Clinical trial NCT02949024
Conditions: Diabetic Macular Edema
Keywords: Diabetes mellitus Diabetic retinopathy Microneedle Microinjection Triamcinolone Choroid Choroid Injection Aflibercept Suprachoroidal Triamcinolone acetonide
Sponsor: Clearside Biomedical, Inc.
Start date: 2016-11-10; Completion date: 2017-10-17
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to demonstrate the safety and tolerability of suprachoroidal CLS-TA alone or in combination with intravitreal aflibercept in subjects with diabetic macular edema associated with diabetes mellitus.

Detailed description:
This is a Phase 1/2, multicenter, open-label study in subject with DME associated with diabetes mellitus.

Subjects will be screened and if eligible, will be assigned to study arm at the Baseline Visit (Visit 1, Day 0).

Following the Baseline Visit, subjects will participate in six monthly follow-up visits (Visit 2-7; Weeks 4-24) for safety and efficacy assessments and to determine whether additional therapy is needed based upon pre-defined criteria.

Arms: arm 1: 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. arm 2: Treatment in the Previous TX arm of the study will consist of one unilateral injection of SC CLS-TA.
Interventions: intervention 1: IVT Aflibercept intervention 2: SC CLS-TA
Intervention descriptions: intervention 1: IVT aflibercept \[2 mg (50 µL)\] intervention 2: \[4 mg (100 µL)\]

Protocol documents:
Prot_SAP_000.pdf: 
Compound Name: 
CLS-TA, triamcinolone acetonide injectable suspension 
Protocol Number: 
CLS1004-101 
IND Number: 
115683 
NCT Number:  
NCT02949024 
Protocol Title 
Open-label study of the safety and efficacy of 
suprachoroidal CLS-TA alone or in combination with 
intravitreal aflibercept for the treatment of diabetic macular 
edema 
Sponsor: 
Clearside Biomedical, Inc. 
900 North Point Parkway, Suite 200 
Alpharetta, GA 30005 
Issue Date: 
Protocol Amendment 1 Date: 
10 October 2016 
23 June 2017 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
June 23, 2017 
Page 1 of 52 
CONFIDENTIAL 
 
 
Clinical Protocol CLS1004-101  
Project: 
1004 
Compound Number/Name: 
CLS-TA, triamcinolone acetonide injectable suspension 
Protocol Number: 
CLS1004-101 
Phase: 
1/2 
IND Number: 
115683 
Protocol Title: 
OPEN-LABEL STUDY OF THE SAFETY AND 
EFFICACY OF SUPRACHOROIDAL CLS-TA 
ALONE OR IN COMBINATION WITH 
INTRAVITREAL AFLIBERCEPT FOR THE 
TREATMENT OF DIABETIC MACULAR EDEMA 
Sponsor: 
Clearside Biomedical, Inc. 
 
1220 Old Alpharetta Rd., Suite #300 
 
Alpharetta, GA  30005 
 
Study Principal Investigator: 
Charles C. Wykoff, MD, PhD 
 
Telephone: (713) 524-3434  
 
 
  
 
 
 
 
Protocol Amendment 1 Date: 
23 June 2017 
Original Protocol Issue Date: 
10 October 2016 
 
  
 
 
____                                                
 
 
 
 
 
 
 
 
 
 
 
 
Jennifer M Kissner, PhD  
 
 
 
 
 
 
 
 
 
 
Date 
Vice President, Clinical Development 
Clearside Biomedical, Inc 
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  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 2 of 52 
CONFIDENTIAL 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for CLS-TA.  I have read the CLS1004-101 
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  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 3 of 52 
CONFIDENTIAL 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Telephone Number 
Clinical Study Leader 
Kathleen Billman 
678.894.0703 
Site Coordinating Leader 
Cassie Cone 
713.394.7537              
Responsible Physician 
24-Hour emergency contact 
Charles Wykoff, MD, PhD 
713.524.3434              
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 4 of 52 
CONFIDENTIAL 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Clearside Biomedical, Inc. 
Name of Investigational Product: 
CLS-TA, triamcinolone acetonide injectable suspension  
Aflibercept 
Name of Active Ingredient: 
Triamcinolone Acetonide  
Aflibercept 
Title of Study:  
CLS1004-101: Open-Label Study of the Safety and Efficacy of Suprachoroidal CLS-TA Alone or in 
Combination with Intravitreal Aflibercept for the Treatment of Diabetic Macular Edema  
Study center(s): Multi-Center; approximately 3 US clinical sites 
Principal Investigator: Charles Wykoff 
Studied period: 6 Month Duration 
Estimated date first patient enrolled: 3Q2016 
Estimated date last patient completed: 2Q2017 
Phase of development:  
Phase 1/2 
Objectives:  
Primary: To demonstrate the safety and tolerability of suprachoroidal CLS-TA alone or in 
combination with intravitreal aflibercept in subjects with diabetic macular edema associated 
with diabetes mellitus 
Secondary:   
 To demonstrate the preliminary efficacy of suprachoroidal CLS-TA in eyes 
previously treated for diabetic macular edema  
 To demonstrate the preliminary efficacy of suprachoroidal CLS-TA in combination 
with intravitreal aflibercept in treatment naïve diabetic macular edema eyes 
Number of patients (planned): approximately 20 
Diagnosis and main criteria for inclusion:  
Treatment naïve or non-naïve patients diagnosed with diabetic macular edema  
Investigational product, dosage and mode of administration:  
CLS-TA, triamcinolone acetonide injectable suspension, 4 mg in 100 µL, suprachoroidal injection; 
EYLEA® (aflibercept) Injection, 2 mg in 50 µL, intravitreal injection 
Reference therapy, dosage and mode of administration: None 
Criteria for evaluation: 
Safety:   
 
Incidence of treatment-emergent adverse events 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 5 of 52 
CONFIDENTIAL 
 
Observed and change from baseline intraocular pressure 
Efficacy:  
 
Mean change from baseline in central subfield thickness  
 
Mean change from baseline in ETDRS best-corrected visual acuity  
 
Mean number of suprachoroidal injections of CLS-TA administered over 6 months 
Exploratory:  
 
Scleral thickness   
 
Suprachoroidal space visualization 
 
Statistical methods: 
The observations and change from baseline will be summarized descriptively at each visit. 
Descriptive statistics include n, mean, median, minimum and maximum values. 
Re-Treatment Criteria: 
Re-treatment will be assessed monthly starting at Month 2. Any subject who meets the following 
criteria should be treated for his/her DME: 
 
CSF > 320 µm AND not improved by at least 20% from either of the previous two visits 
[10% for CSF > 500 µm], (OR) 
 
