Clinical trial NCT02914613
Conditions: Diabetic Macular Edema
Sponsor: OcuTerra Therapeutics, Inc.
Start date: 2016-08-24; Completion date: 2017-05-16
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study was to evaluate the safety and exploratory efficacy of SF0166 Topical Ophthalmic Solution in patients with Diabetic Macular Edema (DME).

Detailed description:
This was a prospective, randomized, double-masked, multicenter, Phase I/II clinical study in which 44 eligible subjects with active Diabetic Macular Edema (DME) were randomized to 1 of 2 treatment arms in a 1:1 ratio as follows: SF0166 low dose twice daily (BID) or SF0166 high dose BID.

Study subjects administered the randomly assigned treatment for 28 days. There was an additional 28-day post-treatment follow-up period. Study subjects returned for examination every 2 weeks for 8 weeks (2 months).

Arms: arm 1: SF0166 low dose instilled in study eye BID for 28 days of treatment. arm 2: SF0166 high dose instilled in study eye BID for 28 days of treatment.
Interventions: intervention 1: SF0166 Topical Ophthalmic Solution
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Number: 
SF0166-C-001 
Protocol Title: 
A Phase I/II Randomized, Double-Masked, Multicenter 
Clinical Trial Designed to Evaluate the Safety and 
Exploratory Efficacy of SF0166 Topical Ophthalmic 
Solution in the Treatment of Diabetic Macular Edema 
(DME) 
Study Phase: 
I/II 
Sponsor Name and Address: 
SciFluor Life Sciences, Inc.  
300 Technology Square, Suite 201 
Cambridge, MA 02139 
Medical Monitor: 
Pharmacovigilance:  
Gary Foulks, MD 
3103 Joy Place 
Wilmington, NC  28409 
Retina Expert: 
Quan Dong Nguyen, MD, MSc 
1421 North 143rd Street 
Omaha, NE 68154 
Investigational Product (IP): 
SF0166 Topical Ophthalmic Solution 
Indication Studied: 
Diabetic Macular Edema 
 
Investigator Agreement: 
 
I have read the clinical study described herein, recognize its confidentiality, and agree to 
conduct the described study in compliance with Good Clinical Practices (GCP), the 
ethical principles contained within the Declaration of Helsinki, this protocol, and all 
applicable regulatory requirements; including United States (US) Food and Drug 
Administration (FDA) 21 Code of Federal Regulations (CFR) 312. 
 
Principal Investigator: 
 
 
Site Name/Address: 
Signature:  
 
Date:  


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SYNOPSIS  
1.0
Sponsor: 
SciFluor Life Sciences, LLC  
300 Technology Square, Suite 201  
Cambridge, MA 02139 
Protocol Number:  
SF0166-C-001 
Protocol Title: 
A Phase I/II Randomized, Double-Masked, Multicenter Clinical 
Trial Designed to Evaluate the Safety and Exploratory Efficacy of 
SF0166 Topical Ophthalmic Solution in the Treatment of Diabetic 
Macular Edema 
Investigational 
Product: 
 
SF0166 Topical Ophthalmic Solution (SF0166) 
Active Ingredient: 
SF0166 (αvβ3 antagonists) 
Number of 
Investigative Sites: 
Approximately 10 
Investigative Site 
Locations: 
US 
Number of Subjects: 
Approximately 40 (20 in each arm) 
Duration of 
Treatment: 
28 days 
Study Population: 
Male and female subjects, aged 18 or older, with diabetic 
macular edema (i.e., retinal thickening secondary to type 1 or 
type 2 diabetes mellitus with DME with central subfield thickness 
≥325 microns (μm) on spectral domain optical coherence 
tomography [OCT]) and no treatment with anti-vascular 
endothelial growth factor (VEGF) therapy within up to 60 days of 
study entry in the study eye 
Objective(s): 
To evaluate the safety and exploratory efficacy of SF0166 topical 
ophthalmic solution in patients with DME 
Study Design & 
Methodology: 
This is a prospective, randomized, double-masked multicenter, 
Phase I/II clinical study in which approximately 40 eligible 
subjects with active DME will be randomized to 1 of 2 treatment 
arms in a 1:1 ratio as follows: 
• SF0166 2.5% low dose twice daily (BID) 
• SF0166 5.0% high dose BID 
 
Randomization will be stratified by best-corrected visual acuity 
(BCVA) using Early Treatment Diabetic Retinopathy Study 
(ETDRS) testing (<40 letters versus ≥40 letters at Visit 1 – 
Screening/Randomization). 
 
Eligibility and all site-related treatment decisions will be made 
based on Investigator assessment of OCT. All OCT images will 
also be reviewed by a central reading facility; however, eligibility 
is based on the Investigator’s assessment at the time the 


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potential study subject is examined. The primary efficacy 
outcome is determined by the OCT assessments from the 
reading center. 
 
Study subjects will administer the randomly assigned treatment 
for 28 days. There is an additional 28-day post-treatment 
follow-up period. All study subjects will return for examination 
every 2 weeks for 8 weeks (2 months). 
 
Clinical assessments will include slit-lamp examination, 
intraocular pressure (IOP) measurement, BCVA, OCT, 
fluorescein angiography (FA), and fundus photography. Adverse 
events (AEs) will be recorded at all study visits. 
 
Rescue therapy with a VEGF inhibitor can be administered to 
any study subject who experiences a significant decrease in 
BCVA, defined as BCVA loss of >7 letters from baseline (Visit 1 
– Screening/Randomization), accompanied by an increase in 
OCT central subfield thickness of >75μm as compared to the 
previous study visit, as assessed by the Investigator.  
 
Potential study participants will be asked to sign an informed 
consent document prior to screening. Once it is determined that 
all eligibility criteria have been met, subjects will be randomized 
to 1 of the 2 treatment arms. All study subjects and site staff will 
be masked to the treatment assignment. 
 
The safety and exploratory efficacy of SF0166 will be evaluated 
over the course of the study. Since this is Phase I/II clinical 
study, no formal hypotheses testing is planned; descriptive 
statistics will be used to summarize the study outcomes.  
Treatments: 
• SF0166 2.5% low dose BID  
• SF0166 5.0% high dose BID 
Subject Selection: 
Inclusion 
Criteria: 
1. Male or female, 18 years of age or older. 
2. Retinal thickening secondary to type 1 or type 2 
diabetes mellitus with DME defined as central 
subfield thickness ≥325 µm on spectral domain 
OCT in the study eye. 
3. BCVA between 78 and 25 letters, inclusive, in the 
study eye at the screening/randomization visit 
using ETDRS testing, with BCVA decrement 
primarily attributable to DME. 
4. Treatment naïve (i.e., no previous anti-VEGF 
treatment in the study eye) or previously treated 
study eye with adequate washout defined below: 
a. Lucentis (ranibizumab): 30-day washout 


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b. Avastin (bevacizumab): 30-day washout 
c. Eylea (aflibercept): 60-day washout 
d. Macugen (pegaptanib): 45-day washout 
5. Willing and able to return for all study visits. 
6. Able to adhere to the study dosing requirements. 
7. Understands and signs the written informed 
consent form. 
Exclusion 
Criteria: 
1. Active proliferative diabetic retinopathy (PDR) in 
the study eye, such as neovascularization of the 
optic disc (NVD), neovascularization elsewhere 
(NVE), vitreous hemorrhage, or neovascular 
glaucoma. 
2. Uncontrolled glaucoma or ocular hypertension in 
the study eye defined as an IOP >25 millimeter of 
mercury (mmHg) regardless of concomitant 
treatment with IOP-lowering medications. 
3. Uncontrolled hypertension defined as systolic 
>180 mmHg or >160 mmHg on 2 consecutive 
measurements (during the same visit) or diastolic 
>100 mmHg on optimal medical regimen. 
4. Screening glycated hemoglobin (HbA1c) blood 
test >12.0%. 
5. Previous panretinal photocoagulation (PRP) in 
the study eye within 4 months of study 
enrollment, or the need for PRP during the study 
based on the Investigator’s opinion. 
6. Previous focal laser photocoagulation in the study 
eye, within the foveal avascular zone. 
7. Intravitreal/periocular/topical ocular steroids of 
any type in the study eye within 90 days (3 
months) prior to study enrollment. 
8. Placement of Iluvien® or Retisert® (fluocinolone 
acetonide intravitreal implant) in the study eye 
within 36 months (3 years) prior to study 
enrollment. 
9. Use of Ozurdex® (dexamethasone intravitreal 
implant) in the study eye within 180 days (6 
months) prior to study enrollment. 
10. Significant epiretinal membrane, posterior 
hyaloidal traction, and/or vitreomacular traction in 
the study eye as determined by the OCT results.  
11. Previous pars plana vitrectomy in the study eye. 
12. Any intraocular surgery in the study eye within 90 
days (3 months) prior to study enrollment. 
13. Yttrium aluminium garnet (YAG) laser treatment 


