Clinical trial NCT05370495
Conditions: Dry Eye Disease
Sponsor: Seinda Pharmaceutical Guangzhou Corporation
Start date: 2022-07-25; Completion date: 2023-03-24
Enrollment: 201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 2, multi-center, double-masked, randomized, vehicle-controlled, dose-response, parallel-group study designed to evaluate the safety and tolerability and ocular efficacy of SY-201 Ophthalmic Solution versus vehicle over a 60-day treatment period in subjects with dry eye disease (DED).

Detailed description:

Arms: arm 1: SY-201 Ophthalmic Solution 2.0% arm 2: SY-201 Ophthalmic Solution 1.0% arm 3: SY-201 Ophthalmic Solution 0.5% arm 4: SY-201 Ophthalmic Solution Vehicle
Interventions: intervention 1: SY-201 Ophthalmic Solution 2.0% intervention 2: SY-201 Ophthalmic Solution 1.0% intervention 3: SY-201 Ophthalmic Solution 0.5% intervention 4: SY-201 Ophthalmic Solution Vehicle
Intervention descriptions: intervention 1: SY-201 Ophthalmic Solution 2.0% intervention 2: SY-201 Ophthalmic Solution 1.0% intervention 3: SY-201 Ophthalmic Solution 0.5% intervention 4: SY-201 Ophthalmic Solution Vehicle

Protocol documents:
Prot_000.pdf: 
NCT05370495
Clinical Study SY201-CS201
Protocol
13 April 2022


Page 
Title 
Pharmaceutical Corp.  
photocopied, disclosed, or transmitted to any other person or party without the advance written approval of Seinda 
is loaned to you for your confidential review on behalf of Seinda Pharmaceutical Corp. only and is not to be 
proprietary nature and may not be disclosed unless such disclosure is required by federal or state law or regulation. It 
This document contains information from Seinda Pharmaceutical Corp. and is of confidential, trade secret, and/or 
Confidentiality Statement 
 
13/April/2022 
Issue Date:  
1.2 
Version No.: 
Guangzhou, Guangdong, China, 510300
Guangzhou International Bio-island 
C401, No. 9 Luoxuan 4th Road  
Seinda Pharmaceutical Guangzhou Corp. 
Sponsor: 
2 
Study Phase: 
Pending 
National Clinical Trial No.:  
SY201-CS201 
Protocol No: 
 
Dry Eye Disease 
Ophthalmic Solution versus Vehicle Control in Subjects with  
Controlled, Dose-Response, Parallel-Group Study of SY-201 
A Phase 2, Multi-Center, Double-Masked, Randomized, Vehicle-
 
 
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Clinical Trial Protocol
SY-201 Ophthalmic Solution
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History 
Revision 
Protocol 
 
 
 
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Confidential
Clinical Trial Protocol
SY-201 Ophthalmic Solution
Seinda Pharmaceutical Guangzhou Corp. 
 


Title: 
A Phase 2, Multi-Center, Double-Masked, Randomized, Vehicle-Controlled, 
Dose-Response, Parallel-Group Study of SY-201 Ophthalmic Solution versus 
Vehicle Control in Subjects with Dry Eye Disease 
Phase: 
2 
Design/Conduct: 
This is a phase 2, multi-center, double-masked, randomized, vehicle-
controlled, dose-response, parallel-group study designed to evaluate the ocular 
and systemic safety and ocular efficacy of SY-201 Ophthalmic Solution over a 
60-day treatment period in subjects with moderate to severe DED.  
During the 14-day single-masked run-in period, approximately 200 subjects 
will instill vehicle as 1 drop in both eyes (OU) twice a day (BID). At Visit 2, 
subjects will be randomized in a 1:1:1:1 ratio to 4 treatment groups: Vehicle 
(n=50) and SY-201 Ophthalmic Solution 2.0% (n=50), 1.0% (n=50), and 0.5% 
(n=50). Double-masked IP will be instilled as 1 drop OU BID for 60 days.
The study will consist of 6 clinic visits: Visit 1 (-14 Days, Screening), Visit 2 
(Day 1, Randomization), Visit 3 (Day 7 ± 2 days), Visit 4 (Day 14 ± 2 days), 
Visit 5 (Day 28 ± 2 days), and Visit 6 (Day 60 ± 3 days, End of Study/Early 
Termination). 
Objectives: 
The primary objective is to assess the ocular safety and efficacy of SY-201 
Ophthalmic Solution in subjects with DED.  
The secondary objective is to assess the systemic safety of SY-201 Ophthalmic 
Solution in subjects with DED. 
Primary Efficacy Endpoints 
Safety Endpoints 
• 
• 
• 
• 
Synopsis 
Protocol 
Best corrected visual acuity (BCVA) 
 
Serum chemistry and hematology 
 
 
Frequency and severity of ocular and non-ocular adverse events (AEs)
 
assessed by: 
201 Ophthalmic Solution will be 
The ocular and systemic safety of SY-
(tCFS; modified National Eye Institute [mNEI] scale, 0-20) 
Mean change from baseline (CFB) in total corneal fluorescein staining 
 
tested sequentially: 
Two primary ocular efficacy endpoints (one sign and one symptom) will be 
Endpoints: 
 
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SY-201 Ophthalmic Solution
Clinical Trial Protocol
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Slit lamp biomicroscopy and external eye exam 
 
Intraocular pressure (IOP) 
 
Dilated ophthalmoscopy 
 
Drop comfort assessment 
Population studied: 
The study population will consist of approximately 200 adult subjects with 
moderate to severe DED.  
The study eye is defined as the eye meeting all inclusion criteria and no 
exclusion criteria, and with the highest tCFS scoring at randomization (Visit 2, 
Day 1). If both eyes meet the inclusion criteria and no exclusion criteria and 
have the same tCFS score, the right eye will be used as the SE. 
Inclusion Criteria 
Individuals will be eligible for study participation if they meet all of the 
following criteria: 
1. Provide written informed consent prior to any study-related 
procedures. 
2. Are 18 years of age or older. 
3. Are willing and able to follow instructions and can be present for the 
required study visits for the duration of the study. 
4. Have a BCVA in each eye, using corrective lenses if necessary, of 
+0.7 logarithm of the minimum angle of resolution (LogMAR) or 
better as assessed by the Early Treatment of Diabetic Retinopathy 
Study (ETDRS) at Visit 1. 
5. If women of childbearing potential (WOCBP), are non-lactating and 
have been sexually inactive (abstinent) for 14 days prior to Visit 1 and 
remain so through 30 days following Visit 6 or the last administration 
of the study 
cycle following the last administration of the study drug, whichever 
period of time is longer. Or they must have been using one of the 
following acceptable methods of birth control for the times specified:
a. 
Intra-uterine device (IUD) in place for at least 3 months prior to 
Visit 1 through 30 days following Visit 6 or last administration of 
cycle following last administration of the study drug, whichever 
period of time is longer. 
b. Barrier method (condom or diaphragm) with spermicide for at 
least 14 days prior to Visit 1 through 30 days following Visit 6 or 
last administration of the study drug or until completion of the 
rual cycle following last administration of the 
study drug, whichever period of time is longer. 
c. 
Stable hormonal contraceptive for at least 3 months prior to Visit 
1 through 30 days following Visit 6 or last administration of the 
study drug or until complet
cycle following administration of the study drug, whichever 
period of time is longer. Note: For Depo-Provera injection 
contraceptives, the statement regarding first menstrual cycle 
following administration of the study drug is not applicable, as 
females receiving this form of contraception will not have 
menses. 
d. Surgical sterilization (vasectomy) of partner at least 6 months 
prior to Visit 1. 
• 
• 
• 
• 
drug or until completion of the subject's first menstrual 
study drug or until completion of the subject's first menstrual 
subject's first menst 
ion of the subject's first menstrual 


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6. If postmenopausal women, have had no menstrual cycle for at least 1 
year prior to Visit 1 or have undergone one of the following 
sterilization procedures at least 6 months prior to Visit 1: 
a. 
Bilateral tubal ligation 
b. Hysterectomy 
c. 
Bilateral oophorectomy 
7. Have a history of DED in both eyes supported by a previous clinical 
diagnosis or have a history of subjective complaints for at least 6 
months rior to Visit 1. 
10. Have normal lid anatomy in the opinion of the investigator. 
11. Are willing to withhold AT for the duration of the study, with the 
exception of rescue use of the study-provided AT (Refresh Plus®).  
Exclusion Criteria 
Individuals will be excluded from study participation if they meet any of the 
followin  criteria: 
2. Any concomitant treatment or prior ocular procedure or surgery in 
either eye or alteration of the dose of systemic medications at the time 
of entry into the study that could interfere in the assessment of the 
judgment or per details below: 
a. 
Prior history of Isotretinoin (Accutane) 
b. Corneal refractive surgery, glaucoma surgery, or corneal 
transplantation within 2 years prior to Visit 1 
c. 
Altered use of nutraceuticals or multivitamins throughout the 
study 
d. Topical ophthalmic medications, including ocular hypotensive 
(glaucoma) medications, eye drops, gels, or AT (other than study-
provided Refresh Plus®) throughout the study 
f. 
Penetrating intraocular surgery within 12 months prior to Visit 1
g. Eyelid surgery or ocular surface surgery within 6 months prior to 
Visit 1 
h. Altered dose of the following used on a chronic basis within 3 
months prior to Visit 1: 
 
Anticholinergics 
 
Antidepressants 
 
Antihistamines 
 
Systemic immunosuppressive agents 
trial, per the Investigator's 
• 
• 
• 
• 


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Clinical Trial Protocol
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Oral steroids (dose must be <11 mg prednisone or 
equivalent/day)  
Dose must remain stable throughout study. 
i. 
In either eye, have had punctal occlusion (cauterization or plugs 
[silicone or dissolvable]) within 3 months prior to Visit 1 or 
anticipate new or additional punctal occlusion during the 
duration of the study.  
NOTE: Permanent plugs lost should be replaced. 
j. 
Any other Investigational Product within 45 days prior to Visit 
1 
k. Prescription treatments for ocular surface disease within 30 days 
prior to Visit 1, including  
 
Topical cyclosporine (Restasis®, Cequa®)  
 
Topical lifitegrast (Xiidra®) 
 
Ocular corticosteroids, including but not limited to 
fluorometholone and loteprednol etabonate (Eysuvis®) 
 
Varenicline (Tyvara®) 
l. 
Autologous serum within 30 days prior to Visit 1 
m. Altered 
dose 
of 
tetracycline 
compounds 
(tetracycline, 
doxycycline, or minocycline) within 30 days prior to Visit 1. 
Dose must remain stable throughout study. 
n. Topical ocular antibiotics, topical ocular antihistamines or mast 
cell stabilizers, topical or nasal vasoconstrictors within 14 days 
prior to Visit 1 
3. Have corneal erosive disease (e.g., confluent staining [NEI grade 4], 
confluent filaments) or other conditions suggestive of extensive 
damage of the cornea in either eye. 
4. Have a history of glaucoma or IOP >25 mmHg at Visit 1 or a history 
of elevated IOP (>25 mmHg) in either eye. 
5. Wear contact lenses for 14 days prior to Visit 1 or throughout the 
study. 
7. Are considered legally blind in either eye (LogMAR BCVA 1.0 or 
Snellen BCVA 20/200). 
9. Have a history of stem cell or bone marrow transplant. 
• 
• 
• 
• 
• 
< 
2 


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g. Significant conjunctival scarring 
h. Chemical burn 
i. 
History of herpetic or neurotrophic keratitis 
j. 
Serious systemic disease or uncontrolled medical condition that, 
in the judgment of the Investigator, could confound study 
assessments or limit compliance. 
11. Have a history of liver, renal or hematological disease that, in the 
judgment of the Investigator, could confound the study assessments 
or impact subject safety. 
12. Have an allergy to any component of the study drug formulation. 
13. Have a documented history of ocular allergies in either eye that, in the 
judgment of the Investigator, are likely to have an acute increase in 
severity due to the expected timing of the exposure to the allergen to 
which the subject is sensitive. Subjects sensitive to seasonal allergens 
that are not expected to be present during the study are permitted. 
14. Have systemic signs of infection (e.g., fever or current treatment with 
antibiotics). 
15. Are an employee of a site that is directly involved in the management, 
administration, or support of this study or an immediate family 
member (grandparent, parent, sibling, child) of the same.  
16. Have a known history of alcohol and/or drug abuse.  
17. Are an active dail
 user of tobacco or mari uana.  
19. Are unwilling or unable to comply with the study protocol.
Investigational products: 
SY-201 Ophthalmic Solution 2.0% 
SY-201 Ophthalmic Solution 1.0% 
SY-201 Ophthalmic Solution 0.5% 
Vehicle solution (run-in and vehicle) 
Dosing regimen: 
Both run-in and IP: 1 drop OU BID, once in the morning and once in the 
evening, 8-12 hours apart  
Assessments/Evaluations: 
Efficacy 
 
tCFS (mNEI scale, 0-20) 
 
• 


Safety 
 
AE monitoring  
 
Safety labs (chemistry and hematology) 
 
BCVA 
 
Slit lamp biomicroscopy and external eye exam 
 
IOP 
 
Dilated ophthalmoscopy 
 
Drop comfort assessment 
Duration of study: 
74 days (14 days of run-in, 60 days of treatment) 
• 
-
-
• 
• 
• 
• 
• 
• 
• 
---
used. 
e dryness score will be 
A similar model for the subject-level mean CFB in ey
for site. An unstructured covariance among repeated measurements is assumed. 
time, and treatment by time interaction as fixed effects, with a random effect 
treatment, 
(MMRM) model. The model will include the baseline measurement, 
model repeated measures 
Mean CFB in tCFS will be analyzed using a mixed-
hypotheses will imply that subsequent tests are non-significant. 
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primary endpoints will be compared sequentially between SY-
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level of SY-201 Ophthalmic Solution compared to v
To control for type I error, comparisons will be made within each active dose 
Mean CFB in tCFS (mNEI scale) 
 
particular, efficacy will be assessed using the following endpoints at Day 60:
DED signs and symptoms in subjects with a documented diagnosis of DED. In 
201 Ophthalmic Solution will be safe and improve 
It is hypothesized that SY-
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Statistical methods: 
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Clinical Trial Protocol
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Clinical Trial Protocol
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Subgroup analyses will be based on MMP-9 level (elevated or normal) in the 
study eye at baseline. 
Safety analyses will be performed on all subjects in the Safety Analysis Set. 
The assessment of safety will be based on the summary of ocular and non-
ocular AEs, laboratory measurements, BCVA, IOP, ophthalmic exams using 
slit lamp biomicroscopy and dilated ophthalmoscopy, and drop comfort 
assessment. Summaries will be provided by treatment group, and for ocular 
assessments separately by eye. 
 
 
 


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Clinical Trial Protocol
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Title Page ....................................................................................................................................... 1
Protocol Revision History ............................................................................................................. 2
Protocol Synopsis .......................................................................................................................... 3
Table of Contents ........................................................................................................................ 10
List of Figures .............................................................................................................................. 14
List of Tables ............................................................................................................................... 14
1. 
Introduction ..................................................................................................................... 15
1.1 
Background ........................................................................................................... 15
1.2 
Study Rationale ..................................................................................................... 16
1.3 
Risk/Benefit Assessment ...................................................................................... 17
1.3.1 
 Known Potential Risks .......................................................................... 17
1.3.2 
 Known Potential Benefits ..................................................................... 17
1.3.3 
Assessment of Benefits and Risks ......................................................... 17
2. 
Study Objectives and Endpoints.................................................................................... 19
2.1 
Study Objectives ................................................................................................... 19
2.2 
Study Endpoints .................................................................................................... 19
2.2.1 
 Primary Efficacy Endpoints .................................................................. 19
2.2.2 
 Secondary Efficacy Endpoints .............................................................. 19
2.2.3 
 Safety Endpoints ................................................................................... 19
3. 
Study Design .................................................................................................................... 21
3.1 
Overall Design of the Study .................................................................................. 21
3.2 
Rationale for the Study Design ............................................................................. 21
3.3 
Dose Justification .................................................................................................. 22
3.4 
End of Study Definition ........................................................................................ 22
4. 
Study Population ............................................................................................................. 23
4.1 
Inclusion Criteria .................................................................................................. 23
4.2 
Exclusion Criteria ................................................................................................. 24
4.3 
Screen Failures ...................................................................................................... 26
Table of Contents 


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5. 
Study Treatments or Interventions ............................................................................... 28
5.1 
Investigational Products ........................................................................................ 28
5.1.1 
 Description ............................................................................................ 28
5.1.2 
 Dosage and Administration................................................................... 29
5.2 
Preparation/Storage/Handling/Accountability ...................................................... 29
5.2.1 
 Acquisition and Accountability ............................................................ 29
5.2.2 
 Product Formulation, Appearance, Packaging and Labeling ................ 30
5.2.3 
 Product Storage and Stability................................................................ 30
5.2.4 
 Preparation ............................................................................................ 30
5.3 
Measures to Minimize Bias: Randomization and Masking .................................. 30
5.4 
Treatment Compliance .......................................................................................... 31
5.5 
Concomitant Therapy............................................................................................ 31
5.5.1 
 Prohibited Medications and Procedures................................................ 31
5.5.2 
 Artificial Tears ...................................................................................... 33
6. 
Study Discontinuation/Participant Withdrawal .......................................................... 34
6.1 
Discontinuation of Study Treatment or Intervention ............................................ 34
6.2 
Participant Discontinuation/Withdrawal from the Study ...................................... 34
6.3 
Lost to Follow-Up ................................................................................................. 35
7. 
Study Procedures ............................................................................................................ 36
7.1 
Visit Descriptions.................................................................................................. 36
7.1.1 
 Screening (Visit 1, -14 days) ................................................................ 36
7.1.2 
 Randomization (Visit 2, Day 1) ............................................................ 37
7.1.3 
 Visit 3 (Day 7 ± 2 days) ........................................................................ 38
7.1.4 
 Visit 4 (Day 14 ± 2 days) ...................................................................... 38
7.1.5 
 Visit 5 (Day 28 ± 2 days) ...................................................................... 39
7.1.6 
 Visit 6 (End of Study/Early Termination, Day 60 ± 3 days) ................ 39
7.1.7 
 Unscheduled Visits ............................................................................... 40
7.1.8 
 Early Termination ................................................................................. 40
8. 
Study Assessments .......................................................................................................... 41
8.1 
Efficacy Evaluations ............................................................................................. 41