Loss of 10 or more letters due to DME from either of the previous two visits  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 6 of 52 
CONFIDENTIAL 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................6 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................11 
5. 
INTRODUCTION ......................................................................................................12 
5.1. 
Disease Background ...................................................................................................12 
5.2. 
Scientific Rationale .....................................................................................................12 
5.3. 
Description of Investigational Product .......................................................................12 
5.4. 
Summary of Clinical Experience and Justification for Route of 
Administration and Dose Selection ............................................................................13 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................15 
6.1. 
Primary Objective .......................................................................................................15 
6.2. 
Secondary Objectives .................................................................................................15 
7. 
INVESTIGATIONAL PLAN .....................................................................................16 
7.1. 
Overall Study Design ..................................................................................................16 
7.2. 
Endpoints ....................................................................................................................16 
7.2.1. 
Safety Endpoints .........................................................................................................16 
7.2.2. 
Efficacy Endpoints ......................................................................................................16 
7.2.3. 
Exploratory Endpoint ..................................................................................................16 
7.3. 
Number of Subjects ....................................................................................................16 
7.4. 
Treatment Assignment ................................................................................................16 
7.5. 
Criteria for Study Termination ...................................................................................17 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................18 
8.1. 
Subject Inclusion Criteria ...........................................................................................18 
8.2. 
Subject Exclusion Criteria ..........................................................................................18 
8.2.1. 
Ophthalmic Exclusion Criteria ...................................................................................18 
8.2.2. 
General Exclusion Criteria .........................................................................................19 
8.3. 
Subject Withdrawal Criteria .......................................................................................19 
8.4. 
Procedures ...................................................................................................................20 
8.4.1. 
Screening/Baseline - Visit 1 (Day 0) ..........................................................................20 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 7 of 52 
CONFIDENTIAL 
8.4.1.1. 
IVT injection of aflibercept (TX Naive arm only) .....................................................21 
8.4.1.2. 
SC Injection of CLS-TA (Both study arms) ...............................................................21 
8.4.1.3. 
Post-Dose Procedures .................................................................................................21 
8.4.2. 
Visit 2 – Month 1 (Day 30 ±3) ...................................................................................22 
8.4.3. 
Follow-up Procedures: Visit 3 [Month 2 (Day 60 ±3)]; Visit 4 [Month 3 
(Day 90 ±3)]; Visit 5 [Month 4 (Day 120 ±3)]; Visit 6 [Month 5 (Day 150 
±3)] .............................................................................................................................22 
8.4.3.1. 
SC Injection of CLS-TA (Both study arms) ...............................................................22 
8.4.3.2. 
Post-Dose Procedures .................................................................................................23 
8.4.4. 
Visit 7 – [Month 6 (Day 180 ±3)] End of Study Visit or Early Termination 
Visit .............................................................................................................................23 
8.4.5. 
Unscheduled Visits .....................................................................................................23 
8.4.6. 
Anterior Segment SD-OCT ........................................................................................24 
9. 
TREATMENT OF SUBJECTS ..................................................................................25 
9.1. 
Description of Study Treatments ................................................................................25 
9.2. 
Study Eye Determination ............................................................................................25 
9.3. 
Fellow Eye Treatment .................................................................................................25 
9.4. 
Re-Treatment Criteria .................................................................................................25 
9.5. 
Concomitant Medications ...........................................................................................26 
9.6. 
Treatment Compliance ................................................................................................26 
9.7. 
Randomization and Masking ......................................................................................26 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................27 
10.1. 
Study Drug ..................................................................................................................27 
10.2. 
Study Drug Packaging and Labeling ..........................................................................27 
10.3. 
Study Drug Storage .....................................................................................................27 
10.4. 
Study Drug Preparation ..............................................................................................27 
10.5. 
Administration ............................................................................................................27 
10.6. 
Study Drug Accountability .........................................................................................28 
10.7. 
Study Drug Handling and Disposal ............................................................................28 
11. 
ASSESSMENT OF EFFICACY ................................................................................29 
11.1. 
Best Corrected Visual Acuity .....................................................................................29 
11.2. 
Central Subfield Thickness .........................................................................................29 
12. 
ASSESSMENT OF SAFETY .....................................................................................30 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 8 of 52 
CONFIDENTIAL 
12.1. 
Safety Parameters .......................................................................................................30 
12.1.1. 
Intraocular Pressure ....................................................................................................30 
12.1.2. 
Biomicroscopy ............................................................................................................30 
12.1.3. 
Indirect Ophthalmoscopy ............................................................................................30 
12.1.4. 
Fluorescein Angiography ............................................................................................30 
12.1.5. 
Fundus Photography ...................................................................................................30 
12.1.6. 
Heart Rate and Blood Pressure ...................................................................................30 
12.1.6.1. 
Laboratory Tests .........................................................................................................31 
12.2. 
Adverse and Serious Adverse Events .........................................................................31 
12.2.1. 
Definition of Adverse Events .....................................................................................31 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................31 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................31 
12.3. 
Relationship to Study Drug ........................................................................................32 
12.4. 
Recording Adverse Events .........................................................................................32 
12.5. 
Reporting Adverse Events ..........................................................................................33 
13. 
STATISTICS ..............................................................................................................34 
13.1. 
Population to be Studied .............................................................................................34 
13.2. 
Study Populations .......................................................................................................34 
13.3. 
Analysis ......................................................................................................................34 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................35 
14.1. 
Study Monitoring ........................................................................................................35 
14.2. 
Audits and Inspections ................................................................................................35 
14.3. 
Institutional Review Board (IRB) ...............................................................................36 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................37 
16. 
ETHICS ......................................................................................................................38 
16.1. 
Ethics Review .............................................................................................................38 
16.2. 
Ethical Conduct of the Study ......................................................................................38 
16.3. 
Written Informed Consent ..........................................................................................38 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................39 
17.1. 
Inspection of Records .................................................................................................39 
17.2. 
Retention of Records ..................................................................................................39 
18. 
PUBLICATION POLICY ..........................................................................................40 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 9 of 52 
CONFIDENTIAL 
19. 
LIST OF REFERENCES ............................................................................................41 
20. 
APPENDICES ............................................................................................................43 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 10 of 52 
CONFIDENTIAL 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................11 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 11 of 52 
CONFIDENTIAL 
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 
BCVA 
Best corrected visual acuity 
CLS-TA 
Clearside triamcinolone acetonide 
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 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IVT 
Intravitreal 
OAE 
Other significant adverse event 
OCT-A 
Optical coherence tomography - angiography 
PI 
Principal Investigator 
The investigator who leads the study conduct at an 
individual study center.  Every study center has a principal 
investigator. 
SAE 
Serious adverse event 
SC / SCS 
Suprachoroidal / Suprachoroidal space 
SD-OCT 
Spectral domain optical coherence tomography 
TX 
Treatment 
VEGF 
Vascular endothelial growth factor 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 12 of 52 
CONFIDENTIAL 
5. 
INTRODUCTION 
5.1. 
Disease Background 
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 
US health care dollars are spent on DM care and our total annual attributable cost for DM is well 
over a quarter of a trillion dollars1. While globally the burden of DM continues to rise, recent 
encouraging data suggest that the prevalence of DM within the USA may be plateauing with 
approximately 50% of our adults affected with frank DM (13%) or pre-DM (38%)2. One of the 
most frequent end-organ manifestations of DR is diabetic macular edema (DME), the most 
common cause of visual loss among working-age populations.3-5  
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.6 More recently, both 
intravitreal anti-vascular endothelial growth factor-A (VEGF) and steroid injections have proven 
effective in DME management7-11 and have progressively replaced focal laser as the primary 
treatment of center-involving DME with visual acuity loss.7, 12-17  Multiple large, randomized, 
controlled trials directly comparing focal laser with either anti-VEGF or steroid 
pharmacotherapies have confirmed superior visual and anatomic outcomes with VEGF 
blockade.7, 13, 17, 18 Currently 4 agents are approved by the Food and Drug Administration for the 
treatment of DME: aflibercept (Eylea®, Regeneron), ranibizumab (Lucentis®, Genentech), 
dexamethasone (Ozurdex®, Allegan), fluocinolone acetonide (Iluvien®, Alimera), and one agent 
is regularly used off label, bevacizumab (Avastin®, Genentech). 
5.2. 
Scientific Rationale 
Anti-VEGF intravitreal injections have become the overwhelming choice for first line treatment 
of DME causing visual acuity loss19.  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.20, 21 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 intravitreal injections through 2 years, a majority 
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, intravitreal triamcinolone 
acetonide was as effective at improving visual acuity as ranibizumab16. No formulation of 
triamcinolone acetonide is currently FDA approved for the treatment of DME.  
5.3. 
Description of Investigational Product  
CLS-TA, triamcinolone acetonide injectable suspension, is a preservative-free, terminally 
sterilized, aqueous suspension, formulated for administration into the eye. It will be administered 
as a single suprachoroidal injection of 4 mg in 100 microliters (L) using Clearside’s proprietary 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 13 of 52 
CONFIDENTIAL 
SCS™ microinjector. The suprachoroidal space (SCS) is the region of the eye between the sclera 
and the choroid (Figure 1).  
Figure 1: 
Anatomy of the Eye 
  
