Clinical trial NCT02980874
Conditions: Macular Edema Retinal Vein Occlusion
Keywords: RVO ME Central Subfield Thickness OCT Optical Coherence Tomography Cystoid Macular Edema Subretinal Fluid Eylea Aflibercept Anti-VEGF Suprachoroidal Triamcinolone acetonide
Sponsor: Clearside Biomedical, Inc.
Start date: 2017-01-31; Completion date: 2018-12-10
Enrollment: 460 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, multicenter, randomized, masked, controlled, parallel group study of 12 months duration in treatment naïve subjects with RVO.

Detailed description:
A randomized, masked, controlled trial to study the safety and efficacy of suprachoroidal CLS-TA in conjunction with intravitreal aflibercept in subjects with retinal vein occlusion

Arms: arm 1: IVT aflibercept (2 mg/0.05 mL) + CLS-TA (4 mg/100 µL) SC injections arm 2: IVT aflibercept (2 mg/0.05 mL) + sham SC procedure
Interventions: intervention 1: suprachoroidal CLS-TA intervention 2: suprachoroidal sham intervention 3: IVT aflibercept
Intervention descriptions: intervention 1: suprachoroidal injection of CLS-TA intervention 2: suprachoroidal sham procedure intervention 3: 2 mg intravitreal injection of aflibercept

Protocol documents:
Prot_SAP_000.pdf: 
Compound Name: 
CLS-TA, triamcinolone acetonide injectable suspension 
Protocol Number: 
CLS1003-301 
IND Number: 
115683 
NCT Number:  
NCT02980874 
Protocol Title 
SAPPHIRE: A Randomized, Masked, Controlled Trial To 
Study The Safety And Efficacy Of Suprachoroidal CLS-TA 
In Conjunction With Intravitreal Aflibercept In Subjects With 
Retinal Vein Occlusion 
Sponsor: 
Clearside Biomedical, Inc. 
900 North Point Parkway, Suite 200 
Alpharetta, GA 30005 
Issue Date: 
Protocol Amendment 1 Date: 
18 November 2016 
31 March 2017 
 


Clinical Study Report 
CLS1003-301 
16.1 Study Information 
Page 1 of 1 
Confidential 
1.
PROTOCOL AND AMENDMENTS
Table 1: 
Protocol CLS1003-301
Original Protocol / 
Amendment 
Date 
Protocol Revision 
Amendment 1 
31 March 2017 
v2.0 
Original Protocol 
18 November 2016 
v1.0 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 1 of 13 
CONFIDENTIAL 
SUMMARY OF CHANGES 
Protocol Amendment 1 
 
Protocol Title: 
SAPPHIRE: A RANDOMIZED, MASKED, CONTROLLED TRIAL 
TO STUDY THE SAFETY AND EFFICACY OF SUPRACHOROIDAL 
CLS-TA IN CONJUNCTION WITH INTRAVITREAL AFLIBERCEPT 
IN SUBJECTS WITH RETINAL VEIN OCCLUSION 
Protocol Number: 
IND: 
CLS1003-301 
115683 
Original Version Date: 
18 November 2016 
Amendment Number: 
1 
Version Date: 
31 March 2017 
 
 
 
 
 
 
 
 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension 
 Clearside Biomedical, Inc  
CLS1003-301 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 2 of 13 
CONFIDENTIAL 
Amendment 1 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Title Page 
For protocol 
identification 
None 
Title Page 
1220 Old Alpharetta Rd., Suite 300 
Alpharetta, GA 30005 
Clearside Biomedical, 
Inc. Address change 
None 
Title Page 
Protocol versioning 
None 
Section 7.4. 
Treatment 
Assignment 
Subjects will be offered continued dosing 
and treated as needed (PRN). Treatment 
provided will be consistent with the 
subject’s assigned treatment group. 
Aflibercept is the most 
effective treatment for 
RVO and allows the 
active and control study 
arms to remain consistent 
in their treatment, except 
for the CLS-TA 
comparison. 
Use of 
aflibercept only 
during PRN 
period. 
Section 7.4. 
Treatment 
Assignment 
Figure 2. 
Updated Figure 2. 
Updating the treatment 
during the PRN dosing 
period. 
None. 
Section 8.1. 
Inclusion Criteria 
Has an ETDRS BCVA score of  ≥ 5 
letters read and ≤ 70 letters read in the 
study eye 
IND and EurdraCT numbers added 
900 North Point Parkway, Suite 200 
Alpharetta, GA 30005 
Addition of Protocol Amendment 1 Date: 
31March2017 
Subjects will be treated, as needed (PRN), 
with aflibercept. 
Figure 2. 
Has an ETDRS BCVA score of  ≥ 20 
letters read and ≤ 70 letters read in the 
study eye 
To ensure changes in 
vision can be measured 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 3 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has, in the study eye, used any topical 
ocular corticosteroid in the 10 days before 
treatment at Visit 2 (Day 0); received any 
intraocular or periocular corticosteroid 
injection in the 2 months before treatment 
at Visit 2; had an OZURDEX® implant in 
the 6 months before treatment at Visit 2;, 
a RETISERT® implant in the 1 year 
before treatment at Visit 2, or an 
ILUVIEN® implant in the 3 years before 
treatment at Visit 2 
 
Has, in the study eye, used any topical 
ocular corticosteroid in the 10 days before 
treatment at Visit 2 (Day 0); has at any 
time received any intraocular or 
periocular corticosteroid injection, an 
OZURDEX® implant, a RETISERT® 
implant, or an ILUVIEN® implant 
To ensure consistency 
with ophthalmic criteria 
None 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has had photocoagulation or cryotherapy 
in the study eye within the 6 months 
before Visit 2 (Day 0)  
Has had >3 macular laser 
photocoagulation treatments; or has had 
photocoagulation or cryotherapy in the 
study eye within the 6 months before Visit 
2 (Day 0) 
 
Eliminate subjects with 
more than 3 macular 
laser photocoagulation 
treatments 
None. 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has significant media opacity precluding 
evaluation of retina and vitreous in the 
study eye. This includes significant 
hemorrhage cataract that is felt to be a 
major contributor to reduced visual acuity 
and/or likely to undergo surgical repair 
within 3 months of randomization 
 
Has significant media opacity precluding 
evaluation of retina and vitreous in the 
study eye. This includes cataract that is 
felt to be a major contributor to reduced 
visual acuity and/or likely to undergo 
surgical repair within 3 months of 
randomization 
To ensure consistency 
with Ophthalmic 
Exclusion criteria 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 4 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
 
History of glaucoma, optic nerve head 
change consistent with glaucoma damage, 
or ocular hypertension in the study eye 
requiring more than one medication; 
Added exclusion criteria 
None 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has a IOP > 22 mmHg or uncontrolled 
glaucoma (open angle or angle closure) in 
the study eye at Visit 1 (Day -14 to -1); 
subjects are not excluded if IOP is ≤ 22 
mmHg in the study eye with no more than 
2 IOP-lowering medications 
Has a IOP > 21 mmHg in the study eye at 
Visit 1 (Day -30 to -1); subjects are not 
excluded if IOP is <22 mmHg in the study 
eye with no more than 1 IOP-lowering 
medication; as long as there is no history 
of glaucoma and the subject has a normal 
optic nerve and no evidence of visual field 
loss; 
 
Updated screening 
window period to match 
protocol 
None 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has a history of glaucoma surgery 
(filtration surgery/trabeculectomy or tube 
shunt) in the study eye; 
Has a history of glaucoma surgery 
(filtration surgery/trabeculectomy or tube 
shunt) in the study eye; has a history of 
laser trabeculoplasty or MIGs surgery in 
the study eye 
Addition of Exclusion 
Criteria 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 5 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.2.2. 
General Exclusion 
Criteria 
Has any uncontrolled systemic disease 
that, in the opinion of the Investigator, 
would preclude participation in the study 
(eg, infection, uncontrolled elevated blood 
pressure, cardiovascular disease, poor 
glycemic control) or put the subject at risk 
due to study treatment or procedures 
Has any uncontrolled systemic disease 
that, in the opinion of the Investigator, 
would preclude participation in the study 
(eg, infection, uncontrolled elevated blood 
pressure, cardiovascular disease, poor 
glycemic control) or put the subject at risk 
due to study treatment or procedures; 
NOTE: Uncontrolled BP at screening may 
be treated before Visit 2 
 
To allow treatment of 
blood pressure prior to 
enrollment. 
None 
Section 8.2.2. 
General Exclusion 
Criteria 
 
History of any inflammatory or other 
medical condition that the investigator 
might reasonably anticipate will require 
treatment with high-dose corticosteroids 
(more than 10mg/day oral prednisone or 
the equivalent) for more than 14 days 
 
Addition of Exclusion 
Criteria 
None 
Section 8.2.3. 
Randomization 
Criteria 
The CRC confirms ME by SD-OCT (from 
Visit 1 SD-OCT data), with or without 
intraretinal or subretinal fluid, caused by 
RVO in the study eye 
 
The CRC confirms ME by SD-OCT (from 
Visit 1 SD-OCT data), with or without 
intraretinal or subretinal fluid 
CRC does not confirm 
RVO 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 6 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.4. Visit 
Procedure 
Descriptions 
All ocular assessments at Visit 1 
(Screening) and Visit 8 (Week 48) will be 
performed on both eyes. Data from other 
ocular assessments at all other visits will 
be performed on the study eye only.   
Perform ophthalmic assessments on the 
study eye only:  
1. ETDRS BCVA 
2. Slit-lamp biomicroscopy  
3. IOP  
4. Dilated indirect ophthalmoscopy 
5. SD-OCT 
All ocular assessments at Visit 1 
(Screening) and Visit 8 (Week 48) will be 
performed on both eyes. IOP will be 
collected in both eyes at all visits. Data 
from all other ocular assessments at all 
other visits will be performed on the study 
eye only.   
Perform ophthalmic assessments on the 
study eye only, unless otherwise 
designated:  
1. ETDRS BCVA 
2. Slit-lamp biomicroscopy, 
including dilated lens grading  
3. IOP (both eyes) 
4. Dilated indirect ophthalmoscopy 
5. SD-OCT 
To collect IOP data on 
the fellow eye at all visits 
for comparison to the 
study eye IOP 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 7 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.4.4.2.2. SC 
Injection of CLS-TA 
(ACTIVE) OR sham 
procedure 
(CONTROL) 
1. Administer SC injection or sham 
after the IVT injection of 
aflibercept when the study eye 
IOP is < 30 mmHg, either 
spontaneously or by treatment, as 
determined by the Investigator 
2. Administer SC injection of 100 
µL of CLS-TA or sham 
procedure approximately 2 or 
more clock hours from the site of 
the IVT injection 
3. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection, 
1. Administer SC injection or sham 
after the IVT injection of 
aflibercept when the study eye 
IOP is < 30 mmHg, either 
spontaneously or by treatment, as 
determined by the Investigator 
2. Prepare study eye for SC 
injection according to the 
Investigator’s standard practice 
3. Administer SC injection of 100 
µL of CLS-TA or sham 
procedure approximately 2 or 
more clock hours from the site of 
the IVT injection 
4. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection, 
Provide detail on 
preparing the eye prior to 
the second injection 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 8 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.4.6.2 PRN 
Injection 
Procedures: Visit 9 
(Week 30), Visit 10 
(Week 36), and Visit 
11 (Week 42) 
If subject qualifies for PRN therapy 
according to the Additional Therapy 
Criteria listed in Section 9.4.2, the 
following injection and post-dose 
procedures should be performed, 
consistent with the subject’s treatment 
group: 
1. Confirm the study eye 
2. Retrieve study drug kit number 
assigned by IWRS 
3. Prepare eye for injection 
according to the Investigator’s 
standard practice 
4. The UNMASKED injecting 
Investigator should perform IVT 
injection of aflibercept, SC 
injection of CLS-TA, and all 
sham procedures to the eye 
 
If subject qualifies for PRN therapy 
according to the Additional Therapy 
Criteria listed in Section 9.4.2, the 
following injection and post-dose 
procedures should be performed, 
consistent with the subject’s treatment 
group: 
1. Confirm the study eye 
2. Retrieve study drug kit number 
assigned by IWRS 
3. Prepare eye for injection 
according to the Investigator’s 
standard practice 
4. The UNMASKED injecting 
Investigator should perform IVT 
injection of aflibercept 
 
Remove reference to SC 
CLS-TA injection during 
PRN period 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 9 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.4.6.2.1. 
IVT injection of 
aflibercept 
1. Prepare study eye for IVT 
injection of aflibercept 
2. Administer aflibercept IVT 
injection according to the 
package insert. The sites of the 
IVT injection and the SC 
injection should be 
approximately 2 or more clock 
hours apart.  A temporal 
quadrant is the recommended 
location for SC injections. 
3. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection, 
4. Measure IOP after injection 
1. Prepare study eye for IVT 
injection of aflibercept 
2. Administer aflibercept IVT 
injection according to the 
package insert. 
3. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection, 
4. Measure IOP after injection 
Remove reference to SC 
CLS-TA injection during 
PRN period 
 
Section 8.4.6.2.2. SC 
Injection of CLS-TA 
(ACTIVE) OR sham 
procedure 
(CONTROL) 
1. Administer SC injection or sham 
after the IVT injection of 
aflibercept when the study eye 
IOP is < 30 mmHg, either 
spontaneously or by treatment, as 
determined by the Investigator 
2. Administer SC injection of 100 
µL of CLS-TA or sham 
procedure approximately 2 or 
more clock hours from the site of 
the IVT injection 
3. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection 
 
Remove reference to 
procedure of SC CLS-
TA reference during 
PRN period 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 10 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.4.6.3. Post-
Dose Procedures: 
Visit 9 (Week 30), 
Visit 10 (Week 36), 
and Visit 11 (Week 
42) 
The following assessments must occur 
after the IVT injection, SC injection, or 
sham procedure:  
 
The following assessments must occur 
after the IVT injection: 
Remove reference to SC 
CLS-TA injection post-
dose procedures during 
PRN period as SC CLS-
TA is no longer 
administered during PRN 
period. 
None 
Section 9.1. 
Treatments to be 
Administered 
Beginning with Visit 9 (Week 30), 
subjects will be assessed for PRN 
treatment that will consist of the same 
treatment, SC CLS-TA in conjunction 
with IVT aflibercept. 
Beginning with Visit 9 (Week 30), 
subjects will be assessed for PRN 
treatment that will consist of IVT 
aflibercept based on PRN criteria (Section 
9.4.2). 
Use of aflibercept only 
during PRN period 
Only approved 
therapy will be 
used during the 
PRN period, 
thus limiting the 
risk to the 
subject 
 
Section 9.4.1. Rescue 
Therapy Criteria 
Beginning at Week 16 (Visit 6), if any of 
the following criteria are met in the study 
eye, the use of a non-investigational 
treatment should be introduced. The 
therapy implemented is left to the 
discretion of the Investigator. 
 
