Clinical trial NCT05700422
Conditions: Sjogren's Syndrome Dry Eye
Sponsor: University of Pennsylvania
Start date: 2023-05-01; Completion date: 2023-08-31
Enrollment: 39 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will investigate how well OC-01 (varenicline) nasal spray can treat the signs and symptoms of dry eye disease in those Sjogren's Syndrome. Patients at least 18 years old with moderate-to-severe Sjogren's dry eye disease may be eligible for this study. If you are eligible to participate in the study and you decide to join, there will be 3 study visits over approximately 1 month. You will also self-administer the nasal spray at home every day, 2 times a day during this month.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Varenicline Nasal Spray
Intervention descriptions: intervention 1: OC-01 (varenicline solution) 0.03 mg nasal spray

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Protocol 851655– The SENSation Study 
OC-01 (varenicline solution) Nasal Spray 
 
 
 
SENSation Study Revision 04/2023 
 
 


 
Protocol 851655- The SENSation Study 
OC-01 (varenicline solution) Nasal Spray 
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CLINICAL RESEARCH PROTOCOL 
 
INVESTIGATIONAL 
PRODUCT(S): 
 
OC-01 (varenicline solution) Nasal Spray 
STUDY 
NUMBER(S): 
IRB 
Number 
851655 
Other 
Protocol 
Identifiers  
N/A 
PROTOCOL(S) TITLE: 
A Single-arm Investigator Initiated Study to Evaluate the 
Efficacy of OC-01 (varenicline solution) Nasal Spray on signs 
and symptoms of Dry Eye Disease in subjects with Sjogren’s 
Syndrome  
 
NUMBER: 
NCT05700422 
REGULATORY 
SPONSOR: 
 
"[Insert Sponsor Name and Address Here]"  
FUNDING SPONSOR(S): 
Oyster Point Pharma 
MEDICAL DIRECTOR 
 
Mina Massaro-Giordano, MD 
ORIGINAL PROTOCOL 
DATE: 
February 16, 2023 
VERSION NUMBER: 
v.2 
VERSION DATE:  
April 27, 2023 
 
 


 
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1 
Study Summary .......................................................................................................... 8 
1.1 
Synopsis .................................................................................................................. 8 
1.2 
Key Roles and Study Governance ..................................................................... 10 
1.3 Schema ....................................................................................................................... 11 
2 
Introduction and RationalE .................................................................................... 13 
2.1 
Study Rationale ................................................................................................... 13 
2.2 
Background .......................................................................................................... 13 
2.2.1 
Pharmacokinetics, Pharmacodynamics and Toxicology ........................... 13 
2.2.2 
Assessment for Potential Study Products Drug-Drug, Drug-Device, 
Device-Device Interactions ........................................................................... 16 
2.2.3 
Clinical Adverse Event Profile ..................................................................... 17 
2.2.4 
Dosing Rationale ........................................................................................... 17 
2.3 
Risk/Benefit Assessment ..................................................................................... 17 
2.3.1 
Known Potential Risks .................................................................................. 17 
2.3.2 
Known Potential Benefits ............................................................................. 17 
2.3.3 
Assessment of Potential Risks and Benefits ................................................ 17 
3 
Study Objectives and Endpoints............................................................................. 19 
4 
Study Plan ................................................................................................................. 20 
4.1 
Study Design ........................................................................................................ 20 
4.2 
Scientific Rationale for Study Design ................................................................ 20 
4.3 
Justification for Dose .......................................................................................... 20 
4.4 
End of Study Definition ...................................................................................... 20 
5 
Study Population ...................................................................................................... 21 
5.1 
Inclusion Criteria ................................................................................................ 21 
5.2 
Exclusion Criteria ............................................................................................... 21 
5.3 
Lifestyle Considerations ..................................................................................... 21 
5.4 
Screen Failures .................................................................................................... 22 
5.5 
Strategies for Recruitment and Retention ........................................................ 23 
6 
Study Intervention ................................................................................................... 24 
6.1 
Study Intervention(s) Administration ............................................................... 24 
6.1.1 
Study Intervention Description .................................................................... 24 
6.1.2 
Dosing and Administration .......................................................................... 25 
6.2 
Preparation/Handling/Storage/Accountability................................................. 25 
6.2.1 
Acquisition and accountability .................................................................... 25 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................ 25 
6.2.3 
Product Storage and Stability ...................................................................... 25 
6.2.4 
Preparation .................................................................................................... 25 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................. 35 
6.4 
Study Intervention Compliance ......................................................................... 35 
6.5 
Concomitant Therapy ......................................................................................... 35 
6.5.1 
Rescue Medicine ............................................................................................ 35 
 


 
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7 
Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal ................................................................................... 36 
7.1 
Discontinuation of Study Intervention .............................................................. 36 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................... 36 
7.3 
Lost To Follow-Up .............................................................................................. 37 
8 
Study Assessment and Procedures ......................................................................... 38 
8.1 
Efficacy Assessments ........................................................................................... 38 
8.2 
Safety and Other Assessments ........................................................................... 38 
8.3 
Adverse Events and Serious Adverse Events ................................................... 39 
8.3.1 
Definition of Adverse Events (AE) .............................................................. 39 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................... 39 
8.3.3 
Unanticipated Adverse Device Effect (UADE) ........................................... 40 
8.3.4 
Classification of an Adverse Event .............................................................. 40 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up ......... 41 
8.3.6 
Adverse Event Reporting ............................................................................. 42 
8.3.7 
Serious Adverse Event Reporting ................................................................ 42 
8.3.8 
Reporting Events to Participants ................................................................. 43 
8.3.9 
Events of Special Interest ............................................................................. 43 
8.3.10 
Reporting of Pregnancy ................................................................................ 43 
8.4 
Unanticipated Problems ..................................................................................... 43 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................ 43 
8.4.2 
Unanticipated Problem Reporting............................................................... 44 
8.4.3 
Reporting Unanticipated Problems To Participants ................................. 45 
8.5 
Device Reporting ................................................................................................. 45 
9 
Statistical Considerations ........................................................................................ 45 
9.1 
Statistical Hypotheses ......................................................................................... 45 
9.2 
Sample Size Determination ................................................................................ 45 
9.3 
Populations for Analyses .................................................................................... 45 
9.4 
Statistical Analyses .............................................................................................. 45 
9.4.1 
General Approach ......................................................................................... 45 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................ 45 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................... 46 
9.4.4 
Safety Analyses .............................................................................................. 46 
9.4.5 
Baseline Descriptive Statistics ...................................................................... 46 
9.4.6 
Planned Interim Analyses............................................................................. 46 
9.4.7 
Sub-Group Analyses ..................................................................................... 46 
9.4.8 
Tabulation of Individual Participant Data ................................................. 46 
9.4.9 
Exploratory Analyses .................................................................................... 46 
10 Supporting Documentation and Operational Considerations ............................. 47 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................. 47 
10.1.1 
Informed Consent Process ............................................................................ 47 


 
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10.1.2 
Study Discontinuation and Closure ............................................................. 47 
10.1.3 
Confidentiality and Privacy ......................................................................... 48 
10.1.4 
Future Use of Stored Specimens and Data ................................................. 49 
10.1.5 
Safety Oversight ............................................................................................ 49 
10.1.6 
Clinical Monitoring ....................................................................................... 49 
10.1.7 
Quality Assurance and Quality Control ..................................................... 49 
10.1.8 
Data Handling and Record Keeping ........................................................... 50 
10.1.9 
Protocol Deviations ....................................................................................... 51 
10.1.10 
Publication and Data Sharing Policy........................................................... 51 
10.1.11 
Conflict of Interest Policy ............................................................................. 51 
10.2 
Additional Considerations .................................................................................. 52 
10.3 
Protocol Amendment History ............................................................................ 52 
11 References ................................................................................................................. 52 
12 APPENDIX ............................................................................................................... 52 
12.1 
Schedule of Activities (SoA) ............................................................................... 56 
 
 
 
 
 


 
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PRINCIPAL INVESTIGATOR SIGNATURE 
 
STUDY 
SPONSOR: 
Oyster Point Pharma 
STUDY TITLE: 
A Single-arm Investigator Initiated Study to Evaluate the Efficacy of OC-01 
(varenicline solution) Nasal Spray on signs and symptoms of Dry Eye 
Disease in subjects with moderate to severe Sjogren’s Syndrome 
STUDY ID 
PROTOCOL 
VERSION 
851655 
v1.0 
I have read the referenced protocol. I agree to conduct the study in accordance to this protocol, in 
compliance with the Declaration of Helsinki, Good Clinical Practices (GCP), and all applicable 
regulatory requirements and guidelines. 
Principal 
Investigator Name  
Giacomina Massaro-
Giordano, MD 
 
Signature 
 
Affiliation: 
Scheie Eye Institute 
 
Date 
 
 
 
 
 
 
 


 
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Abbreviations 
AE 
Adverse Event 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act  
IRB 
Institutional Review Board 
SS 
Sjogren’s Syndrome  
 
 
 


 
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1 STUDY SUMMARY 
1.1 
Synopsis 
Title:  
A Single-arm Investigator Initiated Study to Evaluate the Efficacy of OC-
01 (varenicline solution) Nasal Spray on signs and symptoms of Dry Eye 
Disease in subjects with moderate to severe Sjogren’s Syndrome 
Short Title: 
The SENSation Study 
Study 
Description:  
 
Approximately 40 subjects at least 18 years of age with moderate to 
severe Sjogrens syndrome with confirmed diagnosis of dry eye disease 
(defined as Schirmers test score 10 mm) will receive an application of 
OC-01 (varenicline solution) 0.03 mg nasal spray twice daily (BID) for 
28 days and will be compared to historical control. The study 
hypothesizes that SS patients treated with OC-01 will demonstrate 
significant improvement in their dry eye symptoms. 
 
