 
MMRM 
Mixed model for repeated measurements 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Abbreviation or Specialist Term 
Explanation 
PI 
Principal Investigator 
The Investigator who leads the study conduct at an 
individual study center.  Every study center has a Principal 
Investigator. 
PP 
Per-protocol 
PRN 
Pro re nata; As needed 
RVO 
Retinal vein occlusion 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Suprachoroidal 
SCS 
Suprachoroidal space 
SD-OCT 
Spectral-domain optical coherence tomography 
TA 
Triamcinolone acetonide 
TEAE 
Treatment-emergent adverse event 
VEGF 
Vascular endothelial growth factor 
VA 
Visual acuity 
YAG 
Yttrium-Aluminum-Garnet 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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5. 
INTRODUCTION 
Clearside Biomedical, Inc., is developing a proprietary formulation of triamcinolone acetonide 
(CLS-TA) as a candidate for treating diabetic macular edema (DME) to be administered via 
suprachoroidal injection either with or without an intravitreal (IVT) anti-VEGF agent. This 
Phase 2, multicenter, randomized, masked, controlled, parallel-group study is designed to 
evaluate and compare the safety and efficacy of suprachoroidal (SC) injection of CLS-TA 
administered in combination with intravitreal aflibercept (EYLEA®; Regeneron; Tarrytown, NY) 
given on a quarterly basis in relationship to monthly intravitreal aflibercept in subjects with 
DME.  
Treatment of eye diseases using a suprachoroidal injection approach is novel; a drug can be 
precisely administered to and through the SCS using a minimally invasive injection procedure, 
and thereby have high exposure to the retina and choroid with the potential for pharmacological 
action because of high local concentration at the site of disease. Suprachoroidal injection of 
CLS-TA has been shown in animal models to distribute TA dominantly to posterior segment 
ocular tissues while limiting exposure to anterior structures in the eye, thereby providing the 
potential for efficacy and safety benefits. The purpose of this Phase 2 study is to obtain 
information on the safety and efficacy of suprachoroidal CLS-TA used with intravitreal 
aflibercept initially on quarterly basis and compare these effects to when intravitreal aflibercept 
is used alone and given monthly as monotherapy, in subjects with DME; further, a fixed dosing 
regimen for the first 12 weeks (Month 3) is followed by a protocol predefined as needed dosing 
regimen for the second 12 week portion through Week 24 (Month 6) after assigned arm 
treatment is administered at the Week 12 visit.  
5.1. 
Disease Background and Scientific Rationale 
Diabetes mellitus (DM) and diabetic retinopathy (DR) are major contributors to human 
morbidity and mortality and have a staggering impact on societal productivity. More than 1 in 5 
United States (US) health care dollars are spent on DM care and the total annual attributable cost 
for DM is well over a quarter of a trillion dollars (ADA, 2013). While the burden of DM 
continues to rise globally, recent encouraging data suggest that the prevalence of DM within the 
United States may be plateauing with approximately 50% of adults affected with frank DM 
(13%) or pre-DM (38%) (Menke, 2015). Approximately 1/3 of patients with DM in the United 
States have DR and an estimated 7% will progress to the diagnosis of DME (Ding, 2012; 
Narayan, 2003). One of the most frequent end-organ manifestations of DR is DME, which is the 
most common cause of visual loss among working-age populations (Bourne, 2014; Chen, 2010; 
Sivaprasad, 2012). 
The first validated treatment for DME, laser photocoagulation of the macula, was established by 
the Early Treatment of Diabetic Retinopathy Study (ETDRS) in the 1980s (Early Treatment 
Diabetic Retinopathy Study research group, 1985).  More recently, both IVT anti-VEGF-A and 
steroid injections have proven effective in DME management (Boyer, 2014; Campochiaro, 2012; 
Korobelnik, 2014; Nguyen, 2012; Wells, 2015) and have progressively replaced focal laser as the 
primary treatment of center-involving DME with visual acuity (VA) loss (Boyer, 2014; Brown, 
2015; Campochiaro, 2012; Elman, 2010; Korobelnik, 2014; Mitchell, 2011; Nguyen, 2012).  
Multiple large, randomized, controlled trials directly comparing focal laser with either anti-
VEGF or steroid pharmacotherapies have confirmed superior visual and anatomic outcomes with 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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VEGF blockade (Brown, 2015; Elman, 2011; Korobelnik, 2014; Mitchell, 2011). Currently, 4 
agents are approved by the US Food and Drug Administration (FDA) for the treatment of DME: 
EYLEA® (aflibercept) Injection (Regeneron), LUCENTIS® (ranibizumab injection) 
(Genentech), OZURDEX® (dexamethasone intravitreal implant) (Allergan), and ILUVIEN® 
(fluocinolone acetonide intravitreal implant) 0.19 mg (Alimera Sciences). In addition, 1 agent is 
regularly used off label, AVASTIN® (bevacizumab) (Genentech). 
Anti-VEGF IVT injections have become the overwhelming choice for first-line treatment for 
DME associated with VA loss (2015 American Society of Retina Specialists Global Trends in 
Retina Survey).  The only prospective trial directly comparing the 3 commercially available anti-
VEGF agents was recently reported by the Diabetic Retinopathy Clinical Research Network 
(DRCR.net): Protocol-T, A comparative effectiveness study of intravitreal aflibercept, 
bevacizumab and ranibizumab for DME (Wells, 2015; Well, 2016).  Protocol-T involved 660 
patients with center-involved DME and found that, regardless of medication used and despite 
nearly 20 clinical visits and approximately 15 IVT injections through 2 years, approximately 
50% of eyes demonstrated persistent DME and met criteria for macular laser as the anti-VEGF 
therapy was incompletely effective at treating the DME. Therefore, a significant clinical unmet 
need remains to optimally treat patients with DME.  
Intravitreal steroids have also proven effective for the management of DME. For example, the 
DRCR.net Protocol-I reported that, among pseudophakic eyes, IVT triamcinolone acetonide 
(TA) was as effective at improving VA as ranibizumab (Elman, 2010). No formulation of TA, by 
any route of administration, is currently approved by the FDA for the treatment of DME.  
5.2. 
Description of Investigational Product 
CLS-TA (triamcinolone acetonide injectable suspension) 40 mg/mL, is a preservative-free, 
terminally sterilized, aqueous suspension, formulated for administration into the eye. It will be 
administered as an injection of 4 mg in 100 µL into the SCS using Clearside’s proprietary SCS™ 
microinjector. The SCS is the region of the eye between the sclera and the choroid (Figure 1). 
 