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8.2 
Safety Evaluations ................................................................................................ 41
8.2.1 
 Adverse Events (AEs) and Serious Adverse Events (SAEs) ................ 41
8.2.1.1 Definitions.............................................................................................. 42
8.2.1.2 Classification of Adverse Events ........................................................... 42
8.2.1.3 Adverse Event Reporting Requirements ................................................ 43
8.2.1.4 Other Events of Interest ......................................................................... 44
8.2.1.5 Pregnancy ............................................................................................... 44
8.2.2 
 Clinical Laboratory Tests ...................................................................... 44
9. 
Statistical Considerations ............................................................................................... 46
9.1 
Statistical Hypothesis ............................................................................................ 46
9.2 
Sample Size Determination................................................................................... 46
9.3 
Analysis Populations ............................................................................................. 47
9.4 
Statistical Analyses ............................................................................................... 47
9.4.1 
 Baseline Descriptive Analyses .............................................................. 47
9.4.2 
 Efficacy Analyses ................................................................................. 48
9.4.2.1 Primary Efficacy Analyses .................................................................... 48
9.4.2.2 Secondary Efficacy Analyses ................................................................ 48
9.4.3 
 Safety Analyses ..................................................................................... 49
9.4.3.1 Adverse Events ...................................................................................... 49
9.4.3.2 Clinical Laboratory Tests ....................................................................... 49
9.4.3.3 Other Safety Evaluations ....................................................................... 49
9.5 
Interim Analysis .................................................................................................... 49
9.6 
Subgroup Analyses ............................................................................................... 49
9.7 
Exploratory Analyses ............................................................................................ 50
9.8 
Missing or Unused Data........................................................................................ 50
9.9 
Tabulation of Individual Participant Data............................................................. 50
10. 
Supporting Documentation and Operational Considerations ............................ 51
10.1 
Regulatory Issues, Ethical Concerns, and Study Oversight .................................. 51
10.1.1 
 Informed Consent Process .................................................................... 51
10.1.1.1 Consent Documents ............................................................................... 51


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10.1.1.2 Consent Procedures and Documentation ............................................... 51
10.1.2 
 Study Discontinuation and Closure ...................................................... 51
10.1.3 
 Confidentiality and Privacy .................................................................. 52
10.1.4 
 Clinical Monitoring ............................................................................... 53
10.1.5 
 Quality Assurance and Quality Control ................................................ 53
10.1.6 
 Data Handling and Record Keeping ..................................................... 53
10.1.6.1 Data Collection and Management Responsibilities ............................... 53
10.1.6.2 Study Records Retention........................................................................ 54
10.1.7 
 Protocol Deviations ............................................................................... 54
10.1.8 
 Publication and Data Sharing Policy .................................................... 54
11.
References ................................................................................................................ 56
12. 
Appendices ............................................................................................................... 59
12.1 
Appendix 1:   Schedule of Procedures and Assessments ...................................... 60
12.2 
Appendix 2:   Abbreviations and Definition of Terms ......................................... 61
12.3 
A
endix 3:   Corneal Fluorescein Stainin  CFS  Modified NEI Scale ............ 65
12.6 
Appendix 6:   Bulbar Conjunctival Hyperemia .................................................... 68
12.7 
Appendix 7:   Biomarker Test (MMP-9) .............................................................. 69
12.8 
Appendix 8:   Unanesthetized Schirmer Test ....................................................... 71
12.9 
Appendix 9:   Best Corrected Visual Acuity (BCVA) .......................................... 72
12.10 Appendix 10:   Slit Lamp Biomicroscopy ............................................................ 73
12.11 Appendix 11:   Intraocular Pressure (IOP) ........................................................... 74
12.12 Appendix 12:   Dilated Ophthalmoscopy.............................................................. 75
12.13 Appendix 13:   Drop Comfort Assessment ........................................................... 76
12.14 Appendix 14:   Investigator Agreement ................................................................ 77
12.15 Appendix 15:   Compliance Statement ................................................................. 78
Last page ........................................................................................................................... 79
 
 


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Figure 1: Study Schematic ............................................................................................................ 21
 
 
Table 1: Active and Vehicle IPs ................................................................................................... 28
List of Figures 
List of Tables 


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1. 
Introduction 
1.1 
Background 


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1.2 
Study Rationale 
Global prevalence of DED is estimated at 300 million, or 5% to 50% of select populations, with 
the disease generally more common in women than men and in Asian populations compared to 
Caucasian populations (Stapleton et al., 2017). 
Current treatments for DED include tear replacement, anti-inflammatory agents, serum or 
umbilical cord serum eye drops, and surgical interventions. According to Jones (2017)
that many of the treatments available for the management of dry eye disease lack the necessary 
Approved topical treatments have been 
associated with side effects such as instillation pain and irritation (Schultz 2014, Leonardi 2016), 
ocular hypertension, and cataract formation (Marsh 1999). 
____ _, it is "clear 
Level 1 evidence to support their recommendation" and there are "challenges ... in predicting the 
relative benefits of specific management options." 


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1.3 
Risk/Benefit Assessment 
1.3.1  
Known Potential Risks 
1.3.2  
Known Potential Benefits 
1.3.3 Assessment of Benefits and Risks 


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2. 
Study Objectives and Endpoints 
2.1 
Study Objectives 
The primary objective of this phase 2 study is to assess the ocular safety and efficacy of SY-201 
Ophthalmic Solution in subjects with DED.  
The secondary objective is to assess the systemic safety of SY-201 Ophthalmic Solution in 
subjects with DED. 
2.2 
Study Endpoints 
2.2.1  
Primary Efficacy Endpoints 
Two primary ocular efficacy endpoints (one sign and one symptom) will be tested sequentially at 
Day 60: 
 Mean change from baseline (CFB) in total corneal fluorescein staining (tCFS; modified 
National Eye Institute [mNEI] scale, 0-20) 
2.2.2  
Secondary Efficacy Endpoints 
The following secondary ocular efficacy endpoints will be tested: 
2.2.3  
Safety Endpoints 
The ocular and systemic safety of SY-201 Ophthalmic Solution will be assessed by: 
 Frequency and severity of ocular and non-ocular adverse events (AEs) 
 Serum chemistry and hematology 
 Best corrected visual acuity (BCVA) 
 Slit lamp biomicroscopy and external eye exam 
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 Intraocular pressure (IOP) 
 Dilated ophthalmoscopy 
 Drop comfort assessment 
 
 
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3. 
Study Design 
3.1 
Overall Design of the Study 
This is a phase 2, multi-center, double-masked, randomized, vehicle-controlled, dose-response, 
parallel-group study designed to evaluate the ocular and systemic safety and ocular efficacy of SY-
201 Ophthalmic Solution over a 60-day treatment period in subjects with moderate to severe DED.  
During the 14-day single-masked run-in period, approximately 200 subjects will instill vehicle as 
1 drop BID in both eyes (OU). At Visit 2, subjects will be randomized in a 1:1:1:1 ratio to 4 
treatment groups: Vehicle (n=50) and SY-201 Ophthalmic Solution 2.0% (n=50), 1.0% (n=50), 
and 0.5% (n=50). Double-masked IP will be instilled as 1 drop OU BID for 60 days. 
The study will consist of 6 clinic visits: Visit 1 (-14 Days, Screening), Visit 2 (Day 1, 
Randomization), Visit 3 (Day 7 ± 2 days), Visit 4 (Day 14 ± 2 days), Visit 5 (Day 28 ± 2 days), 
and Visit 6 (Day 60 ± 3 days, End of Study/Early Termination). A study schematic follows (Figure 
1). 
Figure 1: Study Schematic 
 
3.2 
Rationale for the Study Design 
This study will examine the ocular and systemic safety and ocular efficacy of SY-201 Ophthalmic 
Solution versus vehicle dosed OU BID for 60 days in subjects with moderate to severe DED. 
Vehicle 
Run-In 
Day 
-14 
QZIJ 
I 
SY-201 Ophthalmic Solution 2.0.% (n=50) 
SY-201 Ophthalmic Solution 1.0% (n=50) 
SY-201 Ophthalmic Solution 0.5% (n=50) 
Vehicle (n=50) 
Day 1 
Day 7 
Day 14 
Day 28 
±2 
± 2 
± 2 
[y[] 
[2TI 
[2D 
DZ[] 
t 
SCREENING 
RANDOMIZATION 
Day 60 
±3 
[2[] 
I 
STUDY 
TERMINATION 


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SY-201 Ophthalmic Solution and vehicle will each be administered as a topical ophthalmic 
solution. In the single-masked run-in period, vehicle will be dosed OU BID by all subjects to 
normalize baseline conditions between subjects. Subjects will self-administer the first dose in-
clinic at Visit 1 and all remaining doses at home. In the double-masked treatment period, subjects 
will self-administer 1 dose of IP in-clinic at Visit 2 (Day 1) and Visit 6 (Day 60) and all remaining 
doses at home, OU BID.  
Direct instillation is the most efficient method for delivery to the ocular surface and is an accepted 
and widely used method for topical application to the eye. Each dose will be delivered by 
administering 1 drop (
 in each eye from a 
single-use vial. 
3.3 
Dose Justification 
The concentrations of 2.0%, 1.0%, and 0.5% SY-201 Ophthalmic Solution and the dosing schedule 
were chosen based on previous clinical studies, as described in Section 1.3.2.  
3.4 
End of Study Definition 
A subject is considered to have completed the study if he or she has completed all phases of the 
study, including the last visit or the last scheduled procedure shown in the Schedule of Procedures 
and Assessments (Appendix 1). The end of the study is defined as completion of the last visit or 
procedure shown in the schedule in the study. 
 


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4. 
Study Population 
The study population will consist of approximately 200 adult subjects with moderate to severe 
DED.  
The study eye is defined as the eye meeting all inclusion criteria and no exclusion criteria, and 
with the highest tCFS scoring at randomization (Visit 2, Day 1). If both eyes meet the inclusion 
criteria and no exclusion criteria and have the same tCFS score, the right eye will be used as the 
SE. 
4.1 
Inclusion Criteria 
Individuals will be eligible for study participation if they meet all of the following criteria: 
 
1. Provide written informed consent prior to any study-related procedures. 
2. Are 18 years of age or older. 
3. Are willing and able to follow instructions and can be present for the required study visits 
for the duration of the study. 
4. Have a BCVA in each eye, using corrective lenses if necessary, of +0.7 logarithm of the 
minimum angle of resolution (LogMAR) or better as assessed by the Early Treatment of 
Diabetic Retinopathy Study (ETDRS) at Visit 1. 
5. If women of childbearing potential (WOCBP), are non-lactating and have been sexually 
inactive (abstinent) for 14 days prior to Visit 1 and remain so through 30 days following 
 first 
menstrual cycle following the last administration of the study drug, whichever period of 
time is longer. Or they must have been using one of the following acceptable methods of 
birth control for the times specified: 
a. Intra-uterine device (IUD) in place for at least 3 months prior to Visit 1 through 30 
days following Visit 6 or last administration of study drug or until completion of 
whichever period of time is longer. 
b. Barrier method (condom or diaphragm) with spermicide for at least 14 days prior 
to Visit 1 through 30 days following Visit 6 or last administration of the study drug 
administration of the study drug, whichever period of time is longer. 
c. Stable hormonal contraceptive for at least 3 months prior to Visit 1 through 30 days 
following Visit 6 or last administration of the study drug or until completion of the 
whichever period of time is longer. Note: For Depo-Provera injection 
contraceptives, the statement regarding first menstrual cycle following 
Visit 6 or the last administration of the study drug or until completion of the subject's 
the subject's first menstrual cycle following last administration of the study drug, 
or until completion of the subject's first menstrual cycle following last 
subject's first menstrual cycle following administration of the study drug, 


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administration of the study drug is not applicable, as females receiving this form of 
contraception will not have menses. 
d. Surgical sterilization (vasectomy) of partner at least 6 months prior to Visit 1. 
6. If postmenopausal women, have had no menstrual cycle for at least 1 year prior to Visit 1 
or have undergone one of the following sterilization procedures at least 6 months prior to 
Visit 1: 
a. Bilateral tubal ligation 
b. Hysterectomy 
c. Bilateral oophorectomy 
7. Have a history of DED in both eyes supported by a previous clinical diagnosis or have a 
history of subjective complaints for at least 6 months prior to Visit 1. 
11. Are willing to withhold AT for the duration of the study, with the exception of rescue use 
of the study-provided AT (Refresh Plus®).   
4.2 
Exclusion Criteria 
Individuals will be excluded from study participation if they meet any of the following criteria: 
2. Any concomitant treatment or prior ocular procedure or surgery in either eye or alteration 
of the dose of systemic medications at the time of entry into the study that could interfere 
judgment or per details below: 
a. Prior history of Isotretinoin (Accutane) 
b. Corneal refractive surgery, glaucoma surgery, or corneal transplantation within 2 years 
prior to Visit 1 
c. Altered use of nutraceuticals or multivitamins throughout the study 
d. Topical ophthalmic medications, including ocular hypotensive (glaucoma) 
medications, eye drops, gels, or AT (other than study-provided Refresh Plus®) 
throughout the study 
f. Penetrating intraocular surgery within 12 months prior to Visit 1 
g. Eyelid surgery or ocular surface surgery within 6 months prior to Visit 1 
h. Altered dose of the following used on a chronic basis within 3 months prior to Visit 1:
 Anticholinergics 
in the assessment of the trial, per the Investigator's 
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 Antidepressants 
 Antihistamines 
 Systemic immunosuppressive agents 
 Oral steroids (dose must be <11 mg prednisone or equivalent/day)  
Dose must remain stable throughout study. 
i. In either eye, have had punctal occlusion (cauterization or plugs [silicone or 
dissolvable]) within 3 months prior to Visit 1 or anticipate new or additional punctal 
occlusion during the duration of the study.  
NOTE: Permanent plugs lost should be replaced. 
j. Any other Investigational Product within 45 days prior to Visit 1 
k. Prescription treatments for ocular surface disease within 30 days prior to Visit 1, 
including  
 Topical cyclosporine (Restasis®, Cequa®)  
 Topical lifitegrast (Xiidra®) 
 Ocular corticosteroids, including but not limited to fluorometholone and 
loteprednol etabonate (Eysuvis®) 
 Varenicline (Tyvara®) 
l. Autologous serum within 30 days prior to Visit 1 
m. Altered dose of tetracycline compounds (tetracycline, doxycycline, or minocycline)
within 30 days prior to Visit 1.  
Dose must remain stable throughout study. 
n. Topical ocular antibiotics, topical ocular antihistamines or mast cell stabilizers, topical 
or nasal vasoconstrictors within 14 days prior to Visit 1 
3. Have corneal erosive disease (e.g., confluent staining [NEI grade 4], confluent filaments) 
or other conditions suggestive of extensive damage of the cornea in either eye. 
4. Have a history of glaucoma or IOP >25 mmHg at Visit 1 or a history of elevated IOP (>25 
mmHg) in either eye. 
5. Wear contact lenses for 14 days prior to Visit 1 or throughout the study. 
  
7.
 
9. Have a history of stem cell or bone marrow transplant.
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Are considered legally blind in either eye (LogMAR BCVA ~1.0 or Snellen BCVA 
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g. Significant conjunctival scarring
h. Chemical burn 
i. History of herpetic or neurotrophic keratitis 
j. Serious systemic disease or uncontrolled medical condition that, in the judgment of 
the Investigator, could confound study assessments or limit compliance. 
11. Have a history of liver, renal or hematological disease that, in the judgment of the 
Investigator, could confound the study assessments or impact subject safety. 
12. Have an allergy to any component of the study drug formulation. 
13. Have a documented history of ocular allergies in either eye that, in the judgment of the 
Investigator, are likely to have an acute increase in severity due to the expected timing of 
the exposure to the allergen to which the subject is sensitive. Subjects sensitive to seasonal 
allergens that are not expected to be present during the study are permitted. 
14. Have systemic signs of infection (e.g., fever or current treatment with antibiotics). 
15. Are an employee of a site that is directly involved in the management, administration, or 
support of this study or an immediate family member (grandparent, parent, sibling, child) 
of the same.  
16. Have a known history of alcohol and/or drug abuse.  
17. Are an active (daily) user of tobacco or marijuana.  
19. Are unwilling or unable to comply with the study protocol.
4.3 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to the study intervention or entered in the study. Minimal 
information, including demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE) will be recorded. 
Individuals who do not meet the criteria for participation in this trial (screen failure) at the 
completion of Visit 1 because of the following may be rescreened: 
 Prohibited medications from which the subject may discontinue for purposes of screening 
eligibility (with approval from Investigator based on clinical safety). 
 Exclusionary medical history status at time of screening that will change (e.g., ocular 
infection, surgical history duration, etc.). 
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Rescreened subjects will be assigned a new participant number. 
 