Objectives:  
To evaluate the safety and effectiveness of OC-01 (varenicline solution) 
nasal spray among subjects with dry eye disease and moderate to severe 
Sjogren’s Syndrome 
 
Primary 
Endpoint:  
 Mean change in cornea and conjunctival staining from baseline to 
Day 28 
 Mean change in eye dryness score as measured by the Visual 
Analogue Scale (VAS) from baseline to Day 28 
Secondary 
Endpoints: 
 Mean change in best corrected visual acuity from baseline to Day 
28 
 Mean change in dry mouth and dry nose scale as measured by 
from baseline through Day 28 
 Incidence and severity of adverse events 
 
Study 
Population: 
Sample size: n = 40 
Gender: any 


 
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Age: at least age 18yo 
Demographic group: any 
General health status: see specifics in Inclusion Criteria 
Geographic location: patients at Scheie Eye Institute in Philadelphia, PA 
 
Phase: 
Investigator-Initiated Clinical Trial  
Description of 
Sites/Facilities  
Scheie Eye Institute  
51 N 39th St.  
Philadelphia, PA 19104 
Enrolling Sites: 
Scheie Eye Institute will be the only enrolling site.  
Description of 
Study 
Intervention: 
Study Drug: OC-01 (varenicline solution) 0.03 mg nasal spray 
Dose/Route/Schedule:  
Intranasal delivery of OC-01 nasal spray twice daily (BID):   
 40 subjects will receive OC-01 (varenicline 0.03 mg) nasal spray 
for 28 days 
 
Schedule of visits: 
 Visit 1 - Screening – Day 1 
 Visit 2 - Day 14 (Virtual visit)  
 Visit 3 - Day 28 
OR possible early termination 
Study Duration: 
12 months 
Participant 
Duration: 
1 month 
 
 
 


 
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1.2 
Key Roles and Study Governance 
Sponsor 
Medical Director 
 
Mina Massaro-Giordano, MD 
Oyster Point Pharma, Inc. 
Scheie Eye Institute  
202 Carnegie Center, Suite 106, Princeton, NJ 08540 
51 N 39th St, Philadelphia PA 19104 
609-382-9032 
215-662-8100 
pshah@oysterpointrx.com 
mina@pennmedicine.upenn.edu 
 
 


 
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1.3 Schema 
Study Procedure 
Screening/ 
Baseline 
(Visit 1) 
15 minutes 
Post-
administration 
 
 
Visit 2 
 
 
Visit 3 
 
Early 
Termination 
 
Day -0 
Day 0  
Day 14 
(Virtual) 
Day 28 
 
Windows for Visits 
 
 
 
+/- 2 days 
+/- 7 days 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History and 
Concurrent Illnesses 
X 
 
X 
X 
X 
Ocular History 
X 
 
X 
X 
X 
Eligibility Criteria 
X 
 
 
 
 
Urine Pregnancy 
Test* 
X 
 
 
X 
X 
Concomitant 
Medications 
X 
 
X 
X 
X 
Intranasal Exam via 
history 
X 
 
 
 
 
Eye Dryness Score 
(0-100) as measured 
by Visual Analogue 
Scale (VAS) 
X 
 
X 
X 
X 
Nasal Dryness 
Score (0-100) as 
measured by VAS 
X 
 
X 
X 
X 
Dry Mouth Score 
(0-100) as measured 
by VAS 
X 
 
X 
X 
X 
QIDS-SR 
Questionnaire 
X 
 
X 
X 
X 
Tear Film Imager 
(obtain tear film 
thickness) 
X 
X 
 
X  
(15 mins post 
treatment) 
X 


 
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Slit Lamp 
Biomicroscopy 
X 
 
 
X 
X 
Corneal Staining 
using NEI scale & 
Conjunctival 
Staining using Van 
Bijsterveld and 
Utrecht scale  
X 
 
 
X 
X 
Schirmer’s 
Testwithout 
anesthesia 
X 
 
 
X 
X 
Tear sample 
Collection 
X 
 
 
X 
X 
Ophthalmic 
Examination (w/or 
w/o dilated fundus 
exam) 
X 
 
 
 
 
Dispense Study 
Product 
X 
 
 
 
 
Collect Study 
Product 
 
 
 
X 
X 
Adverse Events 
X 
 
X 
X 
X 
*For women of childbearing potential 


 
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2 INTRODUCTION AND RATIONALE 
2.1 
Study Rationale 
Sjögren's syndrome (SS) is a common autoimmune disease affecting about four million 
Americans. It is a systemic condition that affects the entire body, with the most common 
symptoms being dry eyes, dry mouth, fatigue and pain in the joints.  For Sjogren’s patients, 
inflammation occurs to the tear secreting glands that are responsible for tear production, thus 
resulting in chronic dry eye.  Many current treatments include artificial tears, punctal occlusion, 
and/or ophthalmic therapeutics. We hypothesize the use of OC-01 in patients who are diagnosed 
with Sjogren’s Syndrome and have confirmed dry eye disease will show beneficial improvement 
in Schirmer’s test score and corneal/conjunctival staining. 
OC-01 (varenicline solution) nasal spray 0.03mg was developed by Oyster Point Pharma and 
FDA-approved on October 15, 2021 for the treatment of signs and symptoms of dry eye disease. 
OC-01 (varenicline solution) nasal spray is believed to activate the trigeminal parasympathetic 
pathway and stimulate natural tear production to bathe the cornea in a protective layer of tear 
film. This study is testing the hypothesis that OC-01 (varenicline solution) nasal spray 0.03mg 
will improve the signs and symptoms of dry eye disease in subjects with diagnosed Sjogren’s 
syndrome.  
2.2 
Background 
The administration of OC-01 0.03 mg and 0.06 mg (varenicline solution) Nasal Spray was safe, 
well tolerated, and efficacious as assessed in the ONSET-1 study of Dry Eye Disease. The 
ONSET-1 study was a multi-center, randomized, masked vehicle-controlled trial of BID OC-01 
nasal spray administered for 28 days.  OC-01 (varenicline) Nasal Spray was safe and well-
tolerated at all concentrations assessed in the ONSET-1 clinical study. Most treatment-emergent 
AEs were mild to moderate in severity, with only 1 subject reporting a severe treatment-
emergent AE. The most common AE in all treatment groups was sneezing which was temporally 
related to the administration of the study drug and resolved within a short period of time after 
administration. Sneezing AEs were characterized as mild to moderate, with no severe AEs 
reported. 
All AEs that were suspected to be related to the study drug with the exception of AEs with each 
of the following terms; nasal dryness, nasal congestion and throat irritation were reported to be 
recovered/or resolved before study completion. Eleven ocular treatment-emergent AEs were 
reported, 7 of which were reported in the placebo group; all other AEs were classified as non-
ocular. The Investigators considered 3 of the 7 ocular TEAEs (visual acuity reduced, 
conjunctival hemorrhage, and eyelid oedema) to be possibly related to study drug, all resolved, 
and none was categorized as severe. One treatment emergent SAE (anemia) was reported and 
was considered to be unrelated to study drug. No treatment-related treatment-emergent SAEs 
were observed. No deaths occurred during the study. Visual acuity, slit-lamp biomicroscopy, 


