Clinical trial NCT04626128
Conditions: Neovascular Age-related Macular Degeneration
Keywords: AMD Wet-AMD suprachoroidal tyrosine kinase inhibitor Microinjector SCS
Sponsor: Clearside Biomedical, Inc.
Start date: 2020-12-15; Completion date: 2022-10-13
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
To evaluate the safety and tolerability of suprachoroidally administered CLS-AX following intravitreal anti-VEGF therapy in subjects with neovascular age-related macular degeneration (AMD)

Detailed description:
Multi-center, open-label, dose-escalation, phase 1/2a, safety and tolerability study to evaluate four dose groups of suprachoroidally administered CLS-AX following intravitreal anti-VEGF therapy in up to a maximum of 25 subjects with neovascular age-related macular degeneration

Arms: arm 1: Subjects will receive a low dose of 0.03 mg CLS-AX arm 2: Subjects will receive a low-mid dose of 0.10 mg CLS-AX arm 3: Subjects will receive a high-mid dose of 0.50 mg CLS-AX arm 4: Subjects will receive a high-mid dose of 1.0 mg CLS-AX
Interventions: intervention 1: CLS-AX intervention 2: Anti-VEGF
Intervention descriptions: intervention 1: injectable suspension of small molecule tyrosine kinase inhibitor (TKI) intervention 2: Standard of care therapy used to block vascular endothelial growth factor

Protocol documents:
Prot_SAP_000.pdf: 
Compound Name: 
CLS-AX, axitinib injectable suspension 
Protocol Number: 
CLS1002-101 
IND Number: 
132228 
NCT Number:  
NCT04626128 
Protocol Title 
OASIS: Open-label, dose-escalation, phase 1/2a study of 
the safety and tolerability of suprachoroidally administered 
CLS-AX following intravitreal anti-VEGF therapy in 
subjects with neovascular age-related macular degeneration 
Sponsor: 
Clearside Biomedical, Inc. 
900 North Point Parkway, Suite 200 
Alpharetta, GA 30005 
Issue Date: 
Protocol Amendment 1 Date: 
Protocol Amendment 2 Date: 
Protocol Amendment 3 Date: 
Protocol Amendment 4 Date: 
15 October 2020 
26 March 2021 
13 December 2021 
08 March 2022 
15 April 2022 
 


CLS-AX (axitinib injectable suspension) 
 
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CLS1002-101 
Clinical Protocol
Amendment 4 Summary of Changes 
15 April 2022 
Page 1 of 5 
CONFIDENTIAL
A.
SUMMARY OF CHANGES
Protocol Amendment 4
Protocol Title:
OASIS: OPEN-LABEL, DOSE-ESCALATION, PHASE 1/2A STUDY OF THE SAFETY AND 
TOLERABILITY OF SUPRACHOROIDALLY ADMINISTERED CLS-AX FOLLOWING 
INTRAVITREAL ANTI-VEGF THERAPY IN SUBJECTS WITH NEOVASCULAR AGE-RELATED 
MACULAR DEGENERATION
Protocol Number:
IND:
CLS1002-101 
132228 
Original Version Date: 
15 October 2020 
Amendment Number:
4
Version Number and Date:
Version 5, 15 April 2022 
Note: for clarity, deleted text will be denoted with a strikethrough and additional/altered text will appear in bold. 
Minor editorial changes to improve readability will not be documented.










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CLS1002-101 (Version 5.0) 
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Project: 
1002 
Compound Number/Name:
CLS-AX (axitinib injectable suspension)  
Protocol Number: 
CLS1002-101 
IND Number:
132228 
Phase:
1/2a 
Protocol Title: 
OASIS: OPEN-LABEL, DOSE-ESCALATION, PHASE 1/2A 
STUDY OF THE SAFETY AND TOLERABILITY OF 
SUPRACHOROIDALLY ADMINISTERED CLS-AX 
FOLLOWING INTRAVITREAL ANTI-VEGF THERAPY IN 
SUBJECTS WITH NEOVASCULAR AGE-RELATED 
MACULAR DEGENERATION
Sponsor:
Clearside Biomedical, Inc.
900 North Point Parkway, Suite 200 
Alpharetta, GA 30005
Primary Medical Monitor:
Benjamin I. Rubin, M.D. 
Principal Investigator:
To be appointed before the end of the study
Protocol Amendment 4 Date: 
Protocol Amendment 3 Date: 
Protocol Amendment 2 Date: 
Administrative Change Date: 
Protocol Amendment 1 Date:
Issue Date:
15 April 2022 
08 March 2022 
13 December 2021 
19 November 2021 
26 March 2021 
15 October 2020 
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. 


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SIGNATURE PAGE
This study protocol 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:
Thomas Ciulla, M.D.
Chief Medical Officer
Clearside Biomedical, Inc.
ELECTRONIC SIGNATURE 
ON FILE
Sponsor Signatory:
Barbara Bauschka
Vice President, Regulatory Operations
Clearside Biomedical, Inc.
ELECTRONIC SIGNATURE 
ON FILE
Sponsor Signatory:
Colette Hall, M.D.
Vice President, Medical and Safety
Clearside Biomedical, Inc.
ELECTRONIC SIGNATURE 
ON FILE


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CLS1002-101 (Version 5.0) 
Clinical Protocol
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INVESTIGATOR’S AGREEMENT
I have received and read the Investigator’s Brochure for CLS-AX (axitinib injectable 
suspension).  I have read the CLS1002-101 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


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CLS1002-101 (Version 5.0) 
Clinical Protocol
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PROCEDURES IN CASE OF EMERGENCY
Table 1: 
Emergency Contact Information 
Role in Study
Name
Address and Telephone 
number
Clinical Study Leader 
Georgina Debrah
Clearside Biomedical, Inc.
900 North Point Parkway, 
Suite 200 
Alpharetta, GA 30005 
USA
(678) 254-2345 
Responsible Physician
Thomas Ciulla, M.D. 
Clearside Biomedical, Inc.
900 North Point Parkway, 
Suite 200 
Alpharetta, GA 30005 
USA
(678) 392-2318 
Drug Safety Physician 
Colette Hall, M.D. 
Clearside Biomedical, Inc.
900 North Point Parkway, 
Suite 200 
Alpharetta, GA 30005 
USA
(678) 820-4178 
Primary Medical Monitor
(24-Hour Emergency Contact) 
Benjamin I. Rubin, 
M.D. 
MedTrials, Inc.
7801 Renoir Court 
Potomac, MD 
USA
(301) 509-4451 


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CLINICAL LABORATORIES AND MEDICAL INSTITUTIONS
Table 2: 
Names and Addresses of Institutions
Reading Center
Name and Address
Central Laboratory
ACM Global Laboratories 
160 Elmgrove Park 
Rochester, NY 14624 
USA
Electrocardiogram Reading Center
Clario
1818 Market Street
Suite 2600 
Philadelphia, PA 19103-3600 
USA
Pharmacokinetic Evaluation
Covance Laboratories
8211 SciCor Drive 
Indianapolis, IN 46214 
USA
Central Reading Center for Fundus Photographs, Fluorescein 
Angiograms and Spectral Domain Optical Coherence 
Tomography 
Merit CRO, Inc. 
6527 Normandy Lane 
 #100 
Madison, WI 53719 
USA


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REVISION HISTORY
Table 3: 
Revision History
Version Number
Date
Revision summary 
Draft
19 May 2020 
Initial release version for IND.
1.0
15 October 2020 
Initial release of protocol.
2.0
26 March 2021 
Protocol Amendment 1. 
2.1
19 November 2021 Administrative Change 1. 
3.0
13 December 2021 Protocol Amendment 2. 
4.0
08 March 2022 
Protocol Amendment 3. 
5.0
15 April 2022 
Protocol Amendment 4. 