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in the study eye within 30 days (1 month) prior to 
study enrollment. 
14. Concomitant use of any topical ophthalmic 
medications in the study eye, including dry eye or 
glaucoma medications, unless on a stable dose 
for at least 90 days (3 months) prior to study 
enrollment and expected to stay on stable dose 
throughout study participation. Artificial tears are 
allowed. 
15. High myopia in the study eye, with a spherical 
equivalent of >8.00 Diopters (D) at screening. 
16. Chronic or recurrent uveitis in the study eye. 
17. Ongoing ocular infection or inflammation in either 
eye. 
18. A history of cataract surgery complicated by 
vitreous loss in the study eye. 
19. Congenital eye malformations in the study eye. 
20. A history of penetrating ocular trauma in the 
study eye. 
21. Mentally handicapped. 
22. Females of childbearing potential (i.e., who are 
not postmenopausal for at least 1 year or 
surgically sterile for at least 6 weeks prior to Visit 
1 – Screening/Randomization) who are lactating, 
or who are pregnant as determined by a positive 
urine pregnancy test (UPT) at Visit 1 – 
Screening/Randomization. Women of 
childbearing potential must agree to use 
acceptable methods of birth control throughout 
the study. Acceptable methods of birth control 
include tubal ligation, transdermal patch, 
intrauterine devices/systems, 
oral/implantable/injectable or contraceptives, 
sexual abstinence, double barrier method, or 
vasectomized partner.  
23. Participation in any other investigational device or 
drug clinical research study within 30 days of Visit 
1 – Screening/Randomization. 
24. Contraindication to the study medications or 
fluorescein dye.  
25. Other ocular pathologies that in the Investigator’s 
opinion would interfere with the subject’s vision in 
the study eye. 
Assessments: 
• Spectral Domain OCT 


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• Best Corrected Visual Acuity (ETDRS) 
• Slit-Lamp Biomicroscopy 
• IOP by Tonopen or Applanation 
• Indirect Ophthalmoscopy/Dilated Fundus Examination 
• Fundus Photography 
• Fluorescein Angiography 
• AEs 
Outcomes: 
Efficacy: 
 
The primary efficacy outcome is the mean change in 
anatomic center subfield thickness and macular 
volume, measured by OCT. All OCT images will be 
read by the Investigator and a central reading facility. 
The primary efficacy outcome is determined by the 
OCT assessments from the reading center. 
 
The secondary efficacy outcome is the mean change 
from baseline in BCVA. 
Safety: 
Safety parameters to be evaluated include BCVA, 
slit-lamp and fundus findings, IOP, and AEs. 
Statistical Methods: 
Descriptive statistics will be used to tabulate and summarize 
study outcomes. Background and demographic characteristics 
will be presented. Continuous variables will be summarized by 
descriptive statistics (sample size, mean and standard deviation, 
median, minimum and maximum). Discrete variables will be 
summarized by frequencies and percentages. Adverse events 
will be summarized by presenting the number and percentage of 
patients having any adverse event. Any other information 
collected (such as severity or relationship to investigational 
product) will be listed, as appropriate. Any statistical tests 
performed to explore the data will be used only to highlight any 
interesting comparisons that may warrant further consideration. 
Sample Size 
Justification: 
Twenty subjects in each study arm are expected to provide an 
adequate sample size to distinguish any efficacy and safety 
differences between the dose groups. 
 
 
 


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1.1 
Comprehensive Cumulative History 
Protocol Version 3 dated 16Nov2016 supersedes Version 2 dated 12Oct2016. Below 
is a summary of changes: 
• Section 9.2: Usage information was clarified to indicate that a subject may be 
treated bilaterally if a subject qualifies in both eyes, at the discretion of the 
Investigator. 
• Sections 1.0 and 9.3.2: Anti-VEGF washout periods were updated to:  
o Lucentis (ranibizumab): 30-day washout 
o Avastin (bevacizumab): 30-day washout 
o Eylea (aflibercept): 60-day washout 
o Macugen (pegaptanib): 45-day washout 
• Section 1.0: Updated exclusion criterion #5 from: 
Previous PRP in the study eye or the need for PRP within 2 months from the 
time of study enrollment, based on the Investigator’s opinion; 
to 
Previous PRP in the study eye within 4 months of study enrollment, or the need 
for PRP during the study based on the Investigator’s opinion. 
• Section 15.6: FA information was updated to clarify that fluorescein sodium dye is 
injected into the peripheral vein of the arm of the subject. 
Protocol Version 2 dated 12Oct2016 supersedes Version 1 dated 09Jun2016. Below 
is a summary of the changes: 
• General: Minor editorial and formatting changes occurred throughout the 
document for consistency and clarity purposes. 
• Section 1.0: BCVA inclusion criterion was changed from: 
BCVA of 0.3 to 1.2 ETDRS (logarithmic minimum angle of resolution; logMAR) 
in the study eye (85 to 40 letters equivalent),  
to: 
BCVA between 78 and 25 letters, inclusive, in the study eye at the 
screening/randomization visit using ETDRS testing (see Inclusion #3). 
• Section 1.0: The following exclusion criterion was added: Uncontrolled glaucoma 
or ocular hypertension in the study eye defined as an IOP >25 millimeter of 
mercury (mmHg) regardless of concomitant treatment with IOP-lowering 
medications (see Exclusion #2). 
• Section 1.0: Exclusion criterion for Triessence (triamcinolone acetonide) within 90 
days of study enrollment was removed, as this treatment is already excluded 
under the criterion covering intravitreal/periocular steroids in the study eye (see 
Exclusion #7). 
• Section 1.0: Retisert, another fluocinolone acetonide intravitreal implant, was 
added as another exclusion since it is similar to Illuvien (see Exclusion #8). 
• Section 1.0: Exclusions related to pregnant or nursing females were combined into 
one criterion and acceptable contraception language was added (see Exclusion 
#22).  
• Section 1.0: The concurrent enrollment in another clinical study exclusion was 
further defined to include studies evaluating investigational devices or drugs (see 
Exclusion #23). 
• Sections 1.0, 8.0, 10.7, and 15.0: BCVA scores were revised to include required 


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letters by ETDRS testing rather than logMAR equivalents.  
• Section 2.0: Overview of Study Plan was updated to clarify that the Visit 5 
procedures should be completed in the event of early termination visits. A footnote 
was also added to clarify that all ocular assessments are to be completed for both 
eyes. 
• Section 9.3: Permitted treatments were updated to clarify that Anti-VEGF 
treatments are allowed in the non-study eye during study participation. Prohibited 
treatments were updated to include Retisert (fluocinolone acetonide intravitreal 
implant). 
• Section 10.5: It was clarified that the Visit 5 procedures should be completed in 
the event of early termination. 
• Section 15.0: The BCVA with ETDRS testing procedure was updated to note that 
standardized ETDRS procedures should be utilized and the scores should be 
reported in letters. 
 