 
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intranasal examination, and pupil diameter did not indicate clinically significant changes from 
baseline. 
The administration of OC-01 (varenicline solution) nasal spray, 0.03 mg and 0.06 mg was safe, 
well tolerated, and efficacious as assessed in the ONSET-2 study of Dry Eye Disease. The 
ONSET-2 study was a multi-center, randomized, masked vehicle-controlled trial of BID OC-01 
nasal spray administered for 28 days.  In the ONSET-2 study, the most commonly reported 
ocular treatment-emergent AE by PT was conjunctival hyperemia (4.6% and 4.5% of subjects in 
the 0.006 mg/mL and 0.06 mg OC-01 groups, respectively, and 2.8% of subjects in the placebo 
group). The incidences of other commonly reported ocular treatment-emergent AEs by PT were 
similar across the 0.03 mg OC-01, the 0.06 mg OC 01, and the placebo groups: visual acuity 
reduced (3.5%, 3.7%, and 4.4% of subjects, respectively), blepharitis (1.2%, 0.4%, and 0.4% of 
subjects, respectively), and eye irritation (0.4%, 0.4% and 1.2% of subjects, respectively).  
The incidences of the most commonly reported non-ocular treatment-emergent AEs were higher 
in the 0.03 mg and the 0.06 mg OC 01 groups compared with the placebo group: sneezing 
(95.0% and 96.7% vs. 29.1% of subjects, respectively), cough (18.8% and 22.0% vs. 2.0% of 
subjects, respectively), and throat irritation (13.5% and 18.0% vs. 2.0% of subjects, 
respectively). The most common treatment-emergent AE in both the OC-01 and placebo groups, 
sneezing, was likely caused by stimulation of the trigeminal nerve (and to some extent, due to the 
mechanical administration of the nasal spray, as demonstrated by the sneezing in the placebo 
group). With the exception of one instance of cough considered not related to study drug by the 
Investigator in the 0.06 mg OC-01 group, all instances of sneezing, cough, and throat irritation 
were considered related to study drug, and all instances of sneezing, cough, and throat irritation 
were mild and non-serious. 
Most treatment-emergent AEs were mild in severity. The incidence of subjects with severe 
treatment-emergent AEs was low across all treatment groups: 2 (0.8%), 3 (1.2%), and 2 (0.8%) 
subjects in the 0.03 mg OC-01, 0.06 mg OC 01, and placebo groups, respectively; none were 
classified as ocular treatment-emergent AEs.  
No deaths were reported during the ONSET-2 study. Overall, 10 subjects (1.3%) overall reported 
serious treatment-emergent AEs: 2 (0.8%), 5 (2.0%), and 3 (1.2%) subjects in the 0.03 mg OC-
01, 0.06 mg OC-01, and placebo groups, respectively. All serious treatment-emergent AEs were 
either moderate or severe in intensity; none were considered related to study drug, and none were 
fatal.  
Sneezing data collected from subject diaries showed that almost all sneezing instances were mild 
among the treatment groups (no intervention was needed). In the OC-01 groups, approximately 
50% of administrations caused any sneezing; approximately 80% of administrations caused 0 to 
2 sneezes, approximately 20% of administrations caused 3 to 5 sneezes, and ≤5% of 
administrations caused ≥6 sneezes. Among subjects who sneezed after administration, the 
majority of sneezing was experienced within the first minute and stopped within the first 5 
minutes in the OC 01 groups. 


 
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Visual acuity, slit lamp biomicroscopy, intranasal examination, and pupil diameter did not 
indicate any clinically relevant changes from baseline.  
These data from the ONSET-1 and ONSET-2 study suggest that 28 days of BID delivery of OC-
01 (varenicline solution) Nasal Spray is safe and efficacious in subjects with DED.  
The MYSTIC study was designed to provide efficacy and safety data on chronic dosing of OC-
01 (varenicline solution) nasal spray for up to 84 days of BID treatment. OC-01 nasal spray was 
shown to be safe and well tolerated at both concentrations assessed in this clinical study. The 
only ocular treatment-emergent AE reported in more than 1 subject was visual acuity reduced, 
with similar frequencies in the placebo (7.3%) and OC-01 groups (0.03 mg [9.8%] and 0.06 mg 
[7.3%]). 
Most treatment-emergent AEs were mild in severity; no severe treatment-emergent AEs were 
reported. All treatment-emergent AEs assessed as related to the study drug by the Investigator 
were reported to be recovered or resolved before study completion with the exception of two 
cases each of visual acuity reduced and sneezing in subjects treated with OC-01 and eyelid 
edema in 1 subject treated with placebo. No SAEs or deaths were reported. 
2.2.1 
Pharmacokinetics, Pharmacodynamics and Toxicology 
TYRVAYA nasal spray contains varenicline which is a partial nicotinic acetylcholine receptor 
agonist of α4β2, α4α6β2, α3β4, and α3α5β4 receptors and a full α7 receptor agonist. 
Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid 
whose chemical name is 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine, 
(2R,3R)-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. Varenicline tartrate has a 
molecular weight of 361.35 Daltons and a molecular formula of C13H13N3 ⋅ C4H6O6.  
 
TYRVAYA (varenicline solution) nasal spray is formulated for intranasal use as a clear 
0.6 mg/mL strength solution, at pH 6.4. After priming, each actuation delivers a 0.05 mL spray 
containing 0.03 mg varenicline free base, equivalent to 0.05 mg of varenicline tartrate. The 
formulation also contains the following inactive ingredients: 
sodium phosphate dibasic heptahydrate, monobasic sodium phosphate anhydrous, sodium 
chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH) and water for injection. 
 
The efficacy of TYRVAYA in dry eye disease is believed to be the result of varenicline's activity 
at heteromeric sub-type(s) of the nicotinic acetylcholine (nACh) receptor where its binding 
produces agonist activity and activates the trigeminal parasympathetic pathway resulting in 
increased production of basal tear film as a treatment for dry eye disease. Varenicline binds with 
high affinity and selectivity at human α4β2, α4α6β2, α3β4, α3α5β4 and α7 neuronal nicotinic 
acetylcholine receptors. The exact mechanism of action is unknown at this time. 
 
Following administration of 0.12 mg (0.06 mg per 50-μL spray in each nostril), a strength of 
varenicline that is higher than the labeled concentration, varenicline can be detected in plasma by 


 
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5 minutes, generally achieves peak concentration within 2 hours, with a mean Cmax of 0.34 
ng/mL, and has an AUC0-inf of 7.46 h*ng/mL. The systemic exposure (AUC0-inf) following this 
intranasal dose was approximately 7.5% of the exposure observed following a 1 mg oral dose of 
varenicline. 
 
The mean ± SD elimination half-life of varenicline after intranasal administration is 
approximately 19 ± 10 hours. Varenicline undergoes minimal metabolism with 92% excreted as 
unchanged drug in the urine. 
 
NONCLINICAL TOXICOLOGY 
Carcinogenesis 
Lifetime carcinogenicity studies were performed in CD-1 mice and Sprague-Dawley rats. There 
was no evidence of a carcinogenic effect in mice administered varenicline by oral gavage for 2 
years at doses up to 20 mg/kg/day (810 times the maximum recommended human dose 
[MRHD], on a mg/m2 basis). Rats were administered varenicline (1, 5, and 15 mg/kg/day) by 
oral gavage for 2 years. In male rats (n = 65 per sex per dose group), incidences of hibernoma 
(tumor of the brown fat) were increased at the mid dose (1 tumor, 5 mg/kg/day, 405 times the 
MRHD on a mg/m2 basis) and maximum dose (2 tumors, 15 mg/kg/day, 1216 times the MRHD 
on a mg/m2 basis). The clinical relevance of this finding to humans has not been established. 
There was no evidence of carcinogenicity in female rats. 
Mutagenesis 
Varenicline was not genotoxic, with or without metabolic activation, in the following assays: 
Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic 
aberrations in vivo in rat bone marrow and in vitro in human lymphocytes. 
Impairment of Fertility 
There was no evidence of impairment of fertility in either male or female Sprague-Dawley rats 
administered varenicline succinate up to 15 mg/kg/day (1216 times the MRHD on a mg/m2 
basis). Maternal toxicity, characterized by a decrease in body weight gain, was observed at 15 
mg/kg/day. A decrease in fertility was noted in the offspring of pregnant rats administered 
varenicline succinate at an oral dose of 15 mg/kg/day. The decrease in fertility in the offspring of 
treated female rats was not evident at an oral dose of 3 mg/kg/day (243 times the MRHD, on a 
mg/m2 basis). 
 
2.2.2 
Assessment for Potential Study Products Drug-Drug, Drug-Device, Device-Device 
Interactions 
There are no known drug interactions for TYRVAYA varenicline solution) nasal spray.  
 


 
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2.2.3 
Clinical Adverse Event Profile 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 
of another drug and may not reflect the rates observed in practice. 
In three clinical studies of dry eye disease conducted with varenicline solution nasal spray, 349 
patients received at least 1 dose of TYRVAYA. The majority of patients had 31 days of 
treatment exposure, with a maximum exposure of 105 days. 
The most common adverse reactions reported in 82% of TYRVAYA treated patients was 
sneezing. Other common adverse reactions that were reported in >5% of patients include cough 
(16%), throat irritation (13%), and instillation-site (nose) irritation (8%). 
2.2.4 
Dosing Rationale 
These data from the ONSET-1 and ONSET-2 study suggest that 28 days of BID delivery of OC-
01 (varenicline solution) Nasal Spray is safe and efficacious in subjects with DED.  
2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
In 3 clinical studies conducted with OC-01 (varenicline) nasal spray, the most common side 
effects reported in ≥2% of treated subjects at a frequency greater than placebo:  
 sneezing (84%) 
 coughing (19%) 
 throat irritation (16%) 
 instillation site irritation (13%) 
 conjunctival hyperemia (eye redness) (3%) 
 headache (2.4%) 
 rhinorrhea (runny nose) (2.4%) 
 reduced visual acuity (2.1%) 
2.3.2 
Known Potential Benefits 
You may or may not directly benefit medically from taking part in this study. You may gain 
information about your health from the different tests (e.g., eye exams, etc.) that are done. It is 
possible that if you have dry eye disease from Sjogren’s Syndrome, your signs and/or symptoms 
of dry eye disease may get better, stay the same, or get worse. Information from this study may 
help doctors learn things about OC-01 (varenicline solution) nasal spray that could help others 
with dry eye disease due to Sjogren’s. 