 
 
 
 
 
 
Beginning at Week 8 (Visit 4), if any of 
the following criteria are met in the study 
eye, intravitreal aflibercept will be 
administered. 
To ensure that all 
subjects are adequately 
treated during this period 
and aflibercept is 
required in order to keep 
the therapy consistent 
between arms 
 
To ensure that 
all subjects are 
adequately 
treated during 
this period  


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 11 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 9.4.1. Rescue 
Therapy Criteria 
A decrease in BCVA of 10 letters or 
greater between the current visit and the 
BCVA reading from the previous visit 
A decrease in BCVA of 6 letters or 
greater between the current visit and the 
BCVA reading from the previous visit 
with an increase in CST of > 50 µm from 
the previous visit, associated with new 
fluid 
 
To decrease the number 
of letters lost prior to 
qualifying for additional 
treatment 
To ensure that 
all subjects are 
adequately 
treated during 
this period 
 Section 9.4.1. 
Rescue Therapy 
Criteria 
In the Investigator’s medical judgement, 
the complications of RVO in the study 
eye have not improved and the condition 
needs to be addressed 
If vision is worse than approximately 70 
letters read and there is new or persistent 
intraretinal or sub-retinal fluid, that in the 
opinion of the investigator is affecting 
vision, even if CST <340 µm 
 
Provide guidance around 
the investigator’s 
assessment  
To ensure that 
all subjects are 
adequately 
treated during 
this period 
Section 9.4.2. PRN 
Criteria 
During the PRN Dosing and Follow-Up 
Period (Visits 9 through 11 [Weeks 30 
through 42]), treatment will remain 
consistent with randomized group and 
will remain masked (Section 8.1). Dosing 
is not limited to the rescue criteria above. 
The frequency of treatment is at the 
Investigators discretion during this period. 
 
During the PRN Dosing and Follow-up 
Period (Visits 9 through 11 [Weeks 30 
through 42]), study arm will remain 
masked and additional dosing is limited to 
the criteria above. 
Use of aflibercept only 
during PRN period 
Only approved 
therapy will be 
used during the 
PRN period, 
thus limiting the 
risk to the 
subject 
Section 9.5. 
Concomitant 
Treatments 
Changes to topical ophthalmic non-
steroidal anti-inflammatory drugs in the 
study eye 
 
Increases to topical ophthalmic non-
steroidal anti-inflammatory drugs in the 
study eye 
To allow decreases in 
therapy during the study 
Subjects will 
not be required 
to stay on 
therapies that 
are unnecessary 
 
Section 9.5. 
 
High dose systemic corticosteroids (>10 
Addition of prohibited 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 12 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Concomitant 
Treatments 
mg/day of prednisone or equivalent) for 
more than 14 days 
 
concomitant treatment 
Section 9.5. 
Concomitant 
Treatments 
 
 
Macular (grid/focal) laser 
 
Addition of prohibited 
concomitant treatment  
None 
Section 9.7. 
Randomization and 
Masking 
 
In cases where subjects meet rescue 
therapy criteria, the masking of the 
subject, non-injecting physician, and site 
technician measuring BCVA should be 
maintained.  The masked physician will 
perform pre-injection exam procedures in 
accordance with standard subject visits.  If 
the masked physician determines the 
subject meets rescue therapy criteria, the 
masked physician will provide written 
confirmation to the injecting physician 
informing them of the need to administer 
rescue therapy. As the injecting physician 
is unmasked, and has knowledge of the 
treatment to be administered, the injecting 
physician should utilize written 
information from the masked physician in 
conjunction with their knowledge of 
subject treatment, to determine the 
appropriate therapy to be administered, if 
any. 
 
Guidance for the site to 
maintain the masking 
during rescue therapy 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       
 
 Clearside Biomedical, Inc  
CLS1003-301 
 
 
Summary of Changes 
Amendment 1 
31 March 2017 
Page 13 of 13 
CONFIDENTIAL 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 9.7. 
Randomization and 
Masking 
The unmasked Investigator and staff may 
not participate in efficacy assessments 
conducted during the Dosing and 
Evaluation Period. 
 
The unmasked Investigator and staff may 
not participate in efficacy assessments. 
To clarify that unmasked 
staff may not participate 
in efficacy assessments 
at any time 
None 
Section 12.1.1. 
Intraocular pressure will be measured by 
applanation tonometery (Tonopen or 
Goldmann) and results will be recorded in 
mmHg. 
Intraocular pressure will be measured by 
applanation tonometry and results will be 
recorded in mmHg. Where available, 
Goldmann applanation tonometry should 
be used at all visits. Tonopens may be 
used for post-injection pressure checks 
and in cases where no Goldmann is 
available. 
 
Preferred use of 
Goldmann for IOP 
measurement 
None 
Appendix A 
V9, V10, and V11 listed a PRN dose for 
SC CLS-TA or sham injection 
Removal of V9, V10, and V11 PRN SC 
CLS-TA or sham injection 
Corrected to be 
consistent with PRN 
criteria updates 
 
None 
Throughout 
protocol 
Miscellaneous typographical and 
formatting errors  
 
To correct typographical 
and formatting errors  
None 
 




CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
Clinical Protocol 
 
Version Date: 31 March 2017 
Page 2 of 69 
CONFIDENTIAL 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for CLS-TA. I have read the CLS1003-301 
protocol and agree to conduct the study as outlined. I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
Clinical Protocol 
 
Version Date: 31 March 2017 
Page 3 of 69 
 
 
CONFIDENTIAL 
 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Telephone number 
Primary Medical Monitor 
(24-Hour emergency contact) 
Peter Nicholas, MD 
(919) 259-9521 
Sponsor Clinical Lead 
Kathleen Billman 
(678) 894-0703 
Principal Investigator 
The Coordinating Principal Investigator will be appointed by the 
Sponsor before the end of the study.  As part of his or her 
responsibilities, the Coordinating Principal Investigator will 
review the final Clinical Study Report and will sign the report to 
confirm that it accurately describes the conduct and results of the 
study. 
 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
Clinical Protocol 
 
Version Date: 31 March 2017 
Page 4 of 69 
 
 
CONFIDENTIAL 
 
2. 
SYNOPSIS 
Name of Company:  
Clearside Biomedical, Inc.  
Name of Study Drug:  
CLS-TA, triamcinolone acetonide injectable suspension  
Eylea® (aflibercept) Injection 
Name of Active Ingredient 
Triamcinolone Acetonide  
Aflibercept 
Title of Study: SAPPHIRE: A randomized, masked, controlled trial to study the safety and efficacy 
of suprachoroidal CLS-TA in conjunction with intravitreal aflibercept in subjects with retinal vein 
occlusion   
Study center(s): Approximately 150 sites globally 
Protocol Number: CLS1003-301 
Study Duration: 12 Months 
Estimated date first subject enrolled: 1Q2017 
Estimated date last subject completed: 2Q2019 
Study Phase: 3 
Objectives:  
Primary: 
• 
To demonstrate that suprachoroidal (SC) CLS-TA administered in conjunction with intravitreal 
(IVT) aflibercept is superior to IVT aflibercept alone in the proportion of subjects demonstrating 
≥ 15 letter improvement in best corrected visual acuity (BCVA) two months after Baseline 
Secondary: 
• 
To determine the effect of SC CLS-TA administered in conjunction with IVT aflibercept on mean 
change from Baseline in BCVA 
• 
To determine the effect of SC CLS-TA administered in conjunction with IVT aflibercept on mean 
change from Baseline in central subfield thickness  
Number of Subjects: Approximately 460 (230 subjects per group) 
Diagnosis and main criteria for inclusion:  
Treatment naïve patients diagnosed with macular edema secondary to retinal vein occlusion 
Investigational product, dosage and mode of administration:  
CLS-TA, triamcinolone acetonide injectable suspension, 4 mg in 100 µL, SC injection; EYLEA® 
(aflibercept) Injection 2 mg in 50 µL, IVT injection 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Name of Company:  
Clearside Biomedical, Inc.  
Name of Study Drug:  
CLS-TA, triamcinolone acetonide injectable suspension  
Eylea® (aflibercept) Injection 
Name of Active Ingredient 
Triamcinolone Acetonide  
Aflibercept 
Reference therapy, dosage and mode of administration: 
EYLEA® (aflibercept) Injection 2 mg in 50 µL, IVT injection 
Criteria for Evaluation: 
The primary endpoint is the proportion of subjects demonstrating ≥ 15 letter improvement from 
Baseline in Early Treatment of Diabetic Retinopathy Study BCVA at Week 8 (Month 2). 
 
Statistical Methods:  
The primary analysis is a test of superiority of SC CLS-TA (TA) in conjunction with IVT aflibercept 
(IA) vs single-entity IVT aflibercept. Tests will be conducted using two-sided alpha = 0.05. The 
formal hypothesis is: 
H0: IA + TA = IA 
H1: IA + TA ≠ IA 
 
Additional safety and descriptive efficacy data will be collected through Month 12. Treatment codes 
will be broken at Month 2, and the final efficacy analysis will be conducted at this time. A descriptive 
follow-up safety and efficacy analysis will be performed at 6 months to allow filing the New Drug 
Application. Investigators, subjects, and study personnel who have contact with the Investigators or 
subjects will remain masked throughout the study. No adjustment for the follow-up analysis at Month 
6 is required because the final analysis of efficacy is at Month 2 and data from all subsequent visits 
will be descriptive only. 
 
 