Additional information regarding CLS-TA, triamcinolone acetonide injectable suspension, is 
available in the Clinical Investigator’s Brochure.  
Aflibercept (EYLEA®) is a Food and Drug Administration (FDA) approved prescription 
medicine. Full prescribing information for aflibercept in the treatment of diabetic macular edema 
involves injection of 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks for the 
first 5 injections followed by once every 8 weeks. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125387s043lbl.pdf.  
5.4. 
Summary of Clinical Experience and Justification for Route of 
Administration and Dose Selection 
Triamcinolone acetonide (TA) has been used safely and effectively in human ocular therapeutics 
to treat conditions involving inflammation in the eye, for over 50 years. The initial recommended 
dose of the TA formulation approved by the FDA for ocular indications is 4 mg in 100 μL 
(TRIESENCE®). The dose of CLS-TA administered as a single suprachoroidal injection will be 
the same (4 mg in 100 μL). TRIESENCE® and CLS-TA contain the same active and inactive 
ingredients at approximately the same concentrations. Both formulations are aqueous injectable 
suspensions that have been terminally sterilized and designed for ophthalmic use.  
Clearside is developing CLS-TA, a proprietary TA formulation for the treatment of non-
infectious uveitis by suprachoroidal administration and has completed 2 clinical trials in patients 
with non-infectious uveitis and one clinical trial in patients with retinal vein occlusion. 
The completed clinical study, CLS1001-101, was a Phase 1/2, open-label, safety and tolerability 
study in subjects with intermediate-, posterior-, or pan- non-infectious uveitis. Each subject 
received a single suprachoroidal injection of 4 mg in 100 µL TA (Triesence). Nine (9) of the 11 
subject subjects in the safety analysis set (82%) completed the 26-week study. All subjects had at 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 14 of 52 
CONFIDENTIAL 
least one AE, with a total of 37 AEs reported. One unrelated serious adverse event (pulmonary 
emboli; SAE) occurred. No deaths were reported. No significant increases in IOP were reported. 
The most commonly reported AE, eye pain, was reported in 4 subjects.  
The completed clinical study, CLS1001-201, was a Phase 2, randomized, masked safety and 
efficacy study in subjects with macular edema associated with non-infectious uveitis. Twenty-
two subjects were randomized to either a single suprachoroidal injection of CLS-TA, 4 mg in 
100 µL or 0.8 mg in 100 µL. Subjects in the 4.0 mg treatment arm were observed to have a mean 
reduction in central subfield of thickness (CST) of 164 microns (p=0.002) when measured from 
baseline at 2 months; further, a mean improvement in best corrected visual acuity (BCVA) with a 
gain of 9.2 letters when measured from baseline at 2 months was also seen. No subjects 
discontinued due to an adverse event and there were no investigator-reported increases in IOP at 
follow-up visits. 
The completed clinical study, CLS1003-201, was a Phase 2, randomized, masked safety and 
efficacy study in subjects with macular edema following RVO. Forty-six subjects were 
randomized 1:1 to either suprachoroidal injection of CLS-TA administered in conjunction with 
an intravitreal injection of aflibercept (ACTIVE), or an intravitreal injection of aflibercept alone 
(CONTROL). Subjects were evaluated over the three month study period with monthly visits; 
additional intravitreal aflibercept treatments were determined using as needed (PRN) criteria that 
included the presence of central retinal fluid or losses in visual acuity. Since a key goal of the 
study was to determine if suprachoroidal CLS-TA affected the requirement for additional 
treatment when administered along with intravitreal aflibercept, a count of the requirement for 
additional intravitreal aflibercept injections over the 3-month trial served as the primary outcome 
measure. The study met the primary endpoint with sixty percent fewer additional IVT aflibercept 
injections (p=0.013) required in the ACTIVE group receiving the combination of SC CLS-TA 
and IVT aflibercept compared with subjects in the CONTROL arm. In terms of secondary 
endpoints, mean improvements from baseline in BCVA were 16, 20, and 19 ETDRS letters in 
the ACTIVE group and 11, 12, and 11 letters in the CONTROL group at Months 1, 2, and 3 
respectively. Subjects were observed to have a mean reduction in CST of 446 µm in the 
ACTIVE (combination) group, and a 405 µm reduction in the CONTROL group when measured 
from Baseline at Month 1. Further, the approximately 450 µm reduction in CST in the ACTIVE 
(combination) group was maintained through the 3 months of the study while the CONTROL 
group showed only approximately 350 µm reductions in CST at both months 2 and 3. No 
subjects discontinued due to an AE and no SAEs were reported. A total of 4 subjects in the 
active group reported AEs pertaining to elevated IOP:  2 events each of ocular hypertension and 
IOP increase. All events were mild or moderate in intensity and considered to be related to study 
drug.  
Safety profiles have been similar in all three studies with eye pain being the most commonly 
reported AE. Additional information regarding clinical experience with TA administered to the 
SCS, is available in the Investigator’s Brochure. 
The current trial aims to evaluate the safety, tolerability and preliminary efficacy of CLS-TA 
with or without intravitreal aflibercept for the treatment of eyes with DME.  
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 15 of 52 
CONFIDENTIAL 
6. 
TRIAL OBJECTIVES AND PURPOSE 
The purpose of this trial is to evaluate the safety and preliminary efficacy of suprachoroidal 
CLS-TA with or without intravitreal aflibercept in subjects with DME associated with diabetes 
mellitus. 
6.1. 
Primary Objective 
The primary objective of this trial is to demonstrate the safety and tolerability of suprachoroidal 
CLS-TA alone or in combination with intravitreal aflibercept in subjects with diabetic macular 
edema associated with diabetes mellitus 
6.2. 
Secondary Objectives 
 To demonstrate the preliminary efficacy of suprachoroidal CLS-TA in eyes previously 
treated for diabetic macular edema  
 To demonstrate the preliminary efficacy of suprachoroidal CLS-TA in combination with 
intravitreal aflibercept in treatment naïve diabetic macular edema eyes 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 16 of 52 
CONFIDENTIAL 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 1/2, multicenter, open-label study in subjects with DME associated with diabetes 
mellitus. 
Subjects will be screened and if eligible, will be assigned to a study arm at the Baseline Visit 
(Visit 1, Day 0).  
Following the Baseline Visit, subjects will participate in six monthly follow-up visits (Visit 2-7; 
Weeks 4-24) for safety and efficacy assessments and to determine whether additional therapy is 
needed based upon predefined criteria elaborated in this protocol. 
See Appendix A for the Schedule of Events. 
7.2. 
Endpoints 
7.2.1. 
Safety Endpoints 
 Incidence of treatment-emergent adverse events (TEAE) and serious adverse events 
(SAEs), grouped by organ system, relatedness to study treatment and severity 
 Mean change from baseline in intraocular pressure at each follow-up visit 
7.2.2. 
Efficacy Endpoints 
 Mean change from baseline in central subfield thickness at each follow-up visit  
 Mean change from baseline in ETDRS best-corrected visual acuity at each follow-up visit 
 Mean number of suprachoroidal injections of CLS-TA administered over 6 months 
 