Figure 1: 
Anatomy of the Eye 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Additional information regarding CLS-TA (triamcinolone acetonide injectable suspension) 
40 mg/mL, is available in the Investigator’s Brochure.  
Aflibercept IVT injection is a prescription medicine approved in the United States and Europe as 
well as other global markets. Aflibercept is approved for the treatment of patients with Wet Age-
related Macular Degeneration (AMD), ME following retinal vein occlusion (RVO), DME, and 
DR in patients with DME. Full prescribing information for aflibercept for the treatment of DME, 
the recommended dose for EYLEA intravitreal injection is 2 mg/0.05 mL administered by IVT 
injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg/0.05 mL via IVT 
injection once every 8 weeks (2 months). 
5.3. 
Summary of Clinical Experience and Justification for Dose Selection 
Triamcinolone acetonide 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 US FDA for ocular indications is 4 mg in 100 μL (TRIESENCE 
Prescribing Information, 2007). The dose of CLS-TA administered as an SC injection will be 
similar (40 mg/mL). TRIESENCE® (triamcinolone acetonide injectable suspension) 40 mg/mL, 
(Alcon) and CLS-TA contain the same active and inactive ingredients at approximately the same 
concentrations. Both formulations are preservative free, aqueous suspensions that have been 
terminally sterilized and designed for ophthalmic use.  
Clearside has completed 2 clinical trials in patients with non-infectious uveitis and 1 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 
(Goldstein, 2016). Each subject received a single SC injection of 4 mg in 100 µL TA 
(TRIESENCE). Nine of the 11 subjects in the safety analysis set (82%) completed the 26-week 
study. All subjects had at least 1 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. All subjects in the per-protocol analysis set (n=8) 
showed improvements in best corrected visual acuity (BCVA) in this study. 
The completed clinical study, CLS1001-201 (NCT02255032), was a Phase 2, randomized, 
masked, dose-controlled, safety and efficacy study in subjects with ME associated with non-
infectious uveitis. Twenty-two subjects were assigned to receive a single SC injection of CLS-
TA, either 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 
Investigator-reported increases in IOP at follow-up visits. 
The completed clinical study, CLS1003-201 (CT02303184), was a Phase 2, randomized, masked 
safety and efficacy study in subjects with ME following RVO. Forty-six subjects were randomly 
assigned 1:1 to either a suprachoroidal (SC) injection of CLS-TA administered with an 
intravitreal injection of aflibercept (combination therapy; combo; ACTIVE), or an intravitreal 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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(IVT) injection of aflibercept alone (monotherapy; mono; 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. 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. 
Clearside is conducting a phase 1/2, open-label study in subjects with DME associated with 
diabetes mellitus to study the safety, tolerability, and preliminary efficacy of CLS-TA.  
Approximately 20 subjects will be assigned in a 1:1 ratio where approximately 10 subjects will 
be enrolled into the TX Naive arm and approximately 10 subjects will be enrolled into the 
Previous TX arm. Treatment in the TX Naive arm will consist of one unilateral injection of IVT 
aflibercept in combination with one unilateral injection of SC CLS-TA in the same eye.  
Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC 
CLS-TA.  
Safety profiles have been similar in all 3 completed studies with eye pain being the most 
commonly reported AE. Additional information regarding clinical experience with TA 
administered suprachoroidally is available in the Investigator’s Brochure. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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6. 
TRIAL OBJECTIVES AND PURPOSE 
The purpose of this trial is to evaluate the safety and efficacy of suprachoroidal CLS-TA used 
with intravitreal aflibercept in subjects with DME associated with DM.  
6.1. 
Primary Efficacy Objective 
The primary objective of this Phase 2 study is to compare the effects of SC CLS-TA 
administered with IVT aflibercept versus IVT aflibercept alone as measured by BCVA change 
from baseline at Week 24 in subjects with treatment-naïve DME. 
6.2. 
Secondary Efficacy Objectives 
 To compare the effect of SC CLS-TA administered with IVT aflibercept versus IVT aflibercept 
alone in central subfield thickness (CST) as measured by change from baseline at Week 24. 
 To compare the effect of SC CLS-TA administered with IVT aflibercept every 3 months versus 
IVT aflibercept alone as measured by the number of additional IVT aflibercept injections 
required over 24 weeks through visit 5 (Week 12) and from Visit 5 (Week 12) through Visit 8 
(Week 24) 
 To evaluate monthly mean changes from baseline in BCVA as measured by ETDRS letters 
read 
 To evaluate monthly mean changes from baseline in CST as measured by SD-OCT 
 To evaluate mean monthly changes in excess retinal thickness from baseline excess retinal 
thickness in CST 
6.3. 
Safety Objectives 
 To evaluate the incidence of treatment-emergent adverse events and serious adverse events, 
grouped by organ system, relatedness to study treatment, and intensity 
 To evaluate the effect of study therapy on intraocular pressure and on the incidence of 
adverse events and initiation of therapy related to potential elevations of intraocular pressure 
 To evaluate the effect of study therapy on the incidence of and progression of potential 
cataractous changes to the lens 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 2, multicenter, randomized, double-masked, controlled, parallel-group study of 6 
months duration in treatment-naïve subjects with DME. This study is projected to enroll 
approximately 70 subjects, randomly assigned 1:1 to one of two treatment groups. 
The study design includes up to 8 clinic visits over approximately 24 weeks. Subjects will attend 
visits for Screening (Visit 1, Days -30 to 0); Randomization and Baseline (Visit 2, Day 0 before 
dosing); Dosing and Evaluation (Visit 2 after dosing to Visit 5, Day 0 through Week 12); As-
needed (PRN) Dosing and Follow-up (Visit 6 through Visit 7, Week 16 through Week 20), and 
End of Study (Visit 8, Week 24).  
PRN Dosing and Follow-up Period: 
At the conclusion of the dosing and evaluation period (Day 0 through Week 12), subjects will be 
followed for safety through Visit 8 (Week 24). Subjects will be treated, as needed (PRN), with 
aflibercept.   
 
Figure 2: 
Study Design 
 
7.2. 
Endpoints 
7.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change from baseline in BCVA ETDRS letters read at 
Week 24 (Month 6). 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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7.2.2. 
Secondary Efficacy Endpoints 
 Mean monthly changes in BCVA using ETDRS letters read  
 Mean change from baseline in CST at Visit 8 (Week 24) 
 Mean monthly changes in excess retinal thickness from baseline excess retinal thickness 
in CST 
 Mean number of additional intravitreal aflibercept injections administered through Visit 8 
(Week 24), through visit 5 (Week 12) and from Visit 5 (Week 12) through Visit 8 (Week 
24). 
 Number and percentage of subjects gaining ≥5, ≥10, and ≥15 ETDRS letters at Visit 8 
(Week 24) 
7.2.3. 
Safety Endpoints 
 Incidence of treatment-emergent adverse events (TEAE) and SAEs, grouped by organ 
system, relatedness to study treatment, and intensity 
 Mean change from baseline in IOP at each follow-up visit 
 Percentage of subjects exhibiting an IOP change from baseline of 6-10 mmHg, 11-15 
mmHg, 16-20 mmHg, and > 20 mmHg at each visit. 
 Number/percentage of subjects requiring institution of IOP lowering medications 
 Number/percentage of subjects experiencing an IOP ≥ 30 mm Hg 
 Number /percentage of subjects experiencing a ≥ 10 mm increase from baseline in IOP at 
any visit 
 Mean change in lens grading at each visit 
7.3. 
Number of Subjects 
Approximately 70 subjects with DME who are naïve to treatment will be enrolled into 1 of 2 
treatment groups.  
7.4. 
Treatment Assignment 
Subjects enrolled in this study will present with DME in the study eye. After Screening (Day -30 
to Day -1) and Baseline assessments on Day 0, subjects will be randomly assigned 1:1 to 1 of 2 
treatment groups.  
 