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2.
SYNOPSIS
Name of Sponsor/Company:
Clearside Biomedical, Inc.
Name of Investigational Product:
CLS-AX (axitinib injectable suspension)
Name of Active Ingredient:
Axitinib
Title of Study: 
OASIS: Open-label, dose-escalation, phase 1/2a study of the safety and tolerability of 
suprachoroidally administered CLS-AX following intravitreal anti-VEGF therapy in subjects with 
neovascular age-related macular degeneration
Study centers: Multi-Center
Principal Investigators: Multi-Center
Studied period: 16 Week Duration
Estimated date first subject enrolled: December 2020 
Estimated date last subject completed: September 2022 
Phase of development: 
Phase 1/2a 
Background and Rationale:
Currently, anti-vascular endothelial growth factor (VEGF)-A drugs are the standard of care for the 
treatment of neovascular age-related macular degeneration (nAMD) (Flaxel, 2020); however, an 
unmet need remains for significantly improving and maintaining visual acuity in most patients 
(Rofagha, 2013, CATT, 2016, Singer, 2012). 
Axitinib demonstrates intrinsic high potency and achieves pan-VEGF inhibition through tyrosine 
kinase receptor blockade (INLYTA, 2018, Hu-Lowe, 2008); axitinib is a second-generation tyrosine 
kinase inhibitor (TKI) that potently inhibits vascular endothelial growth factor receptors VEGFR-1, 
VEGFR-2, and VEGFR-3 at picomolar concentrations, and inhibits platelet-derived growth factor 
receptors (PDGFR) and c-KIT receptors to a significantly lesser degree, by stabilizing the receptor 
kinase domain in an inactive conformation. In preclinical work by independent investigators, axitinib 
effectively inhibited corneal, retinal and choroidal angiogenesis in multiple preclinical models 
(Riquelme, 2018, Yuan, 2015, Giddabasappa, 2016, Nakano, 2016, Kang, 2013).  Topical axitinib 
more effectively inhibited experimental corneal neovascularization than other topical tyrosine kinase 
receptor inhibitors in a preclinical model (Yuan, 2015).  Furthermore, experimental oral axitinib not 
only inhibited choroidal neovascularization, but also caused regression of established 
neovascularization (Kang, 2013). Importantly, in-vitro assessment has revealed better 
biocompatibility with ocular cells than other tyrosine kinase inhibitors (Thiele, 2013). 
Suprachoroidal (SC) injection is a novel drug-dispensing approach that is a minimally invasive office-
based procedure, performed using Clearside’s proprietary injection device, the SCS Microinjector®. A 
SC injection is the term used to describe this intraocular injection procedure performed in the pars 
plana approximately 4 – 4.5 mm posterior to the limbus, resulting in a sub-scleral dispensing of drug 
product into the suprachoroidal space (SCS) which is the transition region between the sclera and the 
choroid.  Immediately after the SC injection procedure, injectate moves posteriorly from the site of 
the injection, with the fluid being absorbed dominantly into the inner sclera, choroid, retinal pigment 
epithelial (RPE) cells, and retina. Clearside Biomedical Inc. (“Clearside”) is developing a proprietary 
formulation of axitinib, CLS-AX (axitinib injectable suspension) to treat nAMD by injection into the 
















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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS
1. 
TITLE PAGE ................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................7 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................22 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................26 
6.1. 
Primary Objective .......................................................................................................26 
6.2. 
Secondary Objectives .................................................................................................26 
6.3. 
Exploratory Objectives ...............................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Endpoints ....................................................................................................................27 
7.2.1. 
Primary Endpoint ........................................................................................................27 
7.2.2. 
Secondary Endpoints ..................................................................................................27 
7.2.3. 
Pharmacokinetic Endpoints ........................................................................................28 
7.3. 
Number of Subjects ....................................................................................................28 
7.4. 
Treatment Assignment ................................................................................................28 
7.5. 
Dose Adjustment Criteria ...........................................................................................29 
7.5.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................29 
7.5.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses ....................................29 
7.6. 
Criteria for Study Termination and Suspension .........................................................29 
7.6.1. 
Early Discontinuation of the Study.............................................................................29 
7.6.2. 
Suspension of the Study..............................................................................................29 
7.6.3. 
Dose-Escalation Criteria .............................................................................................30 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................32 
8.1. 
Subject Inclusion Criteria ...........................................................................................32 
8.2. 
Subject Exclusion criteria: ..........................................................................................33 


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8.2.1. 
Ophthalmic Exclusion Criteria ...................................................................................33 
8.2.2. 
General Exclusion Criteria .........................................................................................34 
8.3. 
Subject Withdrawal Criteria .......................................................................................35 
8.4. 
Visit Procedure Description ........................................................................................36 
8.4.1. 
General Procedures .....................................................................................................36 
8.4.2. 
Rescreening Procedures ..............................................................................................36 
8.4.3. 
Visit 1 – Screening (Day -28 ± 3 days) ......................................................................36 
8.4.3.1. 
Aflibercept IVT Injection Procedure ..........................................................................38 
8.4.4. 
Visit 2 - Baseline (Day 1) ...........................................................................................38 
8.4.4.1. 
Visit 2 (Day 1) Pre CLS-AX Suprachoroidal Injection Procedures ...........................38 
8.4.4.2. 
CLS-AX Suprachoroidal Injection Procedures ..........................................................39 
8.4.4.3. 
CLS-AX Suprachoroidal Injection Post Dose Procedures .........................................40 
8.4.5. 
Visits 3 and 4 (Weeks 4 and 8) ...................................................................................40 
8.4.5.1. 
Additional IVT Aflibercept Procedure .......................................................................41 
8.4.5.2. 
Post IVT Injection of Aflibercept ...............................................................................41 
8.4.6. 
Visit 5 (Week 12) End of Study/Early Termination ...................................................42 
8.4.7. 
Unscheduled Visits .....................................................................................................43 
9. 
TREATMENT OF SUBJECTS ..................................................................................44 
9.1. 
Treatment Regimen, Dosing, and Duration ................................................................44 
9.2. 
Study Eye Determination ............................................................................................44 
9.3. 
Fellow Eye Treatment .................................................................................................44 
9.4. 
Additional Treatment ..................................................................................................45 
9.4.1. 
Additional Therapy Criteria ........................................................................................45 
9.5. 
Concomitant Medications ...........................................................................................45 
9.5.1. 
Prohibited Medications ...............................................................................................45 
9.6. 
Treatment Compliance ................................................................................................46 
9.7. 
Randomization and Masking ......................................................................................46 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................47 
10.1. 
Study Drug ..................................................................................................................47 
10.2. 
Study Drug Packaging and Labeling ..........................................................................47 
10.3. 
Study Drug Storage .....................................................................................................47 
10.4. 
Study Drug Preparation ..............................................................................................47 