7.2.3. 
Exploratory Endpoint 
 Scleral thickness 
 Suprachoroidal space visualization 
 
7.3. 
Number of Subjects 
Approximately 20 subjects with DME will be enrolled into one of two treatment arms. 
7.4. 
Treatment Assignment 
Eligible subjects will be evaluated for previous treatment for DME in the study eye. Those 
subjects who have never received treatment in the study eye for DME or whose DME treatment 
in the study was more than 1 year prior to the screening date, at the PI’s discretion, will be 
enrolled into the TX Naïve study arm. Those subjects who have received treatment for DME in 
the study eye within the last 12 months, will be enrolled into the Previous TX study arm as 
described below: 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
June 23, 2017 
Page 17 of 52 
CONFIDENTIAL 
 
TREATMENT ARM 
Number of 
Subjects 
TX Naïve: IVT aflibercept [2 mg (50 µL)] + SC CLS-TA [4 mg (100 µL)] 
~10 
Previous TX: SC CLS-TA [4 mg (100 µL)] 
~10 
 
TX Naïve arm: an IVT injection of aflibercept [2 mg (50 µL)] followed by a suprachoroidal 
injection of CLS-TA, triamcinolone acetonide injectable suspension [4 mg (100 µL)] 
Previous TX ARM: a suprachoroidal injection of CLS-TA, triamcinolone acetonide injectable 
solution [4 mg (100 µL)] 
Subjects stratified into either of these 2 arms will be re-treated only with a suprachoroidal 
injection of CLS-TA starting at Month 2 (Visit 3; Week 8) if any retreatment criterion is met. 
7.5. 
Criteria for Study Termination 
The study or parts of the study may be discontinued by the Sponsor, or at the recommendation of 
an Investigator after consultation with Sponsor, at any time.   
If the clinical study is prematurely terminated or suspended, the Sponsor will inform the 
Investigators and the regulatory authorities of the termination/suspension and the reason(s) for 
the termination/suspension. The Investigator should promptly notify the IRB of the termination 
or suspension and of the reasons. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 18 of 52 
CONFIDENTIAL 
 
 
 
 
 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The targeted study population is men or women 18 years and older with DME associated with 
diabetes mellitus 
8.1. 
Subject Inclusion Criteria 
A subject must meet the following criteria to be eligible for inclusion in this study: 
1. Men or women ≥ 18 years of age with type 1 or type 2 diabetes mellitus 
2. DME with central involvement (> 320 µm in the central subfield on SD-OCT) in the study 
eye 
3. ETDRS BCVA letter score of 83 to 14, inclusive (Snellen equivalent of 20/25 to 20/500) 
in the study eye 
4. Understands the language of the informed consent; willing and able to provide written 
informed consent prior to any study procedures; willing to comply with the instructions 
and attend all scheduled study visits  
8.2. 
Subject 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. Evidence of DME due to any cause other than diabetes mellitus in the study eye 
2. Panretinal photocoagulation or focal laser photocoagulation in the study eye within 90 days 
of screening 
3. Intraocular pressure ≥ 22 mmHg or uncontrolled glaucoma (open angle or angle closure) 
in the study eye 
4. History of any previous ophthalmic surgeries in the study eye within 90 days of screening 
5. High Risk Proliferative Diabetic Retinopathy in the 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. Any previous treatment in the study eye with ILUVIEN implant 
7. Previous treatment for DME in the study eye (TX Naïve arm only); treatment in the study 
eye for DME greater than 1 year prior to screening can be considered as treatment naïve, 
at the principal investigator’s discretion 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 19 of 52 
CONFIDENTIAL 
 
 
 
 
 
8. Subjects previously treated for DME cannot have been treated in the study eye with an 
intravitreal injection of anti-VEGF or periocular corticosteroids within 90 days prior to 
screening (Previous TX arm only) 
9. Subjects previously treated for DME cannot have been treated in the study eye with 
intraocular corticosteroids within 6 months prior to screening (Previous TX arm only) 
8.2.2. 
General Exclusion Criteria 
10. Known hypersensitivity to any component of the CLS-TA, fluorescein, or topical 
anesthetic  
11. Uncontrolled blood pressure (defined as > 180/110 mm Hg systolic/diastolic, while 
seated) 
12. If female, the subject must be non-pregnant, non-lactating and not planning a pregnancy. 
Females of childbearing potential must agree to use an acceptable method of contraception 
throughout participation in this study. Acceptable methods of contraception include double 
barrier methods (condom with spermicide or diaphragm with spermicide), hormonal 
methods (oral contraceptives, implantable, transdermal, or injectable contraceptives), or an 
intrauterine contraceptive device with a documented failure rate of less than 1% per year. 
Abstinence may be considered an acceptable method of contraception at the discretion of 
the investigator, but the subject must agree to use one of the acceptable birth control 
methods if she becomes sexually active. 
13. Currently enrolled in an investigational drug or device study or has used an investigational 
drug or device within the last 30 days 
8.3. 
Subject Withdrawal Criteria 
A subject has the right to withdraw from the study at any time, for any reason and without 
repercussion. The investigator has the right to withdraw a subject from the study in the event of 
an intercurrent illness, need for treatment in the study eye that is beyond what is designated in 
the protocol, adverse event (AE), treatment failure, protocol violation, cure, and for 
administrative, or other reasons. 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. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 20 of 52 
CONFIDENTIAL 
 
 
 
 
 
8.4. 
Procedures 
The study will consist of up to 7 study visits over approximately 6 months. Subjects are expected 
to attend all study visits. All ocular assessments will be performed on both eyes for all study 
visits. Subjects will be screened for entry and randomized/treated at Visit 1. At Visit 1 subjects 
will receive either a single, unilateral suprachoroidal injection of CLS-TA or an intravitreal 
injection of aflibercept followed by a suprachoroidal injection of CLS-TA. Subjects will be 
assessed post injection for safety. Additional safety follow-up visits will occur monthly over the 
6-month study period. Subjects will be eligible to receive retreatment of CLS-TA from month 2-
5, if specified criteria are met. The final study visit will occur at month 6 (Visit 7). 
 