 


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5. 
Study Treatments or Interventions 
5.1 
Investigational Products 
Four (4) IPs will be administered during this study:  
 SY-201 Ophthalmic Solution 2.0% 
 SY-201 Ophthalmic Solution 1.0% 
 SY-201 Ophthalmic Solution 0.5% 
 Vehicle solution 
5.1.1  
Description 
Table 1: Active and Vehicle IPs 
 
Active Investigational Product 
Vehicle Control (Placebo) 
Product 
SY-201 Ophthalmic Solution 
SY-201 Placebo 
Dosage form 
Solution/Drops 
Solution/Drops 
Unit dose 
 (2.0% weight by volume 
[w/v]) 
 (1.0% w/v)  
 (0.5% w/v)  
(0.0% w/v) 
Route of administration 
Topical ocular administration 
Topical ocular administration
Ph sical descri tion 
Sterile, colorless, clear li uid  
Sterile, colorless, clear li uid 
 
 
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5.1.2  
Dosage and Administration 
This study includes a run-in period in which 1 drop
of single-masked vehicle will be 
administered OU BID over 14 days. Administration of the double-masked IP, also 1 drop
OU BID, will occur over a 60-day treatment period. In both periods, administration is preferred in
the morning and evening, with 8 to 12 hours between instillations.  
At Visit 1 (Day -14), subjects will be assigned
 of single-masked run-in roduct vehicle  and 
self-administer their first dose under the supervision of the site staff.
 Subjects will be instructed to instill the run-in product as 1 drop into each eye. Subjects will 
then take home their 3 assigned kits (sufficient for up to 15 days) of run-in product for self-
administration. Subjects will dose at home that evening. 
The used and unused 
containing single-masked run-in must be returned to the site at 
Visit 2 (Day 1). Subjects should not dose run-in product the day of Visit 2. 
At Visit 2, randomized subjects will be assigned 2 IP kits of double-masked IP (SY-201 
Ophthalmic Solution 2.0%, 1.0%, or 0.5% or vehicle). The first dose of double-masked IP, taken 
from an assigned kit, will be self-administered in the clinic by the subject under the supervision of 
the site staff. Subjects will be instructed to instill the IP as 1 drop into each eye. Subjects will be 
queried on drop comfort and then take home their 2 assigned kits (sufficient for up to 10 days) of 
double-masked IP for self-administration. Subjects will dose at home that evening. 
Subjects will return the used and unused double-masked IP at each subsequent visit (through Visit 
6) and receive new kits of double-masked IP to take home at Visit 3 (2 kits, sufficient for up to 10
days), Visit 4 (4 kits, sufficient for up to 20 days), and Visit 5 (7 kits, sufficient for up to 35 days).  
5.2 
Preparation/Storage/Handling/Accountability 
5.2.1  
Acquisition and Accountability 
. The IP may be distributed by trained study staff. Used and unused IP will be maintained 
at the site for accountability by the clinical study monitor. When authorized by the Sponsor and 
after the clinical study monitor has verified drug accountability is complete and accurate, all used 
and unused single-masked (run-in) and double-masked IP will be returned
for destruction.  


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5.2.2  
Product Formulation, Appearance, Packaging and Labeling 
Pouch labels will contain the following information: protocol number, contents, batch and pouch
numbers, dosing instructions, storage temperature, Sponsor, and required statement(s) per 
regulatory agency. 
Kit labels will contain the following information: protocol number, contents, batch and kit 
numbers, storage temperature, Sponsor, and required statement(s) per regulatory agency. 
5.2.3  
Product Storage and Stability 
At clinical sites, IP will be stored in a securely locked cabinet or enclosure. Access should be 
strictly limited to the Investigators and their designees. Neither the Investigators nor any designees 
may provide IP to any subject not participating in this study. Subjects will be instructed on the 
proper storage of IP.  
IP should be protected from light and stored 
inside the
5.2.4  
Preparation 
Neither SY-201 Ophthalmic Solution nor vehicle will require on-site preparation by the 
Investigator. 
5.3 
Measures to Minimize Bias: Randomization and Masking 
To minimize bias, the treatment phase of this study is randomized and double-masked. 
Subjects will be randomized to treatment assignment. If unmasking is required, the integrity of the 
study assessments and objectives will be maintained by limiting access to the unmasked data.
A randomization schedule will be generated by the electronic data capture (EDC) system. The 
EDC will be used for randomization and unmasking. 
Double-masked IP
SY-201 (2.0%, 1.0%, or 0.5%) or vehicle
assigned to subjects at 
randomization will be identical in appearance. Sponsor, subjects, and investigative staff will be 
masked to the identity of treatment until completion of the study and final database lock. 


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Appropriate precautions must be taken to prevent unauthorized access to the randomization 
a treatment ass
after consultation with the Sponsor. 
5.4 
Treatment Compliance 
Subjects are required to return all unused and used run-in product, IP, and study-provided AT. The 
materials returned will provide evidence of compliance. 
5.5 
Concomitant Therapy 
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the electronic case report 
form (eCRF) are concomitant prescription medications, over-the-counter medications, and 
supplements.  
All medications that the subject has taken 45 days prior to Visit 1 and through Visit 6 or 
discontinuation from the study will be recorded in the eCRF and the subject chart. The generic 
name of the drug, dose, route of administration, duration of treatment (including start and stop 
dates), frequency, indication, and whether or not the medication was taken due to an AE will be 
recorded for each medication. Prior and concomitant medications (CMs) will be coded using the 
World Health Organization Drug Dictionary (WHODrug). 
5.5.1  
Prohibited Medications and Procedures 
Prohibited medications and procedures that require a washout are also restricted throughout the 
study, unless otherwise noted. 
Medication and Procedures Not Permitted 
Minimum Washout Prior to Visit 1 
(Unless Otherwise Noted) 
Isotretinoin (Accutane) 
Prior history 
Corneal refractive surgery, glaucoma surgery, or corneal 
transplantation 
2 years 
Altered use of nutraceuticals or multivitamins  
Throughout study 
Topical ophthalmic medications, including ocular 
hypotensive (glaucoma) medications, eye drops, gels, or 
AT (other than study-provided Refresh Plus®) 
Throughout study 
Throughout study 
scheme. Unless the subject's safety requires otherwise and if time permits, the decision to unmask 
ignment is to be made jointly by the Investigator and Sponsor's medical monitor 


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Penetrating intraocular surgery 
12 months 
Eyelid surgery or ocular surface surgery 
6 months 
Altered dose of the following used on a chronic basis (see 
end of table for pro re nata [PRN] use): 
 
Anticholinergics 
 
Antidepressants 
 
Antihistamines 
 
Systemic immunosuppressive agents 
 
Oral steroids (dose must be <11 mg prednisone or 
equivalent/day)  
Dose must remain stable throughout study. 
3 months 
In either eye, have had punctal occlusion (cauterization or 
plugs [silicone or dissolvable]) or anticipate new or 
additional punctal occlusion during the duration of the 
study. NOTE: Permanent plugs lost should be replaced. 
3 months 
Any other IP 
45 days 
Prescription treatments for ocular surface disease, 
including  
 
Topical cyclosporine (Restasis®, Cequa®)  
 
Topical lifitegrast (Xiidra®) 
 
Ocular corticosteroids, including but not limited to 
fluorometholone and loteprednol etabonate 
(Eysuvis®) 
 
Varenicline (Tyvara®)  
30 days 
Autologous serum 
30 days 
Altered dose of tetracycline compounds (tetracycline, 
doxycycline, or minocycline). Dose must remain stable 
throughout study. 
30 days 
Contact lenses 
14 days 
Topical ocular antibiotics 
Topical ocular antihistamines or mast cell stabilizers  
Topical or nasal vasoconstrictors 
14 days 
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5.5.2  
Artificial Tears 
AT, whether subject- or study-supplied, is prohibited during the run-in period of the study (Visit 
1 to Visit 2). Any subject who violates this policy will not be randomized to treatment and will be 
discontinued from the study. 
Preservative-free AT (Refresh Plus®) will be provided for rescue use during the treatment phase 
of the study (Visits 2 through 6) 
to record AT use in a diary and return the used and unused AT at clinic Visits 2 through 6; subjects 
will be queried about AT use at each clinic visit. 
 
 
but limited to :S2 instillations per day. Subjects will be required 


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6. 
Study Discontinuation/Participant Withdrawal 
6.1 
Discontinuation of Study Treatment or Intervention 
The study IP may be discontinued by a subject at any time, although every effort will be made to 
ensure consistent subject participation over the 60-day treatment period. In the event of 
discontinuation of IP by a subject, the Investigator will make every attempt to have the subject 
complete Visit 6 assessments as soon as possible. The subject will be discontinued following those 
assessments, and the reason for premature discontinuation will be recorded in the subject chart and 
entered in the eCRF. 
6.2 
Participant Discontinuation/Withdrawal from the Study 
Subjects are free to withdraw from participation in the study at any time upon request. An 
Investigator may discontinue or withdraw a subject from the study for the following reasons: 
 Withdrawal of consent 
 Study terminated by the Sponsor 
 Lost to follow-up 
 Pregnancy 
 Significant study treatment/intervention non-compliance  
 If any clinical adverse event, laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the subject 
 Disease progression that requires discontinuation of the study intervention 
 If the subject meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for subject discontinuation or withdrawal from the study will be recorded on the eCRF. 
Subjects who sign the informed consent form (ICF) and are randomized but do not receive the 
study intervention may be replaced.  
Those who sign the ICF, are randomized, receive the study treatment/intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will not be replaced.  
In the event of study discontinuation, the Investigator will make every attempt to have the subject 
complete Visit 6 assessments as soon as possible. The reason for premature discontinuation will 
be recorded in the subject chart and entered in the eCRF. 
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6.3 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to return for a scheduled visit and 
is unable to be contacted by the study site staff.  
The following actions must be taken if a subject fails to return for a required clinic study visit:
 The site will attempt to contact the subject and reschedule the missed visit within 1 week, 
counsel the subject on the importance of maintaining the assigned visit schedule, and 
ascertain if the subject wishes to and/or should continue in the study. 
 Before a subject is deemed lost to follow-up, the Investigator or designee will make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, 
alent methods). 
 
Should the subject continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up.  
 
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a certified letter to the subject's last known mailing address or local equiv 
These contact attempts will be documented in the subject's medical record or study file. 


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7. 
Study Procedures 
Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) 
authorization will be obtained from all subjects prior to any study-related procedures being 
performed. The Schedule of Procedures and Assessments (Appendix 1) lists the procedures that 
should occur at each study visit.  
7.1 
Visit Descriptions 
7.1.1  
Screening (Visit 1, -14 days) 
Ocular assessments and procedures must be performed in the order specified below. Tasks marked 
with an asterisk may be performed at any point (at Visit 1, after the consent is signed).  
 
and obtain written informed consent and HIPAA authorization. 
 Assign Subject Identification Number. 
 Obtain information including: demographics, CMs, ocular and systemic medical and 
medication history and surgical history. 
 Determine study eligibility based on Inclusion/Exclusion criteria. 
 Administer the following subject-rated symptom assessments: 
 Urine pregnancy test (UPT) for WOCBP* 
 Safety labs: blood samples for chemistry and hematology* 
 BCVA 
Biomicroscopy and external eye exam
 OU tear collection under slit lamp for biomarker test (quantitative point-of-care [POC]
MMP-9 test by Seinda Biomedical Corp.) 
 CFS  
o Note: After CFS grading, wait at least 15 minutes before conducting 
 
 IOP 
 Dilated ophthalmoscopy 
 Enter subject information into EDC to determine the single-masked run-in kit number.
 Dispense 3 kits of single-masked run-in product (sufficient for up to 15 days) and explain 
the method of run-in administration. 
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 Observe as the subject self-administers the first dose (1 drop OU) of single-masked run-in 
at the clinic. All remaining doses (1 drop OU BID) will be administered by the subject at 
home.  
 Assess for AEs. 
 Remind subject:  
o Use of AT during the run-in period is prohibited. Use will 
discontinuation from the study. 
o Run-in product should be administered as 1 drop OU once in the morning and once 
in the evening, 8-12 hours apart. Do not dose run-in product the day of Visit 2.
o Return all used and unused run-in product at Visit 2. 
7.1.2  
Randomization (Visit 2, Day 1) 
The following procedures will be performed at Visit 2: 
 Confirm study eligibility based on Inclusion/Exclusion criteria. 
 Update CMs 
 Assess AEs 
 Administer the following subject-rated symptom assessments: 
 BCVA 
 
 Biomicroscopy and external eye exam 
 OU tear collection under slit lamp for biomarker test (quantitative POC MMP-9) 
 CFS 
o Note: After CFS grading, wait at least 15 minutes before conducting 
 
 IOP 
 Confirm that the subject is eligible for randomization. The trained site staff will then 
conduct the following procedures: 
o Enter subject information into Interactive Web Randomization System (IWRS) to 
determine randomization code and kit number.  
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technique. 
o Dispense 2 double-masked IP kits (sufficient for up to 10 days) to the subject to 
take home.  
o Observe as the subject self-administers the first dose of double-masked IP at the 
clinic/site. All remaining doses will be administered by the subject at home, OU 
BID (morning and evening, instillations approximately 8-12 hours apart). 
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 Drop comfort assessment 
 Issue AT diary and train subject in diary completion.  
 Dispense preservative-free AT (Refresh Plus®) and counsel subject to limit AT use 
instillations per day.  
7.1.3  
Visit 3 (Day 7 ± 2 days) 
The following procedures will be performed at Visit 3:  
 Update CMs 
 Assess AEs 
 Administer the following subject-rated symptom assessments: 
 BCVA 
 
 Biomicroscopy and external eye exam 
 SE tear collection under slit lamp for biomarker test (quantitative POC MMP-9) 
 CFS 
 IOP 
 Collect AT diary and all used and unused AT and IP.  
 Issue new AT diary. 
 Dispense preservative-free AT (Refresh Plus®
instillations per day. 
 Dispense 2 double-masked IP kits (sufficient for up to 10 days) to the subject to take home.  
7.1.4  
Visit 4 (Day 14 ± 2 days) 
The following procedures will be performed at Visit 4: 
 Update CMs 
 Assess AEs 
 Administer the following subject-rated symptom assessments: 
 BCVA 
 
 Biomicroscopy and external eye exam
 SE tear collection under slit lamp for biomarker test (quantitative POC MMP-9) 
 CFS 
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 IOP 
 Collect AT diary and all used and unused AT and IP.  
 Issue new AT diary. 
 Dispense preservative-free AT (Refresh Plus®) and remind subject to limit AT use 
instillations per day.  
 Dispense 4 double-masked IP kits (sufficient for up to 20 days) to the subject to take home.  
7.1.5  
Visit 5 (Day 28 ± 2 days) 
The following procedures are to be performed at Visit 5:  
 Update CMs 
 Assess AEs 
 Administer the following subject-rated symptom assessments: 
 BCVA 
 
 Biomicroscopy and external eye exam 
 SE tear collection under slit lamp for biomarker test (quantitative POC MMP-9) 
 CFS 
 IOP 
 Collect AT diary and all used and unused AT and IP.  
 Issue new AT diary. 
 Dispense preservative-free AT (Refresh Plus®
instillations per day.  
 Dispense 7 double-masked IP kits (sufficient for up to 35 days) to the subject to take home.  
 Dosing and drop comfort assessment will take place in clinic at Visit 6. Advise subject to 
withhold 1 dose of IP on the day of Visit 6. 
7.1.6  
Visit 6 (End of Study/Early Termination, Day 60 ± 3 days) 
The following procedures are to be performed at the End of Study visit:  
 Update CMs 
 Assess AEs 
 Administer the following subject-rated symptom assessments: 
 UPT for WOCBP*  
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 Safety labs: blood samples for chemistry and hematology* 
 BCVA 
 
 Biomicroscopy and external eye exam 
 SE tear collection under slit lamp for biomarker test (quantitative POC MMP-9) 
 CFS 
o Note: After CFS grading, wait at least 15 minutes before conducting 
 
 IOP 
 Dilated ophthalmoscopy 
 IP administration and drop comfort assessment 
 Collect AT diary and all used and unused AT and IP. 
7.1.7  
Unscheduled Visits 
At times outside of normally scheduled visits, assessments will be conducted at the discretion of 
the Investigator.  
7.1.8  
Early Termination 
In the event that a subject exits or is terminated from the study prior to the End of Study visit (Visit 
6), every attempt will be made to ensure that all Visit 6 assessments are performed prior to the 
subject being discharged. 
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8. 
Study Assessments 
The Schedule of Procedures and Assessments (Appendix 1) provides a list of study assessments 
and evaluations to be performed and the timing of each.  
8.1 
Efficacy Evaluations 
Efficacy assessments will be conducted at the time points indicated on the Schedule of Procedures 
and Assessments (Appendix 1).  
 tCFS (mNEI scale, 0-20) (Appendix 3) 
8.2 
Safety Evaluations 
Safety assessments will be performed at the time points indicated on the Schedule of Procedures 
and Assessments (Appendix 1).  
 AE monitoring (Section 8.2.1) 
 Safety labs (chemistry and hematology) (Section 8.2.2) 
 BCVA (Appendix 9) 
 Slit lamp biomicroscopy and external eye exam (Appendix 10) 
 IOP (Appendix 11) 
 Dilated ophthalmoscopy (Appendix 12) 
 Drop comfort assessment (Appendix 13) 
8.2.1  
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
Adverse events will be monitored throughout the study. Subjects will be encouraged to report any 
adverse findings during the study whether or not they are related to IP. These can be collected 
either in an unsolicited fashion without any prompting or in response to a general question such 
 
All AEs will be captured on the appropriate case report form (CRF). Information to be collected 
at minimum includes event description, onset, assessment of severity, relationship to IP, and 
outcome.  
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The Investigator will record all AEs with start dates occurring any time after informed consent is 
obtained until 7 (for nonserious AEs) or 30 days (for SAEs) after the last day of study participation. 
At each study visit, the Investigator will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization. 
Any medical condition that is present at the time that the subject is screened will be considered 
baseline and not reported as an AE. However, if the subject
during the study, it will be recorded as an AE.  
8.2.1.1 Definitions 
An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
intervention. 
Investigator or Sponsor, it results in any of the following outcomes:  
 Death  
 A life-threatening AE  
 Inpatient hospitalization or prolongation of existing hospitalization  
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
 A congenital anomaly or birth defect  
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition.  
8.2.1.2 Classification of Adverse Events 
Severity of Adverse Events 
The severity of all AEs will be assessed by the Investigator and graded as follows:  
 Mild: requires minimal or no treatment and do not interfere with the subject
activities 
 Moderate: results in a low level of inconvenience or concern and may cause some 
interference with functioning 
's condition deteriorates at any time 
An AE or suspected adverse reaction 1s considered "serious" if, m the view of either the 
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 Severe: interrupts a subject
or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
 
