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)
Phase: PHASE2
Conditions: Dry Eye
Sponsor: Silk Technologies, Ltd.

Silk Technologies, Ltd.  
SDP-4 Ophthalmic Solution 
Clinical Trial Protocol: SDP-4-CS201 
 
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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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Silk Technologies, Ltd. 
Clinical Trial Protocol: SDP-4-CS201 
 
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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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