Clinical trial NCT03889886
Conditions: Dry Eye
Sponsor: Silk Technologies, Ltd.
Start date: 2019-04-16; Completion date: 2019-10-11
Enrollment: 305 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
SDP-4-CS201, is a Phase 2, multi-center, double-masked, randomized, vehicle-controlled, dose-response, parallel-group study designed to evaluate the ocular and systemic safety and efficacy of SDP-4 ophthalmic solution in subjects with moderate to severe dry eye disease over a 12-week treatment period. Three concentrations (0.1%, 1.0% and 3.0%) of SDP-4 ophthalmic solution will be given to parallel groups via topical ocular instillation BID.

Detailed description:

Arms: arm 1: Vehicle arm 2: Low concentration of SDP-4 arm 3: Mid concentration of SDP-4 arm 4: High concentration of SDP-4
Interventions: intervention 1: SDP-4 Ophthalmic Solution (0.1%) intervention 2: SDP-4 Ophthalmic Solution (1.0%) intervention 3: SDP-4 Ophthalmic Solution (3.0%) intervention 4: Vehicle
Intervention descriptions: intervention 1: Investigational product (IP) will be administered via topical ocular instillation, one drop per eye, twice daily (BID) for 12 weeks (84 days). Both eyes will be treated. intervention 2: Investigational product (IP) will be administered via topical ocular instillation, one drop per eye, twice daily (BID) for 12 weeks (84 days). Both eyes will be treated. intervention 3: Investigational product (IP) will be administered via topical ocular instillation, one drop per eye, twice daily (BID) for 12 weeks (84 days). Both eyes will be treated. intervention 4: Investigational product (IP) will be administered via topical ocular instillation, one drop per eye, twice daily (BID) for 12 weeks (84 days). Both eyes will be treated.

Protocol documents:
ICF_002.pdf: 
Silk Technologies, Ltd.  
Protocol SDP-4-CS201 
Main ICF Version 1.0, 27Feb2019 
 
Approved by Alpha IRB March 25, 2019 
Version 1.0 
 
Page 1 of 17 
 
 
 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
TITLE OF STUDY:    A Phase 2, Multicenter, Double-Masked, Randomized, Vehicle- 
                                Controlled, Parallel-Group, Dose-Response Study of SDP-4            
                                Ophthalmic Solution in Subjects with Dry Eye Disease (DED) 
                                      
 PROTOCOL NUMBER:  SDP-4-CS201 
 
SPONSOR COMPANY:  Silk Technologies, Ltd.  
 
STUDY DOCTOR:  <<Enter Name of Investigator>> 
 
ADDRESS of STUDY SITE:  <<Enter site name address>> 
 
TELEPHONE NUMBERS:  <<Enter phone numbers below>> 
 
Office:  <<>> 
 
After Hours:  <<>> 
 
Introduction 
 
You are being asked to take part in a research study. The following information describes the study and 
your role as a participant. Before you agree to take part in this study, it is important for you to read all of 
the information in this form. This consent form explains the purpose, procedures, risks, benefits, 
discomforts and precautions of this study. It also explains what other treatments are available for your 
condition if you choose not to be in this study. It is your right to choose not to be in this study and to 
leave this study at any time. The results of this study are not yet known and you may not receive any 
medical benefits from participating in the study.  
 
Key information Points 
 
• 
This research study is being conducted to learn more about the safety and effectiveness of the 
investigational eye drop, SDP-4, in subjects with dry eye disease.   
• 
We expect that your taking part in this research will last about 14 weeks. 
• 
You will receive one drop of the study drug, or vehicle, in each eye twice a day for 84 days. 
• 
Some of the additional study procedures and assessments include collecting your medical history, 
vision/eye exams, and questions regarding your symptoms and drop comfort. For more 
information, see the section, “Study Procedures” 
• 
There are risks associated with your participation. Risks could be minor but there could be risks 
that would be more serious. There may be other risks or side effects that are currently unknown. 
For more information on risks, see section, “What are the Possible Risks or Side Effects of the 
Study Procedures?” 
• 
In case of a study-related side injury, emergency medical care is available. For more information, 
see the section, “What Happens if I have an Injury from Taking Part in the Study?” 
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Protocol SDP-4-CS201 
Main ICF Version 1.0, 27Feb2019 
 
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Page 2 of 17 
 
• 
There may be no direct medical benefit to you for participating in this study. Your dry eye may 
improve, or it may not get better or may get worse during this study. The results of this study may 
help people with dry eye in the future.  
• 
There are other options to treat your dry eye besides taking part in this study. For more 
information, see the section “What Other Treatments Are Available?” 
 
Take your time and read this entire consent form carefully. Please ask the Study Doctor or the Study Staff 
to explain any words or procedures that you do not clearly understand or to answer any other questions 
you may have about this study. You may discuss your decision with your friends and family. 
 
What is the Background and Purpose of This Research Study? 
 
You are being asked to take part in this research study because you suffer from what is called dry eye 
disease.  This is a common disorder of the tears that you produce in order to keep your eyes moist which 
can affect the surface of the eyes.  Dry eye can cause inflammation and/or irritation of the surface of the 
eye resulting in some or all of the following symptoms: burning, stinging, itching, grittiness, scratchiness, 
foreign body sensation, dryness, stickiness and tired eye sensation.  The symptoms are usually gradual 
and affect both eyes.  The symptoms also tend to become more bothersome later in the day and can be 
worsened by environmental factors such as wind or air-conditioning.   
 
The current study is evaluating an investigational study drug called SDP-4 that may help the symptoms of 
your dry eye.  Investigational means it has not been approved by the Food and Drug Administration 
(FDA).  The study drug is an eye drop that is used in both eyes twice a day, once in the morning and once 
at bedtime.  
 
The purpose of this research study is to determine how the study drug, SDP-4, affects how well your eyes 
make tears and relieves your symptoms along with testing the safety of the drops.  You will be provided 
one of 3 different dose strengths of the study drug, or the “vehicle”. The study “vehicle” drops are the 
same formulation as the study “drug” drops, but do not contain the active drug (medicine).    
 
If you participate in the study, you will receive one of the following: 
 
• 
SDP-4     0.1% - one drop in both eyes twice a day 
• 
SDP-4     1.0% - one drop in both eyes twice a day 
• 
SDP-4     3.0% - one drop in both eyes twice a day 
• 
Vehicle    0.0% - one drop in both eyes twice a day 
 
It will be decided randomly (by chance, like pulling numbers from a hat) which drop you will receive. 
This will be either one of the 3 doses of the study eye drop, or the study vehicle, to be used for the 
duration of the study.  This is called being “randomized,” or assigned, to a study eye drop.  You will not 
know which of the eye drops you are using and neither will your Study Doctor or the Study Staff.  
However, the Study Doctor can find out which group you are in if, for medical reasons, it becomes 
necessary to know.  You will have a 3 out of 4 chance of receiving the SDP-4 eye drop and a 1 out of 4 
chance of receiving the vehicle. 
 
About 300 people, aged 18 years and older, are expected to take part in this study at about 25 clinical sites 
within the United States. 
 
 
 
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Protocol SDP-4-CS201 
Main ICF Version 1.0, 27Feb2019 
 
Approved by Alpha IRB March 25, 2019 
Version 1.0 
 
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How Long Will I Be In The Study and What Will I Have To Do? 
 
If you decide to take part in this study, you will visit the Study Doctor about 7 times over 14 weeks (3 ½ 
months).  Each visit will last 1-2 hours.  The first visit is to make sure you can be in the study.  If you can 
be in the study, at the end of this first visit (Visit 1), you will be given the vehicle eye drops to use for the 
next 2 weeks (14-16 days) so you can stop using your previous eye drops and to get used to using the 
drops.  This is called a “run-in” period.  If you are still able to stay in the study after Visit 2, you will use 
the study eye drops randomly selected for you twice a day in both eyes for the next 3 months of the study.  
Once the final visit (Visit 7) has been completed, you will no longer use the study eye drops or be 
required to return for follow-up.  If your Study Doctor feels it is necessary, you may be asked to come in 
for an unscheduled visit(s) during the study. 
 
During the study, you will be asked to: 
 
• 
Visit the Study Doctor about 7 times over 14 weeks (3 ½ months), not including unscheduled 
visits. 
 
• 
Not enroll in any other investigational drug or device study while taking part in this study. 
 
• 
Use the study eye drop as directed by your Study Doctor.  This study eye drop is intended only 
for you and no one else can use it.   
 
 
• 
Tell the Study Staff at each visit about any other medications you are taking, prescription or over 
the counter. 
 
• 
Tell the Study Staff at each visit about any changes in your health or the way that you feel since 
your last visit. 
 
• 
You will be asked to carry a study ID card with you at all times during your participation in this 
study.  This card will be given to you by the Study Staff and will contain information about the 
study. 
 
• 
Use medically acceptable birth control to prevent pregnancy as described in the Pregnancy Risks 
section of this consent form. 
 
During the study, you will not be able to take certain medications by mouth or use any other eye drops 
except for the study eye drops. Your Study Doctor will go over your current medications and discuss 
these with you.  If needed during the study, you can ask your Study Doctor for preservative free artificial 
tears which will be provided at no cost.  Only the artificial tears given to you by your Study Doctor are 
allowed.  No other tears should be used during the study.  If you request tears from your Study Doctor, 
you will be asked to return all used and unused artificial tears and packaging at each study visit.   
 
Contact lenses are not allowed to be worn during the study.  If you wear contact lenses, you must agree 
not to wear them while you are taking part in the study.   
 
 
 
 
 
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Study Procedures 
 
Before you take part in this research study, the study must be explained to you and you must be given the 
chance to ask questions. You must read and sign this informed consent form. You will be given a copy of 
this signed and dated consent form to take home with you. 
 
Each visit will take 1-2 hours to complete.  All study assessments will be performed on both eyes.  If you 
agree to take part in this study, you will complete the following study procedures: 
 
Visit 1 - Screening Visit (to see if you are able to be in the study): 
The following will occur during this visit: 
 
• 
You will be asked to provide information about yourself including date of birth, gender, race, 
ethnicity, iris (colored part of your eye) color and personal data (information). 
 
• 
Medical and eye histories will be recorded. You will be asked about your current health status 
and any important medical history and past and current eye conditions. 
 
• 
A thorough list of all medications, both prescription and over-the-counter, you are taking now 
and have taken in the past will be recorded. 
 
• 
If you are a woman who is able to become pregnant, a urine pregnancy test will be performed. 
 
• 
You will be asked a couple of questions about how often your eyes are dry and how you would 
rate your symptoms. 
 
• 
Your vision will be tested by reading letters on an eye chart.  If you wear glasses, your vision 
will be tested using those.  The Study Staff may try to improve your vision using trial lenses, if 
needed. 
 
• 
The Study Doctor will look at the front part of your eyes and eyelids using a special microscope 
called a slit lamp.  A slit lamp is used to help the Study Doctor determine the overall health of 
your eyes.  
 
• 
Tear break-up time will be recorded. This is a painless exam where a small amount of orange dye 
called fluorescein will be placed into each eye.  You will place your chin in the chin rest and 
forehead against the forehead strap of the slit lamp and the Study Doctor will shine a blue light in 
your eyes.  You will be asked not to blink for ten (10) seconds and the Study Doctor will record 
the time it takes for the tears on the surface of your eye to break-up and create dry spots. 
 
• 
The Study Doctor will then take a look at the surface of your cornea (clear part of the eye), 
which is what covers the colored part of the eye, using the slit lamp with a blue light.  If needed, 
more orange fluorescein dye may be placed in the eye. 
 
• 
A small amount of green dye called lissamine green will also be placed into each eye.  The Study 
Doctor will then take a look at the surface of your conjunctiva, which is the white part of your 
eye, using the slit lamp with a white light. 
 
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• 
You will have a Schirmer’s test to measure the amount of tears your eyes produce.  Tiny paper 
strips are placed just inside the corner of your lower eyelids to measure the amount of tears 
produced in 5 minutes.  Before the paper strips are placed inside your lower eyelids, an 
anesthetic eye drop will be put into both of your eyes.  This drop will numb the surface of your 
eyes so you won’t feel the paper strips. 
 
• 
Your eye pressure will be checked using an instrument called a tonometer, which is attached to 
the slit lamp. This is a painless procedure.  You will be given more drops to numb your eyes. The 
tonometer will touch the surface of your eye to measure the pressure.  
 
• 
You will have a dilated eye exam.  A special eye drop will be placed in both eyes to make your 
pupils (black circles in the center of the colored part of your eyes) bigger or dilated so that the 
Study Doctor can look into the back of your eyes to check their health. 
 
Based on your eye exam results and answers to the questions, there is a chance that you may not be able 
to take part in this study.  If you are able to continue in the study, you will begin a “run-in” period (so that 
you get used to using the eye drops).  The Study Doctor will give you the vehicle (no active drug) eye 
drops.  You will use one drop two times a day in both eyes for at least two weeks (12-16 days).  The 
Study Staff will show you or your caregiver how to put the drops in your eyes.  You or your caregiver 
will put in the first drops while you are at the Study Doctor’s office.   
 
• 
You will be asked how you are feeling and if you have had any recent changes in your health. 
 
You will return 2 weeks later for the Baseline Visit (Visit 2).  You will need to return all used and unused 
run-in medication at that visit.  
 
Visit 2: 
The following will occur during this visit: 
 
• 
You will be asked how you are feeling and if you have had any changes to your health since your 
last visit. 
 
• 
Current medications will be reviewed. 
 
• 
If you are a woman who is able to become pregnant, a urine pregnancy test will be performed. 
 
• 
You will be asked a couple of questions about how often your eyes are dry and how you would 
rate your symptoms on a scale of 1-100. 
 
• 
You will be asked to report what type of dry eye symptoms you have been having and how you 
would rate them on a scale of 1-100.  
 
• 
Study drop comfort assessment:  You will be asked to evaluate the comfort of the eye drops using 
the following scale: 
 
                                             0 = No discomfort 
                                                                 1 = Mild discomfort 
                                                    2 = Moderate discomfort 
                                                    3 = Severe discomfort 
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Main ICF Version 1.0, 27Feb2019 
 
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Page 6 of 17 
 
 
• 
Your vision will be tested by reading letters on a chart.  If you wear glasses, your vision will be 
tested while wearing your glasses. 
 
• 
The Study Doctor will look at the front part of your eyes and eyelids using the slit lamp.   
 
• 
A small amount of orange dye called fluorescein will be placed into each eye.  Tear break-up time 
will be recorded.   
 
• 
The Study Doctor will take a look at the surface of your cornea. 
 
• 
A small amount of green dye called lissamine green will be placed into each eye.  The Study 
Doctor will then take a look at the surface of your conjunctiva. 
 
• 
You will have a Schirmer’s test to measure the amount of tears your eyes produce.  A numbing 
drop will be placed in both eyes. Tiny paper strips are placed just inside the corner of your lower 
eyelids to measure the amount of tears produced in 5 minutes.   
 
• 
All used and unused run-in eye drops and packaging will be collected at this visit.  
 
At this point in the visit, if you are still able to continue in the study based on the results of the exam, you 
will be randomized (like pulling numbers from a hat) to one of 4 groups: 
 
• 
SDP-4 0.1% - one drop in both eyes twice a day 
• 
SDP-4 1.0% - one drop in both eyes twice a day 
• 
SDP-4 3.0% - one drop in both eyes twice a day 
• 
Vehicle – 0.0% - one drop in both eyes twice a day 
 
You will be given your study drops to use in both eyes, twice a day for the remainder of the study.  The 
Study Staff will again show you or your caregiver how to put in the drops, and you will start using the 
study drops at home the same day as your study visit.   
 
You will return once a week for the next 2 weeks for your next 2 study visits (Visit 3 and Visit 4).  You 
will need to return all used and unused study drops and packaging at these visits.  
 
Visits 3 and 4: 
The following will occur during these visits: 
 
• 
You will be asked how you are feeling and if you have had any changes to your health since your 
last visit. 
 
• 
Current medications will be reviewed. 
 
• 
You will be asked a couple of questions about how often your eyes are dry and how you would 
rate your symptoms on a scale of 1-100. 
 
• 
You will be asked to report what type of dry eye symptoms you have been having and how you 
would rate them on a scale of 1-100.  
 
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• 
You will be asked to evaluate the comfort of the eye drops using the same scale as previous visits. 
 
• 
Your vision will be tested by reading letters on a chart.  If you wear glasses, your vision will be 
tested while wearing your glasses. 
 
• 
The Study Doctor will look at the front part of your eyes and eyelids using the slit lamp.   
 
• 
A small amount of orange dye called fluorescein will be placed into each eye.  Tear break-up time 
will be recorded.   
 
• 
The Study Doctor will take a look at the surface of your cornea. 
 
• 
A small amount of green dye called lissamine green will be placed into each eye.  The Study 
Doctor will then take a look at the surface of your conjunctiva. 
 
You will return in 2 weeks for your next study visit (Visit 5).  You will need to return all used and unused 
study drops and packaging at this visit.  
 
Visit 5: 
The following will occur during this visit: 
 
• 
You will be asked how you are feeling and if you have had any changes to your health since your 
last visit. 
 
• 
Current medications will be reviewed. 
 
• 
You will be asked a couple of questions about how often your eyes are dry and how you would 
rate your symptoms on a scale of 1-100. 
 
• 
You will be asked to report what type of dry eye symptoms you have been having and how you 
would rate them on a scale of 1-100.  
 
• 
You will be asked to evaluate the comfort of the eye drops using the same scale as previous visits. 
 
• 
Your vision will be tested by reading letters on a chart.  If you wear glasses, your vision will be 
tested while wearing your glasses. 
 
• 
The Study Doctor will look at the front part of your eyes and eyelids using the slit lamp.   
 
• 
A small amount of orange dye called fluorescein will be placed into each eye.  Tear break-up time 
will be recorded.   
 
• 
The Study Doctor will take a look at the surface of your cornea. 
 
• 
A small amount of green dye called lissamine green will be placed into each eye.  The Study 
Doctor will then take a look at the surface of your conjunctiva. 
 
• 
You will have your eye pressure checked. 
 
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Main ICF Version 1.0, 27Feb2019 
 
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Version 1.0 
 
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• 
All used and unused study drops and packaging will be collected at this visit.  
 
• 
You will receive another box of study eye drops to last until your next visit.  
 
You will return about every 4 weeks for the next 2 visits (Visit 6 and Visit 7).  Visit 7 is the last 
scheduled visit in this study.  You will need to return all used and unused study drops and packaging at 
these visits.  
 
Visits 6 and 7: 
The following will occur during these visits: 
 
• 
You will be asked how you are feeling and if you have had any changes to your health since your 
last visit. 
 
• 
Current medications will be reviewed. 
 
• 
If you are a woman who is able to become pregnant, a urine pregnancy test will be performed. 
(Visit 7 only) 
 
• 
You will be asked a couple of questions about how often your eyes are dry and how you would 
rate your symptoms on a scale of 1-100. 
 
• 
You will be asked to report what type of dry eye symptoms you have been having and how you 
would rate them on a scale of 1-100.  
 
• 
You will be asked to evaluate the comfort of the eye drops using the same scale as previous visits. 
 
• 
Your vision will be tested by reading letters on a chart.  If you wear glasses, your vision will be 
tested while wearing your glasses. 
 
• 
The Study Doctor will look at the front part of your eyes and eyelids using the slit lamp.   
 
• 
A small amount of orange dye called fluorescein will be placed into each eye.  Tear break-up time 
will be recorded.   
 
• 
The Study Doctor will take a look at the surface of your cornea. 
 
• 
A small amount of green dye called lissamine green will be placed into each eye.  The Study 
Doctor will then take a look at the surface of your conjunctiva. 
 
• 
You will have a Schirmer’s test to measure the amount of tears your eyes produce in 5 minutes. 
(Visit 7 only) 
 
• 
Your eye pressure will be checked. (Visit 7 only) 
 
• 
You will have a dilated exam. (Visit 7 only) 
 
• 
All used and unused study drops and packaging will be collected at this visit.  
 
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• 
You will receive another box of study eye drops to last until your next visit. (Visit 6 only) 
 
You will not receive any more eye drops after Visit 7.   
 
You may be asked to return for an unscheduled visit if you leave the study or if you are taken out of the 
study for any reason.  This is to ensure there have been no changes to your health during the study.  You 
must return all used and unused eye drops in the box, pouches and vials at this visit.  If you are asked to 
return for an unscheduled visit, you will complete all of the procedures listed in Visit 7.   
 
 What Are the Possible Risks or Side Effects of the Study Drug? 
 
As with any drug, there is a risk that side effects may occur while using SDP-4.  There have been no 
previous studies of SDP-4 in people.
 
                                                                                        
There may be risks or side effects of SDP-4 that are currently unknown.  Allergic reactions can occur 
with any drug.  It is important to tell your Study Doctor if you start to experience any new symptoms 
while using the eye drops.  Your Study Doctor will monitor you for side effects throughout this study.   
 
What are the Possible Risks or Side Effects of the Study Procedures? 
 
Possible Risks of Dilating Drops 
 
The drops used to dilate your eyes may sting when they are first placed in your eyes.  They may cause 
your vision to be blurred for a few hours, especially your reading vision, and cause sensitivity to light.  
This effect is common. To protect your eyes, you should wear sunglasses while outside.  This will make 
your eyes more comfortable and you should bring your sunglasses with you to Visit 1 and Visit 7, when 
you will be dilated.  If you do not have sunglasses, the Study Doctor can provide you with a disposable 
pair of temporary sunglasses.  You should also avoid driving and any situations that could be potentially 
dangerous until your vision returns to normal.  There is a risk that dilating your eyes could increase your 
eye pressure.  Your Study Doctor will discuss the risk of this with you. 
 
Possible Risks of Dyes (Fluorescein and Lissamine Green) 
 
The orange (fluorescein) and green (lissamine) dyes used to evaluate the front surface of your eyes may 
cause mild, temporary discomfort to your eyes.  It may also change the color of your tears or mucous 
when you blow your nose, turning it a yellow or green color.  This effect is common and will usually go 
away within a few hours. 
 
Possible Risks of Numbing Drops 
 
The numbing drops used for checking your eye pressure may sting for a few seconds when they are first 
placed in your eyes. This is common. If your eyes are sensitive, they may also appear a little red after 
receiving the numbing drops.  It is important not to rub your eyes while they are numb to avoid scratching 
the surface of your eyes.  Your Study Doctor or the Study Staff will explain the side effects to you before 
using the numbing drops. 
 
Possible Risks of Schirmer’s Test 
 
After the Schirmer test, you may have a little discomfort and redness in the area the strips were placed.  
This could last for a few hours. 
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Pregnancy Risks 
 
The effects of the study eye drops, SDP-4, on an unborn baby or nursing infant are not known.  Women 
who are pregnant, planning to become pregnant or nursing a child may not take part in this study. 
 