Relationship of Adverse Events 
All AEs must have their relationship to study intervention assessed by the Investigator who 
examines and evaluates the subject based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical 
study, the IP must always be suspect. 
 Unrelated: no reasonable possibility that the administration of the IP caused the event, no 
temporal relationship between the IP and event onset, or an alternate etiology has been 
established 
 Related: is known to occur with the IP, is a reasonable possibility that the IP caused the 
AE, or there is a temporal relationship between the IP and event. Reasonable possibility 
means that there is evidence to suggest a causal relationship between the IP and the AE.  
Expectedness 
severity that has been observed; or, if an IB is not required or available, is not consistent with the 
also refers to AEs or suspected adverse reactions that are mentioned in the IB, package insert, or 
device labeling as occurring with a class of drugs (or other medical products) or as anticipated 
from the pharmacological properties or other characteristics of the IP, but are not specifically 
mentioned as occurring with the particular IP under investigation. 
The Investigator will be responsible for determining whether an AE is unexpected, i.e., if the 
nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the IP.  
8.2.1.3 Adverse Event Reporting Requirements 
According to federal regulations, an Investigator must immediately report (within 24 hours) to the 
Sponsor any SAE, whether or not considered drug related, including those listed in the protocol or 
IB, and must include an assessment of whether there is a reasonable possibility that the drug caused 
the event. Study endpoints that are SAEs (e.g., all-cause mortality) must be reported in accordance 
with the protocol unless there is evidence suggesting a causal relationship between the drug and 
the event (e.g., death from anaphylaxis). In that case, the Investigator must immediately report the 
event to the Sponsor (See 21 Code of Federal Regulations [CFR] 312.64(b)).  
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The term "severe" does not necessarily equate to "serious." 
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Investigator's Brochure (1B), package insert, or device labeling or is not listed at the specificity or 
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According to federal regulations, the Sponsor must notify the US Food and Drug Administration 
(FDA) and all participating Investigators as soon as possible, but in no case later than 15 calendar 
days after the Sponsor determines that a potential serious risk arising from a clinical study qualifies 
for reporting. The Sponsor must report any suspected adverse reaction that is both serious and 
unexpected. The Sponsor must report an AE as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse event (See 21 CFR 
312.32(c)(1)). 
Furthermore, the Sponsor must also notify FDA of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible but in no case later than 7 calendar days after the 
Sponsor's initial receipt of the information (See 21 CFR 312.32(c)(2)).  
8.2.1.4 Other Events of Interest 
Not applicable. 
8.2.1.5 Pregnancy 
All pregnancies are to be reported from the time informed consent is signed through Visit 6. 
Any report of pregnancy for any female study subject must be reported within 24 hours to the 
female subject must be withdrawn from the study. 
Every effort will be made to gather information regarding the pregnancy outcome and condition 
of the infant. It is the responsibility of the Investigator to obtain this information within 30 calendar 
days after the initial notification and approximately 30 calendar days after delivery. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality are 
Adverse Event Form. Note: An elective abortion is not considered an SAE. 
In addition to the above, if the Investigator determines that the pregnancy meets serious criteria, it 
 
8.2.2  
Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at the time points indicated on the 
Schedule of Procedures and Assessments (Appendix 1) and as detailed below and in the laboratory 
reference manual. 
 Chemistry 
Sponsor's Safety Department or its delegate using the Pregnancy Report Form. The pregnant 
considered SAEs and must be reported to the Sponsor's Safety Department using the Serious 
must be reported as an SAE to the Sponsor's Safety Department. 
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o Sodium, Potassium, BUN, Creatinine, Glucose, Calcium, Phosphorus, Total 
Protein, Albumin, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total 
Bilirubin, Chloride, Bicarbonate 
 Hematology 
o Hemoglobin, Hematocrit, RBC, MCH, MCHC, RDW, WBC, Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils, Platelets 
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9. 
Statistical Considerations 
Continuous measures will be summarized descriptively by the mean, standard deviation, median, 
minimum, and maximum values. Categorical measures will be summarized by the frequency and 
percentage of subjects.  
A separate Statistical Analysis Plan (SAP) will be prepared prior to unmasking of study data. 
9.1 
Statistical Hypothesis 
It is hypothesized that SY-201 Ophthalmic Solution will be safe and improve DED signs and 
symptoms in subjects with a documented diagnosis of DED. In particular, efficacy will be assessed 
using the following endpoints at Day 60: 
 Mean CFB in tCFS (mNEI scale) 
To control for type I error, comparisons will be made within each active dose level of SY-201 
Ophthalmic Solution compared to vehicle. In other words, the primary endpoints will be compared 
sequentially between SY-201 Ophthalmic Solution 2.0% and vehicle, first testing tCFS and, if 
statistically significant, then 
 Should both endpoints achieve statistical 
significance for the 2.0% dose, testing will proceed to SY-201 O hthalmic Solution 1.0% versus 
vehicle, first testing tCFS and, if statistically significant, then
. Should both 
endpoints achieve statistical significance for the 1.0% dose, testing will proceed to SY-201 
Ophthalmic Solution 0.5% and vehicle, first testing tCFS and, if statistically significant, then 
In other words, the first non-significant result in this testing hierarchy of six 
hypotheses will imply that subsequent tests are non-significant. 
9.2 
Sample Size Determination  
For mean change from baseline to Day 60 in tCFS, a sample size of 45 SY-201 treated subjects 
versus 45 vehicle-treated subjects will have 87.9% power to detect an effect size of 2.0 units with 
a standard deviation of 3.0 for an unpaired t-test with a 2-sided alpha = 0.05. 
For mean change from baseline to Day 60 in dry eye symptom
, a sample size of 45 SY-201
treated subjects versus 45 vehicle-treated subjects will have 83.5% power to detect an effect size 
of 1.5 units with a standard deviation of 2.4 for an unpaired t-test with a 2-sided alpha = 0.05.
Fifty (50) subjects per treatment arm, for a total 200 subjects, will be enrolled to allow for some 
dropout of subjects. 
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9.3 
Analysis Populations 
The Full Analysis Set (FAS) consists of all subjects
Subjects will be 
analyzed in the group to which
 This set will be used for the analysis of all 
efficacy endpoints as the primary analysis. 
The Per Protocol (PP) Analysis Set will include all subjects who completed study-required 
treatment and who followed the protocol without significant deviations. The determination of 
significant protocol violations will be made prior to locking the final database and unmasking. 
Subjects will be analyzed in the group according to the treatment received. 
The Safety Analysis Set will include all subjects who took at least one dose of investigational 
product as indicated on the dosing record. Subjects will be analyzed in the group according to the 
treatment received. All safety variables will be analyzed using the Safety Analysis Set and only 
observed data will be included (i.e., missing data will remain missing for the safety analysis).
9.4 
Statistical Analyses 
The statistical analysis of the study will be performed on the data through Day 60, after all subjects 
have either completed the Day 60 visit or discontinued early from the study and after the study 
database has been cleaned, verified, and locked. It is planned that the data from all clinical sites 
that participate in this study will be combined so that the target sample size will be available for 
analysis. 
Analyses will be conducted on individual SY-201 arms versus vehicle arm. 
9.4.1  
Baseline Descriptive Analyses 
Demographic characteristics including age (years), sex, race, and ethnicity will be summarized by 
treatment group and overall. Medical history [coded using the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA)], and prior and concomitant medications (coded 
using the most recent version of the WHODrug) will be summarized by treatment and overall.
The numbers of subjects who were enrolled and completed each visit of the study will be provided, 
as well as the reasons for all enrollment discontinuations, grouped by major reason (e.g., lost to 
follow-up, adverse event, poor compliance, rescue due to lack of efficacy). A list of discontinued 
subjects, protocol deviations, and subjects excluded from the analysis sets will be provided as well.
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9.4.2  
Efficacy Analyses 
In general, efficacy analyses will be performed using the FAS and the observed data at each visit 
for the study eye and qualifying non-study eyes for most ocular measures or overall for subject-
level measurements. In the case of the biomarker test (MMP-9), analysis will be for the study eye
only. Analysis of mean CFB in tCFS and eye dryness score will also be performed using the PP 
Analysis Set as documented in the SAP. 
9.4.2.1 Primary Efficacy Analyses 
Primary Estimands: The primary estimands are the treatment differences between SY-201
Ophthalmic Solution arms and vehicle for mean CFB to Day 60 in tCFS using study eyes and 
mean CFB to Day 60 in eye
score using the FAS. 
Target Population: Subjects with DED who meet the study entry criteria. 
Treatment Condition(s): Treatment condition is based on the randomized treatment group. 
Population-level Summaries: The difference in the mean CFB to Day 60 in tCFS using study 
eyes and the difference in mean CFB to Day 60 in eye
 score and their p-values and 
corresponding 95% confidence intervals. 
The proposed procedures to handle missing data and intercurrent events are as follows: 
 Discontinuation of study therapy with continued participation in the study 
o Treatment Policy  no imputation; use observed data 
 Receipt of rescue therapy 
o Treatment Policy  no imputation; use observed data 
 Missing data with or without withdrawal, regardless of reason 
o Hypothetical approach  missing data will be accounted for assuming missing at 
random (MAR) using mixed-model repeated measures (MMRM). 
Mean CFB in tCFS will be analyzed using an MMRM model. The model will include the baseline 
measurement, treatment, time, and treatment by time interaction as fixed effects, with a random 
effect for site. An unstructured covariance among repeated measurements is assumed. A similar 
model for the subject-level mean CFB in eye
score will be used. 
Additional sensitivity analyses will be described in the SAP. 
9.4.2.2 Secondary Efficacy Analyses 
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9.4.3  
Safety Analyses 
Safety analyses will be performed on all subjects in the Safety Analysis Set. The assessment of 
safety will be based on the summary of ocular and non-ocular AEs, laboratory measurements, 
BCVA, IOP, ophthalmic exams using slit lamp biomicroscopy and dilated ophthalmoscopy, and 
drop comfort assessment. Summaries will be provided by treatment group, and for ocular 
assessments separately by eye. 
9.4.3.1 Adverse Events 
AEs will be coded using MedDRA (most current version) and categorized by system organ class 
using preferred terms. Separate summaries of AEs related to treatment (as reported by the 
Investigator) and by severity will be presented. The number of deaths and SAEs will also be 
presented, and events leading to discontinuation from the study will be listed and tabulated. 
9.4.3.2 Clinical Laboratory Tests 
Summary statistics for observed and CFB for serum chemistry and hematology laboratory tests 
will be presented. 
9.4.3.3 Other Safety Evaluations 
Summary statistics for observed and CFB for BCVA, IOP, and drop comfort assessment will be 
presented. Abnormalities in slit lamp biomicroscopy and dilated ophthalmoscopy will be 
summarized by frequency and percentage. 
9.5 
Interim Analysis 
Not applicable. 
9.6 
Subgroup Analyses 
Subgroup analyses will include testing of the mean CFB in tCFS, eye
score, and secondary 
endpoints in subgroups based on MMP-9 level in the stud  e e at baseline (Visit 2): subjects with 
elevated MMP-9 level and 
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Additional subgroup analyses will be described in the SAP. 
9.7 
Exploratory Analyses 
Not applicable. 
9.8 
Missing or Unused Data 
Missing data for primary endpoints will be considered MAR with the analysis using MMRM. 
Otherwise, observed data will be analyzed. All data collected in this study will be presented in 
individual subject data listings for all subjects at each visit. 
9.9 
Tabulation of Individual Participant Data 
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10. 
Supporting Documentation and Operational Considerations 
10.1 
Regulatory Issues, Ethical Concerns, and Study Oversight 
10.1.1  
Informed Consent Process 
10.1.1.1 
Consent Documents 
Consent forms describing in detail the study intervention, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to any procedures 
being done specifically for the study.  
10.1.1.2 
Consent Procedures and Documentation 
Institutional Review Board (IRB) approved and the participant will be asked to read and review 
the document. The Investigator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suite
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. The participant will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. The participant should have the opportunity to 
discuss the study with his/her family or surrogates or think about it prior to agreeing to participate. 
The participant will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants must be informed that participation is voluntary and that 
they may withdraw from the study at any time, without prejudice. A copy of the signed and dated 
informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the date), 
and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study.  
10.1.2  
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
Investigators, funding agency, the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) Sponsor, and regulatory authorities as applicable. If the study is prematurely 
terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, 
the IRB, and the Sponsor and will provide the reason(s) for the termination or suspension. Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule.  
Informed consent is a process that is initiated prior to the individual's agreeing to participate in the 
study and continues throughout the individual's study participation. Consent forms will be 
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Circumstances that may warrant termination or suspension may include, but are not limited to:
 Determination of unexpected, significant, or unacceptable risk to participants 
 Demonstration of efficacy that would warrant stopping 
 Insufficient compliance to protocol requirements 
 Data that are not sufficiently complete and/or evaluable 
 Determination that the primary endpoint has been met 
 Determination of futility  
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB, and/or FDA.  
10.1.3  
Confidentiality and Privacy 
Participant confidentiality and privacy will be strictly held in trust by the participating 
Investigators, their staff, and the Sponsor(s) and their interventions. This confidentiality will be 
extended to cover testing of laboratory samples in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the Sponsor.  
All research activities will be conducted in as private a setting as possible.  
The Study Monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product will be able to inspect 
all documents and records required to be maintained by the Investigator, including but not limited 
to medical records (i.e., office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records.  
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use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or Sponsor 
requirements.  
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Lexitas Pharma Services, Inc. This will not include the 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and by Lexitas Pharma Services, Inc., research staff 
will be secured and password protected. At the end of the study, all study databases will be de-
identified and archived at Lexitas Pharma Services, Inc.  
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• 
• 
• 
• 
• 
The study participant's contact information will be securely stored at each clinical site for inter 
participant's contact or identifying information. Rather, individual participants and their research 


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10.1.4  
Clinical Monitoring 
Lexitas Pharma Services, Inc., will conduct the clinical monitoring for this study. A Clinical 
Monitoring Plan (CMP) is to be used, which will describe in detail who will conduct the 
monitoring, at what frequency monitoring will be done, at what level of detail monitoring will be 
performed, and the distribution of monitoring reports.  
10.1.5  
Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion. An individualized quality management plan 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.  
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
(ICH) Good Clinical Practice (GCP), and applicable regulatory requirements (e.g., Good 
Laboratory Practice [GLP], Good Manufacturing Practice [GMP]).  
The investigational site will provide direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the Sponsor, and inspection by local and 
regulatory authorities.  
10.1.6  
Data Handling and Record Keeping 
10.1.6.1 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
Copies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study. Data recorded in the eCRF derived from 
source documents should be consistent with the data recorded on the source documents.  
will be developed to describe a site's quality management. 
site's Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 


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Clinical data (including AEs, CMs, and expected adverse reactions data) and clinical laboratory 
data will be entered into IBM Clinical, a 21 CFR Part 11-compliant data capture system provided 
by Lexitas Pharma Services, Inc. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents.  
10.1.6.2 
Study Records Retention 
Subject files and other source data must be kept for the maximum period of time permitted by the 
hospital, institution, or private practice, but not less than 25 years, to meet international registration 
requirements. These documents should be retained for a longer period, however, if required by 
local regulations. No records will be destroyed without the written consent of the Sponsor, if 
applicable. It is the responsibility of the Sponsor to inform the Investigator when these documents 
no longer need to be retained.  
10.1.7  
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Manual 
of Procedures (MOP) requirements. The noncompliance may be on the part of the participant, the 
Investigator, or the study site staff. As a result of major deviations, corrective actions are to be 
developed by the site and implemented promptly. Details concerning minor, major, and critical 
protocol deviations will be outlined in a CMP or MOP. 
deviations. All deviations must be addressed in study source documents, reported to the IRB and 
Lexitas Pharma Services, Inc., and/or Sponsor. Protocol deviations must be sent to the reviewing 
IRB per their policies. The site Investigator is responsible for knowing and adhering to the 
reviewing IRB requirements. Further details about the handling of protocol deviations will be 
included in the MOP.  
10.1.8  
Publication and Data Sharing Policy 
All information provided concerning the drug and clinical trial is confidential and belongs to the 
Sponsor. The Investigator may use this information only in relation to the trial. He/she will also 
be obliged to provide the Sponsor with all data generated in the study. 
All results, data, and information developed, generated, and derived from this clinical trial, 
including any inventions, processes, or improvements that may arise from conducting the clinical 
trial, shall be the sole property of the Sponsor and, therefore, the Investigator agrees to treat this 
information as confidential and secret as mentioned above. The Investigator agrees not to disclose 
the information in any way without the prior written consent of the Sponsor. 
It is the responsibility of the site's Investigator to use continuous vigilance to identify and report 


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The Sponsor and Investigators agree to the publication and wide dissemination of the results of 
this study. This study constitutes a joint effort between the Sponsor and the Investigators and, as 
such, both parties agree that either party can make recommendations on articles or texts which 
shall be considered in preparing final scientific documents for publication or presentation. All 
publications and presentations proposed by the Investigators or their staff and associates that are 
derived or are related to this study must be sent to the Sponsor for review 90 days before 
submission for publication or presentation. 
If the proposed publication or presentation contains patentable aspects that, at the discretion of the 
Sponsor alone, justify the protection of intellectual or industrial property, the Sponsor may delay 
any publication or presentation for a maximum of 90 days in order to request such protection.
In accordance with national and local regulations, this study protocol shall be presented in a clinical 
trial register for public access and shall receive a unique identification number. In addition, the 
results of this clinical study shall be revealed in an accessible clinical trial results database, 
regardless of the outcome. 
  