 
 
 


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OVERVIEW OF STUDY PLAN 
2.0
Visit Number 
1 
2 
3 
4 
5 
Unscheduled  
Visit Window 
0 days 
14 ± 2 
days  
(2 weeks) 
28 ± 2 
days  
(4 weeks) 
42 ± 2 
days  
(6 weeks) 
56 ± 2 days 
(8 weeks) or 
Early 
Termination 
N/A 
Procedure/Assessment 
Informed Consent 
x 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
Medical/Ocular History 
x 
 
 
 
 
 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
Urine Pregnancy Test 
(UPT)1 
x 
 
 
 
x 
(x) 
HbA1c Test 
x 
 
 
 
 
 
BCVA (ETDRS)2 
x 
x 
x 
x 
x 
(x) 
Slit Lamp Biomicroscopy2 
x 
x 
x 
x 
x 
(x) 
IOP by Tonopen or 
Applanation2 
x 
x 
x 
x 
x 
(x) 
Spectral Domain OCT2 
x 
x 
x 
x 
x 
(x) 
Indirect 
Ophthalmoscopy/Dilated 
Fundus Examination2 
x 
x 
x 
x 
x 
(x) 
Fundus Photography2 
x 
x 
x 
x 
x 
(x) 
Fluorescein Angiography2 
x 
 
x 
 
 
(x) 
Inclusion/Exclusion 
x 
 
 
 
 
 
Adverse events 
x3 
x 
x 
x 
x 
x 
Dispense IP 
x 
x 
 
 
 
(x) 
Dispense instructions/diary  
x 
x 
 
 
 
(x) 
Collect IP and dosing diary 
 
x 
x 
 
 
(x) 
(x) = as needed 
1 = Required for females of childbearing potential (i.e., who are not postmenopausal for at least 1 year or surgically sterile for 
at least 6 weeks from Visit 1 – Screening/Randomization) 
2 = Performed on both eyes 
3 = collected from the time of informed consent  
 


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ABBREVIATIONS 
3.0
Abbreviation 
Definition 
AE 
Adverse Event 
AR 
Adverse Reaction 
BCVA 
Best corrected visual acuity 
BID 
Twice daily 
CFR 
Code of Federal Regulations 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
D 
Diopters 
DME 
Diabetic Macular Edema 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Glycated hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HCL 
Hydrochloric Acid 
HPBCD 
Hydroxypropyl-beta-cyclodextrin  
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IOP 
Intraocular pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
logMAR 
Logarithmic minimum angle of resolution 
m 
Meters 
mg 
Milligrams 
mL 
Milliliters 
mm 
Millimeter 
mmHg 
Millimeter of mercury 
NaEDTA 
Disodium ethylene diamine tetra acetate 
NVD 
Neovascularization of the optic disc 
NVE 
Neovascularization elsewhere 
OCT 
Optical coherence tomography 
OD 
Right eye 
OS 
Left eye 
PDR 
Proliferative Diabetic Retinopathy  
pH 
Power of hydrogen 


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Abbreviation 
Definition 
PI 
Principal Investigator 
PP 
Per Protocol 
PRP 
Panretinal photocoagulation 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
UPT 
Urine Pregnancy Test 
US 
United States 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor  
YAG 
Yttrium aluminium garnet 
μm 
Microns 
 
 
 


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TABLE OF CONTENTS 
4.0
 
1.0 
SYNOPSIS ............................................................................................................2 
1.1 Comprehensive Cumulative History ..........................................................7 
2.0 
OVERVIEW OF STUDY PLAN .............................................................................9 
3.0 
ABBREVIATIONS............................................................................................... 10 
4.0 
TABLE OF CONTENTS ...................................................................................... 12 
5.0 
INTRODUCTION ................................................................................................. 14 
6.0 
ETHICS ............................................................................................................... 14 
7.0 
PROTOCOL AMENDMENTS ............................................................................. 15 
8.0 
SUBJECT POPULATION ................................................................................... 16 
9.0 
TREATMENTS ADMINISTERED ....................................................................... 16 
9.1 Identity of Investigational Products (IP) .................................................. 16 
9.1.1 Test Product 1................................................................................. 17 
9.1.2 Test Product 2................................................................................. 17 
9.1.3 Packaging ....................................................................................... 17 
9.2 Usage ......................................................................................................... 17 
9.3 Concomitant Treatments .......................................................................... 18 
9.3.1 Permitted Treatments ..................................................................... 18 
9.3.2 Prohibited Treatments ................................................................... 18 
9.4 Accountability ........................................................................................... 19 
9.5 Compliance ................................................................................................ 19 
9.6 Investigational Product (IP) Shipment and Assignment ........................ 19 
9.7 Subject Confidentiality and Methods Used to Minimize Bias ................ 19 
10.0 STUDY PROCEDURES ...................................................................................... 20 
10.1 Visit 1 – Screening/Randomization .......................................................... 20 
10.2 Visit 2 (Day 14) ........................................................................................... 21 
10.3 Visit 3 (Day 28) ........................................................................................... 22 
10.4 Visit 4 (Day 42) ........................................................................................... 22 
10.5 Visit 5 (Day 56) or Early Termination Visit .............................................. 23 
10.6 Unscheduled Visit(s) ................................................................................. 23 
10.7 Rescue Therapy ........................................................................................ 24 
11.0 
ANALYSIS PLAN ............................................................................................... 25 


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11.1 Analysis Data Sets .................................................................................... 25 
11.2 Demographic and Baseline Characteristics ........................................... 25 
11.3 Efficacy Analyses ...................................................................................... 25 
11.3.1 Primary Efficacy........................................................................... 25 
11.3.2 Secondary Efficacy ...................................................................... 26 
11.3.3 Supportive Efficacy ..................................................................... 26 
11.3.4 Safety Analysis ............................................................................ 26 
11.4 Discontinued Subjects .............................................................................. 26 
12.0 SAFETY .............................................................................................................. 26 
12.1 Safety Outcomes ....................................................................................... 26 
12.2 Safety Definitions ...................................................................................... 27 
12.3 Classification, Relationship, and Intensity ............................................. 28 
12.4 Pregnancy .................................................................................................. 28 
12.5 Procedures for Recording and Reporting ............................................... 29 
12.6 Unmasking of the Study Information....................................................... 29 
12.7 Follow-Up of Safety Information .............................................................. 29 
13.0 DATA HANDLING AND ADMINISTRATIVE REQUIREMENTS ........................ 30 
13.1 Completion of Source Documents and Electronic Case Report 
Forms ......................................................................................................... 30 
13.2 Data Review and Clarifications ................................................................ 30 
13.3 Regulatory Documentation and Records Retention .............................. 31 
13.4 Quality Assurance and Quality Control ................................................... 31 
14.0 REFERENCES .................................................................................................... 31 
15.0 
APPENDICES ..................................................................................................... 33 
15.1 BCVA (ETDRS) .......................................................................................... 33 
15.2 Slit-Lamp Biomicroscopy ......................................................................... 34 
15.3 IOP 
 ......................................................................................................... 35 
15.4 Spectral Domain OCT ............................................................................... 35 
15.5 Indirect Ophthalmoscopy/Dilated Fundus Examination ........................ 35 
15.6 Fluorescein Angiography ......................................................................... 35 
15.7 Fundus Photography ................................................................................ 35 
15.8 Dosing Diary .............................................................................................. 36 
 


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INTRODUCTION 
5.0
Diabetic macular edema is the result of breakdown of the blood-retinal barrier and/or 
insufficient activity of the retinal pigment epithelium to pump out fluid from the retina, 
and is a sight-threatening condition common in diabetic retinopathy. There is 
extensive evidence that angiogenic cytokines (e.g., VEGF) and inflammatory 
cytokines are involved in the development of DME. It is widely thought that these 
cytokines are responsible for the accumulation of fluid within and below the retina 
(Feng 2013, Funatsu 2009, Funk 2009, Kaneda 2011, Noma 2006, and Noma 2011). 
 
Currently available treatments for DME include macular grid laser photocoagulation, 
anti-VEGF agents, and corticosteroids; though, none of these treatments is fully 
satisfactory (Ozkaya 2013). Laser photocoagulation is generally palliative, and may 
take many months to develop a therapeutic effect. Anti-VEGF therapies can require 
monthly intravitreal injections, and some patients do not respond to these treatments. 
Intravitreal corticosteroid therapy can cause cataract and increased IOP with 
long-term treatment, and also is not effective in all patients (Sarao 2014 and Shamsi 
2013).  
 
SF0166 is intended to address the current limitations in the treatment of DME, which 
requires intravitreal injection every 4 to 12 weeks under topical anesthesia. The 
frequent visits to a retina specialist required for intravitreal injection represent a 
significant burden to patients, particularly for DME patients, many of whom are of 
working age. An alternative mode of drug administration, particularly topical eye 
drops, represents a very attractive treatment option.  
 