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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.....................................................................................11 
5.
INTRODUCTION ......................................................................................................13
5.1. 
Disease Background and Scientific Rationale ............................................................13 
5.2. 
Description of Investigational Product .......................................................................14 
5.3. 
Summary of Clinical Experience and Justification for Dose Selection ......................15 
6.
STUDY OBJECTIVES AND PURPOSE ..................................................................17 
6.1. 
Primary Objective .......................................................................................................17 
6.2. 
Secondary Objectives .................................................................................................17 
6.3. 
Exploratory Objectives ...............................................................................................17 
7.
INVESTIGATIONAL PLAN .....................................................................................18 
7.1. 
Overall Study Design ..................................................................................................18 
7.2. 
Endpoints ....................................................................................................................18 
7.2.1. 
Primary Efficacy Endpoint .........................................................................................18 
7.2.2. 
Secondary Efficacy Endpoints ....................................................................................18 
7.2.3. 
Exploratory Efficacy Endpoints .................................................................................18 
7.2.4. 
Safety Endpoints .........................................................................................................18 
7.3. 
Number of Subjects ....................................................................................................19 
7.4. 
Treatment Assignment ................................................................................................19 
7.5. 
Criteria for Study Termination ...................................................................................20 
8.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................21 
8.1. 
Inclusion Criteria ........................................................................................................21 
8.2. 
Exclusion Criteria .......................................................................................................21 
8.2.1. 
Ophthalmic Exclusion Criteria ...................................................................................21 
8.2.2. 
General Exclusion Criteria .........................................................................................22 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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8.2.3. 
Randomization Criteria ...............................................................................................23 
8.3. 
Subject Withdrawal Criteria .......................................................................................23 
8.4. 
Visit Procedure Descriptions ......................................................................................24 
8.4.1. 
General Procedures .....................................................................................................24 
8.4.2. 
Re-Screening Procedures ............................................................................................24 
8.4.3. 
Visit 1 – Screening (Day -30 to -1) ............................................................................24 
8.4.4. 
Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24) .........................................25 
8.4.5. 
Visits 3, 4, 6, and 7 (Weeks 4, 8, 16, and 20) .............................................................28 
8.4.6. 
Visits 9, 10, and 11 (Weeks 30, 36, and 42) ...............................................................29 
8.4.7. 
Visit 12 (Week 48) End of Study/Early Termination .................................................30 
8.4.8. 
Unscheduled Visits .....................................................................................................31 
9. 
TREATMENT OF SUBJECTS ..................................................................................32 
9.1. 
Treatments to be Administered ...................................................................................32 
9.2. 
Study Eye Determination ............................................................................................32 
9.3. 
Fellow Eye Treatment .................................................................................................33 
9.4. 
Additional Treatment ..................................................................................................33 
9.4.1. 
Rescue Therapy Criteria .............................................................................................33 
9.4.2. 
PRN Criteria ...............................................................................................................33 
9.5. 
Concomitant Treatments  ............................................................................................34 
9.6. 
Treatment Compliance ................................................................................................34 
9.7. 
Randomization and Masking ......................................................................................34 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................36 
10.1. 
Study Drug ..................................................................................................................36 
10.2. 
Study Drug Packaging and Labeling ..........................................................................36 
10.3. 
Study Drug Storage .....................................................................................................36 
10.4. 
Study Drug Preparation ..............................................................................................36 
10.5. 
Administration ............................................................................................................36 
10.6. 
Study Drug Accountability .........................................................................................37 
10.7. 
Study Drug Handling and Disposal ............................................................................37 
11. 
ASSESSMENTS OF EFFICACY ..............................................................................38 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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11.1. 
Best Corrected Visual Acuity (BCVA) ......................................................................38 
11.2. 
Central Subfield Thickness as Measured by Spectral Domain Optical 
Coherence Tomography ..............................................................................................38 
11.3. 
Visual Function Questionnaire ...................................................................................38 
11.4. 
EuroQol 5 Dimensions Questionnaire ........................................................................38 
12. 
ASSESSMENTS OF SAFETY ..................................................................................39 
12.1. 
Safety Parameters .......................................................................................................39 
12.1.1. 
Intraocular Pressure ....................................................................................................39 
12.1.2. 
Slit-lamp Biomicroscopy ............................................................................................39 
12.1.3. 
Indirect Ophthalmoscopy ............................................................................................39 
12.1.4. 
Fluorescein Angiography ............................................................................................39 
12.1.5. 
Fundus Photography ...................................................................................................40 
12.1.6. 
Resting Heart Rate and Blood Pressure ......................................................................40 
12.1.7. 
Pregnancy Test ............................................................................................................40 
12.1.8. 
Central Laboratory Tests ............................................................................................40 
12.1.9. 
Review of Body Systems ............................................................................................40 
12.2. 
Adverse and Serious Adverse Events .........................................................................40 
12.2.1. 
Definition of Adverse Events .....................................................................................40 
12.2.2. 
Relationship to Study Drug ........................................................................................41 
12.2.3. 
Recording Adverse Events .........................................................................................41 
12.2.4 
Intensity ......................................................................................................................42 
12.2.5. 
Reporting Adverse Events ..........................................................................................43 
12.2.6. 
Follow-up of AEs and SAEs .......................................................................................43 
13. 
STATISTICAL CONSIDERATIONS .......................................................................44 
13.1. 
Randomization ............................................................................................................44 
13.2. 
Determination of Sample Size and Level of Significance ..........................................44 
13.3. 
Subject Disposition and Demographic and Baseline Characteristics .........................44 
13.4. 
Analysis Populations ..................................................................................................44 
13.4.1. 
Safety Population ........................................................................................................44 
13.4.2. 
Intent-to-Treat Population ..........................................................................................44 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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13.4.3. 
Per Protocol Population ..............................................................................................45 
13.5. 
Analysis Methods .......................................................................................................45 
13.5.1. 
Primary Efficacy Analysis ..........................................................................................45 
13.5.2. 
Secondary Efficacy Analysis ......................................................................................46 
13.5.3. 
Subgroup Analysis ......................................................................................................46 
13.5.4. 
Safety Analysis ...........................................................................................................46 
13.5.5. 
Schedule of Analyses ..................................................................................................46 
13.5.6. 
Procedure for Accounting for Missing, Unused, or Spurious Data ............................47 
14. 
DIRECT ACCESS TO SOURCE DOCUMENTS .....................................................48 
14.1. 
Study Monitoring ........................................................................................................48 
14.2. 
Audits and Inspections ................................................................................................48 
14.3. 
Institutional Review Board/Independent Ethics Committee ......................................49 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................50 
16. 
ETHICS ......................................................................................................................51 
16.1. 
Ethics Review .............................................................................................................51 
16.2. 
Ethical Conduct of the Study ......................................................................................51 
16.3. 
Written Informed Consent ..........................................................................................51 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................52 
17.1. 
Inspection of Records .................................................................................................52 
17.2. 
Retention of Records ..................................................................................................52 
18. 
PUBLICATION POLICY ..........................................................................................53 
19. 
REFERENCES ...........................................................................................................54 
20. 
APPENDICES ............................................................................................................55 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................11 
Table 3. 
 Subject Randomization ..............................................................................................19 
  
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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LIST OF FIGURES 
Figure 1: 
Anatomy of the Eye ....................................................................................................15 
Figure 2.  Study Treatment Schedule ..........................................................................................20 
 
 
 
 
 
 


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


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


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5.
INTRODUCTION
Clearside Biomedical, Inc, is developing a proprietary formulation of triamcinolone acetonide 
(CLS-TA) adjunctively with intravitreal aflibercept to treat macular edema (ME) associated with 
retinal vein occlusion (RVO). This Phase 3, multicenter, randomized, masked, controlled, 
parallel group study is designed to demonstrate that suprachoroidal (SC) CLS-TA delivered in 
conjunction with intravitreal (IVT) aflibercept (Eylea®; Regeneron; Tarrytown, NY and Bayer, 
Berlin, Germany) in subjects with RVO is superior to IVT aflibercept alone. Suprachoroidal 
injection is a novel drug delivery approach that employs Clearside’s proprietary suprachoroidal 
space (SCS™) microinjector and allows drugs to be precisely administered to the SCS via a 
minimally invasive injection procedure. This injection has been shown in animal models to allow 
distribution of CLS-TA directly to the posterior segment ocular tissues while limiting exposure 
to anterior structures in the eye, thereby providing the potential for improved efficacy and safety 
benefits. The purpose of this Phase 3 study is to demonstrate the efficacy of CLS-TA when used 
adjunctively with an anti-vascular endothelial growth factor (VEGF) agent to resolve ME more 
rapidly and to provide earlier clinical benefit in improvement of visual acuity when compared to 
an anti-VEGF agent used as monotherapy, in subjects with RVO.  
5.1. 
Disease Background and Scientific Rationale 
Retinal vein occlusion is the second most common cause of vision loss due to retinal vascular 
disease affecting 16.4 million adults mostly over the age of 40 worldwide. The condition results 
from a blockade in one of the veins returning blood flow from the retina (Rogers, 2010).  
The blockage of a retinal vein leads to hypoperfusion and ischemia accompanied by 
inflammation of the vasculature and edema in the area drained by the affected vein (Ehlers, 
2011). The severity and prognosis depends on the location of the blockage. Three types of RVO 
are generally recognized: branch retinal vein occlusion (BRVO), hemiretinal vein occlusion 
(HRVO), and central retinal vein occlusion (CRVO). Data pooled from 15 population studies in 
the United States (US), Europe, Asia, and Australia suggest that there are approximately 520 
new cases of RVO per million population. These include 442 and 80 cases per million, 
respectively, of BRVO and CRVO (Rogers, 2010).  
One rationale for current RVO treatments is based on restoring blood-retinal barrier (BRB) 
function. The molecular mediators involved include a wide range of cytokines related to 
inflammation. Glucocorticoids are well-recognized anti-inflammatory agents that are widely 
used to reduce ME (Cunningham, 2008) and improve the function of the BRB (Felinski, 2005). 
The efficacy of glucocorticoids in treating ME following RVO is well documented (Kiernan and 
Mieler, 2009; Hahn and Fekrat, 2012; Comyn, 2013). For example, approximately 20% more 
subjects with macular edema following CRVO achieved a ≥ 15 letter improvement in VA 
compared to subjects in the observation group. Approximately 26% and 27% of subjects with 
ME following BRVO achieved a ≥ 15 letter improvement in VA from Baseline to Month 12 
when receiving either 1 mg or 4 mg intravitreal injection of triamcinolone compared to 29% of 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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subjects who received standard care (grid photocoagulation) (Ip, 2009). The number of injections 
required to achieve this VA improvement was approximately two over the 12 month period. 
 A second rationale for current RVO treatments is based on suppressing vascular leakage. The 
molecular mediators involved include VEGF stimulated by ischemia. Recently, several anti-
VEGF agents have shown efficacy in the treatment of this condition (Boyer, 2012; Brown, 
2013). Approximately 40% more subjects with ME following CRVO achieved ≥ 15 letter 
improvement in VA following aflibercept (EYLEA®, 2014) injections compared with those 
subjects receiving sham injections or laser treatments, respectively, from Baseline to Month 6. 
This outcome was achieved with EYLEA® (2 mg) monthly injections (Boyer, 2012; 
Campochiaro, 2015).  
Persistent inadequately treated ME due to RVO can cause significant loss in visual acuity and 
eventually lead to blindness. Clearside is approaching the treatment of RVO by adopting a dual 
strategy to optimize treatment for the patient. The use of an anti-VEGF agent adjunctively with a 
corticosteroid, might be particularly useful since these two agents tackle different aspects of the 
disease. One agent, the anti-VEGF, reduces excess fluid and is required frequently, often 
monthly. The other agent, a corticosteroid, reduces inflammation and edema, restores damage to 
the blood-retinal barrier, and is usually used less often, about once every three to four months. 
Using the two agents adjunctively provides the potential advantage of tackling different aspects 
of the disease in parallel and, therefore, offers the potential for both a more rapid and a better 
clinical outcome in terms of best corrected visual acuity (BCVA) improvement. Further, if each 
agent is able to contribute to reduction in macular edema and improvement in visual acuity, there 
is the potential to reduce the frequency of administration of therapy.  
5.2. 
Description of Investigational Product 
CLS-TA, triamcinolone acetonide injectable suspension, is a preservative-free, terminally 
sterilized, aqueous suspension, formulated for administration into the eye. It will be administered 
as a single injection of 4 mg in 100 µL into the SCS using Clearside’s proprietary SCS™ 
microinjector. The SCS is the region of the eye between the sclera and the choroid (Figure 1).  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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 prescription medicine approved in the United States and Europe as 
well as other global markets. Aflibercept is approved for the treatment of patients with Wet Age-
related Macular Degeneration (AMD), macular edema following Retinal Vein Occlusion (RVO), 
Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) in patients with DME. Full 
prescribing information for aflibercept in the treatment of ME following RVO involves IVT 
injection of 2 mg (0.05 mL) at 4-week intervals.  
5.3. 
Summary of Clinical Experience and Justification for Dose Selection 
Triamcinolone acetonide (TA) has been used safely and effectively in human ocular therapeutics 
to treat conditions involving inflammation for over 50 years. The initial recommended dose of 
the TA formulation approved by the FDA for ocular indications is 4 mg in 100 μL 
(TRIESENCE®). The dose of CLS-TA administered as a single injection into the SCS will be 
similar (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 
suspensions that have been terminally sterilized and designed for ophthalmic use.  
Clearside has completed 2 clinical trials in patients with non-infectious uveitis and one clinical 
trial in patients with RVO. 
The completed clinical study, CLS1001-101 (NCT01789320), was a Phase 1/2, open-label, 
safety and tolerability study in subjects with intermediate, posterior, or pan non-infectious 
uveitis. Each subject received a single SC injection of 4 mg in 100 µL TA (TRIESENCE®). Nine 
of the 11 subjects in the safety analysis set (82%) completed the 26-week study. All subjects had 
at least one adverse event (AE), with a total of 37 AEs reported. One serious adverse event 
(unrelated pulmonary emboli; SAE) occurred. No deaths were reported. No significant increases 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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in intraocular pressure (IOP) were reported. The most commonly reported AE, eye pain, was 
reported in 5 subjects. 
The completed clinical study, CLS1001-201 (NCT02255032), was a Phase 2, randomized, 
masked safety and efficacy study in subjects with ME associated with non-infectious uveitis. 
Twenty-two subjects were randomly assigned to receive either a single SC injection of CLS-TA, 
4 mg in 100 µL or 0.8 mg in 100 µL. Subjects in the 4.0 mg treatment group were observed to 
have a mean reduction in central subfield thickness (CST) of 164 microns (p=0.002) when 
measured from Baseline at 2 months. No subjects discontinued due to an AE, and there were no 
Investigator-reported increases in IOP at follow-up visits. 
The completed clinical study, CLS1003-201 (CT02303184), was a Phase 2, randomized, masked 
safety and efficacy study in subjects with ME following RVO. Forty-six subjects were randomly 
assigned 1:1 to either SC injection of CLS-TA administered in conjunction with an IVT injection 
of aflibercept (ACTIVE), or an IVT injection of aflibercept alone (CONTROL). Subjects were 
observed to have a mean reduction in CST of 445 µm in the ACTIVE group and 342 µm in the 
CONTROL group when measured from Baseline at 3 months. Mean improvements in BCVA 
were 16, 20 and 19 letters in the ACTIVE group and 11, 12 and 11 letters in the CONTROL 
group at Months 1, 2 and 3 respectively. Sixty percent fewer additional intravitreal aflibercept 
injections (p=0.013) were required in the ACTIVE group receiving the combination of 
suprachoroidal CLS-TA and intravitreal aflibercept compared to subjects in the CONTROL arm. 
No subjects discontinued due to an AE and no SAEs were reported. Four subjects in the active 
group reported 4 events of IOP changes, two events of ocular hypertension and two events of 
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 study aims to consider the safety and efficacy of SC CLS-TA in conjunction with 
IVT aflibercept for the treatment of eyes with RVO.  
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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6. 
STUDY OBJECTIVES AND PURPOSE 
The purpose of this study is to demonstrate the safety and efficacy of SC CLS-TA in conjunction 
with IVT aflibercept in subjects with RVO. 
6.1. 
Primary Objective 
To demonstrate that SC CLS-TA in conjunction with IVT aflibercept is superior to IVT 
aflibercept alone in the proportion of subjects demonstrating ≥ 15 letter improvement in BCVA 
two months after Baseline 
6.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To determine the effect of SC CLS-TA administered in conjunction with IVT aflibercept on 
mean change from Baseline in BCVA 
• To determine the effect of SC CLS-TA administered in conjunction with IVT aflibercept on 
mean change from Baseline in CST  
• To determine the safety and tolerability of SC CLS-TA administered in conjunction with IVT 
aflibercept  
6.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To determine the effect of SC CLS-TA administered in conjunction with IVT aflibercept on 
change from Baseline in subject-reported outcomes 
• To determine the effect of SC CLS-TA administered in conjunction with IVT aflibercept on 
changes from Baseline in complications associated with RVO (eg, neovascularization or 
perfusion) 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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7. INVESTIGATIONAL PLAN 
7.1. Overall Study Design 
This is a Phase 3, multicenter, randomized, masked, controlled, parallel group study of 
12 months duration in treatment-naïve subjects with RVO. This study is projected to enroll 
approximately 460 subjects, randomly assigned 1:1 to one of two treatment groups stratified by 
disease (BRVO, CRVO). Randomization will proceed as described until either strata reaches 
55% of the total number patients to be enrolled at which time only patients from the other strata 
will be enrolled.  
The study design includes 12 clinic visits over approximately 50 weeks. Subjects will participate 
in 5 periods: Screening (Visit 1, Days -30 to -1); Randomization and Baseline (Visit 2, Day 0 
before dosing); Dosing and Evaluation (Visit 2 [after dosing] to Visit 8, Day 0 through Week 
24); PRN Dosing and Follow-up (Visit 9 to 11; Weeks 30 through 42); and End of Study (Visit 
12; Week 48). 
7.2. Endpoints 
7.2.1. Primary Efficacy Endpoint 
The primary endpoint is the proportion of subjects demonstrating ≥ 15 letter improvement from 
Baseline in Early Treatment of Diabetic Retinopathy Study (ETDRS) BCVA at Visit 4 
(Month 2). 
7.2.2. Secondary Efficacy Endpoints 
• Mean change from Baseline (Visit 2, Day 0) in BCVA at Visit 4 (Week 8) and Visit 8 
(Week 24) 
• Mean change from Baseline (Visit 2, Day 0) in CST at Visit 4 (Week 8) and Visit 8 
(Week 24) 
7.2.3. Exploratory Efficacy Endpoints 
• Change from Baseline (Visit 2, Day 0) in subject-reported outcomes at Visit 8 (Week 
24) as measured by the Visual Function Questionnaire (VFQ-25) and the EuroQol 5 
Dimensions Questionnaire (EQ-5D)   
• Change from Baseline in signs and complications of RVO (eg, neovascularization, 
perfusion) at Visit 8 (Week 24) and Visit 12 (Week 48) 
7.2.4. Safety Endpoints 
• Incidence of treatment-emergent adverse events (TEAEs) and SAEs, grouped by 
organ system, relatedness to study drug, and intensity  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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• Incidence of changes in safety parameters including: IOP, slit-lamp biomicroscopy, 
indirect ophthalmoscopy, imaging parameters, and vital signs  
7.3. Number of Subjects 
Approximately 460 subjects with RVO who are naïve to treatment will be enrolled into one of 
two treatment groups. 
7.4. Treatment Assignment 
Subjects enrolled in this study will be eligible upon a finding of RVO in the study eye. After 
Screening (Day -30 to Day -1) and Baseline assessments on Day 0, subjects will be randomly 
assigned 1:1 to one of two treatment groups stratified by disease type (BRVO, CRVO). 
Randomization will proceed as described until either strata reaches 55% of the total number 
patients to be enrolled at which time only patients from the other strata will be enrolled.  
 