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10.5. 
Administration ............................................................................................................47 
10.6. 
SCS Microinjector Use Questionnaire ........................................................................48 
10.7. 
Study Drug Accountability .........................................................................................48 
10.8. 
Study Drug Handling and Disposal ............................................................................48 
11. 
PHARMACOKINETIC ASSESSMENTS .................................................................49 
11.1. 
Blood Sample Collection ............................................................................................49 
11.2. 
Urine Sample Collection .............................................................................................49 
12. 
ASSESSMENT OF SAFETY .....................................................................................50 
12.1. 
Safety Variables ..........................................................................................................50 
12.1.1. 
Best Corrected Visual Acuity .....................................................................................50 
12.1.2. 
Spectral Domain Optical Coherence Tomography .....................................................50 
12.1.3. 
Optical Coherence Tomography Angiography ...........................................................50 
12.1.4. 
Intraocular Pressure ....................................................................................................50 
12.1.5. 
Slit-lamp Biomicroscopy ............................................................................................51 
12.1.5.1. 
Cataract Lens Grading ................................................................................................51 
12.1.5.2. 
Anterior Chamber Cells ..............................................................................................51 
12.1.5.3. 
Anterior Chamber Flare ..............................................................................................51 
12.1.6. 
Indirect Ophthalmoscopy ............................................................................................52 
12.1.6.1. 
Vitreous Haze .............................................................................................................52 
12.1.7. 
Fluorescein Angiography ............................................................................................52 
12.1.8. 
Fundus Photography ...................................................................................................53 
12.1.9. 
Vital Signs ..................................................................................................................53 
12.1.10. 
Weight and Height ......................................................................................................53 
12.1.11. 
Review of Body Systems (Physical Examination) .....................................................53 
12.1.12. 
12-Lead Electrocardiogram Assessment ....................................................................53 
12.1.13. 
Laboratory Assessments .............................................................................................53 
12.1.13.1. Pregnancy Screen ........................................................................................................54 
12.1.14. 
Fundus Autofluorescence Imaging .............................................................................54 
12.2. 
Adverse and Serious Adverse Events .........................................................................54 
12.2.1. 
Definition of Adverse Events .....................................................................................54 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................54 


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12.2.1.2. 
Clinical Laboratory Abnormalities and other Abnormal Assessments as 
Adverse Events and Serious Adverse Events .............................................................55 
12.2.1.3. 
Serious Adverse Event (SAE) ....................................................................................55 
12.2.2. 
Evaluating Adverse Events .........................................................................................56 
12.2.2.1. 
Intensity/Severity Grade .............................................................................................56 
12.2.2.2. 
Assessment of Causality .............................................................................................57 
12.2.3. 
Recording Adverse Events .........................................................................................57 
12.2.4. 
Reporting Adverse Events ..........................................................................................58 
12.2.5. 
Follow-up of AEs and SAEs .......................................................................................58 
12.2.6. 
Exposure in utero During Clinical Trials ...................................................................59 
12.2.7. 
Complaint Handling ....................................................................................................59 
13. 
STATISTICS ..............................................................................................................61 
13.1. 
Randomization ............................................................................................................61 
13.2. 
Determination of Sample Size and Level of Significance ..........................................61 
13.3. 
Subject Disposition and Demographic and Baseline Characteristics .........................61 
13.4. 
Analysis Populations ..................................................................................................61 
13.4.1. 
Safety Population ........................................................................................................61 
13.4.2. 
Pharmacokinetic Population .......................................................................................61 
13.5. 
Analysis Methods .......................................................................................................61 
13.5.1. 
Schedule of Analyses ..................................................................................................62 
13.5.2. 
Safety Analysis ...........................................................................................................62 
13.5.3. 
Secondary Safety Analyses .........................................................................................63 
13.5.4. 
Subgroup Analysis ......................................................................................................63 
13.5.5. 
Interim Analysis ..........................................................................................................63 
13.5.6. 
Pharmacodynamic Analysis........................................................................................63 
13.5.7. 
Pharmacokinetic Analysis ..........................................................................................63 
13.5.8. 
Procedure for Accounting for Missing Data ...............................................................63 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................64 
14.1. 
Study Monitoring ........................................................................................................64 
14.2. 
Audits and Inspections ................................................................................................64 
14.3. 
Institutional Review Board (IRB) ...............................................................................65 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................66 


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16. 
ETHICS ......................................................................................................................67 
16.1. 
Ethics Review .............................................................................................................67 
16.2. 
Ethical Conduct of the Study ......................................................................................67 
16.3. 
Written Informed Consent ..........................................................................................67 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................69 
17.1. 
Case Report Forms/Electronic Data Record ...............................................................69 
17.2. 
Inspection of Records .................................................................................................69 
17.3. 
Retention of Records ..................................................................................................69 
18. 
FINANCING AND INSURANCE .............................................................................70 
18.1. 
Finance ........................................................................................................................70 
18.2. 
Insurance .....................................................................................................................70 
19. 
PUBLICATION POLICY ..........................................................................................71 
20. 
REFERENCES ...........................................................................................................72 
21. 
APPENDICES ............................................................................................................75 
APPENDIX A: TIME AND EVENTS SCHEDULE .................................................................75 
LIST OF TABLES
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Names and Addresses of Institutions ............................................................................5 
Table 3: 
Revision History ...........................................................................................................6 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................20 
Table 5: 
Dose Cohorts ..............................................................................................................28 
Table 6: 
Anterior Chamber Cells Grading Scale ......................................................................51 
Table 7: 
Anterior Chamber Flare Grading Scale ......................................................................52 
Table 8: 
Scale for Determining Degree of Vitreous Haze ........................................................52 
Table 9: 
Clinical Laboratory Analytes to be Tested .................................................................54 
Table 10: CTCAE Intensity Grades ............................................................................................56 
LIST OF FIGURES
Figure 1: 
Study Treatment Schedule ..........................................................................................29 


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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 4: 
Abbreviations and Specialist Terms
Abbreviation or Specialist Term
Explanation 
AE
Adverse event 
AMD
Age-related macular degeneration
BCVA
Best corrected visual acuity
BSS
Balanced saline solution
CABG
Coronary artery bypass surgery 
Cmax
Maximum serum concentration 
CNV
Choroidal neovascularization
CRF
Case report form
CST
Central subfield retinal thickness 
CTCAE
Common Terminology Criteria for Adverse Events 
CVA
Cerebrovascular accident
DLT
Dose limiting toxicity
ECG
Electrocardiogram
ETDRS
Early Treatment Diabetic Retinopathy Study 
FA
Fluorescein angiogram
GCP
Good Clinical Practice
GI
Gastrointestinal
IB4
isolectin B4
IC50
50% inhibitory concentration
ICH
International Conference on Harmonization 
IEC
Independent Ethics Committee 
IOP
Intraocular pressure 
IRB
Institutional Review Board 
IVT
Intravitreal(ly)
nAMD
Neovascular age-related macular degeneration
NCI
National Cancer Institute
NVI
Neovascularization of the iris
NYHA
New York Health Association
MedDRA
Medical Dictionary for Regulatory Applications 