8.4.1. 
Screening/Baseline - Visit 1 (Day 0)  
After the subject has provided informed consent, the following procedures will be collected: 
1. 
Assign subject number 
2. 
Collect demographics, medical and ocular history 
3. 
Review current and prior concomitant medications 
4. 
Measure resting heart rate and blood pressure 
5. 
Collect blood for central lab tests prior to FA, including urine pregnancy test 
on females of childbearing potential 
6. 
Perform ophthalmic assessments on both eyes: 
a. 
ETDRS BCVA 
b. 
IOP 
c. 
SD-OCT 
d. 
OCT-A (at participating sites) 
e. 
Fundus photography 
f. 
Fluorescein angiography 
g. 
Slit-lamp biomicroscopy 
h. 
Dilated indirect ophthalmoscopy 
7. 
Verify subject eligibility based on Inclusion/Exclusion requirements 
8. 
Determine study eye based upon eye specific eligibility criteria 
9. 
Determine study arm based upon eligibility criteria 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 21 of 52 
CONFIDENTIAL 
 
 
 
 
 
10. 
Administer study treatment per assigned study arm 
8.4.1.1. 
IVT injection of aflibercept (TX Naive arm only) 
1. Prepare study eye for IVT injection of aflibercept 
2. Administer aflibercept IVT injection per package insert; it is recommended 
that the intravitreal injection and the SC injection are approximately 2 clock 
hours apart. The superior temporal quadrant is the recommended location for 
SC injections. 
3. Measure IOP with contact tonometry after injection 
 SC injection should be administered following the IVT injection of 
aflibercept when the study eye IOP is < 30 mmHg, either 
spontaneously or by treatment, as determined by the investigator. 
4. Immediately following the injection, assess study eye by indirect 
ophthalmoscopy 
8.4.1.2. 
SC Injection of CLS-TA (Both study arms) 
1. Select drug kit and document study kit number 
2. Administer injection of 100 μL of CLS-TA into the SCS of the study eye 
using the Clearside microinjector, preferably in the superior temporal quadrant 
3. For full description injection procedures, see Appendix B 
4. Immediately following the injection, assess study eye by indirect 
ophthalmoscopy 
8.4.1.3. 
Post-Dose Procedures 
1. Assess post dose AE’s 
2. Review changes to concomitant medications 
3. Evaluate IOP 10-30 minutes post injection 
 
If IOP remains elevated, subject must remain on site until IOP is 
under control per investigator judgement 
 
If IOP is < 30 mmHg, the subject may leave the clinic 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 22 of 52 
CONFIDENTIAL 
 
 
 
 
 
8.4.2. 
Visit 2 – Month 1 (Day 30 ±3) 
1. 
Review changes to concomitant medications 
2. 
Assess adverse events 
3. 
Perform ophthalmic assessments on both eyes: 
a. 
ETDRS BCVA 
b. 
IOP 
c. 
SD-OCT 
d. 
Slit-lamp biomicroscopy 
e. 
Dilated indirect ophthalmoscopy 
8.4.3. 
Follow-up Procedures: Visit 3 [Month 2 (Day 60 ±3)]; Visit 4 [Month 3 (Day 90 
±3)]; Visit 5 [Month 4 (Day 120 ±3)]; Visit 6 [Month 5 (Day 150 ±3)] 
1. 
Review changes to concomitant medications 
2. 
Assess adverse events 
3. 
Perform ophthalmic assessments on both eyes: 
a. 
ETDRS BCVA 
b. 
IOP 
c. 
SD-OCT 
d. 
Slit-lamp biomicroscopy 
e. 
Dilated indirect ophthalmoscopy 
4. 
Evaluate re-treatment criteria, if yes: 
8.4.3.1. 
SC Injection of CLS-TA (Both study arms) 
1. Anterior segment SD-OCT (at sites with capability) 
2. Select drug kit and document study kit number 
3. Administer injection of 100 μL of CLS-TA into the SCS of the study eye using the 
Clearside microinjector, preferably in the superior temporal quadrant  
4. For a full description of the SC injection procedure, see Appendix B 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 23 of 52 
CONFIDENTIAL 
 
 
 
 
 
5. Immediately following injection, assess the study eye by indirect ophthalmoscopy 
8.4.3.2. 
Post-Dose Procedures 
1. Assess post dose AE’s 
2. Review changes to concomitant medications 
3. Anterior segment SD-OCT (at sites with capability) 
4. Evaluate IOP 10-30 minutes post injection 
 
If IOP remains elevated, subject must remain on site until IOP is 
under control per investigator judgement 
 
If IOP is < 30 mmHg, the subject may leave the clinic 
8.4.4. 
Visit 7 – [Month 6 (Day 180 ±3)] End of Study Visit or Early Termination Visit 
1. 
Review changes to concomitant medications 
2. 
Assess adverse events 
3. 
Collect blood for central lab tests prior to FA 
4. 
Perform ophthalmic assessments on both eyes: 
a. 
ETDRS BCVA  
b. 
IOP 
c. 
SD-OCT 
d. 
Anterior segment SD-OCT (at sites with capability) 
e. 
OCT-A (at participating sites) 
f. 
Fundus photography 
g. 
Fluorescein angiography 
h. 
Slit-lamp biomicroscopy 
i. 
Dilated Indirect ophthalmoscopy 
8.4.5. 
Unscheduled Visits 
To ensure subject safety during the trial, any subject who requires additional follow-up during 
the study for any reason should see the Investigator, even if such a visit does not fall within a 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 24 of 52 
CONFIDENTIAL 
 
 
 
 
 
scheduled study visit. The investigator/staff should complete assessments deemed necessary by 
evaluating investigators and should record the assessments as an Unscheduled Visit.  
If a subject is early terming the procedures for Visit 7 (Month 6) should be completed. 
 
8.4.6. 
Anterior Segment SD-OCT 
Anterior segment SD-OCT imaging will be performed pre-and post-dose at visits where subject’s 
meet re-treatment and at the exit visit. If a subject has exited the study, they will be called and 
asked to return for one visit to complete anterior segment SD-OCT imaging. Sites will have 3 
months, after the subject has exited, to bring in subjects for anterior segment SD-OCT 
evaluation, for those subjects who have previously completed the study.    
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 25 of 52 
CONFIDENTIAL 
 
 
 
 
 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Treatments 
Subjects will be assigned to one of two treatment arms in the study based upon prior treatment 
for DME in the study eye.  
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.  
Subjects will be assigned to either of the following groups:  
1. TX Naive: IVT aflibercept [2 mg (50 µL)] + SC CLS-TA [4 mg (100 µL)] 
2. Previous TX: SC CLS-TA [4 mg (100 µL)] 
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.  
9.2. 
Study Eye Determination 
The study eye will be the eye receiving the CLS-TA injection or the IVT injection of aflibercept 
followed by a CLS-TA injection depending upon the group to which the subject is enrolled. The 
determination of the study eye will be based on Visit 1 (screening/baseline) information. 
If both eyes meet study criteria, the eye, in the Investigator’s opinion, with the better chance of 
achieving an improvement in anatomic findings on SD-OCT should be used as the study eye. If 
both eyes qualify for the study, and appear similar in their chance of improvement, the right eye 
should be designated as the study eye. The eye that is not designated as the study eye will be 
denoted as the fellow eye. 
9.3. 
Fellow Eye Treatment 
The fellow eye may receive any standard of care therapies necessary for treatment. 
9.4. 
Re-Treatment Criteria 
Re-treatment will be assessed monthly starting at Month 2 through Month 5. Subjects in either 
arm who meet at least one of the following criteria will be allowed retreatment with SC CLS-TA: 
1. CSF > 320 µm AND not improved by at least 20% from either of the previous two visits 
[10% of CSF > 500 µm], (OR) 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 26 of 52 
CONFIDENTIAL 
 
 
 
 
 