Table 3.  
Subject Randomization 
TREATMENT GROUP 
Number of 
Subjects 
ACTIVE: IVT aflibercept (2 mg/0.05 mL) + SC CLS-TA (4 mg/100 µL)   
~230 
CONTROL: IVT aflibercept (2 mg/0.05 mL) + sham SC procedure 
~230 
 
Dosing and Evaluation Period: After randomization, subjects will receive treatment as follows: 
ACTIVE: IVT aflibercept (2 mg/0.05 mL) + CLS-TA (4 mg/100 µL) SC injections: 
Subjects randomly assigned at Baseline to the ACTIVE group will receive an IVT injection of 
aflibercept followed by a SC injection of CLS-TA on Visit 2 (Day 0), Visit 5 (Week 12) and 
Visit 8 (Week 24). Subjects will receive an intravitreal injection of aflibercept only at Visit 3 
(Week 4). 
After the Baseline visit, subjects will return for 6 monthly (every 4 weeks) visits through Visit 8 
(Week 24) to assess safety and efficacy. Evaluation for, and determination of requirement for 
additional therapy based on established criteria will take place from Visit 6 (Week 16) through 
end of study. 
CONTROL: IVT aflibercept (2 mg/0.05 mL) injection + sham SC procedure 
Subjects randomly assigned at Baseline to the CONTROL group will receive monthly IVT 
aflibercept injections beginning at Visit 2 (Day 0) and continuing through Visit 8 (Week 24). To 
maintain masking, subjects in the CONTROL group will also receive a sham SC procedure on 
Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24). 


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Subjects will return for 6 monthly (every 4 weeks) visits through Visit 8 (Week 24) to assess 
safety and efficacy and to determine whether additional therapy is needed based on established 
criteria. 
PRN Dosing and Follow-up Period: 
At the conclusion of the dosing and evaluation period (Day 0 through Week 24), subjects will be 
followed for safety through Visit 12 (Week 48). Subjects will be treated, as needed (PRN), with 
aflibercept.   
 
Figure 2.  
Study Treatment Schedule 
 
7.5. Criteria for Study Termination 
The study or parts of the study may be discontinued by the Sponsor, or at the recommendation of 
an Investigator after consultation with Sponsor, at any time.   
If the clinical study is prematurely terminated or suspended, the Sponsor will inform the 
Investigators and the regulatory authorities of the termination/suspension and the reason(s) for 
the termination/suspension. The Investigator should promptly notify the Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC) of the termination or suspension and of the 
reasons. 


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8. SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. Inclusion Criteria 
Individuals are eligible for participation in this study if he/she meets the following criteria: 
1. Has a clinical diagnosis of RVO in the study eye within ≤ 9 months screening; 
2. Has a CST of ≥ 300 µm in the study eye as measured by spectral-domain optical 
coherence tomography (SD-OCT) with or without intraretinal or subretinal fluid and 
confirmed by the central reading center (CRC); 
3. Has an ETDRS BCVA score of ≥ 20 letters read and ≤ 70 letters read in the study eye; 
4. Is naïve to local pharmacologic treatment for RVO in the study eye; 
5. Is at least 18 years of age, understands the language of the informed consent and is 
willing and able to provide written informed consent before any study procedures, and 
is willing to comply with the instructions and attend all scheduled study visits. 
8.2. Exclusion Criteria 
8.2.1. Ophthalmic Exclusion Criteria 
An individual is ineligible for participation in this study if he/she meets any of the following 
criteria: 
1. Has ME with etiology other than RVO; 
2. Has, in the study eye, used any topical ocular corticosteroid in the 10 days before 
treatment at Visit 2 (Day 0); has at any time received any intraocular or periocular 
corticosteroid injection, an OZURDEX® implant, a RETISERT® implant, or an 
ILUVIEN® implant; 
3. Has evidence of or history of any ophthalmic condition in the study eye that may have an 
associated neovascularization or edema component including, but not limited to, 
age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema 
(DME), retinal detachment, central serous chorioretinopathy, scleritis, optic neuropathy, 
or retinitis pigmentosa;  
4. Has a history of rubeosis irides or other neovascularization in the study eye; any active 
vitreous hemorrhage in the study eye within the last 90 days; 
5. Has a history of any vitreoretinal surgery (scleral buckle placement, pars plana 
vitrectomy, retrieval of dropped nucleus or intraocular lens, sheathotomy) ever in the 
study eye or any ocular surgery in the 3 months before randomization. Prior cataract 
extraction or Yttrium-Aluminum-Garnet (YAG) laser capsulotomy is allowed but must 
have been performed at least 3 months before Visit 2 (Day 0);  


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


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cardiovascular disease, poor glycemic control) or put the subject at risk due to study 
treatment or procedures; NOTE: Uncontrolled BP at screening may be treated before 
Visit 2;  
16. Has a myocardial infarction or stroke within 90 days of treatment; 
17. Has a likely need for hospitalization or surgery within the study period, including planned 
elective surgery or hospitalization; 
18. Has a known hypersensitivity to any component of the formulation of TA, aflibercept, 
fluorescein, topical anesthetics, or the antiseptic used to prepare the eye for injection 
according to the Investigator’s standard practice; 
19. Is currently enrolled in an investigational drug or device study or has used an 
investigational drug within 30 days of entry into this study or participated in an ocular 
device study in the last 90 days. 
20. History of any inflammatory or other medical condition that the investigator might 
reasonably anticipate will require treatment with high-dose corticosteroids (more than 
10mg/day oral prednisone or the equivalent) for more than 14 days. 
8.2.3. Randomization Criteria 
Subjects are eligible for randomization at Visit 2 if the following criteria are met: 
1. The CRC confirms ME by SD-OCT (from Visit 1 SD-OCT data), with or without 
intraretinal or subretinal fluid ; 
2. The CRC confirms a retinal thickness of ≥ 300 μm in the central subfield from the Visit 1 
SD-OCT data;                                                                                                                          
3. The subject gains no more than 10 letters of vision in BCVA between the Screening visit 
and Randomization (Visit 2) in the study eye; 
4. The subject continues to meet all of the inclusion and none of the exclusion criteria. 
8.3. Subject Withdrawal Criteria 
Subjects may withdraw from the study at any time and for any reason without obligation. 
Subjects may be removed from the study at the Investigator’s discretion.  
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.  


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8.4. Visit Procedure Descriptions 
8.4.1. General Procedures 
The study will consist of 12 study visits over approximately 50 weeks. Subjects are expected to 
attend all study visits. All ocular assessments at Visit 1 (Screening) and Visit 12 (Week 48) will 
be performed on both eyes. IOP will be collected in both eyes at all visits. Data from all other 
ocular assessments at all other visits will be collected for the study eye only.  
Subjects will be screened for entry at Visit 1 (Days -30 to -1) and the study eye identified. Each 
eligible subject will return to the clinic within 30 days to be randomly assigned and treated at 
Visit 2 (Day 0). After baseline assessments and randomization on Day 0, subjects will receive an 
IVT injection of aflibercept (according to the package insert) in the study eye, followed by either 
a sham SC injection or an active SC dose of CLS-TA in the study eye, depending on the group 
assigned at randomization. Subjects will be assessed after injection for safety. 
Additional safety follow-up visits will occur approximately every 4 weeks through Month 6 
(Visits 3 through 8; Weeks 4, 8, 12, 16, 20 and 24). Subjects in the CONTROL group will 
receive IVT injections of aflibercept at each of these visits. Subjects in the ACTIVE group will 
receive an IVT injection of aflibercept at Visit 3 (Week 4); a sham IVT injection will be 
performed at Visit 4, 6 and 7 (Weeks 8, 16 and 20) to ensure masking is maintained. 
At Visit 5 (Week 12) and Visit 8 (Week 24) subjects will receive another IVT injection of 
aflibercept (according to the package insert) in the study eye, followed by either a sham SC 
injection or an active SC dose of CLS-TA in the study eye), depending on the group assigned at 
Visit 2 (Day 0).  
After the completion of the Dosing and Evaluation Period (6 months), subjects will enter the 
PRN Dosing and Follow-up Period of the study to be observed and receive PRN treatment every 
6 weeks at Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 (Week 42).  
The final visit of the study occurs at Visit 12 (Week 48). 
8.4.2. Re-Screening Procedures 
Subjects may be re-screened if the reason for their initial screening failure has changed. A 
subject who is designated as a screen failure before being randomly assigned at Visit 2 (Day 0) 
may be re-screened up to 2 additional times, for a total of 3 screenings, upon Sponsor approval.  
Subjects who are re-screened are required to sign a new consent form. Screening assessments 
must be repeated if timings for the assessments fall outside of the specified study windows.  
8.4.3. Visit 1 – Screening (Day -30 to -1) 
At Visit 1, subjects will be screened for eligibility. Written informed consent will be obtained for 
each subject before any study-specific assessments are performed. During Visit 1, the following 
procedures will be performed: 


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1. Obtain written informed consent 
2. Assign subject number 
3. Collect demographic data and medical and ocular history  
4. Review concomitant medications  
5. Perform resting heart rate (resting 5 mins) and blood pressure measurements 
6. Collect blood and urine for central laboratory tests before fluorescein angiogram (FA), 
including serum pregnancy test on females of childbearing potential 
7. Perform a review of body systems 
8. Perform ophthalmic assessments on both eyes:  
a. ETDRS BCVA  
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP  
d. Dilated indirect ophthalmoscopy 
e. SD-OCT*  
9. Perform photographic evaluations:* 
a. FA  
b. Fundus photograph 
10. Assess AEs 
11. Determine study eye based upon eligibility criteria 
12. Schedule subject to return for Visit 2, Randomization/Treatment  
 