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Table 4: 
Abbreviations and Specialist Terms (Continued)
Abbreviation or Specialist Term
Explanation 
OCT-A 
Optical coherence tomography angiography 
PCV
Polypoidal choroidal vasculopathy 
PD
Pharmacodynamics 
PDGFR 
Platelet-derived growth factor receptor
PK
Pharmacokinetics
PRN
Pro re nata; “when necessary”
PSVT
Paroxysmal supraventricular tachycardia
PTCA
Percutaneous transluminal coronary angioplasty 
RAP
Retinal angiomatous proliferation
RPE
Retinal pigment epithelial
SAE
Serious adverse event
SC
Suprachoroidal 
SCS
Suprachoroidal space 
SD-OCT
Spectral Domain Optical Coherence Tomography 
SMC
Safety Monitoring Committee 
SOC
Systemic organ class
SVT
Supraventricular tachycardia
TEAE
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitor
VA
Visual acuity
VEGF
Vascular endothelial growth factor 
VEGFR
Vascular endothelial growth factor receptor
YAG
Yttrium-Aluminum-Garnet


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5.
INTRODUCTION
In developed countries, neovascular age-related macular degeneration (nAMD) is the leading 
cause of irreversible central blindness (Congdon, 2004, The Eye Disease Prevalence Research 
Group, 2004, Wong, 2014). Age-related macular degeneration (AMD) pathogenesis is complex 
and still not fully understood. However, many of the mechanisms involved are already partially 
known and, specifically for the 10-15% of AMD classified as the neovascular type, include the 
vascular endothelial growth factor (VEGF) signaling pathway. In nAMD, abnormal blood vessel 
growth results in choroidal neovascularization (CNV) in the choriocapillaris, a layer of 
capillaries situated immediately below Bruch’s membrane, under the retina and macula. 
Choroidal neovascularization leads to the leakage of blood, lipids, and serum into the retinal 
layers and causes the macula to bulge or lift up from its normal position, distorting or destroying 
central vision (Ambati, 2003). In nAMD, VEGF-A, which acts at VEGF receptors 1 and 2 
(VEGFR-1, VEGFR-2), has been shown to promote abnormal blood vessel growth and is 
therefore an appropriate target for treatment.
Currently, anti-VEGF-A drugs are the standard of care for the treatment of nAMD (Flaxel, 
2020); however, an unmet need remains for significantly improving and maintaining visual 
acuity in most patients (Rofagha, 2013, CATT, 2016, Singer, 2012). Specifically, there may be a 
ceiling of efficacy with current anti-VEGF-A agents, as increased anti-VEGF-A dosage or more 
intense regimens yield no additional best corrected visual acuity (BCVA) benefit (Heier, 2012,
Busbee, 2013, Schmidt-Erfurth, 2014).  Recent data on VEGF regulation may be relevant, as 
anti-VEGF-A therapy has been shown to upregulate other members of the VEGF family in both 
macular degeneration (Cabral, 2018) and colon cancer patients (Lieu, 2013); this secondary 
upregulation of other members of the VEGF family may account for "resistance" to VEGF-A
therapy (Lieu, 2013). Furthermore, the current treatment paradigm of frequent intravitreal (IVT) 
injections is burdensome. For example, recent large “real-world” retrospective studies of nAMD 
demonstrated that patients are undertreated receiving only 6 to 7 injections on average, yielding 
only a mean 1 to 3 letters gained in BCVA one year after initiation of treatment (Ciulla, 2020,
Rao, 2018).
Axitinib demonstrates intrinsic high potency and achieves pan-VEGF inhibition through tyrosine 
kinase receptor blockade (INLYTA, 2018, Hu-Lowe, 2008); it is a second-generation tyrosine 
kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptors VEGFR-1, 
VEGFR-2, and VEGFR-3 at picomolar concentrations, and inhibits platelet-derived growth 
factor receptors (PDGFR) and c-Kit receptors to a significantly lesser degree, by stabilizing the 
receptor kinase domain in an inactive conformation.  Axitinib is currently approved in an oral 
tablet formulation (INLYTA®) for the treatment of advanced renal cell carcinoma after failure of 
1 prior systemic therapy.  In preclinical work by independent investigators, axitinib has shown 
promising results in animal models of ocular angiogenesis. Specifically, it effectively inhibited 
corneal, retinal and choroidal angiogenesis in multiple preclinical models (Riquelme, 2018,
Yuan, 2015, Giddabasappa, 2016, Nakano, 2016, Kang, 2013).  Topical axitinib more effectively 
inhibited corneal neovascularization than other topical tyrosine kinase receptor inhibitors in a 
preclinical model (Yuan, 2015).  Furthermore, oral axitinib not only inhibited choroidal 
neovascularization, but also caused regression of established neovascularization in a preclinical 
model (Kang, 2013), a highly desired therapeutic effect for the treatment of human nAMD. In a 
cell culture study, axitinib consistently exhibited superior cell viability among five different 


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ocular cell lines, even under conditions of oxidative stress, compared to other tyrosine kinase 
inhibitors previously assessed in nAMD clinical trials (Thiele, 2013). 
Clearside Biomedical Inc. (“Clearside”, “Sponsor”) is developing a proprietary formulation of 
axitinib, CLS-AX (axitinib injectable suspension) to treat nAMD by injection into the 
suprachoroidal space (SCS). Suprachoroidal (SC) injection is a novel drug-dispensing approach 
that employs the SCS Microinjector®, a proprietary piston syringe and a needle approximately 1 
mm in length. A SC injection is the term used to describe this intraocular injection procedure 
performed in the pars plana approximately 4 - 4.5 mm posterior to the limbus, resulting in sub 
scleral dispensing of drug product into the SCS which is the transition region between the sclera 
and the choroid.  
Immediately after the SC injection procedure, injectate moves posteriorly from the site of the 
injection, with the fluid being absorbed dominantly into the inner sclera, choroid, retinal pigment 
epithelial (RPE) cells, and retina (based on animal models). Suprachoroidal injection of CLS-
AX, with a resulting ocular distribution of CLS-AX in high amounts into the choroid, RPE cells, 
and retina (based on data from animal models) provides the potential for robust and sustained 
efficacy outcomes in patients with nAMD. While there is high exposure to CLS-AX in the retina, 
RPE cells, and choroid, there is also lower exposure to CLS-AX in the anterior segment and the 
lens, providing the potential for a reduced incidence of ocular adverse events. Systemic levels of 
axitinib following SC injection are low to below the limits of quantification. Further, these 
systemic levels of axitinib are vastly below levels observed following oral administration of 
axitinib.  Suprachoroidal injection with Clearside’s SCS Microinjector has been evaluated in 
humans in the Sponsor’s clinical development program for an ocular corticosteroid (XIPERE™,
triamcinolone acetonide injectable suspension, previously known as CLS-TA) for suprachoroidal 
use, approved in 2021 by the US FDA for the treatment of macular edema associated with uveitis
(XIPERE Prescribing Information, 2021). Suprachoroidal injections may be associated with 
increased ocular pressure at the time of injection, therefore subjects should be appropriately 
assessed following completion of the suprachoroidal injection.  Additionally, risks of ocular 
toxicity and/or inflammation have been mitigated through the single dose escalation design of 
this clinical trial, with an initial dose based on preclinical toxicology studies in two species.  
Procedural risks, such as hemorrhage, infection, ocular hypertension, and retinal tear or 
detachment, have been assessed to be low and acceptable in previous clinical studies with CLS-
TA, which have utilized the identical injector design in over 1000 injection procedures.
Nonclinical pharmacodynamic (PD) studies demonstrate reduced fluorescein leakage and 
reduced growth of new blood vessels after SC injection of CLS-AX, while pharmacokinetic (PK) 
studies demonstrate durability via SC injection, supporting the potential to reduce treatment 
burden associated with frequent IVT injections. 
x
In a laser-induced porcine model of CNV, 8 pigs were administered SC injections of 4 
mg of CLS-AX in the right eye and balanced salt solution (BSS) in the left eye. At 1 and 
2 weeks after the laser-induced injury, the eyes treated with CLS-AX had a significantly 
smaller mean area of fluorescence compared to the BSS-treated eyes (P<0.009).  
Quantification of neovascularization was performed on retinal flat mount tissue by 
measuring the isolectin B4 (IB4) signal. This analysis revealed that eyes treated with CLS-
AX had significantly lower IB4 signal than BSS treated eyes (P=0.0297). 


