Clinical trial NCT06329687
Conditions: Dry Eye Kerato Conjunctivitis Sicca
Sponsor: Oyster Point Pharma, Inc.
Start date: 2024-02-21; Completion date: 2024-02-28
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study is to determine the safety of the Tyrvaya nasal pump.

Detailed description:
The study is testing the hypothesis that the use of the Tyrvaya nasal pump with silicone lubricant does not introduce any additional safety concerns as compared to the safety of the Tyrvaya nasal pump without the additional silicone lubricant.

Arms: arm 1: Tyrvaya nasal pump with additional silicone lubricant
Interventions: intervention 1: Tyrvaya Nasal Pump
Intervention descriptions: intervention 1: Tyrvaya Nasal Pump with Silicone Lubricant

Protocol documents:
Prot_SAP_000.pdf: 
Tyrvaya® 
 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
Page 1 of 38 
 
Clinical Trial Protocol  
Protocol Title: 
A Phase 4, Single-Center, Open-Label Study Evaluating the 
Safety of the Tyrvaya® Nasal Pump 
Protocol Number: 
OPP-010 
Study Phase: 
4 
Study treatment Name: 
Tyrvaya®  
IND Number: 
138645 
Indication: 
Dry Eye Disease  
Investigators: 
Single-Center 
 
Sponsor: 
Oyster Point Pharma, Inc. 
202 Carnegie Center 
Suite 106 
Princeton, NJ 08540 
 
 
 
 
 
Date 
Original Protocol version 1: 
                        21 Nov 2023 
Confidentiality Statement  
This protocol contains confidential, proprietary information of Oyster Point Pharma, Inc. Further 
dissemination, distribution or copying of this protocol or its contents is strictly prohibited. 
 
 


Tyrvaya® 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
21 Nov 2023 
CONFIDENTIAL 
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SPONSOR PERSONNEL 
 
 
  
 
 
 
 


Tyrvaya® 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
21 Nov 2023 
CONFIDENTIAL 
Page 3 of 38 
SYNOPSIS 
Protocol Title: 
A Phase 4, Single-Center, Open-Label Study Evaluating the Safety 
of the Tyrvaya® Nasal Pump 
Protocol Number: 
OPP-010 
Study Treatment 
Tyrvaya® (varenicline solution 0.03 mg) Nasal Pump 
Study Objective: 
Primary objective 
To determine the safety of the Tyrvaya® Nasal Pump.  In addition, 
Tear Film Break-Up Time and Schirmer’s Score will be evaluated, 
and Schirmer Test Strips will be collected at Baseline and Visits 1 
and 2 for analysis to evaluate tear composition.  
Overall Study Design 
Methodology: 
This is a single center study.  30 subjects will participate in this 
study to demonstrate the safety of the Tyrvaya® (varenicline solution 
0.03 mg) nasal pump that has been modified to include additional 
silicone lubricant to improve pump activation.  Subjects will also be 
provided with the nasal guide to utilize with Tyrvaya® 
administration. 
Schirmer Test Strips will also be collected to evaluate tear 
composition.   
Duration: 
This study will consist of two visits over 7 days.  
Controls: 
Not applicable, this is an open-label sub-study. 
Dosing Regimen: 
Subjects will administer Tyrvaya® BID with the use of the nasal 
guide for 7 days.  
Summary of Visit 
Schedule 
At Visit 1, subjects will be dispensed one bottle of Tyrvaya® 
(varenicline solution 0.03 mg) nasal spray using the modified pump 
and administer one spray of nasal spray in each nostril.  Schirmer’s 
score and Test Strips will be collected pre and post treatment for 
tear composition analysis.   
At Visit 2, subjects will administer one spray of nasal spray in each 
nostril.  Schirmer Test Strips will be collected pretreatment for 
exploratory tear composition analysis.     
In between study visits, subjects will administer one spray of the 
nasal spray in each nostril twice daily (BID) with the use of the 
nasal guide approximately 12 hours apart at home.   