NOTE:  
* All images (SD-OCT, fundus photographs, and FA) should be uploaded to the CRC.  
8.4.4. Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24) 
Visit 2 must occur within 30 days of Visit 1 (Screening) and may only occur once subject is 
determined to be eligible for treatment, which includes central laboratory results and 
confirmation of eligibility based on SD-OCT reading by the CRC being received and reviewed 
by the Investigator. No subject may be treated without CRC confirmation of eligibility. 
The Visit 2 randomization procedures should not be conducted until the subject is deemed 
eligible based on meeting all of the inclusion and none of the exclusion criteria. Once randomly 


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assigned, subjects will remain in the same treatment group for the duration of participation in the 
study. 
8.4.4.1.Pre-dose Procedures: Visit 2, Visit 5 and Visit 8 (Day 0, Week 12 and Week 24)  
The following procedures must be performed before the injection (the same day as the injection): 
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform resting heart rate (resting 5 mins) and blood pressure 
4. Administer VFQ-25 and EQ-5D (Visit 2 and Visit 8 only) 
5. Collect urine for pregnancy test in females of child-bearing age 
6. Collect blood and urine for central lab tests before FA, including serum pregnancy test on 
females of childbearing potential (Visit 8 only) 
7. Perform ophthalmic assessments on the study eye only, unless otherwise designated:  
a. ETDRS BCVA 
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP (both eyes)  
d. Dilated indirect ophthalmoscopy 
e. SD-OCT  
8. Perform photographic evaluations (Visit 8 only): 
a. Fluorescein angiogram (FA)  
b. Fundus photograph 
9. Review eligibility criteria (Visit 2 only)  
If subject continues to be eligible for randomization based on results from screening 
and Visit 2 assessments, and subject meets all randomization criteria in 8.2.3, subjects 
will be randomly assigned via the interactive web response system (IWRS) to receive 
either an IVT injection of aflibercept in conjunction with either sham or active SC 
injection of CLS-TA in the study eye. 
10. Log onto the IWRS and randomly assign subject to treatment 
8.4.4.2. Injection Procedures: Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24)  
Injections should be performed the same day as the pre-injection procedures. For details on the 
injection procedure, please see the Investigator Site File. The subject, non-injecting physician, 
Sponsor, study coordinator, visual acuity technician, and the CRC will be masked to treatment. 
The injecting physician and supporting study staff who are present during the injection procedure 


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must be designated as unmasked for the study. Unmasked personnel should not perform efficacy 
assessments at any visit. 
1. Confirm the study eye 
2. Retrieve study drug kit number assigned by IWRS 
3. Prepare eye for injection according to the Investigator’s standard practice 
4. The UNMASKED injecting Investigator should perform IVT injection of aflibercept, SC 
injection of CLS-TA, and all sham procedures to the study eye 
8.4.4.2.1. IVT Injection of aflibercept: 
1. Prepare study eye for IVT injection of aflibercept 
2. Administer aflibercept IVT injection according to the package insert. The sites of the IVT 
injection and the SC injection should be approximately 2 or more clock hours apart. A 
temporal quadrant is the recommended location for SC injections. 
3. Assess study eye by indirect ophthalmoscopy immediately after the injection,  
4. Measure IOP after injection 
8.4.4.2.2. SC Injection of CLS-TA (ACTIVE) OR sham procedure (CONTROL): 
1. Administer SC injection or sham after the IVT injection of aflibercept when the study eye 
IOP is < 30 mmHg, either spontaneously or by treatment, as determined by the 
Investigator 
2. Prepare study eye for SC injection according to the Investigator’s standard practice 
3. Administer SC injection of 100 μL of CLS-TA or sham procedure approximately 2 or 
more clock hours from the site of the IVT injection 
4. Assess study eye by indirect ophthalmoscopy immediately after the injection,  
8.4.4.3. 
Post-Dose Procedures: Visit 2 (Day 0), Visit 5 (Week 12) and Visit 8 (Week 24)  
The following assessments must occur after the IVT injection, SC injection, or sham procedures: 
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform ophthalmic assessments on the study eye only:  
a. Slit-lamp biomicroscopy  
b. Evaluate IOP 10 to 30 minutes after injection 
c. If IOP remains elevated, subject must remain on site until IOP is under control 
according to the Investigator’s best medical judgment. 


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d. If IOP is < 30 mmHg, the subject may leave the clinic 
4. Schedule time for subject to return for next visit  
8.4.5. Visits 3, 4, 6, and 7 (Weeks 4, 8, 16, and 20)  
8.4.5.1. Pre-dose Procedures: Visit 3 (Week 4), Visit 4 (Week 8), Visit 6 (Week 16), and Visit 7 
(Week 20)  
The following procedures must be performed before the injection (the same day as the injection): 
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform resting heart rate (seated 5 mins) and blood pressure measurements 
4. Perform ophthalmic assessments on the study eye only, unless otherwise designated:  
a. ETDRS BCVA 
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP (both eyes)  
d. Dilated indirect ophthalmoscopy 
e. SD-OCT  
8.4.5.2. Injection Procedure: Visit 3 (Week 4), Visit 4 (Week 8), Visit 6 (Week 16), and Visit 7 
(Week 20)  
1. Confirm the study eye 
2. Retrieve aflibercept  
3. Prepare eye for injection according to the Investigator’s standard practice 
4. The UNMASKED injecting Investigator should administer IVT injection of aflibercept 
OR sham IVT procedure to the study eye. (All subjects receive an IVT injection of 
aflibercept at Visit 3 (Week 4)).  
5. Assess study eye by indirect ophthalmoscopy immediately after the injection,  
6. Measure IOP after injection 
8.4.5.3. Post-Dose Procedures: Visit 3 (Week 4), Visit 4 (Week 8), Visit 6 (Week 16), and Visit 7 
(Week 20)  
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform ophthalmic assessments on the study eye only:  


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a.
Slit-lamp biomicroscopy
b. Evaluate IOP 10 to 30 minutes after injection
c.
If IOP remains elevated, subject must remain on site until IOP is under control
according to the Investigator’s best medical judgment.
d. If IOP is < 30 mmHg, the subject may leave the clinic
4. Schedule time for subject to return for next visit
8.4.6. 
Visits 9, 10, and 11 (Weeks 30, 36, and 42) 
Beginning at Visit 9 (Week 30) through Visit 11(Week 42), study treatments will be 
administered PRN. Investigators, subjects, and study personnel will remain masked during the 
PRN Dosing and Follow-up Period. 
8.4.6.1. Pre-dose Procedures: Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 (Week 42) 
The following assessments must be performed; however, dosing is PRN: 
1. Assess AEs
2. Review changes to concomitant medications
3. Perform resting heart rate (seated 5 mins) and blood pressure measurements
4. Collect urine for pregnancy test in females of child-bearing age
5. Perform ophthalmic assessments on the study eye only, unless otherwise designated:
a.
ETDRS BCVA
b. Slit-lamp biomicroscopy, including dilated lens grading
c.
IOP (both eyes)
d. Dilated indirect ophthalmoscopy
e.
SD-OCT
f.
Confirm study eye
8.4.6.2. PRN Injection procedure: Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 (Week 42) 
If subject qualifies for PRN therapy according to the Additional Therapy Criteria listed in      
Section 9.4.2, the following injection and post-dose procedures should be performed, consistent 
with the subject’s treatment group: 
1. Confirm the study eye
2. Retrieve study drug kit number assigned by IWRS
3. Prepare eye for injection according to the Investigator’s standard practice
4. The UNMASKED injecting Investigator should perform IVT injection of aflibercept


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8.4.6.2.1. IVT Injection of aflibercept: 
1. Prepare study eye for IVT injection of aflibercept 
2. Administer aflibercept IVT injection according to the package insert.  
3. Assess study eye by indirect ophthalmoscopy immediately after the injection,  
4. Measure IOP after injection 
8.4.6.3. 
Post-Dose Procedures: Visit 9 (Week 30), Visit 10 (Week 36), and Visit 11 (Week 42)  
The following assessments must occur after the IVT injection: 
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform ophthalmic assessments on the study eye only:  
a. Slit-lamp biomicroscopy  
b. Evaluate IOP 10 to 30 minutes after injection 
c. If IOP remains elevated, subject must remain on site until IOP is under control 
according to the Investigator’s best medical judgment. 
d. If IOP is < 30 mmHg, the subject may leave the clinic 
4.  Schedule time for subject to return for next visit  
8.4.7. 
Visit 12 (Week 48) End of Study/Early Termination 
Visit 12 is the final study visit. Subjects who terminate early should complete all Visit 12 
assessments.  
1. Assess AEs 
2. Review changes to concomitant medications 
3. Perform resting heart rate (seated 5 mins) and blood pressure measurements 
4. Collect blood and urine for central laboratory tests, including serum pregnancy test on 
females of child-bearing potential  
5. Perform a review of body systems 
6. Perform ophthalmic assessments on both eyes: 
a. ETDRS BCVA 
b. Slit-lamp biomicroscopy, including dilated lens grading  
c. IOP  
d. Dilated indirect ophthalmoscopy 


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e. SD-OCT  
7. Administer VFQ-25 and EQ-5D  
8. Perform photographic evaluations: 
a. FA  
b. Fundus photograph  
8.4.8. 
Unscheduled Visits 
To ensure subject safety during the study, any subject who requires additional follow-up or 
treatment for any reason at any time during the study that does not fall on a scheduled study visit 
should have that visit recorded as an Unscheduled Visit.  


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9. TREATMENT OF SUBJECTS  
9.1. Treatments to be Administered 
Subjects will be assigned to one of two treatment groups in the study based upon randomization 
assignment.  
Treatment in the ACTIVE group will consist of three unilateral SC injections of 4 mg of CLS-
TA in 100 µL administered 12 weeks apart (Visits 2, 5, and 8), in conjunction with 4 unilateral 
injections of IVT aflibercept in to the study eye over 24 weeks according to the study schedule.   
Subjects in the ACTIVE group will also receive sham IVT procedures to maintain masking at 
visits where the SC CLS-TA injection is not being administered (Visit 3, 4, 6, and 7). Beginning 
with Visit 9 (Week 30), subjects will be assessed for PRN treatment that will consist of IVT 
aflibercept based on PRN criteria (Section 9.4.2). 
Treatment in the CONTROL group of the study will consist of 7 unilateral IVT injections of 
aflibercept administered 4 weeks apart (Visits 2 through 8) in conjunction with three sham SC 
procedures administered 12 weeks apart (Visits 2, 5, and 8) in to the study eye according to the 
study schedule. Beginning with Visit 9 (Week 30), subjects will be assessed for PRN treatment 
that will consist of the same treatment, IVT aflibercept with sham SC procedure to maintain 
masking. 
Subjects will be assigned to either of the following groups:  
1. ACTIVE: IVT aflibercept [2 mg (50 µL)] + SC CLS-TA [4 mg (100 µL)] 
2. CONTROL: IVT aflibercept [2 mg (50 µL)] + SC sham procedure 
Approximately 460 subjects will be randomly assigned in a 1:1 ratio where approximately 230 
subjects will be assigned to the ACTIVE group and approximately 230 subjects will be assigned 
to the CONTROL group.  
Sham IVT and sham SC procedures will be performed using needleless hubs attached to the 
appropriate syringe to maintain masking. This is a non-invasive procedure. 
All SC injections may only be performed by trained Investigators. Training will be documented 
by the Sponsor in writing. Training documentation will be maintained at the site as well as with 
the Sponsor.  
 
Detailed instructions on the SC injection procedure can be found in the Investigative Site File. 
9.2. Study Eye Determination 
The study eye will be the eye receiving the IVT aflibercept, SC CLS-TA injection, or the sham 
procedures depending upon the group to which the subject is randomly assigned. The 
determination of the study eye will be based on Screening/Baseline information and will be 
determined before randomization. 


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If both eyes meet study criteria, the eye with the better chance of achieving an improvement in 
BCVA, in the Investigator’s opinion, should be used as the study eye. If both eyes qualify for the 
study and appear similar in their chance of improvement, the right eye should be designated as 
the study eye. The eye that is not designated as the study eye will be denoted as the fellow eye. 
9.3. Fellow Eye Treatment 
Only one study eye of each subject may be treated in the study.  
Ocular therapy for the fellow eye is not subject to the requirements of this protocol. Local 
medications are permitted for the fellow eye during the course of this study. Medications used in 
the fellow eye will be recorded in the subject’s medical chart and the case report form (CRF).  
9.4. Additional Treatment 
If, at any time during the study, a subject is considered at immediate risk for a vision-threatening 
event, the Investigator should immediately follow best medical practice in the Investigator’s 
judgment for treating the subject. All additional therapy will be recorded in the subject’s source 
document and the CRF. 
9.4.1. Rescue Therapy Criteria 
Beginning at Week 8 (Visit 4), if any of the following criteria are met in the study eye, 
intravitreal aflibercept will be administered. 
• Macular edema (ME), defined as intraretinal or subretinal fluid (new or persistent), in 
conjunction with a CST ≥ 340 µm as measured by SD-OCT. 
• A decrease in BCVA of 6 letters or greater between the current visit and the BCVA 
reading from the previous visit with an increase in CST of > 50 µm from the previous 
visit, associated with new fluid.  
• A decrease in BCVA of 10 letters or greater from the best measurement (during the 
study) with an increase in CST of > 50 µm from the previous visit, associated with new 
fluid. 
• If vision is worse than approximately 70 letters read and there is new or persistent 
intraretinal or sub-retinal fluid, that in the opinion of the investigator is affecting vision, 
even if CST <340 µm. 
9.4.2. PRN Criteria 
During the PRN Dosing and Follow-up Period (Visits 9 through 11 [Weeks 30 through 42]), 
study arm will remain masked and additional dosing is limited to the criteria above.  All subjects 
will continue to be assessed for safety during the PRN Dosing and Follow-up Period. 


