A Multicenter, Randomized, Double-masked and Placebo-controlled Study Evaluating the Efficacy and Safety of SI-614 Ophthalmic Solution in Patients With Dry Eye
Phase: PHASE3
Conditions: Dry Eye Disease
Sponsor: Seikagaku Corporation

Clinical Trial Protocol 
 
 
A Multicenter, Randomized, Double-masked and Placebo-controlled Study 
Evaluating the Efficacy and Safety of SI-614 Ophthalmic Solution in Patients 
with Dry Eye (The SIDE Study) 
 
 
Version 1.0    23MAR2022 
 
 
NCT05411367 

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Clinical Trial Protocol: 614/1132  
 
 
 
 
 
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Clinical Trial Protocol 
Protocol Title: 
A Multicenter, Randomized, Double-masked and 
Placebo-controlled Study Evaluating the Efficacy and 
Safety of SI-614 Ophthalmic Solution in Patients with 
Dry Eye (The SIDE Study) 
Protocol Number: 
614/1132 
Study Phase: 
3 
Product Name: 
SI-614 ophthalmic solution 
IND Number: 
112,592 
Indication: 
Keratoconjunctivitis sicca (Dry Eye) 
Investigators: 
Multi-Center 
Sponsor: 
Seikagaku Corporation 
6-1, Marunouchi 1-chome 
Chiyoda-ku, Tokyo 100-0005, Japan 
Contract Research 
Organization: 
 
 
 
IRB: 
 
 
 
 
 
 
 
 
Original Protocol: 
March 23, 2022/Version 1.0 
Amendment 1: 
Not applicable 
 
Confidentiality Statement 
This protocol contains confidential, proprietary information of 
 and/or Seikagaku 
Corporation. Further dissemination, distribution or copying of this protocol or its contents 
is strictly prohibited. 
 

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MEDICAL MONITOR 
 
 
Responsible for medical 
management, safety surveillance, 
confirming patient eligibility, and 
reviewing safety data and clinical 
study report 
SPONSOR PERSONNEL 
 
 
Responsible for supervision of 
planning, management of clinical 
trial 
 
 
Responsible for study management 
 PERSONNEL 
 
 
 
Responsible for oversight and 
coordination of clinical trial and 
administrative follow-up 
 
 
 
 
Responsible for oversight of 
clinical planning, management and 
conduct of the clinical trial. 
 
 
 
 
Responsible for planning, 
management, conduct, and 
monitoring of clinical trial 
 
 

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SYNOPSIS 
Protocol Title: 
A Multicenter, Randomized, Double-masked and 
Placebo-controlled Study Evaluating the Efficacy and 
Safety of SI-614 Ophthalmic Solution in Patients 
with Dry Eye (The SIDE Study) 
Protocol Number: 
614/1132 
Study Drug: 
• 0.3% SI-614 ophthalmic solution  
• Placebo (vehicle of SI-614 ophthalmic solution) 
Study Phase: 
3 
Study Objective: 
To evaluate the efficacy and safety of 0.3% SI-614 
ophthalmic solution compared with placebo when 
administered 4 times daily for 84 days in patients 
with dry eye 
Overall Study Design 
Structure: 
Multi-center, double-masked, randomized, placebo-
controlled study 
Duration: 
2 weeks of run-in period and 12 weeks of treatment 
period 
Controls: 
Placebo 
Dosage/Dose Regimen: 
One drop of study drug will be instilled in each eye 4 
times daily (morning, noon, afternoon, evening 
before bedtime) for 84 days. Patients will be 
randomized in a 1:1 ratio into one of the 2 arms of 
the study: 
• 0.3% SI-614 
• Placebo 
Summary of Visit Schedule: 7 visits and 3 phone calls over the course of 
approximately 14 weeks 
• Visit 1, Day -14 ± 3 
• Visit 2, Day 1 
• Visit 3, Day 8 ± 2 
• Visit 4, Day 15 ± 2 
• Phone Call for Drug Compliance, Day 22 ± 2 
• Visit 5, Day 29 ± 3 
• Phone Call for Drug Compliance, Day 43 ± 2 
• Visit 6, Day 57 ± 3 
• Phone Call for Drug Compliance, Day 71 ± 2 
• Visit 7, Day 85 ± 3 

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Measures Taken to Reduce 
Bias: 
This is a randomized and double-masked study. 
Study Population Characteristics 
Number of Patients:   
Approximately 230 (115 per treatment arm) patients 
will be enrolled at up to 10 sites.  
Condition/Disease: 
Keratoconjunctivitis sicca (Dry Eye) 
Inclusion Criteria:  
Patients must: 
1. Be male or female of any race, at least 18 years 
of age at Visit 1. 
2. Have provided verbal and written informed 
consent. 
3. Be able and willing to use eye drops 4 times 
daily with a compliance rate of 80% or greater 
during the run-in period and follow instructions, 
including participation in all study assessments 
and visits. 
4. Have a patient-reported history of dry eye in 
both eyes for at least 6 months prior to Visit 1. 
5. Have used and/or desired to use an artificial tear 
substitute for dry eye symptoms within 6 
months prior to Visit 1. 
6. Have a best-corrected visual acuity score of 
+0.70 logarithm of the minimum angle of 
resolution (logMAR) or better in both eyes at 
Visit 1, as assessed by Early Treatment of 
Diabetic Retinopathy Study (ETDRS) chart. 
7. Report an average score of 2.0 or higher in at 
least 1 of the 5 symptoms over the 7 days prior 
to Visit 2 as measured by the 
 
Ocular Discomfort and 4-Symptom 
Questionnaire from the patient daily diary 
8. Have ALL of the following in the qualifying 
eye(s),
 
 at Visits 1 and 2: 
a) A tear film break-up time (TFBUT) of ≤ 5 
seconds and ≥ 1 second 
b) A fluorescein staining score of ≥ 2 in at 
least 1 region 
 

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c) A conjunctival redness score of ≥ 1 
 
 
d) A total lissamine green staining score of ≥ 2 
 
 
  
9. Demonstrate a response to the 
 at Visits 1 
and 2 in the qualifying eye(s), as defined as 
meeting ALL of the following criteria: 
a) Have an increase of ≥ 3 in fluorescein 
staining score in the cornea
 
 
b) Report a score of ≥ 3 
 
Ocular Discomfort Scale 
 
 
 
 
10. If a female of childbearing potential, have a 
negative urine pregnancy test at Visit 1 and will 
be using an adequate method of birth control 
throughout the study period. [Females are 
considered of childbearing potential unless they 
are surgically sterilized (bilateral tubal ligation, 
hysterectomy or bilateral oophorectomy) or 
post-menopausal (at least 12 months since last 
menses). Adequate birth control is defined as 
use of hormonal contraceptives (oral, 
implantable, injectable or transdermal), 
spermicide in conjunction with a barrier such as 
condom or diaphragm, or an intrauterine 
device, or surgical sterilization of partner. For 
non-sexually active females, abstinence may be 
regarded as an adequate method of birth 
control; however, if the patient becomes 
sexually active during the study, she must agree 
to use adequate birth control as defined above 
for the remainder of the study.] 
Exclusion Criteria:  
Patients must not: 
1. Have any clinically significant slit lamp 
findings at Visit 1 or Visit 2, including active 
blepharitis, meibomian gland dysfunction, lid 
margin inflammation or ocular allergies that 

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requires therapeutic treatment and/or, in the 
opinion of the investigator, may interfere with 
the study parameters. 
2. Be diagnosed with an ongoing ocular infection 
(bacterial, viral or fungal), or active ocular 
inflammation (eg, follicular conjunctivitis) at 
Visit 1 or Visit 2. 
3. Have a history of laser in situ keratomileusis 
(LASIK) surgery in either eye within 12 months 
prior to Visit 1, or have any scheduled LASIK 
surgery during the study period. 
4. Have had any ocular surgical procedure within 
12 months prior to Visit 1, or have any 
scheduled ocular surgical procedure during the 
study period. 
5. Have used contact lenses within 30 days prior 
to Visit 1 or anticipates use of contact lenses 
during the study period. 
6. Have used punctal plugs within 3 months prior 
to Visit 1 or anticipates use of punctal plugs 
during the study period. 
7. Have used nasal spray for dry eye (i.e. 
TYRVAYA®) within 30 days prior to Visit 1 or 
anticipates use of nasal spray for dry eye during 
the study period. 
8. Have used topical ocular cyclosporine (i.e., 
Restasis® or CequaTM) or topical lifitegrast (i.e. 
Xiidra®) within 45 days prior to Visit 1. 
9. Have used any topical ocular prescription 
(including medications for glaucoma) or over-
the-counter (OTC) solutions, artificial tear 
substitutes, gels or scrubs within 24 hours prior 
to Visit 1 or during the study period. 
10. Be currently using any medication known to 
cause ocular drying or increased lacrimation 
that has not been used on a stable dosing 
regimen for at least 30 days prior to Visit 1, or 
anticipates a change in such medication during 
the study period. 
11. Have a current malignancy or has received 
treatment of malignancy within the past 5 years 
prior to Visit 1. Patients who have undergone 

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successful resection of a basal cell or squamous 
cell carcinoma of the skin may be enrolled even 
if the resection was within 5 years. 
12. Have an uncontrolled systemic disease 
including, but not limited to clinically 
significant cardiovascular disease, pulmonary 
disease, or metabolic disease or any other 
systemic disease/symptoms that, in the opinion 
of the investigator, would interfere with study 
parameters. 
13. Have an uncontrolled psychiatric condition that 
required a change in medication in the 30 days 
prior to Visit 1, or anticipates hospitalization or 
change in such medication during the study 
period, or substance or alcohol abuse. 
14. Be a female who is pregnant, nursing an infant, 
or planning a pregnancy. 
15. Have a known allergy and/or sensitivity to the 
study drug or its components. 
16. Have a condition or is in a situation that, in the 
opinion of the investigator, may put the patient 
at significant risk, may confound the study 
results, or may interfere significantly with the 
patients’ participation in the study. 
17. Be currently enrolled in an investigational drug 
or device study, have used an investigational 
drug or device within 45 days prior to Visit 1, 
or have been previously randomized to receive 
SI-614 ophthalmic solutions or placebo. 
Evaluation Criteria 
Efficacy Measures:  
Primary Efficacy Measures: 
The following primary endpoint will be evaluated: 
• Change from baseline 
 in total corneal fluorescein staining score 
 in the study eye.  
Secondary Efficacy Measures: 
The following secondary endpoint will be used: 
• Change from baseline in the average score of 
ocular discomfort and dryness at the bedtime 
assessment from the patient daily diary during 
Day 1 through Day 14. 

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Exploratory Efficacy Measures: 
The following exploratory efficacy measures will be 
used: 
Signs 
• Fluorescein staining score 
 
 
• Lissamine green staining score 
 
  
• TFBUT  
• Conjunctival redness 
 
Symptoms 
• Patient daily diary during dosing period  
• Ocular Surface Disease Index© (OSDI)© 
questionnaire 
• 
 Ocular Discomfort and 4-Symptom 
Questionnaire 
• 
 Ocular Discomfort Scale 
Safety Measures: 
• Best-corrected visual acuity 
• Slit lamp biomicroscopy 
• Adverse event (AE) query 
Other Measures: 
• Urine pregnancy test 
General Statistical Methods and Types of Analyses 
Analysis Populations 
• Intention-to-Treat Population 
The intention-to-treat (ITT) population includes all randomized patients. Subjects 
in the ITT population will be analyzed as randomized. The primary analysis will 
be performed on the ITT population with the primary estimand. 
• Per-Protocol Population 
The per-protocol (PP) population is defined as all ITT patients who have no 
major protocol deviations and completed the trial. Protocol deviations will be 
assessed prior to database lock and unmasking. The PP population will be 
analyzed using observed data only for efficacy variables. Subjects in the PP 
population will be analyzed as treated. 
Safety Population – The safety population will include all patients who receive at 
least 1 dose of randomized study drug. Subjects in the Safety population will be 
analyzed as treated. 
Sample Size 
Difference and standard deviation (SD) estimates are derived from the Phase 2 and 
Phase 2/3 study. 

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The primary endpoint is the change from baseline 
 Day 29 
 in 
total corneal fluorescein staining. The study will be considered successful if and only 
if this endpoint is met. In order to have 90% power to detect a difference of -0.75 
between SI-614 and placebo, 109 patients per treatment arm are required to be 
randomized. This assumes a two-sided test at alpha = 0.05 and a common SD of 1.7 
in both treatment arms.  
Accounting for up to 5% dropouts in the study, 115 patients per treatment arm, or 
230 total patients are required to have 90% power for the primary endpoint. 
The hierarchical, secondary endpoint of the change from baseline in the average 
score of ocular discomfort and dryness at the bedtime assessment from the patient 
daily diary during Day 1 through Day 14 will have 51% power with this sample size, 
assuming a difference between SI-614 and placebo of -0.13. This endpoint will be 
tested conditional upon the primary endpoint being successful, thereby maintaining 
the study-wide type I error rate for both endpoints. The sample size calculation 
assumes a two-sided test at alpha = 0.05 and a common SD of 0.48 in both treatment 
arms.  
Multiplicity 
Hierarchical fixed sequence testing will be used in the analysis of the primary dry 
eye sign endpoint and the secondary dry eye symptom endpoint to maintain study 
wide type I error. The primary endpoint of change from baseline 
 at Day 29 
 of the corneal total fluorescein staining score will be evaluated at a two-
sided study wide alpha level of 0.05. If the primary endpoint is statistically 
significant, then the secondary endpoint of change from baseline of the bedtime 
assessment from the patient daily diary during Day 1 through Day 14 will be 
evaluated at a two-sided study wide alpha level of 0.05. If the primary endpoint is not 
statistically significant, no further formal hypothesis testing will proceed and the 
analyses of the secondary endpoint will be conducted as an exploratory analyses. 
Exploratory endpoints will not be type I error controlled and thus, considered 
exploratory and hypothesis generating. 
  
Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints, the unit of 
analysis will be the “study eye” as defined by the following: 
Study Eye: Eyes are eligible for analysis if they meet all “inclusion criteria” as 
specified in Section 5.3. In the case that both eyes are eligible for analysis, the study 
eye will be the eye with the largest change 
 in corneal 
total fluorescein staining score 
 at 
baseline (Visit 2). If the baseline change 
 in corneal total 
fluorescein staining score is the same in both eyes, then the right eye will be used as 
the study eye. If only one eye meets all inclusion criteria, then the single qualifying 
eye is the study eye. 
Primary Efficacy Analysis 
For the primary efficacy endpoint, change from baseline 
 will be calculated 
as visit – (minus) baseline 
 such that a positive difference indicates a 

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worsening of dry eye signs or symptoms. In addition, treatment comparisons between 
active and placebo will be calculated as 0.3% SI-614 – (minus) placebo, such that a 
negative result indicates a better score for the 0.3% SI-614 (i.e., 0.3% SI-614 
demonstrated less severity in dry eye signs or symptoms than the placebo group). 
The primary analysis of the primary endpoint will use the ITT population with 
multiple imputation methodology as specified in Estimand 1 (defined in Section 
11.4.4) using Analysis of Covariance (ANCOVA) if the rate of missing data for an 
endpoint is balanced between the two treatment groups (as evaluated by the Fisher’s 
exact test at an alpha level of 0.05) or the rate of missing data for an endpoint is ≤ 5% 
in all subjects. If the rate of missing data for an endpoint is imbalanced between 
treatment groups (as demonstrated by the Fisher’s exact test with a p-value < 0.05) 
and the rate of missing data for an endpoint is greater than 5% in all subjects, then 
the primary analyses will utilize the ITT population with observed data only using 
the permutation test with trimmed means methodology with Estimand 2 (defined in 
Section 11.4.4).1 
The ANCOVA model used to compare the change from baseline 
 to Day 29 
 in corneal total fluorescein staining score in the study eye between 0.3% 
SI-614 and placebo will include baseline 
 in corneal total fluorescein 
staining score in the study eye at Visit 2 and treatment group as covariates.  
As supportive analyses, two-sample t-tests and a Wilcoxon rank sum test will be 
conducted to compare the change from baseline 
 at Day 29 
 
between the two treatment groups. Additional exploratory comparisons of the mean 
raw scores of corneal total fluorescein staining score at Day 29 
 and 
baseline 
 (Visit 2, Day 1) between the treatment groups will be conducted 
using two-sample t-tests and Wilcoxon rank sum tests. Quantitative summary 
statistics will be provided for baseline Day 1 
, Day 29 
, and 
change from baseline 
 at Day 29 
. 
Sensitivity analyses will include multiple imputation by placebo group-based pattern 
mixture models (PMM), multiple imputation via randomized treatment group-based 
Markov Chain Monte Carlo (MCMC), single imputation by Last Observation Carried 
Forward (LOCF), tipping point analyses, and analyses of observed data only using 
the ITT and PP populations. 
Secondary Efficacy Analyses 
Analyses of the secondary efficacy endpoint of the change from baseline (Day -7 
through Day -1) in average score of ocular discomfort and dryness at the bedtime 
assessment from the patient daily diary during Day 1 through Day 14 will use a 
Mixed-Model Repeated Measures (MMRM). The model will include the baseline 
average score of ocular discomfort and dryness (average of Day -7 through Day -1), 
treatment group, study day (Day 1 to Day 14 as categorical variables), and the 
interaction between treatment group and study day as fixed effects with correlated 
errors due to study day. The overall treatment differences (0.3% SI-614 versus 
placebo) and the corresponding p-values will be estimated based on the MMRM. As 

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a sensitivity analysis, the above model will also be run without including the baseline 
average score of ocular discomfort and dryness symptom as a covariate. 
As an additional sensitivity analysis of the average score of ocular discomfort and 
dryness symptom, the change from baseline in average ocular discomfort and dryness 
score from Day 1 to Day 14 will also be compared between the 2 treatment groups 
using two-sample t-tests and Wilcoxon rank sum tests for each individual day. In 
addition, an ANCOVA model using the baseline average score of ocular discomfort 
and dryness and treatment group will be used to examine change from baseline at 
each day. 
Analyses of the secondary endpoint will utilize the ITT population using observed 
data only. Sensitivity analyses will include multiple imputation as described in 
Estimand 1, multiple imputation by placebo group-based PMM, multiple imputation 
via randomized treatment group-based MCMC, single imputation by LOCF, and 
analyses of observed data only using the PP population. 
Exploratory Efficacy Analyses 
Exploratory efficacy variables will generally be analyzed on the ITT population 
using observed data. 
For signs 
 (including fluorescein 
staining, lissamine green staining, TFBUT, and conjunctival redness), the change 
 
at each visit will be compared between the 2 treatment groups 
using a two-sample t-test, a Wilcoxon rank sum test, as well as an ANCOVA model 
adjusting for baseline 
 value. In addition, change from time point-matched 
baseline (
) will be analyzed 
similarly. 
For symptom measures (including OSDI, 
 Ocular Discomfort and 4-
symptom Questionnaire), each individual symptom score as well as the change from 
baseline (
 at Visit 2) will be compared between 0.3% SI-614 and placebo for 
each visit using a two-sample t-test, a Wilcoxon rank sum test, and an ANCOVA 
model adjusting for baseline. 
 Ocular Discomfort Scale 
 is measured every 5 
minutes 
 The area under the curve will be 
calculated for each patient using the trapezoidal rule, and compared between 
treatment groups using a two-sample t-test, as well as an ANCOVA model adjusting 
for baseline (Visit 2 area under the curve). 
Safety Variables 
Frequencies and percentages of patients with treatment-emergent adverse events 
(TEAEs), serious TEAEs, and TEAEs causing premature discontinuation will be 
provided by treatment group. An AE is treatment emergent if it occurs or worsens 
after the first dose of study treatment. Furthermore, frequencies will be given of 
patients with TEAEs by system organ class (SOC), by SOC and preferred term (PT), 
by SOC, PT and maximal severity, by SOC, PT and strongest relationship, and by 

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SOC, PT, maximal severity, and strongest relationship. Separate analyses will be 
performed for ocular and non-ocular TEAEs. 
Other safety endpoints including visual acuity, slit lamp biomicroscopy, and corneal 
sensitivity will be summarized by treatment group and visit using descriptive 
statistics. Changes or shifts from baseline will also be summarized where 
appropriate. For assessments performed by eye, study eye and fellow eye will be 
summarized separately. In addition, shifts from baseline to worst on-treatment value 
for ocular safety assessments will be summarized. All safety endpoints will be 
assessed using the Safety population. 
Summary of Known and Potential Risks and Benefits to Human Patients 
SI-614 ophthalmic solution appears to be safe and well-tolerated. In a Phase 2 
clinical trial of SI-614 with 150 dry eye patients, a subgroup of more symptomatic 
dry eye patients treated with 0.3% SI-614 showed statistically significantly reduced 
corneal fluorescein staining and statistically significantly improved dry eye 
symptoms. The most common ocular TEAEs were instillation site reactions (24.7% 
of TEAEs), and possibly but less likely, ocular hyperemia or reduced visual acuity 
(each of which were 1.3% of TEAEs).  In a Phase 2/3 study in 240 patients with dry 
eye, 0.3% SI-614 showed statistically significant improvement in the dry eye 
symptom primary efficacy endpoint, reproducing the results of the Phase 2 study 
subgroup analysis.  The most frequently reported acute AE was instillation site 
pain: 16 patients (13.1%) in the 0.3% SI-614 group and 8 patients (6.8%) in the 
placebo group, and all of these events were mild in severity and were resolved by the 
end of the study. Overall, the incidence of TEAEs in the 0.3% SI-614 group was 
comparable with that in the placebo group.   
Potential Risks: Phase 2 and Phase 2/3 data indicate that SI-614 has an acceptable 
safety profile. 
Potential Benefits: Patients may experience a reduction in various signs and 
symptoms of dry eye disease. 
 
 

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TABLE OF CONTENTS 
SYNOPSIS ..........................................................................................................................3 
TABLE OF CONTENTS ................................................................................................13 
LIST OF ABBREVIATIONS .........................................................................................16 
1 
INTRODUCTION...................................................................................................17 
1.1 Risks and Benefits ..........................................................................................18 
2 
STUDY OBJECTIVES ...........................................................................................20 
3 
CLINICAL HYPOTHESES ..................................................................................21 
4 
OVERALL STUDY DESIGN ................................................................................22 
5 
STUDY POPULATION .........................................................................................24 
5.1 Number of Patients .........................................................................................24 
5.2 Study Population Characteristics ....................................................................24 
5.3 Inclusion Criteria ............................................................................................24 
5.4 Exclusion Criteria ...........................................................................................25 
5.5 Withdrawal Criteria (if applicable) ................................................................26 
6 
STUDY PARAMETERS ........................................................................................28 
6.1 Efficacy Measures ..........................................................................................28 
6.1.1 
Primary Efficacy Measures ...............................................................28 
6.1.2 
Secondary Efficacy Measures ...........................................................28 
6.1.3 
Exploratory Efficacy Measures.........................................................28 
6.2 Safety Measures .............................................................................................28 
6.3 Other Measures ...............................................................................................28 
7 
STUDY MATERIALS ............................................................................................29 
7.1 Study Drug(s) .................................................................................................29 
7.1.1 
Run-In ...............................................................................................29 
7.1.2 
Study Drug(s)/Formulation(s) ...........................................................29 
7.1.3 
Study Drug Packaging Configuration ...............................................29 
7.1.4 
Study Drug Storage and Accountability ...........................................29 
7.1.5 
Instructions for Dispensation, Use, and Administration ...................29 
7.2 Other Study Supplies ......................................................................................30 
8 
STUDY METHODS AND PROCEDURES .........................................................31 
8.1 Patient Entry Procedures ................................................................................31 
8.1.1 
Overview ...........................................................................................31 
8.1.2 
Informed Consent..............................................................................31 
8.1.3 
Washout Intervals .............................................................................31 
8.1.4 
Procedures for Final Study Entry ......................................................31 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................31 
8.2 Concurrent Therapies .....................................................................................32 
8.2.1 
Prohibited Medications/Treatments ..................................................32 
8.2.2 
Escape Medications ..........................................................................33 
8.2.3 
Special Diet or Activities ..................................................................33 
8.3 Examination Procedures .................................................................................33 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s)...........................................................................................33 
8.4 Schedule of Visits, Measurements and Dosing ..............................................42 

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8.4.1 
Scheduled Visits................................................................................42 
8.4.2 
Unscheduled Visits ...........................................................................42 
8.5 Compliance with Protocol ..............................................................................43 
8.6 Patient Disposition .........................................................................................43 
8.6.1 
Completed Patients ...........................................................................43 
8.6.2 
Discontinued Patients........................................................................43 
8.7 Study Termination ..........................................................................................44 
8.8 Study Duration ...............................................................................................44 
8.9 Monitoring and Quality Assurance ................................................................44 
9 
ADVERSE EVENTS ..............................................................................................45 
9.1 Adverse Event ................................................................................................45 
9.1.1 
Severity .............................................................................................45 
9.1.2 
Relationship to Study Drug ...............................................................45 
9.2 Serious Adverse Events ..................................................................................46 
9.3 Procedures for Reporting Adverse Events .....................................................47 
9.3.1 
Reporting a Serious Adverse Event ..................................................47 
9.4 Procedures for Unmasking of Study Drug .....................................................48 
9.5 Type and Duration of the Follow-up of Patients after Adverse Events .........48 
10 
Pregnancy ................................................................................................................49 
11 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES................50 
11.1 Analysis Populations ......................................................................................50 
11.2 Statistical Hypotheses .....................................................................................50 
11.3 Sample Size ....................................................................................................50 
11.4 Statistical Analysis .........................................................................................51 
11.4.1 
General Considerations .....................................................................51 
11.4.2 
Unit of Analysis ................................................................................51 
11.4.3 
Missing Data .....................................................................................51 
11.4.4 
Primary Efficacy Analyses ...............................................................52 
11.4.5 
Secondary Efficacy Variables ...........................................................55 
11.4.6 
Exploratory Efficacy Variables .........................................................55 
11.4.7 
Safety Variables ................................................................................56 
11.4.8 
Adjustment for Multiplicity ..............................................................56 
11.4.9 
Interim Analyses ...............................................................................57 
12 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ................................58 
12.1 Protection of Human Patients .........................................................................58 
12.1.1 
Patient Informed Consent .................................................................58 
12.1.2 
Institutional Review Board Approval ...............................................58 
12.2 Ethical Conduct of the Study ..........................................................................58 
12.3 Patient Confidentiality ....................................................................................58 
12.4 Documentation ...............................................................................................59 
12.4.1 
Retention of Documentation .............................................................59 
12.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ...................................................................................................59 
12.5.1 
Labeling/Packaging...........................................................................59 
12.5.2 
Storage of Study Drug ......................................................................59 

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12.5.3 
Accountability of Study Drug ...........................................................60 
12.5.4 
Return or Disposal of Study Drug ....................................................60 
12.6 Recording of Data on Source Documents and Case Reports Forms (CRFs) .60 
12.7 Handling of Biological Specimens .................................................................60 
12.8 Amendments to the Protocol ..........................................................................60 
12.9 Publications ....................................................................................................61 
13 
REFERENCES ........................................................................................................62 
14 
APPENDICES .........................................................................................................63 
Appendix 1: Schedule of Visits and Measurements ......................................................64 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ..............66 
Appendix 3: List of Ocular Drying or Increased Lacrimation Medications ..............81 
Appendix 4: Key Organizations and Personnel ............................................................82 
Appendix 5: Amendment Summary of Changes...........................................................83 
Appendix 6: Sponsor and 
 Approvals .....................................................................84 
Appendix 7: Investigator’s Signature ............................................................................85 
Appendix 8: COVID-19 PANDEMIC AND SUGGESTED MEASURES .................86 
 
 

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LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
 