2. Loss of 10 or more letters due to DME from either of the previous two visits 
9.5. 
Concomitant Medications 
Use of the following medications are prohibited at any time during the study: 
 Any corticosteroid implant (i.e., Ozurdex®, Iluvien® or Retisert™) in the study eye 
 Topical, periocular or intravitreal corticosteroids in the study eye  
 Any intravitreal agents except those specified in the study protocol 
 Systemic anti-angiogenic drugs (anti-VEGF) including e.g. pegaptanib sodium, 
bevacizumab, ranibizumab 
 Any investigational drug or device 
In cases where there is anticipated need for the above listed medications during the study or if a 
subject presents to the Investigator having initiated treatment during the study with one of these 
medications or classes of medications, it is the responsibility of the Investigator to notify the 
Sponsor immediately. If additional therapy is necessary to treat worsening of DME in the study 
eye and normal standard of care requires these medications, they will be recorded in the subject’s 
case report form and should follow the guidelines presented for re-treatment criteria. Subjects 
will not be discontinued from the study due to initiation/change in a prohibited medication. 
9.6. 
Treatment Compliance 
Study drug will only be administered by trained study investigators (principal investigator or 
sub-investigator) in the office. No study drug will be dispensed to subjects; therefore, subject 
treatment compliance is not applicable.  
9.7. 
Randomization and Masking 
Subjects will be assigned to a study arm based upon their DME treatment history. No 
randomization will occur in this study. This study is an open-label study; no masking is 
necessary. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 27 of 52 
CONFIDENTIAL 
 
 
 
 
 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
CLS-TA, triamcinolone acetonide injectable suspension, is a sterile, preservative-free, aqueous 
suspension formulated for administration into the eye. The drug product is terminally sterilized 
and is intended for single use. CLS-TA is supplied as a 40 mg/mL sterile suspension in a            
2 mL/13 mm TopLyo® single use vial with a rubber stopper and an aluminum seal. 
Additional information regarding CLS-TA is available in the Investigator’s Brochure. 
10.2. 
Study Drug Packaging and Labeling 
The study drug kits for SC injection of CLS-TA will be supplied to each site by the Sponsor and 
will be labeled for “Investigation Use only”. 
Each Investigational Use kit will contain the following components: 
CLS-TA Kit: 
 Vial of CLS-TA (40 mg/mL) 
 Clearside microinjector 
 Vial access device (for drug transfer)  
 900 µm needle 
 1100 µm needle 
 
Sites will provide aflibercept, needles and syringes necessary for administration to subjects in the 
TX Naïve arm. 
10.3. 
Study Drug Storage 
CLS-TA must be stored under ambient temperature conditions at about 20º-20º C (68º-77º F); do 
not freeze. CLS-TA should be protected from light by storing in the carton provided. 
10.4. 
Study Drug Preparation 
Shake the vial of CLS-TA vigorously for 10 seconds, before withdrawal from the vial, to ensure 
a uniform suspension.  
10.5. 
Administration 
CLS-TA will be administered as a single injection of 4 mg in 100 µL. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 28 of 52 
CONFIDENTIAL 
 
 
 
 
 
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 Appendix B. 
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. 
10.6. 
Study Drug Accountability 
Accountability of study drug kits will be conducted by either designated study staff and/or 
monitor. Accountability will be ascertained by performing reconciliation between the number of 
study drug cartons (kits and components) sent to the site, and the number used and unused at the 
time of reconciliation.  
 
Study drug shipment records will be verified and accountability performed by comparing the 
shipment inventory sheet to the actual quantity of drug and microinjectors received at the site. 
Accurate records of receipt and disposition of the study drug and microinjectors (eg, dates, 
quantity, subject number, kits used, kits unused, etc.) must be maintained by the investigator or 
his/her designee. Study drug will be stored ambient at 20 - 25ºC (68 - 77ºF) and this area should 
have limited, controlled access with temperature monitoring. 
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 Clearside 
(or designee) or destroyed at the site and documented per the site’s standard process. Any used 
microinjectors and vials of study drug involved in a product complaint must be maintained and 
return to the Clearside (or designee). All study drug and microinjector accounting procedures 
must be completed before the study is considered complete. 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 29 of 52 
CONFIDENTIAL 
 
 
 
 
 
11. 
ASSESSMENT OF EFFICACY 
11.1. 
Best Corrected Visual Acuity 
BCVA will be evaluated by ETDRS chart using standardized lighting and standardized lanes. 
The results shall be reported as number of letters read. Visual acuity testing should precede any 
examination requiring contact with the eye.  
11.2. 
Central Subfield Thickness 
Retinal thickness and disease characterization will be assessed via spectral domain optical 
coherence tomography (SD-OCT) and OCT angiography (OCT-A). OCT-A will only be 
collected at those sites with available equipment for collecting these images. The technician is 
encouraged to use the same equipment throughout the subject’s study participation. All images 
should be taken by the same photographer, whenever possible, on each subject per research site.  
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 30 of 52 
CONFIDENTIAL 
 
 
 
 
 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
 
12.1.1. 
Intraocular Pressure 
Intraocular pressure (IOP) will be measured by applanation tonometery (Goldmann) and results 
will be recorded in mmHg. Tonometers must be calibrated for accuracy. 
12.1.2. 
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, cornea, 
anterior chamber, iris and lens. All abnormal findings will be described. 
12.1.3. 
Indirect Ophthalmoscopy 
Dilated ophthalmoscopy should be performed according to the investigator’s standard dilation 
procedure. 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 (including but not limited 
to): vitreous, retina, choroid, and optic nerve/disc. Dilated indirect ophthalmoscopy will be 
assessed at every visit. 
12.1.4. 
Fluorescein Angiography 
FA will be performed on the study eye only at all visits at which it is performed. Disease 
characterization will be assessed and will include the area of fluorescein leakage. The technician 
is encouraged to use the same equipment throughout the subject’s study participation. All images 
should be taken by the same photographer, whenever possible, on each subject per research site. 
12.1.5. 
Fundus Photography 
Wide color fundus photos will be obtained. It is recommended that when both fundus photos and 
FA are conducted in the same visit, the Fundus Photos should be taken first. The technician is 
encouraged to use the same equipment throughout the subject’s study participation. All photos 
should be taken by the same photographer, whenever possible, on all subjects per research site. 
12.1.6. 
Heart Rate and Blood Pressure 
Vital signs will be measured on subjects after they have been seated for about 5 minutes. Resting 
heart rate and resting blood pressure (systolic and diastolic, preferably on the same arm each 
time) will be measured at the Screening/Baseline Visit. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 31 of 52 
CONFIDENTIAL 
 
 
 
 
 
12.1.6.1. Laboratory Tests 
Urine pregnancy tests will be performed on all women of childbearing potential at each treatment 
visit. 
HbA1C will be collected on all subjects at Screening and Exit Visits. 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether or 
not considered casually 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. 
 
All AEs that occur after any patient/subject has been enrolled, before treatment or during study 
participation, whether or not they are related to the study, must be recorded. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any study phase (ie, baseline, treatment, 
washout, or follow-up), and at any dose of the investigational product, comparator or placebo, 
that fulfils one or more of the following: 
 Results in death 
 It is immediately life-threatening 
 It requires in-patient hospitalization or prolongation of existing hospitalization 
 It results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
All SAEs that occur after any patient/subject has been enrolled, before treatment, during 
treatment, or during study participation, whether or not they are related to the study, must be 
recorded. 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 32 of 52 
CONFIDENTIAL 
 
 
 
 
 
12.3. 
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.” 
 