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x
Similar results were obtained in a rat laser induced CNV model following SC injections 
of CLS-AX once weekly for 2 weeks. Decreases in the incidence of clinically important 
lesions (scores of 3 or 4) were noted in animals given 0.4 mg/eye CLS-AX, where 8/20 
eyes (40%) showed a general improvement (scores of 0 to 2) and attained statistical 
significance by Day 21, compared to 2/20 eyes (10%) receiving control (saline). These 
results indicate that SC injection of CLS-AX significantly reduced fluorescein leakage 
and growth of new blood vessels at the site of the retinal laser lesion as compared to 
saline treatment. 
With respect to PK, a 10-week study was performed in pigmented Dutch Belted rabbits to 
determine ocular tissue distribution after a single SC administration of CLS-AX. The injection 
was well tolerated. Retinal levels were maintained above the in vitro 50% inhibitory 
concentration (IC50) with a SC injection of CLS-AX at 0.03 mg/eye and at 0.1 mg/eye for the 
entire duration of the study. 
Systemic absorption of axitinib following SC administration of CLS-AX was assessed in two 
non-GLP compliant 2-week single dose tolerability studies (with toxicokinetics (TK)) in rabbits 
and monkeys, one GLP compliant 4-week single dose toxicity studies in rabbits (with TK and a 
26 week recovery period), and one GLP compliant 4-week single dose toxicity study in monkeys 
(with TK); all by SC injection. Plasma from blood collected from rabbits and monkeys during 
the conduct of 4-week toxicity studies was analyzed using an LC-MS/MS method. The lower 
limit of quantification (LLOQ) was 2 ng/mL in both species. 
x
In the 2-week single dose rabbit toxicity study, CLS-AX was administered as a single 
unilateral SC injection (100 μL/right eye) to male New Zealand White rabbits 
(3/group) at 0 (vehicle), 0.4, 1.5, or 4.0 mg axitinib/right eye once on Day 1. Blood 
samples were collected on day 1 pre-dose and 0.5, 1, 2, 4, 12, and 24 hours post-dose. 
Axitinib was below the LLOQ in all plasma samples except two samples (one animal 
given 1.5 mg/right eye [2.11 ng/mL] and one animal given 4.0 mg/right eye [2.28 
ng/mL]) from the 1-hour time point. 
x
In the 4-week single dose rabbit toxicity study with a 26-week recovery phase, CLS-
$;ZDVJLYHQDVDVLQJOHELODWHUDO6&LQMHFWLRQȝ/H\HWRPDOHDQGIHPDOH
pigmented Dutch Belted rabbits (5 animals/sex/group) at 0 (vehicle), 0.105, 1.05, or 
4.2 mg axitinib/eye once on day 1.  Blood samples were collected on day 1 pre-dose 
and 0.25, 0.5, 1, 6, 12, and 24 hours post-dose, and on days 28, 29 or 30, 60, 91, 120, 
and 150. Axitinib was detected in one plasma sample (one animal given 4.2 mg/ eye 
[3.05 ng/mL]) from the 0.25-hour time point on Day 1. All other samples were below 
the LLOQ.
x
In the 2-week single dose monkey toxicity study, CLS-AX was administered as a 
single unilateral SC injection (100 μL/right eye) to male cynomolgus monkeys 
(2/group) at 0 (vehicle), 4.0, 6.0, or 8.0 mg axitinib/right eye once on Day 1. Blood 
samples were collected on day 1 pre-dose, and 0.5, 1, 2, 4, 8, and 24 hours post-dose. 
Axitinib was not detected in any plasma samples at any intervals during this study.  
x
In the 4-week single dose monkey toxicity study, CLS-AX was administered as a 
single unilateral SC injection (100 μL/right eye) to male and female cynomolgus 




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6.
TRIAL OBJECTIVES AND PURPOSE
6.1.
Primary Objective 
To assess safety and tolerability of a single dose of CLS-AX in subjects with neovascular age-
related macular degeneration who show stable visual acuity following >3 injections with an 
intravitreal anti-VEGF therapy in the preceding 5 months. 
6.2.
Secondary Objectives
To evaluate and compare the effect of 4 cohort regimens of a single dose of CLS-AX over 3 
months on visual function and ocular anatomy and the need for additional treatment with 
intravitreal aflibercept.
To evaluate the pharmacokinetics of the 4 cohort regimens of a single dose of CLS-AX over 3 
months. 
6.3.
Exploratory Objectives
To evaluate the safety and performance of the SCS Microinjector.










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Recommendations for initiating the next higher cohort will be the responsibility of the SMC 
based on the totality of all available safety data.  Study drug administration at the next higher 
dose cohort may not proceed until the Investigator receives written confirmation from Clearside 
Biomedical, indicating the available results from the previous dosed cohort were evaluated and it 
is permissible to proceed to the next higher dose cohort. 
























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8.4.7.
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, unless the visit results in study 
discontinuation at which point an attempt should be made to collect all Visit 5 assessments and 
the visit documented as such.






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Use of the following treatments is prohibited at any time during the study: 
In cases where there is anticipated need for any of the treatments listed here during the study
(post Screening Visit), 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 nAMD in the 
study eye and normal standard of care requires additional intervention, the treatment(s) should be 
recorded in the subject’s source document(s) and CRF and should follow the guidelines 
presented for additional therapy criteria. Subjects will not be discontinued from the study 
because of initiation of or change in a prohibited medication. 
9.6.
Treatment Compliance
Study medication will only be administered by trained study Investigators at the site.  No study 
medication will be dispensed to subjects; therefore, subject treatment compliance is not 
applicable.
9.7.
Randomization and Masking
This is a Phase 1/2a dose-escalation study.  Subjects will not be randomly assigned to a treatment 
or dose cohort. 
Enrollment of subjects into the next higher dose cohort will not proceed until the SMC 
recommends initiation following review of all available safety data (Section 7.6.3). 
This is an open-label study; no masking is necessary. 