TREATMENT ARM 
Number of 
Subjects 
ACTIVE: IVT aflibercept [2 mg (0.05 mL)] + SC CLS-TA [40 
mg/mL] 
~35 
CONTROL: Intravitreal aflibercept [2 mg (0.05 mL)] + sham SC 
~35 
 
After randomization, subjects will receive treatment as follows: 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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ACTIVE: IVT aflibercept (2 mg/0.05 mL) + SC CLS-TA (40 mg/mL) 
Subjects randomly assigned at Baseline to the ACTIVE group will receive an IVT injection of 
aflibercept followed by an SC injection of CLS-TA at Visit 2 (Day 0) and Visit 5 (Week 12).  
Subjects will receive sham IVT injections at Weeks 4 and 8 to maintain masking.  
 
CONTROL: IVT aflibercept (2 mg/0.05 mL) injection + sham SC procedure 
Subjects randomly assigned at Baseline to the CONTROL group will receive monthly IVT 
aflibercept injections beginning at Visit 2 (Day 0) and continuing through Visit 5 (Week 12). To 
maintain masking, subjects in the CONTROL group will also receive a sham SC procedure on 
Visit 2 (Day 0) and Visit 5 (Week 12). 
All subjects will return for monthly (every 4 weeks) visits through Visit 8 (Week 24) to assess 
safety and efficacy. Beginning at Week 4 and applying also to Week 8, if any of the additional 
criteria (Section 9.4.1) are met in the study eye, IVT aflibercept should be administered. 
Beginning at Week 16 (Visit 6) continuing through Week 20 (Visit 7), if any of the additional 
criteria (Section 9.4.1) are met in the study eye, all subjects will be treated PRN with IVT 
aflibercept.  
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 the 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. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Inclusion Criteria 
An individual is eligible for participation in this study if all of the following criteria are met: 
1. Has a clinical diagnosis of type 1 or type 2 DM 
2. 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 
An eye is eligible for participation in the study if the following criteria are met: 
3. Has DME with central involvement (> 300 µm in the central subfield on spectral-domain 
optical coherence tomography [SD-OCT], confirmed by the CRC) in the study eye 
4. Has an ETDRS BCVA score of ≥ 20 letters read and ≤ 70 letters read in the study eye 
5. Is naïve to local pharmacologic treatment for DME in the study eye 
8.2. 
Exclusion Criteria 
An individual is ineligible for participation in this study if any of the following criteria are met: 
8.2.1. 
Ophthalmic Exclusion Criteria 
1. Has evidence of or history of ME with etiology other than DME in a study eye 
2. Has a history of panretinal photocoagulation or focal laser photocoagulation in the study 
eye within 90 days of screening 
3. 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 
4. Has a history of any previous ophthalmic surgeries in a study eye within 90 days of 
screening 
5. Has High Risk Proliferative Diabetic Retinopathy in a study eye, for whom enrollment 
into the study, in the Principal Investigator’s opinion, would put the eye at undue risk for 
vision loss  
6. Has a history of any previous treatment in the study eye with an ocular corticosteroid 
implant (eg, ILUVIEN, OZURDEX, RETISERT) 
7. Has a history of pars plana vitrectomy or a history of cataract extraction or Yttrium-
Aluminum-Garnet (YAG) laser capsulotomy within the 3 months before treatment at 
Visit 2 (Day 0)  
8. 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) 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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9. Has evidence of or a history of any 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)  
10. Has scarring from laser photocoagulation in the study eye that would compromise VA; or 
scarring or abnormality from other macular condition, in the investigator’s medical 
judgement, would limit BCVA (such as an epiretinal membrane or macular hole) 
11. 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) 
12. 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 
13. Has a history of glaucoma or optic nerve head change consistent with glaucoma damage; 
or ocular hypertension in the study eye requiring more than one medication  
14. Has ocular hypertension in the study eye requiring more than one medication to maintain 
IOP < 22 mm Hg at baseline 
15. Has a history of glaucoma surgery (filtration surgery/trabeculectomy or tube shunt) in the 
study eye; has a history of laser trabeculoplasty in the study eye 
16. 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 meets the following criteria: 
17. Is a female 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 1 of 
the acceptable birth control methods if she becomes sexually active 
18. 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.   
19. Has had a myocardial infarction, other acute cardiac event requiring hospitalization, 
stroke, transient ischemic attack, or treatment for acute congestive heart failure within 
1 month before enrollment 
20. Has received systemic steroid, anti-VEGF, or pro-VEGF treatment within 4 months 
before Visit 2 (Day 0) or anticipated use during the study 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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21. Has a likely need for hospitalization or surgery within the study period, including planned 
elective surgery or hospitalization 
22. Has a known hypersensitivity to any component of the formulation of TA, aflibercept, 
fluorescein, topical anesthetics, or the antiseptic used to prepare the eye for injection 
according to the Investigator’s standard practice 
23. Has uncontrolled blood pressure (defined as >180/110 mmHg systolic/diastolic, resting) 
at Visit 2 (Day 0) 
a. Uncontrolled BP at screening may be treated before Visit 2 
24. Has a history of chronic renal failure requiring dialysis or kidney transplant 
25. Has required the initiation of intensive (a pump or daily injections) insulin treatment for 
poor glycemic control within the 4 months prior to randomization or it is anticipated that 
such treatment may be needed during the next 4 months. 
26. 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. 
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. 
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 up to 8 study visits over approximately 24 weeks. All ocular 
assessments at Visit 1 (Screening) and Study Exit or Visit 8 (Week 24) will be performed on 
both eyes. Intraocular pressure will be assessed in both eyes at all visits. Data for all other ocular 
assessments at all other visits (Visits 2 to 7) 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 aflibercept (according to the Prescribing Information) in the study eye, followed 
by either a sham SC injection or a SC injection of CLS-TA in the study eye, depending on the 
group assigned at randomization. Subjects will be assessed after injection for safety. 
Subjects in the CONTROL group will receive IVT injections of aflibercept at Visits 2 through 5. 
Subjects in the ACTIVE group will receive a sham IVT injection at Visits 3 and 4 (Weeks 4 and 
8) to ensure masking is maintained. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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After the completion of the dosing period (12 weeks), subjects will enter the PRN dosing period 
of the study to be observed and assessed for PRN treatment beginning at Visit 6 (Week 16) 
through Visit 7 (Week 20). Evaluation for PRN dosing will be similarly conducted at Visit 8 
(Week 24) and the requirement whether criteria for intravitreal aflibercept are met will be 
recorded. Since the Week 24 visit is the exit visit, whether or not intravitreal anti-VEGF agent is 
administered is left to the discretion of the Investigator.  
Subjects in the CONTROL group will receive sham SC injections at Week 12 to maintain 
masking. Additional safety follow-up visits will occur approximately every 4 weeks through 
Month 6 (Visit 3 through Visit 8; Weeks 4, 8, 12, 16, 20, and 24). 
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 and blood pressure measurements 
6. Collect blood and urine for central laboratory tests, including serum for pregnancy test in 
females of childbearing potential, before fluorescein angiogram (FA)  
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. Select study eye/confirm study eye 