12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient/subject and/or in response to an open 
question from the study personnel or revealed by observation will be recorded during the study at 
the investigational site.  Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as AEs.  However, abnormal values that constitute an SAE or lead to 
discontinuation of administration of study drug must be reported and recorded as an AE.  
Information about AEs and Serious Adverse Events (SAEs) will be collected from the signing of 
consent form until the end of the study.  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, serious outcome (if 
applicable), and whether or not it caused the patient to discontinue the study. 
 
Intensity will be assessed according to the following scale: 
 Mild (awareness of sign or symptom, but easily tolerated) 
 Moderate (discomfort sufficient to cause interference with normal activities) 
 Severe (incapacitating, with inability to perform normal activities) 
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 11.2.1.2.  An AE of severe intensity 
may not be considered serious. 
 
Should a pregnancy occur, it must be reported to Clearside Biomedical.  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. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 33 of 52 
CONFIDENTIAL 
 
 
 
 
 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the patient 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. 
 
12.5. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from the signing of consent form until the end 
of the study.  Any SAEs considered possibly or probably 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 within one 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.   
 
Additional follow-up information, if required or available, should all be faxed to Clearside 
Biomedical within one business day of receipt and this should be completed 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 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 trial.  Each site is responsible for 
notifying its IRB of these additional SAEs. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 34 of 52 
CONFIDENTIAL 
 
 
 
 
 
13. 
STATISTICS 
13.1. 
Population to be Studied  
The study population will include approximately 20 adult subjects (18 years or older) with 
diabetic macular edema who meet all of the Inclusion criteria, and Exclusion criteria and receive 
some amount of study drug. Approximately 3 US sites will recruit subjects for this study. 
This study is designed as an open-label study with two treatment groups. As all subjects will be 
assigned to a treatment group based upon DME treatment history, no randomization will occur. 
13.2. 
Study Populations 
All safety analyses will be presented for the safety population, which will include all subjects 
who received at least one dose of study drug. This is a safety and tolerability study however 
efficacy analyses will be presented for the safety population as well. Such an analysis will ensure 
that benefit to risk is properly evaluated. 
13.3. 
Analysis 
All data collected in the study database will be presented in the listings.  Listings will include 
change from baseline.  Baseline is the Visit 1 pre-dose. 
Summary statistics from Investigator findings will be tabulated and summarized descriptively. 
For categorical outcomes (e.g., normal or abnormal). For continuous outcomes (e.g., change in 
IOP), descriptive summary statistics will include the sample size, mean, median, standard 
deviation, standard error, minimum and maximum values. 
No other statistical analysis will be prepared for this study.   
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 35 of 52 
CONFIDENTIAL 
 
 
 
 
 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of Clearside 
Biomedical will evaluate 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 or its 
representatives. This will be documented in a Clinical Study Agreement between 
Clearside Biomedical and the investigator. 
During the study, a monitor from Clearside Biomedical or representative will have regular 
contacts with the investigational site, for the following: 
 Provide information and support to the investigator(s) 
 Confirm that facilities remain acceptable 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
 Perform source data verification. This includes a comparison of the data in the case report 
forms with the patient’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 patient 
(e.g. clinic charts). 
 Record and report any protocol deviations not previously sent to Clearside Biomedical. 
 Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to Clearside Biomedical 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, a regulatory authority, an Independent 
Ethics Committee or an Institutional Review Board may visit the site to perform audits or 
inspections, including source data verification.  The purpose of a Clearside Biomedical audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 36 of 52 
CONFIDENTIAL 
 
 
 
 
 
analyzed, and accurately reported according to the protocol, Good Clinical Practice guidelines of 
the International Conference on Harmonization, and any applicable regulatory requirements.  
The investigator should contact Clearside Biomedical immediately if contacted by a regulatory 
agency about an inspection. 
14.3. 
Institutional Review Board (IRB) 
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 patient 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  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 37 of 52 
CONFIDENTIAL 
 
 
 
 
 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The progress of the study will be monitored by onsite, written, e-mail, and telephone 
communications between personnel at the study center and the Clearside Biomedical. The 
Investigator will allow Clearside Biomedical monitors, or designee(s) to inspect all CRFs, 
subject records (source documents), signed informed consent forms, records of study medication 
receipt, storage, and disposition, and regulatory files related to the study. 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Clearside Biomedical may conduct a quality assurance audit.   
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 38 of 52 
CONFIDENTIAL 
 
 
 
 
 
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 as appropriate.  The investigator 
must submit written approval to Clearside Biomedical before he or she can enroll any 
patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB must approve all advertising used to 
recruit patients for the study.  The protocol must be re-approved by the IRB 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 will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
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/Good Clinical Practice, applicable 
regulatory requirements. 
16.3. 
Written Informed Consent 
The Principal Investigator(s), or his/her designee, at each center will ensure that the patient is 
given full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study.  Patients must also be notified that they are free to discontinue from the 
study at any time.  The patient should be given the opportunity to ask questions and allowed time 
to consider the information provided. 
 
The patient’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 patient. 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 39 of 52 
CONFIDENTIAL 
 
 
 
 
 
17. 
DATA HANDLING AND RECORDKEEPING 
 
17.1. 
Inspection of Records 
Clearside Biomedical 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 following the 
discontinuance of the test article for investigation. If it becomes necessary for Clearside 
Biomedical 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  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 40 of 52 
CONFIDENTIAL 
 
 
 
 
 
18. 
PUBLICATION POLICY 
The institution and investigators participating in this trial shall have no right to publish or present 
the results of this study without the prior written consent of Clearside Biomedical. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 41 of 52 
CONFIDENTIAL 
 
 
 
 
 
19. 
LIST OF REFERENCES 
1. American Diabetes A. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 
2013;36(4):1033-1046. 
2. Menke A, Casagrande S, Geiss L, et al. Prevalence of and Trends in Diabetes Among Adults in the 
United States, 1988-2012. JAMA : the journal of the American Medical Association. 
2015;314(10):1021-1029. 
3. 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. 
4. 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. 
5. 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. 
6. 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. 
7. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. 
Ophthalmology. 2014;121(11):2247-2254. 
8. 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. 
9. 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. 
10. 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. 
11. 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. 
12. 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. 
13. 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. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 42 of 52 
CONFIDENTIAL 
 
 
 
 
 
14. 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. 
15. 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. 
16. Diabetic Retinopathy Clinical Research N, 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. 
17. 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. 
18. 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. 
19. 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. 
20. Diabetic Retinopathy Clinical Research N, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, 
or ranibizumab for diabetic macular edema. The New England journal of medicine. 
2015;372(13):1193-1203. 
21. 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. 
 