If you are a woman of child bearing potential (able to become pregnant), you must use an acceptable 
method of contraception (birth control) to prevent you from getting pregnant throughout your 
participation in the study.  Acceptable methods include use of at least one of the following: intrauterine 
device (IUD), hormonal (pill by mouth, injection, patch, implant, ring), barrier with spermicide (condom, 
diaphragm), or abstinence.  Your Study Doctor or Study Staff will further discuss this with you to make 
sure an adequate form of birth control is being used.  
 
You will be asked to take a urine pregnancy test at the first and second visit and at the end of the study if 
you are not surgically sterile or post-menopausal.  You must have a negative pregnancy test prior to 
starting to use the eye drops and must not become pregnant while in this study.  If you become pregnant 
during this study, you must tell the Study Doctor or Study Staff right away and stop using the eye drops 
immediately.  The Study Doctor will ask for information about your pregnancy and follow-up with you 
until the end of the pregnancy to record the outcome.  You will no longer be able to receive the eye drops 
but you will be asked to complete remaining study visits. 
 
New Information 
 
There may be new information that becomes available during the course of this study regarding risks or 
benefits, your individual research results, or any other changes to the study that may affect your decision 
to continue participating. You will be informed of any new information learned about this study or the 
study eye drops, and you may be asked to sign an updated version of this consent form which will 
describe the new findings. 
 
What Are the Possible Benefits of Taking Part? 
 
Your dry eye may improve while you are taking part in this study; however, this cannot be guaranteed. 
Your eye condition may not get better or may get worse during this study. The results of this study may 
help people with dry eye in the future.  There is a 1 in 4 chance that you will receive the vehicle (no active 
medicine) in this study.  If SDP-4 is effective in treating dry eye, subjects receiving vehicle may not 
receive the same benefit as those who receive the active medicine SDP-4. 
 
What Other Treatments Are Available? 
 
You do not have to be in this study to receive treatment for dry eye.  Other treatment options include, but 
are not limited to, artificial tears, punctal (tear drainage duct) plugs or prescription eye drops.  Each of 
these treatments has some benefits and some risks, and you should discuss all other treatment options 
including their important risks and benefits with the Study Doctor before you decide to participate in this 
study.  
 
What are the Costs of Taking Part? 
 
There will be no cost to you for your participation in this study. The assigned eye drops, study-related 
procedures, and study visits will be provided at no cost to you or your insurance company. 
 
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You or your insurance will be billed for any standard care, such as eye exams not related to the study, that 
you receive during your participation in the study. 
 
Is There Payment for Taking Part in this Study? 
 
For your time and inconvenience related to your participation in this study, you will be paid for each visit 
you complete as follows: 
 
Visit 
Payment 
Visit 1 
$<<Insert Payment>> 
Visit 2 
$<<Insert Payment>> 
Visit 3 
$<<Insert Payment>> 
Visit 4 
$<<Insert Payment>> 
Visit 5 
$<<Insert Payment>> 
Visit 6 
$<<Insert Payment>> 
Visit 7 
$<<Insert Payment>> 
Total 
$<<Insert Payment>> 
 
If the Study Doctor asks you to return for an unscheduled visit, you will be paid $<<Insert Payment>>for 
each unscheduled visit you complete. 
 
If you do not complete this study, for any reason, you will receive payment for the study visits you do 
complete.  If you do not complete an entire study visit, you will not receive payment for that visit.  
 
Payment will be made in the form of <<a XXXX>> and will be provided to you << insert site specific 
payment schedule>>. 
 
Information from this study may lead to discoveries and inventions or development of a commercial 
product. If commercial products or other valuable discoveries result from the research using your data, 
you and your family will not receive any financial benefits or compensation from or have rights in any 
developments, inventions, or other discoveries that might come from this information. 
 
Do I have To Take Part? 
 
Your participation in this study is voluntary.  You may decide to not participate or you may leave the 
study at any time.  Your decision will not result in any penalty or loss of benefits to which you are 
entitled.  Your decision to participate in this study will not interfere with your future care at this facility.   
 
Your Study Doctor, and/or the Sponsor may stop your participation in the study without your permission 
at any time for the following reasons:   
 
• 
You withdraw (take back) your consent 
 
• 
The Sponsor stops the study 
 
• 
It is in your best interest to stop taking part 
 
Your Study Doctor, the Investigator and/or the Sponsor may stop you from using the eye drops but ask 
that you still complete the study visits for the following reasons: 
 
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• 
You experience an injury related to the study 
 
• 
You are a female who becomes pregnant 
 
• 
You request to stop taking the eye drops 
 
• 
You do not take the study eye drops as instructed 
 
The Sponsor may stop the study at any time without giving a reason.  If you wish to leave this study 
before completing all the visits, please inform the Study Doctor or Study Staff by telephone using the 
number listed on the first page of this consent document.  
 
Any information collected from you up to the point you exit the study remains part of the study database 
and may not be removed. 
 
Your Primary Care Physician (PCP) should know that you are taking part in this study.  You should take 
steps to inform your Primary Care Physician of your participation in this study. 
 
What Happens if I have an Injury from Taking Part in the Study? 
 
If you have any side effects after taking the study eye drops or are injured during the study, you must tell 
your Study Doctor as soon as possible.  Your Study Doctor will make sure you receive medical 
treatment.   
 
If side effects or other physical injuries are a direct result of receiving the study eye drops or study 
procedures, immediate medical care will be provided to you.  The study Sponsor, Silk Technologies, Ltd., 
will cover any reasonable costs to treat such an injury.  If an injury results for any of the following 
reasons, the Sponsor may not cover the costs of treatment:  
 
• 
You did not follow the instructions given to you by your Study Doctor or Study Staff. 
• 
You caused your own injury.  
• 
The Study Doctor or Study Staff did not follow the study plan 
• 
The injury is a normal progression of an underlying, pre-existing medical condition. 
 
If your injury or illness is not a direct result of being in this study, you or your medical insurance will be 
billed for the cost of treatment.   
 
The Sponsor has no plans to provide compensation for any types of expenses other than the cost of 
immediate medical treatment of an illness or injury that is a direct result of receiving the study eye drops 
or the study procedures.  This does not prevent you from pursuing other legal options.  You do not give 
up any legal rights by signing this form. 
 
To help avoid injury, it is very important to follow all study directions given to you by your Study Doctor 
or Study Staff. 
 
How is My Health Information Used and Disclosed (shared)? 
 
Your study-related medical records and this consent form may be reviewed and/or copied by the Sponsor, 
Alpha Independent Review Board (Alpha IRB), the ethics committee overseeing this study, and 
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regulatory authorities, such as the U.S. Food and Drug Administration (FDA), Department of Health and 
Human Services (DHHS) or similar regulatory authorities in other countries. 
 
Your identity will remain confidential to the extent required by applicable law.  If your protected health 
information is shared with the parties listed above and/or others who are not required to comply with the 
laws that protect the privacy of your protected health information, it will no longer be protected by such 
law and could be used or disclosed in ways other than those listed above.   
 
If the results of this study are published, you will not be identifiable in the published study results.  
 
Your information collected as part of the research, even if identifiers are removed, will not be used or 
distributed for future research studies. 
 
Who Can I Contact with Questions or Concerns? 
 
You have the right to ask questions about this study at any time and are encouraged to do so.  If you have 
questions, concerns, or complaints about this study or need to report a study related injury, contact the 
Study Doctor or Study Staff at the telephone number(s) listed on page 1 of this consent form. 
 
If you are unable to reach anyone at the numbers listed above, and you need medical attention, 
please go to the nearest emergency room.  Please remember to bring your Study ID card with you. 
 
If you have questions, concerns or complaints about your rights as a research volunteer or about taking 
part in this study, or to obtain information or offer input, you may contact Alpha Independent Review 
Board (IRB), Attn: Marianne Thornton, toll free at (888) 265-5766 between the hours of 8:00am-5:00pm 
Pacific Time.   
 
 
Alpha Independent Review Board 
1001 Avenida Pico, Suite C #497 
San Clemente, CA 92673 
(888) 265-5766 (toll free) 
 
Alpha IRB is a group of people who perform an independent review of research studies to protect the 
rights and welfare of study participants. Although Alpha IRB has approved the information provided in 
this informed consent form and has approved the Study Doctor to conduct the study, this does not mean 
Alpha IRB has approved you being in the study, or that the study is without risks. You must consider the 
information in this consent form for yourself and decide if you want to be in this study. 
 
This study is sponsored by Silk Technologies, Ltd. referred to as “the Sponsor”.  The Study Doctor is 
being paid by the Sponsor to carry out this study.  
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
 
You will receive a copy of this signed and dated consent form. 
 
 
 
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Acknowledgment of Consent and Provision of Authorization: 
 
I have read this consent document which is in a language that I can read and understand.  The study has 
been discussed with me and my questions about the study and possible risks and side effects have been 
answered.  I am aware that by signing this consent form I am authorizing (giving permission for) the use 
and possible disclosure (sharing) of my protected health information.  I am also aware that by signing this 
form I will not be giving up any of my legal rights.  I am aware that I may withdraw my consent and 
authorization at any time by contacting the Study Doctor listed on page 1 of this form, in writing, and 
telling the Study Doctor that I withdraw my consent and authorization. 
 
Based on this information, I volunteer to take part in this study. 
 
 
 
_________________________________        ________________________________         ___________ 
Printed Name of Participant                    
 Signature of Participant                              Date 
 
 
 
_________________________________          _______________________________          ___________ 
Printed Name of Person Obtaining Consent      Signature of Person Obtaining Consent          Date 
 
 
 
 
 
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AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH 
INFORMATION 
 
 
How is My Health Information Used and Disclosed (shared)? 
 
During the course of the study, the Study Doctor will collect personal and health-
related information about you. This information will be used to learn about how 
safe and effective the study eye drops will be. Your protected health information 
(PHI) is generally information that is, or has been, gathered or kept by the Study 
Doctor as a result of your healthcare.  This includes data (information) gathered for 
this research study that can be traced back to you.  Using or sharing (“disclosing”) 
such data must follow state and federal privacy laws and rules. All efforts, within 
reason, will be made to keep your PHI private in accordance with the applicable 
privacy laws and rules.  By signing the consent form for this study, you are 
agreeing to (“authorizing”) the use and likely sharing of your PHI.  All such use 
and likely sharing must comply with applicable state and federal privacy laws.  If 
you decide to be in this research study, you are also agreeing to let the study team 
use and share your PHI as described below.  
Your study-related medical records and this consent form may be reviewed and/or 
copied by the Sponsor, Alpha Independent Review Board (Alpha IRB), the ethics 
committee overseeing this study, and regulatory authorities, such as the U.S. Food 
and Drug Administration (FDA), Department of Health and Human Services 
(DHHS) or similar regulatory authorities in other countries. 
Your identity will remain confidential to the extent required by applicable law.  If 
your protected health information is shared with the parties listed above and/or 
others who are not required to comply with the laws that protect the privacy of 
your protected health information, it will no longer be protected by such law and 
could be used or disclosed in ways other than those listed above.   
 
If the results of this study are published, you will not be identifiable in the 
published study results.  
 
What if I choose not to share my information? 
Your consent and authorization to use or share your PHI does not expire for 50 
years, unless you tell the Study Doctor otherwise. You have the right to revoke 
(withdraw or take back) your consent and authorization to use or share your PHI at 
any time as follows. If you want to revoke your consent, you must write to the 
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Study Doctor at the study site address listed on page 1 of this consent form and 
inform the Study Doctor that you withdraw your consent and authorization.  After 
the Study Doctor receives your written withdrawal, the Study Doctor will then stop 
collecting study-related data about you.  But, the study-related data already 
collected before receipt of the writing where you withdrew your consent may still 
be used for reporting and research quality.  If you withdraw your consent and 
authorization, you will no longer be a participant in this study.   
 
Possible Transfer of Your Health Information Out of the Country 
The study Sponsor may send your study data (with your initials and a code 
number, but not your name) outside of the United States for the reasons described 
in this form.  Please know that the laws in other countries may not provide the 
same level of data and privacy protection as in the United States and those laws 
may not stop your study data from being disclosed to others not involved in the 
study. 
 
Your Right to See and/or Copy Your Study-Related Health Information 
You may see and copy your study-related health information for as long as the 
Study Doctor is required to keep this information.  You may also, under applicable 
privacy and data protection laws, have the right to ask that any mistakes in your 
study-related health information be corrected.  However, you may not be able to 
see or copy your study-related health information until after the study has been 
completed. Otherwise, it could affect the study. 
 
By signing this authorization document, you are giving your permission to use and 
give out your PHI. If you do not give your permission, you will not be able to be in 
this study. 
 
You will be provided with a copy of this signed document.    
 
 
 
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STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained.  My questions have been 
answered. I voluntarily agree to allow study staff to collect, use, and share my 
health data as specified in this form.  I will receive a signed and dated copy of this 
form for my records.  Except as specifically outlined in this form, I am not giving 
up any legal rights by signing and dating this form. 
 
 
__________________________________________ 
First and Last Name of Participant (Print) 
 
 
__________________________________________ 
________________ 
Signature of Participant  
 
 
 
 
Date  
 
 
 
STATEMENT OF PERSON EXPLAINING AUTHORIZATION 
 
I have carefully explained to the subject the nature and purpose of this form.  I 
have been available to answer any questions that the subject has about this form. 
 
 
__________________________________________ 
First and Last Name of Person Explaining Authorization (Print) 
 
 
__________________________________________ 
________________ 
Signature of Person Explaining Authorization 
 
Date  
 
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Silk Technologies, Ltd.  
SDP-4 Ophthalmic Solution 
Clinical Trial Protocol: SDP-4-CS201 
 
Page 1  
 
SDP-4-CS201 Protocol 
SDP4_CS201_pro_FA-1.docx/03 April 2019 
 
CLINICAL TRIAL PROTOCOL: SDP-4-CS201 
Study Title: 
A Phase 2, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, 
Parallel-Group, Dose-Response Study of SDP-4 Ophthalmic Solution in 
Subjects with Dry Eye Disease (DED) 
Study Number: 
SDP-4-CS201 
Study Phase: 
2 
Product Name: 
SDP-4 Ophthalmic Solution 
Indication: 
Dry eye disease 
Investigators: 
Multicenter 
Sponsor: 
Silk Technologies, Ltd. 
Sponsor Contact: 
Brian Lawrence, PhD 
Medical Monitor: 
Charles Slonim, MD 
 
 
Date 
Original Protocol: 
27 February 2019 
Amendment 1: 
03 April 2019 
 
Confidentiality Statement 
The information contained in this document is confidential and proprietary property of Silk 
Technologies, Ltd. Neither this document nor the information contained herein may be divulged, 
transmitted, reproduced, published, or otherwise used by others without the express written 
permission of Silk Technologies, Ltd.  
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SYNOPSIS 
Sponsor: Silk Technologies, Ltd. 
Name of Finished Product: SDP-4 Ophthalmic Solution 
Name of Active Ingredient: Silk-Derived Protein-4 (SDP-4) 
Study Title: 
A Phase 2, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, Parallel-Group, 
Dose-Response Study of SDP-4 Ophthalmic Solution in Subjects with Dry Eye Disease (DED) 
Study Number: SDP-4-CS201 
Study Phase: 2 
Primary Objective:  
Assess the safety and efficacy of SDP-4 ophthalmic solution in subjects with DED over a 12-week (84-
day) treatment period. 
Study Design: 
This is a Phase 2, multicenter, double-masked, randomized, vehicle-controlled, dose-response, parallel-
group study designed to evaluate the ocular and systemic safety and efficacy of SDP-4 ophthalmic 
solution in subjects with moderate to severe DED in both eyes (OU) over a 12-week (84-day) treatment 
period.  
Subjects will be randomized to 1 of 3 concentrations (0.1%, 1.0% and 3.0%) of SDP-4 Ophthalmic 
Solution or vehicle in a 1:1:1:1 ratio in parallel groups. All investigational product (SDP-4 
concentrations and vehicle) will be provided in single-use doses (SUDs) contained in foil pouches. 
Subjects, the Investigator, and all site personnel responsible for performing study assessments will 
remain masked to treatment assignment.  
Investigational product (IP) will be administered via topical ocular instillation, one drop per eye, twice 
daily (BID) for 12 weeks (84 days). Both eyes will be treated. A 2-week screening/run-in period on 
BID vehicle will precede the 12-week randomized treatment period. 
Subjects must have a Symptom Assessment in Dry Eye (SANDE) total score of ≥ 40 at 
Visit 1/Screening and Visit 2/Day 1 to enter the trial. For subjects with a qualifying SANDE score who 
meet all other inclusion/exclusion criteria, the eye with the lower tear break-up time (TBUT) at Visit 
2/Day 1 will be designated as the study eye. In the event both eyes have the same TBUT scores, the eye 
with the lower Schirmer’s test score will be designated as the study eye. If both eyes have the same 
TBUT and Schirmer’s test scores, the right eye will be designated as the study eye. 
The study will consist of 7 clinic visits, 2 visits during the screening period and 5 on-treatment visits: 
Visit 1 (Day -14 ± 2/Screening Visit), followed by the 2-week run-in on BID vehicle, Visit 2 
(Day 1/Confirmatory and Randomization Visit), Visit 3 (Day 7 ± 2), Visit 4 (Day 14 ± 2), Visit 5 (Day 
28 ± 2), Visit 6 (Day 56 ± 4) and Visit 7 (Day 84 ± 4/End of Study Assessments).  
If a subject complains of persistent dry eye symptoms, the site may provide the subject with 
unpreserved artificial tears (provided by the Sponsor), to be used only if necessary. The subject must 
return all used and unused artificial tears at each visit so the site can conduct accountability to assess 
the use of artificial tears. Artificial tears may not be used within 2 hours prior to any study visit.  
Study Population:  
Number of Subjects Planned: 
A total of 300 randomized subjects are planned, with 75 subjects assigned to each dose group of SDP-4 
Ophthalmic Solution (0.1%, 1.0% and 3.0%) or vehicle. 
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Inclusion Criteria: 
Individuals must meet the following criteria at Screening (Visit 1/Day -14) and Visit 2/Day 1: 
1. Willing and able to understand and sign an informed consent form prior to any study-related 
procedures. 
2. Male or female patients 18 years of age or older. 
3. Willing and able to follow study instructions, able to self-administer IP or have IP administered 
by a caregiver throughout the study period, and able to be present for the required study 
visits/assessments for the duration of the study. 
4. Have DED in both eyes, as supported by a subject-reported history of daily symptoms of dry 
eye for ≥ 6 months prior to Visit 1/Screening.  
5. Total score ≥ 40 on the SANDE questionnaire. 
6. History of artificial tear use in the 30 days prior to Visit 1/Screening and willingness to 
discontinue use during the study.  
7. Tear break-up time (TBUT) of ≤ 6 seconds in both eyes. 
8. Anesthetized Schirmer’s test tear volume ≥ 3 mm and <10 mm in both eyes.  
9. Best-corrected visual acuity (BCVA) of +0.7 logMAR or better in each eye as assessed by 
logMAR chart.  
10. Female patients must be 1 year postmenopausal, surgically sterilized, or females of 
childbearing potential with a negative urine pregnancy test at Visit 1/Screening and Visit 2/Day 
1. Females of childbearing potential must use an acceptable form of contraception throughout 
the study. Acceptable methods include the use of at least one of the following: intrauterine 
device (IUD), hormonal (oral, injection, patch, implant, ring), barrier with spermicide 
(condom, diaphragm), or abstinence. 
Exclusion Criteria: 
Ocular 
1. Ocular surface corneal disease, other than DED. 
2. Diagnosis of Sjögren’s disease. 
3. Lid margin disorder other than meibomian gland dysfunction (MGD) (e.g., active anterior 
blepharitis including staphylococcal, demodex or seborrheic; excessive lid laxity, floppy eyelid 
syndrome, ectropion, entropion) that in the Investigator’s opinion could affect study 
parameters/assessments. 
4. Presence of any ocular condition (e.g., pterygium) that in the Investigator’s opinion could 
affect study parameters.  
5. Any previous reconstructive or cosmetic eyelid surgery that may affect the normal function of 
the lids (e.g., blepharoplasty, ptosis repair, entropion/ectropion repair). 
6. Any previous invasive glaucoma (e.g., trabeculectomy, shunt) and/or corneal surgery (e.g., 
penetrating keratoplasty, lamellar keratoplasty, Descemet’s stripping endothelial keratoplasty 
[DSEK]). 
7. Corneal refractive surgery (e.g., laser-assisted in situ keratomileusis [LASIK], photorefractive 
keratectomy [PRK], limbal relaxing incision [LRI]) within 12 months prior to 
Visit 1/Screening. 
8. Cataract extraction, with or without minimally invasive glaucoma surgery (MIGS), within 
90 days prior to Visit 1/Screening. 
9. Cauterization of the punctum or punctal plug (silicone or collagen) insertion or removal within 
30 days prior to Visit 1/Screening or planned during the study. If a subject has a punctal plug at 
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Visit 1/Screening for ≥ 30 days and it falls out during the study, it should be replaced with a 
new plug of the same type. 
Exclusion Criteria (continued): 
Prior Medications 
10. Contact lens wear. 
11. Use of isotretinoin (Accutane®) within 60 days prior to Visit 1/Screening. 
12. Use of topical cyclosporine (Restasis®, Cequa®) or topical lifitegrast (Xiidra®) within 45 days 
prior to Visit 1/Screening. 
13. Use of any of the following medications within 30 days prior to Visit 1/Screening: 
• 
Topical ophthalmic corticosteroids or topical ophthalmic non-steroidal anti-inflammatory 
drugs (NSAIDs) 
• 
Autologous serum 
• 
Topical ophthalmic antibiotics or antivirals 
• 
Topical ophthalmic antihistamines or mast cell stabilizers 
• 
Topical ophthalmic medications for lowering of intraocular pressure (IOP) for treatment of 
glaucoma or ocular hypertension 
• 
Systemic immunosuppressive agents 
• 
Systemic (i.e., oral, intravenous, intra-articular, intrathecal, epidural, or intramuscular) 
corticosteroids (intranasal, inhaled, dermatologic, or peri-anal steroids are allowed) 
• 
Tetracycline compounds (tetracycline, doxycycline or minocycline) 
Current Medications 
14. Any changes in the dosing of any chronically used systemic drug within 90 days prior to Visit 
1/Screening and throughout the study period, including but not limited to the following: 
• 
Anticholinergics 
• 
Antidepressants including selective serotonin reuptake inhibitors (SSRIs), selective 
serotonin norepinephrine reuptake inhibitors (SSNRIs), tricyclics, and benzodiazepines 
• 
Antihistamines 
• 
Systemic H1-receptor antagonists 
• 
β-adrenoceptor antagonists 
• 
Calcium channel blockers 
15. Any changes in the dosing of aspirin and aspirin-containing products within 30 days prior to 
Visit 1/Screening and throughout the study period. 
General 
16. Stevens-Johnson syndrome. 
17. History of immunodeficiency disorder, HIV, positive hepatitis B, C, or evidence of acute active 
hepatitis A (anti–HAV IgM). 
18. History of organ or bone marrow transplant. 
19. History of graft versus host disease (GvHD). 
20. Systemic lupus erythematosus. 
21. Chronic pain syndrome (e.g., fibromyalgia). 
22. Systemic signs of infection (e.g., fever or current treatment with antibiotics). 
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Exclusion Criteria: 
General (continued): 
23. Serious systemic disease or uncontrolled medical condition that in the judgment of the 
Investigator could confound study assessments or limit compliance, including, but not limited 
to, severe cardiopulmonary disease, uncontrolled hypertension, and/or uncontrolled diabetes. 
24. Known history of alcohol and/or drug abuse within 12 months prior to Visit 1/Screening that, 
in the opinion of the Investigator, may interfere with study compliance, outcome measures, 
safety parameters, and/or the general medical condition of the subject.  
25. Known allergy or contraindication to any component of IP formulation or diagnostic agents. 
26. Participation in any drug or device clinical investigation within 30 days prior to 
Visit 1/Screening and/or during the period of study participation. 
27. Screening and enrollment of more than one individual who resides in the same household at the 
same time (participation is allowed after the other individual has been determined to be a 
screen failure or after the other individual has completed Visit 7/Day 84). 
28. Screening and enrollment of employees of the clinical site. 
Investigational Product, Dose, and Mode of Administration:  
SDP-4 Ophthalmic Solution (0.1%, 1.0% and 3.0%), 1 drop in each eye BID 
Reference Therapy, Dosage and Mode of Administration:  
Vehicle, 1 drop in each eye BID 
Duration of Treatment:  
Twelve (12) weeks (84 days) 
Efficacy Assessments: 
Symptoms 
• 
SANDE 
• 
Rating on visual analogue scale (0-100 mm) of individual symptoms: 
– 
Itching 
– 
Foreign body sensation 
– 
Burning/stinging 
– 
Fluctuating vision 
– 
Eye dryness 
– 
Eye discomfort 
– 
Photophobia 
– 
Eye pain 
Signs 
• 
TBUT 
• 
Corneal fluorescein staining 
• 
Conjunctival lissamine green staining 
• 
Conjunctival hyperemia 
• 
Anesthetized Schirmer’s test 
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Safety Assessments: 
• 
Ocular and non-ocular adverse event (AE) monitoring 
• 
BCVA 
• 
Biomicroscopy 
• 
IP comfort assessment 
• 
Dilated fundus exam 
• 
IOP measurement 
Criteria for Evaluation: 
Primary Efficacy Endpoint 
• 
Mean change from baseline in total SANDE score at Visit 7/Day 84 
Secondary Efficacy Endpoints 
• 
Mean and mean change from baseline at each visit for each of the following evaluations: 
– 
Conjunctival lissamine green staining (combined and each zone) 
– 
Corneal fluorescein staining (combined and each zone) 
– 
TBUT  
– 
Anesthetized Schirmer’s test 
– 
Conjunctival hyperemia 
– 
Individual symptom VAS scores, separately for each symptom  
• 
SANDE 
– 
Mean change from baseline in total SANDE score at each visit 
– 
Mean total SANDE score at each visit 
– 
Mean and mean change from baseline in each component of SANDE at each visit 
Statistical Methods:  
A detailed Statistical Analysis Plan (SAP) will be finalized prior to database lock. 
General Considerations 
All continuous study assessments will be summarized by treatment and visit (as applicable) using 
descriptive statistics (n, mean, median, standard deviation, minimum, and maximum). All categorical 
study assessments will be summarized by treatment and visit (as applicable) using frequency counts 
and percentages.   
All study data will be listed by treatment, subject, and visit (as applicable). 
The unit of analysis for efficacy will be the study eye. 
Sample Size Rationale  
A sample size of 70 subjects per treatment group will have 80% power to detect a treatment difference 
of 11.7 units in SANDE total score and 1.2 seconds in TBUT at 12 weeks using a t-test with a 0.05 
two-sided significance level. Over-enrollment of 5 subjects per group/20 subjects per study is planned 
to account for discontinuations.  
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Statistical Methods (continued):  
Analysis Populations 
The intent-to-treat (ITT) population will include all randomized subjects who received IP.  
The per protocol (PP) population is a subset of the ITT population, which will include all subjects who 
complete the study without major protocol deviations.  
The safety population will include all subjects who received IP. 
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Table 1 
Schedule of Visits and Examinations 
 