10. Perform photographic evaluations:* 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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a. FA  
b. Fundus photos 
11. Schedule subject to return for Visit 2, Baseline Evaluation  
NOTE: *All images (SD-OCT, fundus photographs, and FA) should be uploaded to the central 
reading center (CRC).  
8.4.4. 
Visit 2 (Day 0) and Visit 5 (Week 12) 
Visit 2 must occur within 30 days of Visit 1 (Screening) and may only occur once the 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 (Day 0) and Visit 5 (Week 12) 
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 and blood pressure 
4. Collect urine for pregnancy test in females of childbearing potential 
5. Perform ophthalmic assessments on the study eye only:  
a. ETDRS BCVA 
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP (both eyes) 
d. Dilated indirect ophthalmoscopy 
e. SD-OCT  
6. Review eligibility criteria (Visit 2 only)  
a. If subject continues to be eligible for randomization based on results from 
screening and Visit 2 assessments in Section 8.2.3, subjects will be randomly 
assigned via the interactive web response system (IWRS) to receive either an IVT 
injection of aflibercept in conjunction with either sham or active SC injection of 
CLS-TA in the study eye. 
7. Log onto the IWRS and randomly assign subject to treatment 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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8.4.4.2. 
Injection Procedures: Visit 2 (Day 0) and Visit 5 (Week 12) 
The injection 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 IWRS 
3. Prepare eye for injection according to the Investigator’s standard practice 
4. The UNMASKED injecting Investigator should perform IVT injection of aflibercept, SC 
injection of CLS-TA, and all sham procedures to the study eye 
8.4.4.2.1. IVT Injection of aflibercept: 
1. Prepare study eye for IVT injection of aflibercept according to the Investigator’s standard 
practice 
2. Administer aflibercept IVT injection according to the Prescribing Information. The sites 
of the IVT injection and the SC injection should be approximately 2 or more clock hours 
apart. 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 (study eye) 
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 
2. Administer SC injection of 100 μL of CLS-TA or sham procedure approximately 2 or 
more clock hours from the site of the IVT injection 
3. Assess study eye by indirect ophthalmoscopy immediately after the injection 
8.4.4.3. 
Post-Dose Procedures: Visit 2 (Day 0) and Visit 5 (Week 12) 
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. Slit-lamp biomicroscopy  
b. Evaluate IOP 10 to 30 minutes after injection  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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i. If IOP remains elevated, subject must remain on site until IOP is under 
control according to the Investigator’s best medical judgment. 
ii. If IOP is < 30 mmHg, the subject may leave the clinic 
c. Indirect ophthalmoscopy 
4. Schedule time for subject to return for next visit  
8.4.5. 
Visit 3 (Week 4) and Visit 4 (Week 8) 
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 and blood pressure measurements 
4. Perform ophthalmic assessments on the study eye only, unless otherwise specified:  
a. ETDRS BCVA 
b. Slit-lamp biomicroscopy, including dilated lens grading 
c. IOP (both eyes) 
d. Dilated indirect ophthalmoscopy 
e. SD-OCT  
8.4.5.1. 
Injection Procedure: Visit 3 (Week 4) and Visit 4 (Week 8)  
1. Confirm the study eye 
2. Retrieve study drug kit number assigned by IWRS 
3. Prepare eye for injection according to the Investigator’s standard practice 
4. The UNMASKED injecting Investigator should administer IVT injection of aflibercept 
OR sham IVT procedure to the study eye. (All subjects who meet PRN criteria will 
receive IVT aflibercept regardless of the arm to which they are assigned).  
5. Assess study eye by indirect ophthalmoscopy immediately after the injection 
6. Measure IOP after injection (study eye) 
7. Schedule time for subject to return for next visit  
8.4.6. 
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 and blood pressure measurements 
4. Perform ophthalmic assessments on the study eye only, unless otherwise specified:  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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a. ETDRS BCVA 
b. Slit-lamp biomicroscopy, including dilated lens grading 
c. IOP (both eyes) 
d. Dilated indirect ophthalmoscopy 
e. SD-OCT  
8.4.6.1. 
Injection Procedure: Visit 6 (Week 16) and Visit 7 (Week 20)  
1. If treatment is required, confirm the study eye 
2. Retrieve aflibercept 
3. Prepare eye for injection according to the Investigator’s standard practice 
4. The UNMASKED injecting Investigator should administer IVT injection of aflibercept. 
(All subjects who meet PRN criteria will receive IVT aflibercept regardless of the arm to 
which they are assigned).  
5. Assess study eye by indirect ophthalmoscopy immediately after the injection 
6. Measure IOP after injection (study eye) 
7. Schedule time for subject to return for next visit  
8.4.7. 
Visit 8 (Week 24) End of Study/Early Termination 
Visit 8 is the final study visit. Subjects who terminate early should complete all Visit 8 
assessments.  
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform resting heart rate and blood pressure measurements 
4. Collect blood and urine for central laboratory tests, including serum for pregnancy test in 
females of childbearing potential, before fluorescein angiogram (FA)  
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. Perform photographic evaluations: 
a. FA  
b. Fundus photograph  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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8.4.8. 
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.  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Treatments to be Administered 
Subjects will be assigned to 1 of 2 treatment groups in the study based upon randomization 
assignment.  
Treatment in the ACTIVE group will consist of 2 unilateral SC injections of 40 mg/mL of CLS-
TA administered 12 weeks apart (Visits 2 and 5), in conjunction with 2 unilateral injections of 
IVT aflibercept to the study eye.  Subjects in the ACTIVE group will also receive sham IVT 
procedures to maintain masking at visits where the SC CLS-TA injection is not being 
administered (Visits 3 and 4).  
Treatment in the CONTROL group of the study will consist of 4 unilateral IVT injections of 
aflibercept administered 4 weeks apart (Visits 2 through 5) in conjunction with 2 sham SC 
procedures administered 12 weeks apart (Visits 2 and 5) in the study eye.  
Subjects will be assigned to either of the following groups:  
1. ACTIVE: IVT aflibercept [2 mg (0.05 mL)] + SC CLS-TA [40 mg/mL] 
2. CONTROL: IVT aflibercept [2 mg (0.05 mL)] + SC sham procedure 
Approximately 70 subjects will be randomly assigned in a 1:1 ratio where approximately 35 
subjects will be assigned to the ACTIVE group and approximately 35 subjects will be assigned 
to the CONTROL 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.  
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 aflibercept, 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. 
The eye that is not designated as the study eye will be denoted as the fellow eye. 
9.3. 
Fellow Eye Treatment 
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).  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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. 
Additional Therapy Criteria 
Beginning at Week 4 (Visit 3) and applying also to Week 8 (Visit 4), if any of the following 
criteria are met in a study eye, IVT aflibercept should be administered. These evaluations will be 
carried out by the masked investigator for all subjects in the study, regardless of initial treatment 
arm assignment. 
 Macular edema (ME), defined as intraretinal or subretinal 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. 
9.4.2. 
PRN Period Treatment Criteria 
During the PRN dosing period (Visits 6 through 7 [Weeks 16 through 20]), treatments based on 
the criteria defined above in 9.4.1 may be administered using IVT aflibercept. The study arms 