 
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2.3.3 
Assessment of Potential Risks and Benefits 
 
Based on clinical trial data, most treatment-emergent AEs were mild in severity; no severe 
treatment-emergent AEs were reported. 
Benefits include possible improvement in dry eye symptoms.  


 
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3 STUDY OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Evaluate the safety and 
effectiveness of OC-01 
(varenicline solution) nasal spray 
among subjects with dry eye 
disease and moderate to severe 
Sjogren’s Syndrome 
Mean change in cornea and 
conjunctival staining from 
baseline to Day 28 
Mean change in eye dryness score 
as measured by the Visual 
Analogue Scale (VAS) from 
baseline to Day 28 
 
Secondary 
 
 
 
Mean change in best corrected 
visual acuity from baseline to 
Day 28 
Mean change in dry mouth and 
dry nose scale as measured by 
from baseline through Day 28 
Incidence and severity of 
adverse events 
 
To assess secondary 
endpoints such as visual 
acuity, safety, dry 
mouth/nose. 


 
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4 STUDY PLAN 
4.1 
Study Design 
This is a single-center, single-arm study to assess the efficacy of OC-01 (varenicline solution) 
nasal spray in signs and symptoms of dry eye disease for subjects with diagnosed Sjogren’s 
syndrome. 
Approximately 40 subjects at least 18 years of age with moderate to severe Sjogren’s syndrome 
with confirmed diagnosis of dry eye disease (defined as Schirmer’s test score ≤10 mm and 
meeting all other study eligibility criteria. 40 subjects will receive an application of OC-01 
(varenicline solution) 0.03 mg nasal spray twice daily (BID) and will be compared to age-
matched historical control.    
Subjects who terminate early during the application period will be asked to complete safety 
assessments (if subjects agree) prior to study exit. Subjects who are terminated early from the 
study will not be replaced. 
4.2 
Scientific Rationale for Study Design 
This study is a single center, single-arm, investigator-initiated study to investigate the efficacy of 
OC-01 on signs and symptoms of dry eye disease with moderate to severe Sjogren’s syndrome.   
4.3 
Justification for Dose 
The dosing and schedule is as was used in previous clinical trials of this drug.  
4.4 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit.


 
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Study Population 
4.5 
Inclusion Criteria 
Subjects must: 
 Provide signed written consent prior to study-related procedures 
 Be at least 18 years of age at the screening visit 
 Have diagnosed moderate to severe Sjogrens Syndrome via blood work or biopsy 
Category 2 staining score for Conjunctiva based on the Van Bjisterveld and Utrect scale 
and 3 staining score for cornea based on the NEI scale 
 Have continuous use of all topical ocular medication for > 3 months and willingness to 
continue until completion of the study 
 Be literate and able to complete questionnaires independently 
 Be able and willing to use the study drug and participate in all study assessments and 
visits 
 Have sufficient hand strength, in the opinion of the Investigator, to be able to 
independently administer the study drug 
 Have provided verbal and written informed consent 
 If a female is of childbearing potential, they must: use an acceptable means of birth 
control (acceptable methods of contraception include: hormonal oral, implantable, 
injectable, or transdermal contraceptives, mechanical spermicide in conjunction with a 
barrier such as a diaphragm or condom, IUD, or surgical sterilization of partner), and 
have a negative urine pregnancy test on Day 1 
4.6 
Exclusion Criteria 
Subjects must not: 
 Have undergone previous ocular surgery (e.g., intraocular, oculoplastic, corneal or 
refractive surgical procedure) in the past 1 year 
 Have had thermal pulsation or IPL in prior 3 months 
 Have used topical ophthalmic corticosteroid therapy in prior 4 weeks 
 Have had cataract surgery in the last 6 months 
 Have clinically significant ocular trauma. 
 Have active ocular Herpes simplex or Herpes Zoster infection 
 Have ocular inflammation (uveitis, iritis, scleritis, episcleritis, keratitis, conjunctivitis) at 
the discretion of the investigator. 
 Have ocular infection (e.g., viral, bacterial, mycobacterial, protozoan or fungal infection 
or the cornea, conjunctiva, lacrimal gland, lacrimal sac or eyelids including 
hordeolum/stye). 
 Have retinal pathology that can limit visual potential and refractive outcomes in the 
opinion of the investigator 


 
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 Have severe (Grade 3 or 4) inflammation of the eyelid (e.g., blepharochalasis, 
staphylococcal blepharitis or seborrheic blepharitis) 
 Have eyelid abnormalities that significantly affect the lid function (e.g., entropion, 
ectropion, tumor, edema, blepharospasm, lagophthalmos, severe trichiasis, severe ptosis). 
 Have ocular surface abnormality that may compromise the corneal integrity (e.g., prior 
chemical burn, recurrent corneal erosion, corneal epithelial defect, Grade 3 corneal 
fluorescein staining, map dot fingerprint dystrophy, or the effect of any other ophthalmic 
medication that might in the opinion of the investigator compromise the ocular surface 
integrity). 
 Have a systemic condition or disease not stabilized or judged by the Investigator to be 
incompatible with participation in the study or with the lengthier assessments required by 
the study (e.g., current systemic infection, uncontrolled autoimmune disease, 
uncontrolled immunodeficiency disease, history of myocardial infarction or heart disease, 
etc.) 
 Have chronic or recurrent epistaxis, coagulation disorders or other conditions that, in the 
opinion of the Investigator, may lead to clinically significant risk of increased bleeding. 
 Have had nasal or sinus surgery (including history of application of nasal cautery) or 
significant trauma to these areas 
 Be currently treated with nasal continuous positive airway pressure 
 Have any untreated nasal infection at Visit 1 
 Have a vascularized polyp, severely deviated septum, chronic recurrent nosebleeds, or 
severe nasal obstruction as confirmed by intranasal examination performed at Visit 1. 
 Have a known hypersensitivity to any of the procedural agents or study drug components 
 Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 30 days prior to Visit 1 and during the treatment 
period. 
 Be a female who is pregnant, nursing, or planning a pregnancy at Visit 1. Be a woman of 
childbearing potential who is not using an acceptable means of birth control; acceptable 
methods of contraception include: hormonal oral, implantable, injectable, or transdermal 
contraceptives; mechanical spermicide in conjunction with a barrier such as a diaphragm 
or condom; IUD; or surgical sterilization of partner. The risks of OC-01 among pregnant 
patients are not known. 
4.7 
Lifestyle Considerations 
During this study, patients will be asked to refrain from activities as listed above in the exclusion 
criteria. If they are unable to do so, then they will be excluded from the study.  
4.8 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not eligible to entered in the study. A minimal set of screen failure information is required to 


 
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ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
4.9 
Strategies for Recruitment and Retention 
Subjects will be recruited in the outpatient clinic setting from dry eye patients who are seen at 
Scheie Eye Institute. *** 


 
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5 STUDY INTERVENTION 
5.1 
Study Intervention(s) Administration 
5.1.1 
Study Intervention Description 
Package Insert Patient information: 
 


 
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5.1.2 
Dosing and Administration 
Spray TYRVAYA once in each nostril twice daily (approximately 12 hours apart). If a dose is 
missed, resume regular dosing at the next scheduled dose time. 
 
Priming Instructions 
Priming: Prime TYRVAYA before initial use by pumping seven (7) actuations into the air away 
from the face. When TYRVAYA has not been used for more than 5 days, re-prime with 1 spray 
into the air. Do not shake. 
 
DOSAGE FORMS AND STRENGTHS 
Nasal spray delivering 0.03 mg of varenicline in each spray (0.05 mL). 
5.2 
Preparation/Handling/Storage/Accountability 
5.2.1 
Acquisition and accountability 
Oyster Point Pharma will provide sufficient drug for the study in its commercially available 
form.  
5.2.2 
Formulation, Appearance, Packaging, and Labeling 
Investigational drug will be provided in multi-use intranasal applicator.  
The investigational drug must be stored in accordance with the pharmacy manual for this study, 
which contains detailed information regarding the storage and administration 
The study drug will be delivered as a 50 microliter (µL) intranasal spray in each nostril BID: 
 OC-01 (varenicline solution) nasal spray, 0.03 mg  
General Appearance 
 OC-01 (varenicline solution) will be formulated at the desired concentration in 
sodium phosphate buffers and sodium chloride as an aqueous solution and presented 
in a multi-use preservative-free nasal pump. 
 The product is preservative-free and intended for intranasal use only. The product 
should not be used if cloudy or if particulate matter is present. 
 OC-01 (varenicline solution) must be administered without dilution.  
5.2.3 
Product Storage and Stability 
 Store TYRVAYA nasal spray at 20°C to 25°C (68°F to 77°F). Do not freeze. 
 Discard TYRVAYA nasal spray bottle 30 days after opening bottle. 