Visit 1 
Day -14 ± 2 
Screening 
Visit 2 
Day 1 
Randomization 
Visit 3 
Day 7 ± 2 
Treatment 
Visit 4 
Day 14 ± 2 
Treatment 
Visit 5 
Day 28 ± 2 
Treatment 
Visit 6 
Day 56 ± 4 
Treatment 
Visit 7 
Day 84 ± 4 
End of 
Treatment 
Informed consent 
X 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical and ocular history 
X 
 
 
 
 
 
 
Concomitant medication/review  
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
X 
 
 
 
 
X 
SANDE 
X 
X 
X 
X 
X 
X 
X 
VAS assessment of individual symptoms 
 
X 
X 
X 
X 
X 
X 
IP comfort assessment  
 
X 
X 
X 
X 
X 
X 
Best-corrected visual acuity 
X 
X 
X 
X 
X 
X 
X 
Biomicroscopy and external eye exam 
X 
X 
X 
X 
X 
X 
X 
Tear break-up time 
X 
X 
X 
X 
X 
X 
X 
Corneal fluorescein staining by zone 
X 
X 
X 
X 
X 
X 
X 
Conjunctival lissamine green staining by zone 
X 
X 
X 
X 
X 
X 
X 
Anesthetized Schirmer‘s test 
X 
X 
 
 
 
 
X 
Intraocular pressure measurement 
X 
 
 
 
X 
 
X 
Dilated fundus exam 
X 
 
 
 
 
 
X 
Dispense run-in medication/instruction on run-in 
administration/evaluate administration 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Dispense investigational product (IP)/instruction on IP 
administration 
 
X 
 
 
X 
X 
 
Dispense artificial tearsa 
X 
X 
X 
X 
X 
X 
 
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Visit 1 
Day -14 ± 2 
Screening 
Visit 2 
Day 1 
Randomization 
Visit 3 
Day 7 ± 2 
Treatment 
Visit 4 
Day 14 ± 2 
Treatment 
Visit 5 
Day 28 ± 2 
Treatment 
Visit 6 
Day 56 ± 4 
Treatment 
Visit 7 
Day 84 ± 4 
End of 
Treatment 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
Run-in medication/IP/artificial tear accountability (if applicable)a 
 
X 
X 
X 
X 
X 
X 
IP = investigational product; SANDE = Symptom Assessment in Dry Eye; VAS = visual analogue scale 
a  If a subject complains of persistent dry eye symptoms, the site may provide the subject with unpreserved artificial tears (provided by the Sponsor), to be used 
only if necessary. The subject must return all used and unused artificial tears at each visit so the site can conduct accountability to assess the use of artificial 
tears. Artificial tears may not be used within 2 hours prior to any study visit; the subject may either be rescheduled or may wait at the site until 2 hours have 
passed since instillation if this occurs. 
 
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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL: SDP-4-CS201 ....................................................... 1 
SYNOPSIS .................................................................................................................. 2 
TABLE OF CONTENTS ........................................................................................... 10 
LIST OF IN-TEXT TABLES .................................................................................... 14 
LIST OF IN-TEXT FIGURES................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 16 
1. 
INTRODUCTION .................................................................................. 18 
2. 
STUDY OBJECTIVES .......................................................................... 20 
2.1. 
Primary Objective ................................................................................... 20 
3. 
INVESTIGATIONAL PLAN ................................................................. 21 
3.1. 
Overall Study Design and Plan ............................................................... 21 
3.2. 
Rationale for Study Design and Control Group ..................................... 21 
3.3. 
Study Duration and Dates ....................................................................... 22 
4. 
STUDY POPULATION SELECTION .................................................. 23 
4.1. 
Study Population ..................................................................................... 23 
4.2. 
Inclusion Criteria .................................................................................... 23 
4.3. 
Exclusion Criteria ................................................................................... 23 
5. 
STUDY TREATMENT(S) ..................................................................... 27 
5.1. 
Description of Treatment(s) .................................................................... 27 
5.1.1. 
Study Drug .............................................................................................. 27 
5.1.2. 
Control .................................................................................................... 27 
5.2. 
Selection, Timing and Administration of Dose for Each Patient ........... 27 
5.3. 
Method of Assigning Patients to Treatment Groups .............................. 27 
5.4. 
Masking .................................................................................................. 28 
5.5. 
Concomitant Therapy ............................................................................. 28 
5.6. 
Restrictions ............................................................................................. 29 
5.6.1. 
Prohibited Medications and Treatments ................................................. 29 
5.6.2. 
Treatment Compliance ............................................................................ 30 
5.7. 
Packaging and Labeling .......................................................................... 30 
5.8. 
Storage and Accountability ..................................................................... 31 
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5.9. 
Investigational Product Dispensing and Retention at Study Site ........... 31 
6. 
STUDY PROCEDURES ........................................................................ 32 
6.1. 
Informed Consent ................................................................................... 32 
6.2. 
Demographics and Background Characteristics ..................................... 32 
6.2.1. 
Demographics ......................................................................................... 32 
6.2.2. 
Medical/Ocular History .......................................................................... 32 
6.2.3. 
Medication History ................................................................................. 32 
6.2.4. 
Urine Pregnancy Test ............................................................................. 32 
6.3. 
Efficacy Assessments ............................................................................. 32 
6.3.1. 
Symptoms ............................................................................................... 32 
6.3.1.1. 
SANDE (Symptom Assessment in Dry Eye) Questionnaire .................. 32 
6.3.1.2. 
Measurement of Individual Dry Eye Symptoms .................................... 33 
6.3.2. 
Signs ....................................................................................................... 35 
6.3.2.1. 
Tear Break-up Time ................................................................................ 35 
6.3.2.2. 
Corneal Fluorescein Staining .................................................................. 35 
6.3.2.3. 
Conjunctival Hyperemia ......................................................................... 36 
6.3.2.4. 
Conjunctival Lissamine Green Staining ................................................. 36 
6.3.2.5. 
Anesthetized Schirmer’s Test ................................................................. 36 
6.4. 
Adverse and Serious Adverse Events ..................................................... 37 
6.4.1. 
Definition of Adverse Events ................................................................. 37 
6.4.1.1. 
Adverse Event (AE) ................................................................................ 37 
6.4.1.2. 
Serious Adverse Event (SAE) ................................................................ 37 
6.5. 
Relationship to Investigational Product .................................................. 38 
6.6. 
Recording Adverse Events ..................................................................... 38 
6.7. 
Reporting Adverse Events ...................................................................... 39 
6.8. 
Other Safety Assessments ....................................................................... 40 
6.8.1. 
Best-Corrected Visual Acuity ................................................................. 40 
6.8.2. 
Biomicroscopy and External Eye Exam ................................................. 40 
6.8.3. 
Dilated Fundus Exam ............................................................................. 40 
6.8.4. 
Intraocular Pressure Measurement ......................................................... 40 
6.8.5. 
Investigational Product Comfort Assessment ......................................... 41 
6.9. 
Screen Failures ........................................................................................ 41 
6.10. 
Subject Withdrawal Criteria ................................................................... 41 
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6.11. 
Appropriateness of Measurements ......................................................... 41 
7. 
STUDY ACTIVITIES ............................................................................ 42 
7.1. 
Visit 1 (Day -14 ± 2/Screening Visit) ..................................................... 42 
7.2. 
Treatment Period (Day 1 to Day 84 ± 4) ................................................ 43 
7.2.1. 
Visit 2 (Day 1/Confirmatory and Randomization Visit) ........................ 43 
7.2.2. 
Visit 3 (Day 7 ± 2) .................................................................................. 43 
7.2.3. 
Visit 4 (Day 14 ± 2) ................................................................................ 44 
7.2.4. 
Visit 5 (Day 28 ± 2) ................................................................................ 44 
7.2.5. 
Visit 6 (Day 56 ± 4) ................................................................................ 45 
7.3. 
Visit 7 (Day 84 ± 4) or Early Termination Procedures .......................... 45 
8. 
QUALITY CONTROL AND ASSURANCE ........................................ 47 
9. 
STATISTICS .......................................................................................... 48 
9.1. 
General Considerations ........................................................................... 48 
9.2. 
Determination of Sample Size ................................................................ 48 
9.3. 
Analysis Populations .............................................................................. 49 
9.3.1. 
Intent-to-Treat (ITT) Population ............................................................. 49 
9.3.2. 
Per Protocol (PP) Population .................................................................. 49 
9.3.3. 
Safety Population .................................................................................... 49 
9.4. 
Demographics and Baseline Characteristics ........................................... 49 
9.5. 
Efficacy Endpoints and Analyses ........................................................... 49 
9.5.1. 
Primary Efficacy Endpoint ..................................................................... 49 
9.5.2. 
Secondary Efficacy Endpoints ................................................................ 49 
9.5.3. 
Efficacy Analyses ................................................................................... 50 
9.6. 
Safety Variables and Analysis ................................................................ 50 
9.6.1. 
Safety Variables ...................................................................................... 50 
9.6.2. 
Safety Analysis ....................................................................................... 51 
10. 
ADMINISTRATIVE CONSIDERATIONS .......................................... 52 
10.1. 
Institutional Review Board (IRB) Approval ........................................... 52 
10.2. 
Ethical Conduct of the Study .................................................................. 52 
10.3. 
Subject Information and Consent ........................................................... 52 
10.4. 
Subject Confidentiality ........................................................................... 52 
10.5. 
Study Monitoring .................................................................................... 53 
10.6. 
Case Report Forms and Study Records .................................................. 54 
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10.7. 
Protocol Deviations ................................................................................ 54 
10.8. 
Access to Source Documentation ........................................................... 54 
10.9. 
Data Generation and Analysis ................................................................ 54 
10.9.1. 
Retention of Data .................................................................................... 55 
10.10. 
Publication and Disclosure Policy .......................................................... 55 
11. 
REFERENCE LIST ................................................................................ 56 
12. 
SUMMARY OF CHANGES .................................................................. 57 
12.1. 
Changes Implemented in Protocol SDP-4-CS201 Amendment 1 .......... 57 
APPENDIX A. SPONSOR SIGNATURES ........................................................... 58 
APPENDIX B. INVESTIGATOR’S SIGNATURE ............................................... 59 
 
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LIST OF IN-TEXT TABLES 
Table 1 
Schedule of Visits and Examinations ....................................................... 8 
Table 2 
Sample Sizes: Two-Group t-test of Equal Means ................................... 48 
 