 
CFR 
Code of Federal Regulations 
eCRF 
electronic case report form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
HA 
sodium hyaluronate 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IRB 
institutional/independent review board 
ITT 
intention-to-treat 
IVRS/IWRS 
Interactive Voice/Web Response System 
LASIK 
laser in situ keratomileusis 
LOCF 
last observation carried forward 
logMAR 
logarithm of the minimum angle of resolution 
LS 
least squares 
MCMC 
Markov Chain Monte Carlo 
OSDI 
Ocular Surface Disease Index 
OTC 
over-the-counter 
PMM 
pattern mixture models 
PP 
per-protocol 
PT 
preferred term 
SAE 
serious adverse event 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TFBUT 
tear film break-up time 
TEAE 
treatment-emergent adverse event 
US 
United States 
WOCBP 
women of childbearing potential 
 
 

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1 
INTRODUCTION 
Dry eye is a multifactorial condition characterized by tear hyperosmolarity and tear film 
instability, which can lead to corneal surface damage and an inflammatory component 
that worsens the condition. Patients with dry eye experience symptoms of discomfort and 
visual disturbance. The first line of therapy for patients with mild to moderate dry eye is 
tear supplementation with products generally categorized as artificial tears. These 
products, however, do not accurately mimic the unique physical and chemical properties 
of natural tear films, which are a complex mixture of lipids, an aqueous solution of 
proteins and electrolytes, and a mucous component. Most artificial tear products are 
hypotonic or isotonic buffered solutions containing electrolytes, surfactants and various 
types of viscosity agents. Macromolecular complexes added to artificial tear solutions act 
as viscosity agents for the aqueous layer; carboxymethylcellulose is the most commonly 
used agent in the United States (US). Most artificial tear solutions are minimally effective 
and must be instilled many times per day. 
SI-614 is a chemically modified sodium hyaluronate (HA). HA is a biopolymer that is 
present in the vitreous body of the eye, extracellular matrix of the skin, and synovial fluid 
within joints. HA is composed of linear chains of disaccharide units (N-acetyl-
glucosamine and glucuronate) in varying molecular weights. HA molecules possess 
unique physical and chemical properties such as viscoelasticity and water retention. HA 
is used in a variety of medical applications, including ocular surgery, arthritis treatment 
and dermatology applications. In most of these applications, the product utilizing HA is 
classified as a medical device based on the viscoelastic properties. HA is the active 
ingredient in several contact lens wetting solutions. 
HA has been investigated as a viscosity agent in artificial tear formulations for the 
treatment of dry eye. 0.2% HA demonstrated significantly longer ocular surface residence 
times than 0.3% hydroxypropylmethylcellulose or 1.4% polyvinyl alcohol.2 Some early 
clinical studies reported improvement of dry eye signs and symptoms in patients treated 
with HA-containing solutions compared to other lubricant solutions, whereas others did 
not.3-6 Recent clinical studies have demonstrated improvement in dry eye signs and 
symptoms.7-10 
Lubricant preparations containing HA as the active ingredient have been approved for use 
in the treatment of dry eye in multiple countries, but not in the US. HA ophthalmic 
solution 0.1% and 0.3% has been marketed in Japan since 1995 and in some other Asian 
countries under the trade names Hyalein®. Current usage is over 40 million units per year. 
HA ophthalmic solution 0.18% has also been marketed in Europe, Australia, and parts of 
Asia under the trade names Vismed®, Vislube®, and Hylovis®. In the US, HA is listed as 
an inactive ingredient in an over-the-counter (OTC) artificial tear product (Blink® Tears). 
SI-614 has demonstrated improved tear film stabilization compared to HA in pre-clinical 
studies, and in Phase 2 and Phase 2/3 clinical studies. In the Phase 2 study, statistically 
significant reductions in corneal fluorescein staining and improved dry eye symptoms 
were seen. In the Phase 2/3 study, SI-614 demonstrated statistically significant 
improvements for dry eye symptoms (ocular discomfort and dryness) and secondary 
analyses supported indicated that statistically significant improvements in all symptoms 
began within the first 5 days of dosing and remained efficacious for the entire 28 days 

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treatment period. Despite its effect on symptomatology, 0.3% SI-614 ophthalmic solution 
failed to show a statistically significant reduction in corneal fluorescein staining score in 
the study eye at Day 28 (primary sign). The detailed results from nonclinical and prior 
clinical stuies can be found in the latest version of the investigator’s brochure. 
The objective of the current Phase 3 study is to evaluate the efficacy and safety of 
0.3% SI-614 ophthalmic solution compared to placebo when administered 4 times daily 
for 84 days in patients with dry eye.  
1.1 
Risks and Benefits 
Treatment with SI-614 appeared to be safe and well-tolerated in Phase 2 and Phase 2/3 
studies conducted in patients with dry eye. 
A Phase 2, multicenter, randomized, double-masked, parallel-group study was conducted 
to evaluate the efficacy and safety of 2 concentrations (0.3% and 0.5%) of SI-614 
ophthalmic solution compared to placebo (vehicle) when administered 4 times daily for 
28 days in 150 patients with dry eye. Neither SI-614 concentration met the protocol-
defined efficacy objectives. However, treatment with 0.3% SI-614 statistically 
significantly reduced corneal fluorescein staining at Day 28 and statistically significantly 
improved dry eye symptoms during Day 0 through Day 13 compared to placebo in a 
subgroup of more symptomatic patients (ie, those who had a worst symptom score ≥ 2.5 
during Day -7 through Day -1). The 0.3% SI-614 appeared to be more effective in 
reducing dry eye symptoms rapidly than 0.5% SI-614. Both concentrations of SI-614 
were safe and well-tolerated. Most of the adverse events (AEs) were of mild severity, 
with no severe AEs. The most common ocular treatment-emergent adverse events 
(TEAEs) were instillation site reactions (37 [24.7%], of which 25 were in the SI-614 
treatment groups and 12 were in the placebo group), ocular hyperemia (2 [1.3%], 1 in 
each of the SI-614 groups), and reduced visual acuity (2 [1.3%], 1 in each of the SI-614 
groups). 
A Phase 2/3 study was conducted to evaluate the efficacy and safety of 0.3% SI-614 
compared to placebo (vehicle) when administered 4 times daily for 28 days int 240 
patiens with dry eye. Statistically significant improvements were seen for the primary 
efficacy symptom objective of mean change from baseline in average score of ocular 
discomfort and dryness at the bedtime assessment from the patient daily diary during 
Day 0 through Day 13. SI-614 failed to meet the primary sign endpoint of mean change 
 
in the study eye at Day 28. The majority of AEs were mild in severity and 
no AEs were severe. No serious adverse events (SAEs) were reported. The most 
frequently reported ocular TEAE and non-ocular TEAE were instillation site pain (20 
[16.4%] patients in the 0.3% SI-614 group and 16 [13.6%] patients in the placebo group) 
and nosopharyngitis (4 [3.3%] patients in the 0.3% SI-614 group and 3 [2.5%] patients in 
the placebo group). Four TEAEs led to the premature discontinuation of 2 patients; 1 
patient in the 0.3% SI-614 group (conjunctivitis right eye, conjunctivitis left eye) and 1 
patient in the placebo group (conjunctivitis right eye, conjunctivitis left eye). No safety 
concerns were raised in terms of visual acuity and slit lamp biomicroscopy assessments. 

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Potential Risks: Based on the results of Phase 2 and Phase 2/3 studies with SI-614, the 
most likely AEs that patients may experience include instillation site reactions, and, 
possibly but less likely, reduced visual acuity. AEs reported in published safety data from 
clinical trials of HA ophthalmic solutions in dry eye patients included worsening of dry 
eye symptoms, eye pain, or foreign body sensation. Additionally, based on results from 
animal studies with SI-614, patients may also experience discharge and redness of the 
eye. 
Potential Benefits: Patients may experience a reduction in various signs and symptoms of 
dry eye. 
 
 

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2 
STUDY OBJECTIVES  
To evaluate the efficacy and safety of 0.3% SI-614 ophthalmic solution compared with 
placebo when administered 4 times daily for 84 days in patients with dry eye  
 

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3 
CLINICAL HYPOTHESES 
The clinical hypotheses for this study are that 0.3% SI-614 ophthalmic solution is 
superior to placebo for the primary endpoints of signs, as follows: 
• 
Patients receiving 0.3% SI-614 ophthalmic solution will have a statistically 
significantly smaller increase in total corneal fluorescein staining score at Day 29 
(Visit 5) 
 
compared with patients receiving placebo (primary sign). 
 
 

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4 
OVERALL STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-masked study designed to evaluate the 
efficacy and safety of 0.3% SI-614 ophthalmic solution compared to placebo in patients 
with dry eye. Approximately 230 male and female patients at least 18 years of age with a 
patient-reported history of dry eye in both eyes and meeting all other study eligibility 
criteria will be randomized to receive treatment with 0.3% SI-614 or placebo in a 1:1 
ratio (approximately 115 patients in each treatment group). This study will consist of 2 
periods: a 14-day run-in period and a 84-day treatment period. A study flow chart appears 
below: 
Visit 1 
(Day -14 ± 3) 
Informed Consent 
Demographics, Medical/Medication & Ocular History 
Urine Pregnancy Testing (as needed) 
Symptom Questionnaires, Best-corrected Visual Acuity 
 
 
 
Run-in Vials & Patient Daily Diary Dispensed 
 
 
Placebo Run-in Period (14 ± 3 days) 
 
 
Visit 2 
(Day 1) 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Best-corrected Visual Acuity 
 
 
 
Randomization 
Study Drug Vials & Patient Daily Diary Dispensed 
 
 
Visit 3 
(Day 8 ± 2) 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Best-corrected Visual Acuity 
Eye Evaluations 
Patient Daily Diary Dispensed 
 
 
Visit 4 
(Day 15 ± 2) 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Best-corrected Visual Acuity 
 
 
 
Study Drug Vials & Patient Daily Diary Dispensed 
 
 
Compliance Phone Call (Day 22 ± 2) 
 
 
Visit 5 
(Day 29 ± 3) 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Best-corrected Visual Acuity 
 
 
 
Study Drug Vials & Patient Daily Diary Dispensed 
 
Compliance Phone Call (Day 43 ± 2) 
 
 

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Visit 6 
(Day 57 ± 3) 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Best-corrected Visual Acuity 
 
 
 
Study Drug Vials & Patient Daily Diary Dispensed 
 
Compliance Phone Call (Day 71 ± 2) 
 
 
Visit 7 
(Day 85 ± 3) 
Medical/Medication Update: AE Query 
Urine Pregnancy Testing (as needed) 
Symptom Questionnaires, Best-corrected Visual Acuity 
 
 
 
Study Exit 
 
Patients who terminate early during the treatment period will be asked to complete safety 
and efficacy assessments prior to commencement of any alternative dry eye therapy (if at 
all possible). Patients who are terminated early from the study will not be replaced. 
In this study, the vehicle of SI-614 ophthalmic solution has been selected as the placebo 
control to objectively evaluate the efficacy and safety of 0.3% SI-614 ophthalmic 
solution. In addition, randomized assignment and double-masked design features has 
been implemented to minimize any bias for patient selection and data evaluation. 
 
 

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5 
STUDY POPULATION 
5.1 
Number of Patients  
It is estimated that approximately 230 patients (115 in each arm) will be enrolled. 
Patients will be randomized in a 1:1 ratio of 0.3% SI-614 to placebo. 
5.2 
Study Population Characteristics 
All patients must meet all inclusion criteria and none of the exclusion criteria. 
5.3 
Inclusion Criteria 
Patients must: 
1. Be male or female of any race, at least 18 years of age at Visit 1. 
2. Have provided verbal and written informed consent. 
3. Be able and willing to use eye drops 4 times daily with a compliance rate of 80% or 
greater during the run-in period and follow instructions, including participation in all 
study assessments and visits. 
4. Have a patient-reported history of dry eye in both eyes for at least 6 months prior to 
Visit 1. 
5. Have used and/or desired to use an artificial tear substitute for dry eye symptoms 
within 6 months prior to Visit 1. 
6. Have a best-corrected visual acuity score of +0.70 logarithm of the minimum angle of 
resolution (logMAR) or better in both eyes at Visit 1, as assessed by Early Treatment 
of Diabetic Retinopathy Study (ETDRS) chart 
7. Report an average score of 2.0 or higher in at least 1 of the 5 symptoms over the 7 
days prior to Visit 2 as measured by the 
 Ocular Discomfort and 4-
Symptom Questionnaire from the patient daily diary 
8. Have ALL of the following in the qualifying eye(s), 
 at Visits 1 and 2: 
a) A tear film break-up time (TFBUT) of ≤ 5 seconds and ≥ 1 second 
b) A fluorescein staining score of ≥ 2 in at least 1 region 
 
c) A conjunctival redness score of ≥ 1 
 
d) A total lissamine green staining score of ≥ 2 
 
  
9. Demonstrate 
 at Visits 1 and 2 in the qualifying eye(s), as 
defined as meeting ALL of the following criteria: 
a) Have an increase of ≥ 3 in fluorescein staining score in the cornea 
 
b) Report a score of ≥ 3 
 Ocular Discomfort Scale at 2 or more 
consecutive time points 
 (if patient reports a score of 3 at 
Time 0, the patient must have a score of 4 at 2 or more consecutive time points) 