The objective of this study is to determine an efficacy and safety profile of SF0166 in 
humans. Preclinical studies with SF0166 have demonstrated notable anti-angiogenic 
activity, and shown that the fluorination in the compound does have a positive impact 
on the ability for the treatment to get to the back of the eye. Activity of SF0166 in 
VEGF-driven models appears similar to anti-VEGF biologics. Moreover, SF0166 also 
blocks angiogenic signaling driven by other growth factors (platelet-derived and 
fibroblast growth factor), so clinical efficacy could exceed that of marketed drugs that 
only target VEGF.  
 
Based on the pre-clinical information, it is expected that the benefits of SF0166 
outweigh the risks of its use. 
 
 
ETHICS 
6.0
This clinical study will be conducted in accordance with the principles of the 
Declaration of Helsinki, in compliance with the International Conference on 
Harmonization (ICH) E6 GCP Consolidated Guideline, and other applicable 
regulations. The Investigator and personnel will conduct the clinical study in 
compliance with the protocol. The Investigator will ensure that all personnel involved 
in the conduct of the study are qualified to perform their assigned responsibilities 
through relevant education, training, and experience. 
 


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Prior to study initiation, this protocol, the informed consent form, and any other 
written information given to subjects must be approved by an Independent Ethics 
Committee/Institutional Review Board (IEC/IRB). The Investigator must provide 
documentation of the IEC/IRB approval to the Sponsor. The approval must be dated 
and must identify the applicable protocol, amendments (if any), informed consent 
form, applicable recruiting materials, written information for the subject, and subject 
compensation. The IEC/IRB must be provided with a copy of the Investigator’s 
Brochure (IB), any periodic safety updates, and all other information as required by 
local regulation and/or the IEC/IRB. At the end of the study, the Investigator will notify 
the IEC/IRB about the study’s completion. The IEC/IRB must also be notified if the 
study is terminated prematurely. Finally, the Investigator will report to the IEC/IRB on 
the progress of the study at intervals stipulated by the IEC/IRB. 
 
Voluntary informed consent will be obtained from every subject (and/or legal 
representative, as applicable) prior to the initiation of any screening or other study-
related procedures. The Investigator should have a defined process for obtaining 
consent. Specifically, the Investigator, or designee, will explain the clinical study to 
each potential subject and the subject must indicate voluntary consent by signing and 
dating the approved informed consent form. The subject must be provided an 
opportunity to ask questions of the Investigator, and if required by local regulation, 
other qualified personnel. The Investigator must provide the subject with a copy of 
the consent form written in a language the subject understands.  
 
The consent document must meet all applicable local laws and will provide subjects 
with information regarding the purpose, procedures, requirements, and restrictions of 
the study, along with any known risks and potential benefits associated with the IP, 
the available compensation, and the established provisions for maintaining 
confidentiality of personal protected health information. Subjects will be told about the 
voluntary nature of participation in the study. Subjects will be provided with contact 
information for the appropriate individuals should questions or concerns arise during 
the study. The subject also will be told that their records may be accessed by 
appropriate authorities and Sponsor-designated personnel. The Investigator must 
keep the original, signed copy of the consent and must provide a duplicate copy to 
each subject. 
 
 
PROTOCOL AMENDMENTS 
7.0
Modification of the protocol is prohibited without prior written agreement in the form of 
a protocol amendment. All amendments will be created by the Sponsor and must be 
approved by the IEC/IRB prior to implementation; except when required to mitigate 
immediate safety risks or when the changes involve only logistical or administrative 
revisions. Amendments may necessitate that the informed consent and other study-
related material be revised. If the consent form is revised, all subjects currently 
enrolled in the study may be required by the IRB/IEC to sign the approved, revised 
informed consent form.  
 
This is Version 3 (Amendment 2) of this protocol. 


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SUBJECT POPULATION 
8.0
The study population includes approximately 40 subjects, 18 years of age or older, 
randomized at approximately 10 sites. The goal is to enroll 40 subjects, 20 in each 
study arm, allowing for a minimum of 30 subjects to complete the study. To 
participate in the study, the subject must have center-involved diabetic macular 
edema (i.e., retinal thickening secondary to type 1 or type 2 diabetes mellitus with 
DME and central subfield thickness ≥325 µm on spectral domain OCT) in the study 
eye, either be treatment naïve or have been previously treated in the study eye with 
an adequate washout period (see Sections 1.0 and 9.3), achieve BCVA between 78 
and 25 letters, inclusive, in the study eye using ETDRS testing, with BCVA 
decrement primarily attributable to DME, be willing able to attend all study visits and 
adhere to study regimen, and be willing to give written informed consent.  
 
The duration of study participation is 8 weeks (± 2 days); including an on-treatment 
period of 28 days, and a post-treatment follow-up period of 28 days.  
 
The complete inclusion and exclusion criteria are presented in Section 1.0.  
 
 
TREATMENTS ADMINISTERED 
9.0
Upon signing the informed consent form, the subject will be screened for eligibility. 
Once it is determined that all eligibility criteria have been met, subjects will be 
randomized to 1 of the 2 treatment arms according to the Interactive Web Response 
System (IWRS) system.  
 
9.1 
Identity of Investigational Products (IP) 
The formulation of SF0166 Ophthalmic Solution consists of SF0166, 
hydroxypropyl-beta-cyclodextrin (HPBCD) (50 milligrams [mg]/milliliter [mL]), boric 
acid (10 mg/mL), disodium ethylene diamine tetra acetate (NaEDTA) (0.1%), 
benzalkonium chloride (0.02%) in water at power of hydrogen (pH) of 8. Two doses 
will be used in this study; a low dose (SF0166 2.5%) administered BID and a high 
dose (SF0166 5.0%) administered BID. The chemical composition of the IP is 
presented in Table 9-1. 
 
 
 


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TABLE 9-1: SF0166 COMPOSITION 
Ingredient 
Function 
Concentration  
(w/v) 
SF0166 
Active pharmaceutical 
ingredient 
5.0% (high 
dose) or 2.5% 
(low dose) 
Hydroxypropyl 
β- Cyclodextrin 
Permeation enhancer 
and precipitation 
prevention 
5.0% 
Boric Acid 
Buffering agent 
1% 
Na-EDTA 
Metal chelator 
0.1% 
1N 
Hydrochloric 
Acid (HCl) 
pH adjustment 
As needed 
Benzalkonium 
chloride 
Preservative 
0.02% 
Sterile Water 
for Injection 
Diluent 
88.88% (high 
dose) or 91.38% 
(low dose) 
 
 
9.1.1 
Test Product 1 
SF0166 2.5% (low dose) BID 
 
9.1.2 
Test Product 2 
SF0166 5.0% (high dose) BID 
 
9.1.3 
Packaging 
SF0166 will be packaged in multi-use, pre-sterilized, low-density polyethylene 
dropper bottles with a tamper-evident cap. 
 
Both doses of the test product will be provided with investigational labels; including kit 
number, site number, subject number, instructions for use, and investigational use 
statement. The randomization kit boxes will include 2 cartons with the kit number, 
each containing 3 bottles of SF0166 and bearing the same kit number.  
 
9.2 
Usage  
If a subject meets inclusion/exclusion criteria at Visit 1, the site will enter the required 
data into the IWRS in order to randomize the subject to a treatment arm. After 
subjects are randomized, they are dispensed SF0166 in 1 of 2 dose groups. The 
subject will use SF0166 BID for 28 days (1 drop in the study eye). If a subject 
qualifies in both eyes, SF0166 may be administered to both eyes (study eye and 
non-study eye) at the discretion of the Investigator. The study eye is defined as the 
eye with the worse BCVA at baseline (Visit 1 - Screening/Randomization). 
 


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At Visit 1, the site staff will dispense 1 carton (3 bottles) from the subject kit. At Visit 
2, the site staff will collect the used IP bottles, and dispense an additional carton (3 
bottles) from the kit. It is expected that subjects will use 2 bottles between each visit. 
The additional 3rd bottle in each carton is a back-up supply. If a subject requires a 
re-supply for any reason, an unscheduled re-supply can be completed through the 
IWRS.  
 
SF0166 should be stored at 2–8ºC and protected from light.  
 
Throughout the study, the Investigator or designee will be responsible for the 
accounting of all IP. The Investigator must ensure that the IP are not used in an 
unauthorized manner. 
 