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9.5. Concomitant Treatments  
The list of prohibited treatments provided below is not intended to be comprehensive, but rather 
to help guide the Investigator’s medical judgment. In cases where a subject presents with a 
treatment not included on the following list, or should there be any question on the part of the 
Investigator, Investigators are encouraged to confer with the Medical Monitor for any 
clarification. 
Use of the following treatments is prohibited at any time during the study: 
• Increases to topical ophthalmic non-steroidal anti-inflammatory drugs in the study eye  
• Any corticosteroid implant (ie, Ozurdex®, ILUVIEN® or Retisert®) in the study eye 
• Topical, periocular, or IVT corticosteroids in the study eye  
• High dose systemic corticosteroids (>10 mg/day of prednisone or equivalent) for more 
than 14 days 
• Any IVT agents except those specified in the study protocol 
• Systemic anti-angiogenic drugs (anti-VEGF) including, for example, bevacizumab 
• Macular (grid/focal) laser 
• Any investigational drug or device 
In cases where there is anticipated need for any of the treatments listed here during the study, or 
if a subject presents to the Investigator having initiated treatment during the study with one of 
these treatments, it is the responsibility of the Investigator to notify the Sponsor immediately. If 
additional therapy is necessary to treat worsening of RVO in the study eye and normal standard 
of care requires additional intervention, the treatment(s) should be recorded in the subject’s CRF 
and should follow the guidelines presented for rescue criteria. Subjects will not be discontinued 
from the study because of initiation of or 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’ randomized treatment assignments will be protected using a masked allocation 
schedule created by a clinical allocation schedule system. Subjects, non-injecting physicians, site 
technicians measuring BCVA, and the CRC for images will be masked to treatment assignments. 
The randomization code will not be available to these individuals until after the study is 
completed and the database is locked. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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In the event of a medical need, the injecting physician and supporting study staff who are present 
during the injection procedure are unmasked, thus immediate emergency unmasking is not 
necessary. Emergency unmasking of subjects by other Investigators or authorized clinical site 
personnel will occur via the IWRS. 
Site technicians, CRC personnel, and designated readers and graders should not unmask the 
subject’s randomized treatment assignment without the Sponsor’s approval unless immediately 
required in response to an SAE. If the Sponsor is not notified before the unmasking event, the 
Investigator must immediately contact the Sponsor informing them of the specific details of the 
occurrence. The Sponsor personnel involved in the collection, interpretation, analysis, review, or 
any decision-making stemming from the study data will remain masked to subject status for the 
duration of the study unless otherwise warranted. 
The subject will be masked to treatment throughout the study. The subject shall not discuss the 
study drug with any masked study personnel. All designated readers and graders, the subjects, 
the Sponsor’s masked personnel, and masked monitors involved in reporting, obtaining, and 
reviewing the clinical evaluations for subjects will not be aware of the specific randomized 
treatment assignment for any subject.  
Only study staff who are designated by the Investigator to prepare and administer study drug and 
conduct test article accountability may know the randomized treatment assignment. The 
unmasked Investigator and staff may not participate in efficacy assessments. The unmasked 
Investigator may participate in ophthalmic examinations before and after injection for safety.  
Designee(s) will not discuss the test article with other site personnel or the Sponsor monitors and 
will instruct subjects not to discuss the study drug or appearance of the packaging with the 
Investigator, sub-Investigator(s) or any other study staff while the study is ongoing. This level of 
masking will be maintained throughout the conduct of the study. 
The external packaging for the test article and sham control will be identical.  
If masking is compromised, any masked personnel who become unmasked will not conduct any 
further masked clinical evaluations with the subject whose treatment has been unmasked. In the 
case of unmasking, the site will notify the IRB and Sponsor/designee; follow-up training may be 
required. 
In cases where subjects meet rescue therapy criteria, the masking of the subject, non-injecting 
physician, and site technician measuring BCVA should be maintained.  The masked physician 
will perform pre-injection exam procedures in accordance with standard subject visits.  If the 
masked physician determines the subject meets rescue therapy criteria, the masked physician will 
provide written confirmation to the injecting physician informing them of the need to administer 
rescue therapy. As the injecting physician is unmasked, and has knowledge of the treatment to be 
administered, the injecting physician should utilize written information from the masked 
physician in conjunction with their knowledge of subject treatment, to determine the appropriate 
therapy to be administered, if any.  
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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10. STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. Study Drug 
CLS-TA, triamcinolone acetonide injectable suspension, 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 (active SC kit and sham SC kit) will be supplied 
to each site by the Sponsor and will be labeled for “Investigational Use only”. 
Commercially available aflibercept, needles, and syringes necessary for IVT administration and 
sham IVT administration will be provided by the Sponsor. 
10.3. Study Drug Storage 
CLS-TA will be stored at ambient temperatures between 15°C and 25°C (59°F-77°F) in an area 
with limited, controlled access and temperature monitoring; do not freeze. CLS-TA should be 
protected from light by storing in the carton provided. 
Aflibercept should be stored according to the approved label. 
10.4. Study Drug Preparation 
Shake the vial of CLS-TA vigorously for 10 seconds to ensure a uniform suspension before 
withdrawing the product from the vial.  
Preparation of aflibercept will be performed according to the approved label. 
10.5. Administration 
CLS-TA will be administered as a single SC injection of 4 mg in 100 µL. 
All CLS-TA injections may only be performed by trained Investigators. Training will be 
documented by the Sponsor in writing. Training documentation will be maintained at the site as 
well as with the Sponsor.  
Detailed instructions on the CLS-TA injection procedure can be found in the Investigative Site 
File. 
The date and time of the injection will be recorded in the subject’s medical chart and the CRF. 
All needles used and the needle length used for injection will also be recorded. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Administration of aflibercept will be according to the approved label. 
10.6. Study Drug Accountability 
Accountability of study drug kits will be conducted by either designated study staff and/or the 
study monitor. Accountability will be ascertained by performing reconciliation between the 
number of study drug cartons (kits and components) sent to the site and the number used and 
unused at the time of reconciliation.   
Study drug shipment records will be verified and accountability performed by comparing the 
shipment inventory sheet to the actual quantity of drug and injectors received at the site. 
Accurate records of receipt and disposition of the study drug and injectors (eg, dates, quantity, 
subject number, kits used, kits unused) must be maintained by the Investigator or his/her 
designee.  
10.7. Study Drug Handling and Disposal 
At the end of the study and after study drug kit accountability has been verified, all study drug 
(used and unused vials) and unused microinjector components will be returned to the Sponsor (or 
designee) or destroyed at the site and documented according to the site’s standard process. Any 
used injectors and vials of study drug involved in a product complaint must be maintained and 
return to the Sponsor (or designee). All study drug and injector accounting procedures must be 
completed before the study is considered complete. 
 


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


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


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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registered and photographers certified for the imaging procedures. De-identified images will be 
uploaded to the CRC.  
12.1.5. Fundus Photography 
Color fundus photographs will be obtained. It is recommended that when both fundus 
photographs and FA are conducted in the same visit, the fundus photographs should be taken 
first. All photographs should be taken by the same photographer, whenever possible, on all 
subjects per research site. Digital equipment will be registered and photographers certified for 
the imaging procedures. De-identified images will be uploaded to the CRC.  
12.1.6. Resting Heart Rate and Blood Pressure 
Resting heart rate and resting blood pressure (systolic and diastolic, preferably on the same 
group each time) will be measured at every visit after the subject has rested for about 5 minutes.  
12.1.7. Pregnancy Test 
Pregnancy tests will be performed on all females of childbearing potential. Urine pregnancy tests 
will be performed at Visits 2, 5, 8 through 11. Serum and urinalysis tests will be performed at 
Visits 1, 8 and 12. 
12.1.8. Central Laboratory Tests 
Non-fasting clinical laboratory tests will be performed at Visits 1, 8 and 12. These laboratory 
tests include serum chemistry, hematology, and urinalysis and are to rule out any underlying 
disease that may exclude the subject from participation.  
12.1.9. Review of Body Systems 
A review of body systems will include an assessment of each of the following as normal or 
abnormal: skin, cardiovascular, respiratory, neurological, and musculoskeletal systems. All 
abnormal findings will be described. This exam may be performed by any medical doctor or 
legally qualified personnel according to local laws/regulations.  
12.2. Adverse and Serious Adverse Events 
12.2.1. Definition of Adverse Events 
12.2.1.1. Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition after or during exposure to a pharmaceutical product, whether or 
not considered causally related to the product. In clinical studies, an AE can include an 
undesirable medical condition occurring at any time, including baseline or washout periods, even 
if no study treatment has been administered. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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All AEs that occur after any subject has signed consent, before treatment, during treatment, or 
during the study participation, whether or not they are related to the study, must be recorded on 
the forms provided. 
12.2.1.2. Serious Adverse Event 
An SAE is an AE occurring during any study phase (ie, baseline, treatment, washout, or follow-
up), and at any dose of the investigational product, comparator, or placebo, that fulfils one or 
more of the following: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
All SAEs that occur after any subject has been enrolled, before treatment, during treatment, or 
during study participation, whether or not they are related to the study, must be recorded. 
12.2.2. Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated or Related). The Investigator should decide 
whether, in his or her medical judgment, there is a reasonable possibility that the event may have 
been caused by the investigational product. If no valid reason exists for suggesting a relationship, 
then the AE should be classified as “unrelated.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the AE, then the AE should be considered “related.” 
12.2.3. Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes in laboratory values, blood pressure, and pulse 
need not be reported as AEs. However, abnormal values that constitute an SAE or lead to 
discontinuation of administration of study drug must be reported and recorded as an AE.  
Information about AEs will be collected from the signing of the consent form until the end of the 
study. Serious adverse event information will be collected from signing of the consent form until 
the end of study participation. The AE term should be reported in standard medical terminology 
when possible. For each AE, the Investigator will evaluate and report the onset (date and time), 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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resolution (date and time), intensity, causality, action taken, seriousness outcome (if applicable), 
and whether or not it caused the subject to discontinue the study. 
 