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10. If a female of childbearing potential, have a negative urine pregnancy test at Visit 1 
and will be using an adequate method of birth control throughout the study period. 
[Females are considered of childbearing potential unless they are surgically sterilized 
(bilateral tubal ligation, hysterectomy or bilateral oophorectomy) or post-menopausal 
(at least 12 months since last menses). Adequate birth control is defined as use of 
hormonal contraceptives (oral, implantable, injectable or transdermal), spermicide in 
conjunction with a barrier such as condom or diaphragm, or an intrauterine device, or 
surgical sterilization of partner. For non-sexually active females, abstinence may be 
regarded as an adequate method of birth control; however, if the patient becomes 
sexually active during the study, she must agree to use adequate birth control as 
defined above for the remainder of the study.] 
5.4 
Exclusion Criteria 
Patients must not: 
1. Have any clinically significant slit lamp findings at Visit 1 or Visit 2, including active 
blepharitis, meibomian gland dysfunction, lid margin inflammation or ocular allergies 
that requires therapeutic treatment and/or, in the opinion of the investigator, may 
interfere with the study parameters. 
2. Be diagnosed with an ongoing ocular infection (bacterial, viral or fungal), or active 
ocular inflammation (eg, follicular conjunctivitis) at Visit 1 or Visit 2. 
3. Have a history of laser in situ keratomileusis (LASIK) surgery in either eye within 12 
months prior to Visit 1, or have any scheduled LASIK surgery during the study 
period. 
4. Have had any ocular surgical procedure within 12 months prior to Visit 1, or have any 
scheduled ocular surgical procedure during the study period. 
5. Have used contact lenses within 30 days prior to Visit 1 or anticipates use of contact 
lenses during the study period. 
6. Have used punctal plugs within 3 months prior to Visit 1 or anticipates use of punctal 
plugs during the study period. 
7. Have used nasal spray for dry eye (i.e. TYRVAYA®) within 30 days prior to Visit 1 
or anticipates use of nasal spray for dry eye during the study period. 
8. Have used topical ocular cyclosporine (ie, Restasis® or CequaTM) or topical lifitegrast 
(i.e. Xiidra®) within 45 days prior to Visit 1. 
9. Have used any topical ocular prescription (including medications for glaucoma) or 
OTC solutions, artificial tear substitutes, gels or scrubs within 24 hours prior to Visit 
1 or during the study period. 
10. Be currently using any medication known to cause ocular drying or increased 
lacrimation that has not been used on a stable dosing regimen for at least 30 days 
prior to Visit 1, or anticipates a change in such medication during the study period. 
11. Have a current malignancy or has received treatment of malignancy within the past 5 
years prior to Visit 1. Patients who have undergone successful resection of a basal 

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cell or squamous cell carcinoma of the skin may be enrolled even if the resection was 
within 5 years. 
12. Have an uncontrolled systemic disease including, but not limited to clinically 
significant cardiovascular disease, pulmonary disease, or metabolic disease or any 
other systemic disease/symptoms that, in the opinion of the investigator, would 
interfere with study parameters. 
13. Have an uncontrolled psychiatric condition that required a change in medication in 
the 30 days prior to Visit 1, or anticipates hospitalization or change in such 
medication during the study period, or substance or alcohol abuse. 
14. Be a female who is pregnant, nursing an infant, or planning a pregnancy. 
15. Have a known allergy and/or sensitivity to the study drug or its components. 
16. Have a condition or is in a situation that, in the opinion of the investigator, may put 
the patient at significant risk, may confound the study results, or may interfere 
significantly with the patients’ participation in the study. 
17. Be currently enrolled in an investigational drug or device study, have used an 
investigational drug or device within 45 days prior to Visit 1, or have been previously 
randomized to receive SI-614 ophthalmic solutions or placebo.  
5.5 
Withdrawal Criteria (if applicable) 
Patients are free to discontinue their participation in this study at any time and for any 
reason, specified or unspecified, without prejudice. In addition, the Investigator may 
decide to discontinue a patient from the study for safety reasons or when it is in the best 
interest of the patient. No constraints will be placed on ordinary patient management, and 
patients (when appropriate) will be placed on other conventional therapy upon request or 
whenever clinically necessary as determined by their physician. 
Reasons for patient withdrawal may include but are not limited to the following: 
• 
Either at the Investigator's request, for safety reasons (eg, serious or severe AE), 
or at the patient’s request. 
• 
Non-compliance (eg, failure to follow dosing instructions, missing visits, using 
prohibited medications). 
• 
When a concomitant therapy likely to interfere with the results of the study is 
reported or required by the patient (the Investigator will report all such 
information on the source documents/electronic case report forms (eCRFs) and 
decide, in accordance with the Sponsor, whether the patient is to be withdrawn). 
• 
A confirmed positive pregnancy test at any time during the study. 
• 
When a patient is lost to follow-up. The Investigator (or designee) will attempt 3 
times to reach the patient by telephone, and will send a follow-up letter by 
certified mail before considering the patient as lost to follow-up. These actions 
will be documented in the source document and recorded on the End of Study 
eCRF, and a copy of the follow-up letter maintained in the Investigator's file. 

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• 
When a patient is erroneously admitted into the study or does not meet eligibility 
criteria. 
In addition, the Sponsor also reserves the right to discontinue the study at any time for 
either clinical or administrative reasons. 
Patients not completing the entire study should be fully evaluated when possible. If, for 
any reason, a patient is discontinued before completing Visit 5, the patient should return 
to the clinic to return all used and unused study drug vials and patient daily diary and 
perform all the safety assessments scheduled for Visit 5 including but not limited to AE 
query, pregnancy test, best-corrected visual acuity and slit lamp biomicroscopy 
evaluation, and the reason for termination entered in the source document and End of 
Study eCRF. 
All early terminations and their reasons must be carefully documented by the Investigator 
on the End of Study eCRF and, if applicable, on the Adverse Event eCRF. No patient 
who has been randomized can be replaced by another if the patient is discontinued 
prematurely for any reason. 
 
 

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6 
STUDY PARAMETERS 
6.1 
Efficacy Measures  
6.1.1 Primary Efficacy Measures 
The following primary endpoint will be evaluated: 
• 
Change from baseline 
 to Day 29 
 in total corneal fluorescein 
staining score 
 
6.1.2 Secondary Efficacy Measures 
The following secondary endpoint will be evaluated: 
• 
Change from baseline in the average score of ocular discomfort and dryness at the 
bedtime assessment from the patient daily diary during Day 1 through Day 14. 
6.1.3 Exploratory Efficacy Measures 
The following exploratory efficacy measures will be used: 
Signs 
• 
Fluorescein staining score 
 
• 
Lissamine green staining score 
  
• 
TFBUT  
• 
Conjunctival redness 
 
Symptoms 
• 
Patient daily diary during dosing period  
• 
Ocular Surface Disease Index (OSDI) questionnaire 
• 
 Ocular Discomfort and 4-Symptom Questionnaire 
• 
 Ocular Discomfort Scale 
6.2 
Safety Measures 
• 
Best-corrected visual acuity 
• 
Slit lamp biomicroscopy 
• 
AE query 
6.3 
Other Measures 
• 
Urine pregnancy test  
 
 

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7 
STUDY MATERIALS 
7.1 
Study Drug(s) 
7.1.1 Run-In 
The placebo (vehicle) solution is formulated as a clear, colorless, sterile, aqueous solution 
for topical ocular administration. The solution is composed of the same formulation as 
SI-614 ophthalmic solution but does not contain the active ingredient, SI-614. The 
placebo container is identical to the SI-614 ophthalmic solution vials. 
7.1.2 Study Drug(s)/Formulation(s) 
• 
0.3% SI-614 ophthalmic solution  
SI-614 ophthalmic solution is formulated as a clear, colorless, sterile aqueous 
solution for topical ocular administration containing: the active ingredient (SI-614 
0.3% w/v), sodium chloride, potassium chloride, dibasic sodium phosphate, 
sodium dihydrogen phosphate and water for injection, adjusted to pH 5.0 to 6.0. It 
is packaged in low-density polyethylene vials.  
• 
Placebo ophthalmic solution 
The placebo ophthalmic solution is formulated as a clear, colorless, sterile 
aqueous solution for topical ocular administration. The solution is composed of 
the same formulation as SI-614 ophthalmic solution but does not contain the 
active ingredient, SI-614. The placebo container is identical to the SI-614 
ophthalmic solution vials. 
7.1.3 Study Drug Packaging Configuration 
Nineteen pouches will be packed in a two-week clinical kit. Each pouch will contain 1 
day’s supply of study medication for 4 times daily dosing. Each pouch contains of 5 
vials. Pouches will be labeled and the two-week clinical kits will be labeled. 
7.1.4 Study Drug Storage and Accountability 
Study drug(s) must be stored at controlled room temperature (25°C or less, Do Not 
Freeze), protected from light, and secured at the investigational site in a locked container, 
with access limited to the Investigator and designated study personnel. 
The study drug is to only be prescribed by the principal investigator or his/her named sub 
investigator(s), and is to only be used in accordance with this protocol. The study drug 
must only be distributed to patients properly qualified under this protocol to receive study 
drug. The investigator must keep an accurate accounting of the study drug by maintaining 
a detailed inventory. This includes the amount of study drug received by the site, amount 
dispensed to patients, amount returned to the site by the patients, and the amount returned 
to the Sponsor or destroyed upon the completion of the study. 
7.1.5 Instructions for Dispensation, Use, and Administration 
Patients will instill 1 drop of study drug (0.3% SI-614 or placebo) into each eye 4 times 
daily (morning, noon, afternoon, evening before bedtime) for 84 days. Study drug will be 

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stored in light protective foil pouches, which will contain 5 vials. Four vials of study drug 
will be insilled daily, one vial for back-up. Unused vial will be returned to the site. 
Patients should not open a foil pouch until they are ready to use the first vial of the 
pouch. Patients will be instructed to dose both eyes with 1 vial, as each vial is for single-
use dosing. 
7.2 
Other Study Supplies 
Urine pregnancy test kits, fluorescein sodium solution and lissamine green strips will also 
be required for the study. 
 
 

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8 
STUDY METHODS AND PROCEDURES 
8.1 
Patient Entry Procedures 
8.1.1 Overview 
Patients as defined by the criteria in Section 5.2, 5.3 and 5.4 will be considered for entry 
into this study. 
8.1.2 Informed Consent 
Prior to a patient’s participation in the trial (ie, prior to changes in a patient’s medical 
treatment and/or prior to study related procedures), the study will be discussed with each 
patient, and patients wishing to participate must give written informed consent using an 
informed consent form (ICF). The ICF must be the most recent version that has received 
approval/favorable review by a properly constituted Institutional Review Board (IRB). 
8.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the Exclusion Criteria 
(Section 5.4). They include: 
• 
LASIK – 12 months prior to Visit 1 and throughout study period 
• 
Ocular surgery – 12 months prior to Visit 1 and throughout study period 
• 
Contact lenses – 30 days prior to Visit 1 and throughout study period 
• 
Punctal Plugs – 3 months prior to Visit 1 and throughout study period  
• 
Nasal spray (TYRVAYA®) – 30 days prior to Visit 1 and throughout study period 
• 
Topical ocular cyclosporine (Restasis® or CequaTM) – 45 days prior to Visit 1 and 
throughout study period 
• 
Topical lifitigrast (Xiidra®) – 45 days prior to Visit 1 and throughout study period 
• 
Topical Eyedrops – 24 hours prior to Visit 1 and throughout study period 
• 
Unstable medication causing ocular drying or increased lacrimation – 30 days 
prior to Visit 1 and throughout study period  
• 
Investigational drug or device – 45 days prior to Visit 1 and throughout study 
period 
8.1.4 Procedures for Final Study Entry 
Patients must meet all inclusion and none of the exclusion criteria. 
8.1.5 Methods for Assignment to Treatment Groups: 
At Visit 1, patients who provide written informed consent will be assigned a unique 5-
digit screening number, which includes the 2-digit site number plus a unique 3-digit 
screening number beginning with 001 (eg, 11-001, 11-002, 11-003, etc.). Screening 
numbers must be assigned in ascending consecutive order. 

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Prior to Visit 2, the Medical Monitor will review the medical and medication history, 
screening results and screening eligibility criteria for each patient who enters the run-in 
period, and confirm the patient’s eligibility for the study. If there is a change in medical 
or medication status between Visits 1 and 2, the Medical Monitor will review and 
confirm the patient’s eligibility for the study prior to randomization at Visit 2 (if possible) 
or as soon as possible after Visit 2. 
At Visit 2, a patient who meets all the eligibility criteria will be randomized to receive 
treatment with 0.3% SI-614 or placebo in a 1:1 ratio. The Interactive Voice/Web 
Response System (IVRS/IWRS) will be used to account for the stratification factors.  
Patient’s will be stratified by the following factors and cut-offs:  
1. Average of dryness and ocular discomfort at bedtime assessment for Run-in patient 
daily diary mean (Day -7 through Day -1). 
a. 
≤ 2.5 
b. 
> 2.5 
 
2. Change 
 in total corneal fluorescein staining at Visit 2 
a. 
≤ 3.5 
b. 
> 3.5 
Both strata will be entered into the IVRS/IWRS, which will assign the randomization 
number and the assigned kit number for the patient. The site staff will dispense to the 
patient the study kit labeled with the corresponding kit number. Both the randomization 
number and the dispensed study drug kit number will be recorded on the patient’s source 
document and eCRF. 
8.2 
Concurrent Therapies 
The use of any concurrent medication, prescription or OTC, is to be recorded on the 
patient’s source document and corresponding eCRF along with the reason the medication 
was taken. Concomitant medications that are considered necessary for the patient’s 
welfare, but will not interfere with study assessments and evaluations, will be allowed 
during the study at the Investigator’s discretion. 
Use of medications known to cause ocular drying or increased lacrimation (see 
Appendix 3) is allowed; however, any use of medications known to cause ocular drying 
or increased lacrimation must be on a stable dosing regimen for at least 30 days prior to 
Visit 1, and should remain stable during the study period. A change in the use of a 
medication known to cause ocular drying or increased lacrimation during the study period 
will be recorded as a protocol deviation. 
Concurrent enrollment in another investigational drug or device study is not permitted. 
8.2.1 Prohibited Medications/Treatments 
Disallowed medications/treatments during the study are outlined in the Exclusion Criteria 
(Section 5.4).  