 
 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 43 of 52 
CONFIDENTIAL 
 
 
 
 
 
20. 
APPENDICES 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 44 of 52 
CONFIDENTIAL 
 
 
 
 
 
APPENDIX A – Schedule of Events 
 
 
1. Urine pregnancy test will be done for females of child bearing potential on treatment visits 
2. IOP will be measured by applanation tonometry (Goldmann) 
3. Sites with capability to acquire OCT-A 
 
  
Screen & 
Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Visit 
1 
2 
3 
4 
5 
6 
7 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical/Ophthalmic 
History 
X 
 
 
 
 
 
 
Vitals 
X 
 
 
 
 
 
 
Pregnancy Test¹ 
X 
 
X 
X 
X 
X 
 
Inclusion/ Exclusion 
X 
 
 
 
 
 
 
HbA1C 
X 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
BCVA (ETDRS) 
X 
X 
X 
X 
X 
X 
X 
Intraocular Pressure² 
X 
X 
X 
X 
X 
X 
X 
SD-OCT (OU) 
X 
X 
X 
X 
X 
X 
X 
OCT-Angiography (OU)³ 
X 
 
 
X 
 
 
X 
Anterior segment SD-
OCT3 
 
 
 
X 
X 
X 
X 
Fundus Photography 
X 
 
 
 
 
 
X 
Fluorescein 
Angiography 
X 
 
 
 
 
 
X 
Indirect 
Ophthalmoscopy/ Slit 
Lamp 
X 
X 
X 
X 
X 
X 
X 
Intravitreal Aflibercept 
X 
 
 
 
 
 
 
Study Drug Treatment 
X 
 
X 
X 
X 
X 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 45 of 52 
CONFIDENTIAL 
 
 
 
 
 
 
APPENDIX B – Suprachoroidal Injection Instructions  
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 46 of 52 
CONFIDENTIAL 
 
 
 
 
 
APPENDIX B TO BE INSERTED HERE PRIOR TO RELEASE 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
Page 47 of 52 
CONFIDENTIAL 
 
 
 
 
 
APPENDIX B TO BE INSERTED HERE PRIOR TO RELEASE


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
 
Page 48 of 52 
CONFIDENTIAL 
 
 
 
 
 
APPENDIX C:  Summary of Changes for Amendments 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
 
Page 49 of 52 
CONFIDENTIAL 
 
 
 
 
 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Title Page 
 
IND number added 
For protocol 
identification 
None 
Table 1: Emergency 
Contact 
Information 
Site Coordinating Leader Name: Chelsey 
Moore 
Telephone Number: 713.394.7575 
 
Responsible Physician: Charles Wykoff, 
MD 
Site Coordinating Leader Name: Cassie 
Cone 
Telephone Number: 713.394.7537 
 
Responsible Physician: Charles Wykoff, 
MD, PhD 
To update Site 
Coordinating Leader and 
telephone number 
 
To correct the 
responsible physician’s 
title 
None 
2. Synopsis 
 
Exploratory:   
 
Scleral thickness 
 
Suprachoroidal space 
visualization 
To add scleral thickness, 
and suprachoroidal space 
visualization as 
exploratory endpoints 
None 
7.2.3. Exploratory 
Endpoint 
 
 
Scleral space thickness 
 
Suprachoroidal space 
visualization 
To add scleral thickness, 
and suprachoroidal space 
visualization as 
exploratory endpoints 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
 
Page 50 of 52 
CONFIDENTIAL 
 
 
 
 
 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
8.4.3.1. SC Injection 
of CLS-TA (Both 
study arms) 
1. Select drug kit and document study 
kit number 
2. Administer injection of 100 μL of 
CLS-TA into the SCS of the study 
eye using the Clearside 
microinjector, preferably in the 
superior temporal quadrant  
3. For a full description of the SC 
injection procedure, see Appendix B 
4. Immediately following injection, 
assess the study eye by indirect 
ophthalmoscopy 
 
1. Anterior segment SD-OCT (at sites 
with capability) 
2. Select drug kit and document study 
kit number 
3. Administer injection of 100 μL of 
CLS-TA into the SCS of the study 
eye using the Clearside 
microinjector, preferably in the 
superior temporal quadrant  
4. For a full description of the SC 
injection procedure, see Appendix B 
5. Immediately following injection, 
assess the study eye by indirect 
ophthalmoscopy 
 
To add collection of 
anterior segment SD-
OCT  
None 
8.4.3.2. Post-Dose 
Procedures 
1. Assess post dose AE’s 
2. Review changes to concomitant 
medications 
3. Evaluate IOP 10-30 minutes post 
injection 
 
If IOP remains elevated, subject 
must remain on site until IOP is 
under control per investigator 
judgement 
 
If IOP is < 30 mmHg, the 
subject may leave the clinic 
 
1. Assess post dose AE’s 
2. Review changes to concomitant 
medications 
3. Anterior segment SD-OCT (at sites 
with capability) 
4. Evaluate IOP 10-30 minutes post 
injection 
 
If IOP remains elevated, subject must 
remain on site until IOP is under 
control per investigator judgement 
 
If IOP is < 30 mmHg, the subject 
may leave the clinic 
 
To add collection of 
anterior segment SD-
OCT 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
 
Page 51 of 52 
CONFIDENTIAL 
 
 
 
 
 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
8.4.4. Visit 7 – 
[Month 6 (Day 180 
±3)] End of Study 
Visit or Early 
Termination Visit 
4. Perform ophthalmic assessments on 
both eyes: 
a. 
ETDRS BCVA  
b. IOP 
c. 
SD-OCT 
d. OCT-A (at participating sites) 
e. 
Fundus photography 
f. 
Fluorescein angiography 
g. Slit-lamp biomicroscopy 
h. Dilated Indirect ophthalmoscopy 
 
4. 
Perform ophthalmic assessments on 
both eyes: 
a. 
ETDRS BCVA  
b. IOP 
c. 
SD-OCT 
d. Anterior segment SD-OCT (at 
sites with capability) 
e. 
OCT-A (at participating sites) 
f. 
Fundus photography 
g. Fluorescein angiography 
h. Slit-lamp biomicroscopy 
i. 
Dilated Indirect ophthalmoscopy 
To add collection of 
anterior segment SD-
OCT 
None  
8.4.6. Anterior 
Segment SD-OCT 
 
Anterior segment SD-OCT imaging will 
be performed pre-and post dose at visits 
where subjects meet re-treatment and at 
the exit visit. If a subject has exited the 
study, they will be called and asked to 
return for one visit to complete anterior 
segment SD-OCT imaging. Sites will 
have 3 months, after the subject has 
exited, to bring in subjects who have 
previously completed the study.    
To determine scleral and 
suprachoroidal space 
thickness 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1004-101 
 
Clinical Protocol 
 
 
 
June 23, 2017 
 
Page 52 of 52 
CONFIDENTIAL 
 
 
 
 
 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol 
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Appendix A – 
Schedule of Events 
 
Added anterior segment SD-OCT to V4, 
V5, V6 and V7 (at sites with capability) 
To add collection of 
anterior segment SD-
OCT 
None 
Throughout 
protocol 
Miscellaneous typographical and 
formatting errors 
 
To correct typographical 
and formatting errors 
None 
Throughout 
protocol 
Various 
Miscellaneous administrative 
clarifications 
To clarify various text 
throughout the protocol 
None 
 


Clearside Biomedical, Inc. - Document Approval 
CLS-CLIN-000064 v1.0:  CLS1004-101 Study Protocol with Amendment 1 - HULK (v2.0)
Approved:  06 Jul 2017 - CLS-CLIN-000064 v1.0
Regulatory
Approved
Barbara Bauschka
Senior Director, Regulatory Operations
27-Jun-2017 17:37:21 GMT+0000
Medical
Approved
Rick Beckman
Chief Medical Officer
27-Jun-2017 18:24:10 GMT+0000
Clinical Science
Approved
Glenn Noronha
Chief Scientific Officer
27-Jun-2017 20:18:08 GMT+0000
Clinical
Approved
Jennifer Kissner
Vice President, Clinical Development
06-Jul-2017 14:51:11 GMT+0000