 
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5.2.4 
Preparation 
Preparation 
1. Tear off removable portion of vial label and place on appropriate source 
document.  Ensure that subject ID is noted on vial label. 
2. Remove plastic safety clip and cap from the nasal pump (see Figure 1).  
 
3. Discard the plastic safety clip and remove and set the cap aside (Figure 2). 


 
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4. Hold the nasal pump upright and away from your face.  Place one finger on each 
side of the base of the nasal applicator and your thumb underneath the bottle (see 
Figure 3). 


 
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5.  Completely press (pump) the nasal pump 7 times by squeezing your thumbs and 
fingers together. This will prime the pump for use (see Figure 4). 
 
6. OC-01 is now ready to administer. 


 
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Administration 
7. Instruct the subject to blow their nose to clear their nostrils (see Figure 5). 
 
8. Have the subject hold the bottle upright (see Figure 6). 


 
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9. Have the subject tilt their head back slightly (see Figure 7). 
 
NOTE: Nasal applicator MUST be held in an upright position to deliver the correct 
dose.  Do not instruct the subject to lie down or tilt their head too far back while 
OC-01 is being administered.  
 
10. Instruct the subject to insert the intranasal applicator into the left or right nostril.  
Have the subject keep the intranasal applicator in the opposite hand from the 
nostril which they are administering spray info.  Have them place the tip into the 
nasal cavity far enough to avoid nasal hairs.  Have them aim the tip of the nasal 
spray pump to the top of their ear on the same side as the nostril (see Figure 8). 


 
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11. Instruct the subject to place their tongue to the roof of their mouth (closing the 
soft palate to minimize drug into the throat) and have them breathe in (inhale) 
gently while they pump the intranasal applicator one time, aiming outward toward 
the top of the ear on the same side (see Figure 9).   
 
 
12. Have the subject gently breathe in through the nose and out through the mouth 
several times. 
13. Have the subject repeat this administration with the other nostril. 
14. Instruct the subject to wipe the intranasal applicator with a clean tissue (see 
Figure 10). 
15.  


 
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16. Replace plastic safety cap (see Figure 11). 
 


 
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5.3 
Measures to Minimize Bias: Randomization and Blinding 
This is a single-arm study which does not involve randomization or blinding.  
5.4 
Study Intervention Compliance 
Adherence to protocol will be documented in the electronic medical record and use of the drug 
will be self-reported by patients.  
5.5 
Concomitant Therapy 
At the discretion of their physician, patients may continue to receive all medications and 
standard treatments administered for other conditions. 
5.5.1 
Rescue Medicine 
Not applicable.  


 
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6 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
6.1 
Discontinuation of Study Intervention 
Discontinuation from use of the study drug does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol. If a 
clinically significant finding is identified (including, but not limited to changes from baseline) 
after enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event 
(AE). 
The data to be collected at the time of study intervention discontinuation (i.e. Early Termination 
visit) will include the following: 
 Record of any changes in medical/surgical history  
 Collection of current ocular and systemic medications 
 Eye/Nasal/Mouth Dryness Score as measured by Visual Analogue Scale 
 QIDS-SR Questionnaire 
 Tear Film Imager (5 mins post treatment administration) 
 Subjective Refraction  
 Best-corrected visual acuity 
 Slit lamp biomicroscopy 
 Corneal and Conjunctival Staining 
 Schirmer’s Test without Anesthesia 
 Collect Schirmer’s test strips  
 Adverse Events (AEs): Documentation of monitoring of AEs 
 Collect Study Product 
6.2 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 Pregnancy 
 Significant drug non-compliance 
 If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
 Disease progression which requires discontinuation of the drug 


 
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 If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 Participant unable to receive drug for 1 day 
 
6.3 
Lost To Follow-Up 
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 The site will attempt to contact the participant and reschedule the missed visit within 1 
week and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
 Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


 
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7 STUDY ASSESSMENT AND PROCEDURES 
7.1 
Efficacy Assessments 
 Eye Dryness Score as measured by Visual Analogue Scale (VAS): Symptoms of ocular 
comfort and dryness will be graded for each eye on a scale of 0-100, where 0=no 
discomfort and 100=maximum discomfort. An average rating will be provided for the 
morning, afternoon and evening (See Appendix I) 
 Nasal Dryness Score as measured by VAS: Symptoms of nasal dryness will be graded for 
each nostril on a scale of 0-100, where 0=no discomfort and 100=maximum discomfort. 
An average rating will be provided for the morning, afternoon and evening (see Appendix 
I) 
 Mouth Dryness Score as measured by VAS: Symptoms of mouth dryness will be graded 
on a scale of 0-100, where 0=no discomfort and 100=maximum discomfort. An average 
rating will be provided for the morning, afternoon and evening (see Appendix I) 
 The Quick Inventory of Depressive Symptomatology Self report (QIDS-SR): It is a self-
report tool of 16 questions designed to screen for depression and measure changes in 
severity of symptoms. (See Appendix II) 
 The Tear Film Imager quantifies the dynamic properties of the tear film inner layers 
(muco-aqueous layer and lipid layer) using a single non-contact measurement. The Tear 
Film Imager’s measurement features the natural behavior of the tears while allowing the 
patient to blink naturally (See Appendix III) 
 Eye Examination 
 Best-corrected visual acuity - routine visual acuity (not standardized or by certified 
technician) 
 Slit lamp biomicroscopy: assessment of eyelids, conjunctiva, cornea, lens, iris, and 
anterior chamber. Observations will be graded as Normal or Abnormal.  Abnormal 
findings, which are clinically significant, will be described. 
 Corneal Staining/Conjunctival Staining: The appearance of tissue disruption or other 
pathophysiological changes in the anterior eye.  These changes are typically seen with the 
use of fluorescein dye. The NEI scale is the method that will be used to measure corneal 
staining using fluorescein strips.  It divides the corneal and conjunctival surfaces to help 
measure fluorescein uptake. The Van Bijsterveld and Utrecht scale is the method that will 
be used to measure conjunctival staining while using lissamine green dye (See Appendix 
IV) 
 Schirmer’s Test without anesthesia: A filter paper inside the lower lid of the eye to 
determine whether the eye produces enough tears.  The paper is removed after 5-minutes 
and the moisture is measured 
 Collection of Schirmer’s test strips: Place Schirmer’s strips into tubes for further study.  
Place tubes into a -20 to -80 degree freezer until shipped onto dry ice to lab.  (See 
Appendix V) 


 
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 Dilated Fundus Exam: assessment of posterior retina, lens, and vitreous.  
7.2 
Safety and Other Assessments 
 Collection of current ocular and systemic medications 
 Eye/Nasal/Mouth Dryness Score as measured by Visual Analogue Scale 
 QIDS-SR Questionnaire 
 Tear Film Imager (5 mins post treatment administration) 
 Subjective Refraction  
 Best-corrected visual acuity 
 Slit lamp biomicroscopy 
 Corneal and Conjunctival Staining 
 Schirmer’s Test without Anesthesia 
 Collect Schirmer’s test strips  
 Urine Pregnancy Test 
 Adverse Events (AEs): Documentation of monitoring of AEs 
7.3 
Adverse Events and Serious Adverse Events 
7.3.1 
Definition of Adverse Events (AE) 
An adverse event (AE) is any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention related. Intercurrent illnesses or 
injuries should be regarded as adverse events. 
A pre-existing condition should be recorded as an adverse event if the frequency, intensity or the 
character of the condition changes. 
7.3.2 
Definition of Serious Adverse Events (SAE)  
Serious Adverse Events (SAE) 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that, 
in the view of either the investigator or the sponsor, is: 
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 


 
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 an important medical event when the event does not fit the other outcomes, but the event 
may jeopardize the patient and may require medical or surgical intervention (treatment) 
to prevent one of the other outcomes. 
 required intervention to prevent permanent impairment or damage (for devices only) 
Important medical events are those that may not be immediately life threatening but are clearly 
of major clinical significance. They may jeopardize the subject and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
7.3.3 
Unanticipated Adverse Device Effect (UADE) 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or application, or 
any other unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects. 
Classification of an Adverse Event 
7.3.3.1 
Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity. 
 Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
 Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
 Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”. 
7.3.3.2 
Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to the drug assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. In a 
clinical trial, the study product must always be considered. 
 Related – The AE is known to occur with the drug, there is a reasonable possibility that 
the drug caused the AE, or there is a temporal relationship between the drug and event. 