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If a specific medication/therapy has the potential to interfere with the treatment effect of 
the study drug or interpretation of the study results, the Investigator should contact the 
Medical Monitor prior to use. 
Any patient using a prohibited medication/therapy during the course of the study that 
could interfere with the treatment effect of the study drug or interpretation of the study 
results may be withdrawn from the study at the discretion of the Investigator and/or 
Sponsor. However, the Investigator should not withdraw a patient without first 
confirming it with the Medical Monitor and/or Sponsor. Use of a prohibited medication 
during the applicable washout period or during the study period will be recorded as a 
protocol deviation. 
8.2.2 Escape Medications 
No escape medications are required for this study. 
8.2.3 Special Diet or Activities 
No special diets or activities are required for this study. 
8.3 
Examination Procedures 
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
The following procedures will be performed (see Appendix 1 for description): 
Visit 1 (Day -14 ±3) 
• 
Informed consent/Health Information Portability and Accountability Act (HIPAA) 
• 
Demographic data and medical/medication & ocular history 
• 
Urine pregnancy test (for females of childbearing potential) 
• 
 Ocular Discomfort & 4-Symptom Questionnaire 
• 
 Ocular Discomfort Scale 
• 
OSDI 
• 
Best-corrected visual acuity 
• 
Review of qualification criteria 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Waiting period of at least 20 minutes  

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• 
Run-in solution instillation 
o A trained study technician will instill the first dose of run-in solution (1 
drop in each eye) in-office. 
• 
Waiting period of up to 10 minutes following dose of run-in solution 
• 
 
 
 
 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Review of qualification criteria 
• 
AE query 
• 
Patient instillation of run-in solution 
o Qualified patient will self-administer 1 drop of run-in solution in both eyes 
under study staff observation. 
• 
Run-in solution dispensation 
o Qualified patients will be instructed to instill 1 drop of run-in solution 4 
times daily in each eye starting in the evening of Visit 1 and continuing 
through the morning of Visit 2. 
• 
Dispensation of diaries and patient instructions 
o Qualified patients will also be dispensed a patient daily diary to be 
completed 4 times daily, and instructed to record each dose of run-in 
solution taken. Patients will also be instructed to complete the symptom 
assessments in the morning and in the evening before dosing with run-in 
solution. 
• 
Schedule patients for Visit 2 
o Qualified patients will be scheduled to return for Visit 2, and will be 
instructed to instill the morning dose of run-in solution at least 1 hour 
before the start of Visit 2. 
Visit 2 (Day 1) 
• 
Collection and review of run-in vials and patient diaries for qualification and 
compliance 
• 
Medical/medication & ocular history updates 

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• 
AE query 
• 
 Ocular Discomfort & 4-Symptom Questionnaire 
• 
 Ocular Discomfort Scale 
• 
OSDI 
• 
Best-corrected visual acuity 
• 
Review of qualification criteria 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Waiting period of at least 20 minutes 
• 
Run-in solution instillation 
o A trained study technician will instill a dose of run-in solution (1 drop in 
each eye) in-office. 
• 
Waiting period of up to 10 minutes following dose of run-in solution 
• 
 
 
 
 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Review of qualification criteria 
• 
Randomization 
• 
Study drug dispensation and instillation 
o Randomized patients will be dispensed 1 treatment kit assigned by 
IVRS/IWRS, and a trained study technician will instill the first dose of 
study drug (1 drop in each eye) in-office. 
o Randomized patients will be instructed to instill 1 drop of study drug 4 
times daily in each eye starting in the evening of Visit 2 and continuing 
through the morning of Visit 3. 

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• 
Patient daily diary dispensation 
o Randomized patients will also be dispensed a new patient daily diary to be 
completed 4 times daily, and instructed to record each dose of study drug 
taken. Patients will also be instructed to complete the symptom 
assessments in the morning and in the evening before dosing with study 
drug. 
• 
AE query; 
• 
Schedule patients for Visit 3 
o Randomized patients will be scheduled to return for Visit 3 and will be 
instructed to instill the morning dose of study drug at least 1 hour before 
the start of Visit 3. 
Visit 3 (Day 8 ± 2): 1-Week Follow-Up  
• 
Collection and review of study drug and patient diaries for compliance 
• 
Medical/medication & ocular history updates 
• 
AE query 
• 
 Ocular Discomfort & 4-Symptom Questionnaire 
• 
 Ocular Discomfort Scale 
• 
OSDI 
• 
Best-corrected visual acuity 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Study drug dispensation and instillation 
o Patients will not be dispensed new treatment kit at Visit 3, and a trained 
study technician will instill a dose of study drug (1 drop in each eye) in-
office from the kit dispensed at Visit 2. 
o Patients will be instructed to instill 1 drop of study drug 4 times daily in 
each eye starting in the evening of Visit 3 and continuing through the 
morning of Visit 4. 
• 
Patient daily diary dispensation 
o Patients will also be dispensed a new patient daily diary to be completed 4 
times daily, and instructed to record each dose of study drug taken. 

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Patients will also be instructed to complete the symptom assessments in 
the morning and in the evening before dosing with study drug. 
• 
AE query 
• 
Schedule patients for Visit 4 
o Patients will be scheduled to return for Visit 4 and will be instructed to 
instill the morning dose of study drug at least 1 hour before the start of 
Visit 4. 
Visit 4 (Day 15 ± 2): 2-Week Follow-Up 
• 
Collection and review of study drug and patient diaries for compliance 
• 
Medical/medication & ocular history updates 
• 
AE query 
• 
 Ocular Discomfort & 4-Symptom Questionnaire 
• 
 Ocular Discomfort Scale 
• 
OSDI 
• 
Best-corrected visual acuity 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Waiting period of at least 20 minutes 
• 
Study drug instillation 
o A trained study technician will instill a dose of study drug (1 drop in each 
eye) in-office from returned kit. 
• 
Waiting period of up to 10 minutes following dose of study drug 
• 
 
 
 
 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 

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• 
Lissamine green staining 
 
• 
Study drug dispensation and instillation 
o Patients will be dispensed 1 new treatment kits assigned by IVRS/IWRS, 
and a trained study technician will instill the first dose of study drug (1 
drop in each eye) in-office from a new kit. 
o Patients will be instructed to instill 1 drop of study drug 4 times daily in 
each eye starting in the evening of Visit 4 and continuing through the 
morning of Visit 5. 
• 
Patient daily diary dispensation 
o Patients will also be dispensed a new patient daily diary to be completed 4 
times daily, and instructed to record each dose of study drug taken. 
Patients will also be instructed to complete the symptom assessments in 
the morning and in the evening before dosing with study drug. 
• 
AE query 
• 
Schedule patients for Phone Call and Visit 5 
o Patients will be scheduled for a phone call at around week 3 (Day 22 ± 2) 
and return for Visit 5 and will be instructed to instill the morning dose of 
study drug at least 1 hour before the start of Visit 5. 
Phone Call for Drug Compliance: Day 22 ± 2 
• 
The patient will be contacted by telephone and told the following: 
o Patients will be reminded to continue instilling 1 drop of study drug 4 
times daily in each eye; and to complete the symptom assessments before 
dosing with study drug and to record each dose of study drug taken. 
• AE query 
Visit 5 (Day 29 ± 2): 4-Week Follow-Up 
• 
Collection and review of study drug and patient diaries for compliance 
• 
Medical/medication & ocular history updates 
• 
AE query 
• 
 Ocular Discomfort & 4-Symptom Questionnaire 
• 
 Ocular Discomfort Scale 
• 
OSDI 
• 
Best-corrected visual acuity 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 

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• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Waiting period of at least 20 minutes 
• 
Study drug instillation 
o A trained study technician will instill a dose of study drug (1 drop in each 
eye) in-office from returned kit. 
• 
Waiting period of up to 10 minutes following dose of study drug 
• 
 
 
 
 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Study drug dispensation and instillation 
o Patients will be dispensed 2 new treatment kits assigned by IVRS/IWRS, 
and a trained study technician will instill the first dose of study drug (1 
drop in each eye) in-office from a new kit. 
o Patients will be instructed to instill 1 drop of study drug 4 times daily in 
each eye starting in the evening of Visit 5 and continuing through the 
morning of Visit 6. 
• 
Patient daily diary dispensation 
o Patients will also be dispensed a new patient daily diary to be completed 4 
times daily, and instructed to record each dose of study drug taken. 
Patients will also be instructed to complete the symptom assessments in 
the morning and in the evening before dosing with study drug. 
• 
AE query 
• 
Schedule patients for Phone Call and Visit 6 
Patients will be scheduled for a phone call at around week 6 (Day 43 ± 2) and return for 
Visit 6 and will be instructed to instill the morning dose of study drug at least 1 hour 
before the start of Visit 6. 
Phone Call for Drug Compliance: Day 43 ± 2 

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• 
The patient will be contacted by telephone and told the following: 
o Patients will be reminded to continue instilling 1 drop of study drug 4 
times daily in each eye; and to complete the symptom assessments before 
dosing with study drug and to record each dose of study drug taken. 
• AE query 
Visit 6 (Day 57 ± 3): 8-Week Follow-Up 
• 
Collection and review of study drug and patient diaries for compliance 
• 
Medical/medication & ocular history updates 
• 
AE query 
• 
 Ocular Discomfort & 4-Symptom Questionnaire 
• 
 Ocular Discomfort Scale 
• 
OSDI 
• 
Best-corrected visual acuity 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Waiting period of at least 20 minutes 
• 
Study drug instillation 
o A trained study technician will instill a dose of study drug (1 drop in each 
eye) in-office from returned kit. 
• 
Waiting period of up to 10 minutes following dose of study drug. 
• 
 
 
 
 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Study drug dispensation and instillation 

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o Patients will be dispensed 2 new treatment kits assigned by IVRS/IWRS, 
and a trained study technician will instill the first dose of study drug (1 
drop in each eye) in-office from a new kit. 
o Patients will be instructed to instill 1 drop of study drug 4 times daily in 
each eye starting in the evening of Visit 5 and continuing through the 
morning of Visit 6. 
• 
Patient daily diary dispensation 
o Patients will also be dispensed a new patient daily diary to be completed 4 
times daily, and instructed to record each dose of study drug taken. 
Patients will also be instructed to complete the symptom assessments in 
the morning and in the evening before dosing with study drug. 
• 
AE query 
Phone Call for Drug Compliance: Day 71 ± 2 
• 
The patient will be contacted by telephone and told the following: 
o Patients will be reminded to continue instilling 1 drop of study drug 4 
times daily in each eye; and to complete the symptom assessments before 
dosing with study drug and to record each dose of study drug taken. 
• AE query 
Visit 7 (Day 85 ± 3): 12-Week Follow-Up 
• 
Collection and review of study drug and patient diaries for compliance 
• 
Medical/medication & ocular history updates 
• 
AE query 
• 
Urine pregnancy test (for females of childbearing potential) 
• 
 Ocular Discomfort & 4-Symptom Questionnaire 
• 
 Ocular Discomfort Scale 
• 
OSDI 
• 
Best-corrected visual acuity 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Waiting period of at least 20 minutes 

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• 
Study drug instillation 
o A trained study technician will instill a dose of study drug (1 drop in each 
eye) in-office from returned kit. 
• 
Waiting period of up to 10 minutes following dose of study drug. 
• 
 
 
 
 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness 
 
• 
TFBUT 
• 
Fluorescein staining 
 
• 
Lissamine green staining 
 
• 
Best-corrected visual acuity 
• 
AE query 
• 
Study exit 
Early Termination/Discontinuation 
If a patient is discontinued from the study prior to Visit 7, then all safety evaluations and 
efficacy evaluations that are to be performed at Visit 7 should be performed on the day of 
discontinuation (early termination) prior to commencement of any alternative dry eye 
therapy (if at all possible).  
8.4 
Schedule of Visits, Measurements and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2 Unscheduled Visits 
These visits may be performed in order to ensure patient safety. All procedures 
performed at an unscheduled visit will be recorded in the source documents and on the 
Unscheduled Visit eCRF pages. Any procedure indicated in the eCRF that is not 
performed should be indicated as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
• 
Slit-lamp biomicroscopy; 
• 
Best-corrected visual acuity; 
• 
Pregnancy test; 
• 
Assessment of AEs; 

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• 
Assessment of concomitant medications and/or treatments; and 
• 
Any other assessments needed in the judgment of the investigator. 
8.5 
Compliance with Protocol 
Patients will be instructed on proper use of the patient daily diary and proper instillation 
and storage of study drug at the end of Visits 1, 2, 3, 4, 5, and 6, and given written 
instructions. The patient daily diaries and used and unused study drug vials will be 
collected at each visit from Visit 2 up to and including Visit 7 to assess dosing and 
symptom assessment compliance. Dosing compliance will be based off of the used and 
unused vial count. If the patient is less than 75% or more than 125% compliant with 
dosing based on the expected number of used vials, then the patient will be deemed non-
compliant and a deviation should be recorded.  
In the patient daily diary, if more than 25% of Dose Taken boxes are checked “no”, left 
blank, or missing for a diary period, a patient will be deemed non-compliant and a diary 
deviation will be recorded. If more than 25% of the total diary symptom assessments for 
that dosing period are missed, these patients will be deemed non-compliant and a diary 
symptom assessment deviation will be recorded. These guidelines will be used by the 
Investigator for determining the patient’s necessary compliance for the study and for 
recording deviations from this compliance.  
8.6 
Patient Disposition 
8.6.1 Completed Patients 
A completed patient is one who has not been discontinued from the study and has 
successfully completed Visit 7. 
8.6.2 Discontinued Patients 
Patients may be discontinued prior to their completion of the study due to: 
• 
AE 
• 
Protocol violation 
• 
Administrative reasons (eg, inability to continue) 
• 
Lack of efficacy 
• 
Lost to follow-up 
• 
Pregnancy 
• 
Sponsor termination of study 
• 
Other 
Note: In addition, any patient may be discontinued for any sound medical reason. 
Notification of a patient discontinuation and the reason for discontinuation will be made 
to 
 and/or Sponsor and will be clearly documented on the patient’s source documents 
and eCRF. 