Tyrvaya® 
 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
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Measures Taken to 
Reduce Bias: 
Not applicable.  This is an open label study.  


Tyrvaya® 
 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
Page 5 of 38 
 
Study Population Characteristics 
Number of 
Subjects: 
30 subjects 
Condition/Disease: 
Dry Eye Disease 
Inclusion Criteria: 
Subjects must: 
1. Be at least 18 years of age 
 
 
 
3. Have provided verbal and written informed consent. 
 
 
 
 
 
6. Willing to comply with all study-related visits and 
procedures. 
 
 
  
Exclusion Criteria: 
 
 
   
 
 
3. 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.   
Study Endpoints: 
Primary endpoints 
 Incidence of adverse events 
Safety Measures: 
 Adverse Events 
Exploratory 
Endpoints: 
 Tear Film Break Up Time (TFBUT) 
 EDS (Eye Dryness Score) 
 Schirmer’s Cytokine Analysis 


Tyrvaya® 
 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
Page 6 of 38 
 
Statistical Methods: 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Summary of Known and Potential Risks and Benefits to Human Subjects 
Refer to the Tyrvaya® Package Insert regarding the risks and benefits to human subjects.  
There are no known risks associated with the use of the nasal pump or nasal guide. 
 


Tyrvaya® 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
21 Nov 2023 
CONFIDENTIAL 
Page 7 of 38 
TABLE OF CONTENTS 
SYNOPSIS ..................................................................................................................................... 3
TABLE OF CONTENTS ............................................................................................................. 7
LIST OF ABBREVIATIONS .................................................................................................... 11
1 
TYRVAYA® (varenicline solution 0.03 mg) NASAL PUMP ........................................... 12
2 
STUDY OBJECTIVES ....................................................................................................... 12
3 
CLINICAL HYPOTHESIS................................................................................................ 12
4 
OVERALL STUDY DESIGN ............................................................................................ 12
5 
STUDY POPULATION ..................................................................................................... 13
5.1
Number of Subjects..................................................................................................... 13
5.2
Study Population Characteristics .............................................................................. 13
5.3
Inclusion Criteria ........................................................................................................ 13
5.4
Exclusion Criteria ....................................................................................................... 13
5.5
Withdrawal Criteria ................................................................................................... 14
6 
STUDY PARAMETERS .................................................................................................... 14
6.1
Primary Endpoint ....................................................................................................... 14
6.2
Safety Measures .......................................................................................................... 14
6.3
Exploratory Endpoints ............................................................................................... 14
7 
STUDY MATERIALS ........................................................................................................ 14
7.1
Silicone Nasal Pump ................................................................................................... 14
7.2
Tyrvaya® ...................................................................................................................... 14
8 
STUDY METHODS AND PROCEDURES ..................................................................... 15
8.1
Subject Entry Procedures .......................................................................................... 15
8.1.1 Overview .................................................................................................................. 15
8.1.2 Informed Consent ................................................................................................... 15


Tyrvaya® 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
21 Nov 2023 
CONFIDENTIAL 
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8.1.3 Washout Intervals ................................................................................................... 15 
8.1.4 Procedures for Final Study Entry ......................................................................... 15 
8.1.5 Methods for Assignment to Treatment Groups ................................................... 15 
8.2 
Concomitant Therapies .............................................................................................. 15 
8.2.1 Prohibited Medications .......................................................................................... 15 
8.2.2 Escape Medications ................................................................................................. 15 
8.2.3 Special Diet or Activities ........................................................................................ 15 
8.3 
Examination Procedures ............................................................................................ 16 
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objectives(s) ........................................................................................................................ 16 
8.4 
Schedule of Visits, Measurements and Dosing ......................................................... 17 
8.4.1 Scheduled Visits ...................................................................................................... 17 
8.4.2 Unscheduled Visits .................................................................................................. 17 
8.5 
Compliance with Protocol .......................................................................................... 17 
8.6 
Subject Disposition...................................................................................................... 17 
8.6.1 Completed Subjects ................................................................................................ 17 
8.6.2 Discontinued Subjects ............................................................................................. 18 
8.7 
Study Termination ...................................................................................................... 18 
8.8 
Study Duration ............................................................................................................ 18 
8.9 
Monitoring and Quality Assurance ........................................................................... 18 
9 
SAFETY DEFINITIONS, MONITORING AND REPORTING ................................... 19 
9.1 
Adverse Events ............................................................................................................ 19 
9.1.1 Severity..................................................................................................................... 19 
9.1.2 Relationship ............................................................................................................. 19 
9.1.3 Expectedness ............................................................................................................ 20 