9.3 
Concomitant Treatments 
9.3.1 
Permitted Treatments 
Medications not specifically excluded in Section 9.3.2 may be taken as necessary. 
For clarity, the following are permitted: 
• Anti-VEGF injections for treatment of the non-study eye, including: 
o Eylea (aflibercept) 
o Lucentis (ranibizumab) 
o Avastin (bevacizumab)  
o Macugen (pegaptanib) 
• Concomitant treatment with antibiotics at the discretion of the Investigator  
• Artificial tears 
 
9.3.2 
Prohibited Treatments 
Use of the following treatments is not allowed during the study and for the timeframes 
specified: 
• Within 36 months (3 years) prior to study enrollment 
o Illuvien (fluocinolone acetonide intravitreal implant) 
o Retisert (fluocinolone acetonide intravitreal implant) 
• Within 180 days (6 months) prior to study enrollment 
o Ozurdex (dexamethasone intravitreal implant) 
• Within 90 days (3 months) prior to study enrollment 
o Focal laser photocoagulation or intravitreal/periocular/topical ocular 
steroids of any type in the study eye 
o Any intraocular surgery in the study eye 
o Any change in dose to a concomitant topical ophthalmic medication in 
the study eye 
• Within 60 days (2 months) prior to study enrollment 
o Eylea (aflibercept) in the study eye 
• Within 45 days prior to enrollment 
o Macugen (pegaptanib) in the study eye 
• Within 30 days (1 month) prior to enrollment 


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o Lucentis (ranibizumab) in the study eye 
o Avastin (bevacizumab) in the study eye 
o YAG laser treatment in study eye 
Subjects taking a stable dose of topical ophthalmic medications at study enrollment 
should be instructed not to dose study medication within 1 hour of investigational 
product dosing. 
 
9.4 
Accountability 
Upon receipt of the IP, site personnel designated to handle the IP will conduct an 
inventory of the shipment(s). The site personnel designated to handle the IP must 
maintain sufficient accountability records for the duration of the study. Study 
treatment dispensation and collection for each subject should be included in the IP 
accountability records. The records must be made available to the Clinical Research 
Associate (CRA) for the purposes of verifying and accounting the clinical IP. Any 
discrepancies between the observed disposition and the written account must be 
recorded along with an explanation. The Investigator is ultimately responsible, 
although he/she may delegate this responsibility, to return all used/unused IP at the 
conclusion of the study.  
 
9.5 
Compliance 
Compliance will be assessed by comparing study drug accountability records with the 
dosing information recorded daily by the subject. The site will document this 
comparison along with verification of the numbers of used and unused study product 
bottles. The numbers of missed doses as assessed at each clinic visit should be 
documented in the electronic Case Report Form (eCRF). 
 
9.6 
Investigational Product (IP) Shipment and Assignment 
The site will confirm all IP shipments received from the sponsor within the IWRS. 
Details of this process are outlined in a separate manual. Upon confirmation, the 
shipment will show as part of the site’s IP stock.  
 
9.7 
Subject Confidentiality and Methods Used to Minimize Bias 
The Investigator must ensure that the subject’s anonymity is maintained throughout 
the course of the study. In particular, the Investigator must keep an enrollment log 
with confidential identifying information that corresponds to the subject numbers and 
initials of each study participant. At the end of the study, the Sponsor will collect a 
copy of the enrollment log without any identifying subject information. All documents 
submitted to the Sponsor will identify the subjects exclusively by number and 
demographic information. No other personally identifying information should be 
transmitted to the Sponsor, including subject initials. 
 
The intent of masking is to limit the occurrence of conscious and unconscious bias in 
the conduct and interpretation of the clinical study. Bias could arise from the influence 
that the knowledge of a specific treatment assignment may have on the recruitment 
of subjects, their subsequent care, the assessment of endpoints, the handling of 


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withdrawals, etc. Therefore, the essential aim of masking is to prevent identification 
of the treatments by the Investigator, subject, and others associated with the conduct 
of the study.  
 
Subjects will be assigned to a study arm according to the next available 
randomization schedule as assigned by the IWRS. The randomization schedule will 
be blocked to ensure a balance of study arms at the study level. The randomization 
scheme will be generated and maintained by the Sponsor. Individual subject 
randomization schemes will be unmasked after all study data has been verified, 
validated, and the database is locked. 
 
Using a masked study team is a required activity designed to protect the masking of 
the study personnel at the site and at the Sponsor. The Sponsor involved in 
reporting, obtaining, and/or reviewing the clinical data will not be aware of the specific 
dose being administered.  
 
For purposes of this study, the subject, Principal Investigator (PI), and site staff will 
be masked to the IP dose. Investigators, site staff members, and sponsor personnel 
directly involved with the study will not be aware of the randomized dose group for 
each randomized subject. In the event of a medical emergency where the knowledge 
of dose group is required, the Investigator will have the ability to learn the dose group 
in order to properly treat the medical emergency, but should only exercise this ability 
when absolutely necessary. 
 
The masked site personnel must coordinate all study activities as necessary to 
protect masking and minimize bias during the study. This level of masking will be 
maintained throughout the conduct of the study.  
 
 
STUDY PROCEDURES 
10.0
10.1 Visit 1 – Screening/Randomization 
After obtaining written informed consent and Health Insurance Portability and 
Accountability Act (HIPAA) authorization, site staff will perform/assess the following in 
the order suggested below. 
 
1. Each screened subject should be assigned a subject identifying number, 
based on the next available number in the eCRF. 
2. Collect subject demographic information. 
3. Collect ocular and non-ocular medical history. 
4. Collect concomitant medications taken during the previous 12 months. Ask 
specifically about the use of Iluvien during the previous 36 months. 
5. Administer UPT for female subjects of child-bearing potential. 
6. Conduct in-office HbA1c test following test manufacturer guidelines.  
7. Conduct the following ocular assessments on both eyes (refer to Section 15.0 
for further details): 


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a. BCVA by ETDRS 
b. Slit-lamp Biomicroscopy 
c. IOP by Tonopen or Applanation 
d. Spectral Domain OCT 
e. Indirect Ophthalmoscopy/Dilated Fundus Examination 
f. Fundus Photography 
g. Fluorescein Angiography  
8. Assess inclusion/exclusion criteria.  
9. If subject is eligible, randomize the subject by entering information into the 
IWRS.  
10. Dispense kit number provided by IWRS and provide dosing instructions/diary 
to the subject. 
11. The first dose of study medication should be administered within the clinic 
under site staff supervision, and subsequent doses will be self-administered 
following the subject’s visit. 
12. Assess for any AEs occurring from the time of informed consent.  
13. Provide instruction for the subject to:  
a. Dose IP as instructed 
b. Complete dosing information in subject diary.  
c. Return for Visit 2 (Day 14) in 2 weeks (± 2 days).  
14. Prepare and upload OCT images to the central reading center, and upload 
fundus photography to ShareFile.  
Note: Subjects can be re-screened at the discretion of the Investigator if there is 
reasonable clinical evidence to suggest the subject may qualify after initial screen 
failure. The Investigator should contact the Sponsor to discuss re-screenings prior 
to conducting the visits. 
 
10.2 Visit 2 (Day 14) 
This visit will occur on Day 14 ± 2 days as calculated from Visit 1 (Day 0), and the 
following evaluations will be performed: 
 
1. Collect and record any AEs occurring since the last visit. 
2. Collect and record any new or changed concomitant medications since the last 
visit.  
3. Conduct the following ocular assessments on both eyes (refer to Section 15.0 
for further details): 
a. BCVA by ETDRS 
b. Slit-lamp Biomicroscopy 
c. IOP by Tonopen or Applanation 
d. Spectral Domain OCT 
e. Indirect Ophthalmoscopy/Dilated Fundus Examination 


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f. Fundus Photography 
4. Collect used IP kit/dosing diary and conduct drug accountability. Ensure that 
any dosing noncompliance is addressed with the subject. 
5. Dispense kit number provided by IWRS and provide dosing instructions/diary 
to the subject. 
6. Provide instruction for the subject to:  
a. Dose IP as instructed. 
b. Complete dosing information in subject diary.  
c. Return for Visit 3 (Day 28) in 2 weeks (± 2 days). 
7. Prepare and upload OCT images to the central reading center, and upload 
fundus photography to ShareFile. 
 