will remain masked and additional dosing is limited to the criteria above. The frequency of 
treatment is at the Investigator’s discretion during this period. All subjects will continue to be 
assessed for safety during the PRN dosing 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 are prohibited at any time during the study: 
 Increases to topical ophthalmic non-steroidal anti-inflammatory drugs in the study eye  
 Any corticosteroid implant (e.g. 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 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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 Systemic anti-angiogenic drugs (anti-VEGF) including, for example, bevacizumab 
 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 DME or DR 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 rescue criteria. Subjects will not be 
discontinued from the study because of initiation of or change in a prohibited medication or 
treatment. 
9.6. 
Treatment Compliance 
Study drug will be administered only 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 by 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 IWRS. 
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.  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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 
case of unmasking, the site will notify the IRB and Sponsor/designee; follow-up training may be 
required. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
CLS-TA (triamcinolone acetonide injectable suspension) 40 mg/mL, 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 SCHOTT TopLyo® single-use vial with a rubber 
stopper and an aluminum seal. 
Additional information regarding CLS-TA is available in the Investigator’s Brochure. 
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 for “Investigational Use only”. 
Commercially available aflibercept, 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 and 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. 
Aflibercept should be stored according to the approved label. 
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 aflibercept will be performed according to the approved label. 
10.5. 
Administration 
CLS-TA will be administered as an SC injection of 4 mg in 100 µL. 
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.  
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 aflibercept will be according to the approved label. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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 with the actual quantity of study drug kits 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 
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. 
ASSESSMENT OF EFFICACY 
For additional information on an assessment, see the Investigative Site File. 
11.1. 
Best Corrected Visual Acuity  
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. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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12. 
ASSESSMENT OF SAFETY 
For additional information on an assessment, see the Investigative Site File. 
12.1. 
Safety Parameters 
12.1.1. 
Vital Signs 
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. 
12.1.2. 
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 examination may be performed by any medical doctor 
or legally qualified personnel according to local laws/regulations. 
12.1.3. 
Laboratory Assessments 
Non-fasting clinical laboratory tests will be performed at Visits 1 and 8. These laboratory tests 
include serum chemistry, hematology, and urinalysis and are to rule out any underlying disease 
that may exclude the subject from participation. 
12.1.3.1. Pregnancy Screen 
Pregnancy tests will be performed on all females of childbearing potential. Serum or urine 
pregnancy tests are acceptable and will be performed at Visits 1, 2, 5 and 8.  
12.1.3.2. Ophthalmic Screening 
12.1.3.2.1. Intraocular Pressure  
Intraocular pressure will be measured in both eyes by applanation tonometery and results will be 
recorded in mm Hg. 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 for all 
pre-injection and non-injection measurements throughout the subject’s study participation. At 
any visit where both IVT aflibercept/sham and SC CLS-TA/sham injections are to be 
administered, IOP will be measured 3 times: before IVT aflibercept injection, after IVT 
aflibercept 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. 
12.1.3.2.2. 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. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Slit lamp examination of the iris is to rule out neovascularization of the iris (NVI). 
12.1.3.2.3. Cataract Lens Grading  
If an abnormal finding of cataract is noted during the slit-lamp examination, the cataract should 
be graded using a standardized scale for nuclear opalescence, cortical opacity, and posterior 
subcapsular opacity. Graders must verify training on the grading procedures. 
12.1.3.2.4. Indirect Ophthalmoscopy  
Indirect ophthalmoscopy should be performed according to the Investigator’s standard procedure 
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, and absence of neovascularization.  
12.1.3.2.5. 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 
registered and photographers certified for the imaging procedures. De-identified images will be 
uploaded to the CRC.  
12.1.3.2.6. 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. 
12.2. 
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 includes any laboratory value that is 
considered clinically significant by the Investigator or that requires additional testing or 
additional therapy. 
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 by Clearside. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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 1 
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 1 of the outcomes listed above. 
All SAEs that occur after any subject has been enrolled, before treatment, during treatment, or 
during study participation, whether or not they are related to the study, must be recorded on 
forms provided by Clearside. 
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 (Unrelated or Related).  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 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 (that are considered 
clinically significant by the Investigator or that requires additional testing or additional therapy) 
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. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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 
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. An AE of severe intensity 
may not be considered serious. 
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. 
12.2.5. 
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 1 business day 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 1 business day of receipt. The information should be recorded 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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. 
Clearside Biomedical is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Principal Investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all unexpected, serious, drug-related 
events (7/15-Day Safety Reports) that occur during the clinical study. Each site is responsible for 
notifying its IRB/IEC of these additional SAEs. 
12.2.6. 
Follow-up of AEs and SAEs 
All AEs and SAEs reported during study conduct must be followed until resolution, the 
condition stabilizes, 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.   
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 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.  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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13. 
STATISTICS 
A detailed statistical analysis plan (SAP) 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.  
13.1. 
Randomization 
There will be approximately 70 subjects randomly assigned 1:1 to 1 of 2 treatment groups. 
Assignment of subjects to treatment groups will be performed via the IWRS. 
13.2. 
Determination of Sample Size and Level of Significance 
The sample size of the study is based on the primary variable of the study: the change from 
baseline mean BCVA at Week 24.  
 