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Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
21 Nov 2023 
CONFIDENTIAL 
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9.2 
Serious Adverse Events .............................................................................................. 20 
9.3 
Procedures for Reporting Adverse Events ............................................................... 21 
9.3.1 Reporting a Suspected Unexpected Adverse Reaction ........................................ 21 
9.3.2 Reporting a Serious Adverse Event....................................................................... 21 
9.4 
Procedures for Unmasking......................................................................................... 22 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ................ 22 
10 STATISTICAL METHODS .............................................................................................. 22 
10.1 
Primary Endpoint ....................................................................................................... 22 
10.1.1 
Primary Endpoint ............................................................................................... 22 
10.2 
Analysis Populations ................................................................................................... 22 
10.2.1 
Safety Population ................................................................................................ 22 
10.3 
Statistical Analysis ...................................................................................................... 22 
10.3.1 
General Considerations ...................................................................................... 23 
10.3.2 
Safety Analysis .................................................................................................... 23 
10.3.3 
Interim Analysis .................................................................................................. 24 
11 Compliance with Good Clinical Practices, Ethical Considerations, and Administrative 
Issues ............................................................................................................................................ 24 
11.1 
Protection of Human Subjects ................................................................................... 24 
11.1.1 
Subject Informed Consent ................................................................................. 24 
11.1.2 
Institutional Review Board Approval ............................................................... 25 
11.2 
Ethical Conduct of Study ........................................................................................... 25 
11.3 
Subject Confidentiality ............................................................................................... 25 
11.4 
Documentation ............................................................................................................ 25 
11.4.1 
Retention of Documentation .............................................................................. 25 
11.5 
Labeling, Packaging, Storage, Accountability, and Return or Disposal................ 26 


Tyrvaya® 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
21 Nov 2023 
CONFIDENTIAL 
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11.5.1 
Labeling and Packaging ..................................................................................... 26 
11.5.2 
Storage of Tyrvaya® and the Nasal Guide ........................................................ 26 
11.5.3 
Accountability of Tyrvaya® and the Nasal Guide ............................................ 26 
11.5.4 
Return or Disposal of Tyrvaya® and the Nasal Guide..................................... 27 
11.6 
Recording of Data on Source Documents and Electronic Case Reports Forms ... 27 
11.7 
Handling of Biological Specimens ............................................................................. 27 
11.8 
Publications ................................................................................................................. 27 
12 REFERENCES .................................................................................................................... 29 
13. Appendices ........................................................................................................................... 30 
Schedule of Visits And Measurements .......................................................... 30 
Appendix 1: 
Appendix 2: 
Examination Procedures, Tests, Equipment, and Techniques ................... 31 
Tear Film Break-Up Time (TFBUT)..................................................................................... 31 
Eye Dryness Score (EDS) Using a Visual Analog Scale (VAS) ........................................... 31 
TYRVAYA® Instructions for Use.................................................................. 32 
TYRVAYA® Nasal Guide Instructions for Use............................................ 35 
Sponsor Approvals .......................................................................................... 37 
Appendix 3: 
Appendix 4: 
Appendix 5: 
Appendix 6: 
Investigator’s Signature ................................................................................. 38 


Tyrvaya® 
 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
BID 
Twice a Day 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
eCRF 
Electronic Case Report Form 
EDS 
Eye Dryness Score 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ISS 
Integrated Summary of Safety 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
PI 
Package Insert 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TFBUT 
Tear Film Break Up Time 
US 
United States 
VAS 
Visual Analog Scale 