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8.7 
Study Termination 
The study may be stopped at any time by the investigator, the Sponsor, and/or 
 with 
appropriate notification. 
8.8 
Study Duration 
An individual patient’s participation will involve 7 visits over approximately a 14-week 
period (98 days). 
8.9 
Monitoring and Quality Assurance 
During the course of the study a monitor, sponsor, or designee, will make routine site 
visits to review protocol compliance, assess study drug accountability, patient safety, and 
ensure the study is being conducted according to the pertinent regulatory requirements. 
The review of the patients’ medical records will be performed in a manner that 
adequately maintains patient confidentiality. Further details of the study monitoring will 
be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, 
/sponsor quality 
assurance and or its designees may carry out on-site inspections and/or audits, which may 
include source data checks. Therefore direct access to the original source data will be 
required for inspections and/or audits. All inspections and audits will be carried out 
giving consideration to data protection as well as patient confidentiality to the extent that 
local, state, and federal laws apply. 
 
 

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9 
ADVERSE EVENTS 
9.1 
Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not the event is considered drug-related. An AE can therefore be 
any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, or 
disease occurring after the patient started dosing with the study drug, without any 
judgment about causality. Any pre-existing medical condition that worsens after 
administration of the study drug will be considered a new AE, but exacerbation of 
conditions related to the signs and symptoms of dry eye will not be reported as an AE 
unless they persist and/or result in the discontinuation of the patient. 
Any medical condition present prior to the administration of the study drug that remains 
unchanged or improved should not be recorded as an AE at subsequent visits. 
AEs (both elicited and observed) and SAEs will be monitored throughout the study. The 
investigator will promptly review all AEs (both elicited and observed) for accuracy and 
completeness. All AEs will be documented on the appropriate source document and 
eCRF. 
A worsening in best-corrected visual acuity from Visit 1 
 of greater than or 
equal to 0.22 logMAR units is considered an AE. 
Pregnancy is not to be considered an AE, but it is an important medical event that must 
be followed up as described in Section 10. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to study drug, action(s) taken, seriousness, and outcome of any sign 
or symptom observed by the physician or reported by the patient upon indirect 
questioning. 
9.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an 
AE as determined by the investigator or reported to him/her by the patient. The 
assessment of severity is made irrespective of relationship to study drug or seriousness of 
the event and should be evaluated according to the following scale: 
• 
Mild: Event is noticeable to the patient, but is easily tolerated and does not 
interfere with the patient’s daily activities. 
• 
Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the patient’s daily activities. 
• 
Severe: Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the patient’s daily activities. 
9.1.2 Relationship to Study Drug 
The relationship of each AE to the study drug should be determined by the investigator 
using these explanations: 

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• 
Suspected: A reasonable possibility exists that the study drug caused the AE. 
• 
Not Suspected:  A reasonable possibility does not exist that the study drug caused 
the AE. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the study drug caused the AE. “Reasonable possibility” means there is evidence to 
suggest a causal relationship between the study drug and the AE. Types of evidence that 
would suggest a causal relationship between the study drug and the AE include: a single 
occurrence of an event that is uncommon and known to be strongly associated with drug 
exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome); 1 or more 
occurrences of an event that is not commonly associated with drug exposure, but is 
otherwise uncommon in the population exposed to the drug (eg, tendon rupture); an 
aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
9.2 
Serious Adverse Events 
An AE 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; 
Note: An AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or patient at immediate 
risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even 
if less than 24 hours). For chronic or long-term inpatients, inpatient admission 
includes transfer within the hospital to an acute/intensive care inpatient unit. 
Inpatient hospitalization does not include: emergency room visits; 
outpatient/same-day/ambulatory procedures; observation/short stay units; 
rehabilitation facilities; hospice facilities; nursing homes; or clinical 
research/phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension 
of an inpatient hospitalization beyond the stay anticipated or required for the 
reason for the initial admission as determined by the investigator or treating 
physician. 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
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Note: A SAE specifically related to visual threat would be interpreted as any 
potential impairment or damage to the patient’s eyes (eg, hemorrhage, retinal 
detachment, central corneal ulcer or damage to the optic nerve). 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
9.3 
Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to 
 the study sponsor, and the IRB as 
required by the IRB, federal, state, or local regulations and governing health authorities 
and recorded on the appropriate eCRF. 
9.3.1 Reporting a Serious Adverse Event 
To ensure patient safety, all SAEs, regardless of relationship to the study drug, must be 
immediately reported. All information relevant to the SAE must be recorded on the 
appropriate eCRF. The investigator is obligated to pursue and obtain information 
requested by 
 and/or the sponsor in addition to that information reported on the eCRF. 
All patients experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the investigator must notify 
 and the sponsor immediately; 
obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
patient; provide 
 and the study sponsor with a complete case history, which includes a 
statement as to whether the event was or was not suspected to be related to the use of the 
study drug; and inform the IRB of the AE within their guidelines for reporting SAEs. 
Contact information for reporting SAEs:  
 
 
 
 
 
  
 
 
 
 
 
 
 
 

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9.4 
Procedures for Unmasking of Study Drug 
All patients, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to treatment assignments. When medically necessary, the 
investigator may need to determine what treatment has been assigned to a patient. When 
possible (ie, in non-emergent situations), 
 and/or Sponsor should be notified before 
unmasking study drug.  
Serious unexpected suspected adverse reactions, which are patient to expedited reporting, 
will be unmasked before submission to the Regulatory Authorities. The procedure for 
unmasking will be described in a separate Safety Plan for this study. 
9.5 
Type and Duration of the Follow-up of Patients after Adverse 
Events 
The investigator will follow unresolved suspected AEs to resolution until the patient is 
lost to follow-up or until the AE is otherwise explained. Resolution means the patient has 
returned to baseline state of health or the investigator does not expect any further 
improvement or worsening of the AE. 
Non-SAEs identified on the last scheduled contact must be recorded on the Adverse 
Event eCRF with the status noted. 
SAEs identified on the last scheduled contact must be recorded on the Adverse Event 
eCRF and reported to 
 and the Sponsor according to the procedure outlined in 
Section 9.3.1. These events may include previously reported or new SAEs. Any new 
SAEs reported by the patient to the investigator that occurred after the last scheduled visit 
and are determined by the investigator to be reasonably associated with the use of the 
study drug will be reported to the Sponsor. These events may include SAEs that are 
captured on follow-up telephone contact or at any other time after the defined study 
period. The investigator should follow serious related AEs identified after the last 
scheduled contact until the events are resolved or the patient is lost to follow-up. The 
investigator should continue to report any significant follow-up information to the 
Sponsor until the event is resolved. 
 
 

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10 Pregnancy 
Women of Childbearing Potential (WOCBP) include any females who have experienced 
menarche and who have not undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation or bilateral oophorectomy) or are not postmenopausal at least 12 
months since last menses. WOCBP will be required to use designated methods of birth 
control during the course of the study, all women who are pregnant, nursing an infant, or 
planning a pregnancy will be excluded from participation.  
During the study, all WOCBP should be instructed to contact the Investigator 
immediately if they suspect they might be pregnant (eg, missed or late menstrual period). 
If a patient or Investigator suspects that the patient may be pregnant prior to study drug 
administration, the study drug must be withheld until the results of pregnancy testing are 
available. If pregnancy is confirmed, the patient must not receive study drug and must not 
be enrolled in the study. If pregnancy is suspected while the patient is receiving study 
drug treatment, the study drug must immediately be withheld until the result of pregnancy 
testing is known. If pregnancy is confirmed, the study drug will be permanently 
discontinued, and patient will be withdrawn from the study and followed until the 
pregnancy comes to term.  
If a female has a positive pregnancy test during the study, then the investigator will notify 
 immediately. The investigator shall request from the patient and/or the patient’s 
physician copies of all related medical reports during the pregnancy and shall document 
the outcome of the pregnancy. The investigator will retain these reports together with the 
patient’s source documents and will provide a copy of all documentation to 
 A 
Pregnancy Report form will be submitted to the Sponsor and 
 at a minimum initially 
and at the end of the pregnancy. The Investigator is also encouraged to submit to the 
Sponsor and 
 trimester follow up reports during the pregnancy. The outcome of the 
pregnancy and any complications occurring during the pregnancy or the delivery must be 
reported to the Sponsor and 
 
The contact person at 
 to report a pregnancy is: 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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11 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
11.1 Analysis Populations 
Intention-to-Treat Population (ITT) – The intention-to-treat (ITT) population includes all 
randomized patients. Subjects in the ITT population will be analzyed as randomized. The 
primary analysis will be performed on the ITT population with the primary estimand.  
Per-Protocol (PP) Population – The PP population is defined as all ITT patients who have 
no major protocol deviations and completed the trial. Protocol deviations will be assessed 
prior to database lock and unmasking. The PP population will be analyzed using observed 
data only for efficacy variables. Subjects in the PP population will be analyzed as treated. 
Safety Population – The safety population will include all patients who receive at least 1 
dose of randomized study drug. Subjects in the Safety population will be analyzed as 
treated.  
11.2 Statistical Hypotheses 
The statistical hypotheses are stated in terms of one-sided hypotheses, although statistical 
testing will be two-sided at a significance level of 0.05. The primary and secondary 
endpoints will be tested in a hierarchical fixed sequence in the following order: 
H01: There is no difference between 0.3% SI-614 and placebo in the change 
 in corneal total fluorescein staining score 
 in 
the study eye at Visit 5 (Day 29). 
HA1: Change from baseline 
 to Day 29 
 in corneal total fluorescein 
staining score 
 in the study eye is less with 0.3% SI-614 
than with placebo. 
H02: There is no difference between 0.3% SI-614 and placebo in the change from 
baseline in the average score of ocular discomfort and dryness at the bedtime 
assessment from the patient daily diary during Day 1 through Day 14. 
HA2: Change from baseline in the average score of ocular discomfort and dryness at the 
bedtime assessment from the patient daily diary during Day 1 through Day 14 is 
less with 0.3% SI-614 than with placebo. 
11.3 Sample Size 
The power and sample size for this study were calculated based on the results from the 
previous Phase 2 and Phase 2/3 study. 
In order to have 90% power to detect a difference of -0.75 between SI-614 and placebo, 
109 patients per treatment arm are required to be randomized. This assumes a two-sided 
test at alpha = 0.05 and a common standard deviation (SD) of 1.7 in both treatment arms.  
Accounting for up to 5% dropouts in the study, 115 patients per treatment arm, or 230 
total patients are required to have 90% power for the primary endpoint. 

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The hierarchical, secondary endpoint of the change from baseline in the average score of 
ocular discomfort and dryness at the bedtime assessment from the patient daily diary 
during Day 1 through Day 14 will have 51% power with this sample size, assuming a 
difference between SI-614 and placebo of -0.13. This endpoint will be tested conditional 
upon the primary endpoint being successful, thereby maintaining the study-wide type I 
error rate for both endpoints. The sample size calculation assumes a two-sided test at 
alpha = 0.05 and a common SD of 0.48 in both treatment arms.  
11.4 Statistical Analysis 
11.4.1 General Considerations 
The quantitative variables will be summarized using mean, median, SD, minimum, and 
maximum. The qualitative variables will be summarized using counts and percentages. 
All efficacy analyses will present two-sided 95% confidence intervals around the 
difference between treatments (SI-614 – placebo).  
All summaries will be presented by treatment group. Summaries will be provided for 
demographics and patient disposition. 
Baseline measures are defined as the last time point-matched measure prior to the 
initiation of randomized study drug treatment unless otherwise specified. Change from 
baseline will be calculated as follow-up visit value minus baseline value. Treatment 
comparisons between active and vehicle will be calculated as active minus vehicle. For 
measures from daily patient diaries, baseline is defined as the average of all days during 
Day -7 to Day -1, calculated separately for the morning, bedtime, and daily averages. 
Daily scores are first obtained by averaging the AM and PM scores for that day, as 
applicable. 
11.4.2 Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints, the unit of 
analysis will be the “study eye” as defined by the following: 
Study Eye: Eyes are eligible for analysis if they meet all “inclusion criteria” as specified 
in Section 5.3. In the case that both eyes are eligible for analysis, the study eye will be the 
eye with the greatest change 
 
in corneal total fluorescein staining score 
 
at baseline (Visit 2). If the baseline change 
 in corneal total 
fluorescein staining score is the same in both eyes, then the right eye will be used as the 
study eye. If only one eye meets all inclusion criteria, then the single qualifying eye is the 
study eye. 
11.4.3 Missing Data 
The primary efficacy analyses will be performed using the multiple imputation 
methodology specified in Estimand 1 if the rate of missing data for an endpoint is 
balanced between the two treatment groups (as evaluated by the Fisher’s exact test at an 
alpha level of 0.05) or the rate of missing data for an endpoint is ≤ 5% in all subjects. If 
the rate of missing data for an endpoint is imbalanced between treatment groups (as 

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demonstrated by the Fisher’s exact test with a p-value < 0.05) and the rate of missing data 
for an endpoint is greater than 5% in all subjects, then the primary analyses will utilize 
the ITT population with observed data only specified in Estimand 2 using the 
permutation test with trimmed means methodology. Additional sensitivity analyses will 
be executed including: 
• Multiple imputation via placebo group-based pattern mixture models (PMM) 
imputation with the ITT population under the assumption of missing not at 
random; 
• Multiple imputation via randomized treatment group-based Markov Chain Monte 
Carlo (MCMC) with the ITT population under the assumption of missing at 
random; 
• Last observation carried forward (LOCF) imputation methodology using the ITT 
population; 
• Tipping point analyses; 
• Observed data only using ITT and PP populations. 
 