The sample size was determined such that the difference in visual acuity between the ACTIVE 
treatment group (SC CLS-TA administrated with IVT aflibercept) and CONTROL treatment 
group (IVT aflibercept) could be estimated within +/- five ETDRS letters. Week 24 data from the 
Eylea prescribing information were used to estimate the variance. The pooled standard deviation 
was 9.17 letters. With 28 subjects per arm, a two-sided 90% confidence interval with a distance 
from the mean difference to the limits (half of interval width) will be less than 5 letters.   
 
To account for a drop-out rate of approximately 5%, at least 30 patients per group will be 
randomized. In the event that the withdrawal rate exceeds 5%, additional patients may be 
enrolled to ensure that at least 58 patients complete the Week 12 study period. The sample size 
calculation was performed using NCSS PASS (NCSS LLC, Kaysville, Utah). 
13.3. 
Subject Disposition and Demographic and Baseline Characteristics 
Subject disposition and demographic and baseline characteristics will be summarized 
descriptively by treatment group and overall. 
13.4. 
Analysis Populations 
13.4.1. 
Safety Population 
The Safety Population will include all randomly assigned subjects who are administered at least 
1 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 who have received at 
least 1 study treatment. Subjects will be analyzed as originally allocated after randomization. The 
ITT Population will be used for efficacy analyses.  
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 and who complete the Week 12 visit. The rules for determining 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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. 
13.5. 
Analysis Methods 
Efficacy and safety endpoints are provided in Section 7.2.  
13.5.1. 
Primary Efficacy Analysis 
The primary analysis is to compare the outcome from the ACTIVE treatment group with the 
CONTROL treatment, using the mean change from baseline (Visit 2, Day 0) BCVA at Week 24. 
The primary efficacy analysis comparing ACTIVE with CONTROL on the mean change from 
baseline (Visit 2, Day 0) BCVA at Week 12 will be performed using a Mixed Model for 
Repeated Measurements (MMRM). This model will include treatment (ACTIVE or CONTROL), 
visit (Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12), Visit 6 (Week 16), Visit 7 
(Week 20) and Visit 8 (Week 24), and the 2-way interactions of treatment and visit, and the 
BCVA baseline will be included as the covariate. The dependent variable is the mean change 
from baseline BCVA at each time point. Taking into account the correlation of the BCVA 
measurements at each visit, the covariance structure may be assumed to be unstructured. The 
two-sided 90% confidence interval for the difference in the mean change from baseline in the 
ACTIVE and CONTROL treatment group will be presented.  The p-values for testing the 
treatment difference will also be reported based on MMRM.  
The primary analysis will be performed on the ITT population, with a supportive analysis 
conducted on the PP analysis set. 
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 an analysis of covariance (ANCOVA) model in the ITT population. These 
sensitivity analyses will be detailed in the SAP and finalized before the study database lock. 
13.5.2. 
Secondary Efficacy Analysis 
13.5.2.1. Secondary Efficacy Endpoints 
 Mean monthly changes in BCVA using ETDRS letters read 
 Mean change from baseline in CST at Visit 8 (Week 24) 
 Mean monthly changes in excess retinal thickness from baseline excess retinal 
thickness in CST 
 Mean number of additional intravitreal aflibercept injections administered through 
Visit 8 (Week 24) through visit 5 (Week 12) and from Visit 5 (Week 12) through 
Visit 8 (Week 24). 
A descriptive analysis will also be performed for all secondary endpoints. Additional analysis 
(eg: Kaplan-Meier method for time to first additional IVT aflibercept injection) will be added 
appropriately and these analyses will be detailed in the SAP and finalized before the study 
database lock. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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13.5.3. 
Subgroup Analysis 
No subgroup analyses are planned. 
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. 
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 sign measurements  
13.5.5. 
Schedule of Analyses 
Additional safety and descriptive efficacy data will be collected through Week 24. Treatment 
codes will be broken at Month 6. Investigators, subjects, and study personnel who have contact 
with the Investigators or subjects will remain masked throughout the study.  
Procedure for Accounting for Missing, Unused, or Spurious Data 
Any missing, unused, or spurious data will be noted in the final clinical study report. 
For the primary efficacy endpoint analysis, missing data will be compensated for by the 
statistical analysis model. Specifically, an MMRM analysis will be used for the primary efficacy 
analysis. The MMRM analysis uses all available data to compensate for missing values and is 
generally recommended for handling missing data (Siddiqui, 2009) when the missing mechanism 
is Missing at Random (MAR).  
For the ANCOVA model, the Last Observation Carried Forward (LOCF) method will be used if 
visits are missed in the ITT Population.  
For the intent to treat population, all data points will be set to missing after a subject’s receipt of 
a rescue medication only following the Week 12 evaluation and treatment when both groups will 
be dosed PRN.  
No imputation is planned for safety data. Methodology for handling missing or partial dates will 
be addressed in the SAP. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Clearside 
Biomedical, Inc., will visit the investigational study site to: 
 Determine the adequacy of the facilities 
 Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of 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 representative will have regular 
contacts with the investigational 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. 
 Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to Clearside Biomedical, Inc., and those SAEs that met criteria for 
reporting have been forwarded to the IRB 
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 IEC or an 
IRB may visit the site to perform audits or inspections, including source data verification.  The 
purpose of a Clearside Biomedical, Inc., 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 (GCP) guidelines of the International Council for 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator should 
contact Clearside Biomedical, Inc., immediately if contacted by a regulatory agency about an 
inspection. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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14.3. 
Institutional Review Board 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study, including the subject consent form and 
recruitment materials, must be maintained by the 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 
To ensure compliance with GCP and all applicable regulatory requirements, Clearside 
Biomedical, Inc., may conduct a quality assurance audit.  
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 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 ICH/GCP and applicable regulatory 
requirements. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center 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., or designee will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow 
the monitor to inspect the drug storage area, 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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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  
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19. 
LIST OF REFERENCES 
2015 American Society of Retina Specialists Global Trends in Retina Survey 
https://www.asrs.org/content/documents/2015_global_trends_in_retina_survey_-
_for_website.pdf. 
American Diabetes Association (ADA). Economic costs of diabetes in the U.S. in 2012. Diabetes 
Care. 2013;36(4):1033-1046. 
Bourne RR, Jonas JB, Flaxman SR, et al. Prevalence and causes of vision loss in high-income 
countries and in Eastern and Central Europe: 1990-2010. Br J Ophthalmol. 2014;98(5):629-638. 
Boyer DS, Yoon YH, Belfort R, Jr., 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, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular 
edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 
2015;122(10):2044-2052. 
Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide 
vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. 
Ophthalmology. 2012;119(10):2125-2132. 
Chen E, Looman M, Laouri M, et al. Burden of illness of diabetic macular edema: literature 
review. Current Medical Research and Opinion. 2010;26(7):1587-1597. 
Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, 
bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-
1203. 
Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, et al. Randomized trial 
evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for 
diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077 e1035. 
Ding J, Wong TY.  Current epidemiology of diabetic retinopathy and diabetic macular edema.  
Curr Diab Rep 2012;12:346-54. 
Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year follow-up of ranibizumab plus prompt or 
deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 
2011;118(4):609-614. 
EYLEA® [Prescribing Information]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc., 2016. 
EYLEA® [Summary of Product Characteristics]. Berlin, Germany: Bayer Pharma AG, 2012 
Goldstein DA, Do D, Noronha G, Kissner JM, Srivastava SK, Nguyen, QD. Suprachoroidal 
Corticosteroid Administration: A novel route for local treatment of noninfectious uveitis. Transl 
Vis Sci Technol. 2016;5(6):14. 
Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular 
edema. Ophthalmology. 2014;121(11):2247-2254. 
Menke A, Casagrande S, Geiss L, et al. Prevalence of and Trends in Diabetes Among Adults in 
the United States, 1988-2012. JAMA. 2015;314(10):1021-1029. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab 
monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. 
Ophthalmology. 2011;118(4):615-625. 
Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for diabetes mellitus in the United 
States. JAMA 2003;290:1884-90. 
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results 
from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801. 
Siddiqui O, Hung OMJ, O’Neill R. MMRM Vs. LOCF: A comprehensive comparison based on 
simulation study and 25 NDA datasets. J Biopharm Statistics. 2009;19:227–246. 
Sivaprasad S, Gupta B, Crosby-Nwaobi R, et al. Prevalence of diabetic retinopathy in various 
ethnic groups: a worldwide perspective. Survey of Ophthalmology. 2012;57(4):347-370. 
Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study 
report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 
1985;103(12):1796-1806. 
TRIESENCE® [Prescribing Information]. Fort Worth, TX: Alcon Laboratories, Inc., 2016. 
Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab for 
Diabetic Macular Edema: Two-year results from a comparative effectiveness randomized clinical 
trial. Ophthalmology.2016;123(6):1351-1359. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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20. 
APPENDICES