 
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Reasonable possibility means that there is evidence to suggest a causal relationship 
between the drug and the AE. 
 Not Related – There is not a reasonable possibility that the administration of the drug 
caused the event, there is no temporal relationship between the drug and event onset, or 
an alternate etiology has been established. 
7.3.3.3 
Expectedness  
The PI will be responsible for determining whether an adverse event (AE) is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the drug. 
7.3.4 
Time Period and Frequency for Event Assessment and Follow-Up 
Safety will be assessed by monitoring and recording potential adverse effects at each study visit. 
Participants will be monitored by medical histories and physical examinations. If grading does 
not exist for an adverse event, the severity of mild, moderate, severe, life-threatening, and death, 
corresponding to Grades 1-5, will be used whenever possible. 
At each contact with the subject, the investigator will seek information on adverse events by non-
directive questioning and, as appropriate, by examination. Adverse events may also be detected 
when they are volunteered by the subject during the screening process or between visits, or 
through physical examination, laboratory test, or other assessments. Information on all adverse 
events will be recorded in the source documentation. To the extent possible, adverse events will 
be recorded as a diagnosis and symptoms used to make the diagnosis recorded within the 
diagnosis event. 
As much as possible, each adverse event or follow-up information will be evaluated to 
determine: 
1. Severity grade (CTCAE Grade 1-5) 
2. Duration (start and end dates) 
3. Relationship to the study treatment or process – [Reasonable possibility that AE is 
related: No (unrelated/ not suspected) or Yes (a suspected adverse reaction)]. If yes 
(suspected) - is the event possibly, probably or definitely related to the investigational 
treatment? 
4. Expectedness to study treatment or process – [Unexpected – if the event severity and/or 
frequency is not described in the investigator brochure (if applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment or process (none, dose 
adjusted, temporarily interrupted, permanently discontinued, unknown, not applicable) 
6. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 


 
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7. Whether the event is serious 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to 
be permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
7.3.5 
Adverse Event Reporting 
Reporting Period 
Adverse events will be reported from the time of informed consent until study completion. 
Investigator Reporting: Notifying the Study Sponsor 
Every SAE, regardless of suspected causality (e.g., relationship to study product(s) or study 
procedure(s) or disease progression) must be reported to the sponsor within 24 hours of learning 
of its occurrence. 
Recurrent episodes, complications, or progression of the initial SAE must be reported to the 
Sponsor as a follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information. A SAE considered completely unrelated to a previously reported one 
should be reported separately as a new event. 
Send the SAE report to the PI. 
New information regarding the SAE will be reported as it becomes available and in the same 
manner that the initial SAE (i.e. SAE form). The investigator must follow the event to resolution 
or until the event is deemed and documented irreversible, whichever is longer. 
Investigator Reporting: Local Reporting Requirements 
The investigator will report AEs and SAEs to the IRB/EC of record and other local regulatory 
groups per the local requirements. 
7.3.6 
Serious Adverse Event Reporting  
The study clinician will immediately report to the sponsor any serious adverse event, whether or 
not considered drug related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the drug caused the 
event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported 
in accordance with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g., death from anaphylaxis). In that case, the investigator must 
immediately report the event to the sponsor. 
New information regarding the SAE will be reported as it becomes available and in the same 
manner that the initial SAE (i.e. SAE form). All serious adverse events (SAEs) will be followed 
until satisfactory resolution or until the site investigator deems the event to be chronic or the 


 
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participant is stable. Other supporting documentation of the event may be requested by the Data 
Coordinating Center (DCC)/study sponsor and should be provided as soon as possible. 
The SAE reports to the Sponsor should be sent to : the study sponsor.  
The study sponsor will be responsible for notifying the FDA of any unexpected fatal or life-
threatening suspected adverse reaction per applicable regulations. In addition, the sponsor must 
notify FDA, as applicable and all participating investigators of potential serious risks, from 
clinical trials or any other source, as per the applicable regulation. 
7.3.7 
Reporting Events to Participants  
AEs, SAs, and study-related results will be reported to participants on an aggregate level.  
7.3.8 
Events of Special Interest  
Not applicable.  
7.3.9 
Reporting of Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug or 
process may have interfered with the effectiveness of a contraceptive medication or method. 
When a pregnancy has been confirmed in a subject, and the fetus is exposed to study drug and/or 
process (maternally or paternally), the following procedures should be followed to ensure subject 
safety: 
 
Stopping the drug.  
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation. Follow-
up should be conducted for each pregnancy to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
7.4 
Unanticipated Problems 
7.4.1 
Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all the following criteria: 
 Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 


 
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 Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
 Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.4.2 
Unanticipated Problem Reporting 
Unanticipated problems (UPs) such as: 
 
Post-marketing withdrawal of a drug, device, or biologic used in a research protocol due 
to safety concerns. 
 
FDA ban of a drug, device, or biologic used in a research protocol due to safety concerns. 
 
Complaint of a participant when the complaint indicates unexpected risks, or the 
complaint cannot be resolved by the research team 
 
Breach of confidentiality 
 
Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain on 
the study 
 
Premature closure of a study (e.g., due safety, lack of efficacy, feasibility, financial 
reasons, etc.) 
should be reported by the investigator to the Sponsor, reviewing Institutional Review Board 
(IRB) and to the lead principal investigator (PI). The UP report will include the following 
information: 
 Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
 A detailed description of the event, incident, experience, or outcome;  
 An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 
 A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
 UPs that are serious adverse events (SAEs) will be reported as any other SAE. 


 
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 Any other UP will be reported to the <Sponsor, IRB and to the DCC/study sponsor 
within <insert timeline in accordance with SOP and policy> of the investigator becoming 
aware of the problem. 
 All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and 
the Office for Human Research Protections (OHRP) within appropriate timeline of the 
IRB’s receipt of the report of the problem from the investigator. 
7.4.3 
Reporting Unanticipated Problems To Participants  
Unanticipated problems will be reported to participants on an aggregate level.  
7.5 
Device Reporting 
Safety reporting for the device(s) will be according to 21 CFR 812.150. 
8 STATISTICAL CONSIDERATIONS 
8.1 
Statistical Hypotheses 
No formal sample size calculation will be made in this small directional signal seeking study. 
Demographic and baseline characteristics will be summarized descriptively. Continuous 
variables will be summarized with mean, median, and standard deviation. Categorical variables 
will be summarized with frequency and percentage. Independent t tests will compare between the 
two groups and paired t tests to compare data before and after treatment within groups 
8.2 
Sample Size Determination 
No formal sample size calculation will be made in this small directional signal seeking study.  
8.3 
Populations for Analyses 
All participants will be included in the analysis.  
8.4 
Statistical Analyses 
8.4.1 
General Approach 
Demographic and baseline characteristics will be summarized descriptively. Continuous 
variables will be summarized with mean, median, and standard deviation. Categorical variables 
will be summarized with frequency and percentage. Independent t tests will compare between the 
two groups and paired t tests to compare data before and after treatment within groups. 
8.4.2 
Analysis of the Primary Efficacy Endpoint(s) 
Mean change in cornea and conjunctival staining from baseline to Day 28 


 
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Mean change in eye dryness score as measured by the Visual Analogue Scale (VAS) from 
baseline to Day 28 
8.4.3 
Analysis of the Secondary Endpoint(s) 
Mean change in best corrected visual acuity from baseline to Day 28 
Mean change in dry mouth and dry nose scale as measured by from baseline through Day 28 
Incidence and severity of adverse events 
8.4.4 
Safety Analyses 
Summary statistics of adverse events will be presented in a table.  
8.4.5 
Baseline Descriptive Statistics 
Demographic and baseline characteristics will be summarized descriptively.  
8.4.6 
Planned Interim Analyses  
Not applicable. 
8.4.7 
Sub-Group Analyses 
Due to small sample size, sub-group analyses will not be performed.  
8.4.8 
Tabulation of Individual Participant Data 
Individual participant data will not be tabulated.  
8.4.9 
Exploratory Analyses 
Mean change in Muco-Aqueous layer thickness (MALT) and Lipid Map Uniformity (LMU) 
values from baseline to 15 minutes post treatment as measured by the Tear Film Imager 
masked reading center evaluation 
Mean change in Muco-Aqueous layer thickness (MALT) and Lipid Map Uniformity (LMU) 
values from baseline to Day 28 as measured by the Tear Film Imager masked reading center 
evaluation[Insert Text Here] 


 
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9 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
9.1 
Regulatory, Ethical, and Study Oversight Considerations 
9.1.1 
Informed Consent Process 
9.1.1.1 
Consent/Assent and Other Informational Documents Provided To Participants 
Consent forms describing in detail the drug, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering drug. The following consent materials are submitted with this 
protocol: consent form. 
9.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. The investigator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of 
the informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the date), 
and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
9.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated by the Sponsor or the PI at 
any site if there is sufficient reasonable cause. Written notification, documenting the reason for 
study suspension or termination, will be provided by the suspending or terminating party to 
investigator and participants. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), 
and sponsor and will provide the reason(s) for the termination or suspension. Study participants 
will be contacted, as applicable, and be informed of changes to study visit schedule. 