12.2.4 Intensity 
The intensity of each AE will be graded using National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v 4.03. The criteria can be accessed 
at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
The term “severe” is a measure of intensity. A severe AE is not necessarily an SAE. 
Grade refers to the intensity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of intensity for each AE based on this general guideline: 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention 
indicated; limiting age-appropriate instrumental activities of 
daily living (ADL) 
Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of the 
hospitalization indicated; disabling; limiting self-care ADL 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the provided pregnancy form.  
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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12.2.5. Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from the signing of the consent form until the 
end of study participation. Any SAEs considered related to the investigational product and 
discovered by the Investigator at any time after the study should be reported. All SAEs must be 
reported to Clearside Biomedical, or its designee, within 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, or its designee.   
Additional follow-up information, if required or available, should be faxed to Clearside 
Biomedical, or its designee, within one business day of receipt. The information should be 
recorded on a follow-up SAE form and placed with the original SAE information and kept with 
the appropriate section of the CRF and/or study file. 
Clearside Biomedical is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Principal Investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all unexpected, serious, drug-related 
events (7/15-Day Safety Reports) that occur during the clinical study. Each site is responsible for 
notifying its IRB/IEC of these additional SAEs. 
12.2.6. Follow-up of AEs and SAEs 
All AEs and SAEs reported during study conduct must be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or the subject is lost to follow-up.  
Subjects will be followed for any treatment-related SAEs reported at the end of participation 
until the condition stabilizes, the event is otherwise explained, the subject is lost to follow-up, or 
the subject withdraws consent.   
NOTE: “Resolution” means the subject has returned to baseline state of health, or the 
Investigator does not expect any further improvement in the subject’s condition or does not 
expect worsening of the AE. 
For a non-serious AE that is first identified on the last scheduled contact, the event must be 
recorded on the AE CRF with the current status noted, but no further follow-up needs to be 
performed. 
Post-Study SAEs:  Investigators are not obligated to actively seek SAE information in former 
study participants; however, any new SAE reported by the subject to the Investigator that occurs 
after the last scheduled contact and is determined by the Investigator to be associated with the 
use of study drug, should be reported to the Sponsor. The Investigator should follow related 
SAEs identified after the last scheduled contact until the event has resolved or stabilized or the 
subject is lost to follow-up.  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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13. STATISTICAL CONSIDERATIONS 
A detailed statistical analysis plan will be prepared for this study. The plan will contain a 
discussion of the statistical methods, a description of the computational algorithms and data 
handling conventions, and specifications for the data summaries and listings. It will be finalized 
before database lock.  
13.1. Randomization 
There will be approximately 460 subjects randomly assigned 1:1 to one of two treatment groups 
stratified by disease (BRVO, CRVO). Randomization will proceed as described until either strata 
reaches 55% of the total number patients to be enrolled at which time only patients from the 
other strata will be enrolled. Assignment of subjects to treatment groups will be performed via 
the IWRS. 
13.2. Determination of Sample Size and Level of Significance 
With a total sample size of 460 subjects in a 1:1 randomization, this study will have 90% power 
to detect a difference of 15% between treatments if the actual proportion of subjects showing 
improvement of 15 letters is 0.50 for the control aflibercept group at 2 months.  
Power was based on a Pearson chi-squared difference in proportions of subjects showing 
improvement in BCVA at Month 2. The estimate for the IVT aflibercept proportion was set at 
0.5, which is a worst-case scenario analysis because the variance of the proportion was maximal 
at 0.5. This, in turn, makes the power estimate robust with regard to the actual value of the IVT 
aflibercept proportion. The proportion for SC injection of CLS-TA was estimated over a range of 
values. A minimal clinical effect of 15% greater improvement was selected. For 90% power, this 
will require 227 subjects/group.  
13.3. Subject Disposition and Demographic and Baseline Characteristics 
Subject disposition and demographic, and baseline characteristics will be summarized 
descriptively by treatment group and overall. 
13.4. Analysis Populations 
13.4.1. Safety Population 
The Safety Population will include all randomly assigned subjects who are administered at least 
one dose of the study drug. All safety analyses will be based on the Safety Population. 
13.4.2. Intent-to-Treat Population 
The Intent-to-treat (ITT) Population will include all randomized subjects who have received at 
least one study treatment. Subjects will be analyzed as originally allocated after randomization. 
The ITT Population will be used for efficacy analyses.  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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13.4.3. Per Protocol Population 
The Per-protocol (PP) Population will include all subjects in the ITT population who do not have 
significant protocol deviations and who complete the Week 24 Visit. The rules for determining 
exclusions from the PP Population will be finalized after a clinical review of the data and 
resolution of all queries but before unmasking of treatment assignments. 
13.5. Analysis Methods 
Efficacy and safety endpoints are provided in Section 7.2.  
13.5.1. Primary Efficacy Analysis 
The primary endpoint is the proportion of subjects demonstrating ≥ 15 letter improvement from 
Baseline in ETDRS BCVA at Week 8 (Month 2).  
The primary analysis is a test of superiority of SC CLS-TA. The primary analysis will use the 
Cochran-Mantel-Haenszel test to evaluate differences in the proportion of subjects in the two 
groups who show 15 or more letters improvement in BCVA at the 2-month visit after adjusting 
for effects for disease type. Subjects who either receive rescue medication or withdraw from the 
study prior to the 2-month visit will be considered as treatment failures for the primary endpoint 
analysis. 
Tests to evaluate the treatment superiority of SC CLS-TA (TA) in combination with IVT 
aflibercept (IA) compared with IVT aflibercept alone will conducted using a two-sided 
alpha = 0.5 
The formal hypothesis is: 
H0: IA + TA = IA 
H1: IA + TA ≠ IA 
The Breslow-Day test will be used to assess homogeneity of results across Investigators. 
These methods were chosen because the subjects are stratified by disease type. For measures 
such as BCVA, differences across strata may be large enough to have impact on the overall 
results. 
The Cochran-Mantel-Haenszel test adjusts for differences in results between disease types and 
the Breslow-Day test assesses homogeneity of results across Investigators. 
13.5.1.1 Sensitivity Analyses of Primary Efficacy Endpoint 
To evaluate the robustness of the analysis of the primary efficacy endpoint, sensitivity analyses will 
be performed using a placebo-based multiple imputation Pattern Mixture Model (PMM) and a 
tipping point analysis of the PMM in the ITT population. These sensitivity analyses will be detailed 
in the statistical analysis plan (SAP) and finalized prior to the study database lock. 
 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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13.5.2. Secondary Efficacy Analysis 
13.5.2.1. Secondary Efficacy Endpoint 
• Mean change from Baseline (Visit 2, Day 0) in BCVA at Visit 4 (Week 8) and Visit 8 
(Week 24) 
• Mean change from Baseline (Visit 2, Day 0) in CST at Visit 4 (Week 8) and Visit 8 
(Week 24) 
13.5.2.2. Exploratory Endpoints 
• Change from Baseline (Visit 2, Day 0) in subject-reported outcomes at Visit 8 (Week 
24) as measured by the VFQ-25 and the EQ-5D 
• Change from Baseline in signs and complications of RVO (eg, neovascularization, 
perfusion) at Visit 8 (Week 24) 
13.5.3. 
Subgroup Analysis 
No subgroup analyses are planned. 
13.5.4. Safety Analysis  
13.5.4.1. Extent of Exposure 
The extent of exposure (ie, whether a subject received the injection and whether it was a 
complete or partial injection) will be listed. 
13.5.4.2. Safety Endpoints 
• Incidence of TEAEs and SAEs, grouped by organ system, relatedness to study drug, and 
intensity  
• Incidence of changes in safety parameters including: IOP, slit-lamp biomicroscopy, 
indirect ophthalmoscopy, imaging parameters, and vital signs  
13.5.5. 
Schedule of Analyses 
Additional safety and descriptive efficacy data will be collected through Month 12. Treatment 
codes will be broken at Month 2, and the final efficacy analysis will be conducted at this time. A 
descriptive follow-up safety and efficacy analysis will be performed at 6 months to allow filing 
the New Drug Application. Investigators, subjects, and study personnel who have contact with 
the Investigators or subjects will remain masked throughout the study. No adjustment for the 
analysis at Month 6 is required because the final analysis of efficacy is at Month 2 and data from 
all subsequent visits will be descriptive only.  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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13.5.6. 
Procedure for Accounting for Missing, Unused, or Spurious Data 
Any missing, unused, or spurious data will be noted in the final clinical study report. 
The Last Observation Carried Forward (LOCF) method will be used if visits are missed in the 
ITT Population. No imputation for missed visits will be used in the PP Population. This provides 
an indication of the sensitivity of the data to missing observations.  
Likewise, the LOCF method will be used if a subject requires rescue therapy. All data points will 
be set to missing after a subject’s receipt of a rescue medication; the last recorded data before the 
rescue will be carried forward to all subsequent visits for the ITT Population. No imputation for 
rescue mediations will be used in the PP Population.  
No imputation is planned for safety data. Methodology for handling missing or partial dates will 
be addressed in the Statistical Analysis Plan. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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14. DIRECT ACCESS TO SOURCE DOCUMENTS 
14.1. Study Monitoring 
Before an investigator can enter a subject into the study, a representative of Clearside 
Biomedical, Inc will visit the study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence and the responsibilities of Clearside Biomedical, Inc or its 
representatives. This will be documented in a Clinical Study Agreement between 
Clearside Biomedical, Inc and the Investigator. 
During the study, a monitor from Clearside Biomedical, Inc or its representative will have 
regular contacts with the study site to: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRFs, and that investigational product accountability checks 
are being performed 
• Perform source data verification. This includes a comparison of the data in the CRFs with 
the subject’s medical records at the hospital or practice, and other records relevant to the 
study. This will require direct access to all original records for each subject (eg, clinic 
charts). 
• Record and report any protocol deviations not previously sent to Clearside Biomedical, 
Inc or designee. 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to Clearside Biomedical, Inc or designee and those SAEs that met 
criteria for reporting have been forwarded to the IRB/IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
14.2. Audits and Inspections 
Authorized representatives of Clearside Biomedical, a regulatory authority, an Independent 
Ethics Committee or an Institutional Review Board may visit the study site to perform audits or 
inspections, including source data verification. The purpose of a Clearside Biomedical audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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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/Independent Ethics Committee 
The Principal Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC 
approval and all materials approved by the IRB/IEC for this study, including the subject consent 
form and recruitment materials, must be maintained by the Investigator and made available for 
inspection. 


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


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


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


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


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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19. REFERENCES 
Boyer D, Heier J, Brown DM, Clark WL, Vitti R, Berliner AJ, et al. Vascular endothelial growth 
factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results 
of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5):1024-32. 
Brown DM, Heier JS, Clark WL, Boyer DS, Vitti R, Berliner AJ, et al. Intravitreal aflibercept 
injection for macular edema secondary to central retinal vein occlusion: 1-year results from the 
phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429-37. 
Campochiaro PA, Clark WL, Boyer DS, Heier JS, Brown DM, Vitti R, et al. Intravitreal 
aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the 
VIBRANT study. Ophthalmology. 2015;122(3)538-44. 
Comyn O, Lightman SL, Hykin PG. Corticosteroid intravitreal implants vs. ranibizumab for the 
treatment of vitreoretinal disease. Curr Opin Opthalmol. 2013;24(3):248-54. 
Cunningham MA, Edelman JL, Kaushal S. Intravitreal steroids for macular edema: the past, the 
present, and the future. Surv Ophthalmol. 2008r;53(2):139-49. 
Ehlers JP, Fekrat S. Retinal vein occlusion: beyond the acute event. Surv Ophthalmol. 
2011;56(4):281-99. 
EYLEA® [Package Insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc., 2016. 
EYLEA® [Summaryof Product Characteristics]. Berlin, Germany: Bayer Pharma AG, 2012 
Felinski EA, Antonetti DA. Glucocorticoid regulation of endothelial cell tight junction gene 
expression: novel treatments for diabetic retinopathy. Curr Eye Res. 2005;30(11):949-57. 
Hahn P, Fekrat S. Best practices for treatment of retinal vein occlusion. Curr Opin Ophthalmol. 
2012;23(3):175-81. 
Kiernan DF, Mieler WF. The use of intraocular corticosteroids. Expert Opin Pharmacother. 
2009;10(15):2511-25. 
Rogers S, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchell P, et al; International Eye Disease 
Consortium. The prevalence of retinal vein occlusion: pooled data from population studies from 
the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117(2):313-9. 
Ip MS, Scott IU, VanVeldhuisen PC, Oden NL, Blodi BA, Fisher M, et al; SCORE Study 
Research Group. A randomized trial comparing the efficacy and safety of intravitreal 
triamcinolone with observation to treat vision loss associated with macular edema secondary to 
central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion 
(SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101-14. 
TRIESENCE® [Package Insert]. Fort Worth, TX: Alcon Laboratories, Inc., 2007. 


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


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


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


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APPENDIX B:  Summary of Changes for Amendments 
Amendment 1 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol 
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Title Page 
For protocol 
identification 
None 
Title Page 
1220 Old Alpharetta Rd., Suite 300 
Alpharetta, GA 30005 
Clearside Biomedical, 
Inc. Address change 
None 
Title Page 
Protocol versioning 
None 
Section 7.4. 
Treatment 
Assignment 
Subjects will be offered continued dosing 
and treated as needed (PRN). Treatment 
provided will be consistent with the 
subject’s assigned treatment group. 
Aflibercept is the most 
effective treatment for 
RVO and allows the 
active and control study 
arms to remain consistent 
in their treatment, except 
for the CLS-TA 
comparison. 
Use of 
aflibercept only 
during PRN 
period. 
Section 7.4. 
Treatment 
Assignment 
Figure 2. 
Updated Figure 2. 
Updating the treatment 
during the PRN dosing 
period. 
None. 
Section 8.1. 
Has an ETDRS BCVA score of  ≥ 5 
IND and EurdraCT numbers added 
900 North Point Parkway, Suite 200 
Alpharetta, GA 30005 
Addition of Protocol Amendment 1 Date: 
31March2017 
Subjects will be treated, as needed (PRN), 
with aflibercept. 
Figure 2. 
Has an ETDRS BCVA score of  ≥ 20 
To ensure changes in 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Inclusion Criteria 
letters read and ≤ 70 letters read in the 
study eye 
letters read and ≤ 70 letters read in the 
study eye 
 
vision can be measured  
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has, in the study eye, used any topical 
ocular corticosteroid in the 10 days before 
treatment at Visit 2 (Day 0); received any 
intraocular or periocular corticosteroid 
injection in the 2 months before treatment 
at Visit 2; had an OZURDEX® implant in 
the 6 months before treatment at Visit 2;, 
a RETISERT® implant in the 1 year 
before treatment at Visit 2, or an 
ILUVIEN® implant in the 3 years before 
treatment at Visit 2 
 
Has, in the study eye, used any topical 
ocular corticosteroid in the 10 days before 
treatment at Visit 2 (Day 0); has at any 
time received any intraocular or 
periocular corticosteroid injection, an 
OZURDEX® implant, a RETISERT® 
implant, or an ILUVIEN® implant 
To ensure consistency 
with ophthalmic criteria 
None 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has had photocoagulation or cryotherapy 
in the study eye within the 6 months 
before Visit 2 (Day 0)  
Has had >3 macular laser 
photocoagulation treatments; or has had 
photocoagulation or cryotherapy in the 
study eye within the 6 months before Visit 
2 (Day 0) 
 
Eliminate subjects with 
more than 3 macular 
laser photocoagulation 
treatments 
None. 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
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Version Date: 31 March 2017 
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Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has significant media opacity precluding 
evaluation of retina and vitreous in the 
study eye. This includes significant 
hemorrhage cataract that is felt to be a 
major contributor to reduced visual acuity 
and/or likely to undergo surgical repair 
within 3 months of randomization 
 
Has significant media opacity precluding 
evaluation of retina and vitreous in the 
study eye. This includes cataract that is 
felt to be a major contributor to reduced 
visual acuity and/or likely to undergo 
surgical repair within 3 months of 
randomization 
To ensure consistency 
with Ophthalmic 
Exclusion criteria 
None 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
 
History of glaucoma, optic nerve head 
change consistent with glaucoma damage, 
or ocular hypertension in the study eye 
requiring more than one medication; 
Added exclusion criteria 
None 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has a IOP > 22 mmHg or uncontrolled 
glaucoma (open angle or angle closure) in 
the study eye at Visit 1 (Day -14 to -1); 
subjects are not excluded if IOP is ≤ 22 
mmHg in the study eye with no more than 
2 IOP-lowering medications 
Has a IOP > 21 mmHg in the study eye at 
Visit 1 (Day -30 to -1); subjects are not 
excluded if IOP is <22 mmHg in the study 
eye with no more than 1 IOP-lowering 
medication; as long as there is no history 
of glaucoma and the subject has a normal 
optic nerve and no evidence of visual field 
loss; 
 