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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APPENDIX A:  Study Design and Schedule of Assessments, Visits 1-5 
Visit # 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
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 
Assessments 
 
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 
● 
● 
 
● 
 
● 
 
● 
 
Fluorescein Angiogram 
● 
 
 
 
 
 
 
 
 
Fundus Photos 
● 
 
 
 
 
 
 
 
 
IWRS/Randomize 
 
● 
 
 
 
 
 
 
 
IVT Aflibercept or Sham Injection3, 
 
● 
 
● 
 
● 
 
● 
 
SC CLS-TA or Sham Injection3,4 
 
● 
 
 
 
 
 
● 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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APPENDIX A:  Study Design and Schedule of Assessments, Visits 6-8 
Visit # 
Visit 6 
Visit 7 
Visit 8  
Visit Type 
PRN Dosing and Follow Up 
End of Study 
Visit Window 
Week 16 
Day 112 ± 5 
Week 20 
Day 140 ± 5 
Week 24 
Day 168 ± 5 
Assessments 
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 
● 
 
● 
 
 
Fluorescein Angiogram 
 
 
 
 
● 
Fundus Photos 
 
 
 
 
● 
IWRS/Randomize 
 
 
 
 
 
IVT Aflibercept or Sham Injection3, 
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. 
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 aflibercept injection (once IOP is < 30 mmHg). 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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APPENDIX B: Summary of Changes 
Amendment 1 
Section Changed 
 
 
2.0 
6.1 
 
 
 
 
 
 
 
 
 
2.0 
6.2 
 
 
 
 
 
 
 
 
 
Previous Protocol  
(Changed From) 
 
The primary objective of this 
Phase 2 study is to compare the 
effects of SC CLS-TA 
administered with IVT 
aflibercept versus IVT 
aflibercept alone as measured 
by BCVA change from baseline 
at Week 12 in subjects with 
treatment-naïve DME 
 
 
 
To compare the effect of SC 
CLS-TA administered with IVT 
aflibercept versus IVT 
aflibercept alone in central 
subfield thickness (CST) as 
measured by change from 
baseline at Week 12. 
 
 
 
 
 
Modified Protocol  
(Changed To) 
 
The primary objective of this 
Phase 2 study is to compare the 
effects of SC CLS-TA 
administered with IVT 
aflibercept versus IVT 
aflibercept alone as measured 
by BCVA change from baseline 
at Week 24 in subjects with 
treatment-naïve DME  
 
 
 
Deleted text  
 
 
 
 
 
 
 
 
 
 
Reason for Change 
 
 
Six months is a more 
appropriate evaluation 
time frame for this 
therapeutic approach in 
patients with diabetic 
macular edema; thus the 
3-month primary 
endpoint has been 
changed to a 6-month 
primary endpoint 
 
 
Six months is a more 
appropriate evaluation 
time frame for this 
therapeutic approach in 
patients with diabetic 
macular edema; thus the 
3-month primary 
endpoint has been 
changed to a 6-month 
primary endpoint 
 
 
 
Impact on Subjects 
(Risk/Benefit) 
 
None 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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APPENDIX B: Summary of Changes 
Amendment 1 
2.0 
6.2 
 
 
 
 
 
 
 
 
 
2.0 
6.2 
 
 
 
 
 
 
2.0 
6.2 
 
 
 
 
 
To compare the effect of SC 
CLS-TA administered with IVT 
aflibercept versus IVT 
aflibercept alone as measured 
by BCVA at Week 24  
 
 
 
 
 
 
Additional text added to 
original protocol  
 
 
 
 
 
 
 
To compare the effect of SC 
CLS-TA administered with IVT 
aflibercept every 3 months 
versus IVT aflibercept alone as 
measured by the number of IVT 
aflibercept injections required 
over 24 weeks 
 
Deleted Text  
 
 
 
 
 
 
 
 
 
To evaluate mean monthly 
changes in excess retinal 
thickness from baseline excess 
retinal thickness in CST 
 
 
 
 
 
To compare the effect of SC 
CLS-TA administered with IVT 
aflibercept every 3 months 
versus IVT aflibercept alone as 
measured by the number of IVT 
aflibercept injections required 
over 24 weeks through visit 5 
(week 12) and from Visit 5 
(week 12) through Visit 8 (week 
24) 
Six months is a more 
appropriate evaluation 
time frame for this 
therapeutic approach in 
patients with diabetic 
macular edema; thus the 
3-month primary 
endpoint has been 
changed to a 6-month 
primary endpoint 
 
 
Additional endpoint to 
describe change in 
retinal thickness 
 
 
 
 
 
 
Endpoint clarification 
for analysis to expand 
the endpoint to include 
analysis both at Week 
12 and week 24 
 
 
 
None  
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 None 
 
 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-201 
 
Clinical Protocol 
19 January 2018 
Amendment 1.0  
 
Page 59 of 63  
 
Confidential 
 
APPENDIX B: Summary of Changes 
Amendment 1 
2.0 
7.1 
7.3 
13.1 
 
 
 
 
 
7.4  
9.1 
13.2 
 
 
 
 
 
 
7.2.1 
 
 
 
 
 
 
 
This study is projected to enroll 
approximately 60 subjects, 
randomly assigned 1:1 to one of 
two treatment groups. 
 
 
 
 
 
Approximately 60 subjects will 
be randomly assigned in a 1:1 
ratio where approximately 30 
subjects will be assigned to the 
ACTIVE group and 
approximately 30 subjects will 
be assigned to the CONTROL 
group.  
 
 
 
The primary efficacy endpoint 
is the mean change from 
baseline in BCVA ETDRS 
letters read at Week 12 (Month 
3). 
 
 
 
 
This study is projected to enroll 
approximately 70 subjects, 
randomly assigned 1:1 to one of 
two treatment groups. 
 
 
 
 
 
Approximately 70 subjects will 
be randomly assigned in a 1:1 
ratio where approximately 35 
subjects will be assigned to the 
ACTIVE group and 
approximately 35 subjects will 
be assigned to the CONTROL 
group.  
 
 
 
The primary efficacy endpoint 
is the mean change from 
baseline in BCVA ETDRS 
letters read at Week 24 (Month 
6). 
 