 
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LIST OF IN-TEXT FIGURES 
Figure 1: 
Symptom Assessment in Dry Eye (SANDE) Questionnaire .................. 33 
Figure 2: 
Division of the Corneal Surface for Measuring Fluorescein Uptake ..... 36 
Figure 3: 
Division of the Conjunctival Surface for Measuring Lissamine Green 
Staining ................................................................................................... 36 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ANOVA 
Analysis of variance 
BCVA 
Best-corrected visual acuity 
BID 
Twice daily 
CFR 
Code of Federal Regulations 
CRA 
Clinical research associate 
DED 
Dry eye disease 
DSEK 
Descemet’s stripping endothelial keratoplasty 
eCRF 
Electronic case report form 
eDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HCLE 
Human corneal limbal epithelial (cells) 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IL 
Interleukin 
IND 
Investigational New Drug  
IOP 
Intraocular pressure 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous  
IWRS 
Interactive Web Response System 
ITT 
Intent-to-treat 
LASIK 
Laser-assisted in situ keratomileusis 
LLOQ 
Lower limit of quantification 
LRI 
Limbal relaxing incision 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MIGS 
Minimally invasive glaucoma surgery 
MMP 
Matrix metalloprotease 
MW 
Molecular weight 
NF-κB 
Nuclear factor κB 
NSAID 
Non-steroidal anti-inflammatory drug 
OHT 
Ocular hypertension 
OU 
Both eyes 
PP 
Per protocol 
PRK 
Photorefractive keratectomy 
SAE 
Serious adverse event 
SANDE 
Symptom Assessment in Dry Eye 
SDP-4 
Silk-derived protein-4 
SOP 
Standard operating procedure 
SSNRI 
Selective serotonin norepinephrine reuptake inhibitors 
SSRI 
Selective serotonin reuptake inhibitor 
SUD 
Single-use dose  
TEAE 
Treatment-emergent adverse event 
TBUT 
Tear break-up time 
TNF-α 
Tumor necrosis factor-alpha 
US 
United States 
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1. 
INTRODUCTION 
Silk-derived protein-4 (SDP-4) is a novel biotherapeutic being developed by Silk 
Technologies, Ltd. (Silk Technologies) as a treatment for the signs and symptoms of dry eye 
disease (DED). Dry eye disease, as defined by the Tear Film and Ocular Surface Society 
(TFOS) Dry Eye Workshop (DEWS) II, is a “multifactorial disease of the ocular surface 
characterized by loss of homeostasis of the tear film and accompanied by ocular symptoms, 
in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, 
and neurosensory abnormalities play etiological roles” (Craig et al., 2017).  
The disease results in corneal irregularities that can create sight-limiting outcomes over time 
due to chronic inflammation governed by nuclear factor κB (NF-κB) signaling, which is 
thought to play a significant role in disease pathogenesis (Lan et al., 2012). Inflammatory 
mediators regulated by NF-κB, such as matrix metalloprotease (MMP)-9, tumor necrosis 
factor alpha (TNF-α), and interleukin (IL)-8 have been found in the tear fluid at high 
concentrations in patients exhibiting severe DED (Solomon et al., 2001; Smith et al., 2001). 
Furthermore, topical administration of MMP-9 to DED MMP-9-knockout mice subjected to 
dry eye via cholinergic blockade significantly increases corneal epithelial permeability, 
implicating MMP-9 in increased corneal epithelial disruption and damage (Pflugfelder et al., 
2005). Collectively, these observations suggest a relationship between disruption of the 
corneal epithelium, increased secretion of MMP-9 through NF-κB signaling, and the signs 
and symptoms of DED.  
Silk fibroin protein is the primary fibrous component of the Bombyx mori silkworm cocoon. 
In vivo, aqueous silk fibroin protein solution was successfully used to treat DED in a murine 
animal model, improving clinical outcomes (increased tear production, decreased corneal 
irregularity, inhibited epithelial cell detachment, and increased goblet cell density) and 
reducing inflammatory cytokine presence (intercellular adhesion molecule [ICAM]-1, 
vascular cell adhesion molecule [VCAM]-1, MMP-2 and MMP-9) (Kim et al, 2017).  
Silk-derived protein (SDP) is a partially hydrolyzed population derived from the silk fiber 
protein fibroin with a molecular weight (MW) distribution of 2000–300, 000 Daltons (Da). 
In vitro studies in immortalized hCLE cells subjected to scratch wound denudement 
demonstrated that aqueous SDP improved corneal epithelial wound healing through 
accelerated cell migration, proliferation and enhanced cell-matrix attachment (Abdel-Naby et 
al., 2017). Cultures treated with SDP displayed significant increases in cell-matrix focal 
adhesion formation and basement membrane adhesive strength compared to untreated 
cultures. In vivo, treatment with SDP accelerated the acute healing phase of injured rabbit 
corneal epithelial tissues, as shown by significantly increased epithelial migration rate, and 
produced a dose-dependent, 8-fold decrease in MMP-9.  
Through a series of additional manufacturing steps, the subpopulation, SDP-4, is produced 
with a MW range of 10,000-30,000 Da. In nonclinical studies, SDP-4 has demonstrated a 
dual mechanism of action that both inhibits inflammation and physically improves the 
stability of the tear film. SDP-4 inhibits NF-κB driven expression of known dry eye 
inflammatory mediators produced by ocular surface cells, including MMP-9, TNF-α, and 
IL-8.  
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Multiple in vitro assays revealed that SDP-4 inhibits NF-κB-driven expression of known dry 
eye inflammatory mediators produced by the corneal epithelium. SDP-4 treatment inhibited 
secretion of IL-8 by stimulated hCLE cells in a dose-dependent manner. Treatment with 
SDP-4 also impaired chemokine activation and subsequent mobilization of immune-like cells 
in an in vitro co-culture model. Direct impairment of NF-κB activity by SDP-4 was 
confirmed using a human embryonic kidney cell line containing a NF-κB-responsive reporter 
gene. SDP-4 inhibited reporter gene expression dose dependently at concentrations ranging 
from 0.1%-10%.  
Cardiovascular and respiratory safety pharmacology studies were conducted in the monkey 
and rat, respectively, with SDP-4 administered by intravenous (IV) injection. No statistically 
significant effects on respiratory rate, tidal volume or minute volume or on cardiovascular 
function, e.g., electrocardiographic waveforms, QT, heart rate, were observed at doses of 0, 
10, 50 and 75 mg/kg. 
The pivotal 90-day toxicity study in rabbits was conducted at SDP-4 concentrations of 0% 
(vehicle), 1%, 3%, 5% or 10% instilled four times/day into both eyes. Ocular findings in all 
groups, including controls, occurred sporadically throughout the dosing phase with no 
relationship to dose or duration of treatment. Irritation observed during the study tended to 
resolve during the dosing phase as the study progressed. No histopathological changes in the 
ocular tissue were observed. Plasma levels of SDP-4 were either below the lower limit of 
quantification (LLOQ) or approximated the LLOQ at the highest dose. Based on the results, 
the no observed adverse effect level (NOAEL) for this study was 10%, the highest dose 
examined. 
A pivotal 28-day IV toxicity study in rats was undertaken at doses of 0, 10, 50 and 75 mg/kg. 
No SDP-4-related toxicity was observed. Microscopically, dose-related cytoplasmic 
vacuolation was noted in the proximal convoluted tubule segment of the renal nephron, 
which was reduced in severity following the 14-day recovery phase but not completely 
resolved. Because there were no other histopathological changes observed in the kidney and 
no clear evidence of altered renal function at any dose, the finding is considered to have 
limited toxicological significance. A dose proportional increase in plasma levels of SDP-4 
was observed. The half-life was approximately 0.5-1 hr and no accumulation of SDP-4 was 
evident. 
The pharmacological and toxicological data for SDP-4 are considered adequate to support the 
safe clinical use of the SDP-4 drug product for the initial Phase 2 clinical trial. Based on the 
results of the toxicology program, the estimated margin of safety on a body surface area basis 
was determined to be 128-fold. Therefore, ocular instillation of SDP-4 twice daily to patients 
with a maximum clinical concentration of 3% administered twice daily for up to 12 weeks is 
considered safe for the initial Phase 2 clinical study. 
SDP-4 Ophthalmic Solution is a topical treatment for DED that has not been evaluated in 
clinical trials. The planned first in human (FIH) study is a multicenter, double-masked, 
randomized, vehicle-controlled, dose-response, parallel-group study designed to evaluate the 
ocular and systemic safety and efficacy of SDP-4 in subjects with moderate to severe DED in 
both eyes over a 12-week (84-day) treatment period. For additional information regarding 
SDP-4 Ophthalmic Solution, please refer to the Investigator’s Brochure (IB).  
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective  
The primary objective of this study is to assess the safety and efficacy of SDP-4 Ophthalmic 
Solution in subjects with DED over a 12-week (84-day) treatment period. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 2, multicenter, double-masked, randomized, vehicle-controlled, dose-
response, parallel-group study designed to evaluate the ocular and systemic safety and 
efficacy of SDP-4 ophthalmic solution in subjects with moderate to severe DED in both eyes 
(OU) over a 12-week (84-day) treatment period.  
Subjects will be randomized to 1 of 3 concentrations (0.1%, 1.0% and 3.0%) of SDP-4 
Ophthalmic Solution or vehicle in a 1:1:1:1 ratio in parallel groups. All investigational 
product (IP) (SDP-4 concentrations and vehicle) will be provided in single-use dose (SUD) 
containers seal packed into foil pouches. Subjects, the Investigator, and all site personnel 
responsible for performing study assessments will remain masked to treatment assignment.  
The IP will be administered via topical ocular instillation, one drop per eye, twice daily 
(BID) for 12 weeks (84 days). Both eyes will be treated. A 2-week screening/run-in period 
on BID vehicle will precede the 12-week randomized treatment period.  
Subjects must have a Symptom Assessment in Dry Eye (SANDE) total score of ≥ 40 at 
Visit 1/Screening and Visit 2/Day 1 to enter the trial. For subjects with a qualifying SANDE 
score who meet all other inclusion/exclusion criteria, the eye with the lower tear break-up 
time (TBUT) at Visit 2/Day 1 will be designated as the study eye. In the event both eyes have 
the same TBUT scores, the eye with the lower Schirmer’s test score will be designated as the 
study eye. If both eyes have the same TBUT and Schirmer’s test scores, the right eye will be 
designated as the study eye. 
The study will consist of 7 clinic visits, 2 visits during the screening period and 
5 on-treatment visits: Visit 1 (Day -14 ± 2/Screening Visit), followed by the 2-week run-in 
period on BID vehicle, Visit 2 (Day 1/Confirmatory and Randomization Visit), Visit 3 
(Day 7 ± 2), Visit 4 (Day 14 ± 2), Visit 5 (Day 28 ± 2), Visit 6 (Day 56 ± 4) and Visit 7 
(Day 84 ± 4/End of Study Assessments).  
If a subject complains of persistent dry eye symptoms, the site may provide the subject with 
unpreserved artificial tears (provided by the Sponsor), to be used only if necessary. The 
subject must return all used and unused artificial tears at each visit so the site can conduct 
accountability to assess the use of artificial tears. Artificial tears may not be used within 
2 hours prior to any study visit. 
See Table 1, Schedule of Visits and Examinations. 
3.2. 
Rationale for Study Design and Control Group 
It is hypothesized that by reducing pro-inflammatory mediators of DED, and providing a 
mucin replacement to enhance spreading and wetting of the tear film, SDP-4 may produce 
improvement in the symptoms of DED, as measured by the total SANDE score, and in the 
physical characteristics of the tear film, as measured by TBUT. These are designated primary 
(SANDE) and secondary (TBUT) endpoints. The study is also designed to measure 
additional secondary endpoints including individual symptoms (itching, foreign body 
sensation, burning/stinging, fluctuating vision, eye dryness, eye discomfort, photophobia, and 
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eye pain) and additional signs (anesthetized Schirmer’s test, corneal fluorescein staining, 
conjunctival lissamine green staining, and conjunctival hyperemia). Three concentrations of 
SDP-4, (0.1%, 1.0% and 3.0%) will be dosed topically BID versus vehicle control to test the 
hypotheses of this protocol. The SDP-4 concentrations are among those shown in nonclinical 
pharmacology studies to be effective in inhibiting inflammatory mediators, with the 1% 
concentration producing maximal inhibition of NF-κB activity. The 12-week (84-day) 
treatment period allows adequate assessment of the comparative efficacy of the IP 
concentrations being compared and their effects over time. The control is the vehicle without 
the active ingredient of the drug product to be used in the study. 
3.3. 
Study Duration and Dates 
The duration of study treatment is 12 weeks (84 days). The overall duration of the study is 
14 weeks, which includes a 2-week screening/run-in period on vehicle and 12 weeks of 
treatment. 
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4. 
STUDY POPULATION SELECTION 
4.1. 
Study Population 
A total of 300 randomized subjects with DED (see Section 4.2) are planned, with 75 subjects 
assigned to each dose group of SDP-4 Ophthalmic Solution (0.1%, 1.0% and 3.0%) or 
vehicle.  
4.2. 
Inclusion Criteria 
Individuals must meet the following criteria at Screening (Visit 1/Day -14) and 
Visit 2/Day 1: 
1. Willing and able to understand and sign an informed consent form prior to any study-
related procedures. 
2. Male or female patients 18 years of age or older. 
3. Willing and able to follow study instructions, able to self-administer IP or have IP 
administered by a caregiver throughout the study period, and able to be present for 
the required study visits/assessments for the duration of the study. 
4. Have DED in both eyes, as supported by a subject-reported history of daily symptoms 
of dry eye for ≥ 6 months prior to Visit 1/Screening. 
5. Total score ≥ 40 on the Symptom Assessment in Dry Eye (SANDE) questionnaire. 
6. History of artificial tear use in the 30 days prior to Visit 1/Screening and willingness 
to discontinue use during the study.  
7. Tear break-up time (TBUT) of ≤ 6 seconds in both eyes. 
8. Anesthetized Schirmer’s test tear volume ≥ 3 mm and <10 mm in both eyes.  
9. Best-corrected visual acuity (BCVA) of +0.7 logMAR or better in each eye as 
assessed by logMAR chart.  
10. Female patients must be 1 year postmenopausal, surgically sterilized, or females of 
childbearing potential with a negative urine pregnancy test at Visit 1/Screening. 
Females of childbearing potential must use an acceptable form of contraception 
throughout the study. Acceptable methods include the use of at least one of the 
following: intrauterine device (IUD), hormonal (oral, injection, patch, implant, ring), 
barrier with spermicide (condom, diaphragm), or abstinence. 
4.3. 
Exclusion Criteria 
Individuals who meet any of the following criteria will be excluded from the study. 
Ocular 
1. Ocular surface corneal disease, other than DED. 
2. Diagnosis of Sjögren’s disease. 
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3. Lid margin disorder other than meibomian gland dysfunction (MGD) (e.g., active 
anterior blepharitis including staphylococcal, demodex or seborrheic; excessive lid 
laxity, floppy eyelid syndrome, ectropion, entropion) that in the Investigator’s 
opinion could affect study parameters/assessments. 
4. Presence of any ocular condition (e.g., pterygium) that in the Investigator’s opinion 
could affect study parameters.  
5. Any previous reconstructive or cosmetic eyelid surgery that may affect the normal 
function of the lids (e.g., blepharoplasty, ptosis repair, entropion/ectropion repair). 
6. Any previous invasive glaucoma (e.g., trabeculectomy, shunt) and/or corneal surgery 
(e.g., penetrating keratoplasty, lamellar keratoplasty, Descemet’s stripping endothelial 
keratoplasty [DSEK]). 
7. Corneal refractive surgery (e.g., laser-assisted in situ keratomileusis [LASIK], 
photorefractive keratectomy [PRK], limbal relaxing incision [LRI]) within 12 months 
prior to Visit 1/Screening. 
8. Cataract extraction, with or without minimally invasive glaucoma surgery (MIGS), 
within 90 days prior to Visit 1/Screening. 
9. Cauterization of the punctum or punctal plug (silicone or collagen) insertion or 
removal within 30 days prior to Visit 1/Screening or planned during the study.  If a 
subject has a punctal plug at Visit 1/Screening for ≥ 30 days and it falls out during the 
study, it should be replaced with a new plug of the same type. 
10. Contact lens wear. 
Prior Medications 
11. Use of isotretinoin (Accutane®) within 60 days prior to Visit 1/Screening. 
12. Use of topical cyclosporine (Restasis®, Cequa®) or topical lifitegrast (Xiidra®) within 
45 days prior to Visit 1/Screening. 
13. Use of any of the following medications within 30 days prior to Visit 1/Screening: 
• Topical ophthalmic corticosteroids or topical ophthalmic non-steroidal 
anti-inflammatory drugs (NSAIDs) 
• Autologous serum 
• Topical ophthalmic antibiotics or antivirals 
• Topical ophthalmic antihistamines or mast cell stabilizers 
• Topical ophthalmic medications for lowering of intraocular pressure (IOP) for 
treatment of glaucoma or ocular hypertension 
• Systemic immunosuppressive agents 
• Systemic (i.e., oral, intravenous, intra-articular, intrathecal, epidural, or 
intramuscular) corticosteroids (intranasal, inhaled, dermatologic, or peri-anal 
steroids are allowed) 
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• Tetracycline compounds (tetracycline, doxycycline or minocycline) 
Current Medications 
14. Any changes in the dosing of any chronically used systemic drug within 90 days prior 
to Visit 1/Screening and throughout the study period, including but not limited to the 
following: 
• Anticholinergics 
• Antidepressants including selective serotonin reuptake inhibitors (SSRIs), 
selective serotonin norepinephrine reuptake inhibitors (SSNRIs), tricyclics, and 
benzodiazepines 
• Antihistamines 
• Systemic H1-receptor antagonists 
• β-adrenoceptor antagonists 
• Calcium channel blockers 
15. Any changes in the dosing of aspirin and aspirin-containing products within 30 days 
prior to Visit 1/Screening and throughout the study period. 
General 
16. Stevens-Johnson syndrome. 
17. History of immunodeficiency disorder, HIV, positive hepatitis B, C, or evidence of 
acute active hepatitis A (anti–HAV IgM). 
18. History of organ or bone marrow transplant. 
19. History of graft versus host disease (GvHD). 
20. Systemic lupus erythematosus. 
21. Chronic pain syndrome (e.g., fibromyalgia). 
22. Systemic signs of infection (e.g., fever or current treatment with antibiotics). 
23. Serious systemic disease or uncontrolled medical condition that in the judgment of 
the Investigator could confound study assessments or limit compliance, including, but 
not limited to, severe cardiopulmonary disease, poorly controlled hypertension, 
and/or poorly controlled diabetes.  
24. Known history of alcohol and/or drug abuse within 12 months prior to 
Visit 1/Screening that, in the opinion of the Investigator, may interfere with study 
compliance, outcome measures, safety parameters, and/or the general medical 
condition of the subject.  
25. Known allergy or contraindication to any component of IP formulation or diagnostic 
agents. 
26. Participation in any drug or device clinical investigation within 30 days prior to 
Visit 1/Screening and/or during the period of study participation. 
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27. Screening and enrollment of more than one individual who resides in the same 
household at the same time (participation is allowed after the other individual has 
been determined to be a screen failure or after the other individual has completed 
Visit 7/Day 84). 
28. Screening and enrollment of employees of the clinical site. 
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5. 
STUDY TREATMENT(S) 
5.1. 
Description of Treatment(s) 
5.1.1. 
Study Drug 
SDP-4 Ophthalmic Solution is a non-preserved aqueous solution of SDP-4 for topical 
ophthalmic use and will contain the active substance (SDP-4) and polysorbate-80, sodium 
acetate trihydrate, glacial acetic acid, magnesium chloride hexahydrate, and dextrose 
monohydrate. 
5.1.2. 
Control 
The vehicle solution will be the same as the SDP-4 except for the omission of the active 
substance (SDP-4).  
All subjects who meet study entry criteria at Screening/Visit 1 (Day -14 ± 2) will receive a 
supply of vehicle solution prior to randomization to the double-masked study to be 
administered during the 14-day (± 2) screening/run-in period. 
5.2. 
Selection, Timing and Administration of Dose for Each Patient 
Subjects will be randomized to treatment with 1 of 3 concentrations (0.1%, 1.0% and 3.0%) 
of SDP-4 Ophthalmic Solution or vehicle which will be administered to each eye BID, 
approximately 12 hours apart, for 84 days. 
Subjects (or their caregiver, if the subject is not able to self-administer the IP) will administer 
IP topically OU BID for 84 days. At the Screening and Baseline visits, site personnel will 
instruct the subject (or caregiver) in topical ocular drop administration procedures. After 
instilling a drop in each eye, the used single-use dose (SUD) should be stored in the storage 
container provided by site personnel and placed back in the box. 
Twice each day, approximately 12 hours apart, the subject (or caregiver) will open a new 
SUD and administer 1 drop to each eye, store the used SUD in the foil pouch, and place it in 
the box (or storage container) for return to the clinical site so accountability can be 
documented in the source document and electronic case report form (eCRF). All IP, 
including the box, used SUDs/foil pouches and any unopened SUDs will be returned to the 
clinical site where the used and unopened IP will be documented at Visits 2 through 7.  
5.3. 
Method of Assigning Patients to Treatment Groups 
Subjects will be randomized in a 1:1:1:1 ratio to 0.1%, 1.0% or 3.0% SDP-4 or vehicle in 
parallel groups. A computer-generated randomization code for allocating the solutions will 
be prepared by an independent unmasked biostatistician not involved in the day-to-day 
running of the study. 
If subjects meet eligibility criteria at Screening (Visit 1/Day -14) and Visit 2/Day 1 (see 
Section 4 for eligibility criteria), subjects will be randomly assigned to IP at Visit 2. Clinical 
sites will utilize the Interactive Web Response System (IWRS) to assign kits to subjects. The 
IP kit randomization number will be recorded in the subject’s eCRF. The randomized IP may 
vary slightly in hue from nearly clear to a slight tint. This variability is normal. 
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5.4. 
Masking 
The study will be double-masked. All SDP-4 concentrations and vehicle will be provided in 
SUDs seal packed into foil pouches which are enclosed in a box and dispensed in one-month 
supplies at Visits 2, 5, and 6. Subjects, the Investigator, and all site personnel responsible for 
performing study assessments will remain masked to treatment assignment. 
Should it be necessary to unmask a subject’s treatment assignment in case of emergency, the 
Investigator may obtain the treatment code for a given randomized subject from the IWRS. 
The treatment code is to be obtained only if a medical emergency exists and knowledge of 
the medication being taken will influence the medical management of the subject. 
The following procedure should be followed: 
1. The Investigator should contact the Medical Monitor via phone immediately before 
unmasking a subject, unless it is not possible to do so without risk to the subject. 
2. The Investigator should document the serious adverse event (SAE), if applicable, and 
justification for unmasking in the eCRF.  
3. The subject may continue to participate in the study to be followed for safety at the 
Investigator’s discretion. If the subject is to be discontinued from study participation, 
then ALL procedures described in the Early Discontinuation Visit (Section 7.3) 
should be completed. 
4. The Investigator should contact Oculos Clinical Research (Oculos), the clinical 
research organization (CRO), at SilkTech-safety@oculoscr.com within 24 hours with 
the randomization number, subject initials, details of the adverse event (AE) or SAE, 
any action taken, and whether the subject is continuing in the study. 
5.5. 
Concomitant Therapy 
Therapy considered necessary for the subject’s welfare that will not interfere with the 
evaluation of the IP may be given at the discretion of the Investigator and in consultation 
with the Medical Monitor. If there is any question as to whether the medication may 
interfere, the Investigator should contact the Medical Monitor or Sponsor. 
If a subject complains of persistent dry eye symptoms, the site may provide the subject with 
unpreserved artificial tears (provided by the Sponsor), to be used only if necessary. The 
subject must return all used and unused artificial tears at each visit so the site can conduct 
accountability to assess the use of artificial tears. Artificial tears may not be used within 2 
hours prior to any study visit; the subject may either be rescheduled or may wait at the site 
until 2 hours have passed since instillation if this occurs.  
Permitted steroid medications include intranasal, inhaled, dermatologic, or peri-anal,  
steroids. 
Whenever possible, medications should be administered in dosages that remain stable 
throughout the study duration. All concomitant medications will be recorded in the eCRF. 
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5.6. 
Restrictions 
The Medical Monitor should be notified before prohibited medication or therapy is 
administered, unless the safety of the subject requires immediate action. The decision to 
administer a prohibited medication or therapy should be done with the safety of the subject as 
the primary consideration. The Medical Monitor should be contacted to determine the 
permissibility of a specific medication or therapy and whether or not the subject should 
continue with study participation. 
5.6.1. 
Prohibited Medications and Treatments 
The following medications are prohibited as specified: 
Within 60 days prior to Visit 1/Screening and throughout the study duration: 
• Use of isotretinoin (Accutane) 
Within 45 days prior to Visit 1/Screening and throughout the study duration: 
• Use of topical cyclosporine (Restasis, Cequa) or topical lifitegrast (Xiidra) 
Within 30 days prior to Visit 1/Screening and throughout the study duration: 
• Topical ophthalmic corticosteroids or topical ophthalmic NSAIDs 
• Autologous serum 
• Topical ophthalmic antibiotics or antivirals 
• Topical ophthalmic antihistamines or mast cell stabilizers 
• Topical ophthalmic medications for lowering of IOP for treatment of glaucoma or 
OHT 
• Systemic immunosuppressive agents other than corticosteroids 
• Systemic (oral, intravenous, intra-articular, intrathecal, epidural or intramuscular) 
corticosteroids 
• Tetracycline compounds (e.g., tetracycline, doxycycline or minocycline) 
Any change in the dosing of the following within 90 days prior to Visit 1/Screening and 
throughout the study duration: 
• Anticholinergics 
• Antidepressants including selective serotonin reuptake inhibitors (SSRIs), 
selective serotonin norepinephrine reuptake inhibitors (SSNRIs), tricyclics, and 
benzodiazepines 
• Antihistamines 
• Systemic H1-receptor antagonists 
• β-adrenoceptor antagonists 
• Calcium channel blockers 
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Any change in the dosing of the following within 30 days prior to Visit 1/Screening and 
throughout the study duration: 
• Aspirin and aspirin-containing products 
The following procedures are prohibited as specified: 
Any previous: 
• Reconstructive or cosmetic eyelid surgery that may affect the normal function of 
the lids (e.g., blepharoplasty, ptosis repair, entropion/ectropion repair) 
• Invasive glaucoma (e.g., trabeculectomy, shunt) and/or corneal surgery (e.g., 
penetrating keratoplasty, lamellar keratoplasty, DSEK) 
Within 12 months prior to Visit 1/Screening: 
• Corneal refractive surgery (e.g., LASIK, PRK, LRI) 
Within 90 days prior to Visit 1/Screening: 
• Cataract extraction, with or without MIGS 
Within 30 days prior to Visit 1/Screening and throughout the study period: 
• Cauterization of the punctum or punctal plug (silicone or collagen) insertion or 
removal. If a subject has a punctal plug at Visit 1/Screening for ≥ 30 days and it 
falls out during the study, it should be replaced with a new plug of the same type. 
Contact lens wear prior to and during the study is prohibited. 
5.6.2. 
Treatment Compliance 
Treatment compliance will be monitored by IP accountability throughout the study. The 
amount of used and unused run-in vehicle returned at Visit 2/Day 1 and used and unused 
randomized IP returned at Visit 5/Day 28, Visit 6/Day 56, and Visit 7/Day 84 will be 
documented by site personnel. Additionally, the amount of used and unused artificial tears 
will be documented by site personnel starting at Visit 2 through Visit 7 if the artificial tears 
were required by the subject. 
5.7. 
Packaging and Labeling 
The IP will be filled into blow-fill-seal (BFS) containers composed of low density 
polyethylene (LDPE). The individual cartridges of 5 SUDs will be seal packed into a foil 
pouch. The foil-wrapped cartridges will be packaged 7 at a time into a cardstock storage box 
that will contain a total of 35 SUDs for the 2-week run-in period. The foil-wrapped cartridges 
will be packaged 16 at a time into a cardstock storage box that will contain a total of 
80 SUDs dispensed monthly at Visits 2, 5 and 6 during the randomized treatment period. A 
label bearing the required IP labeling information per Code of Federal Regulations (CFR) 
Part 312, Section 312.6 will be added on the outside of the foil wrapping and the outside of 
the IP storage box. 
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5.8. 
Storage and Accountability 
The IP should be stored at a controlled temperature at 15°- 25°C (59°-77°F) in a secured 
area. A temperature log will be maintained at each clinical site. Subjects should be instructed 
to store IP at home at room temperature. After opening a foil pouch, the remaining SUDs 
should be stored in the pouch until used. Subjects will retain all used and unused IP materials 
(SUDs, foil pouches, boxes) to return to the site. 
5.9. 
Investigational Product Dispensing and Retention at Study Site 
At Visit 1/Screening, if the eligibility criteria are met, vehicle solution for the 
screening/run-in period will be dispensed to the subject with instructions to return the used 
and unused IP at Visit 2/Day 1. When the run-in study materials are returned by the subject, 
accountability will be performed and the box will be retained at the site in a secured location.  
At Visit 2/Day 1, Kit 1 will be dispensed after the subject is randomized. Kits 2 through 3 
will remain in a secured location at the site. The subject will be instructed to return the box 
along with all used and unused IP study materials at Visit 5/Day 28. 
At Visit 5/Day 28, when Kit 1 is returned by the subject, accountability will be performed 
and the kit will be retained at the site in a secured location. The site will dispense Kit 2 to the 
subject according to randomization number with instructions to return the box along with 
used and unused IP study materials at Visit 6/Day 56. 
At Visit 6/Day 56, when Kit 2 is returned by the subject, accountability will be performed 
and the kit will be retained at the site in a secured location. The site will dispense Kit 3 to the 
subject with instructions to return the box along with used and unused IP study materials at 
Visit 7/Day 84. 
At Visit 7/Day 84, when Kit 3 is returned by the subject, accountability will be performed 
and the kit will be retained at the site in a secured location for the clinical research associate 
(CRA) to perform IP accountability and reconciliation. At the end of the study, the site or 
CRA will ship the IP study materials back to the packager for destruction. 
Note: If at any visit, the subject complains of persistent dry eye symptoms and a supply of 
artificial tears is provided, the subject must return all used and unused artificial tears at each 
subsequent visit so the site can perform accountability to assess the use of artificial 
tears/resupply artificial tears as needed. 
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6. 
STUDY PROCEDURES 
6.1. 
Informed Consent 
Prior to entry into the study or initiation of any study-related procedures, the subject must 
read, sign, and date the current Institutional Review Board (IRB)-approved version of the 
informed consent form. A full discussion of informed consent is presented in Section 10.3. 
6.2. 
Demographics and Background Characteristics 
6.2.1. 
Demographics 
Demographic information including age, gender, race, ethnicity, and date of informed 
consent will be recorded. 
6.2.2. 
Medical/Ocular History 
Clinically significant medical and ocular history will be documented and will include any 
previously diagnosed ocular abnormalities and ocular surgeries, including laser and non-laser 
procedures. 
6.2.3. 
Medication History 
All current medications (prescription and over-the-counter) taken at Screening, 90 days prior 
to Screening, and throughout the course of the study will be recorded in the Concomitant 
Medications page of the eCRF. Information regarding the dates of first and last dose, site of 
dosing (e.g., right eye, left eye, OU, systemic), and the reason the medication is being taken 
must be recorded in the eCRF.  
6.2.4. 
Urine Pregnancy Test 
A urine pregnancy test will be performed at Visit 1/Screening and Visit 2/Day 1 and repeated 
at Visit 7/Day 84 or the Early Discontinuation Visit for women of childbearing potential 
only. 
6.3. 
Efficacy Assessments 
Efficacy will be measured by assessment of DED symptoms (SANDE total score, individual 
symptoms rated on a visual analogue scale (VAS): itching, foreign body sensation, 
burning/stinging, fluctuating vision, eye dryness, eye discomfort, photophobia, and eye pain) 
and signs (TBUT, Schirmer’s test [anesthetized], corneal fluorescein staining, conjunctival 
lissamine green staining, and conjunctival hyperemia). All efficacy assessments will be 
conducted at the timepoints shown on the Schedule of Visits and Examinations (Table 1). 
6.3.1. 
Symptoms 
6.3.1.1. 
SANDE (Symptom Assessment in Dry Eye) Questionnaire 
The SANDE contains two questions regarding the frequency and severity of DED symptoms 
as shown in Figure 1. 
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Figure 1: 
Symptom Assessment in Dry Eye (SANDE) Questionnaire 
1. Frequency of symptoms: 
Please place a mark on the line to indicate how often, on average, your eyes feel dry 
and/or irritated: 
 