 


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11. 
References 


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12. 
Appendices 
 
 
 


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 12.1 Appendix 1:   Schedule of Procedures and Assessments 
aMMP-9 will be assessed OU at Visits 1 and 2 and SE thereafter.  
bWait at least 15 minutes after grading CFS before conducting
 
Abbreviations: AE = adverse event; AT = artificial tears; BCVA = best corrected visual acuity;
 CFS = corneal fluorescein staining; ET = early termination  IOP = intraocular ressure  IP = investi ational 
product; MMP-9 = matrix metalloproteinase-9; POC: point-of-care;
SE = study eye; UPT = urine pregnancy test; WOCBP = women of childbearing potential
 
 
Study Period 
Screening 
Treatment Period 
End of 
Study/ET
Visit No. 
1 
2 
3 
4 
5 
6 
Study Day 
-14 
1 
7 
14 
28 
60
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Demographics/medical history 
X 
 
 
 
 
 
Concomitant medications query 
X 
X 
X 
X 
X 
X 
AE query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UPT for WOCBP 
X 
 
 
 
 
X 
Serum chemistry and hematology 
X 
 
 
 
 
X 
BCVA 
X 
X 
X 
X 
X 
X 
Biomicroscopy and external eye 
exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tear collection for biomarker test 
(POC MMP-9)a 
X 
X 
X 
X 
X 
X 
CFS 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
IOP 
X 
X 
X 
X 
X 
X 
Dilated ophthalmoscopy 
X 
 
 
 
 
X 
In-clinic administration of run-in 
product or IP  
X 
X 
 
 
 
X 
Drop comfort assessment 
 
X 
 
 
 
X 
Dispense run-in product or IP for 
home administration 
X 
X 
X 
X 
X 
 
Dispense preservative-free AT 
 
X 
X 
X 
X 
 
Issue and/or collect AT diary 
 
X 
X 
X 
X 
X 
Collect used and unused run-in 
product, AT, and/or IP 
 
X 
X 
X 
X 
X 


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12.2 
Appendix 2:   Abbreviations and Definition of Terms 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase test, serum glutamic pyruvic 
transaminase 
AST (SGOT) 
Aspartate aminotransferase test, serum glutamic-oxaloacetic 
transaminase 
AT 
Artificial tears 
BCVA 
Best corrected visual acuity 
BFS 
Blow-fill-seal 
BID 
Bis in die (twice daily) 
BUN 
Blood urea nitrogen 
CFB 
Change from baseline 
CFR 
Code of Federal Regulations  
CFS 
Corneal fluorescein staining 
CMs 
Concomitant medications 
CMP 
Clinical monitoring plan 
CRF 
Case report form 
CS 
Clinically significant 
DED 
Dry eye disease 
DMFC 
Disposable micro-capillary fluid collector  
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ET 
Early termination 


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ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
 
ICH 
International Council for Harmonisation 
IDE 
Investigational Device Exemption 
IL 
Interleukin 
IND 
Investigational New Drug 
IOP 
Intraocular pressure 
IP 
Investigational product 
IPL 
Intense pulsed light 
IRB 
Institutional Review Board 
IUD 
Intra-uterine device 
IWRS 
Interactive Web Randomization System 
LogMAR 
Logarithm of the minimum angle of resolution 
M1 
Classically activated macrophages 
M2 
Alternatively activated macrophages 
Investigator's Brochure 


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MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP-9 
Matrix metalloproteinase-9 
MMPs 
Matrix metalloproteinases 
MMRM 
Mixed-model repeated measures 
mNEI 
Modified National Eye Institute (scale) 
MOP 
Manual of Procedures 
NCS 
Non-clinically significant 
NEI 
National Eye Institute 
NIH 
National Institutes of Health 
OSDI 
Ocular Surface Disease Index 
OU 
Oculus uterque (both eyes) 
PI 
Principal Investigator 
POC 
Point-of-care 
PP 
Per Protocol 
PRN 
Pro re nata (as needed) 
QC 
Quality control 
RBC 
Red blood cell count 
RDW 
Red cell distribution width 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 


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SE 
Study eye 
SOP 
Standard Operating Procedure 
TBUT 
Tear film break-up time 
tCFS 
Total corneal fluorescein staining 
TNTC 
Too numerous to count 
Treg 
Regulatory T cell 
UPT 
Urine pregnancy test 
US 
United States 
VA 
Visual acuity 
WBC 
White blood cell count 
WHODrug 
World Health Organization Drug Dictionary  
WOCBP 
Women of childbearing potential 
w/v 
Weight by volume 


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12.3 
Appendix 3:   Corneal Fluorescein Staining (CFS), Modified NEI Scale 
The Investigator should use sufficient unpreserved saline solution (study stock) to wet the entire 
area of fluorescein impregnation on a 1.0 mg strip. If the strip becomes too saturated, discard and 
begin again with a new strip. Within 15 seconds of wetting the strip, taking care not to touch the 
strip to the eye, instill the fluorescein sodium in the inferior cul-de-sac. Instruct the subject to blink 
several times to distribute the fluorescein staining. 
The Investigator should wait approximately 2 minutes after instillation of fluorescein before 
evaluating staining. A Wratten #12 yellow filter will be used to enhance the ability to grade 
fluorescein staining.  
The cornea is divided into 5 sectors (central, superior, inferior, nasal, and temporal), each of which 
is scored on a scale of 0 4 in increasing increments of 0.5. Grade each of the 5 sectors of the cornea 
(central, superior, inferior, nasal, and temporal) in each eye. Total score (0-20) is obtained by 
summing the 5 sections of the cornea.  
 
The grading results for each area, as well as the total score obtained from the scoring of the cornea, 
are to be recorded in the eCRF. Whenever possible, the same Investigator should perform the 
grading per subject.  
 
Section 1 = Central, 2 = Superior, 3= Temporal, 4 = Nasal, 5= Inferior 
 
OD: Oculus dexter (right eye)  
OS: Oculus sinister (left eye)  
 
 
 
 
 
Grade 
Punctate Stain Spots
0 
0 spots 
0.5 
1-7 spots 
1.0 
8-15 spots 
1.5 
16-22 spots 
2.0 
23-30 spots 
2.5 
31-37 spots 
3.0 
to count (TNTC), must be 
<½ area, may be confluent 
but not coalescent 
3.5 
>½ area, may be confluent 
but not coalescent 
4.0 
must 
have coalescent area 
2:3 8 spots or too numerous 
OD 
OS 
2:3 8 spots or TNTC, must be 
2:3 8 spots or TNTC, 


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12.4 
Appendix 4:  
 
 


Sei n da P har mace utical G ua n gz h o u C or p.  
 
S Y- 2 0 1 O p ht hal mic S ol uti o n
Cli nical Trial Pr ot oc ol
C o nfi de nti al  
 
Pa ge 6 7 of 7 9
Versi o n 1. 2 _ 1 3 A pr 2 0 2 2 
1 2 .5  
A p p en d ix  5 :  


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12.6 
Appendix 6:   Bulbar Conjunctival Hyperemia 
Investigators will rate overall bulbar conjunctival hyperemia using the CCLRU grading scale. A 
score of 0 will be given if there is no bulbar redness. 
 
 
 
 
CCLRU @ GRADING SCALES 
Corneo ond Contoct Lens Research Unit, School of Optometry, University of New South Woles 
BULBAR 
REDNESS 


Sei n da P har mace utical G ua n gz h o u C or p.  
 
S Y- 2 0 1 O p ht hal mic S ol uti o n
Cli nical Trial Pr ot oc ol
C o nfi de nti al  
 
Pa ge 6 9 of 7 9
Versi o n 1. 2 _ 1 3 A pr 2 0 2 2 
1 2. 7 
A p p e n di x 7:   Bi o m ar ker T est ( M M P- 9) 
T he M M P- 9 p oi nt- of-care kit is m a n ufact ure d b y Sei n da Bi o me dical C or p. ( G ua n gz h o u, C hi na) 
a n d c o ntai ns a dis p osa ble micr o-ca pillar y fl ui d c oll ect or ( D M F C), M M P- 9 test car d, dr o p per 
b ottle of reacti o n b uffer, a n d i-I m m u n D x
 A nal y zer. M M P- 9 is t o be c oll ecte d O U at Visits 1 
a n d 2 a n d o nl y S E t hereafter. 
C oll ect n o n-sti m ulate d tear fl ui d fr o m t he o uter c or ner of t h e e ye at t he lateral ca nt h us usi n g t he 
D M F C, wit h a slit la m p.  
W he n tear fl ui d fills t h e micr oca pill ar y ti p of t he D M F C, st o p c oll ecti n g a n d dis pe nse tear fl ui d 
i n t h e sa m ple h ole of t he pr o vi de d M M P- 9 test car d. A p pl y 3 dr o ps of reacti o n b uffer. W ait 1 5 
mi n utes, t h e n i nsert t he test car d i nt o t he i-I m m u n D x
 A nal y zer a n d o bt ai n a q ua ntitati ve res ult.
T M 
T M 


Sei n da P har mace utical G ua n gz h o u C or p.
S Y- 2 0 1 O p ht hal mic S ol uti o n
Cli nical Trial Pr ot oc ol
C o nfi de nti al
Pa ge 7 0 of 7 9
Versi o n 1. 2 _ 1 3 A pr 2 0 2 2


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12.8 
Appendix 8:   Unanesthetized Schirmer Test 
The Schirmer test will be conducted on unanesthetized eyes. A 35 mm x 5 mm filter paper strip is 
used to measure the amount of tears produced over 5 minutes. The strip is placed in the lower 
eyelid margin of both eyes. After 5 minutes, the strip is removed and the amount of wetting is 
measured in millimeters. 
Unanesthetized Schirmer test must be performed at least 15 minutes after fluorescein application 
and evaluation of CFS. 
 


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12.9 
Appendix 9:   Best Corrected Visual Acuity (BCVA) 
Visual acuity (VA) testing should precede any examination requiring contact with the eye or 
instillation of study dyes, as is detailed in the order of assessments for each visit in Section 7.1. 
LogMAR visual acuity must be assessed using an ETDRS or modified ETDRS chart. VA testing 
lenses (spectacles only) 
or pinhole refraction. 
either reflectance or retro-illuminated), the subject must view the chart from a distance of exactly 
4 meters (13.1 f
subject viewing distance should be exactly 10 feet. Reflectance wall charts should be frontally 
illuminated (60-watt bulb or a well-lit room). 
The subject should be positioned according to the elevation of the chart (either seated or standing) 
so that the chart is at a comfortable viewing angle. The right eye should be tested first. The subject 
should attempt to read each letter, line-by-line, left to right, beginning with line 1 at the top of the 
chart. The subject should be told that the chart has letters only, no numbers. If the subject reads a 
number, he or she should be reminded that the chart contains no numbers, and the examiner should 
then request a letter instead of the number. The subject should be asked to read slowly, about 1 
letter per second, to achieve the best identification of each letter. He/she is not to proceed to the 
next letter until he/she has given a definite response. If the subject changes a response before he 
has read aloud the next letter, then the change must be accepted. 
Maximum effort should be made to identify each letter on the chart; the subject should be 
encouraged to guess. When it becomes evident that no further meaningful readings can be made, 
the examiner should stop the test. The number of letters missed or read incorrectly should be noted.
In order to provide standardized and well-controlled assessments of visual acuity during the study, 
the same lighting conditions must be used consistently throughout the study  
Calculations: LogMAR VA = Baseline value + (n X 0.02)  
where:  the baseline value is the LogMAR number of the last line read (at least 1 letter read 
ncluding the last line 
 
 
 
should be performed with best correction using subject's own corrective 
An ETDRS or modified ETDRS chart may be used. If a Lighthouse chart is used (24.5" by 25"; 
eet). If smaller reproductions (18" by 18", e.g., Prevent Blindness) are used, the 
correctly in this line), and "n" is the total number of letters missed up to and i 
read, and "0.02" is the value for each letter. 


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12.10 Appendix 10:   
Slit Lamp Biomicroscopy 
The biomicroscopy exam should be performed with the slit lamp using a beam width and intensity 
that provide optimal evaluation of the anterior segment. 
This procedure will be the performed in the same manner for all subjects observed at the 
and the Investigator will evaluate the abnormal or present findings as non-clinically significant 
(NCS) or clinically significant (CS). CS and NCS abnormal findings will be recorded in the source 
documentation. However, only CS abnormal descriptions will be captured in the eCRF.  
Anterior Chamber Cells  
0 = No cells seen  
1 = 1-5 cells  
2 = 6-15 cells  
3 = 16-30 cells  
4 = > 30 cells 
Anterior Chamber 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) 
Eyelid 
 
Eyelid Hyperemia 
 
Eyelid Edema 
0 = None  
1 = Mild  
2 = Moderate 
3 = Severe  
Conjunctiva 
 
Edema (Chemosis) 
 
Conjunctival Discharge/Exudate 
0 = None  
1 = Mild  
2 = Moderate 
3 = Severe 
Corneal Edema 
0 = None  
1 = Mild  
2 = Moderate 
3 = Severe 
Corneal Endothelium 
0 = Normal  
1= Abnormal (pigment, keratoprecipitates, guttata) 
Iris 
0 = Normal 
1 = Abnormal 
Pupil 
0 = Normal 
1 = Abnormal 
Lashes 
0 = Normal 
1 = Abnormal 
Lens 
0 = Normal 
1 = Abnormal 
Investigator's site. The site will record all abnormal or present findings in the source document 
• 
• 
• 
• 


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12.11 Appendix 11:   
Intraocular Pressure (IOP) 
Intraocular pressure must be measured (mmHg) by Goldmann Applanation tonometry with every 
effort to ensure the same examiner using the same tonometer for all visits. 


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12.12 Appendix 12:   
Dilated Ophthalmoscopy 
This procedure will occur after instillation of dilating drops and upon Investigator confirmation 
that both eyes are fully dilated (recommended time of 20 minutes). As dilating drops will be 
instilled, dilated ophthalmoscopy must be performed after Pinhole Distance VA, IOP, and 
assessments of corneal staining and healing. Dilated ophthalmoscopy will include assessment of 
the vitreous, retina, macula, choroid, optic nerve, and vertical optic nerve cup-to-disc ratio. After 
the ophthalmoscopy procedure, the Investigator will determine if findings are within normal limits 
or are abnormal. For abnormal findings at screening, the Investigator will determine whether the 
abnormality would exclude the subject from study participation. All abnormalities should be noted 
in the source and clinically significant or non-clinically significant should be marked.  
 
  
 
 
 
 
 
 


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12.13 Appendix 13:   
Drop Comfort Assessment 
At Visits 2 and 6, ask the subject to rate the comfort of the drop for both eyes as one score at 1 
minute and 5 minutes post-dose. 
 
COMFORT/TOLERABILITY OF INVESTIGATIONAL PRODUCT 
Overall Comfort of Investigational Product:  0=Comfortable and 10=Uncomfortable 
 
0                                               5                                                  10 
|                                                                                                     | 
 
 
 
 
 


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12.14 Appendix 14:   
Investigator Agreement 
 
A Phase 2, Multi-Center, Double-Masked, Randomized, Vehicle-
Controlled, Dose-Response, Parallel-Group Study of SY-201 
Ophthalmic Solution versus Vehicle Control in Subjects with  
Dry Eye Disease 
 
 
Version No.: 1.2 
Issue Date: 13 April 2022 
 
 
I have read the clinical study protocol and understand it. I agree to conduct the study as outlined 
in this document and in accordance with Good Clinical Practice Guidelines, all local and federal 
requirements and regulations, and in compliance with those precepts set forth in the Declaration 
of Helsinki with respect to the use of human subjects in clinical studies and investigations.   
Further, I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.  
 
 
Signature of Investigator: 
 


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12.15  Appendix 15: 
Compliance Statement 
 
The study will be conducted in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP), with the United States (US) Code of Federal Regulations (CFR) 
applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, 
and/or 21 CFR Part 812), and as stipulated in the Declaration of Helsinki (2013) with respect to 
the use of human subjects in clinical studies and investigations. 
 
The Principal Investigator (PI) will assure that no deviation from, or changes to the protocol will 
take place without prior agreement from the Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) Sponsor, funding agency and documented approval from the Institutional 
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the study 
participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding whether 
a new consent needs to be obtained from participants who provided consent, using a previously  
a    roved consent form. 