10.3 Visit 3 (Day 28) 
This visit will occur on Day 28 ± 2 days as calculated from Visit 1 (Day 0), and the 
following evaluations will be performed: 
 
1. Collect and record any AEs occurring since the last visit. 
2. Collect and record any new or changed concomitant medications since the last 
visit.  
3. Conduct the following ocular assessments on both eyes (refer to Section 15.0 
for further details): 
a. BCVA by ETDRS 
b. Slit-lamp Biomicroscopy 
c. IOP by Tonopen or Applanation 
d. Spectral Domain OCT 
e. Indirect Ophthalmoscopy/Dilated Fundus Examination 
f. Fundus Photography 
g. Fluorescein Angiography  
4. Collect used IP kit/dosing diary and conduct drug accountability.  
5. Provide instruction for the subject to:  
a. Return for Visit 4 (Day 42) in 2 weeks (± 2 days). 
6. Prepare and upload OCT images to the central reading center, and upload 
fundus photography to ShareFile. 
 
10.4 Visit 4 (Day 42) 
This visit will occur on Day 42 ± 2 days as calculated from Visit 1 (Day 0), and the 
following evaluations will be performed: 
 
1. Collect and record any AEs occurring since the last visit. 


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2. Collect and record any new or changed concomitant medications since the last 
visit.  
3. Conduct the following ocular assessments on both eyes (refer to Section 15.0 
for further details): 
a. BCVA by ETDRS 
b. Slit-lamp Biomicroscopy 
c. IOP by Tonopen or Applanation 
d. Spectral Domain OCT 
e. Indirect Ophthalmoscopy/Dilated Fundus Examination 
f. Fundus Photography 
4. Provide instruction for the subject to:  
a. Return for Visit 5 (Day 56) in 2 weeks (± 2 days). 
5. Prepare and upload OCT images to the central reading center, and upload 
fundus photography to ShareFile. 
 
10.5 Visit 5 (Day 56) or Early Termination Visit  
This visit will occur on Day 56 ± 2 days as calculated from Visit 1 (Day 0), or on the 
date of early termination, if applicable. The following evaluations will be performed: 
 
1. Collect and record any AEs occurring since the last visit. 
2. Collect and record any new or changed concomitant medications since the last 
visit.  
3. Administer UPT to females of child-bearing potential. 
4. Conduct the following ocular assessments on both eyes (refer to Section 15.0 
for further details): 
a. BCVA by ETDRS 
b. Slit-lamp Biomicroscopy 
c. IOP by Tonopen or Applanation 
d. Spectral Domain OCT 
e. Indirect Ophthalmoscopy/Dilated Fundus Examination 
f. Fundus Photography 
5. Prepare and upload OCT images to the central reading center, and upload 
fundus photography to ShareFile. 
 
10.6 Unscheduled Visit(s) 
Unscheduled visits may occur at any time for any reason. The following evaluations 
should be performed during these visits:  
 
1. Collect and record any AEs occurring since the last visit. 


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2. Collect and record any new or changed concomitant medications since the last 
visit.  
The following evaluations may be performed during these visits:  
 
3. Administer UPT to females of child-bearing potential. 
4. Conduct the following ocular assessments on both eyes (refer to Section 15.0 
for further details): 
a. BCVA by ETDRS 
b. Slit-lamp Biomicroscopy 
c. IOP by Tonopen or Applanation 
d. Spectral Domain OCT 
e. Indirect Ophthalmoscopy/Dilated Fundus Examination 
f. Fundus Photography  
g. Fluorescein Angiography  
5. Dispense kit number provided by IWRS and provide dosing instructions/diary 
to the subject. 
6. Collect used IP kit/dosing diary and conduct drug accountability. 
7. Provide instruction for the subject to:  
a. Dose IP as instructed, if applicable 
b. Complete dosing information in subject diary, if applicable 
c. Return for next regularly scheduled visit, or follow-up unscheduled visit. 
8. Prepare and upload OCT images to the central reading center, and upload 
fundus photography to ShareFile. 
10.7 Rescue Therapy 
Rescue therapy with a VEGF inhibitor can be administered to any study subject who 
experiences a significant decrease in BCVA, defined as BCVA loss of >7 letters from 
baseline (Visit 1 – Screening/Randomization), accompanied by an increase in OCT 
center subfield thickness of >75μm as compared to the previous study visit, as 
assessed by the Investigator. The OCT images completed during the assessment for 
rescue therapy initiation should also be uploaded to the central reading center. 
Therapies can include: 
• Avastin (bevacizumab), or 
• Lucentis (ranibizumab), or  
• Eylea (aflibercept), or 
• Macugen (pegaptanib) 
Note: Steroid and focal laser photocoagulation rescue is not permitted during the 
study. 
 


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Subjects who discontinue IP and are started on rescue therapy should continue with 
the visit schedule and assessments through the end of the study.  
 
 
ANALYSIS PLAN 
11.0
11.1 Analysis Data Sets 
The primary analysis population will be the Per Protocol (PP) population, defined as 
all subjects who were randomized, completed the study as planned (i.e., after 28-day 
on-treatment period and 28-day follow-up period), and did not have significant 
protocol deviations. Protocol deviations will be reviewed by the study team and 
assessed for importance (i.e., the potential exclusion of a subject) prior to database 
lock.  
 
The modified intent-to-treat (ITT) population will include subjects who were 
randomized and completed at least 1 on-IP study visit. The safety analysis set will 
include all randomized subjects.  
 
11.2 Demographic and Baseline Characteristics 
Descriptive statistics will be used to tabulate and summarize study outcomes. 
Background and demographic characteristics will be presented.  
 
11.3 Efficacy Analyses 
11.3.1 
Primary Efficacy 
The primary efficacy outcome is the mean change in anatomic center subfield 
thickness and macular volume, measured by OCT. All OCT images will be read by 
the Investigator and a central reading facility. The primary efficacy outcome is 
determined by the OCT assessments from the reading center. The Investigator 
assessed OCT values will be analyzed for informational purposes. 
 
 
11.3.1.1 Statistical Hypotheses 
Not applicable, as no formal hypothesis testing is planned. 
  
11.3.1.2 Analysis Methods 
Both the Investigator assessed OCT values and the centrally read OCT values will be 
collected and analyzed. Descriptive statistics will be used to summarize the study 
outcomes. Continuous variables will be summarized by descriptive statistics (sample 
size, mean and standard deviation, median, minimum and maximum). Discrete 
variables will be summarized by frequencies and percentages. Any statistical tests 
performed to explore the data will be used only to highlight any interesting 
comparisons that may warrant further consideration. 


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11.3.2 
Secondary Efficacy 
The secondary efficacy outcome is the mean change from baseline in BCVA.  
 
11.3.2.1 Statistical Hypotheses  
Not applicable, as no formal hypothesis testing is planned.  
 
11.3.2.2 Analysis Methods  
Descriptive statistics will be used to summarize the study outcomes. Continuous 
variables will be summarized by descriptive statistics (sample size, mean and 
standard deviation, median, minimum and maximum). Discrete variables will be 
summarized by frequencies and percentages. Any statistical tests performed to 
explore the data will be used only to highlight any interesting comparisons that may 
warrant further consideration. 
 
11.3.3 
Supportive Efficacy 
Not applicable. 
 
11.3.4 
Safety Analysis 
Safety parameters to be evaluated include BCVA, slit-lamp and fundus findings, IOP 
and AEs. Adverse events will be summarized by presenting the number and 
percentage of subjects having any adverse event. Any other information collected 
(such as severity or relationship to investigational product) will be listed as 
appropriate.  
 
11.4 Discontinued Subjects 
Discontinued subjects will not be replaced. If a subject requires discontinuation of IP 
and placement on rescue therapy, that subject should be continued in the study and 
followed through the end of the study. 
 
 
SAFETY 
12.0
12.1 Safety Outcomes 
The safety parameters for the study include: 
• BCVA 
• Slit-lamp findings 
• Fundus findings 
• IOP  
• AEs 


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The Investigator may choose to discontinue a subject at any time, if in his/her 
opinion, it is in the best interest of the subject’s safety. 
 