 
2. Severity of symptoms: 
Please place a mark on the line to indicate how severe, on average, you feel your 
symptoms of dryness and/or irritation are: 
 
 
Source: Schaumberg et al., 2007 
The frequency and severity scores (SANDE) will be recorded in the eCRF. The total score is 
the square root of the frequency score times the square root of the severity score (range 
0-100) and will be calculated by the electronic data capture (eDC) system. 
6.3.1.2. 
Measurement of Individual Dry Eye Symptoms 
The following individual symptoms of DED will be evaluated using a separate VAS scale for 
each symptom and will include: itching, foreign body sensation, burning/stinging, fluctuating 
vision, eye dryness, eye discomfort, photophobia, and eye pain.  
The subject will be asked to make a mark on the line to indicate how he/she feels about each 
symptom since the last visit. 
Itching 
 
 
 
  Doesn’t itch at all  
 
 
 
 
 
 
 
 
 
 
Want to scratch my eyes out 
Rarely  
 
 
 
 
 
 
 
 
                                                 All the time
Very mild  
 
 
 
 
 
 
 
 
                                           Very severe
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Foreign Body Sensation 
 
 
 
Burning/Stinging 
 
 
 
Fluctuating Vision  
 
 
 
Eye Dryness  
 
 
 
  Don’t feel like I have something in my eye                               Feel like I have sand in my eye 
  Doesn’t burn/sting at all 
                                                                                               Severe  
  Vision is fine                                                                                   Vision constantly changes 
  Not dry at all                                                                                                       Extremely dry 
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Eye Discomfort  
 
 
 
Photophobia  
 
 
 
Eye Pain  
 
 
 
The score for each symptom will be recorded in the eCRF. 
6.3.2. 
Signs 
6.3.2.1. 
Tear Break-up Time 
The tear film will be observed under the slit-lamp and timed until the tear film breaks up (i.e., 
tiny dry spots develop) (Nichols et al., 2004). The procedure is conducted 2 times for each 
eye and the TBUT for each is measured in seconds and recorded in the eCRF. The average 
for each eye will be calculated by the eDC system. Consult the Study Reference Manual for 
specific details regarding the evaluation procedures. 
6.3.2.2. 
Corneal Fluorescein Staining 
Following evaluation of TBUT, corneal fluorescein staining using a Wratten #12 filter (or 
equivalent) will be measured using the National Eye Institute (NEI) standardized grading 
system to grade each of the 5 areas of the cornea on a 0-3 scale (as shown in Figure 2)(range: 
0 – 15) (Lemp, 1995). Consult the Study Reference Manual for specific details regarding the 
evaluation procedures. 
  Very comfortable                                                                             Extremely uncomfortable 
  Not sensitive to light                                                                 Extremely sensitive to light 
  No eye pain 
                                                                                            Need pain medicine 
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Figure 2: 
Division of the Corneal Surface for Measuring Fluorescein Uptake 
 
Source: Lemp, 1995 
6.3.2.3. 
Conjunctival Hyperemia 
Conjunctival hyperemia will be graded during the slit-lamp examination using the 
McMonnies photographic scale (McMonnies and Chapman, 1987a; McMonnies and 
Chapman, 1987b). This photographic reference scale consists of 6 levels or grades of 
conjunctival hyperemia (0 = none, 5 = severe). Please note that these were designed for 
contact lens wearers, but validated for non-contact lens wearers (McMonnies and Ho, 1991). 
Consult the Study Reference Manual for specific details regarding the evaluation procedures. 
6.3.2.4. 
Conjunctival Lissamine Green Staining 
After corneal staining, lissamine green conjunctival staining will be measured. Six (6) areas 
of the conjunctiva will be evaluated (Figure 3) (Lemp, 1995). The Investigator will record a 
score for each area of each eye. The scores for each eye will be summed, excluding superior 
zones 2 and 4. Consult the Study Reference Manual for specific details regarding the 
evaluation procedures. 
 
Figure 3: 
Division of the Conjunctival Surface for Measuring Lissamine Green 
Staining 
 
6.3.2.5. 
Anesthetized Schirmer’s Test 
An anesthetized Schirmer’s test will be performed at least 5 minutes after the lissamine green 
conjunctival staining to allow for any reflex tearing to subside (Li et al., 2012; Tsubota et al., 
1999). Following instillation of topical anesthetic, filter paper strips will be placed in both 
eyes inside the lower eyelid (conjunctival sac) at the same time. The eyes are closed for 
5 minutes. The paper is then removed and the amount of moisture on each strip in 
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millimeters (mm) is measured and recorded in the eCRF (Wolffsohn et al., 2017). Consult 
the Study Reference Manual for specific details regarding the evaluation procedures. 
6.4. 
Adverse and Serious Adverse Events 
6.4.1. 
Definition of Adverse Events 
6.4.1.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a clinical study subject administered an IP that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (for example, an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an IP, whether or not considered 
related to this IP.  
Note: IP in this study refers to all concentrations of SDP-4 and to the vehicle (control). 
Medical conditions/diseases present before starting the investigational treatment are only 
considered AEs if they worsen after starting the investigational treatment. Abnormal test 
results constitute AEs only if they induce clinical signs or symptoms, are considered 
clinically significant, or require therapy. 
The occurrence of AEs should be sought by open-ended questioning of the subject at each 
visit during the study. At each clinic visit, study personnel should ask the following question: 
"Have you had any problems since your last visit?” Adverse events also may be detected 
when they are volunteered by the subject during or between visits or through study 
assessments. 
6.4.1.2. 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening or sight-threatening 
Note: The term "life-threatening" refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Results in persistent or significant disability/incapacity (excluding 
progression/outcome of the disease under study) 
• Is a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Is medically significant; i.e., defined as an event that jeopardizes the health of the 
subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above 
Treatment on an outpatient emergency basis that does not result in hospital admission, or a 
hospitalization that is elective or is a preplanned treatment for a pre-existing condition that is 
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unrelated to the indication under study and has not worsened since the start of the study, is 
not considered an SAE. 
All SAEs that are ongoing at the time of completion or discontinuation from the study will be 
followed until stabilization or resolution of the event. 
6.5. 
Relationship to Investigational Product 
The relationship of AEs to the IP should be assessed by the Investigator using the definitions 
below. 
Not suspected: The temporal relationship of the event to the IP makes a causal relationship 
unlikely, or, other drugs, therapeutic interventions or underlying conditions provide a 
sufficient explanation for the observed event. 
Suspected: The temporal relationship of the event to the IP makes a causal relationship 
possible or other drugs, therapeutic interventions or underlying conditions do not provide a 
sufficient explanation for the observed event. 
If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the IP and the occurrence of the AE, then the AE should be considered 
“suspected.” 
If the relationship between the AE/SAE and the IP is determined by the Sponsor to be 
“suspected” the event will be considered to be related to the IP for the purposes of expedited 
regulatory reporting. 
6.6. 
Recording Adverse Events 
Adverse events (AEs) spontaneously reported by the subject and/or in response to an open 
question from the study personnel or revealed by observation, regardless of severity or 
potential association with the IP or study procedures, will be recorded in the eCRF. Changes 
from baseline assessments that are part of the disease being studied will not necessarily be 
recorded as AEs unless the Investigator deems them as such. Investigators are advised to 
consider reporting an increase in IOP of 10 mmHg or greater, or a visual acuity decrease of 3 
lines EDTRS (15 letters) or greater as an AE.  If ongoing at the time of the subject's last 
study visit, Investigators should follow the event until the subject has returned to baseline or 
the event has resolved.   
All AEs that occur following consent and until the final study visit (Visit 7/Day 84) should 
be collected and recorded on the AE eCRF page. AEs that occur during the screening/run-in 
period (Visit 1/Day-14 ± 2 to Visit 2/Day 1) will be summarized separately from AEs that 
occur from the first dose of double-masked treatment on Day 1 to the Day 84 Visit or Early 
Discontinuation. Serious adverse events (SAEs) will be followed until the event is resolved 
or stabilized. 
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The AE term should be reported in standard medical terminology when possible. For each 
AE, the Investigator will evaluate and report the following: 
• Onset (date) 
• Resolution (date) 
• Severity grade (mild, moderate, severe) 
• Relationship to IP (not suspected, suspected) 
• Action taken (none, IP temporarily interrupted, IP permanently discontinued; 
concomitant medication taken; hospitalization/prolonged hospitalization; other) 
• Serious outcome (yes/no) 
The severity grade should be determined by the Investigator using the definitions below: 
• Mild: Discomfort noticed but no disruption of normal daily activity 
• Moderate: Discomfort sufficient to cause interference with normal daily activity 
• Severe: Incapacitating, with inability to perform normal activities 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity (as defined directly above) whereas seriousness is defined by the criteria under 
Section 6.4.1.2. An AE of severe intensity may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the pregnancy form. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. The subject will stop using 
the IP, be withdrawn from the study, and followed through conclusion of pregnancy. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented. 
6.7. 
Reporting Adverse Events 
All AEs (suspected and not suspected) will be recorded following consent and until the final 
study visit, Visit 7/Day 84. Any SAEs “suspected” to be related to the IP and discovered by 
the Investigator at any time after the study should be reported.  
Any SAE that occurs must be reported within 24 hours of its occurrence or within 24 hours 
of learning of its occurrence by entering the information in the appropriate eCRF page in the 
EDC system. Recurrent episodes, complications, or progression of the initial SAE must be 
reported as follow-up to the original episode within 24 hours of the Investigator receiving the 
information. Information about all SAEs will be collected and recorded on the SAE form. All 
pertinent medical records and information collected during the treatment and follow-up of the 
subject should be maintained at the site with a copy emailed to 
SilkTech-Safety@oculoscr.com only if requested and after thorough de-identification/ 
removal of all personal health information (PHI). The Investigator must assess the SAE 
relationship to the IP/study treatment and severity and complete the SAE form. Silk 
Technologies/Oculos may request additional information. Follow-up information (e.g., 
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discharge summary) will be retained in the subject’s chart and a copy will be emailed to 
SilkTech-Safety@oculoscr.com. 
In addition, all SAEs should be recorded on the Adverse Event eCRF page with the serious 
question marked “Yes”. 
All subjects who experience an SAE should be followed clinically and undergo the 
appropriate diagnostic evaluations until stabilization or resolution of the event. 
It is the Investigator’s responsibility to notify the approving IRB of any site-specific SAEs 
per the IRB’s reporting requirements. 
Silk Technologies will report all SAEs to the United States (US) Food and Drug 
Administration (FDA) on the appropriate schedule depending if the event is IP related or not 
IP related, expected or unexpected (based on the available information in the IB). 
Any death occurring during the study and follow up period should be reported as an SAE. 
For any death occurring through the end of the study, regardless of the degree of relationship 
to IP, the SAE resulting in the death must be reported to Silk Technologies or designee. A 
death occurring after completion of the study does not require completion of the SAE form. 
6.8. 
Other Safety Assessments 
6.8.1. 
Best-Corrected Visual Acuity 
Best-corrected visual acuity (BCVA) measurement will be performed in each eye at all study 
visits with the logMAR eye chart using the subject’s best corrective lens prescription 
eyeglasses or trial frame lenses, if applicable. The subject's BCVA must be determined (via 
refraction) if corrected or uncorrected visual acuity is not logMAR 0.0 (equivalent to 20/20). 
This refraction must be used for all VA assessments for the duration of the study. The subject 
must wear the same glasses/trial frame, if applicable, at each visit. Ambient room lighting 
should be consistent for a given subject throughout the study period. Consult the Study 
Reference Manual for specific details regarding the evaluation procedures. 
6.8.2. 
Biomicroscopy and External Eye Exam 
A slit-lamp examination will be conducted at each study visit to assess the anterior ocular 
structures, including lid, cornea, conjunctiva, anterior chamber, iris, lens, and posterior 
capsule (if pseudophakic). Abnormalities will be documented. Consult the Study Reference 
Manual for specific details regarding the evaluation procedures. 
6.8.3. 
Dilated Fundus Exam 
A fundus exam consisting of the vitreous, optic nerve, macula, and peripheral retina will be 
conducted, and the structures will be graded as normal or abnormal. Consult the Study 
Reference Manual for specific details regarding the evaluation procedures. 
6.8.4. 
Intraocular Pressure Measurement  
Intraocular pressure will be measured utilizing a Goldmann tonometer. If possible, the same 
observer should perform the assessment and the same calibrated instrument should be used 
for a given subject throughout the study. To avoid IOP changes due to the diurnal rhythm, the 
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IOP measurements should be performed at approximately the same time of the day each 
time. Consult the Study Reference Manual for specific details regarding the evaluation 
procedures. 
6.8.5. 
Investigational Product Comfort Assessment 
Subjects will rate the comfort of IP instillation according to the following 4-point scale: 
0 = No discomfort 
1 = Mild discomfort 
2 = Moderate discomfort 
3 = Severe discomfort 
6.9. 
Screen Failures 
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
criteria or met at least 1 of the exclusion criteria, and has not been randomized into the study. 
Based on Investigator discretion and Sponsor approval, subjects who initially failed to meet 
the inclusion/exclusion criteria may be rescreened at a later time if their eligibility status has 
changed. The subject will retain the same subject identification number that he/she was 
assigned at the first screening. 
6.10. 
Subject Withdrawal Criteria 
The following are the criteria for considering withdrawal from the study: 
• Withdrawal of subject consent. The subject may request for any reason at any 
time to be withdrawn from the study. 
• The Sponsor terminates the study. 
If a subject withdraws from the study, the reason for withdrawal will be recorded in the 
eCRF. 
If a study subject fails to attend a study visit at any point during the study period, every effort 
should be made to keep the subject in the study and conduct all study visits as scheduled; all 
attempts to contact the subject must be documented. If the subject relocates during the study 
period, the CRO should be contacted to determine if there is a possibility that the subject 
could continue at another clinical site.  
6.11. 
Appropriateness of Measurements 
The efficacy and safety assessments in this study are standard for ophthalmologic 
investigations, and their reliability, accuracy, and relevance is well established. Collection of 
AEs to monitor drug safety is standard in clinical studies. 
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7. 
STUDY ACTIVITIES 
Table 1 provides a tabular summary of all scheduled visits and procedures to be performed 
during the clinical study. 
7.1. 
Visit 1 (Day -14 ± 2/Screening Visit) 
Procedures performed at Screening, Visit 1/Day -14 ± 2 will include the following: 
• Obtain written informed consent 
• Inclusion/exclusion criteria 
• Demographics 
• Medical and ocular history 
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
• SANDE 
• BCVA (logMAR) 
• Biomicroscopy/external eye exam 
• TBUT 
• Corneal fluorescein staining 
• Conjunctival lissamine green staining  
• Anesthetized Schirmer’s test  
• IOP measurement 
• Dilated fundus exam 
• Re-review inclusion/exclusion criteria 
• Dispense run-in medication/provide instruction on administration/in-clinic 
administration/evaluate administration 
• AE assessment 
Eligible subjects must have daily symptoms of DED for ≥ 6 months, a total score ≥ 40 on the 
SANDE questionnaire, history of artificial tear use in the 30 days prior to Screening, TBUT 
≤ 6 seconds in both eyes, and anesthetized Schirmer’s test tear volume ≥ 3 mm and <10 mm 
in both eyes. 
If a subject complains of persistent dry eye symptoms after run-in medication is dispensed 
and between or during study subsequent visits, the site may provide the subject with 
unpreserved artificial tears (provided by the Sponsor), to be used only if necessary. The 
subject must return all used and unused artificial tears at each study visit so the site can 
conduct accountability to assess the use of artificial tears. Artificial tears may not be used 
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within 2 hours prior to any study visit; the subject may either be rescheduled or may wait at 
the site until 2 hours have passed since instillation if this occurs. 
7.2. 
Treatment Period (Day 1 to Day 84 ± 4) 
7.2.1. 
Visit 2 (Day 1/Confirmatory and Randomization Visit) 
Procedures performed at Visit 2/Day 1 include: 
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
• SANDE 
• Individual symptom assessment (VAS) 
• IP comfort assessment 
• BCVA (logMAR) 
• Biomicroscopy/external eye exam 
• TBUT 
• Corneal fluorescein staining 
• Conjunctival lissamine green staining 
• Anesthetized Schirmer’s test 
• Review inclusion/exclusion criteria 
• Randomize eligible subjects 
• Dispense IP/provide instruction on administration 
• Dispense artificial tears (if needed) 
• AE assessment 
• Run-in medication accountability 
• Artificial tear accountability, if applicable 
7.2.2. 
Visit 3 (Day 7 ± 2) 
Procedures performed at Visit 3/Day 7 ± 2 include: 
• Concomitant medication review 
• SANDE 
• Individual symptom assessment (VAS) 
• IP comfort assessment 
• BCVA (logMAR) 
• Biomicroscopy/external eye exam 
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• TBUT 
• Corneal fluorescein staining 
• Conjunctival lissamine green staining 
• Dispense artificial tears (if needed) 
• AE assessment 
• Artificial tear accountability (if applicable) 
7.2.3. 
Visit 4 (Day 14 ± 2) 
Procedures performed at Visit 4/Day 14 ± 2 include: 
• Concomitant medication review 
• SANDE 
• Individual symptom assessment (VAS) 
• IP comfort assessment 
• BCVA (logMAR) 
• Biomicroscopy/external eye exam 
• TBUT 
• Corneal fluorescein staining 
• Conjunctival lissamine green staining 
• Dispense artificial tears (if needed) 
• AE assessment 
• Artificial tear accountability (if applicable) 
7.2.4. 
Visit 5 (Day 28 ± 2) 
Procedures performed at Visit 5/Day 28 ± 2 include: 
• Concomitant medication review 
• SANDE 
• Individual symptom assessment (VAS) 
• IP comfort assessment 
• BCVA (logMAR) 
• Biomicroscopy/external eye exam 
• TBUT 
• Corneal fluorescein staining 
• Conjunctival lissamine green staining 
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• IOP measurement  
• Dispense IP 
• Dispense artificial tears (if needed) 
• AE assessment 
• IP accountability 
• Artificial tear accountability (if applicable) 
7.2.5. 
Visit 6 (Day 56 ± 4) 
Procedures performed at Visit 6 include: 
• Concomitant medication review 
• SANDE 
• Individual symptom assessment (VAS) 
• IP comfort assessment 
• BCVA (logMAR) 
• Biomicroscopy/external eye exam 
• TBUT 
• Corneal fluorescein staining 
• Conjunctival lissamine green staining 
• Dispense IP 
• Dispense artificial tears (if needed) 
• AE assessment 
• IP accountability 
• Artificial tear accountability (if applicable) 
7.3. 
Visit 7 (Day 84 ± 4) or Early Termination Procedures 
At Visit 7/Day 84 ± 4 or the Early Termination Visit, all of the following end of treatment 
procedures must be completed: 
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
• SANDE 
• Individual symptom assessment (VAS) 
• IP comfort assessment 
• BCVA (logMAR) 
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• Biomicroscopy/external eye exam 
• TBUT 
• Corneal fluorescein staining 
• Conjunctival lissamine green staining 
• Anesthetized Schirmer’s test 
• IOP measurement 
• Dilated fundus exam 
• AE assessment 
• IP accountability 
• Artificial tear accountability (if applicable) 
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8. 
QUALITY CONTROL AND ASSURANCE 
Silk Technologies and/or their contracted agents utilize standard operating procedures 
(SOPs) designed to ensure that research procedures and documentation are consistently 
conducted/prepared to the highest quality standards. These SOPs require compliance with 
FDA regulations and the International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) guidance. 
The study will be monitored by CRAs/monitors to verify that the rights and well-being of 
human subjects are being protected, the reported data are accurate, complete, and verifiable, 
and that the conduct of the study is in compliance with the currently approved protocol, with 
ICH GCP, and with the applicable regulatory requirements. 
To ensure compliance with GCP and all applicable regulatory requirements, Silk 
Technologies or its agent may conduct a quality assurance audit at any time during or after 
completion of a study. The Investigator will be given adequate notice if he/she is selected for 
an audit. The audit will include, but is not limited to: a review of all informed consent forms, 
medical records, and regulatory documentation; an assessment of study conduct and protocol 
compliance; and a review of the study materials receipt, storage, and administration. At the 
conclusion of an audit, the auditor will conduct a brief meeting with the Investigator to 
review the findings of the audit. 
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9. 
STATISTICS 
9.1. 
General Considerations 
This is a Phase 2, multicenter, randomized, double-masked, vehicle-controlled, 
dose-response, parallel group study to evaluate the ocular and systemic safety and efficacy of 
SDP-4 ophthalmic solution in subjects with moderate to severe DED. 
Subjects with DED are planned to be randomized to 1 of 3 concentrations of SDP-4 (0.1%, 
1.0%, or 3.0%) or vehicle in a 1:1:1:1 ratio, with 75 subjects randomized to each group. 
A biostatistician will perform statistical analyses as agreed with the Sponsor according to the 
Statistical Analysis Plan (SAP). 
All continuous study assessments will be summarized by treatment and visit (as applicable) 
using descriptive statistics (n, mean, median, standard deviation, minimum, and maximum). 
All categorical study assessments will be summarized by treatment and visit (as applicable) 
using frequency counts and percentages.  
All study data will be listed by treatment, subject, and visit (as applicable). 
The unit of analysis for efficacy will be the study eye. 
Efficacy analysis will be conducted on the intent-to-treat (ITT) population (primary efficacy 
analysis) and the per protocol (PP) population (secondary efficacy analysis). Safety analyses 
will be performed using the safety analysis population. Definitions for the analysis 
populations may be found in Section 9.3. 
9.2. 
Determination of Sample Size 
A sample size of 70 subjects per treatment group will have 80% power to detect a treatment 
difference of 11.7 units in SANDE total score and 1.2 seconds in TBUT at Visit 7/Day 84 
using a t-test with a 0.05 two-sided significance level. This calculation is based on the 
assumptions shown in Table 2. Note: TBUT is one of several secondary outcomes planned to 
be analyzed, but the sample size was derived using assumptions based on expected SANDE 
and TBUT values. Over-enrollment of 5 subjects per group/20 subjects per study is planned 
to account for discontinuations.  
Table 2 
Sample Sizes: Two-Group t-test of Equal Means 
Assumptions 
SANDE 
TBUT 
Test significance level,  
0.050 
0.050 
1 or 2 sided test 
2 
2 
Difference in means, 1-2 
11.684 
1.192 
Common standard deviation 
24.500 
2.500 
Effect size,  = |1-2|/ 
0.477 
0.477 
Power (%) 
80 
80 
n per group 
70 
70 
 