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SAP_001.pdf: 
NCT05370495
Clinical Study SY201-CS201
Statistical Analysis Plan
28 November 2023


Seinda 
 
    SY201-CS201 
Statistical Analysis Plan 
 
 
 
Confidential 
 
Page 1 of 38 
Final Version 2.0 2023-11-28 
 
Statistical Analysis Plan for A Phase 2, Multi-Center, Double-Masked, 
Randomized, Vehicle-Controlled, Dose-Response, Parallel-Group Study 
of SY-201 Ophthalmic Solution versus Vehicle Control in Subjects with 
Dry Eye Disease 
 
 
 
Protocol No: 
SY201-CS201 
Protocol Date: 
2022-04-13 (Version 1.2) 
Sponsor:  
Seinda Pharmaceutical Guangzhou Corp. 
C401, No. 9 Luoxuan 4th Road 
Guangzhou International Bio-island 
Guangzhou, Guangdong, China, 510300 
  
SAP Version: 
 
SAP Date: 
 
 
 
 
 
 
2.0
2023-11-28 (Final)
Confidentiality Statement  
This document contains information from Seinda and is of confidential, trade secret, and/or proprietary nature and may not be 
disclosed unless such disclosure is required by federal or state law or regulation. It is loaned to you for your confidential review on 
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Statistical Analysis Plan 
 
 
SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
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TABLE OF CONTENTS 
LIST OF TABLES .......................................................................................................................... 5 
LIST OF FIGURES ........................................................................................................................ 6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................. 7 
PROTOCOL SYNOPSIS ............................................................................................................. 10 
9.5. 
Efficacy and Safety Variables ............................................................................................ 17 
9.5.1. 
Efficacy and Safety Measurements Assessed and Flow Chart ................................... 17 
9.5.1.1. 
Visit and Procedure Schedule ............................................................................. 17 
9.5.1.2. 
Demographics and Baseline Characteristics ....................................................... 17 
9.5.1.3. 
Efficacy Assessments .......................................................................................... 18 
9.5.1.4. 
Safety Assessments ............................................................................................. 19 
9.5.2. 
Appropriateness of Measurements ............................................................................. 21 
9.5.3. 
Primary Efficacy Variable(s) ...................................................................................... 21 
9.5.4. 
Drug Concentration Measurements ............................................................................ 21 
9.6. 
Data Quality Assurance ..................................................................................................... 22 
9.6.1. 
Training and Education of Investigators and Study Site Personnel ........................... 22 
9.6.2. 
Monitoring of Study Sites........................................................................................... 22 
9.6.3. 
Data Entry and Verification of Database Used for Analysis and Reporting .............. 22 
9.6.4. 
Clinical Study Report ................................................................................................. 23 
9.6.5. 
Inter-Laboratory Standardization Methods ................................................................ 23 
9.7. 
Statistical Methods Planned in the Protocol and Determination of Sample Size .............. 24 
9.7.1. 
Statistical and Analytical Plans .................................................................................. 24 
9.7.1.1. 
Analysis Populations ........................................................................................... 26 
9.7.1.2. 
Analysis of Subject Disposition .......................................................................... 27 
9.7.1.3. 
Analysis of Demographic and Baseline Characteristics ..................................... 27 
9.7.1.4. 
Analysis of Study Medication Compliance and Exposure .................................. 28 
9.7.1.5. 
Analysis of Efficacy ............................................................................................ 29 
9.7.1.6. 
Analysis of Safety ............................................................................................... 32 
9.7.2. 
Determination of Sample Size .................................................................................... 35 
9.8. 
Changes in the Conduct of the Study or Planned Analyses ............................................... 36 
9.8.1. 
Protocol Amendments ................................................................................................ 36 


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9.8.2. 
Changes from Protocol-Specified Analyses ............................................................... 36 
9.8.3. 
SAP Amendments....................................................................................................... 36 
REFERENCES ............................................................................................................................. 37 
APPENDIX I: SCHEDULE OF ASSESSMENTS ...................................................................... 38 
 
 


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LIST OF TABLES 
Table 1: Schedule of Assessments ................................................................................................ 38 
 
 
 
 


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LIST OF FIGURES 
Figure 1: Study Schematic ............................................................................................................ 17 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase test, serum glutamic pyruvic transaminase 
AST (SGOT) 
Aspartate aminotransferase test, serum glutamic-oxaloacetic transaminase 
AT 
Artificial tears 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice daily 
BOCF 
Baseline observation carried forward 
BUN 
Blood urea nitrogen 
CCLRU 
Cornea and Contact Lens Research Unit 
CFB 
Change from baseline 
CFR 
Code of Federal Regulations  
CFS 
Corneal fluorescein staining 
CMP 
Clinical Monitoring Plan 
CMs 
Concomitant medications 
CRF 
Case report form 
CS 
Clinically significant 
DED 
Dry eye disease 
eCRF 
Electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
ICH 
International Conference on Harmonisation  
IOP 
Intraocular Pressure 
IP 
Investigational product 


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IPL 
Intense pulsed light 
IRB 
Institutional Review Board 
IUD 
Intra-uterine device 
LOCF 
Last observation carried forward 
LogMAR 
Logarithm of the Minimum Angle of Refraction 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP-9 
Matrix metalloproteinase-9 
MMRM 
Mixed-model repeated measures 
mNEI 
Modified National Eye Institute (scale) 
NCS 
Non-clinically significant 
NEI 
National Eye Institute 
OU 
Oculus uterque (both eyes) 
POC 
Point-of-care 
PP 
Per Protocol 
PT 
Preferred term 
QC 
Quality control 
RBC 
Red blood cell count 
RDW 
Red cell distribution width 
SAE 
Serious adverse event 
SD 
Standard deviation 
SE 
Study eye 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
TBUT 
Tear film break-up time 


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tCFS 
Total corneal fluorescein staining 
TEAE 
Treatment emergent adverse event 
UPT 
Urine pregnancy test 
WBC 
White blood cell count 
WOCBP 
Women of childbearing potential 
WHODrug 
World Health Organization Drug Dictionary 
 
 
 


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PROTOCOL SYNOPSIS 
 
Title: 
A Phase 2, Multi-Center, Double-Masked, Randomized, Vehicle-Controlled, 
Dose-Response, Parallel-Group Study of SY-201 Ophthalmic Solution versus 
Vehicle Control in Subjects with Dry Eye Disease 
Phase: 
2 
Design/Conduct: 
This is a phase 2, multi-center, double-masked, randomized, vehicle-
controlled, dose-response, parallel-group study designed to evaluate the ocular 
and systemic safety and ocular efficacy of SY-201 Ophthalmic Solution over a 
60-day treatment period in subjects with moderate to severe DED.  
During the 14-day single-masked run-in period, approximately 200 subjects 
will instill vehicle as 1 drop in both eyes (OU) twice a day (BID). At Visit 2, 
subjects will be randomized in a 1:1:1:1 ratio to 4 treatment groups: Vehicle 
(n=50) and SY-201 Ophthalmic Solution 2.0% (n=50), 1.0% (n=50), and 0.5% 
(n=50). Double-masked IP will be instilled as 1 drop OU BID for 60 days. 
The study will consist of 6 clinic visits: Visit 1 (-14 Days, Screening), Visit 2 
(Day 1, Randomization), Visit 3 (Day 7 ± 2 days), Visit 4 (Day 14 ± 2 days), 
Visit 5 (Day 28 ± 2 days), and Visit 6 (Day 60 ± 3 days, End of Study/Early 
Termination). 
Objectives: 
The primary objective is to assess the ocular safety and efficacy of SY-201 
Ophthalmic Solution in subjects with DED.  
The secondary objective is to assess the systemic safety of SY-201 Ophthalmic 
Solution in subjects with DED. 
Endpoints: 
Primary Efficacy Endpoints 
Two primary ocular efficacy endpoints (one sign and one symptom) will be 
tested sequentially: 
• 
Mean change from baseline (CFB) in total corneal fluorescein staining 
(tCFS; modified National Eye Institute [mNEI] scale, 0-20) 
Secondary Efficacy Endpoints 
Safety Endpoints 
The ocular and systemic safety of SY-201 Ophthalmic Solution will be 
assessed by: 
• 
Frequency and severity of ocular and non-ocular adverse events (AEs) 
• 
Serum chemistry and hematology 


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• 
Best corrected visual acuity (BCVA) 
• 
Slit lamp biomicroscopy and external eye exam 
• 
Intraocular pressure (IOP) 
• 
Dilated ophthalmoscopy 
• 
Drop comfort assessment 
Population studied: 
The study population will consist of approximately 200 adult subjects with 
moderate to severe DED.  
The study eye is defined as the eye meeting all inclusion criteria and no 
exclusion criteria, and with the highest tCFS scoring at randomization (Visit 2, 
Day 1). If both eyes meet the inclusion criteria and no exclusion criteria and 
have the same tCFS score, the right eye will be used as the SE. 
Inclusion Criteria 
Individuals will be eligible for study participation if they meet all of the 
following criteria: 
1. Provide written informed consent prior to any study-related 
procedures. 
2. Are 18 years of age or older. 
3. Are willing and able to follow instructions and can be present for the 
required study visits for the duration of the study. 
4. Have a BCVA in each eye, using corrective lenses if necessary, of 
+0.7 logarithm of the minimum angle of resolution (LogMAR) or 
better as assessed by the Early Treatment of Diabetic Retinopathy 
Study (ETDRS) at Visit 1. 
5. If women of childbearing potential (WOCBP), are non-lactating and 
have been sexually inactive (abstinent) for 14 days prior to Visit 1 and 
remain so through 30 days following Visit 6 or the last administration 
of the study drug or until completion of the subject’s first menstrual 
cycle following the last administration of the study drug, whichever 
period of time is longer. Or they must have been using one of the 
following acceptable methods of birth control for the times specified: 
a. 
Intra-uterine device (IUD) in place for at least 3 months prior to 
Visit 1 through 30 days following Visit 6 or last administration of 
study drug or until completion of the subject’s first menstrual 
cycle following last administration of the study drug, whichever 
period of time is longer. 
b. Barrier method (condom or diaphragm) with spermicide for at 
least 14 days prior to Visit 1 through 30 days following Visit 6 or 
last administration of the study drug or until completion of the 
subject’s first menstrual cycle following last administration of the 
study drug, whichever period of time is longer. 
c. 
Stable hormonal contraceptive for at least 3 months prior to Visit 
1 through 30 days following Visit 6 or last administration of the 
study drug or until completion of the subject’s first menstrual 
cycle following administration of the study drug, whichever 
period of time is longer. Note: For Depo-Provera injection 
contraceptives, the statement regarding first menstrual cycle 
following administration of the study drug is not applicable, as 
females receiving this form of contraception will not have 
menses. 


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d. Surgical sterilization (vasectomy) of partner at least 6 months 
prior to Visit 1. 
6. If postmenopausal women, have had no menstrual cycle for at least 1 
year prior to Visit 1 or have undergone one of the following 
sterilization procedures at least 6 months prior to Visit 1: 
a. 
Bilateral tubal ligation 
b. Hysterectomy 
c. 
Bilateral oophorectomy 
7. Have a history of DED in both eyes supported by a previous clinical 
diagnosis or have a history of subjective complaints for at least 6 
months rior to Visit 1. 
10.
Have normal lid anatomy in the opinion of the investigator.
11. Are willing to withhold AT for the duration of the study, with the 
exception of rescue use of the study-provided AT (Refresh Plus®).  
Exclusion Criteria 
Individuals will be excluded from study participation if they meet any of the 
following criteria: 
 
2.
Any concomitant treatment or prior ocular procedure or surgery in 
either eye or alteration of the dose of systemic medications at the time 
of entry into the study that could interfere in the assessment of the 
trial, per the Investigator’s judgment or per details below: 
a. 
Prior history of Isotretinoin (Accutane) 
b. Corneal refractive surgery, glaucoma surgery, or corneal 
transplantation within 2 years prior to Visit 1 
c. 
Altered use of nutraceuticals or multivitamins throughout the 
study 
d. Topical ophthalmic medications, including ocular hypotensive 
(glaucoma) medications, eye drops, gels, or AT (other than study-
provided Refresh Plus®) throughout the study 
f. 
Penetrating intraocular surgery within 12 months prior to Visit 1 
g. Eyelid surgery or ocular surface surgery within 6 months prior to 
Visit 1 
h. Altered dose of the following used on a chronic basis within 3 
months prior to Visit 1: 
• 
Anticholinergics 
• 
Antidepressants 
• 
Antihistamines 


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• 
Systemic immunosuppressive agents 
• 
Oral steroids (dose must be <11 mg prednisone or 
equivalent/day)  
Dose must remain stable throughout study. 
i. 
In either eye, have had punctal occlusion (cauterization or plugs 
[silicone or dissolvable]) within 3 months prior to Visit 1 or 
anticipate new or additional punctal occlusion during the 
duration of the study.  
NOTE: Permanent plugs lost should be replaced. 
j. 
Any other Investigational Product within 45 days prior to Visit 
1 
k. Prescription treatments for ocular surface disease within 30 days 
prior to Visit 1, including  
• 
Topical cyclosporine (Restasis®, Cequa®)  
• 
Topical lifitegrast (Xiidra®) 
• 
Ocular corticosteroids, including but not limited to 
fluorometholone and loteprednol etabonate (Eysuvis®) 
• 
Varenicline (Tyvara®) 
l. 
Autologous serum within 30 days prior to Visit 1 
m. Altered 
dose 
of 
tetracycline 
compounds 
(tetracycline, 
doxycycline, or minocycline) within 30 days prior to Visit 1.  
Dose must remain stable throughout study. 
n. Topical ocular antibiotics, topical ocular antihistamines or mast 
cell stabilizers, topical or nasal vasoconstrictors within 14 days 
prior to Visit 1 
3. Have corneal erosive disease (e.g., confluent staining [NEI grade 4], 
confluent filaments) or other conditions suggestive of extensive 
damage of the cornea in either eye. 
4. Have a history of glaucoma or IOP >25 mmHg at Visit 1 or a history 
of elevated IOP (>25 mmHg) in either eye. 
5. Wear contact lenses for 14 days prior to Visit 1 or throughout the 
study. 
7. Are considered legally blind in either eye (LogMAR BCVA ≥1.0 or 
Snellen BCVA ≤20/200). 
9. Have a history of stem cell or bone marrow transplant. 


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g. Significant conjunctival scarring 
h. Chemical burn 
i. 
History of herpetic or neurotrophic keratitis 
j. 
Serious systemic disease or uncontrolled medical condition that, 
in the judgment of the Investigator, could confound study 
assessments or limit compliance. 
11. Have a history of liver, renal or hematological disease that, in the 
judgment of the Investigator, could confound the study assessments 
or impact subject safety. 
12. Have an allergy to any component of the study drug formulation. 
13. Have a documented history of ocular allergies in either eye that, in the 
judgment of the Investigator, are likely to have an acute increase in 
severity due to the expected timing of the exposure to the allergen to 
which the subject is sensitive. Subjects sensitive to seasonal allergens 
that are not expected to be present during the study are permitted. 
14. Have systemic signs of infection (e.g., fever or current treatment with 
antibiotics). 
15. Are an employee of a site that is directly involved in the management, 
administration, or support of this study or an immediate family 
member (grandparent, parent, sibling, child) of the same.  
16. Have a known history of alcohol and/or drug abuse.  
17. Are an active dail
 user of tobacco or mari uana.  
19. Are unwilling or unable to comply with the study protocol. 
Investigational products: 
SY-201 Ophthalmic Solution 2.0% 
SY-201 Ophthalmic Solution 1.0% 
SY-201 Ophthalmic Solution 0.5% 
Vehicle solution (run-in and vehicle) 
Dosing regimen: 
Both run-in and IP: 1 drop OU BID, once in the morning and once in the 
evening, 8-12 hours apart  
Assessments/Evaluations: 
Efficacy 
• 
tCFS (mNEI scale, 0-20) 


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Safety 
• 
AE monitoring  
• 
Safety labs (chemistry and hematology) 
• 
BCVA 
• 
Slit lamp biomicroscopy and external eye exam 
• 
IOP 
• 
Dilated ophthalmoscopy 
• 
Drop comfort assessment 
Duration of study: 
74 days (14 days of run-in, 60 days of treatment) 
Statistical methods: 
For mean change from baseline to Day 60 in tCFS, a sample size of 45 SY-
201–treated subjects versus 45 vehicle-treated subjects will have 87.9% power 
to detect an effect size of 2.0 units with a standard deviation of 3.0 for an 
unpaired t-test with a 2-sided alpha = 0.05. For mean change from baseline to 
Day 60 in dry eye symptom
, a sample size of 45 SY-201–treated subjects 
versus 45 vehicle-treated subjects will have 83.5% power to detect an effect 
size of 1.5 units with a standard deviation of 2.4 for an unpaired t-test with a 2-
sided alpha = 0.05. Fifty (50) subjects per treatment arm, for a total 200 
subjects, will be enrolled to allow for some dropout of subjects. 
It is hypothesized that SY-201 Ophthalmic Solution will be safe and improve 
DED signs and symptoms in subjects with a documented diagnosis of DED. In 
particular, efficacy will be assessed using the following endpoints at Day 60: 
• 
Mean CFB in tCFS (mNEI scale) 
• 
To control for type I error, comparisons will be made within each active dose 
level of SY-201 Ophthalmic Solution compared to vehicle. In other words, the 
primary endpoints will be compared sequentially between SY-201 Ophthalmic 
Solution 2.0% and vehicle, first testing tCFS and, if statistically significant, 
then 
 Should both endpoints achieve statistical significance 
for the 2.0% dose, testing will proceed to SY-201 Ophthalmic Solution 1.0% 
versus vehicle, first testing tCFS and, if statistically significant, then 
 Should both endpoints achieve statistical significance for the 1.0% 
dose, testing will proceed to SY-201 Ophthalmic Solution 0.5% and vehicle, 
first testing tCFS and, if statistically significant, then
. In 
other words, the first non-significant result in this testing hierarchy of six 
hypotheses will imply that subsequent tests are non-significant. 
Mean CFB in tCFS will be analyzed using a mixed-model repeated measures 
(MMRM) model. The model will include the baseline measurement, treatment, 
time, and treatment by time interaction as fixed effects, with a random effect 
for site. An unstructured covariance among repeated measurements is assumed. 
A similar model for the subject-level mean CFB in eye dryness score will be 
used. 


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Subgroup analyses will be based on MMP-9 level (elevated or normal) at
baseline. 
Safety analyses will be performed on all subjects in the Safety Analysis Set. 
The assessment of safety will be based on the summary of ocular and non-
ocular AEs, laboratory measurements, BCVA, IOP, ophthalmic exams using 
slit lamp biomicroscopy and dilated ophthalmoscopy, and drop comfort 
assessment. Summaries will be provided by treatment group, and for ocular 
assessments separately by eye. 
 
 
 
 
 
 
 


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9.5. 
EFFICACY AND SAFETY VARIABLES 
9.5.1. 
Efficacy and Safety Measurements Assessed and Flow Chart 
The primary objective of this phase 2 study is to assess the ocular safety and efficacy of SY-201 
Ophthalmic Solution in subjects with DED. The secondary objective is to assess the systemic 
safety of SY-201 Ophthalmic Solution in subjects with DED. 
Figure 1 summarizes the design of the study. 
 