Secondary efficacy analyses will be conducted similarly.  
Exploratory efficacy analyses will be conducted using the ITT population with observed 
data only. 
11.4.4 Primary Efficacy Analyses 
For the primary endpoint, change from baseline will be calculated as visit – baseline such 
that a positive difference indicates a worsening of dry eye signs. In addition, treatment 
comparisons between 0.3% SI-614 and placebo will be calculated as 0.3% SI-614 – 
placebo, such that a negative result indicates a better score for 0.3% SI-614 (i.e., 0.3% 
SI-614 demonstrated less severity in dry eye signs than the placebo group). 
The primary analysis of the primary endpoint will use the ITT population. If the rate of 
missing data for an endpoint is balanced between the two treatment groups (as evaluated 
by the Fisher’s exact test at an alpha level of 0.05) or the rate of missing data for the 
endpoint is ≤ 5% in all subjects then primary analysis will be executed using ANCOVA 
with multiple imputation methodology using the following Estimand 1: 
Estimand 1: 
• Population: 
o ITT population 
• Endpoint: 
o Change from baseline 
 in total corneal fluorescein staining score 
in the study eye at Day 29 
 in the ITT population 
• Intercurrent event: 

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o Discontinuation of study medications is ignored. Measures obtained after 
discontinuation of study medication will be analyzed. [treatment policy 
strategy] 
o Non-optimal compliance is ignored. Measures will be analyzed regardless 
of treatment compliance. [treatment policy strategy] 
o Use of prohibited concomitant medications is ignored. Measures obtained 
after use of prohibited concomitant medications will be analyzed. 
[treatment policy strategy] 
o Withdrawal due to lack of efficacy or adverse events. Missing values 
assumed to be missing not at random will be multiply imputed using 
placebo group-based PMM imputation. [hypothetical strategy] 
o Missing data with withdrawal or withdrawal due to reasons other than lack 
of efficacy or adverse events. Missing values assumed to be missing at 
random will be multiply imputed using randomized treatment group-based 
MCMC imputation. [hypothetical strategy] 
• Population-level summary: 
o Difference in the mean change from baseline 
 in total corneal 
fluorescein staining score in the study eye at Day 29 
  between 
0.3% SI-614 and placebo in the ITT population. 
The permutation test with trimmed means as specified in Estimand 2 will then be 
executed as additional sensitivity analyses. 
If the rate of missing data for the endpoint is imbalanced between treatment groups 
(demonstrated by Fisher’s exact test with a p-value of <0.05) and the rate of missing data 
for the endpoint is greater than 5% in all subjects, then the primary analyses will utilize 
the ITT population with observed data only using the permutation test with trimmed 
means methodology with Estimand 2: 
Estimand 2: 
• Population: 
o ITT population 
• Endpoint: 
o Change from baseline 
 in total corneal fluorescein staining score 
in the study eye at Day 29 
 in the ITT population 
• Intercurrent event: 
o Discontinuation of study medications is ignored. Measures obtained after 
discontinuation of study medication will be analyzed. [treatment policy 
strategy] 
o Non-optimal compliance is ignored. Measures will be analyzed regardless 
of treatment compliance. [treatment policy strategy]  

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o Use of prohibited concomitant medications is ignored. Measures obtained 
after use of prohibited concomitant medications will be analyzed. 
[treatment policy strategy] 
o Withdrawal or missed assessments for any reason. Missing values will be 
trimmed from analyses in accordance to trimmed means methodology. 
[hypothetical strategy] 
• Population-level summary: 
o Difference in the mean change from baseline 
 in total corneal 
fluorescein staining score in the study eye at Day 29 
 between 
0.3% SI-614 and placebo in the ITT population.  
Analyses using the ITT population with multiple imputation with Estimand 1 will be 
additional sensitivity analyses. 
The proportion of data trimmed in the permutation test with trimmed means analysis will  
be dependent on the maximum rate of missing data in any treatment group using the 
following: 
Maximum Rate of Missing 
Data (%) 
Data Trimmed (%) 
 
>5% to <10% 
10% 
 
10% to <20% 
20% 
 
20% to <30% 
30% 
In the event that the maximum rate of missing data exceeds 30% in any treatment group, 
then the percentage trimmed will increase by a decile until the percentage trimmed 
exceeds the maximum rate of missing data in any treatment group.  
The ANCOVA model used to compare the change from baseline 
 to Day 29 
 in corneal total fluorescein staining score in the study eye between 0.3% 
SI-614 and placebo will include baseline 
 in corneal total fluorescein staining 
score in the study eye at Visit 2 and treatment group as covariates.  
As supportive analyses, two-sample t-tests and a Wilcoxon rank sum test will be 
conducted to compare the change from baseline 
 at Day 29 
 between 
the two treatment groups. Additional exploratory comparisons of the mean raw scores of 
corneal total fluorescein staining score at Day 29 
 and baseline 
 (Visit 
2, Day 1) between the treatment groups will be conducted using two-sample t-tests and 
Wilcoxon rank sum tests. Quantitative summary statistics will be provided for baseline 
Day 1 
 Day 29 
 and change from baseline 
 at Day 29 
. 
Least Squares (LS) means with standard errors (SEs) for each treatment group and LS 
mean differences between treatment groups with SEs will be presented from the 

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ANCOVA model together with two-sided p-values and two-sided 95% confidence 
intervals. Sample means, sample mean differences with SEs, two-sided 95% confidence 
intervals, and two-sided p-values will be reported from the two-sample t-tests. Two-sided 
p-values will be reported from the Wilcoxon rank sum tests for observed data only 
analyses and LOCF analyses only. Trimmed means of each treatment group, trimmed 
mean differences between treatment groups, two-sided exact p-values and two-sided 
exact 95% confidence intervals will be presented from the permutation test with trimmed 
means. 
Sensitivity analyses will include multiple imputation by placebo group-based PMM, 
multiple imputation via randomized treatment group-based MCMC, single imputation by 
LOCF, and analyses of observed data only using the ITT and PP populations. 
11.4.5 Secondary Efficacy Variables 
Analyses of the secondary efficacy endpoint of the change from baseline (Day -7 through 
Day -1) in average score of ocular discomfort and dryness at the bedtime assessment 
from the patient daily diary during Day 1 through Day 14 will use a MMRM. The model 
will include the baseline average score of ocular discomfort and dryness (average of Day 
-7 through Day -1), treatment group, study day (Day 1 to Day 14 as categorical 
variables), and the interaction between treatment group and study day as fixed effects 
with correlated errors due to study day. The overall treatment differences (0.3% SI-614 
versus placebo) and the corresponding p-values will be estimated based on the MMRM. 
As a sensitivity analysis, the above model will also be run without including the baseline 
average score of ocular discomfort and dryness symptom as a covariate. 
As an additional sensitivity analysis of the average score of ocular discomfort and 
dryness symptom, the change from baseline in average ocular discomfort and dryness 
score from Day 1 to Day 14 will also be compared between the two treatment groups 
using two-sample t-tests and Wilcoxon rank sum tests for each individual day. In 
addition, an ANCOVA model using the baseline average score of ocular discomfort and 
dryness and treatment group will be used to examine change from baseline at each day. 
Analyses of the secondary endpoint will utilize the ITT population using observed data 
only. Sensitivity analyses will include multiple imputation as described in Estimand 1, 
multiple imputation by placebo group-based PMM, multiple imputation via randomized 
treatment group-based MCMC, single imputation by LOCF, and analyses of observed 
data only using the PP population. 
11.4.6 Exploratory Efficacy Variables 
Exploratory efficacy variables will generally be analyzed on the ITT population using 
observed data. 
For signs 
 (including fluorescein 
staining, lissamine green staining, TFBUT, and conjunctival redness), the change 
 
 measure at each visit and the change 
 at baseline  
 at each visit will be compared between the 2 treatment groups using a two-
sample t-test, a Wilcoxon rank sum test, as well as an ANCOVA model adjusting for 

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baseline 
 value. In addition, change from time point-matched baseline 
 will be analyzed similarly. 
For symptom measures (including OSDI, 
 Ocular Discomfort and 4-symptom 
Questionnaire), each individual symptom score as well as the change from baseline (
 at Visit 2) will be compared between 0.3% SI-614 and placebo for each visit using a 
two-sample t-test, a Wilcoxon rank sum test, and an ANCOVA model adjusting for 
baseline. 
 Ocular Discomfort Scale 
 is measured every 5 minutes 
 The area under the curve will be calculated for each 
patient using the trapezoidal rule, and compared between treatment groups using a two-
sample t-test, as well as an ANCOVA model adjusting for baseline (Visit 2 area under the 
curve). 
11.4.7 Safety Variables 
AEs will be coded using the Medical Dictionary for Regulatory Activities dictionary. 
Frequencies and percentages of patients with TEAEs, serious TEAEs, and TEAEs 
causing premature discontinuation will be provided by treatment group. An AE is 
treatment emergent if it occurs or worsens after the first dose of study treatment. 
Furthermore, frequencies will be given of patients with TEAEs by system organ class 
(SOC), by SOC and preferred term (PT), by SOC, PT and maximal severity, by SOC, PT 
and strongest relationship, and by SOC, PT, maximal severity, and strongest relationship. 
Separate analyses will be performed for ocular and non-ocular TEAEs. 
Other safety endpoints including visual acuity, slit lamp biomicroscopy, and corneal 
sensitivity will be summarized by treatment group and visit using descriptive statistics. 
Changes or shifts from baseline will also be summarized where appropriate. For 
assessments performed by eye, study eye and fellow eye will be summarized separately. 
In addition, shifts from baseline to worst on-treatment value for ocular safety assessments 
will be summarized. All safety endpoints will be assessed using the Safety population.  
11.4.8 Adjustment for Multiplicity 
Hierarchical fixed sequence testing will be used in the analysis of the primary dry eye 
sign endpoint and the secondary dry eye symptom endpoint to maintain study wide type I 
error. The primary endpoint of change from baseline 
 at Day 29 
 of the 
corneal total fluorescein staining score will be evaluated at a two-sided study wide alpha 
level of 0.05. If the primary endpoint is statistically significant, then the study will be 
declared a success for the primary endpoint and then the secondary endpoint of change 
from baseline of the bedtime assessment from the patient daily diary during Day 1 
through Day 14 will be evaluated. If the primary endpoint is not statistically significant, 
no further formal hypothesis testing will proceed and the analyses of the secondary 
endpoint will be conducted as an exploratory analyses. 
Exploratory endpoints will not be type I error controlled and thus, considered exploratory 
and hypothesis generating. 

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11.4.9 Interim Analyses 
There will be no planned interim analyses. 
 
 

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12 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, Good Clinical Practices, 
including the International Conference on Harmonization (ICH) Guidelines, and in 
general, consistent with the Declaration of Helsinki. In addition, all applicable local, 
state, and federal requirements relevant to the use of study drugs in the countries involved 
will be adhered to. 
12.1 Protection of Human Patients 
12.1.1 Patient Informed Consent 
Informed consent must take place before any study specific procedures are initiated. 
Signed and dated written informed consent must be obtained from each patient and/or 
from the patient’s parent or legal guardian prior to enrollment into the study. 
All ICFs must be approved for use by the sponsor and receive approval/favorable opinion 
from an IRB prior to their use. If the consent form requires revision (eg, due to a protocol 
amendment or significant new safety information), it is the investigator’s responsibility to 
ensure that the amended informed consent is reviewed and approved by Sponsor and 
 
prior to submission to the governing IRB and that it is read, signed and dated by all 
patients subsequently enrolled in the study as well as those currently enrolled in the 
study. 
If informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by 
 and/or study sponsor and 
provided in writing by 
 and/or study sponsor prior to the consent process. 
12.1.2 Institutional Review Board Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 Code of 
Federal Regulations [CFR] Part 56.103). The investigator must obtain appropriate IRB 
approval before initiating the study and re-approval at least annually. 
Only an IRB approved version of the ICF will be used. 
12.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
12.3 Patient Confidentiality 
All personal study patient data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data in accordance with local, state, and federal laws 
and regulations. 

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Monitors, auditors and other authorized representatives of 
 the sponsor, the IRB 
approving this study, the Food and Drug Administration, the Department of Health and 
Human Services, other domestic government agencies, and other foreign regulatory 
agencies will be granted direct access to the study patient’s original medical and study 
records for verification of the data and/or clinical trial procedures. Access to this 
information will be permitted to the aforementioned individuals to the extent permitted 
by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s identity will not be disclosed in these documents. 
12.4 Documentation 
Source documents may include a patient’s medical records, hospital charts, clinic charts, 
the investigator’s study patient files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and electrocardiographs. The investigator’s copy of the eCRFs 
serves as the investigator’s record of a patient’s study-related data. 
12.4.1 Retention of Documentation 
All study related correspondence, patient records, consent forms, record of the 
distribution and use of all study drug and copies of eCRFs should be maintained on file 
for at least 2 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region; or 
until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the study drug. These documents will be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the sponsor. 
It is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 
12.5 Labeling, Packaging, Storage, Accountability, and Return or 
Disposal of Study Drug 
12.5.1 Labeling/Packaging 
Nineteen pouches will be packed in a two-week clinical kit. Each pouch will contain 5 
vials. Pouches will be labeled and the two-week clinical kits will be labeled. The labels 
will include instructions for use. 
12.5.2 Storage of Study Drug 
The study drug must be stored in a secure area accessible only to the investigator and 
his/her designees, and must be maintained at controlled room temperature (25°C or less, 
Do Not Freeze) and protected from light. The study drug will be administered only to 

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patients entered into the clinical study, in accordance with the conditions specified in this 
protocol. 
12.5.3 Accountability of Study Drug 
The study drug is to only be prescribed by the principal investigator or his/her named sub 
investigator(s), and is to only be used in accordance with this protocol. The study drug 
must only be distributed to patients properly qualified under this protocol to receive study 
drug. 
The investigator must keep an accurate accounting of the study drug received from the 
supplier. This includes the amount of study drug dispensed to patients, amount of study 
drug returned to the investigator by the patients, and the amount returned or disposed 
upon the completion of the study. A detailed inventory must be completed for the study 
drug. 
12.5.4 Return or Disposal of Study Drug 
All study drug will be returned to the sponsor or their designee or destroyed at the study 
side. The return or disposal of study drug will be specified in writing. 
12.6 Recording of Data on Source Documents and Case Reports Forms 
(CRFs) 
All patient data will be captured in the patient source documents which will be 
transcribed in the eCRFs. The investigator is responsible for ensuring that study data is 
completely and accurately recorded on each patient’s eCRF, source documents, and all 
study-related materials. All study data should also be attributable, legible, 
contemporaneous, and original. Recorded datum should only be corrected in a manner 
that does not obliterate, destroy, or render illegible the previous entry (eg, by drawing a 
single line through the incorrect entry and writing the revision next to the corrected data). 
An individual who has corrected a data entry should make clear who made the correction 
and when, by adding to the correction his/her initials as well as the date of the correction.  
Data entry of all enrolled and randomized patients will use software that conforms to 21 
CFR Part 11 requirements, and will be performed only by staff who have been trained on 
the system and have access to the system. Data will not be entered for screen failure 
patients. An audit trail will be maintained within the electronic system to capture all 
changes made within the eCRF database. After the end of the study and database lock, 
compact discs containing copies of all applicable patients’ eCRFs will be provided to 
each Investigator Site to be maintained on file by the Investigator. 
12.7 Handling of Biological Specimens 
Not applicable.  
12.8 Amendments to the Protocol 
Any amendment containing major modifications (particularly if it may involve an 
increased risk to the patients) must be approved by the IRB before it may be 

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implemented. No change in the conduct of the study can be instituted without written 
approval from the Sponsor. 
12.9 Publications 
Information collected during this clinical study concerning SI-614 ophthalmic solution 
and results of the data obtained are proprietary and strictly confidential. The Sponsor 
reserves all rights to any such information. Authorship and manuscript composition will 
reflect cooperation among all parties involved in the study. Authorship will be 
established before writing the manuscript. Sponsor and 
 will have the final decision 
regarding the manuscript and publication. 
 