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9.3. 
Analysis Populations  
9.3.1. 
Intent-to-Treat (ITT) Population 
The ITT population will include all randomized subjects who received IP. This population 
will be the primary population for efficacy analyses and will be used to summarize all 
efficacy variables and will summarize subjects as randomized. 
9.3.2. 
Per Protocol (PP) Population 
The PP population is a subset of the ITT population, which will include all subjects who 
complete the study without major protocol deviations. This population will be the secondary 
population for efficacy analyses and will be used to summarize a subset of efficacy variables. 
The PP population will summarize subjects as treated.  
9.3.3. 
Safety Population 
The safety population will include all subjects who received IP. This population will be used 
to summarize safety variables and will summarize subjects as treated. 
9.4. 
Demographics and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized in tables. Summary 
tables will be supported with individual subject data listings. 
9.5. 
Efficacy Endpoints and Analyses 
9.5.1. 
Primary Efficacy Endpoint 
Mean change from baseline in total SANDE score at Visit 7/Day 84 
9.5.2. 
Secondary Efficacy Endpoints 
• Mean and mean change from baseline at each visit for each of the following 
evaluations: 
− Conjunctival lissamine green staining (combined and each zone) 
− Corneal fluorescein staining (combined and each zone) 
− TBUT 
− Anesthetized Schirmer’s test 
− Conjunctival hyperemia 
− Individual symptom VAS scores, separately for each symptom 
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• SANDE 
− Mean change from baseline in total SANDE score at each visit 
− Mean total SANDE score at each visit 
− Mean and mean change from baseline in each component of SANDE at each 
visit 
9.5.3. 
Efficacy Analyses 
The primary efficacy endpoint (SANDE) will be summarized using continuous summary 
statistics by treatment group and visit. The primary analysis will utilize a repeated measures 
mixed model where the dependent variable is the change from baseline score, treatment 
group is a fixed effect, baseline score is a covariate, and visit is a repeated measure on 
subject. The repeated measures mixed model is utilized to account for the effect of missing 
data under the assumption that the data are missing at random. Least squares means will be 
used to test each concentration of SDP-4 to vehicle. Sensitivity analyses for the primary 
endpoint will be performed using last observation carried forward (LOCF) as well as 
observed data only. 
In order to minimize the impact of multiplicity in this dose-response study, the following 
hierarchy for analyses will be conducted (note: TBUT is one of several secondary outcomes 
planned to be analyzed, but the sample size was derived using assumptions based on 
expected SANDE and TBUT values): 
1. Primary (SANDE) high concentration vs. vehicle  
2. Primary (SANDE) middle concentration vs. vehicle  
3. Primary (SANDE) low concentration vs. vehicle  
4. Secondary (TBUT) high concentration vs. vehicle  
5. Secondary (TBUT) middle concentration vs. vehicle  
6. Secondary (TBUT) low concentration vs. vehicle 
The comparisons will be conducted at α = 0.05. Each comparison will be made in order until 
P > (exceeds) 0.05. If P ≤ 0.05, the comparison is statistically significant and testing is 
continued. 
The planned analyses for all efficacy outcomes will be described in detail in the SAP, which 
will be finalized prior to database lock. 
9.6. 
Safety Variables and Analysis 
9.6.1. 
Safety Variables  
Safety variables are as follows: 
• Ocular and non-ocular AE monitoring 
• BCVA 
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• Biomicroscopy 
• Intraocular pressure 
• Dilated fundus exam  
• IP comfort assessment 
9.6.2. 
Safety Analysis 
Safety and IP comfort data will be presented in tables of descriptive statistics and frequency 
distribution. All summary tables will be supported with individual subject data listings. 
AEs that occur during the screening/run-in period (Visit 1/Day-14 ± 2 to Visit 2/Day 1) will 
be summarized separately from AEs that occur from the first dose of double-masked 
treatment on Day 1 to the Day 84 Visit or Early Discontinuation. 
The primary safety analysis will summarize ocular and non-ocular treatment-emergent 
adverse events (TEAEs) using discrete summaries at the subject level by system organ class 
and preferred term for each treatment group. A TEAE will be defined as occurring after the 
first dose of IP. Serious adverse events (SAEs) and treatment-related ocular and non-ocular 
TEAEs will be summarized similarly. Ocular and non-ocular TEAEs will also be 
summarized by severity. 
Biomicroscopy and dilated indirect ophthalmoscopy measures will be summarized by 
tabulating the distribution of score shifts between baseline and post-baseline assessments  
Best-corrected visual acuity (BCVA; logMAR) and IOP (mm Hg) will be summarized at 
each visit, using continuous and discrete summary statistics, including change from baseline 
and the proportion of study eyes with pre-defined increases from baseline, specifically, eyes 
with a 3-line decrease in BCVA or eyes with ≥ 10 mm Hg increase in IOP.  
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10. 
ADMINISTRATIVE CONSIDERATIONS 
10.1. 
Institutional Review Board (IRB) Approval 
The IRB must review, approve, and provide continuing review of the clinical study protocol, 
protocol amendments, the informed consent documents, subject recruitment advertisements, 
and any other written information to be provided to the subjects. Initial IRB approval is an 
affirmative decision that the clinical study has been reviewed and may be conducted at the 
study site within the constraints set forth by the IRB, the institution, GCP, and applicable 
regulatory requirements. A copy of the IRB approval letter for the protocol, the informed 
consent, the intended advertising, and any written material to be provided to the subject must 
be submitted to Silk Technologies or designee prior to release of investigational supplies to 
the study site. Progress reports and notifications of serious adverse reactions will be provided 
to the IRB according to local regulations and guidelines. The IRB must be notified of 
completion or termination of the study. The study site must maintain an accurate and 
complete record of all reports, documents, and other submissions made to the IRB 
concerning this protocol. 
10.2. 
Ethical Conduct of the Study 
The study will be conducted according to all stipulations of the protocol, including all 
statements regarding confidentiality, and in compliance with ICH guidelines, and all 
applicable US federal regulations and local legal and regulatory requirements. 
10.3. 
Subject Information and Consent 
A sample informed consent form containing the required elements of informed consent will 
be provided by Silk Technologies or designee. Any changes made to this sample must be 
approved by Silk Technologies or designee prior to submission to the IRB. After approval by 
Silk Technologies or designee, the informed consent form must be submitted to and approved 
by the IRB. The informed consent must be written in a language in which the subject is 
fluent. Regulations require that foreign language informed consent forms be submitted to the 
IRB for approval. The foreign language translation is required to contain a statement of 
certification of the translation. The Investigator must forward a copy of the consent forms, 
the certified foreign language translation, and an IRB approval letter to Silk Technologies or 
designee. 
It is the responsibility of the Investigator to inform each subject of the purpose of this clinical 
trial, including possible risks and benefits, and to document the informed consent process. 
Prior to undergoing any study-related procedures, the subject must read, sign, and date the 
current IRB-approved version of the informed consent form. The original informed consent 
form is to be retained by the study site, and a copy of the signed consent form is to be given 
to the subject. 
10.4. 
Subject Confidentiality 
Data generated for the study should be stored in a limited-access file area and be accessible 
only to representatives of the study site, Silk Technologies, Oculos, the IRB, and 
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FDA/relevant regulatory agencies. Medical information resulting from a subject’s 
participation in this study may be given to the subject’s personal physician or to the 
appropriate medical personnel responsible for the subject’s welfare. No information that can 
be related to a specific individual subject will be released or used in any fashion without the 
signed written consent of that subject. All reports and communications relating to study 
subjects will identify subjects only by initials and subject identification number. Complete 
subject identification will be kept by the Investigator for purposes of long-term follow-up, if 
needed. This information will be treated with strict adherence to professional standards of 
confidentiality. 
10.5. 
Study Monitoring 
The study will be monitored by Silk Technologies or designee in accordance with current 
GCP to assure compliance with the study protocol and the quality of the data collected. 
Monitoring visits will occur as required and could include a study initiation visit, monitoring 
visit(s), and a study close-out visit. Training will be provided for key investigative personnel 
in all aspects of study conduct. The Investigator will be responsible for making sure that site 
personnel are provided adequate training on conducting delegated tasks.  
Before a site can enter a subject into the study, a representative of the Sponsor will: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities 
regarding protocol adherence and the responsibilities of the Sponsor and or its 
representatives 
This study will utilize eDC to optimize the eCRF source verification process with limited 
separate source documentation. Monitors will review e-source data and overall study 
data/consistency remotely and query discrepancies based upon eCRF entries (eCRF initial 
entry is the source). During this monitoring, data are reviewed as entered by the site, and the 
monitors will flag any abnormalities, trends, or safety signals for Medical Monitor review 
and monitor follow-up onsite, if necessary. Refer to the Study Reference Manual and/or 
Regulatory Binder for details regarding the direct data entry of study assessments and 
requirements for maintaining additional source documentation via paper/medical record. 
During visits to the study site, the monitor may review the source documents including but 
not limited to signed informed consent forms, inclusion/exclusion checklist, medical/ocular 
history, concomitant medications, study material accountability and storage, completed 
SANDE questionnaires and subject-completed VAS assessments, the reporting procedures 
for AEs, SAEs, and protocol deviations.  The CRA will review the study documents 
maintained in the Regulatory Binder to ensure all documentation is current and only qualified 
and trained staff are appropriately delegated study related tasks.  The CRA will also review 
the site-specific processes and research-related SOPs to ensure appropriate Investigator 
oversight is being maintained and documented as required by GCP/ICH. 
All data generated during this study and the medical records/documents from which they 
originated are subject to inspection by the Sponsor or designee, the FDA, and other 
regulatory agencies. The Investigator must notify the Sponsor or designee promptly of any 
inspections scheduled by regulatory authorities. 
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Upon completion of the study, the clinical monitor will conduct a final visit (closeout) to the 
site. The objectives of this visit are to ascertain that all regulatory records and reports are 
complete, verify that the IP and other supplies have been accounted for (returned/destroyed), 
and ensure that the Investigators are aware of their responsibilities once the study ends.  
The Investigator is responsible for permitting the Sponsor or designee direct access to any 
study documents for monitoring and auditing purposes, for providing adequate space for 
monitoring, and for addressing any questions or issues that might be raised by the monitor or 
auditor on a timely basis. 
10.6. 
Case Report Forms and Study Records 
Data relating to study procedures may be entered by site personnel directly onto eCRFs 
available in the study’s eDC system. When the eCRF is the first study data is recorded, it will 
be the source document; exceptions are detailed in the Study Reference Manual. Paper source 
documents will be retained at the study site when appropriate. 
10.7. 
Protocol Deviations 
The Investigator should not deviate from the requirements of this protocol except in the event 
of a medical emergency.  
A reportable protocol deviation is defined as nonadherence to the protocol that involves 
inclusion/exclusion criteria, affects subject safety, or has the potential to affect the integrity 
of the data. All protocol deviations will be reported to Silk Technologies by entering the 
event in the appropriate eCRF page. Protocol deviations should be reported to the IRB in 
accordance with IRB-specific guidelines. If there is any question as to whether the deviation 
is reportable, Silk Technologies or designee and the IRB should be contacted. 
All changes to the protocol will be made by the Sponsor or designee as an approved 
amendment to the protocol, submitted to the FDA, and approved by the IRB prior to 
implementation. 
10.8. 
Access to Source Documentation 
A trial-related monitoring audit, review by the IRB, and/or regulatory inspection may be 
conducted at any time during or after completion of a study (Section 8). The Investigator will 
be given adequate notice if he/she is selected for an audit and must provide direct access to 
study documentation. The audit may include, but is not limited to, a review of all informed 
consent forms; a review of medical records; a review of regulatory documentation; an 
assessment of study conduct and protocol compliance; and a review of the study materials 
receipt, storage, and administration. 
10.9. 
Data Generation and Analysis 
Management of data and the production of the clinical study report will be the responsibility 
of Silk Technologies or its designee. 
During the course of the trial, data queries will be generated for data items that are 
potentially erroneous and require appropriate clarification or correction. Such clarifications 
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and corrections will be discussed with and approved by site personnel and appropriately 
documented. Prior to database lock, data listings will be generated, and anomalous values 
investigated. 
10.9.1. 
Retention of Data 
Investigators should retain study-related records at the site until informed by the Sponsor. 
The Investigator will not move study documents or discard any records without notifying 
Silk Technologies. If the Principal Investigator moves from the current clinical site, Silk 
Technologies should be notified of the name of the person who will assume responsibility for 
maintenance of the records at the clinical site or the new address at which the records will be 
stored. The Investigator will notify Silk Technologies as soon as possible in the event of 
accidental loss or destruction of any study documentation. If it becomes necessary for Silk 
Technologies or designee, or the FDA or relevant regulatory authorities to review any 
documentation relating to the study, the Investigator must permit access to such records. 
10.10. 
Publication and Disclosure Policy 
All information concerning SDP-4 and the operations of Silk Technologies, such as patent 
applications, formulas, manufacturing processes, basic scientific data or formulation 
information not previously published, are considered CONFIDENTIAL and shall remain the 
sole property of Silk Technologies. The Investigator agrees to use this information only in 
accomplishing this study and will not use it for other purposes without the written consent of 
Silk Technologies 
The publication policy is addressed in a separate agreement. 
 
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11. 
REFERENCE LIST 
Abdel-Naby W, Cole B, Liu A, et al. Silk-Derived Protein Enhances Corneal Epithelial 
Migration, Adhesion, and Proliferation. Invest Ophthalmol Vis Sci. 2017;58(3):1425-33. 
Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification 
Report. Ocul Surf. 2017;15:276-283. 
Kim CE, Lee JH, Yeon YK, et al. Effects of silk fibroin in murine dry eye. Sci Rep. 
2017;7:44364. 
Lan W, Petnick A, Heryati S, et al. Nuclear factor kB: Central regulator in ocular surface 
inflammation and diseases. Ocul Surf. 2012;10:137-148. 
Li N, Deng XG, He MF. Comparison of the Schirmer I test with and without topical 
anesthesia for diagnosing dry eye. Int J Ophthalmol. 2012;5:478-81. 
Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry 
Eyes. CLAO J. 1995;21:221-32. 
McMonnies CW, Chapman-Davies A. Assessment of conjunctival hyperemia in contact lens 
wearers. Part I. Am J Optom Physiol Opt. 1987;64:246-50. (McMonnies and 
Chapman-Davies, 1987a) 
McMonnies CW, Chapman-Davies A. Assessment of conjunctival hyperemia in contact lens 
wearers. Part II. Am J Optom Physiol Opt. 1987;64:251-5. (McMonnies and 
Chapman-Davies, 1987b) 
McMonnies CW, Ho A. Conjunctival hyperaemia in non-contact lens wearers. Acta 
Ophthalmol (Copenh). 1991;69:799-801. 
Nichols KK, Mitchell GL, Zadnik K. The repeatability of clinical measurements of dry eye. 
Cornea. 2004;23:272-85. 
Pflugfelder SC, Farley W, Luo L, et al. Matrix metalloproteinase-9 knockout confers 
resistance to corneal epithelial barrier disruption in experimental dry eye. Am J Ophthamol. 
2005;166:61-71.  
Smith VA, Rishmawi H, Hussein H, et al. Tear film MMP accumulation and corneal disease. 
Br J Ophthalmol. 2001;85:147-53. 
Schaumberg DA, Gulati A, Mathers WD, et al. Development and validation of a short global 
dry eye symptom index. Ocul Surf. 2007;5:50-7. 
Solomon A, Dursun D, Liu Z, et al. Pro- and anti-inflammatory forms of interleukin-1 in the 
tear fluid and conjunctiva of patients with dry eye disease. Invest Ophthalmol Vis Sci. 
2001;42:2283-2292. 
Tsubota K, Kaido M, Yagi Y, et al. Diseases associated with ocular surface abnormalities: 
the importance of reflex tearing. Br J Ophthalmol. 1999;83:89-91. 
Wolffsohn JS, Arita R, Chalmers R, et al. TFOS DEWS II Diagnostic Methodology report. 
Ocul Surf. 2017;15:539-574. 
 
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12. 
SUMMARY OF CHANGES 
12.1. 
Changes Implemented in Protocol SDP-4-CS201 Amendment 1 
The following substantive changes were made to the original protocol: 
Location 
Description of Change 
Rationale for Change 
Synopsis Inclusion 
Criteria;  
4.2. Inclusion Criteria; 
7.1. Visit 1 (Day -14 
± 2/Screening Visit) 
Change  
Anesthetized Schirmer’s test tear 
volume ≥ 4 mm and <10 mm in both 
eyes.” 
to 
Anesthetized Schirmer’s test tear 
volume ≥ 3 mm and <10 mm in both 
eyes.” 
To allow for greater 
flexibility in enrollment of 
subjects. 
Synopsis Exclusion 
Criteria; 
4.3. Exclusion Criteria; 
5.6.1. Prohibited 
Medications and 
Treatments 
Add 
If a subject has a punctal plug at Visit 
1/Screening for ≥ 30 days and it falls 
out during the study, it should be 
replaced with a new plug of the same 
type. 
To clarify that punctal 
plugs that fall out from the 
eye during the study must 
be reinserted. 
Synopsis Exclusion 
Criteria; 
4.3. Exclusion Criteria; 
5.6.1. Prohibited 
Medications and 
Treatments 
Change 
The following medications are 
prohibited within 30 days prior to 
Visit 1/Screening and throughout the 
study duration: 
• 
Systemic (i.e., oral, intravenous, 
intra-articular, or intramuscular) 
corticosteroids (intranasal, inhaled, 
dermatologic, peri-anal, or intrathecal 
steroids are allowed) 
to 
• 
Systemic (i.e., oral, intravenous, 
intra-articular, intrathecal, epidural, 
or intramuscular) corticosteroids 
(intranasal, inhaled, dermatologic, or 
peri-anal steroids are allowed) 
To clarify that intrathecal 
and epidural steroids are 
considered systemic 
steroids, and therefore 
prohibited within 30 days 
of Screening and 
throughout the study 
period. 
Note that administrative and editorial changes were made to the protocol for consistency and 
clarity. Such changes are not itemized. 
 
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APPENDIX B. INVESTIGATOR’S SIGNATURE 
Study Title: 
A Phase 2, Multicenter, Double-Masked, Randomized, 
Vehicle-Controlled, Parallel-Group, Dose-Response Study of SDP-4 
Ophthalmic Solution in Subjects with Dry Eye Disease (DED) 
Study Number: 
SDP-4-CS201 
Final Date: 
03 April 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
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SAP_001.pdf: 
Silk Technologies, Ltd.
.
PROTOCOL SDP-4-CS201
STATISTICAL ANALYSIS PLAN
PROTOCOL: SDP-4-CS201
A Phase 2, Multicenter, Double-Masked, Randomized, 
Vehicle-Controlled, Parallel-Group, Dose-Response 
Study of SDP-4 Ophthalmic Solution in Subjects with 
Dry Eye Disease (DED)
SPONSOR:
Silk Technologies, Ltd.
3700 Annapolis Lane North, Suite 105
Plymouth, MN 5544765 
PRODUCT :
SDP-4 Ophthalmic Solution
AUTHOR:
James Zhou, Ph.D.
Contract Statistician
FHL Health LLC 
6701 Democracy Blvd. Suite 300
Bethesda, MD 20817
DATE:
24 June 2019
STATUS:
Final Version 1.0
North, Suite 105
th, Suite 1
765 
mic Solution
Solution
ou, Ph.D.
Ph.D.
t Statistician
atistician
Health LLC 
h LLC 
1 Democracy Blv
emocracy
ethesda
sd , MD
M
208
208
24 June 
June 2019
2019
Finalal Versi
V


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Protocol SDP-4-CS201
Statistical Analysis Plan: Final Version 1.0, 24 June 2019
Page | 2
SIGNATURE PAGE
PREPARED BY:
James Zhou, PhD
Biostatistician
Date
APPROVED BY:
Brian Levy, OD, MSc
Date
Acting Chief Medical Officer (CMO)
cer (CMO)
CMO


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.
Protocol SDP-4-CS201
Statistical Analysis Plan: Final Version 1.0, 24 June 2019
Page | 3
TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................3
AMEMDMENT HISTORY .....................................................................................5
LIST OF ABBREVIATIONS .................................................................................6
1
INTRODUCTION .............................................................................................7
1.1
Study Objectives.....................................................................................................7
1.2
Study Design ..........................................................................................................7
1.3
Sample Size Estimation..........................................................................................8
1.4
Randomization and Masking...................................................................................8
1.5
Planned Interim Analysis ........................................................................................9
1.6
Criteria for Evaluations Defined in Protocol:............................................................9
1.6.1
Screen Failures ................................................................................................................... 9
1.6.2
Demographics and Background Characteristics ................................................................. 9
1.6.3
Treatment Compliance ........................................................................................................ 9
1.6.4
Efficacy Assessments.......................................................................................................... 9
1.6.5
Safety................................................................................................................................. 11
1.6.6
Other Assessment............................................................................................................. 12
1.6.7
Subject Withdrawal Criteria ............................................................................................... 12
1.7
Study Data............................................................................................................13
2
GENERAL ANALYSIS DEFINITIONS ..........................................................13
2.1
Study Eye .............................................................................................................13
2.2
Treatment Groups.................................................................................................13
2.3
Treatment Period, Visit, and Day ..........................................................................13
2.4
Definition of Baseline ............................................................................................14
2.5
Out of Window and Unscheduled Visits ................................................................14
2.6
Analysis Populations.............................................................................................14
2.6.1
Screened Population ......................................................................................................... 14
2.6.2
Intent-to-Treat (ITT) Population......................................................................................... 14
2.6.3
Per Protocol (PP) Population............................................................................................. 14
2.6.4
Safety Population .............................................................................................................. 14
2.7
Unit of Analysis.....................................................................................................14
2.8
Definition of Subgroups.........................................................................................15
2.9
Descriptive Summaries.........................................................................................15
3
SUBJECT INFORMATION............................................................................16
3.1
Disposition Information .........................................................................................16
3.2
Study Visits...........................................................................................................16
3.3
Demographics and Baseline Characteristics.........................................................16
3.4
Medical and Ocular History...................................................................................16
3.5
Pregnancy Status .................................................................................................16
3.6
Protocol Deviations...............................................................................................16
4
TREATMENTS AND MEDICATIONS ...........................................................17
4.1
Prior Medications..................................................................................................17
4.2
Concomitant Medications......................................................................................17
4.3
Extent of Exposure ...............................................................................................17
4.3.1
Extent of Exposure to Run-in Study Medication................................................................ 17
4.3.2
Extent of Exposure to Randomized Study Medication ...................................................... 17
.
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4.4
Artificial Tears.......................................................................................................17
5
EFFICACY.....................................................................................................19
5.1
Efficacy Endpoints ................................................................................................19
5.1.1
Primary Efficacy Endpoint ................................................................................................. 19
5.1.2
Secondary Efficacy Endpoints........................................................................................... 19
5.2
Type 1 Error Control for Multiple Tests..................................................................19
5.3
Handling of Missing Data......................................................................................19
5.4
Methods of Efficacy Analysis ................................................................................19
5.5
Approaches to Efficacy Analyses..........................................................................21
6
SAFETY ........................................................................................................23
6.1
Adverse Events.....................................................................................................23
6.2
Visual Acuity.........................................................................................................23
6.3
Intraocular Pressure..............................................................................................23
6.4
Slit-Lamp Examination..........................................................................................24
6.5
Dilated Fundus Examination .................................................................................24
7
OTHER ASSESSMENT ................................................................................24
8
CHANGES FROM PROTOCOL....................................................................25
REFERENCES ..............................................................................................26
9
TABLES, LISTING, FIGURES ......................................................................27
9.1
List of Tables ........................................................................................................27
9.2
List of Listings.......................................................................................................29
9.3
List of Figures.......................................................................................................29
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S ......................
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.. .................
.......
............................
..
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......... ..........
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AMEMDMENT HISTORY
None