Figure 1: Study Schematic 
9.5.1.1. 
Visit and Procedure Schedule 
See Table 1 in Appendix I for a complete visit and procedure schedule. 
9.5.1.2. 
Demographics and Baseline Characteristics 
9.5.1.2.1. Demographics and Disease Characteristics 
Demographic characteristics including age (years), sex, race, and ethnicity will be collected at 
Visit 1. Baseline disease characteristics include tCFS score (mNEI scale),
 
9.5.1.2.2. Medical and Surgical History 
Ocular and non-ocular medical history will be collected at Visit 1. 


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9.5.1.2.3. Prior and Concomitant Medications 
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the electronic case report 
form (eCRF) are concomitant prescription medications, over-the-counter medications, and 
supplements.  
All medications that the subject has taken 45 days prior to Visit 1 and through Visit 6 or 
discontinuation from the study will be recorded in the eCRF and the subject chart. The generic 
name of the drug, dose, route of administration, duration of treatment (including start and stop 
dates), frequency, indication, and whether or not the medication was taken due to an AE will be 
recorded for each medication. Prior and concomitant medications (CMs) will be coded using the 
World Health Organization Drug Dictionary (WHODrug). 
AT, whether subject- or study-supplied, is prohibited during the run-in period of the study (Visit 
1 to Visit 2). Any subject who violates this policy will not be randomized to treatment and will be 
discontinued from the study. 
Preservative-free AT (Refresh Plus®) will be provided for rescue use during the treatment phase 
of the study (Visits 2 through 6) but limited to ≤2 instillations per day. Subjects will be required 
to record AT use in a diary and return the used and unused AT at clinic Visits 2 through 6; subjects 
will be queried about AT use at each clinic visit. 
Restricted and prohibited prior and comcomitant therapy are outlined in the protocol Section 5.5.1. 
9.5.1.3. 
Efficacy Assessments 
9.5.1.3.1. Primary Efficacy Assessment(s) 
Corneal staining will be assessed at each in-clinic visit. The modified National Eye Institute 
(mNEI) scale defines 5 regions (central, superior, temporal, nasal, and inferior) of the eye and 
assigns a score of 0-4 to each region in increments of 0.5 to assess the severity of corneal staining. 
The sum of the 5 regions provides the total score.  
9.5.1.3.2. Secondary Efficacy Assessments 


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9.5.1.3.3. Exploratory Efficacy Assessments 
Not applicable. 
9.5.1.4. 
Safety Assessments 
The safety of SY-201 Ophthalmic Solution will be evaluated using the following assessments, 
conducted at each in-clinic visit unless otherwise noted. 
1. Adverse event (AE) monitoring 
2. Safety labs (chemistry and hematology) – Visits 1 and 6 
3. Best Corrected Visual Acuity (BCVA) 
4. Slit lamp biomicroscopy and external eye exam 
5. Intraocular pressure (IOP) 
6. Dilated ophthalmoscopy – Visits 1 and 6 
7. Drop comfort assessment – Visits 2 and 6 
9.5.1.4.1. Adverse Events 
An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
intervention. 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death  
• A life-threatening AE  
• Inpatient hospitalization or prolongation of existing hospitalization  
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
• A congenital anomaly or birth defect  


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Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. 
Severity of AEs is described with the following scale: 
• Mild: requires minimal or no treatment and do not interfere with the subject’s daily 
activities 
• Moderate: results in a low level of inconvenience or concern and may cause some 
interference with functioning 
• Severe: interrupts a subject’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
The term “severe” does not necessarily equate to “serious.” 
Relationship of adverse events to study intervention is classified according to the following scale: 
• Unrelated: no reasonable possibility that the administration of the IP caused the event, no 
temporal relationship between the IP and event onset, or an alternate etiology has been 
established 
• Related: is known to occur with the IP, is a reasonable possibility that the IP caused the 
AE, or there is a temporal relationship between the IP and event. Reasonable possibility 
means that there is evidence to suggest a causal relationship between the IP and the AE. 
9.5.1.4.2. Safety Labs (Chemistry and Hematology) 
The following clinical laboratory tests will be performed at Visits 1 and 6. 
• Chemistry 
o Sodium, Potassium, BUN, Creatinine, Glucose, Calcium, Phosphorus, Total 
Protein, Albumin, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total 
Bilirubin, Chloride, Bicarbonate 
• Hematology 
o Hemoglobin, Hematocrit, RBC, MCH, MCHC, RDW, WBC, Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils, Platelets 
9.5.1.4.3. Best Corrected Visual Acuity (BCVA) 
The BCVA is measured on both eyes in LogMAR at every in-clinic visit. LogMAR is calculated 
as Baseline value + (n × 0.02); where the baseline value is the LogMAR number of the last line 
read (at least one letter read correctly in this line), “n” is the total number of letters missed up to 
and including the last line read, and “0.02” is the value for each letter. 
9.5.1.4.4. Slit Lamp Biomicroscopy and External Eye Exam 
The biomicroscopy exam should be performed at every in-clinic visit with the slit lamp using a 
beam width and intensity that provide optimal evaluation of the anterior segment. 


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This procedure will be the performed in the same manner for all subjects observed at the 
Investigator’s site. The site will record all abnormal or present findings in the source document 
and the Investigator will evaluate the abnormal or present findings as non-clinically significant 
(NCS) or clinically significant (CS). CS and NCS abnormal findings will be recorded in the source 
documentation. However, only CS abnormal descriptions will be captured in the eCRF. 
Anterior chamber cells and flare will be graded on 5-point scales. Eyelid hyperemia and edema, 
corneal edema, and conjunctival edema (chemosis) and discharge/exudate will be graded on a 4-
point scale (None, Mild, Moderate, Severe). 
Normality for iris, pupil, lashes, lens, and corneal endothelium will be collected. 
9.5.1.4.5. Intraocular Pressure (IOP) 
Intraocular pressure must be measured by Goldmann Applanation tonometry with every effort to 
ensure the same examiner using the same tonometer for all visits. 
9.5.1.4.6. Dilated Ophthalmoscopy 
Dilated ophthalmoscopy will be completed at Visits 1 and 6 and will include assessment of the 
vitreous, retina, macula, choroid, optic nerve, and vertical optic nerve cup-to-disc ratio. Findings 
will be graded as normal or abnormal. All abnormalities will be recorded in the source 
documentation and CS or NCS will be indicated. Clinically significant abnormal findings will be 
reported in the medical history or adverse event eCRF. 
9.5.1.4.7. Drop Comfort Assessment 
At Visits 2 and 6, subjects will be asked to rate the comfort of the drop for both eyes as one score 
at 1 minute and 5 minutes post-dose. Integer scores range from 0 (Comfortable) to 10 
(Uncomfortable). 
9.5.2. 
Appropriateness of Measurements 
All assessments used in this study are widely used and generally recognized as reliable, accurate, 
and relevant. 
9.5.3. 
Primary Efficacy Variable(s) 
Two primary ocular efficacy endpoints (one sign and one symptom) will be tested sequentially: 
• Mean change from baseline (CFB) in total corneal fluorescein staining (tCFS; modified 
National Eye Institute [mNEI] scale, 0-20) 
9.5.4. 
Drug Concentration Measurements 
No drug concentration measurements will be made for this study. 


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9.6. 
DATA QUALITY ASSURANCE 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.  
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.  
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
(ICH) Good Clinical Practice (GCP), and applicable regulatory requirements (e.g., Good 
Laboratory Practice [GLP], Good Manufacturing Practice [GMP]).  
The investigational site will provide direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the Sponsor, and inspection by local and 
regulatory authorities. 
9.6.1. 
Training and Education of Investigators and Study Site Personnel 
 
An Investigator Meeting will be held before study initiation and attended by the Investigators 
and/or Sub-Investigators from each study site, study coordinators from each study site, if possible, 
and personnel from the sponsor and the Contract Research Organization (Lexitas Pharma Services, 
Inc., hereafter referred to as Lexitas). The purpose of this meeting is to train and instruct the 
Investigators and the study coordinators on the proper conduct of the clinical trial and ensure that 
all subjects are aware of their obligations set out by the protocol, ICH guidelines, GCP guidelines, 
and other applicable regulatory requirements. 
9.6.2. 
Monitoring of Study Sites 
Lexitas Pharma Services, Inc., will conduct the clinical monitoring for this study. A Clinical 
Monitoring Plan (CMP) is to be used, which will describe in detail who will conduct the 
monitoring, at what frequency monitoring will be done, at what level of detail monitoring will be 
performed, and the distribution of monitoring reports. 
This clinical trial will be monitored at regular intervals. All information dealt with during these 
visits will be treated as strictly confidential. All monitoring and study management will be 
conducted according to GCP and United States Code of Federal Regulations. 
9.6.3. 
Data Entry and Verification of Database Used for Analysis and 
Reporting 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site’s Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 


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Lexitas will review the eCRFs entered by investigational site staff for completeness and accuracy 
and instruct the investigational site staff to make any required corrections or additions. After data 
have been entered into the study database, a system of computerized data validation checks will 
be implemented and applied to the database. Queries will be sent to the investigational site and 
designated investigational site staff are required to respond to the query and edit data, as necessary. 
All changes to the study database will be documented. 
It is the responsibility of the monitor to make certain that all data are completed on the eCRFs. At 
the end of each study period, the Investigator will sign and date the eCRF to attest to the 
authenticity of the collected data and coherence between the data in the eCRF and the data in the 
source documents. 
9.6.4. 
Clinical Study Report 
The final clinical study report will be reviewed, audited, and approved by medical, clinical, 
statistical, and regulatory staff from the sponsor, and key study contributors from Lexitas. 
9.6.5. 
Inter-Laboratory Standardization Methods 
Not applicable. A single, qualified, and certified central clinical laboratory will be used to analyze 
and report clinical laboratory data. 


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9.7. 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE 
This section of the analysis plan describes the analyses explicitly mentioned in the protocol as well 
as additional analyses not explicitly mentioned in the protocol but planned prior to breaking the 
treatment mask. Section 9.8 describes any changes to analyses that were explicitly mentioned in 
the protocol or statistical analysis plan. 
9.7.1. 
Statistical and Analytical Plans 
General Conventions 
Summary statistics for the data collected during this study will be presented to give a general 
description of the subjects studied. Data from all sites will be combined in the computation of these 
descriptive summaries. Categorical variables will be summarized by the frequency and percentage 
of subjects in each category. Continuous variables will be summarized using N, mean, standard 
deviation (SD), median, minimum, and maximum values. 
Number of subjects, minimums, and maximums will be calculated to the same number of decimal 
places as the source data. Means, medians, standard deviations, and quartiles will be calculated to 
one more decimal place than the source data. Percentages will be calculated to the nearest one 
decimal place. Zero count cells will be displayed as “0” with percentage of (0%). Unless otherwise 
noted, summaries will be performed by the treatment group and presented in the order of: SY-201 
2.0% or 1.0% or 0.5% (efficacy analyses only), SY-201, 2.0%; SY-201, 1.0%; SY-201, 0.5%; 
Vehicle. 
Statistical tests will be presented as two-sided p-values rounded to four decimal places; p-values 
less than 0.0001 will be presented as '<0.0001' and p-values = 1 will be presented as '>0.9999' in 
all tables. Unless otherwise indicated, statistical testing will be carried out at the α = 0.05 
significance level. 
Baseline values will be defined as the last measurement prior to dosing of double-masked study 
medication. Ocular measurements will use the most recent measurement for each eye. 
Numeric laboratory data may be recorded at limits of detection (with a ‘<’ or ‘>’ sign, i.e. < 0.1 or 
> 0.1). To summarize the data, the original value will be converted to one unit less or more at the 
level of measured precision (e.g. 0.4 in the case of < 0.5 and to 0.6 in the case of > 0.5). The actual 
values will be presented in the data listings. 
MMP-9 data may be recorded at limits of detection of < 5 ng/mL or > 1000 ng/mL. To summarize 
the data, the original value will be converted to either 4 ng/mL or 1010 ng/mL, respectively. The 
actual values will be presented in the data listings. 
All data collected in this study will be presented in individual subject data listings for all subjects. 
Computations for all results will be performed using SAS (Version 9.4, SAS/STAT 15.2) computer 
software package (SAS Institute, Inc, 2013, 2020), unless otherwise specified. 


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Strata and Covariates 
For analysis of efficacy endpoints, longitudinal models will model the change from baseline of 
each endpoint as the dependent variable with the baseline measurement of the corresponding 
endpoint as a covariate and treatment group as the main effect. A random effect for site will be 
added to account for site-to-site variability. 
Subgroups 
Subgroup analyses will include testing of the mean CFB in tCFS, 
Subgroup analyses by sex and age group (<65 years, ≥65 years) may also be performed. 
Multiplicity 
To control for type I error, comparisons will be made within each active dose level of SY-201 
Ophthalmic Solution compared to Vehicle. In other words, the primary endpoints will be compared 
sequentially between SY-201 Ophthalmic Solution 2.0% and Vehicle, first testing tCFS and, if 
statistically significant, 
. Should both endpoints achieve statistical significance 
for the 2.0% dose, testing w
procee to
Y-201 Ophthalmic Solution 1.0% versus Vehicle, first 
testing tCFS and, if statistically significant,
. Should both endpoints achieve 
statistical significance for the 1.0% dose, testing will proceed to SY-201 Ophthalmic Solution 
0.5% and Vehicle, first testing tCFS and, if statistically significant,
. In other 
words, the first non-significant result in this testing hierarchy of six hypotheses will imply that 
subsequent tests are non-significant. 
Missing Data and Outliers 
Every attempt will be made to capture all study data. All analyses will utilize observed data only. 
Analysis of continuous efficacy endpoints using MMRM assumes missing at random (MAR). 
Sensitivity analyses of the primary endpoints will be performed utilizing control-based pattern 
imputation, last observation carried forward (LOCF), and baseline observation carried forward 
(BOCF). 
Visit Windows 
The nominal visits listed in the eCRF will be used in the summaries. In general, unscheduled visits 
will not be summarized in tables unless otherwise noted. 
Missing Dates 


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Missing dates that occur for prior or concomitant medications or adverse events will be queried 
for a date. If no date is obtained, the following imputation rules will apply: 
• For start dates, if the given year (or year-month) is the same as study drug administration, 
the start date will be imputed as study drug administration date; otherwise, missing month-
day (or day) will be imputed as ’01-01’ (or ’01’). 
• For stop dates, missing months will be imputed as ‘12’ and missing days will be imputed 
as the last day of the month. If this creates a date after discontinuation/completion, the date 
of discontinuation/completion will be used. 
Imputed dates will only be used to classify events or medications, such as occurring before or after 
the start of treatment. Imputed dates will only be used in tables. Listings will display the available 
date data. 
Interim Analysis 
There is no unmasked efficacy or futility interim analysis for this study. 
9.7.1.1. 
Analysis Populations 
9.7.1.1.1. Populations 
The Full Analysis Set (FAS) consists of all subjects
. Subjects will be 
analyzed in the group to which
. This set will be used for the analysis of all 
efficacy endpoints. 
The Safety Analysis Set will include all subjects who took at least one dose of double-masked 
investigational product as indicated on the dosing record. Subjects will be analyzed in the group 
according to the treatment received. All safety variables will be analyzed using the Safety Analysis 
Set and only observed data will be included (i.e., missing data will remain missing for the safety 
analysis). If the safety analysis set is the same as the FAS, then safety results will be provided 
using the FAS. 
9.7.1.1.2. Analysis Eyes 
Subjects in the FAS will have at least one eye that qualifies based on the criteria in the protocol. 
Both eyes may qualify based on the criteria.  
Efficacy analyses will be performed in the study eye and non-study eyes. 
The study eye is defined as the eye meeting all inclusion criteria and no exclusion criteria, and 
with the highest tCFS scoring at randomization (Visit 2, Day 1). If both eyes meet the inclusion 
criteria and no exclusion criteria and have the same tCFS score, the right eye will be used as the 
SE. 
Safety analyses will be presented for both eyes. 


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9.7.1.2. 
Analysis of Subject Disposition 
The number of subjects randomized at each site will be summarized by treatment group and 
overall. 
Subjects’ enrollment and disposition during the study will be summarized by treatment group and 
overall using Randomized Subjects. The reasons for discontinuation will be displayed in the order 
as they appear on the eCRF. 
The summary table will include the following. The percentages will be calculated based on the 
number of subjects randomized. For reason for discontinuation from study, percentages are based 
on the number of subjects who discontinued the study. 
• Number of subjects screened  
• Number and percentage of subjects randomized 
• Number and percentage of subjects randomized with any protocol deviation 
• Number and percentage of subjects treated 
• Number and percentage of subjects treated with any protocol deviation 
• Number and percentage of subjects in the Safety, Full, and Per Protocol Analysis Sets 
• Number and percentage of subjects treated who completed the study 
• Number and percentage of subjects treated who discontinued from the study 
• The reasons for study discontinuation 
• Number and percentage of subjects attending each scheduled study visit. 
A listing of subjects who do not meet all inclusion criteria or meet exclusion criteria will be 
provided. 
9.7.1.3. 
Analysis of Demographic and Baseline Characteristics 
9.7.1.3.1. Demographics and Disease Characteristics 
Demographic characteristics including age (years), age group (<65 years, ≥65 years), sex, race, 
ethnicity, qualifying eyes (1 or 2), study eye (OD/OS), and baseline tCFS score
MMP-9, and 
will be summarized descriptively by treatment group and overall using the
FASand Safety Analysis Sets. For categorical parameters, the percentages will be calculated 
overall and based on the number of subjects in each treatment group based on non-missing 
observations. The baseline characteristic parameters will be summarized for both the study eye 
and the non-study eye if the assessments were done on each eye separately. 
9.7.1.3.2. Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
Version 25.0, Mozzicato, 2009). The frequency and percentage of subjects with any medical 
history will be summarized by treatment group using the FAS. System organ class (SOC) will be 
sorted alphabetically and preferred term (PT) within each SOC will be sorted by overall 
descending order of frequency according to the following rules in order: 


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1. Descending frequency within SY-201, 2.0%; 
2. Descending frequency within SY-201, 1.0%; 
3. Descending frequency within SY-201, 0.5%;  
4. Descending frequency within Vehicle; 
5. PT in alphabetical order. 
The medical history will include both the ocular and the general (non-ocular) history. Ocular 
medical history and general (non-ocular) medical history will be summarized separately. Ocular 
and non-ocular medical histories are identified according to which CRF the event is recorded. 
Ocular medical history will be summarized separately for study eye, non-study eye, and either eye. 
9.7.1.3.3. Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) (Version 2022-03, Lagerlund et al., 2020) for anatomical therapeutic 
chemical (ATC) classification and preferred drug name.  
The frequency and percentage of subjects with coded medications will be summarized by treatment 
group using the Safety Analysis Set. A subject who used multiple medications will be counted 
only once for each ATC and preferred drug name. Therapeutic Subgroup is sorted alphabetically, 
and preferred term is sorted by descending frequency overall within each Level 3 term according 
to:  
1. Descending frequency within SY-201, 2.0%; 
2. Descending frequency within SY-201, 1.0%; 
3. Descending frequency within SY-201, 0.5%; 
4. Descending frequency within Vehicle;  
5. PT in alphabetical order. 
Prior and concomitant medications will be summarized separately. Ocular medications are defined 
as those medications for which an eye has been specified (OD, OS, or OU). Ocular and non-ocular 
medications will be summarized separately. Ocular medications will be summarized separately for 
study eye, non-study eye, and either eye. 
Prior medications are defined as any medications that started and stopped prior to the first dose of 
double-masked study drug. Concomitant medications are defined as any medications that (1) start 
prior to the first dose of double-masked study drug and stop or are ongoing at or after the date of 
first dose of double-masked study drug; or (2) start at or after the first dose of double-masked study 
drug. Medications taken after Visit 6 or withdrawal from the study are not considered concomitant. 
9.7.1.4. 
Analysis of Study Medication Compliance and Exposure 
The overall treatment compliance and exposure will be assessed by the data from the in-clinic 
administration, IP accountability, and study completion eCRFs and will be summarized by 
treatment group using the Safety Analysis Set. 