Tyrvaya® 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
21 Nov 2023 
CONFIDENTIAL 
Page 12 of 38 
1 TYRVAYA® (varenicline solution 0.03 mg) NASAL PUMP 
 
 
 
   
 
 
 
 
 
2 STUDY OBJECTIVES 
To determine the safety of the Tyrvaya® (varenicline solution 0.03 mg) Nasal Pump with silicone 
lubricant.  In addition, Schirmer Test Strips will be collected at baseline and Visits 1 and 2 for 
analysis to evaluate tear composition.   
3 CLINICAL HYPOTHESIS 
This study is testing the hypothesis that the use of the Tyrvaya® nasal pump with the additional 
silicone lubricant does not introduce any additional safety concerns as compared to the safety of 
the Tyrvaya® nasal pump without the additional silicone lubricant.   
4 OVERALL STUDY DESIGN 
This is a single center, open-label study to evaluate the safety of the Tyrvaya® (varenicline 
solution 0.03 mg) nasal pump with silicone lubricant.  In addition, Schirmer Test Strips will be 
collected to evaluate tear composition.   
At Visit 1, subjects will be dispensed one bottle of Tyrvaya® (varenicline solution 0.03 mg) nasal 
spray that is coated with an additional silicone lubricant and administer one spray of nasal spray 
in each nostril with the use of the nasal guide.  Tear Film Break up Time will be assessed, and 
Schirmer’s score and Test Strips will be collected pre and post treatment for tear composition 
analysis.   


Tyrvaya® 
 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
Page 13 of 38 
 
At Visit 2, subjects will administer one spray of nasal spray in each nostril with the use of the 
nasal guide.  Tear Film Break up Time will be assessed, and Schirmer Test Strips will be 
collected pre  treatment for tear composition analysis.          
In between study visits, subjects will administer one spray of the nasal spray in each nostril twice 
daily (BID) with the use of the nasal guide approximately 12 hours apart at home.   
5 STUDY POPULATION 
5.1 
Number of Subjects 
30 subjects will be enrolled at one study site in the United States (US).    
5.2 
Study Population Characteristics  
All subjects must be at least 18 years of age, of any gender and race and must meet all inclusion 
criteria and none of the exclusion criteria.  
5.3 
Inclusion Criteria 
1. Be at least 18 years of age. 
 
 
3. Have provided verbal and written informed consent. 
 
 
 
 
 
6. Willing to comply with all study related visits and procedures. 
 
 
 
5.4 
Exclusion Criteria  
 
  
   
 
 
 
3. 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.   


Tyrvaya® 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
21 Nov 2023 
CONFIDENTIAL 
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5.5 
Withdrawal Criteria  
If at any time during the study the Investigator determines that a subject’s safety has been 
compromised, the subject may be withdrawn from the study, but will be followed for safety for 
the duration of the study, unless they refuse to attend follow-up visits.  
A subject may withdraw consent from the study at any time.  
The Sponsor and/or the Investigator may discontinue any subject from study treatment for non-
compliance or for any valid medical reason during the study (see Section 8.6.2).  
6 STUDY PARAMETERS 
6.1 
Primary Endpoint 

Incidence of adverse events
6.2 
Safety Measures 

Adverse events
6.3 
Exploratory Endpoints 

TFBUT

Schirmer’s Cytokine Analysis

EDS
7 STUDY MATERIALS 
7.1 
Silicone Nasal Pump 
An additional silicone lubricant has been added to the nasal pump for Tyrvaya to improve pump 
activation. 
7.2 
Tyrvaya® 
Please see Tyrvaya package insert for additional information.  