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LIST OF ABBREVIATIONS
Abbreviation
Term
AE
adverse event
ANCOVA
analysis of covariance
BCVA
best-corrected visual acuity
BID
twice daily
CSR
clinical study report
DED
dry eye disease
eCRF
electronic case report form
IOP
Intraocular Pressure
IP
investigational product
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model for repeated measures
NE
Non-Study Eye
OD
right eye
OS
left eye
OU
both eyes
PP
Per Protocol
PT
Preferred Term
SAE
Serious adverse event
SAF
Safety Population
SANDE
Symptom Assessment in Dry Eye
SAP
statistical analysis plan
SCRN
Screened Population
SD
standard deviation
SE
Study Eye
SOC
System Organ Class
SUD
single-use dose
TBUT
tear break-up time
TEAE
Treatment-emergent AEs
TFLs
Tables, Figures, and Listings
VAS
visual analogue scale
WHO-DD
World Health Organization-Drug Dictionary
e System
stem
forward
Regulatory Activ
ulatory A
eated measures
d measu
col
d Term
rm
s adverse event
verse ev
ety Po
Population
pulation
ymptom Assessm
om Assessm
statistical analysi
tatistical analys
Screened 
reened Popu
Popu
standard dev
da
dy Eye
y E
m O


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1
INTRODUCTION
This statistical analysis plan (SAP) describes the final statistical analysis for
subject information, efficacy data, and safety data to be done for the study 
entitled “A Phase 2, Multicenter, Double-Masked, Randomized, Vehicle-
Controlled, Parallel-Group, Dose-Response Study of SDP-4 Ophthalmic Solution 
in Subjects with Dry Eye Disease (DED)” (Date Amendment 1: 03APR2019).
Mock shells are also produced as a separate working document to facilitate 
programming of Tables, Figures, and Listings (TFLs) according to finalized SAP. 
The SAP is to be interpreted in conjunction with the protocol, and supersedes the 
statistical considerations identified in the protocol. If the final clinical study report 
(CSR) contains changes to any planned statistical analyses, the justification for 
any such differences will be fully documented in the CSR.
1.1
Study Objectives
The primary objective of this study is to assess the safety and efficacy of SDP-4 
Ophthalmic Solution in subjects with DED over a 12-week (84-day) treatment 
period.
1.2
Study Design
This is a Phase 2, multicenter, double-masked, randomized, vehicle-controlled, 
dose-response, parallel-group study designed to evaluate the ocular and 
systemic safety and efficacy of SDP-4 ophthalmic solution in subjects with 
moderate to severe DED in both eyes (OU) over a 12-week (84-day) treatment 
period. 
Subjects will be randomized to 1 of 3 concentrations (0.1%, 1.0% and 3.0%) of
SDP-4 Ophthalmic Solution or vehicle in a 1:1:1:1 ratio, with 75 subjects 
randomized to each group in parallel. All investigational products (IP) (SDP-4 
concentrations and vehicle) will be provided in single-use dose (SUD) containers 
seal packed into foil pouches. 
The IP will be administered via topical ocular instillation, one drop per eye, twice 
daily (BID) for 12 weeks (84 days). Both eyes will be treated. A 2-week 
screening/run-in period on BID vehicle will precede the 12-week randomized 
treatment period.
Subjects must have a Symptom Assessment in Dry Eye (SANDE) total score of 
40 at Visit 1/Screening and Visit 2/Day 1 to enter the trial. The study will consist 
of 7 clinic visits, 2 visits during the screening period and 5 on treatment visits: 
Visit 1 (Day -14 ± 2/Screening Visit), followed by a 2-week run-in on BID vehicle, 
Visit 2 (Day 1/Confirmatory and Randomization Visit), Visit 3 (Day 7 ± 2), Visit 4 
(Day 14 ± 2), Visit 5 (Day 28 ± 2), Visit 6 (Day 56 ± 4) and Visit 7 (Day 84 ± 
4/End of Study Assessments).
If a subject complains of persistent dry eye symptoms, the site may provide the 
subject with unpreserved artificial tears (provided by the Sponsor), to be used 
l 
n the CS
the C
assess the 
s th
safety 
sa
ED over a 12
over a 12-wee
double
ble-masked, 
mask
up study designed
tudy des
cy of SDP
f SDP-4 ophth
4 o
D in both eyes
both eyes (OU
domized to 1 of 3
domized to 1 of
c Solution or veh
olution or veh
ch group
rou
in par
n
ehicle) wi
cle
ches


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only if necessary. The subject must return all used and unused artificial tears at 
each visit so the site can conduct accountability to assess the use of artificial 
tears. Artificial tears may not be used within 2 hours prior to any study visit.
1.3
Sample Size Estimation
A sample size of 70 subjects per treatment group will have 80% power to detect 
a treatment difference of 11.7 units in SANDE total score and 1.2 seconds in 
TBUT at Visit 7/Day 84 using a t-test with a 0.05 two-sided significance level. 
This calculation is based on the assumptions shown in Table 1. Sample size was 
derived using assumptions based on expected SANDE and TBUT values, TBUT 
being one of several secondary outcomes to be analyzed. Over-enrollment of 5 
subjects per group/20 subjects per study is planned to account for 
discontinuations.
Table 1. Sample Size Estimation 
Assumptions
SANDE
TBUT
Test significance level, 
0.050
0.050
1 or 2 sided test
2
2
Difference in means, 
1 -
2
11.684
1.192
Common standard deviation
24.500
2.500
Effect size, = |
1 -
2|/
0.477
0.477
Power (%)
80
80
n per group
70
70
1.4
Randomization and Masking
Subjects will be randomized in a 1:1:1:1 ratio to 0.1%, 1.0% or 3.0% SDP-4 
Ophthalmic Solution or vehicle in parallel groups. A randomization code for 
allocating the treatment groups will be prepared by an independent unmasked 
biostatistician not involved in the day-to-day running of the study. If subjects meet 
eligibility criteria at Screening (Visit 1/Day -14) and Visit 2/Day 1, subjects will be 
randomly assigned to investigational product (IP) at Visit 2. Clinical sites will 
utilize the Interactive Web Response System (IWRS) to randomize and assign 
kits to subjects. The assigned subject randomization number and IP kit numbers
will be recorded in the subject’s electronic case report form (eCRF). All SDP-4 
concentrations and vehicle will be dispensed in one-month supplies at Visits 2, 5,
and 6.
The study will be double-masked. Subjects, the Investigator, and all site 
personnel responsible for performing study assessments will remain masked to 
treatment assignment. 
Should it be necessary to unmask a subject’s treatment assignment in case of 
emergency, the Investigator may obtain the treatment code for a given 
randomized subject from the IWRS. The treatment code is to be obtained only if 
a medical emergency exists and knowledge of the medication being taken will 
influence the medical management of the subject.
e
SA
and Masking
Masking
omized in 
ed in a 1:1:1
a 1:1:1
n or vehicle in pa
or vehicle in p
atment groups
nt group wi
wi
nvolved in the
ved
eening 
en
est


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1.5
Planned Interim Analysis
No interim analyses are planned. 
1.6
Criteria for Evaluations Defined in Protocol:
1.6.1 Screen Failures 
A screen failure is a subject who has given informed consent and failed to meet 
the inclusion criteria or met at least 1 of the exclusion criteria, and has not been 
randomized into the study. Based on Investigator discretion and Sponsor 
approval, subjects who initially failed to meet the inclusion/exclusion criteria may 
be rescreened at a later time if their eligibility status has changed. The subject 
will retain the same subject identification number that he/she was assigned at the 
first screening.
1.6.2 Demographics and Background Characteristics
Demographic information including age, gender, race, ethnicity, and date of 
informed consent will be recorded. Clinically significant medical and ocular 
history will be documented and will include any previously diagnosed ocular 
abnormalities and ocular surgeries, including laser and non-laser procedures. All 
current medications (prescription and over-the-counter) taken at Screening, 90 
days prior to Screening, and throughout the course of the study will be recorded. 
Information regarding the dates of first and last dose, site of dosing (e.g., right 
eye (OD), left eye (OS), both eyes (OU), systemic), and the reason the 
medication is being taken must be recorded in the eCRF. A urine pregnancy test 
will be performed at Visit 1/Screening and Visit 2/Day 1 and repeated at Visit 
7/Day 84 or the Early Discontinuation Visit for women of childbearing potential
only.
1.6.3 Treatment Compliance
The amount of used and unused run-in vehicle returned at Visit 2/Day 1 and 
used and unused randomized IP returned at Visit 5/Day 28, Visit 6/Day 56, and 
Visit 7/Day 84 will be documented by site personnel and captured on eCRF to be 
used should the need arise. Additionally, the amount of used and unused artificial 
tears will be documented by site personnel starting at Visit 2 through Visit 7 if the 
artificial tears were required by the subject.
1.6.4 Efficacy Assessments
Efficacy will be measured by assessment of DED symptoms and signs. More 
details are described in the following table.
cteristics
stics
ender, race, ethni
er, race, e
cally significant m
signific
lude any
any previou
prev
ncluding laser an
ding la
and over
over-the-coun
oughout the cours
hout the 
s of first and last 
first and l
h eyes (
es (OU
OU), syst
, 
must be recorded
t be reco
t 1/Screening and
Screening
Discontinuation V
ontinuation V
Compliance
mpliance
 and unuse
d u
omized
m


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Table 2. Summary of Efficacy Assessments
Assessment
Measurements 
Visits
SANDE 
questionnaire
Frequency of symptoms: 0-100 (Rarely – All 
the time)
Severity of symptoms: 0-100 (Very mild – Very 
severe)
Total score, captured by eCRF calculated as 
the square root of the frequency score times 
the square root of the severity score: 0 - 100
All
Individual dry 
eye symptoms
rated on a 
visual 
analogue 
scale (VAS)
Itching: 0-100 (Doesn’t itch at all – Want to 
scratch my eyes out)
Foreign Body Sensation: 0-100 (Don’t feel like 
I have something in my eye – Feel like I have 
sand in my eye)
Burning/Stinging: 0-100 (Doesn’t burn/sting at 
all – Severe)
Fluctuating Vision: 0-100 (Vision is fine –
Vision constantly changes)
Eye Dryness: 0-100 (Not dry at all – Extremely 
dry)
Eye Discomfort: 0-100 (Very comfortable –
Extremely uncomfortable)
Photophobia: 0-100 (Not sensitive to light –
Extremely sensitive to light)
Eye Pain: 0-100 (No eye pain – Need pain 
medicine)
Days 1, 7, 
14, 28, 56, 
84
Tear break-up 
time (seconds)
The procedure is conducted 2 times for each eye. 
The calculated average for each eye will be 
captured by eCRF.
All
Corneal 
fluorescein 
staining
Each of the 5 areas (central, superior, 
temporal, nasal, inferior) of the cornea, graded 
on a 0-3 scale
Total summed per eye: 0 - 15
All
Slit-lamp 
examination
Conjunctival hyperemia, graded to 6 levels based 
on McMonnies photographic scale (0 – 5)
All
at all 
at a
on: 0-100 (Don’t f
100 (Do
my eye 
ye – Feel lik
F
g: 0-100 (Doesn’
100 (Do
g Vision: 0
sion: 0-100 (V
10
onstantly change
tantly ch
Dryness: 0
ess: 0-100 (N
10
)
Eye Discomfort: 0
Discomfort: 0
Extremely unco
Extremely unc
Photophobia
hotoph
Extremely
rem


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Conjunctival 
Lissamine 
Green Staining
Each of the 6 areas (Zone 1: temporal/canthal, 
Zone 2: superior mid-temporal, Zone 3: inferior 
mid-temporal, Zone 4: superior mid-nasal, 
Zone 5: inferior mid-nasal, Zone 6: 
nasal/canthal) of the conjunctiva, graded on a 
0-3 scale for each eye
Total summed per eye, excluding superior 
zones 2 and 4: 0 - 12
All
Anesthetized 
Schirmer’s 
Test (mm)
Following instillation of topical anesthetic, filter 
paper strips will be placed in both eyes inside the 
lower eyelid (conjunctival sac) at the same time. 
The eyes are closed for 5 minutes. The paper is 
then removed and the amount of moisture on 
each strip in millimeters (mm) is measured.
Screening, 
Days 1, 84
1.6.5 Safety
Safety assessments will include monitoring of adverse events (AEs), best-
corrected visual acuity (BCVA), slit-lamp examination, dilated fundus examination
and intraocular pressure.
More details are described in following table.
Table 3. Summary of Safety Assessments
Assessment
Measurements 
Visits
Adverse 
Events
AE term (verbatim and MedDRA preferred 
term and system organ class)
Location (OD, OS, OU, Non-Ocular)
Onset (date)
Resolution (date)
Severity grade (mild, moderate, severe)
Relationship to IP (not suspected, suspected)
Action taken (none, IP temporarily interrupted, 
IP permanently discontinued; concomitant 
medication taken; hospitalization/prolonged 
hospitalization; other)
Serious outcome (yes/no)
All
Best-Corrected 
Visual Acuity
logMAR per eye
All
AE term (verbati
AE term (ver
term and syste
term and syste
Location (O
oca
set (d
se
at th
at 
nutes. Th
tes. T
unt of moistur
f moistu
mm) is measured
) is measu
itoring of adverse
ng of a
lamp examinatio
mp examin
following table.
wing table
ety Assessments
Assessm
urements 
ments


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Slit-lamp 
examination
Results, abnormal findings, and clinical 
significance of abnormal findings for following 
anterior ocular structures:
Lid (negative, positive): erythema (0-3, 
CS/NCS), edema (0-3, CS/NCS), other 
(CS/NCS)
Conjunctiva (negative, positive): edema (0-
3, CS/NCS), other (CS/NCS
Cornea (negative, positive): edema (0-3, 
CS/NCS), other (CS/NCS)
Anterior chamber (negative, positive): cells 
(0-4, CS/NCS), flare (0-4, CS/NCS), other
(CS/NCS)
Iris/Pupil (negative, positive): other
(CS/NCS)
Lens status (phakic, pseudophakic, 
aphakic): lens opacity (0-4, CS/NCS) if 
phakic, posterior capsule opacity (clear, 
open, clouding, CS/NCS) if pseudophakic
All
Dilated Fundus 
Exam
Results (normal, abnormal NCS, abnormal CS, 
not done) and abnormal findings for following 
ocular structures:
Vitreous
Peripheral retina
Macula
Optic nerve
Cup-to-disc ratio
Screening, 
Day 84
Intraocular 
Pressure 
Measurement
(mmHg)
Intraocular pressure in mmHg, measured utilizing 
a Goldmann tonometer
Screening, 
Days 28, 
84
1.6.6 Other Assessment
Subjects will rate the comfort of IP instillation at Days 1, 7, 14, 28, 56, 84 
according to the following 4-point scale:
0 = No discomfort
1 = Mild discomfort
2 = Moderate discomfort
3 = Severe discomfort
1.6.7 Subject Withdrawal Criteria
The following are the criteria for considering withdrawal from the study:
ocular p
cula
mal, abnormal NC
abnormal
nd abnormal 
bnorm
find
uctures:
res:
Vitreous
us
Peripheral retin
eripheral retin
Macula
acula
O
4, C
, C
positive)
ve : other
oth
akic, pseudophak
pseudo
s opacity (0
acity (0-4, CS
terior capsule opa
r capsu
uding, CS/NCS
, CS/
) if
ptic nerve
ptic nerve
Cup
Cup-to
t -d
man


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Withdrawal of subject consent. The subject may request for any reason at 
any time to be withdrawn from the study.
The Sponsor terminates the study.
If a subject withdraws from the study, the reason for withdrawal will be recorded 
in the eCRF.
If a study subject fails to attend a study visit at any point during the study period, 
every effort should be made to keep the subject in the study and conduct all 
study visits as scheduled; all attempts to contact the subject must be 
documented. 
1.7
Study Data
The study data to be analyzed include all clinical data captured by eCRF. The 
eCRF database will be locked for the final analyses.
2
GENERAL ANALYSIS DEFINITIONS
All analysis dataset preparations and statistical analyses will be performed using 
SAS® version 9.4 or higher. No imputation will be performed for missing data 
unless stated otherwise. Listings for CSR Appendix 16.2 will include, as a 
minimum, all the subject data points to be used for analyses. Data listings will be 
provided for all subjects with data available.
2.1
Study Eye
Based on the protocol, for subjects with a qualifying SANDE score who meet all 
other inclusion/exclusion criteria, the eye with the lower TBUT at Visit 2/Day 1 will 
be designated as the study eye. In the event both eyes have the same TBUT 
scores, the eye with the lower Schirmer’s test score will be designated as the 
study eye. If both eyes have the same TBUT and Schirmer’s test scores, the right 
eye will be designated as the study eye. 
The study eyes for analyses were based on the study eyes designated by eCRF
according to above criteria.
2.2
Treatment Groups
All the analyses will be conducted by four individual treatment groups that will be 
labelled as 0.1% SDP-4, 1.0% SDP-4, 3.0% SDP-4, and Vehicle. The subjects 
receiving SDP-4 may be pooled for data summary as appropriate, and will be 
labeled as “All SDP-4”. 
2.3
Treatment Period, Visit, and Day
The overall study consists of initial Screening, Run-In, and one Treatment Period. 
A reference date refers to the date of the first randomized IP administration. All 
efficacy and safety assessments at all visits will be assigned a day relative to this 
date. The relative day will be defined as: visit date – reference date + 1 for visits 
on or after the reference date, and visit date – reference date for visits before the 
al data c
 data
nalyses
es.
S
statistical analyse
stical ana
utation will be per
n will b
or CSR Appendix
CSR Ap
oints to 
to be 
b
used 
us
fo
ata available
available.
or subjects with a
ubjects w
on criteria, the ey
riteria, the ey
e study eye. In th
e study eye. In th
th the lower Schi
the lower Schi
eyes have the s
s have the s
ed as the s
as t
ses


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reference date.
2.4
Definition of Baseline
In general, the baseline is defined as the last assessment before the intake of the 
first randomized IP unless specifically stated otherwise. Pre-dose unscheduled 
assessments will be taken into account for baseline determination.
2.5
Out of Window and Unscheduled Visits
All scheduled assessments after first administration of randomized IP will be 
used. The protocol defined windows for scheduled visits will not be used in the 
analyses by visit.  Data will be assigned to the scheduled visit closer in time to 
the scheduled visit. Unscheduled visit data will only be used in an analysis if 
there is no other available data closer in time to a scheduled visit. Post first dose 
unscheduled assessments will be taken into account for worst-case 
determination as applicable. All unscheduled visit data will be included in data 
listings.
2.6
Analysis Populations
2.6.1 Screened Population
All subjects who were screened and signed the informed consent are included in 
the Screened Population (SCRN).
2.6.2 Intent-to-Treat (ITT) Population
The ITT population will include all randomized subjects who received IP. This 
population will be the primary population for efficacy analyses and will be used to 
summarize all efficacy variables by the treatment group as randomized.
2.6.3 Per Protocol (PP) Population
The PP population is a subset of the ITT population, which will include all 
subjects who complete the study without major protocol deviations. This 
population will be the secondary population for efficacy analyses and will be used 
to summarize a subset of efficacy variables by the treatment group as treated.
2.6.4 Safety Population
All safety endpoints will be evaluated on the Safety Population (SAF), consisting 
of all randomized subjects who received at least one dose of randomized IP and 
will be analyzed by the treatment group as treated.
All protocol deviations that occur during the study will be considered for their 
severity/impact and will be taken into consideration when subjects are assigned 
to analysis populations prior to final database lock.
A summary table of number (%) of patients in each analysis population/set will be 
provided.  
2.7
Unit of Analysis
a sc
a s
ccount for
unt fo
d visit data will b
data w
and signed the in
signed 
RN).
Population
ulation
nclude all random
de all ran
primary population
ary populatio
cy variables 
iables by 
b th
ol (PP) 
PP) Populatio
Populatio
is a subset o
su
e the stu
he
on


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In general, the unit of analysis will be study eye and non-study eye for eye-level 
measurements, and subject for subject-level measurements.  
2.8
Definition of Subgroups
No subgroup analyses are planned.
2.9
Descriptive Summaries
Summary statistics and statistical analyses will generally only be performed for 
subjects included in the relevant analysis population. For the calculation of 
summary statistics and statistical analysis, unrounded data will be used. All 
tabulated summaries will include all 4 individual treatment groups and the All 
SDP-4 group (combined from the 3 SDP-4 dosing groups) as described in
Section 2.2. For endpoints that are continuous in nature: number of observations, 
mean, median, minimum and maximum, and standard deviation (SD) values will
be presented as descriptive statistics summary for both observed values and 
change from baseline values at each scheduled visit if applicable. For endpoints 
that are categorical in nature: frequency counts and percentages will be 
presented as descriptive statistics summary at each scheduled visit if applicable. 
The number of decimal places to display for calculated data will be determined 
by the original scale of the data. Means and medians will be reported with one (1) 
additional decimal place. Standard deviation will be reported with two (2) 
additional decimal places. Minimum and maximum will be reported with the same 
number of significant digits as the method of capture.
 na
n
standard d
ndard 
ary for both ob
r both o
duled visit if appl
ed visit if a
counts and perce
nts and 
mmary
ry at each sc
at each
splay y for calculat
or calc
Means
ns and 
and media
ard deviation will
deviation
nimum and maxim
m an
as the method of
he metho