12.2 Safety Definitions 
• AE: Any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered drug related.  
• Adverse Reaction (AR): any AE caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions where there is reason to conclude 
that the drug caused the event.  
• Suspected Adverse Reaction (SAR): Any AE for which there is a reasonable 
possibility that the drug caused the AE. For the purposes of Investigational 
New Drug (IND) safety reporting, “reasonable possibility” means there is 
evidence to suggest a causal relationship between the drug and the AE. A 
SAR implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug.  
• Unexpected: An AE or SAR is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has 
been observed; or, if an Investigator’s Brochure is not required or available, is 
not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application.  
• Life-threatening: An AE or SAR is considered “life-threatening” if, in the view of 
either the Investigator or sponsor, its occurrence places the subject at 
immediate risk of death. It does not include an AE or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death.  
• Serious Adverse Event (SAE): Any AE or suspected adverse reaction 
occurring at any dose that:  
o Results in death. 
o Is life-threatening. 
o Results in a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions. 
o Requires inpatient hospitalization. 
o Prolongs inpatient hospitalization. 
o Is a congenital anomaly/birth defect. 
o Is a significant medical event (i.e., one that may jeopardize the subject 
or may require intervention to prevent one or more of the other 
outcomes listed above). 
• Non-serious AE: Any AE that does not meet the definitions for SAEs as 
described above.  
 


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12.3 Classification, Relationship, and Intensity 
Each AE will be classified as serious or non-serious using the definitions provided 
above. 
The severity of each ae will be classified as mild, moderate, or severe using the 
following definitions: 
• Mild: An AE is mild if the subject is aware of but can easily tolerate the sign or 
symptom. 
• Moderate: An AE is moderate if the sign or symptom results in discomfort 
significant enough to cause interference with the subject’s usual activities. 
• Severe: An AE is severe if the sign or symptom is incapacitating and results in 
the subject’s inability to work or engage in their usual activities. 
The Investigator will review each event and assess its relationship to use of IP 
(unrelated, unlikely, possibly, probably, definitely). The AE will be assessed using the 
following definitions: 
• Unrelated 
o Event occurring before dosing. 
o Event or intercurrent illness due wholly to factors other than IP use. 
• Unlikely 
o Poor temporal relationship with IP use. 
o Event easily explained by subject’s clinical state or other factors. 
• Possible 
o Reasonable temporal relationship with IP use. 
o Event could be explained by subject’s clinical state or other factors.  
• Probable 
o Reasonable temporal relationship with IP use. 
o Likely to be known reaction to agent or chemical group, or predicted by 
known pharmacology. 
o Event cannot easily be explained by subject’s clinical state or other 
factors. 
• Definite 
o Distinct temporal relationship with IP use. 
o Known reaction to agent or chemical group, or predicted by known 
pharmacology. 
o Event cannot be explained by subject’s clinical state or other factors.  
 
12.4 Pregnancy  
Pregnancy occurring during study conduct should be reported immediately to the 
sponsor on an SAE form, following the reporting requirements listed in Section 12.5. 
The reason for reporting should be noted as “significant medical event.” 
 


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12.5 Procedures for Recording and Reporting 
All AEs must be documented on the AE eCRF by the site and are monitored on a 
routine basis by the Sponsor. AEs are collected from the time of informed consent. 
Any pre-existing medical conditions or symptoms present in a subject are not 
considered AEs in the study unless there is a clinically significant worsening. 
 
The Investigator must also promptly (i.e., within 24 hours of awareness) document all 
SAEs with details including the date of occurrence, severity, treatment (if applicable), 
outcome, and assessments of the seriousness and causality. The site must submit all 
available information on SAEs to the study Sponsor immediately as follows: 
• All available information should be reported into the eCRF and on paper SAE 
form within 24 hours of becoming aware of the event. 
• Document all relevant information from discharge summary, autopsy report, 
certificate of death, etc. (as applicable), in narrative section of SAE eCRF. 
Copies of this relevant source documentation should also be redacted and 
submitted to the Contract Research Organization (CRO), Lexitas Pharma 
Services, via fax. 
• Additional relevant information after initial reporting is to be entered into the 
eCRF and on paper SAE form as soon as the data become available. 
• Document any changes to concomitant medications on the appropriate 
eCRFs. 
The Investigator must also report all SAEs to the IRB/IEC, according to the 
institution’s requirements. 
 
12.6 Unmasking of the Study Information 
Masked information on the identity of the randomized treatment should not be 
disclosed during the study. If the treatment code needs to be broken in the interest of 
subject safety, the Investigator is encouraged to contact an appropriate study 
Sponsor representative prior to unmasking the information. Dependent upon the 
individual circumstances (i.e., medical emergency), the code may be broken prior to 
contact with the study Sponsor. However, the Sponsor does not anticipate the need 
for this as all subjects will be on active treatment at varying dose levels. If unmasking 
does occur without Sponsor consultation, the study Sponsor must be informed of all 
cases in which the code was broken and of the circumstances involved. Additionally, 
the study Sponsor may be required to unmask the information in order to fulfill 
expedited regulatory reporting requirements. 
 
12.7 Follow-Up of Safety Information 
The Investigator is responsible for adequate and safe medical care of subjects during 
the study and for ensuring that appropriate medical care and relevant follow-up 
procedures are maintained after the study. The Investigator should provide the study 
Sponsor with any new safety information (which includes new AEs and changes to 
previously reported AEs) that may affect the safety evaluation of the IP. Any 


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additional data from these follow-up procedures must be documented and available 
upon the study Sponsor’s request. 
 
 
DATA HANDLING AND ADMINISTRATIVE REQUIREMENTS 
13.0
13.1 Completion of Source Documents and Electronic Case Report Forms 
The nature and location of all source documents will be identified to ensure that 
original data required to complete the eCRFs exist and are accessible for verification 
by the site monitor. If electronic records are maintained, the method of verification 
must be determined in advance of starting the study. At a minimum, source 
documents should include the following information for each subject: 
• Subject identification (name, sex, race/ethnicity). Documentation of subject 
eligibility 
• Date of informed consent 
• Dates of visits 
• Documentation that protocol specific procedures were performed 
• Results of study parameters, as required by the protocol 
• IP accountability records 
• Documentation of AEs and other safety parameters (if applicable) 
• Records regarding medical histories and the use of concomitant therapies 
prior to and during the study 
• Date of study completion and reason for early discontinuation, if applicable 
It is required that the author of an entry in the source documents be identifiable. 
Direct access to source documentation (medical records) must be allowed for the 
purpose of verifying that the data recorded on the eCRF are consistent with the 
original source data. 
 
eCRFs will be provided to the sites via a web-based program, and only designated 
individuals may complete the eCRFs. The eCRFs will be submitted at regular 
intervals based upon the clinical study visit schedule. It is expected that all data 
reported will have corresponding entries in the source documents and that the 
Principal Investigator will review the reported data and certify that the eCRFs are 
accurate and complete. No subject identifiers should be recorded on the eCRFs 
beyond subject number, and demographic information. 
 
13.2 Data Review and Clarifications 
The eCRF data will be reviewed against the subject’s source data by the study 
monitors to ensure completeness and accuracy. After monitoring has occurred at the 
clinical sites and the eCRFs have been submitted, additional data clarifications 
and/or additions may be needed. Data clarifications and/or additions are documented 
and are part of each subject’s eCRFs. 
 


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13.3 Regulatory Documentation and Records Retention 
The Investigator is required to maintain up-to-date, complete regulatory 
documentation as indicated by the Sponsor and the Investigator’s files will be 
reviewed as part of the ongoing study monitoring. Financial information is not subject 
to regulatory inspection and should be kept separately. 
 
Additionally, the Investigator must keep study records and source documents until 
the Sponsor provides written approval for their destruction. If the Investigator retires, 
relocates, or for any other reason withdraws from responsibility of keeping the study 
records, the Sponsor must be notified and suitable arrangements made for retention 
of study records and source documents needed to comply with national and 
international regulations (generally 2 years after discontinuing clinical development or 
after the latest marketing approval). 
 
13.4 Quality Assurance and Quality Control 
The Sponsor will be responsible for implementing and maintaining quality assurance 
and quality control systems to ensure the study is conducted and data are generated, 
documented and reported in compliance with the protocol, GCP and applicable 
regulatory requirements. The Sponsor will secure agreement from all involved parties 
to ensure direct access to all study related sites, source data and documents, and 
reports for the purpose of monitoring and auditing by the Sponsor, and inspection by 
domestic and foreign regulatory authorities. Quality control will be applied to each 
stage of data handling to ensure that all data are reliable and have been processed 
correctly. Agreements made by the Sponsor with the Investigator/Institution and any 
other parties involved in the clinical study will be provided in writing as part of the 
protocol or as a separate agreement. 
 