Updated screening 
window period to match 
protocol 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.2.1. 
Ophthalmic 
Exclusion Criteria 
Has a history of glaucoma surgery 
(filtration surgery/trabeculectomy or tube 
shunt) in the study eye; 
Has a history of glaucoma surgery 
(filtration surgery/trabeculectomy or tube 
shunt) in the study eye; has a history of 
laser trabeculoplasty or MIGs surgery in 
the study eye 
Addition of Exclusion 
Criteria 
None 
Section 8.2.2. 
General Exclusion 
Criteria 
Has any uncontrolled systemic disease 
that, in the opinion of the Investigator, 
would preclude participation in the study 
(eg, infection, uncontrolled elevated blood 
pressure, cardiovascular disease, poor 
glycemic control) or put the subject at risk 
due to study treatment or procedures 
Has any uncontrolled systemic disease 
that, in the opinion of the Investigator, 
would preclude participation in the study 
(eg, infection, uncontrolled elevated blood 
pressure, cardiovascular disease, poor 
glycemic control) or put the subject at risk 
due to study treatment or procedures; 
NOTE: Uncontrolled BP at screening may 
be treated before Visit 2 
 
To allow treatment of 
blood pressure prior to 
enrollment. 
None 
Section 8.2.2. 
General Exclusion 
Criteria 
 
History of any inflammatory or other 
medical condition that the investigator 
might reasonably anticipate will require 
treatment with high-dose corticosteroids 
(more than 10mg/day oral prednisone or 
the equivalent) for more than 14 days 
 
Addition of Exclusion 
Criteria 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
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Version Date: 31 March 2017 
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Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.2.3. 
Randomization 
Criteria 
The CRC confirms ME by SD-OCT (from 
Visit 1 SD-OCT data), with or without 
intraretinal or subretinal fluid, caused by 
RVO in the study eye 
 
The CRC confirms ME by SD-OCT (from 
Visit 1 SD-OCT data), with or without 
intraretinal or subretinal fluid 
CRC does not confirm 
RVO 
None 
Section 8.4. Visit 
Procedure 
Descriptions 
All ocular assessments at Visit 1 
(Screening) and Visit 8 (Week 48) will be 
performed on both eyes. Data from other 
ocular assessments at all other visits will 
be performed on the study eye only.   
Perform ophthalmic assessments on the 
study eye only:  
1. ETDRS BCVA 
2. Slit-lamp biomicroscopy  
3. IOP  
4. Dilated indirect ophthalmoscopy 
5. SD-OCT 
All ocular assessments at Visit 1 
(Screening) and Visit 8 (Week 48) will be 
performed on both eyes. IOP will be 
collected in both eyes at all visits. Data 
from all other ocular assessments at all 
other visits will be performed on the study 
eye only.   
Perform ophthalmic assessments on the 
study eye only, unless otherwise 
designated:  
1. ETDRS BCVA 
2. Slit-lamp biomicroscopy, 
including dilated lens grading  
3. IOP (both eyes) 
4. Dilated indirect ophthalmoscopy 
5. SD-OCT 
To collect IOP data on 
the fellow eye at all visits 
for comparison to the 
study eye IOP 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
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Version Date: 31 March 2017 
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Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.4.4.2.2. SC 
Injection of CLS-TA 
(ACTIVE) OR sham 
procedure 
(CONTROL) 
1. Administer SC injection or sham 
after the IVT injection of 
aflibercept when the study eye 
IOP is < 30 mmHg, either 
spontaneously or by treatment, as 
determined by the Investigator 
2. Administer SC injection of 100 
µL of CLS-TA or sham 
procedure approximately 2 or 
more clock hours from the site of 
the IVT injection 
3. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection, 
1. Administer SC injection or sham 
after the IVT injection of 
aflibercept when the study eye 
IOP is < 30 mmHg, either 
spontaneously or by treatment, as 
determined by the Investigator 
2. Prepare study eye for SC 
injection according to the 
Investigator’s standard practice 
3. Administer SC injection of 100 
µL of CLS-TA or sham 
procedure approximately 2 or 
more clock hours from the site of 
the IVT injection 
4. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection, 
Provide detail on 
preparing the eye prior to 
the second injection 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
Clinical Protocol 
 
Version Date: 31 March 2017 
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Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.4.6.2 PRN 
Injection 
Procedures: Visit 9 
(Week 30), Visit 10 
(Week 36), and Visit 
11 (Week 42) 
If subject qualifies for PRN therapy 
according to the Additional Therapy 
Criteria listed in Section 9.4.2, the 
following injection and post-dose 
procedures should be performed, 
consistent with the subject’s treatment 
group: 
1. Confirm the study eye 
2. Retrieve study drug kit number 
assigned by IWRS 
3. Prepare eye for injection 
according to the Investigator’s 
standard practice 
4. The UNMASKED injecting 
Investigator should perform IVT 
injection of aflibercept, SC 
injection of CLS-TA, and all 
sham procedures to the eye 
 
If subject qualifies for PRN therapy 
according to the Additional Therapy 
Criteria listed in Section 9.4.2, the 
following injection and post-dose 
procedures should be performed, 
consistent with the subject’s treatment 
group: 
1. Confirm the study eye 
2. Retrieve study drug kit number 
assigned by IWRS 
3. Prepare eye for injection 
according to the Investigator’s 
standard practice 
4. The UNMASKED injecting 
Investigator should perform IVT 
injection of aflibercept 
 
Remove reference to SC 
CLS-TA injection during 
PRN period 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
Clinical Protocol 
 
Version Date: 31 March 2017 
Page 65 of 69 
CONFIDENTIAL 
 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.4.6.2.1. 
IVT injection of 
aflibercept 
1. Prepare study eye for IVT 
injection of aflibercept 
2. Administer aflibercept IVT 
injection according to the 
package insert. The sites of the 
IVT injection and the SC 
injection should be 
approximately 2 or more clock 
hours apart.  A temporal 
quadrant is the recommended 
location for SC injections. 
3. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection, 
4. Measure IOP after injection 
1. Prepare study eye for IVT 
injection of aflibercept 
2. Administer aflibercept IVT 
injection according to the 
package insert. 
3. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection, 
4. Measure IOP after injection 
Remove reference to SC 
CLS-TA injection during 
PRN period 
 
Section 8.4.6.2.2. SC 
Injection of CLS-TA 
(ACTIVE) OR sham 
procedure 
(CONTROL) 
1. Administer SC injection or sham 
after the IVT injection of 
aflibercept when the study eye 
IOP is < 30 mmHg, either 
spontaneously or by treatment, as 
determined by the Investigator 
2. Administer SC injection of 100 
µL of CLS-TA or sham 
procedure approximately 2 or 
more clock hours from the site of 
the IVT injection 
3. Assess study eye by indirect 
ophthalmoscopy immediately 
after the injection 
 
Remove reference to 
procedure of SC CLS-
TA reference during 
PRN period 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
Clinical Protocol 
 
Version Date: 31 March 2017 
Page 66 of 69 
CONFIDENTIAL 
 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 8.4.6.3. Post-
Dose Procedures: 
Visit 9 (Week 30), 
Visit 10 (Week 36), 
and Visit 11 (Week 
42) 
The following assessments must occur 
after the IVT injection, SC injection, or 
sham procedure:  
 
The following assessments must occur 
after the IVT injection: 
Remove reference to SC 
CLS-TA injection post-
dose procedures during 
PRN period as SC CLS-
TA is no longer 
administered during PRN 
period. 
None 
Section 9.1. 
Treatments to be 
Administered 
Beginning with Visit 9 (Week 30), 
subjects will be assessed for PRN 
treatment that will consist of the same 
treatment, SC CLS-TA in conjunction 
with IVT aflibercept. 
Beginning with Visit 9 (Week 30), 
subjects will be assessed for PRN 
treatment that will consist of IVT 
aflibercept based on PRN criteria (Section 
9.4.2). 
Use of aflibercept only 
during PRN period 
Only approved 
therapy will be 
used during the 
PRN period, 
thus limiting the 
risk to the 
subject 
 
Section 9.4.1. Rescue 
Therapy Criteria 
Beginning at Week 16 (Visit 6), if any of 
the following criteria are met in the study 
eye, the use of a non-investigational 
treatment should be introduced. The 
therapy implemented is left to the 
discretion of the Investigator. 
 
 
 
 
 
 
 
Beginning at Week 8 (Visit 4), if any of 
the following criteria are met in the study 
eye, intravitreal aflibercept will be 
administered. 
To ensure that all 
subjects are adequately 
treated during this period 
and aflibercept is 
required in order to keep 
the therapy consistent 
between arms 
 
To ensure that 
all subjects are 
adequately 
treated during 
this period  


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
Clinical Protocol 
 
Version Date: 31 March 2017 
Page 67 of 69 
CONFIDENTIAL 
 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 9.4.1. Rescue 
Therapy Criteria 
A decrease in BCVA of 10 letters or 
greater between the current visit and the 
BCVA reading from the previous visit 
A decrease in BCVA of 6 letters or 
greater between the current visit and the 
BCVA reading from the previous visit 
with an increase in CST of > 50 µm from 
the previous visit, associated with new 
fluid 
 
To decrease the number 
of letters lost prior to 
qualifying for additional 
treatment 
To ensure that 
all subjects are 
adequately 
treated during 
this period 
 Section 9.4.1. 
Rescue Therapy 
Criteria 
In the Investigator’s medical judgement, 
the complications of RVO in the study 
eye have not improved and the condition 
needs to be addressed 
If vision is worse than approximately 70 
letters read and there is new or persistent 
intraretinal or sub-retinal fluid, that in the 
opinion of the investigator is affecting 
vision, even if CST <340 µm 
 
Provide guidance around 
the investigator’s 
assessment  
To ensure that 
all subjects are 
adequately 
treated during 
this period 
Section 9.4.2. PRN 
Criteria 
During the PRN Dosing and Follow-Up 
Period (Visits 9 through 11 [Weeks 30 
through 42]), treatment will remain 
consistent with randomized group and 
will remain masked (Section 8.1). Dosing 
is not limited to the rescue criteria above. 
The frequency of treatment is at the 
Investigators discretion during this period. 
 
During the PRN Dosing and Follow-up 
Period (Visits 9 through 11 [Weeks 30 
through 42]), study arm will remain 
masked and additional dosing is limited to 
the criteria above. 
Use of aflibercept only 
during PRN period 
Only approved 
therapy will be 
used during the 
PRN period, 
thus limiting the 
risk to the 
subject 
Section 9.5. 
Concomitant 
Treatments 
Changes to topical ophthalmic non-
steroidal anti-inflammatory drugs in the 
study eye 
 
Increases to topical ophthalmic non-
steroidal anti-inflammatory drugs in the 
study eye 
To allow decreases in 
therapy during the study 
Subjects will 
not be required 
to stay on 
therapies that 
are unnecessary 
 
Section 9.5. 
 
High dose systemic corticosteroids (>10 
Addition of prohibited 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
Clinical Protocol 
 
Version Date: 31 March 2017 
Page 68 of 69 
CONFIDENTIAL 
 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Concomitant 
Treatments 
mg/day of prednisone or equivalent) for 
more than 14 days 
 
concomitant treatment 
Section 9.5. 
Concomitant 
Treatments 
 
 
Macular (grid/focal) laser 
 
Addition of prohibited 
concomitant treatment  
None 
Section 9.7. 
Randomization and 
Masking 
 
In cases where subjects meet rescue 
therapy criteria, the masking of the 
subject, non-injecting physician, and site 
technician measuring BCVA should be 
maintained.  The masked physician will 
perform pre-injection exam procedures in 
accordance with standard subject visits.  If 
the masked physician determines the 
subject meets rescue therapy criteria, the 
masked physician will provide written 
confirmation to the injecting physician 
informing them of the need to administer 
rescue therapy. As the injecting physician 
is unmasked, and has knowledge of the 
treatment to be administered, the injecting 
physician should utilize written 
information from the masked physician in 
conjunction with their knowledge of 
subject treatment, to determine the 
appropriate therapy to be administered, if 
any. 
 
Guidance for the site to 
maintain the masking 
during rescue therapy 
None 


CLS-TA, triamcinolone acetonide injectable suspension                                                       Clearside Biomedical, Inc  
CLS1003-301 
 
Clinical Protocol 
 
Version Date: 31 March 2017 
Page 69 of 69 
CONFIDENTIAL 
 
Amendment 1 
 
 
 
 
Section Changed 
Initial Protocol  
(Changed From) 
Modified Protocol  
(Changed To) 
Reason for Change 
Impact on 
Subjects 
(Risk/Benefit) 
Section 9.7. 
Randomization and 
Masking 
The unmasked Investigator and staff may 
not participate in efficacy assessments 
conducted during the Dosing and 
Evaluation Period. 
 
The unmasked Investigator and staff may 
not participate in efficacy assessments. 
To clarify that unmasked 
staff may not participate 
in efficacy assessments 
at any time 
None 
Section 12.1.1. 
Intraocular pressure will be measured by 
applanation tonometery (Tonopen or 
Goldmann) and results will be recorded in 
mmHg. 
Intraocular pressure will be measured by 
applanation tonometry and results will be 
recorded in mmHg. Where available, 
Goldmann applanation tonometry should 
be used at all visits. Tonopens may be 
used for post-injection pressure checks 
and in cases where no Goldmann is 
available. 
 
Preferred use of 
Goldmann for IOP 
measurement 
None 
Appendix A 
V9, V10, and V11 listed a PRN dose for 
SC CLS-TA or sham injection 
Removal of V9, V10, and V11 PRN SC 
CLS-TA or sham injection 
Corrected to be 
consistent with PRN 
criteria updates 
 
None 
Throughout 
protocol 
Miscellaneous typographical and 
formatting errors  
 
To correct typographical 
and formatting errors  
None