 

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associated with dry eye syndrome. Eye (Lond). 2002;16:601-607. 
10. Vogel R, Crockett RS, Oden N, Laliberte TW, Molina L. Demonstration of efficacy 
in the treatment of dry eye disease with 0.18% sodium hyaluronate ophthalmic 
solution (vismed, rejena). Am J Ophthalmol. 2010;149:594-601. 
 
 

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14 APPENDICES 

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Appendix 1: Schedule of Visits and Measurements 
Visit 
Day 
Visit 1 
-14±3 
Visit 2 
1 
Visit 3 
8±1 
Visit 4 
15±2 
Tel. 
22±2 
Visit 5 
29±3 
Tel. 
43±2 
Visit 6 
57±3 
Tel. 
71±2 
Visit 7 
85±3 
Placebo Run-in Administration 
 
 
Study Drug Administration 
 
 
Patient Daily Diary Symptom 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent/HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Medication & Ocular History 
Update 
X 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Eligibility Criteria 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
4-Symptom Questionnaire (in-office) 
X 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Ocular Discomfort (in-office) 
X 
X2 
 
X 
X2 
 
X 
X 
X2 
 
 
X 
X2 
 
 
X 
X2 
 
 
X 
X2 
 
OSDI 
X 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Best-Corrected Visual Acuity 
X 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Slit Lamp Biomicroscopy 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Conjunctival Redness 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
TFBUT 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Fluorescein Staining 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Lissamine Green Staining 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Run-in Vials Dispensed 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Run-in Instilled (in office) 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Run-in Vials Collected/Accountability 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Vials Dispensed 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Study Drug Instilled (in office) 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Study Drug Vials 
Collected/Accountability 
 
 
 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Daily Diary Dispensed 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Daily Diary Collected 
 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Adverse Event Query 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 

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Visit 
Day 
Visit 1 
-14±3 
Visit 2 
1 
Visit 3 
8±1 
Visit 4 
15±2 
Tel. 
22±2 
Visit 5 
29±3 
Tel. 
43±2 
Visit 6 
57±3 
Tel. 
71±2 
Visit 7 
85±3 
Placebo Run-in Administration 
 
 
Study Drug Administration 
 
 
Patient Daily Diary Symptom 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exit from Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: 
 HIPAA. Health Insurance Portability and Accountability Act; OSDI, ocular surface disease index; Tel., Telephone call 
(to check drug compliance); TFBUT, tear film breakup time 
1For females of childbearing potential 
 

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Appendix 2: Examination Procedures, Tests, Equipment, and 
Techniques 
The following examination procedures, tests, equipment and techniques are listed in this 
Appendix:  
Visual Acuity Procedures ..................................................................................................67 
Slit-lamp Biomicroscopy ...................................................................................................69 
 
 ..............................................................................70 
 
 ........................................71 
 
 ...........................................................................72 
 
 .........................................................................74 
Tear Film Break-Up Time (TFBUT) .................................................................................75 
Fluorescein Staining...........................................................................................................76 
 
 .....................................................77 
Lissamine Green Staining ..................................................................................................78 
 
 .....................................................79 
Patient Diary ......................................................................................................................80 
 
 

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Visual Acuity Procedures 
LogMAR Visual Acuity must be assessed using an ETDRS chart. The procedure used 
will be consistent with the recommendations provided for using the ETDRS eye chart. 
Visual Acuity should be evaluated at the beginning of each visit in the study (ie, prior to 
slit-lamp examination). Patients should use most recent correction to attain their best- 
corrected visual acuity. 
Equipment 
The visual acuity chart to be used is the ETDRS chart. If smaller reproduction (18" by 
18", eg, from Prevent Blindness) wall charts are used, the patient viewing distance should 
be exactly 10 feet (or as specified by the manufacturer). In ALL cases, for purposes of 
standardizing the testing conditions during the study, all sites must use only ETDRS 
Series 2000 Chart 1 & 2, and the right eye should be tested first. For reflectance (wall) 
charts, the chart should be placed frontally and well illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. 
The patient should attempt to read each letter, line-by-line, left to right, beginning with 
line 1 at the top of the chart. The patient should be told that the chart has letters only, no 
numbers. If the patient reads a number, he/she should be reminded that the chart contains 
no numbers, and the examiner should then request a letter in lieu of the number. The 
patient should be asked to read slowly, so as 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 patient changes a response (eg, 'that was a "C" not an "O"') before he/she has read 
aloud the next letter, then the change must be accepted. If the patient changes a response 
having read the next letter, then the change is not accepted. The examiner should never 
point to the chart or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the patient 
says he/she cannot read a letter, he/she should be encouraged to guess. If the patient 
identifies a letter as 1 of 2 letters, he/she should be asked to choose 1 letter and, if 
necessary, to guess. When it becomes evident that no further meaningful readings can be 
made, despite encouragement to read or guess, the examiner should stop the test for that 
eye. However, all letters on the last line should be attempted as letter difficulties vary and 
the last may be the only one read correctly. The number of letters missed or read 
incorrectly should be noted. 
LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. 
To this value will be added the number "N x 0.02" where 'N' represents the total number 
of letters missed up to and including in the last line read. This total sum represents the 
logMAR visual acuity for that eye. 

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For Example: Patient correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 
0.1 line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR visual acuity 
= 0.18 
 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of visual acuity during 
the study, all visual acuity assessments at a single site must be consistently done using the 
same lighting conditions and same correction if possible during the entire study. If the 
same correction cannot be used (ie, a patient forgets his/her glasses), the reason for the 
change in correction should be documented. 
Note: A clinically significant visual acuity decrease (defined as an increase of 0.22 or 
greater in logMAR score) from baseline (Visit 1) will be considered an AE. 
 
 

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Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy will be performed during the study. Observations will be graded 
as Normal or Abnormal. Abnormal findings, which are clinically significant, will be 
described. The following will be examined at each visit: 
• 
Cornea  
• 
Conjunctiva  
• 
Anterior Chamber 
• 
Iris 
• 
Lens 
• 
Lid 
 
External magnification and biomicroscopy will be performed using a slit lamp. 
Magnification will be consistent with standard clinical practice. The patient will be 
seated. 
 
 

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Ocular Surface Disease Index© (OSDI©) 
 
 

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Tear Film Break-Up Time (TFBUT)  
The examiner will instill 5 µL of 2% preservative-free sodium fluorescein solution into 
the inferior conjunctival cul-de-sac of each eye. To thoroughly mix the fluorescein with 
the tear film, the patient will be instructed to blink several times. In order to achieve 
maximum fluorescence, the examiner should wait approximately 30 seconds after 
instillation before evaluating TFBUT. 
With the aid of a slit lamp, the examiner will monitor the integrity of the tear film, noting 
the time it takes to form micelles from the time that the eye is opened. TFBUT will be 
measured in seconds using a stopwatch and a digital image recording system for the right 
eye followed by the left eye. A Wratten #12 yellow filter will be used to enhance the 
ability to grade TFBUT. 
For each eye, 2 measurements will be taken and averaged unless the 2 measurements are 
> 2 seconds apart and are each < 10 seconds, in which case, a third measurement would 
be taken and the 2 closest of the 3 would be averaged. 
 
 

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Fluorescein Staining  
The examiner will instill 5 µL of 2% preservative-free sodium fluorescein solution into 
the inferior conjunctival cul-de-sac of each eye. In order to achieve maximum 
fluorescence, the examiner should wait approximately 3-5 minutes after instillation 
before evaluating fluorescein staining. A Wratten #12 yellow filter will be used to 
enhance the ability to grade fluorescein staining. The staining will be graded with the 
 
 
. Digital images of fluorescein staining 
may be taken for digital analysis. 
 
 

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Lissamine Green Staining  
The Investigator will instill 10 µL of lissamine green solution into the inferior 
conjunctival cul-de-sac and wait approximately 30 seconds before evaluating staining. 
The patient will be instructed to blink several times to distribute the lissamine green. The 
staining will be graded with the 
  
 
 

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Patient Diary 
Patients will be instructed to complete patient daily diary prior to dosing 4 times daily.  
 
 

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Appendix 3: List of Ocular Drying or Increased Lacrimation 
Medications 
The following classes of concomitant medications are prohibited if the specific 
concomitant medication is known to cause ocular drying or increased lacrimation (i.e. 
ocular dryness or increased lacrimation is listed among the AEs or side effects section of 
the medication’s labeling) and the medication has not been used at a stable dose for at 
least 30 days prior to Visit 1. 
Ocular Drying 
• 
Antihistamines 
• 
Anti-depressants 
• 
β-blockers 
• 
Antipsychotic 
• 
Codeine 
• 
Decongestants 
• 
Diuretics 
 
Increased Lacrimation 
• 
Cholinergic drugs 
 
 

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Appendix 4: Key Organizations and Personnel 
Name and Contact Information 
Responsibility 
Seikagaku Corporation 
Address: 6-1, Marunouchi 1-chome Chiyoda-ku Tokyo  
 
100-0005 JAPAN 
Sponsor 
- Trial design 
- Study management  
- Data management 
- Statistical analysis 
- Review of adverse events 
 
 
 
 
 
 
 
 
 
CRO 
- Trial design 
- Management of the 
clinical study 
- Investigational drug 
management 
- Medical writing 
 
 
 
 
 
Statistical analysis, IRT and 
data management 
 
 
 
 
 
 
Medical Monitor 
- Medical management 
- Safety surveillance  
- Confirm the patient’s 
eligibility for the study 
- Review safety data and 
clinical study report 
 
 

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Appendix 5: Amendment Summary of Changes  
Not applicable 
 

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Appendix 6: Sponsor and 
 Approvals 
Protocol Title: 
A Multicenter, Randomized, Double-masked and Placebo-
controlled Study Evaluating the Efficacy and Safety of SI-614 
Ophthalmic Solution in Patients with Dry eye (The SIDE 
Study) 
Protocol Number: 
614/1132 
Final Date: 
March 23, 2022 / Version 1.0 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor. The following personnel contributed to writing and/or approving this protocol. 
Signed: 
 
Date: 
 
 
 
 
 
Signed: 
 
Date: 
 
 
 
Signed: 
 
Date: 
 
 
 
Signed: 
 
Date: 
 
 
 
 
Signed: 
 
Date: 
 
 
  
 
 
Signed: 
 
Date: 
 
 
 
 
 

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Appendix 7: Investigator’s Signature 
Protocol Title: 
A Multicenter, Randomized, Double-masked and Placebo-
controlled Study Evaluating the Efficacy and Safety of SI-614 
Ophthalmic Solution in Patients with Dry eye (The SIDE Study) 
Protocol Number: 
614/1132 
Final Date: 
March 23, 2022 / Version 1.0 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to 
maintain all information supplied by 
 and the sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB) or another group, it will 
be submitted with a designation that the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
 
Name:  
 
 
 
Title:  
 
 
 
Site:  
 
 
 
Address:  
 
 
 
Phone Number:  
 
 
 
 
 

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Appendix 8: COVID-19 PANDEMIC AND SUGGESTED MEASURES 
This section is provided in response to the “FDA Guidance on Conduct of Clinical Trials 
of Medical Products during COVID-19 Pandemic Public Health Emergency” issued by 
the FDA on March 2020 and updated on August 2021. Taking the COVID-19 impact into 
account, this section provides guidance to Investigators and their site staff to mitigate 
risks and suggested measures to modify operations. Each Investigator may choose to 
implement different measures according to their sites’ operations; which may include, but 
are not limited to the following items. 
 
Screening Questions to Identify Potential COVID-19 Exposure 
When scheduling an on-site visit for subjects, consider asking the subjects a few, short 
questions regarding potential exposure to COVID-19 before their on-site visit (in-person 
interactions). For example: 
1. Have you had any of the following symptoms in the past 14 days without 
confirmation of etiology such as a positive flu test, existing chronic medical 
condition, etc. 
• 
Fever greater than 100.4 dgrees  
• 
Fahrenheit 
• 
Cough 
• 
Difficulty breathing 
• 
Sore throat 
2. In the last 14 days, have you lived with, visited, cared for, or been in a room for a 
prolonged period of time with someone who is under investigation or has been 
confirmed for COVID-19? 
 
Remote Monitoring 
Due to travel restrictions, shelter in place or stay at home mandates, sites’ change in 
operations, and a number of other reasons to try to contain the spread of the virus and 
minimize exposure, it is reasonable to conduct monitoring visits remotely, instead of in-
person, whenever feasible. Site staff/Investigator will work with CRO and the assigned 
CRA to define and understand the logistics of the remote visit such as source data 
verification. 
 
Data Management 
In order to confirm the effect of COVID-19 on this study, the following information will 
be captured in eCRF. 
• 
Missed visit due to COVID-19 
• 
Missed assessment due to COVID-19 

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• 
Screen failed subject due to COVID-19 
• 
Early discontinuation due to COVID-19 
• 
AE related to COVID-19