 
REFERENCES 
14.0
Feng, J., Zhao, T., Zhang, Y., Ma, Y., & Jiang, Y. (2013). Differences in aqueous 
concentrations of cytokines in macular edema secondary to branch and central 
retinal vein occlusion. PLoS ONE, 8(7), e68149. doi:10.1371/journal.pone.0068149. 
 
Funatsu, H., Noma, H., Mimura, T., Eguchi, S., & Hori, S. (2009). Association of 
vitreous inflammatory factors with diabetic macular edema. Ophthalmology, 116(1), 
73–79. doi:10.1016/j.ophtha.2008.09.037. 
 
Funk, M., Kriechbaum, K., Prager, F., Benesch, T., Georgopoulos, M., Zlabinger, G. 
J., & Schmidt-Erfurth, U. (2009). Intraocular concentrations of growth factors and 
cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. 
Investigative Ophthalmology & Visual Science, 50(3), 1025–1032. 
doi:10.1167/iovs.08-2510. 
 
Kaneda, S., Miyazaki, D., Sasaki, S., Yakura, K., Terasaka, Y., Miyake, K., Inoue, Y. 
(2011). Multivariate analyses of inflammatory cytokines in eyes with branch retinal 
vein occlusion: Relationships to bevacizumab treatment. Investigative Ophthalmology 
& Visual Science, 52(6), 2982–2988. doi:10.1167/iovs.10-6299. 


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Noma, H., Funatsu, H., Mimura, T., Eguchi, S., Shimada, K., & Hori, S. (2011). 
Vitreous levels of pigment epithelium–derived factor and vascular endothelial growth 
factor in macular edema with central retinal vein occlusion. Current Eye Research, 
36(3), 256–263. doi:10.3109/02713683.2010.513090. 
 
Noma, H., Funatsu, H., Yamasaki, M., Tsukamoto, H., Mimura, T., Sone, T., … 
Mishima, H. K. (2006). Aqueous humour levels of cytokines are correlated to vitreous 
levels and severity of macular oedema in branch retinal vein occlusion. Eye, 22(1), 
42–48. doi:10.1038/sj.eye.6702498. 
 
Ozkaya, A., Celik, U., Alkin, Z., Faiz Turan, M., Yazici, A. T., & Demirok, A. (2013). 
Comparison between Intravitreal Triamcinolone with grid laser photocoagulation 
versus bevacizumab with grid laser photocoagulation combinations for branch retinal 
vein occlusion. ISRN Ophthalmology, 2013, e141279. doi:10.1155/2013/141279. 
 
Sarao, V., Veritti, D., Boscia, F., & Lanzetta, P. (2014). Intravitreal steroids for the 
treatment of retinal diseases. The Scientific World Journal, 2014, e989501. 
doi:10.1155/2014/989501. 
 
Shamsi, H. N. A., Masaud, J. S., & Ghazi, N. G. (2013). Diabetic macular edema: 
New promising therapies. World Journal of Diabetes, 4(6), 324–338. 
doi:10.4239/wjd.v4.i6.324. 
 
 
 


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APPENDICES 
15.0
15.1 BCVA (ETDRS)  
The site staff should follow their standard procedures for conducting BCVA using 
ETDRS testing. The general procedure is as follows:  
 
Overview 
1. BCVA at a single site should be done consistently throughout the study using 
the same equipment, lighting conditions etc.  
2. BCVA should be performed prior to instillation of any drops to dilate or 
anesthetize the eye and prior to any examination that requires contact with the 
eye, including the measurement of IOP. 
3. Subjective refraction, using standard ETDRS methods, should be performed 
prior to measurement of BCVA and the appropriate correction worn in a trial 
frame. 
4. The subject may be seated or may stand and the chart should be at eye level. 
5. All eyes are first tested at 4 meters (m) including those that could not be 
refracted at 4m. Note: for eyes refracted at 1 meter, the additional +0.75 D 
sphere should be subtracted from the spherical correction before testing vision 
at 4m.  
6. The right eye (OD) should be is tested first using Chart 1 then the left eye (OS) 
is tested using Chart 2.  
7. Each chart should remain hidden from view until the eye in question is to be 
examined.  
8. If less than 20 letters are read with either eye at 4m the eye(s) with the 
reduced acuity is tested at 1m. 
ETDRS Scoring 
1. At the end of the test count up the number of letters read correctly by each 
eye. 
2. If 1-meter testing was not required, then add 30 to get the ETDRS letters 
score. 
3. If 1-meter testing was required, the ETDRS letters score is the sum of the 
letters read at 4 meters and at 1 meter. 
To qualify for SF0166-C-001, the subject must have BCVA between 78 and 25 
letters, inclusive, in the study eye at the screening/randomization visit using ETDRS 
testing. There is no visual acuity requirement for the non-study eye. 


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15.2 Slit-Lamp Biomicroscopy  
The biomicroscopy exam will be performed using the Investigator’s standard 
procedure. Areas to be assessed include conjunctiva, cornea, anterior chamber, and 
lens. Grading scales for these are below. 
 
Conjunctiva 
Bulbar Injection 
0 
Absent 
1 
Mild 
2 
Moderate 
3 
Severe 
Erythema  
0 
Absent 
1 
Mild 
2 
Moderate 
3 
Severe 
 
Cornea 
Edema 
0 
Absent 
1 
Mild 
2 
Moderate 
3 
Severe 
 
Anterior Chamber 
Cells 
0 
No cells seen 
1 
1 - 5 cells 
2 
6 - 15 cells 
3 
16 - 30 cells 
4 
Greater than 30 cells 
Flare 
0 
None 
1 
Mild (trace to clearly noticeable, visible) 
2 
Moderate (without plastic aqueous humor) 
3 
Marked (with plastic aqueous humor) 
4 
Severe (with fibrin deposits and/or clots) 
Hyphema 
0 
Absent 
1 
Mild 
2 
Moderate 
3 
Severe 
 
 


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Lens 
Opacity 
0 
No opacity in the lens 
1 
Any opacity in the lens 
 
 
 
15.3 IOP  
IOP will be measured using a Tonopen or Goldmann applanation. The same method 
of measurement should be used throughout the study. However, if Tonopen is 
primarily used and IOP measures ≥25 mmHg during a visit, the measurement should 
be repeated for confirmation using Goldmann applanation according to the 
Investigator’s standard procedure. All pressures will be recorded in mmHg. 
 
15.4 Spectral Domain OCT 
SD-OCT will be performed using either Spectralis Ophthalmic Imaging System 
SD-OCT (Heidelberg Engineering Inc., Carlsbad, CA 92008) or Cirrus HD-OCT (Carl 
Zeiss Meditec, Inc., Dublin, CA 94568). The subject’s pupil should be dilated and the 
fast macular thickness map protocol should be utilized. This method obtains data 
from 6 radial line scans over a diameter of 6 millimeter (mm). Both the average 
center subfield thickness and the macular volume are of interest in the study. The 
OCT results will be read by the Investigator and a central reading facility.  
 
15.5 Indirect Ophthalmoscopy/Dilated Fundus Examination 
Indirect ophthalmoscopy/dilated fundus examination will be performed according to 
the Investigator’s standard protocol. Areas to be assessed include vitreous, fundus, 
optic nerve (including cup to disc ratio), macula and choroid, vessels and peripheral 
retina. An assessment of normal or abnormal will be made for each area. The 
specific finding for areas that are abnormal will be recorded.  
 
15.6 Fluorescein Angiography 
Fluorescein angiography (FA) will be performed according to the Investigator’s 
standard procedure, by injecting fluorescein sodium dye into a peripheral vein of the 
arm of the subject.  
 
15.7 Fundus Photography 
Fundus photographs with a Zeiss FF450 (or comparable) camera will be taken before 
and after FA, for visits with FA completed. For all other visits, photographs will be 
taken once during indirect ophthalmoscopy/dilated fundus examination. Images will 
be uploaded to ShareFile and printed for filing in the subject source documents.  
 
 
 


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15.8 Dosing Diary 
Subjects will be asked to record the following information related to administration of 
IP each day: 
 
• Date 
• Time of Administration 
 
This will be in the format of an IRB-approved dosing diary. The subjects will be 
requested to bring the diary to the clinic for Visit 2 and Visit 3. 
 
 


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