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Tonopens may be used for post-injection pressure checks and in cases where no Goldmann is 
available.  The technician is encouraged to use the same tonometry method throughout the 
subject’s study participation.  IOP will be measured 2 times at all visits in which a study 
treatment is administered including the IVT aflibercept injection at Screening (Visit 1), the CLS-
AX injection at Baseline (Visit 2), and any additional IVT aflibercept injection administered 
PRN at Visits 3 and 4 (Weeks 4 and 8):  before treatment and 10 to 30 minutes after treatment.
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. IOP will be assessed at all visits.
12.1.5.
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, pupil and 
conjunctiva, cornea, anterior chamber, iris, and lens. All abnormal findings will be described. 
Slit lamp examination of the iris is to rule out neovascularization of the iris (NVI). Slit lamp 
biomicroscopy will be assessed at all visits.
12.1.5.1.
Cataract Lens Grading 
If an abnormal finding of cataract is noted during the slit-lamp examination, the cataract should 
be graded for nuclear opalescence, cortical opacity, and posterior subcapsular opacity. Graders 
must verify training on the grading procedures. Cataract classification will be based on the Lens 
Opacities Classification System III (LOCS III) grading scale (Chylack, 1993). Grading should be 
done by the same Investigator, whenever possible, on each subject per research site.
12.1.5.2.
Anterior Chamber Cells
Anterior chamber cells will be assessed clinically using a field size of 1 mm slit beam and using 
a standardized grading scale ranging from 0 to 4+, as defined in Table 6 (SUN, 2005).
Table 6: 
Anterior Chamber Cells Grading Scale
Score
Cells in Field
0
<1
0.5+ 
1-5 
1+ 
6-15 
2+ 
16-25 
3+ 
26-50 
4+ 
>50 
12.1.5.3.
Anterior Chamber Flare
Anterior chamber flare will be assessed clinically via slit lamp using a standardized scale ranging 
from 0 to 4+, as defined in Table 7 (SUN, 2005). 








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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 subject has signed informed consent, or during the study 
participation, whether or not they are related to the study drug, SCS Microinjector system or 
study procedure, must be recorded on the appropriate form provided.  Each AE is to be evaluated 
for duration, intensity, and causal relationship with the study medication or other factors.
At every visit, patients should be asked about AEs in an open-ended manner as well as asked 
about the status of any previously reported AEs. 
When possible, a specific disease or syndrome rather than an individual associated sign or 
symptom should be identified by the Investigator and recorded on the form.  If an observed or 
reported sign or symptom is not considered a component of a specific disease or syndrome by the 
Investigator, it should be recorded as a separate AE on the form. 
NOTE: A significant or unexpected worsening or exacerbation of the condition/indication under 
investigation should be reported as an AE.  However, anticipated day-to-day fluctuations or 
expected progression of the disease under investigation (based upon the Investigator’s clinical 
judgment) are not to be considered AEs. 
12.2.1.2.
Clinical Laboratory Abnormalities and other Abnormal Assessments as Adverse 
Events and Serious Adverse Events
Abnormal laboratory findings (e.g., clinical chemistry, hematology, and urinalysis) or other
abnormal assessments (e.g., ocular assessments, ECGs, and vital signs) that are judged by the 
Investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition 
of an AE or SAE.  Clinically significant abnormal laboratory findings or other abnormal 
assessments that are detected during the study or are present at baseline and significantly worsen 
following exposure to study drug are to be reported as AEs or SAEs.  However, clinically 
significant abnormal laboratory findings or other abnormal assessments that are associated with 
the disease being studied, unless judged by the Investigator as more severe than expected for the 
patient’s condition, or that are present at the start of the study and do not worsen, should not be 
reported as AEs or SAEs. 
The Investigator will exercise medical and scientific judgment in deciding whether an abnormal 
laboratory or assessment is clinically significant and if it requires reporting.
12.2.1.3.
Serious Adverse Event (SAE)
An SAE is defined as an AE that meets any of the following criteria: 
x
Results in death.
x
It is immediately life-threatening NOTE:  The term “life threatening” refers to an 
event in which the patient is at risk of death at the time of the event.  It does not refer 
to an event which hypothetically might have caused death if it was more severe. 
x
It requires in-patient hospitalization or prolongation of existing hospitalization.  
NOTE:  Hospitalization for an elective or procedure planned prior to the signing of 


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the informed consent to treat a preexisting condition is not considered an SAE unless 
it results in one of the other outcomes listed in this section.
x
It results in persistent or significant disability or incapacity.
x
Results in a congenital abnormality or birth defect. 
x
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 subject has signed informed consent, whether or not they are 
related to the study, must be recorded on the forms provided. 
12.2.2.
Evaluating Adverse Events 
12.2.2.1.
Intensity/Severity Grade
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: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf. 
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 12.2.1.3. An AE of severe intensity 
may not be considered serious. 
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: 
Table 10: 
CTCAE Intensity Grades
Grade
Description
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2
Moderate; minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of the hospitalization indicated; 
disabling; limiting self-care ADL
Grade 4
Life-threatening consequences; urgent intervention indicated 
Grade 5
Death related to AE


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12.2.2.2.
Assessment of Causality 
The Investigator is responsible for making an assessment of the causal relationship between the 
AE and the study drug, drug delivery system, and/or study procedure based on the available 
information. 
The causal relationship of the AE is assessed using a binary system, and AEs are classified as 
either Related or Unrelated to the study drug, drug delivery system, and/or study procedure. 
In assessing this relationship, the Investigator should consider the potential etiologies for the 
observed AE.  An AE may be related to: 
x
The study drug(s). 
x
Other concomitant medications.
x
Underlying disease pathology. 
x
A pre-treatment condition.
x
A procedure performed in the course of the study. 
x
Other alternative reason. 
Among the potential etiologies, the Investigator should make a determination based on the most 
likely causal relationship.  The causality assessment provided for an AE or SAE should be 
accompanied by all available supporting evidence, including but not limited to supporting 
laboratory tests, histopathology, history of the presenting event, medical history, temporal 
association, and results of relevant diagnostic procedures. 
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 on the CRF.  Information about AEs will be collected from the time of 
signing of the consent form until 30 days after the end of study participation. Detailed 
information regarding all SAEs should be collected from the signing of the informed consent 
until the end of the study.  SAEs that are considered related to the use of study drug, the drug 
delivery system, and/or study procedure by the Investigator may be reported by the Investigator 
if they occur after the end of the study.  The Investigator must continue to follow the patient until 
the SAE has resolved, the condition has become chronic in nature, the condition stabilizes (in the 
case of persistent impairment), the patient experiences a fatal outcome or is lost to follow up. 
The AE term should be reported in standard medical terminology as concisely as possible.  In 
general, the AE recorded should not be a procedure, outcome, or clinical/laboratory 
measurement, but should reflect the event leading to the procedure, outcome or the cause of the 
clinical/laboratory abnormality, if known.  Whenever possible, AEs should be evaluated and 
recorded as a diagnosis, rather than as individual signs or symptoms.  However, if a definitive 
diagnosis is not possible, the individual signs and symptoms should be recorded.  For each AE, 
the Investigator will evaluate and report the onset (date and time), resolution (date and time), 