 
 
Updated to reflect 
enrollment metrics to 
allow for a slightly 
larger population which 
will produce more 
robust evaluation of the 
therapy and to reflect 
the enrollment metrics  
 
 
Updated to reflect 
enrollment metrics to 
allow for a slightly 
larger population which 
will produce more 
robust evaluation of the 
therapy and to reflect 
the enrollment metrics  
 
 
 
Six months is a more 
appropriate evaluation 
time frame for this 
therapeutic approach in 
patients with diabetic 
macular edema; thus the 
3-month primary 
endpoint has been 
changed to a 6-month 
primary endpoint 
None  
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-201 
 
Clinical Protocol 
19 January 2018 
Amendment 1.0  
 
Page 60 of 63  
 
Confidential 
 
APPENDIX B: Summary of Changes 
Amendment 1 
2.0 
7.2.2 
13.5.2.1 
 
 
 
 
 
2.0 
7.2.2 
13.5.2.1  
 
 
 
 
 
 
2.0 
7.2.2 
 
 
 
 
 
 
 
Mean change from baseline in 
CST at Visit 5 (Week 12) and 
mean change from baseline in 
BCVA at Visit 8 (week 24)  
 
 
 
 
Additional text added 
 
 
 
 
 
 
 
 
Number and percentage of 
subjects gaining ≥5, ≥10, and 
≥15 ETDRS letters at Visit 5 
(Week 12) 
 
 
 
 
 
 
Deleted text 
 
 
 
 
 
 
Mean monthly changes in 
BCVA using ETDRS letters 
read and mean monthly changes 
in excess retinal thickness from 
baseline excess retinal thickness 
in CST 
 
 
 
 
Number and percentage of 
subjects gaining ≥5, ≥10, and 
≥15 ETDRS letters at Visit 8 
(Week 24) 
 
 
 
 
 
 
To maintain 
consistency with 
change to 6-month 
primary endpoint 
 
 
 
 
Additional endpoint to 
evaluate endpoints 
monthly 
 
 
 
 
 
 
Six months is a more 
appropriate evaluation 
time frame for this 
therapeutic approach in 
patients with diabetic 
macular edema; thus the 
3-month primary 
endpoint has been 
changed to a 6-month 
primary endpoint 
 
None 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
None  
 
 
 
 
 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-201 
 
Clinical Protocol 
19 January 2018 
Amendment 1.0  
 
Page 61 of 63  
 
Confidential 
 
APPENDIX B: Summary of Changes 
Amendment 1 
2.0 
7.2.2 
 
 
 
 
 
12.1.3.2.4 
 
 
 
 
 
 
 
13.2 
 
 
 
 
 
 
 
 
2.0 
13.2 
Mean number of additional 
intravitreal aflibercept 
injections administered through 
visit 8 (week 24)  
 
 
 
 
Indirect ophthalmoscopy should 
be performed according to the 
Investigator’s standard 
procedure.   
 
 
 
 
The sample size of the study is 
based on the primary variable of 
the study: the change from 
baseline mean BCVA at Week 
12 
 
 
 
 
 
With 28 subjects per arm, a 
two-sided 95% confidence 
interval with a distance from the 
Mean number of additional 
intravitreal aflibercept 
injections administered through 
visit 8 (week 24), through visit 
5 (week 12) and from Visit 5 
(week 12) through visit 8 (week 
24) 
 
 
Indirect ophthalmoscopy should 
be performed according to the 
Investigator’s standard practice. 
 
 
 
 
The sample size of the study is 
based on the primary variable of 
the study: the change from 
baseline mean BCVA at Week 
24 
 
 
 
 
 
With 28 subjects per arm, a 
two-sided 90% confidence 
interval with a distance from the 
Endpoint clarification 
for analysis to expand 
the endpoint to include 
analysis both at week 
12 and 24 
 
 
 
 
Clarified procedure vs. 
standard of practice 
 
       
 
 
Six months is a more 
appropriate evaluation 
time frame for this 
therapeutic approach in 
patients with diabetic 
macular edema; thus the 
3-month primary 
endpoint has been 
changed to a 6-month 
primary endpoint. 
 
 
Wider confidence 
intervals allow for 
None  
 
 
 
 
 
 
 
None 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
None 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-201 
 
Clinical Protocol 
19 January 2018 
Amendment 1.0  
 
Page 62 of 63  
 
Confidential 
 
APPENDIX B: Summary of Changes 
Amendment 1 
13.5.1 
 
 
 
 
 
 
 
2.0 
13.5.1 
 
 
 
 
 
 
2.0 
13.5.1 
 
 
 
 
 
 
 
 
mean difference to the limits 
(half of interval width) will be 
less than 5 letters.   
 
 
 
The primary analysis is to 
compare the outcome from the 
ACTIVE treatment group with 
the CONTROL treatment, using 
the mean change from baseline 
(Visit 2, Day 0) BCVA at Week 
12. 
 
 
 
This model will include 
treatment (ACTIVE or 
CONTROL), visit (Visit 3 
(Week 4), Visit 4 (Week 8), and 
Visit 5 (Week 12), and the 2-
way interactions of treatment 
and visit, and the BCVA 
baseline will be included as the 
covariate 
 
 
 
 
mean difference to the limits 
(half of interval width) will be 
less than 5 letters.   
 
 
 
The primary analysis is to 
compare the outcome from the 
ACTIVE treatment group with 
the CONTROL treatment, using 
the mean change from baseline 
(Visit 2, Day 0) BCVA at Week 
24. 
 
 
 
This model will include 
treatment (ACTIVE or 
CONTROL), visit (Visit 3 
(Week 4), Visit 4 (Week 8), and 
Visit 5 (Week 12), Visit 6 
(Week 16), Visit 7 (Week 20) 
and Visit 8 (Week 24), and the 
2-way interactions of treatment 
and visit, and the BCVA 
baseline will be included as the 
covariate 
 
 
evaluation of trends in 
this Phase 2 study 
 
 
 
 
To maintain 
consistency with 
change to 6-month 
primary endpoint 
 
 
 
 
 
Six months is a more 
appropriate evaluation 
time frame for this 
therapeutic approach in 
patients with diabetic 
macular edema; thus the 
3-month primary 
endpoint has been 
changed to a 6-month 
primary endpoint. 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-201 
 
Clinical Protocol 
19 January 2018 
Amendment 1.0  
 
Page 63 of 63  
 
Confidential 
 
APPENDIX B: Summary of Changes 
Amendment 1 
 
 
13.5.5 
 
 
 
 
13.5.5 
 
 
 
  
Treatment codes will be broken 
at Month 3 
 
 
 
No adjustment for the analysis 
at Week 24 is required because 
the final analysis of efficacy is 
at Month 3 and data from all 
subsequent visits will be 
descriptive only.  
 
 
 
 
 
 
Treatment codes will be broken 
at Month 6 
 
 
 
Deleted text 
 
 
 
To maintain 
consistency with 
change to 6-month 
primary endpoint 
 
To maintain 
consistency with 
change to 6-month 
primary endpoint 
None 
 
 
 
 
None  
 
 
 


Clearside Biomedical, Inc. - Document Approval 
CLS-CLIN-000195 v2.0:  CLS1004-201 Study TYBEE Protocol Amendment 1
Approved:  22 Jan 2018 - CLS-CLIN-000195 v2.0
Clinical
Approved
This electronic signature indicates agreement by the
individual that, with respect to their area of
responsibility, the document is acceptable.
Jennifer Kissner
Vice President, Clinical Development
22-Jan-2018 20:37:59 GMT+0000
Electronic signatures are certified as the legally
binding equivalent of a traditional handwritten
signature.
Regulatory
Approved
This electronic signature indicates agreement by the
individual that, with respect to their area of
responsibility, the document is acceptable.
Barbara Bauschka
Senior Director, Regulatory Operations
22-Jan-2018 22:13:43 GMT+0000
Electronic signatures are certified as the legally
binding equivalent of a traditional handwritten
signature.