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3
SUBJECT INFORMATION
In general, all subject information will be summarized for the ITT Population 
based on randomized treatment group, unless stated otherwise.
3.1
Disposition Information 
Summaries will be provided for number and percentage of completed or 
discontinued study with the reasons of discontinuation as collected on eCRF.
3.2
Study Visits
The number and percentage of subjects completing each scheduled visit will be 
tabulated. 
3.3
Demographics and Baseline Characteristics
Descriptive statistics or frequency tabulation will be provided for age, gender, 
race, ethnicity, and iris color.
3.4
Medical and Ocular History
A summary table will be prepared for the medical history data, and one for ocular 
history data. Conditions will be categorized according to Medical Dictionary for 
Regulatory Activities (MedDRA). This table will indicate the number and 
percentage of subjects who presented with previous history overall and by 
system organ class and preferred term.
3.5
Pregnancy Status
The data for urine pregnancy testing will be presented in a listing, for female 
subjects with childbearing potential only.  
3.6
Protocol Deviations 
All reported major protocol deviations and determined exclusions from any 
analysis population(s) will be documented and included in the CSR. The number 
and percentage of subjects who met any inclusion or exclusion exceptions will be 
summarized by excepted inclusion and exclusion criteria.  
eristics
ics
n will be provide
ll be prov
for the medica
he medical hi
ategorized accord
orized a
). This table will 
his table w
presented with pr
ented w
eferred term.
red term.
s
regnancy testing w
ncy testing w
bearing potential 
earing potential
viations 
on
ocol de
co
b


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4
TREATMENTS AND MEDICATIONS
In general, all treatment parameters will be summarized for the Safety Population 
based on actual treatment group, unless stated otherwise. All reported 
medications will be coded using World Health Organization-Drug Dictionary
(WHO-DD).
4.1
Prior Medications
Summary tables will be prepared for the reported use of all non-study drugs by 
generic name (including prescribed and over the counter medications) that were 
taken prior to enrollment but that were discontinued prior to receiving the first 
administration of the randomized study treatment at Visit 2. 
4.2
Concomitant Medications
Summary tables will be prepared for the reported use of all non-study drugs by 
generic name (including prescribed and over the counter medications) that were 
taken subsequent to receiving the first administration of the randomized study 
treatment at Visit 2, regardless of when use started.
4.3
Extent of Exposure
4.3.1 Extent of Exposure to Run-in Study Medication
Extent of exposure to run-in study medication will be calculated as days on 
vehicle, defined as one plus the difference in days between the date of last 
instillation as recorded at Day 1 and the visit date at which medication was first 
dispensed (Screening). 
Overall, extent of exposure to run-in study medication will be summarized using 
descriptive statistics. Extent of exposure to run-in study medication will also be 
presented (N and %) by the following intervals: 1 to 7 days, and >7 days.
4.3.2 Extent of Exposure to Randomized Study Medication
Extent of exposure to randomized study medication is calculated as days on 
therapy, defined as one plus the difference in days between the date of last 
instillation and the date at which randomized medication was first dispensed. For 
subjects for whom the date of last dose is unknown, extent of exposure will be 
calculated based on the date of last contact.  
Overall, extent of exposure to randomized study medication will be summarized 
using descriptive statistics. Extent of exposure to randomized study medication 
will also be presented (N and %) by the following intervals: < 8 days, 8 to 28 
days, 29 to 56 days, 57 to 84 days, and > 84 days.
4.4
Artificial Tears
The amount of used and unused artificial tears will be documented by site 
personnel starting at Visit 2 through Visit 7 if the artificial tears were required by 
the subject. The number and percentage of subjects who used artificial tears at 
ported use of all 
ed use of 
over the counter m
the count
administration of 
inistratio
en use started.
se sta
un-in Study Medi
n Study M
study medication
dy medic
us the difference 
e differen
at Day 
ay 1 and the v
and t
). 
xposure 
posure to run
o run-ini
ics. Extent of exp
Extent of exp
%) by the follo
y t
re to 
re


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least once during the study will be tabulated. Among subjects who used artificial 
tears at least once during the study, the overall amount of used artificial tears will 
be summarized using descriptive statistics.


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5
EFFICACY
5.1
Efficacy Endpoints
5.1.1 Primary Efficacy Endpoint
Mean change from baseline in total SANDE score at Visit 7/Day 84
5.1.2 Secondary Efficacy Endpoints
Mean and mean change from baseline at each visit for each of the 
following evaluations:
Conjunctival lissamine green staining (combined and each zone)
Corneal fluorescein staining (combined and each zone)
TBUT 
Anesthetized Schirmer’s test at Visit 7/Day 84
Conjunctival hyperemia
Individual symptom VAS scores, separately for each symptom
SANDE
Mean and mean change from baseline in total SANDE score at 
each visit, excluding Visit 7/Day 84
Mean and mean change from baseline in SANDE severity score 
at each visit
Mean and mean change from baseline in SANDE frequency 
score at each visit
5.2
Type 1 Error Control for Multiple Tests
In order to minimize the impact of multiplicity in this dose-response study, a 
gatekeeping procedure will be followed to conduct the following analyses in a 
hierarchical order:
1. Primary (SANDE) high concentration vs. vehicle 
2. Primary (SANDE) middle concentration vs. vehicle 
3. Primary (SANDE) low concentration vs. vehicle 
The comparisons will be conducted at 
= 0.05.  Each comparison will be made 
in order until p > (exceeds) 0.05.  If p 
0.05, the comparison is statistically 
significant and testing is continued.
5.3
Handling of Missing Data
For efficacy analyses, use of a mixed model for repeated measures (MMRM)
approach requires only that data are missing at random so that no other method 
will be employed to deal with missing data. It may be necessary to test whether 
this assumption applies to the data set. For sensitivity analysis the last 
observation carried forward (LOCF) will be used for missing data imputation.
5.4
Methods of Efficacy Analysis
t Visit 7
Visit 
cores, separately
es, separa
ge from baseline 
om basel
sit 7/Day 84
/Day 8
hange from base
ge from b
an cha
hange from b
nge fro
isit
ntrol for Multiple
for Multipl
the impact of mul
mpact of mul
dure will be follow
ure will be follo
:
SANDE) high
DE
NDE) m
DE
E)


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Each endpoint will be summarized for each visit where that endpoint is assessed.  
Where appropriate, the change from baseline value will be used to assess the 
difference between each concentration of SDP-4 and vehicle.  
Change from baseline endpoints will be analyzed using MMRM analysis with 
terms for baseline measurement, treatment, visit, and treatment-by-visit 
interaction. An unstructured variance-covariance matrix will be employed to 
account for within subject correlation in the repeated measures. In case of model 
non-convergence a simpler variance-covariance matrix will be employed. Within 
treatment estimate of least square mean change from baseline and associated
standard error will be provided by visit. Also, estimate of difference in least 
square means of change from baseline between each SDP-4 group and Vehicle 
(i.e. the estimand) and associated standard error and 95% confidence interval 
will be provided by visit. 
The MMRM analysis is based on a standard linear mixed model, defined as:
Y = µ + Bi + Tt + Vj + TVtj + itj
Where Y denotes an outcome variable, µ is the overall mean, Bi is the baseline
value, Tt is the fixed effect due to tth treatment group, Vj is the fixed effect due to 
the jth visit, TVtj is the treatment by visit interaction, and itj is the measurement 
error associated with the individual subject.
Following is a sample SAS code for MMRM analysis:
proc sort data=datain; by subject_id visit;
ods select diffs lsmeans;
proc mixed data=datain method=reml;
class subject_id treat visit;
  model cfb_var= baseline treat visit visit*treat / solution rcorr;
  repeated visit / type=un subject=subject_id rcorr;
  lsmeans visit*treat / pdiff;
run; quit;
For variables with only one post-baseline assessments (e.g. Schirmer’s test), 
change from baseline will be analyzed utilizing analysis of covariance (ANCOVA) 
with terms for baseline measurement and treatment.  The mathematical form of 
the ANCOVA model is also based on a standard linear mixed model, defined as:
Y = µ + Bi + Tt + it
Where Y denotes an outcome variable, µ is the overall mean, Bi is the baseline
value, Tt is the fixed effect due to tth treatment group, and it is the measurement 
error associated with the individual subject.
Following is a sample SAS code for ANCOVA analysis:
proc sort data=datain; by subject_id;
ods select diffs lsmeans;
proc mixed data=datain method=reml;
class treat;
a
d linear mixed m
ar mixed
e, µ is the overall 
s the ove
treatment group,
tment g
y visit interaction, 
it inter
ual subject.
subject.
ode for MMRM an
or MM
in; by subject_id 
y subject
means;
ans;
a=datain method=
atain method
ct_id treat
reat visit;
visi
_var= ba
ar= baseline 
seline tre
tr
visit / type=un s
/ type=un s
it*treat
eat / pdi


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Statistical Analysis Plan: Final Version 1.0, 24 June 2019
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model cfb_var= baseline treat / solution rcorr;
lsmeans treat / pdiff;
run; quit;
5.5
Approaches to Efficacy Analyses
The following table describes detailed approaches to analyze each specific 
efficacy endpoint.  
Table 4. Summary of efficacy analyses
Endpoint
Type
Statistical 
Method
Population
(Eye)
Missing 
Data 
Handling
Mean change from 
baseline in total SANDE 
score at Visit 7/Day 84
(including all post-
baseline visits in the 
analysis)
Primary
MMRM
ITT
MMRM
Supportive
MMRM
PP
MMRM
Sensitivity
MMRM
ITT
LOCF
Mean change from 
baseline at each visit for
TBUT (including all post-
baseline visits in the 
analysis)
Secondary
MMRM
ITT (SE&NE)
MMRM
Mean change from 
baseline at each visit for 
conjunctival lissamine 
green staining 
(combined and each 
zone)
Secondary
MMRM
ITT (SE&NE)
MMRM
Mean change from 
baseline at each visit for 
corneal fluorescein 
staining (combined and 
each zone)
Secondary
MMRM
ITT (SE&NE)
MMRM
Mean change from 
baseline at Day 84 for 
Schirmer’s test
Secondary
ANCOVA
ITT (SE&NE)
No 
imputation
Mean change from 
baseline at each visit for
conjunctival hyperemia
Secondary
MMRM
ITT (SE&NE)
MMRM
RM
ITT
ITT
MMRM
RM
PP
P
MMRM
MMRM
IT
ondary
ary
MMRM
MM
sit for 
t for 
mine 
e
Secondary
Secondary


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Mean change from 
baseline at each visit for
Individual symptom VAS 
scores, separately for 
each symptom
Secondary
MMRM
ITT
MMRM
Mean change from 
baseline in SANDE 
severity score at each 
visit
Secondary
MMRM
ITT
MMRM
Mean change from 
baseline in SANDE 
frequency score at each 
visit
Secondary
MMRM
ITT
MMRM
Note: SE = Study Eye, NE = Non-Study Eye
Eye


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6
SAFETY 
All safety parameters will be summarized based on the actual treatment group 
based on the Safety Population. Subject is the unit of analysis for all safety 
variables. Subject-level data will be generated for eye-specific safety variables as 
described below.
6.1
Adverse Events
Treatment-emergent adverse events (TEAEs) are those with onset after 
randomization or if occurring prior to randomization, worsened after 
randomization. Only treatment-emergent events will be summarized. All events in 
the clinical database regardless of when they occurred will be provided in data 
listings. Adverse events will be classified according to the MedDRA to the levels 
of System Organ Class (SOC) and primary Preferred Term (PT).
Run-in AEs that occurred during the run-in period on vehicle (Note: subjects may 
be on run-in vehicle for up to 16 days, but no less than 12 days) will be 
summarized separately.
An overall summary will be presented which gives the number and percentage of 
subjects that experienced any TEAE, experienced any treatment related TEAE, 
permanently discontinued treatment due to a TEAE, interrupted treatment due to 
a TEAE, experienced a treatment emergent SAE, and that died.
The number and percentage of subjects experiencing one or more events will be 
tabulated separately for ocular AEs and non-ocular AEs by SOC and PT. In 
addition similar tables by SOC and PT will be displayed further by maximum 
severity, and by closest relationship to treatment.
In summary tables for ocular adverse events, AEs occurring in both eyes will be 
summarized once at the greater severity or closer relationship to study drug. 
The number of and percentage of subjects experiencing AEs leading to 
premature discontinuation from the study will be tabulated and listed.
A listing of serious TEAEs will be also provided.
A glossary listing that shows the verbatim terms assigned to each SOC and PT 
will be provided. 
6.2
Visual Acuity
Descriptive statistics of the observed and change from baseline BCVA expressed 
as equivalent logMAR will be tabulated for each eye (study eye and non-study 
eye) by visit. In addition, the number and percentage of subjects with a 
3-line 
decrease from baseline in BCVA will be tabulated for each eye (study eye and 
non-study eye) by visit and at any visit.
6.3
Intraocular Pressure
cur
ding to t
ing to
Preferred Term
rred Ter
n period on vehicl
riod on ve
ut no less than 1
o less th
2
ted which gives th
which giv
EAE, experienced
experi
ment due to a TE
nt due to a
ment emergent S
emerg
ge of subjects ex
f subjects
ocular 
lar AEs 
AEs and n
a
by SOC and PT 
SOC and PT 
sest relationship t
sest relationsh
s for ocular adve
r ocular adve
at the greater
e 
centag
e


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Page | 24
Descriptive statistics of the observed and change from baseline IOP will be 
tabulated for each eye (study eye and non-study eye) by visit. In addition, the
number and percentage of subjects with 
crease from baseline in 
IOP will be tabulated for each eye (study eye and non-study eye) by visit and at 
any visit.
6.4
Slit-Lamp Examination
Observed results will be summarized for each anterior ocular structure (Lid, 
Conjunctiva, Cornea, Anterior chamber, Iris/Pupil, Lens status) in frequency 
tables for each eye (study eye and non-study eye) by visit. 
6.5
Dilated Fundus Examination
Observed results will be summarized for each structure (i.e. vitreous, optic nerve, 
macula, peripheral retina, cup-to disc ratio) in frequency tables for each eye 
(study eye and non-study eye) by visit. 
7
OTHER ASSESSMENT
IP comfort assessment results will be summarized in a frequency table by visit. 
structur
ructu
frequency ta
quency 
e summarized
mmariz
in


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8
CHANGES FROM PROTOCOL
Following analyses have been removed from hierarchy of analyses as 
described in protocol Section 9.5.3 Efficacy analysis:
o
Secondary (TBUT) high concentration vs. vehicle
o
Secondary (TBUT) middle concentration vs. vehicle
o
Secondary (TBUT) low concentration vs. vehicle
IP comfort assessment has been disregarded as one of the safety 
assessments.


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REFERENCES
None


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9
TABLES, LISTING, FIGURES
9.1
List of Tables
Table 
Number
Table Title
Study 
Population
14.1.1
Analysis Populations
ITT
14.1.2.1
Subject Disposition
ITT
14.1.2.2
Subject Disposition by Site
ITT
14.1.3
Visit Participation
ITT
14.1.4
Demographics
ITT
14.1.5.1
Medical History
ITT
14.1.5.2
Ocular History
ITT
14.1.6.1
Prior Medications (Ocular and Non-ocular)
SAF
14.1.6.2
Concomitant Medications (Ocular and Non-ocular)
SAF
14.1.7.1
Treatment Exposure
SAF
14.1.7.2
Treatment of Artificial Tears
SAF
14.1.8.1
Major Protocol Deviations
ITT
14.1.8.2
Inclusion and Exclusion Exceptions
ITT
14.2.1.1.1
Mean Change from Baseline in Total SANDE Score
ITT
14.2.1.1.2
Mean Change from Baseline in Total SANDE Score
PP
14.2.1.1.3
Mean Change from Baseline in Total SANDE Score (LOCF)
ITT
14.2.1.2.1
Mean Change from Baseline in SANDE Severity Score
ITT
14.2.1.2.2
Mean Change from Baseline in SANDE Severity Score
PP
14.2.1.3.1
Mean Change from Baseline in SANDE Frequency Score
ITT
14.2.1.3.2
Mean Change from Baseline in SANDE Frequency Score
PP
14.2.2.1
Mean Change from Baseline in Tear Break-up Time - Study Eye
ITT
14.2.2.2
Mean Change from Baseline in Tear Break-up Time - Non-Study 
Eye
ITT
14.2.3
Mean Change from Baseline in Individual Symptom VAS Scores
ITT
14.2.4.1
Mean Change from Baseline in Conjunctival Lissamine Green 
Staining - Study Eye
ITT
14.2.4.2
Mean Change from Baseline in Conjunctival Lissamine Green 
Staining - Non-Study Eye
ITT
14.2.5.1
Mean Change from Baseline in Corneal Fluorescein Staining -
Study Eye
ITT
14.2.5.2
Mean Change from Baseline in Corneal Fluorescein Staining -
Non-Study Eye
ITT
14.2.6.1
Mean Change from Baseline in Conjunctival Hyperemia - Study 
Eye
ITT
14.2.6.2
Mean Change from Baseline in Conjunctival Hyperemia - Non-
Study Eye
ITT
14.2.7.1
Mean Change from Baseline in Schirmer’s Test - Study Eye
ITT
14.2.7.2
Mean Change from Baseline in Schirmer’s Test - Non-Study Eye
ITT
14.3.1.1
Summary of Treatment-Emergent Adverse Events
SAF
14.3.1.2.1
Frequency of Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term
SAF
14.3.1.2.2
Frequency of Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term
SAF
r)
Non-ocular)
ocular
ptions
e in Total SANDE Sc
Total SA
ine in Total SANDE 
n Total SAN
seline in Total SAND
in Total
Baseline in SANDE S
ine in SAN
m Baseline in SANDE
eline i
om Baseline in SAN
aseline in S
from Baseline in SA
Baseline
ge from Baseline in T
om Baseline in
ange from Baseline i
from Baseline i
Change from Basel
hange from Basel
n Change from Bas
ange from Bas
- Study Eye
tudy
nge from
e f
St


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14.3.1.3.1
Frequency of Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term and by Maximum 
Severity
SAF
14.3.1.3.2
Frequency of Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term and by Maximum 
Severity
SAF
14.3.1.4.1
Frequency of Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term and by Closest 
Relatedness
SAF
14.3.1.4.2
Frequency of Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term and by Closest 
Relatedness
SAF
14.3.1.5.1
Frequency of Ocular Treatment-Emergent Adverse Events Leading 
to Permanent Withdrawal of Study Medication by System Organ 
Class and Preferred Term
SAF
14.3.1.5.2
Frequency of Non-Ocular Treatment-Emergent Adverse Events 
Leading to Permanent Withdrawal of Study Medication by System 
Organ Class and Preferred Term
SAF
14.3.1.6.1
Frequency of Ocular Run-in Adverse Events by System Organ 
Class and Preferred Term
SAF
14.3.1.6.2
Frequency of Non-Ocular Run-in Adverse Events by System Organ 
Class and Preferred Term
SAF
14.3.1.7
Adverse Event - MedDRA Glossary
SAF
14.3.2
Listing of Serious Treatment Emergent Adverse Events
SAF
14.3.3.1
Mean Change from Baseline in Visual Acuity - Study Eye
SAF
14.3.3.2
Categorized Change from Baseline in Visual Acuity - Study Eye
SAF
14.3.3.3
Mean Change from Baseline in Visual Acuity - Non-Study Eye
SAF
14.3.3.4
Categorized Change from Baseline in Visual Acuity - Non-Study 
Eye
SAF
14.3.4.1
Mean Change from Baseline in Intraocular Pressure - Study Eye
SAF
14.3.4.2
Categorized Change from Baseline in Intraocular Pressure - Study 
Eye
SAF
14.3.4.3
Mean Change from Baseline in Intraocular Pressure - Non-Study 
Eye
SAF
14.3.4.4
Categorized Change from Baseline in Intraocular Pressure - Non-
Study Eye
SAF
14.3.5.1
Slit-Lamp Examination Results - Study Eye
SAF
14.3.5.2
Slit-Lamp Examination Results - Non-Study Eye
SAF
14.3.6.1
Dilated Fundus Examination Results - Study Eye
SAF
14.3.6.2
Dilated Fundus Examination Results - Non-Study Eye
SAF
14.3.7
Investigational Product Comfort Assessment
SAF
rgent 
Medicat
vents by Sy
Adverse Eve
ossary
Emerge
ine in Visua
om Baseli
Baseline in 
e from Ba
from Baseline i
ized Change from
nge from
C


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9.2
List of Listings
Listing 
Number
Listing Title
Study 
Population
16.1.7
Randomization
ITT
16.2.1.1
Screen Failures
SCRN
16.2.1.2
Subject Disposition
ITT
16.2.1.3
Analysis Visits
ITT
16.2.2.1
Inclusion and Exclusion Criteria Exceptions
ITT
16.2.2.2
Protocol Deviations
ITT
16.2.3
Analysis Populations
ITT
16.2.4.1
Demographics
ITT
16.2.4.2.1
Significant Medical History
ITT
16.2.4.2.2
Significant Ocular History
ITT
16.2.4.3.1
Prior Ocular Medications
SAF
16.2.4.3.2
Concomitant Ocular Medications
SAF
16.2.4.3.3
Prior Non-Ocular Medications
SAF
16.2.4.3.4
Concomitant Non-Ocular Medications
SAF
16.2.5.1
Run-In Exposure
SAF
16.2.5.2
Run-In Medication Dispensation and Return
SAF
16.2.5.3
Treatment Exposure
SAF
16.2.5.4
Treatment Medication Dispensation and Return
SAF
16.2.5.5
Artificial Tears
SAF
16.2.6.1
SANDE Symptom Score
ITT
16.2.6.2
Tear Break-up Time 
ITT
16.2.6.3
Individual Symptom VAS Scores
ITT
16.2.6.4
Conjunctival Lissamine Green Staining Results
ITT
16.2.6.5
Corneal Fluorescein Staining Results
ITT
16.2.6.6
Conjunctival Hyperemia Results
ITT
16.2.6.7
Schirmer’s Test Results
ITT
16.2.7.1
Treatment Emergent Adverse Events
SAF
16.2.7.2
Run-in Adverse Events
SAF
16.2.8.1
Visual Acuity
SAF
16.2.8.2
Intraocular Pressure
SAF
16.2.8.3
Slit-Lamp Examination
SAF
16.2.8.4
Dilated Fundus Examination
SAF
16.2.8.5
Investigational Product Comfort Assessment
SAF
16.2.8.6
Urine Pregnancy Test
SAF
16.2.8.7
General Comments
SAF
9.3
List of Figures
None
ons
ons
Medications
dications
ispensation and 
ensatio
re
cation Dispensatio
n Dispens
mptom Score
m Score
k-up Time 
p Time 
al Symptom 
mptom VAS 
VAS 
nctival Lissamine 
nctival Lissam
neal Fluorescein S
al Fluorescein S
junctival Hypere
tival Hy
er’s Test R
s Te
Eme
E