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intensity, causality, action taken, seriousness, outcome (if applicable), and whether or not it 
caused the patient to discontinue the study.
12.2.4.
Reporting Adverse Events
All AEs (related and unrelated) will be recorded from the signing of consent form until 30 days 
after the end of study participation.  All SAEs occurring during subject participation, and all 
SAEs considered related to the study drug, drug delivery system, and/or study procedure and 
discovered by the Investigator at any time after the study should be reported.  All such SAEs 
must be reported to Clearside Biomedical, or its designee, within one 24 hours of the knowledge 
of the occurrence 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 email (CLS001Safety@medtrials.com) to Clearside Biomedical, 
or its designee. 
Additional follow-up information, if required or available, should all be emailed or faxed to 
Clearside Biomedical, or its designee, within one business day of receipt.  This information
should be recorded on a follow-up SAE form and placed with the original SAE information and 
kept with the appropriate section of the CRF and/or study file. 
Clearside Biomedical and/or its designee is responsible for notifying the relevant regulatory 
authorities of certain events.  It is the Principal Investigator’s responsibility to notify and submit 
required safety information to their IRB or IEC.  This information includes, but is not limited to, 
any safety alert letter received from the Sponsor and any SAEs occurring at their investigative 
site.
Investigators will also be notified of all unexpected, serious, drug-related events, drug delivery 
system related events and study procedure related events (7/15 Day Safety Reports) that occur 
during the clinical trial.  Each site is responsible for notifying its IRB or IEC of these additional 
SAEs.  A copy of these reports must be retained at the investigative site and file in the Trial 
Master File.
12.2.5.
Follow-up of AEs and SAEs
All AEs and SAEs reported during study conduct must be followed until resolution, or until the 
Investigator assesses them as stable or chronic, the subject withdraws consent, or the subject is 
lost to follow-up. Subjects will be followed for any treatment-related, drug delivery system 
related, and/or study procedure related SAEs reported at the end of participation until the 
condition stabilizes, the event is otherwise explained, the subject is lost to follow-up, the subject 
withdraws consent, or the subject experiences a fatal outcome. 
NOTE: “Resolution” means the subject has returned to baseline state of health, or the 
Investigator does not expect any further improvement in the subject’s condition or does not 
expect worsening of the AE. 
For a non-serious AE that is first identified on the last scheduled contact, the event must be 
recorded on the AE CRF with the current status noted, but no further follow-up needs to be 
performed unless deemed necessary by the Investigator or the Sponsor. 


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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, the use of the drug delivery system, and/or study procedure, should be 
reported to the Sponsor. The Investigator should follow related SAEs identified after the last 
scheduled contact until the event has resolved or stabilized or the subject is lost to follow-up. 
12.2.6.
Exposure in utero During Clinical Trials
The Sponsor must be notified of any patient who becomes pregnant while participating in the 
clinical trial.  Although pregnancy is not considered an AE, all pregnancies must be followed to 
conclusion to determine their outcome.  This information is important for both drug safety and 
public health concerns.  It is the responsibility of the Investigator or designee to report any 
pregnancy in a subject that occurs during the study.  Should a patient in the study become 
pregnant, the site must complete the Exposure in utero reporting form.  Notification should be 
made within 24 hours of awareness of the event.
It is the responsibility of the Investigator, or designee, to report any pregnancy and the 
anticipated date of birth that occurs while receiving, or within 30 days of discontinuing the study 
drug, via the Exposure in utero reporting form.  If the pregnancy is to be terminated, the 
anticipated date of termination should be provided. 
If it is the partner, rather than the subject, who is found to be pregnant, after obtaining the 
partner’s consent, the Exposure in utero reporting form should be completed with the anticipated 
date of birth/termination and details regarding the partner should be entered in the narrative 
section of the form. 
The patient/partner should be followed by the Investigator until completion of the pregnancy.  If 
the pregnancy ends for any reason before the anticipated date of birth/termination, the 
Investigator should notify the Sponsor.  At the completion of the pregnancy, the Investigator will 
document the outcome of the pregnancy.  If the outcome of the pregnancy meets criteria for 
immediate classification as an SAE (i.e., post-partum complications, spontaneous abortion, 
miscarriage, still birth, neonatal death, or congenital anomaly (even of an aborted fetus), the 
Investigator should follow the procedures for reporting an SAE.  Note, elective termination of a 
pregnancy would not meet criteria as an SAE and in these cases a follow up pregnancy report 
should be provided by the Investigator. 
12.2.7.
Complaint Handling
Clearside collects product complaints on study drugs and drug delivery systems used in clinical 
studies in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by Clearside 
will be reported via product complaint forms. 
The complainant (the Investigator, site staff, etc.) or his/her designee is responsible for handling 
the following aspects of the product complaint process in accordance with the instructions 
provided for this study: 


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x
Recording a complete description of the product complaint reported and any 
associated AEs using the study-specific complaint forms provided for this purpose. 
x
Emailing the completed product complaint form within 24 hours of awareness to 
Clearside at the following address:  complaints.QA@clearsidebio.com. 
x
Returning a Study drug/drug delivery system for investigation when directed by 
Clearside.




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Safety endpoints are provided in Section 7.2.  Additional endpoints will be described in the 
statistical analysis plan.
13.5.1.
Schedule of Analyses
The study duration per cohort will consist of up to 4 weeks of screening followed by a 12-week 
post-treatment period.
Cohorts 1 and 2: 
Analyses of study data for evaluating each dose cohort will be performed after all subjects 
enrolled into the dose cohort have completed the Week 12 visit (or have been discontinued from 
the study prior to this visit) and the data has been locked.
Cohort 3: 
Analyses of all available safety data will be performed after the fourth subject enrolled into the 
dose cohort has completed at least Visit 3 (Week 4) (or discontinued prematurely from the study 
prior to this visit).  These analyses will include all available study data and will be performed on 
data that has not been fully audited. 
Analysis of study data will be performed after all subjects enrolled into the dose cohort have 
completed the Week 12 visit (or have been discontinued from the study prior to this visit) and the 
data has been locked. 
At study completion: 
Analyses of study data for comparing across dose cohorts will be performed after all subjects 
enrolled into the last cohort have completed the Week 12 visit (or have been discontinued from 
the study prior to this visit) and the data has been locked. 
13.5.2.
Safety Analysis 
The summary of adverse events (and SAEs) will be limited to TEAEs.  Treatment-emergent 
adverse events are defined as an event that emerges during treatment with CLS-AX having been 
absent pre-treatment or worsens relative to the pre-treatment state.
For summarizing adverse events, each reported adverse event term will be coded to a preferred 
term and its corresponding system organ class (SOC) using the Medical Dictionary for 
Regulatory Activities (MedDRA) coding dictionary.  Summary tables will be presented by dose 
cohort. 
Summary tables of TEAEs will be produced for the following categories divided into Study Eye 
TEAEs, Fellow Eye TEAEs, ocular TEAEs, non-ocular TEAEs and overall TEAEs, grouped by 
SOC and preferred term: 
x
All TEAEs. 
x
All treatment-related TEAEs. 
x
All TEAEs leading to study discontinuation. 
x
All SAEs. 