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The total number of doses of double-masked study drug that were taken will be calculated as the 
number of used vials returned to the clinic. Each single use vial contains product for one OU dose. 
Treatment compliance for double-masked study drug is defined as the proportion of doses taken 
out of the expected number of doses for the double-masked treatment period. The overall 
compliance (%) will be calculated as (total number of doses taken / expected number of doses) × 
100. The expected number of doses is defined as doses per day × days in double-masked treatment 
period, i.e., [2 × (last double-masked dose date - first double-masked dose date + 1)]. Last double-
masked dose date will be taken from the study completion eCRF. Since the expected number of 
doses is based on last dose, compliance is adjusted for the early withdrawals. Treatment 
compliance for the run-in period is defined as (total number of doses taken / expected number of 
doses) × 100 where the expected doses are [2 × (Visit 2 date – Visit 1 date)]. 
Duration of exposure of double-masked study drug will be calculated as the total number of days 
from the first double-masked dose date to the last double-masked dose date plus 1 (one) regardless 
of temporary dose interruptions.  
Total number of doses of double-masked study drug that were taken, compliance, and the duration 
of exposure to double-masked study drug (days) will be summarized by descriptive statistics. The 
frequency and percentage of subjects in the following study drug compliance categories (≥ 80%, 
< 80%) will be summarized by treatment group. The percentages will be calculated based on the 
number of non-missing observations in each treatment group of the Safety Analysis Set. No 
inferential statistics will be calculated. 
Total number of doses of single-masked run-in drops taken, duration (in days), compliance, and 
compliance categories (≥ 80%, < 80%) during the run-in period will be summarized by treatment 
group based on Safety Analysis Set. No inferential statistics will be calculated. 
9.7.1.5. 
Analysis of Efficacy 
Summary descriptive statistics will be presented for all study visits at which efficacy data are 
collected. Efficacy analyses will be presented by the study eye and non-study eyes. 
For subjects who discontinue treatment prior to Visit 6, data collected using Early Termination 
eCRFs will not be summarized separately unless the termination occurred on a scheduled visit 
(within the visit windows of a particular visit). 
All longitudinal models will be fit using the MIXED procedure in SAS. Categorical analyses will 
be conducted using the FREQ procedure. 
All efficacy analyses will be conducted using the FAS Analysis Sets. 
To control for type I error, comparisons will be made within each active dose level of SY-201 
Ophthalmic Solution compared to Vehicle. In other words, the primary endpoints will be compared 
sequentially between SY-201 Ophthalmic Solution 2.0% and Vehicle, first testing tCFS and, if 
statistically significant, 
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for the 2.0% dose, testing will proceed to SY-201 Ophthalmic Solution 1.0% versus Vehicle, first 
testing tCFS and, if statistically significant, 
. Should both endpoints achieve 
statistical significance for the 1.0% dose, testing will proceed to SY-201 Ophthalmic Solution 
0.5% and Vehicle, first testing tCFS and, if statistically significant, 
. In other 
words, the first non-significant result in this testing hierarchy of six hypotheses will imply that 
subsequent tests are non-significant. 
Testing of all active doses combined compared to vehicle will also be performed. 
9.7.1.5.1. Primary Efficacy Analysis 
Primary Estimands: The primary estimands are the treatment differences between SY-201 
Ophthalmic Solution arms and vehicle for mean CFB to Day 60 in tCFS using study eyes and 
mean CFB to Day 60 in eye
using the FAS. 
Target Population: Subjects with DED who meet the study entry criteria. 
Endpoints: Change from baseline at Day 60 for tCFS using study eyes and change from baseline 
at Day 60 for eye dryness score. 
Treatment Condition(s): Treatment condition is based on the randomized treatment group. 
Population-level Summaries: The difference in the mean CFB to Day 60 in tCFS using study 
eyes and the difference in mean CFB to Day 60 in eye dryness score and their p-values and 
corresponding 95% confidence intervals. 
The proposed procedures to handle missing data and intercurrent events are as follows: 
• Discontinuation of study therapy with continued participation in the study 
o Treatment Policy – no imputation; use observed data 
• Receipt of rescue therapy 
o Treatment Policy – no imputation; use observed data 
• Missing data with or without withdrawal, regardless of reason 
o Hypothetical approach – missing data will be accounted for assuming missing at 
random (MAR) using mixed-model repeated measures (MMRM). 
Mean CFB in tCFS will be analyzed using a MMRM model. The model will include the baseline 
measurement, treatment, time, and treatment by time interaction as fixed effects, with a random 
effect for site. An unstructured covariance among repeated measurements is assumed. A similar 
model for the subject-level mean CFB in eye dryness score will be used. 
Sample repeated measures model code: 
PROC MIXED DATA=indata; 
 CLASS subject center visit treatment(REF=’Vehicle’); 
 MODEL change = baseline_value visit treatment visit*treatment / Solution DDFM=KR; 
 REPEAT visit / SUBJECT=subject TYPE=UN; 


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 RANDOM center; 
 LSMEANS treatment*visit / slice = visit DIFF CL; 
RUN; 
 
If the model fails to converge using this covariance structure, spatial power or compound 
symmetry will be implemented in this order. 
Sensitivity analyses of the primary endpoints will be performed utilizing control-based pattern 
imputation, last observation carried forward (LOCF), and baseline observation carried forward 
(BOCF). 
Control-based pattern imputation would be performed using code similar to the below. The first 
call is to ensure a monotone missing data pattern. The second call is to perform the control-based 
pattern imputation. 
 
PROC MI DATA=indata SEED= OUT=monotone MINIMUM=0 0 0 0 0 MAXIMUM=4 4 4 4 4 ROUND=0.5 
NIMPUTE=25; 
  MCMC IMPUTE = MONOTONE; 
  VAR value_V2 value_V3 value_V4 value_V5 value_V6; 
RUN; 
PROC MI DATA=monotone SEED= OUT= MINIMUM=. 0 0 0 0 0 MAXIMUM=. 4 4 4 4 4 ROUND=0.5 
NIMPUTE=1; 
  by _imputation_; 
  CLASS treatment; 
  VAR value_V2 value_V3 value_V4 value_V5 value_V6; 
  MONOTONE reg(/details); 
  MNAR model(value_V3 value_V4 value_V5 value_V6 / modelobs= (treatment = ‘vehicle’)); 
RUN; 
Comparisons among individual arms will be obtained from the lsmeans statement. Comparisons between 
the combined SY-201 arm and Vehicle (least-squares means, treatment differences, 95% confidence 
intervals, and p-values) will be obtained using estimate statements. Assume treatments are ordered: 
1. SY-201 2.0%;  
2. SY-201 1.0%; 
3. SY-201 0.5%; 
4. Vehicle. 
 
And visits 3, 4, 5, and 6 are ordered numerically. Let 𝑛2.0%, 𝑛1.0%, and 𝑛0.5% be the total number of 
subjects for the appropriate arms in the respective analysis set (FAS or Per Protocol). Define 
𝑝2.0 = 
𝑛2.0% 
𝑛2.0%+𝑛1.0%+𝑛0.5% with 𝑝1.0 and 𝑝0.5 defined similarly. 
 
To generate the estimates for the combined SY-201 for Visit 3, see the below code for an example for 
Visit 3. 
 
estimate ‘SY-201 Average V3’    
intercept       1 
      baseline        <<overall average at baseline for all subjects>> 
 
visit           1 0 0 0 
 
treatment       𝑝2.0 𝑝1.0 𝑝0.5 0 


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visit*treatment 𝑝2.0 𝑝1.0 𝑝0.5 0 0 0 0 0 
                        0   0  0  0 0 0 0 0; 
 
estimate ‘SY-201 Average minus Vehicle V3’   
 
treatment       𝑝2.0 𝑝1.0 𝑝0.5 -1 
visit*treatment 𝑝2.0 𝑝1.0 𝑝0.5 -1 0 0 0 0 
                        0   0  0  0 0 0 0 0; 
 
9.7.1.5.2. Secondary Efficacy Analyses 
9.7.1.5.3. Exploratory Efficacy Analysis 
Not applicable. 
9.7.1.6. 
Analysis of Safety 
Safety will be evaluated by: 
1. Adverse event (AE) monitoring 
2. Safety labs (chemistry and hematology) 
3. Best Corrected Visual Acuity (BCVA) 
4. Slit lamp biomicroscopy and external eye exam 
5. Intraocular pressure (IOP) 
6. Dilated ophthalmoscopy 
7. Drop comfort assessment 
The Safety Analysis Set will be used for all safety analyses. All data will be summarized as 
observed, and no data imputation will be performed. No statistical treatment group comparisons 


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will be performed, unless otherwise specified. Analyses will be presented by study eye and non-
study eye, if applicable. 
9.7.1.6.1. Adverse Events 
AEs are coded using MedDRA Version 25.0. Treatment-emergent adverse events (TEAE) are 
defined as events that start on or after the first dose administration of double-masked study 
medication up to and including the last dose of double-masked study medication plus 30 days. 
Pretreatment adverse events are events that begin prior to first dose administration of double-
masked study medication. Ocular AEs are defined as those events for which an eye has been 
specified (OD, OS, or OU). 
Ocular and non-ocular TEAEs will be summarized separately. Ocular TEAEs will be presented by 
study eye and non-study eye and overall (OU) if an event occurs in either eye. 
In all summaries of TEAEs, percentages are calculated based on the number of subjects in each 
treatment group of the Safety Analysis Set. 
Overall summaries of TEAEs by treatment will include:  
• the number of TEAEs and serious TEAEs reported;  
• the number and percentage of subjects who experienced any TEAE;  
• the number and percentage of subjects who experienced any serious TEAE and the reason 
for seriousness;  
• the number and percentage of subjects with any TEAE by worst severity and worst 
relationship. 
• the number and percentage of subjects with any TEAEs leading to discontinuation of 
double-masked study drug; 
• the number and percentage of subjects with any TEAEs leading to study termination. 
Summaries of the frequency and percentage of subjects with TEAEs by SOC and preferred term 
by treatment group will include: 
• All TEAEs by SOC and preferred term; 
• All TEAEs by SOC, preferred term, and maximum severity; 
• All TEAEs by SOC, preferred term, and maximum relationship. 
System organ class (SOC) will be sorted alphabetically, and preferred term (PT) within each SOC 
will be sorted by overall descending order of frequency according to the following rules in order: 
1. Descending frequency within SY-201, 2.0%; 
2. Descending frequency within SY-201, 1.0%; 
3. Descending frequency within SY-201, 0.5%; 
4. Descending frequency within Vehicle; 
5. PT in alphabetical order. 


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Subjects are counted only once for each SOC and PT. In summaries of maximum severity and 
maximum relationship, subjects with multiple occurrences of events will only be counted once at 
the maximum severity/relationship per SOC and PT. 
Any treatment-emergent AEs that have a missing severity will be presented as severe in the 
summary table but will be presented with a missing severity in the data listing. Any treatment-
emergent AEs that have a missing relationship will be presented as “Related” in the summary table 
but will be presented with a missing relationship in the data listing. 
All AEs are displayed in listings. In addition, separate listings will be provided for: 
• Subjects with any treatment-emergent adverse event leading to study drug discontinuation 
or study termination; 
• Subjects with any serious adverse event (treatment-emergent or otherwise); 
• Subject deaths. 
9.7.1.6.2. Safety Labs (Chemistry and Hematology) 
Descriptive summaries of the observed test results at Visits 1 and 6 as well as the change from 
baseline at Visit 6 will be presented for serum chemistry and hematology labs. The frequency and 
percentage of subjects with observed values of Low, Normal, High as well as the categorical shift 
from baseline at Visit 6 will be tabulated. The percentages are calculated based on the number of 
subjects at each visit in each treatment group of the Safety Analysis Set. 
It is expected that all samples will be analyzed by a central laboratory. If a local laboratory is used 
(such as for an unscheduled visit), the results will be included in the listings of laboratory data, but 
will not be included in descriptive summaries. 
The results of pregnancy tests for women of childbearing potential will be presented in a listing. 
9.7.1.6.3. Best Corrected Visual Acuity (BCVA) 
Descriptive summaries of the observed values of LogMAR at each scheduled visit as well as the 
change from baseline at each post-baseline visit will be presented for both eyes. A categorical 
analysis of subjects who lose 0.3 lines ETDRS in either eye at each visit will be conducted.  
9.7.1.6.4. Slit Lamp Biomicroscopy and External Eye Exam 
The frequency and percentage of subjects with observed values of each categorical response or 
grade as well as the categorical shift from baseline at each post-baseline visit will be tabulated at 
each scheduled visit for both eyes. The percentages are calculated based on the number of subjects 
at each visit in each treatment group of the Safety Analysis Set. 
9.7.1.6.5. Intraocular Pressure (IOP) 
Descriptive summaries of the observed values at each scheduled visit as well as the change from 
baseline at each post-baseline visit will be presented for both eyes. A categorical analysis of 
subjects who gain 10 mmHg or more in IOP at each visit will be conducted.  


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9.7.1.6.6. Dilated Ophthalmoscopy 
The frequency and percentage of subjects with observed values of each categorical response at 
Visits 1 and 6 as well as the categorical shift from baseline at Visit 6 will be tabulated for both 
eyes. The percentages are calculated based on the number of subjects at each visit in each treatment 
group of the Safety Analysis Set.  
Descriptive summaries of the observed cup-to-disc ratio at Visits 1 and 6 as well as the change 
from baseline at Visit 6 will be presented for both eyes. 
9.7.1.6.7. Drop Comfort Assessment 
Descriptive summaries of the observed values at Visits 2 and 6 at 1 minute and 5 minutes post-
dose will be presented. 
9.7.2. 
Determination of Sample Size 
For mean change from baseline to Day 60 in tCFS, a sample size of 45 SY-201–treated subjects 
versus 45 vehicle-treated subjects will have 87.9% power to detect an effect size of 2.0 units with 
a standard deviation of 3.0 for an unpaired t-test with a 2-sided alpha = 0.05. For mean change 
from baseline to Day 60 in dry eye symptom
, a sample size of 45 SY-201–treated subjects 
versus 45 vehicle-treated subjects will have 83.5% power to detect an effect size of 1.5 units with 
a standard deviation of 2.4 for an unpaired t-test with a 2-sided alpha = 0.05. 
Fifty (50) subjects per treatment arm, for a total 200 subjects, will be enrolled to allow for some 
dropout of subjects. 


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9.8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES 
9.8.1. 
Protocol Amendments 
Not applicable. 
9.8.2. 
Changes from Protocol-Specified Analyses 
Time to first use of artificial tears will not be performed. 
9.8.3. 
SAP Amendments 
The SAP was amended to modify the MMP-9 subgroup analyses to be based on baseline tCFS. 
A Per Protocol Analysis Set will not be defined. 
 
 
 
 
 


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REFERENCES 
1. Mozzicato P. (2009). MedDRA: An overview of the medical dictionary for regulatory 
activities. Pharmaceutical Medicine 23: 65-75. 
2. Lagerlund O, Strese S, Fladvad M & Lindquist M. (2020). WHODrug: A global, validated 
and updated dictionary for medicinal information. Therapeutic Innovation & Regulatory 
Science 54: 1116–1122. 
3. SAS Institute Inc. What’s New in Base SAS® 9.4 and SAS® Viya®. (2013). SAS Institute 
Inc., Cary, NC, USA.  
4. SAS Institute Inc. (2020). SAS/STAT User’s Guide. SAS Institute Inc., Cary, NC, USA.


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Statistical Analysis Plan 
 
 
 
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APPENDIX I: SCHEDULE OF ASSESSMENTS 
 
Table 1: Schedule of Assessments 
 
Study Period 
Screening 
Treatment Period 
End of 
Study/ET 
Visit No. 
1 
2 
3 
4 
5 
6 
Study Day 
-14 
1 
7 
14 
28 
60 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Demographics/medical history 
X 
 
 
 
 
 
Concomitant medications query 
X 
X 
X 
X 
X 
X 
AE query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UPT for WOCBP 
X 
 
 
 
 
X 
Serum chemistry and hematology 
X 
 
 
 
 
X 
BCVA 
X 
X 
X 
X 
X 
X 
Biomicroscopy and external eye 
exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tear collection for biomarker test 
(POC MMP-9)a 
X 
X 
X 
X 
X 
X 
CFS 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
IOP 
X 
X 
X 
X 
X 
X 
Dilated ophthalmoscopy 
X 
 
 
 
 
X 
In-clinic administration of run-in 
product or IP  
X 
X 
 
 
 
X 
Drop comfort assessment 
 
X 
 
 
 
X 
Dispense run-in product or IP for 
home administration 
X 
X 
X 
X 
X 
 
Dispense preservative-free AT 
 
X 
X 
X 
X 
 
Issue and/or collect AT diary 
 
X 
X 
X 
X 
X 
Collect used and unused run-in 
product, AT, and/or IP 
 
X 
X 
X 
X 
X 
 
aMMP-9 will be assessed OU at Visits 1 and 2 and SE thereafter.  
bWait at least 15 minutes after grading CFS before conducting Schirmer test. 
Abbreviations: AE = adverse event; AT = artificial tears; BCVA = best corrected visual acuity
; CFS = corneal fluorescein staining; ET = early termination; IOP = intraocular ressure; IP = investi ational 
product; MMP-9 = matrix metalloproteinase-9; POC: point-of-care;
; 
SE = study eye; UPT = urine pregnancy test; WOCBP = women of childbearing potential 






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