 
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Circumstances that may warrant termination or suspension include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to participants 
 Demonstration of efficacy that would warrant stopping 
 Insufficient compliance to protocol requirements 
 Data that are not sufficiently complete and/or evaluable 
 Determination that the primary endpoint has been met 
 Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
In terminating the study, the Sponsor and the Principal Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 
9.1.3 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the <specify name of Data Coordinating Center>. 
This will not include the participant’s contact or identifying information. Rather, individual 
participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used by clinical sites and by <specify name 
of Data Coordinating Center> research staff will be secured and password protected. At the end 


 
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of the study, all study databases will be de-identified and archived at the <specify name of Data 
Coordinating Center>. 
9.1.4 
Future Use of Stored Specimens and Data  
Data collected for this study will be analyzed and stored at the <specify name of Data 
Coordinating Center >. After the study is completed, the de-identified, archived data will be 
transmitted to and stored at the <specify name of Data Repository>, for use by other researchers 
including those outside of the study. Permission to transmit data to the <specify name of Data 
Repository> will be included in the informed consent. 
There will be no biological samples stored.  
9.1.5 
Safety Oversight 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
composed of individuals with the appropriate expertise. Members of the DSMB should be 
independent from the study conduct and free of conflict of interest, or measures should be in 
place to minimize perceived conflict of interest. The DSMB will meet at least semiannually to 
assess safety and efficacy data on each arm of the study. The DSMB will operate under the rules 
of an approved charter that will be written and reviewed at the organizational meeting of the 
DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. 
The DSMB will provide its input to the study sponsor.  
9.1.6 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). 
9.1.7 
Quality Assurance and Quality Control 
All monitoring and audits are to be performed according to ICH GCP E6(R2). 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.  
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated, and specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 


 
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Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
9.1.8 
Data Handling and Record Keeping  
9.1.8.1 
Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data and follow ALCOAC standards (attributable, legible, contemporaneous, 
original, accurate, and complete). 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study. Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into <specify name of data capture 
system>, a 21 CFR Part 11-compliant data capture system provided by the <specify Data 
Coordinating Center>. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents.] 
If using the Penn CTMS, the following text may be included: 
[Clinical and laboratory data will be entered into a 21 CFR Part 11-compliant electronic data 
capture system (EDC) that includes individual user account level password protection. This EDC 
(Velos version 9) supports programmable data entry validation rules and edit checks to identify 
data entry errors.] 
9.1.8.2 
Study Records Retention  
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harmonization (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the drug. These 
documents should be retained for a longer period, however, if required by local regulations. No 
records will be destroyed without the written consent of the sponsor, if applicable. It is the 


 
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responsibility of the sponsor to inform the investigator when these documents no longer need to 
be retained. 
9.1.9 
Protocol Deviations 
The PI and the study team should document all scenarios where the protocol is not followed and 
provide, in particular: 
 Who deviated from the protocol 
 What was the deviation 
 When did the deviation occur 
 How did the deviation happen 
 What is the impact of the deviation 
 A root cause analysis of why the deviation occurred 
If the assessment results in a determination that any of the following are potentially affected, the 
deviation would be considered of significant impact: 
 having the potential to adversely affect subject safety; OR 
 increases risks to participants; OR 
 adversely affects the integrity of the data; OR 
 violates the rights and welfare of participants, OR 
 affects the subject’s willingness to participate in research.  
 there is a potential for an overall impact on the research that should be shared with the 
IRB for consideration and development of next best steps to address it 
 
9.1.10 
Publication and Data Sharing Policy 
This study will comply with the data sharing agreement. 
The Sponsor must approve all sharing of information/data prior to its occurrence. 
9.1.11 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 


 
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have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. 
9.2 
Additional Considerations 
Not applicable. 
9.3 
Protocol Amendment History 
 
Version 
Date 
Description of Change  
Brief Rationale 
V.2 
24Apr2023 
Inclusion/Exclusion and Procedure 
Changes 
Error in previous protocol  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Robinson, S. R. and P. J. Wormald (2006). "Endoscopic vidian neurectomy." Am J Rhinol 20(2): 
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Schaumberg, D. A., R. Dana, J. E. Buring and D. A. Sullivan (2009). "Prevalence of dry eye 
disease among US men: estimates from the Physicians' Health Studies." Arch Ophthalmol 
127(6): 763-768. 
 
Schaumberg, D. A., D. A. Sullivan and M. R. Dana (2002). "Epidemiology of dry eye 
syndrome." Adv Exp Med Biol 506(Pt B): 989-998. 
 
Schaumberg, D. A., D. A. Sullivan, J. E. Buring and M. R. Dana (2003). "Prevalence of dry eye 
syndrome among US women." Am J Ophthalmol 136(2): 318-326. 
 
Schaumberg, D. A., R. Dana, J. E. Buring and D. A. Sullivan (2009). "Prevalence of dry eye 
disease among US men: estimates from the Physicians' Health Studies." Arch Ophthalmol 
127(6): 763-768. 
 
Semba, C. P., G. L. Torkildsen, J. D. Lonsdale, E. B. McLaurin, J. A. Geffin, T. K. Mundorf, K. 
S. Kennedy and G. W. Ousler (2012). "A phase 2 randomized, double-masked, placebo-
controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye." Am J 
Ophthalmol 153(6): 1050-1060 e1051. 
 
Sheppard, J. D., G. L. Torkildsen, J. D. Lonsdale, F. A. D'Ambrosio, Jr., E. B. McLaurin, R. A. 
Eiferman, K. S. Kennedy, C. P. Semba and O.-S. Group (2014).  
"Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 
phase 3 study." Ophthalmology 121(2): 475-483. 
 
 
Sosne, G. and G. W. Ousler (2015). "Thymosin beta 4 ophthalmic solution for dry eye: a 
randomized, placebo-controlled, Phase II clinical trial conducted using the controlled adverse 
environment (CAE) model." Clin Ophthalmol 9: 877-884. 
 
Stapleton et al. (2007). "The epidemiology of dry eye disease: report of the Epidemiology 
Subcommittee of the International Dry Eye WorkShop (2007)." Ocul Surf 5(2): 93-107.  
 


 
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Stapleton, J. A. and G. Sutherland (2011). "Treating heavy smokers in primary care with the 
nicotine nasal spray: randomized placebo-controlled trial." Addiction 106(4): 824-832. 
 
Tauber, J., P. Karpecki, R. Latkany, J. Luchs, J. Martel, K. Sall, A. Raychaudhuri, V. Smith, C. 
P. Semba and O.-. Investigators (2015). "Lifitegrast Ophthalmic Solution 5.0% versus Placebo 
for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study." 
Ophthalmology 122(12): 2423-2431. 
 
Thuerauf N, K. Markovic, G. Braun, S. Bleich, U. Reulbach, J. Kornhuber and J. Lunkenheimer 
(2006). "The influence of mecamylamine on trigeminal and olfactory chemoreception of 
nicotine." Neuropsychopharmacology 31(2): 450-461. 
 
Tsubota, K. (1991). "The importance of the Schirmer test with nasal stimulation." Am J 
Ophthalmol 111(1): 106-108. 
 
Tsubota, K., M. Yamada and K. Urayama (1994). "Spectacle side panels and moist inserts for the 
treatment of dry-eye patients." Cornea 13(3): 197-201. 
 
Wall PD, Gutnick M. Ongoing activity in peripheral nerves: the physiology and pharmacology of 
impulses originating from a neuroma. Exp Neurol 1974b;43(3):580–593. 
 
Walt JG, R. M., Stern KL (1997). "Evaluating the functional impact of dry eye: the Ocular 
Surface Disease Index [abstract]." Drug In J 31: 1436. 
 
11 APPENDIX  
11.1 
 Schedule of Activities (SoA) 
 
Study Procedure 
Screening/ 
Baseline 
(Visit 1) 
15 minutes 
Post-
administration 
 
 
Visit 2 
 
 
Visit 3 
 
Early 
Terminatio
n 
 
Day -0 
Day 0  
Day 14 
(Virtual) 
Day 28 
 


 
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Windows for Visits 
 
 
 
+/- 2 days 
+/- 7 days 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History and 
Concurrent Illnesses 
X 
 
X 
X 
X 
Ocular History 
X 
 
X 
X 
X 
Eligibility Criteria 
X 
 
 
 
 
Urine Pregnancy 
Test* 
X 
 
 
X 
X 
Concomitant 
Medications 
X 
 
X 
X 
X 
Intranasal Exam via 
history 
X 
 
 
 
 
Eye Dryness Score 
(0-100) as measured 
by Visual Analogue 
Scale (VAS) 
X 
 
X 
X 
X 
Nasal Dryness 
Score (0-100) as 
measured by VAS 
X 
 
X 
X 
X 
Dry Mouth Score 
(0-100) as measured 
by VAS 
X 
 
X 
X 
X 
QIDS-SR 
Questionnaire 
X 
 
X 
X 
X 
Tear Film Imager 
(obtain tear film 
thickness) 
X 
X 
 
X  
(15 mins post 
treatment) 
X 
Slit Lamp 
Biomicroscopy 
X 
 
 
X 
X 
Corneal Staining 
using NEI scale & 
Conjunctival 
Staining using Van 
Bijsterveld and 
Utrecht scale  
X 
 