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x
All treatment-related SAEs. 
x
All TEAEs leading to death.
x
All TEAEs related to the SC procedure, based on the Investigator’s assessment. 
For each summary, adverse events will be summarized by presenting the number and percentage 
of subjects reporting each event at least once, and the total number of events reported. 
13.5.3.
Secondary Safety Analyses 
Secondary safety analyses will be performed on all subjects in the Safety Population.  Ocular 
safety will be assessed by evaluating IOP, BCVA and outcomes obtained from the slit-lamp 
biomicroscopy, indirect ophthalmoscopy, SD-OCT, fundus photography and angiography 
examinations.  Summaries will be provided for each dose cohort for the Study eye. 
Systemic safety will be assessed by evaluating vital signs, clinical laboratory tests, 12-lead 
electrocardiograms and concomitant medications.  Summaries will be provided for each dose 
cohort. 
13.5.4.
Subgroup Analysis
No subgroup analyses are planned. 
13.5.5.
Interim Analysis
The schedule of analyses of safety data from each cohort are described in Section 13.5.1. No 
formal statistical testing will be conducted.  All inferential statistics will be for descriptive 
purposes only; therefore, no adjustments will be made to the type 1 error rate to account for 
multiple analyses of the data.
13.5.6.
Pharmacodynamic Analysis 
Not applicable.
13.5.7.
Pharmacokinetic Analysis
Standard population PK parameters will be calculated from plasma CLS-AX concentrations.  To 
characterize the population PK of CLS-AX, PK parameters will be related to dose cohort.  
Analysis will be conducted according to the nonlinear mixed-effects approach and will provide 
estimates of population characteristics that define the population distribution of the PK 
parameters.
13.5.8.
Procedure for Accounting for Missing Data
Any missing, unused, or spurious data will be noted in the final clinical study report. 
No imputation for missing data will be used in the Safety Populations. 
Algorithms for handling partial or incomplete dates for adverse events, concomitant medications, 
and diagnoses will be defined in the statistical analysis plan. 


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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 or its designee will assess the investigational study site to:
x
Determine the adequacy of the facilities and personnel. 
x
Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Clearside Biomedical, Inc. or its 
designee.  This will be documented in a Clinical Study Agreement between Clearside 
Biomedical, Inc. and the Investigator. 
x
Ensure adequate training of Principal Investigator/sub-Investigators for use of the 
microinjector. 
During the study, a monitor from Clearside Biomedical, Inc. or representative will have regular 
contacts (oral, written, onsite, virtual) with the investigational site, for the following:
x
Provide information and support to the Investigator (s). 
x
Confirm that facilities and personnel remain acceptable.
x
Confirm that the investigational team is adhering to applicable standards for 
conducting trials (e.g., ICH, GCP) the protocol, that data are being accurately 
recorded in the case report forms, and that study drug accountability checks are being 
performed. 
x
Perform source data verification.  This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, and other 
source documents relevant to the study.  This will require direct access to all original 
records for each patient (e.g., clinic charts).
x
Record and report any protocol deviations not previously sent to Clearside 
Biomedical, Inc. or designee. 
x
Confirm AEs and SAEs have been properly documented on CRFs and confirm any 
SAEs have been forwarded to Clearside Biomedical, Inc, or designee, and those 
SAEs that met criteria for reporting have been forwarded to the IRB/IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs
information or advice. 
14.2.
Audits and Inspections
Authorized representatives of Clearside Biomedical, Inc, a regulatory authority, an Independent 
Ethics Committee or an Institutional Review Board may visit the 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, 


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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, Inc immediately if contacted by a 
regulatory agency about an inspection. 
14.3.
Institutional Review Board (IRB)
The Principal Investigator must obtain IRB/IEC approval for the investigation.  Initial IRB/IEC
approval, and all materials approved by the IRB/IEC for this study including the subject consent 
form and recruitment materials must be maintained by the Investigator and made available for 
inspection. 


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15.
QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Clearside or it’s agent(s) or designee(s) will conduct periodic monitoring 
visits to ensure the protocol and Good Clinical Practice (GCPs) are being followed.  The 
progress of the study will also be monitored by written, e-mail, and telephone communications 
between personnel at the study site and the Sponsor and its agent(s) or designee(s). The 
Investigator will allow Sponsor monitors, or designee(s), direct access 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 to perform verification 
and to confirm that the data recorded on CRFs is accurate. 
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Clearside, or 
companies working with or on behalf of Clearside, and/or to inspection by appropriate regulatory 
authorities.
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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16.
ETHICS 
16.1.
Ethics Review
The final study protocol, including the final version of the Informed Consent Form, and other 
relevant documents, e.g., recruitment advertisements, if applicable, 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 patients 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 study drug.  
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. 
All correspondence with the IRB/IEC should be retained in the Investigator File.   
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 local 
regulatory requirements and laws.  In addition, the study will be conducted in accordance with 
the protocol. 
The Investigator will inform Clearside and/or its agent(s) immediately of any urgent safety 
measures taken by the Investigator to protect the study subjects against any immediate hazard, 
and of any serious breaches of this protocol or of ICH GCP that the Investigator becomes aware 
of.
16.3.
Written Informed Consent
The Principal Investigator(s) at each center will be responsible for ensuring that the patient is 
given full and adequate oral and written information about the nature, purpose, 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 informed consent document must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements. The informed consent document used in this 
study, and any changes made during the course of the study, must be prospectively approved by 
both the IRB/IEC and Clearside and/or its agent(s) before use.  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 
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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. 


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17.
DATA HANDLING AND RECORDKEEPING
17.1.
Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included subject.  The completed original 
CRFs are the sole property of Clearside and should not be made available in any form to third 
parties, except for authorized representatives of Clearside or appropriate regulatory authorities, 
without written permission from Clearside.
The Investigator has ultimate responsibility for the collection and reporting of all clinical, safety 
and laboratory data entered on the CRFs and any other data collection forms (source documents) 
and ensuring that they are accurate, authentic / original, attributable, complete, consistent, 
legible, timely (contemporaneous), enduring and available when required. 
17.2.
Inspection of Records
Clearside Biomedical, Inc or its 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 study drug storage area, study drug inventory, study 
drug accountability records, subject charts and study source documents, and any other records 
relative to study conduct.  
17.3.
Retention of Records
The Principal Investigator must maintain all records 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, Inc or the Regulatory Authority to review any documentation relating to the study, 
the Investigator must permit access to such records.


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18.
FINANCING AND INSURANCE
18.1.
Finance
This study is supported by Clearside Biomedical, Inc. 
18.2.
Insurance
Documentation of product liability insurance is on file at Clearside and is available upon request.


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19.
PUBLICATION POLICY
All information concerning CLS1002-101 and the operations of Clearside Biomedical, Inc., such 
as patent, applications, formulas, manufacturing processes, basic scientific data or formulation 
information not previously published, are considered CONFIDENTIAL and shall remain the sole 
property of Clearside Biomedical Inc. The Investigator agrees to use this information only in 
accomplishing this study and will not use it for other purposes without the written consent of 
Clearside Biomedical Inc. 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.


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20.
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