 
X 
X 
Schirmer’s Test 
without anesthesia 
X 
 
 
X 
X 
Tear sample 
Collection 
X 
 
 
X 
X 


 
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Ophthalmic 
Examination (w/or 
w/o dilated fundus 
exam) 
X 
 
 
 
 
Dispense Study 
Product 
X 
 
 
 
 
Collect Study 
Product 
 
 
 
X 
X 
Adverse Events 
X 
 
X 
X 
X 
*For women of childbearing potential 


 
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APPENDICES 
 
Appendix I: Visual Analogue Scale  
 
 
 Eye Dryness Score (EDS) Using a Visual Analog Scale (VAS) 
The participant will be asked to rate their ocular symptoms (both eyes simultaneously) due to eye 
dryness by placing a vertical mark on the horizontal line to indicate the level of discomfort; 0 
corresponds to “no discomfort” and 100 corresponds to “maximal discomfort.” The assessment 
line length of the scale will be 100 mm. 
Please rate your current eye dryness by drawing a vertical line on the line below: 
     
                                            
 
 
 
 
 
 
 
 
The EDS is an instrument that has been used in other studies.(Sheppard, Torkildsen et al. 2014, 
Tauber, Karpecki et al. 2015)   
 
Please rate your current nose dryness by drawing a vertical line on the line below: 
     
                                            
 
 
 
 
 
No 
Discomfort 
Maximal 
Discomfort 


 
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Please rate your current mouth dryness by drawing a vertical line on the line below: 
     
                                            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix II: QIDS-SR Questionnaire 
No 
Discomfort 
Maximal 
Discomfort 
No 
Discomfort 
Maximal 
Discomfort 


 
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The Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report) (QIDS-SR16) 
Pg. 1 of 2 
Name or ID: 
 
Date:   
 
CHECK THE ONE RESPONSE TO EACH ITEM THAT BEST DESCRIBES YOU FOR THE PAST SEVEN DAYS. 
During the past seven days... 
During the past seven days... 
1. Falling Asleep: 
0 
I never take longer than 30 minutes to fall asleep. 
1 
I take at least 30 minutes to fall asleep, less than 
half the time. 
 
2 
I take at least 30 minutes to fall asleep, more than 
half the time. 
3 
I take more than 60 minutes to fall asleep, more than 
half the time. 
2. Sleep During the Night 
0 
I do not wake up at night. 
1 
I have a restless, light sleep with a few brief 
awakenings each night. 
2 
I wake up at least once a night, but I go back to 
sleep easily. 
3 
I awaken more than once a night and stay awake 
for 20 minutes or more, more than half the time. 
3. Waking Up Too Early: 
 
0 
Most of the time, I awaken no more than 30 minutes 
before I need to get up. 
1 
More than half the time, I awaken more than 30 
minutes before I need to get up. 
2 
I almost always awaken at least one hour or so 
before I need to, but I go back to sleep eventually. 
3 
I awaken at least one hour before I need to, and 
can't go back to sleep. 
4. Sleeping Too Much: 
0 
I sleep no longer than 7-8 hours/night, without 
napping during the day. 
1 
I sleep no longer than 10 hours in a 24-hour period 
including naps. 
2 
I sleep no longer than 12 hours in a 24-hour period 
including naps. 
3 
I sleep longer than 12 hours in a 24-hour period 
including naps. 
5. Feeling Sad: 
0 
I do not feel sad. 
1 
I feel sad less than half the time. 
2 
I feel sad more than half the time. 
3 
I feel sad nearly all of the time. 
Please complete either 6 or 7 (not both) 
6. Decreased Appetite: 
0 
There is no change in my usual appetite. 
1 
I eat somewhat less often or lesser amounts of food than 
usual. 
2 
I eat much less than usual and only with personal effort. 
3 
I rarely eat within a 24-hour period, and only with 
extreme personal effort or when others persuade me to 
eat. 
- OR - 
7. Increased Appetite: 
0 
There is no change from my usual 
appetite. 
1 
I feel a need to eat more frequently than usual. 
2 
I regularly eat more often and/or greater amounts of 
food than usual. 
3 
I feel driven to overeat both at mealtime and between 
meals. 
Please complete either 8 or 9 (not both) 
8. Decreased Weight (Within the Last Two Weeks): 
0 
I have not had a change in my weight. 
1 
I feel as if I have had a slight weight loss. 
2 
I have lost 2 pounds or more. 
3 
I have lost 5 pounds or more. 
- OR - 
9. Increased Weight (Within the Last Two Weeks): 
0 
I have not had a change in my weight. 
1 
I feel as if I have had a slight weight gain. 
2 
I have gained 2 pounds or more. 
3 
I have gained 5 pounds or more. 


 
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During the past seven days... 
During the past seven days... 
10. Concentration / Decision Making: 
14. Energy Level: 
0 
There is no change in my usual capacity to 
concentrate or make decisions. 
1 
I occasionally feel indecisive or find that my attention 
wanders. 
2 
Most of the time, I struggle to focus my attention or 
to make decisions. 
0 
There is no change in my usual level of energy. 
1 
I get tired more easily than usual. 
2 
I have to make a big effort to start or finish my usual daily 
activities (for example, shopping, homework, cooking, or 
going to work). 
3 
I cannot concentrate well enough to read or cannot 
make even minor decisions. 
11. View of Myself: 
3 
I really cannot carry out most of my usual daily activities 
because I just don't have the energy. 
 
15. Feeling Slowed Down: 
0 
I see myself as equally worthwhile and deserving as 
other people. 
1 
I am more self-blaming than usual. 
2 
I largely believe that I cause problems for others. 
0 
I think, speak, and move at my usual rate of speed. 
1 
I find that my thinking is slowed down or my voice 
sounds dull or flat. 
2 
It takes me several seconds to respond to most 
questions and I'm sure my thinking is slowed. 
3 
I think almost constantly about major and minor 
defects in myself. 
3 
I am often unable to respond to questions without 
extreme effort. 
12. Thoughts of Death or Suicide: 
16. Feeling Restless: 
0 
I do not think of suicide or death. 
1 
I feel that life is empty or wonder if it's worth living. 
2 
I think of suicide or death several times a week for 
several minutes. 
0 
I do not feel restless. 
1 
I'm often fidgety, wringing my hands, or need to shift 
how I am sitting. 
2 
I have impulses to move about and am quite restless. 
3 
I think of suicide or death several times a day in 
some detail, or I have made specific plans for 
suicide or have actually tried to take my life. 
3 
 At times, I am unable to stay seated and need to pace 
around. 
13. General Interest 
0 
There is no change from usual in how interested I 
am in other people or activities. 
1 
I notice that I am less interested in people or 
activities. 
2 
I find I have interest in only one or two of my 
formerly pursued activities. 
3 
I have virtually no interest in formerly pursued 
activities. 


 
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Appendix III: Tear Film Imager 
 
 
TFI quantifies the dynamic properties of the tear film inner layers (muco-aqueous and lipid) 
using a single non-contact measurement 
 
Appendix IV: NEI Scale 
 
 
 
 


 
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Appendix IV: Van Bijsterveld and Utercht Scale 
 
 
Appendix VI: Schirmer’s Test without Topical Anesthesia and Tear Collection 
 
Schirmer’s Strips without Topical Anesthesia: 
2. Instruct the participant to keep the eyes gently closed for one minute.    
3. After opening the eyes and allowing the eyes to recover for approximately one additional 
minute, remove the excess moisture in the inferior fornix with a spear.  
4. Place Schirmer’s strips (35 mm x 5 mm size filter paper strip) in each eye at the junction 
of the middle and lateral thirds of the lower eye lid.   
5. Under ambient light, instruct the participant to look forward and to blink normally during 
the course of the test. The test should be performed in a room with no direct air or 
sunlight on the participant’s face.  
6. The Schirmer’s strips should remain in place until five minutes have elapsed or both 
strips have reached maximum score.  
7. After five minutes, remove the Schirmer strips from both eyes and record the amount of 
wetting. 
8. Use forceps to hold the strip and cut 2-3mm above the tear migration line (dye line) and 
place into the collection tube.  
9. Place one strip into each of the collection tubes that were provided.  On the label, please 
indicate if it is Right or Left eye (R = right and L = left) next to the subject ID (ex: 115-
001-R; 115-001-L).  Place the label on the applicable collection tube. 
 
 Kit Content: 
 2 Collection Tubes (Eppendorf Tubes)  
 2 Schirmer’s Strips 
 2 Labels (one for each tube) 
 
Schirmer’s test and collection  
Once both strips have been placed into their own labeled vial, insert both vials back into the 
labeled collection kit box and store at -20C until further instructions for shipment.  


 
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Samples may be batch shipped.  Ship all samples overnight on Dry Ice  


 
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END OF DOCUMENT


 
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