Tyrvaya® 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
21 Nov 2023 
CONFIDENTIAL 
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8 STUDY METHODS AND PROCEDURES 
8.1 
Subject Entry Procedures 
8.1.1 Overview  
Subjects as defined by the criteria in Section 5.2, Section 5.3 and Section 5.4 will be considered 
for entry into this study.  
8.1.2 Informed Consent  
Prior to a subject’s enrollment in the trial (i.e., prior to any study-related procedures), the study 
will be discussed with each potential subject and subject wishing to participate must be 
administered and provide written informed consent using an Institutional Review Board (IRB)-
approved informed consent form (ICF). The ICF must be the most recent version that has 
received approval by a properly constituted IRB.  
8.1.3 Washout Intervals  
There are no washout intervals for this study. 
8.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion criteria. 
8.1.5 Methods for Assignment to Treatment Groups 
Not applicable as this is an open label study.   
8.2 
Concomitant Therapies  
The use of any concurrent medication, prescription or over the counter, is to be recorded on the 
subject’s source document and corresponding eCRF along with the reason the medication was 
taken.  
8.2.1 Prohibited Medications 
There are no prohibited medications for this study.   
8.2.2 Escape Medications 
No escape medications are required for this study. 
8.2.3 Special Diet or Activities  
No special diets or activity is required for this study. 


Tyrvaya® 
 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
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8.3 
Examination Procedures  
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study Objectives(s) 
The following procedures will be performed (see Appendix 1 for description).   
This is a single center, open-label study to evaluate the safety of the Tyrvaya® (varenicline 
solution 0.03 mg) nasal pump with additional silicone lubricant.  Tear Film Break up time will be 
assessed and Schirmer’s Score and Test Strips will be collected to evaluate tear composition.  In 
between study visits, subjects will administer one spray of the nasal spray in each nostril twice 
daily (BID) with the use of the nasal guide approximately 12 hours apart at home.   
Visit 1 (Day 1): Screening and Enrollment 
 Informed consent/Health Information Portability and Accountability Act (HIPAA) 
consent 
 Demographic data, medical history, prior medication (s), and ocular history 
 Eye Dryness Score (EDS) 
 Tear Film Break up Time (TBUT) 
 Schirmer’s Test and tear strip collection (pre-treatment) 
 Eligibility Criteria 
 Enrollment 
 Review Tyrvaya® Instructions for Use (IFU)  
 Review Tyrvaya Nasal Guide IFU 
 Dispense Tyrvaya® 
 Subject Administration of Tyrvaya®  
 Schirmer’s Test (concurrent with treatment) and tear collection 
 Adverse Event Query 
Visit 2 (Day 7±2) 
 EDS 
 TFBUT 
 Schirmer’s Test and tear strip collection 
 Subject administration of Tyrvaya®  
 Concomitant Medications 
 Adverse Events Query 


Tyrvaya® 
 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
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Early Termination 
 EDS 
 TFBUT 
 Schirmer’s Test and tear strip collection 
 Concomitant Medications 
 Adverse Event Query 
8.4 
Schedule of Visits, Measurements and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2 Unscheduled Visits  
These visits may be performed to ensure subject safety. All procedures performed at an 
unscheduled visit will be recorded in the source documents and on the Unscheduled Visit eCRF 
pages. Any procedure indicated in the eCRF that is not performed should be indicated as “Not 
done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
 Assessment of AEs 
 EDS 
 TFBUT 
 Schirmer’s Test 
 Any other assessments needed in the judgment of the Investigator. 
8.5 
Compliance with Protocol  
Subjects will be instructed on the proper use and storage of Tyrvaya®, the nasal guide, and 
written instructions for use at Visit 1. 
8.6 
Subject Disposition  
8.6.1 Completed Subjects  
A Completed Subject is one who has completed Visit 1 and Visit 2.   


Tyrvaya® 
 
Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
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8.6.2 Discontinued Subjects 
Subjects may be discontinued from treatment, or from involvement in the study at any time prior 
to their completion of the study due to: 
 Non-fatal adverse event 
 Protocol violations 
 Disease progression 
 Lost to follow-up. 
 Physician decision 
 Subject non-compliance 
 Death 
 Study terminated by the Sponsor 
 Withdraw by subject (e.g., withdrawal of consent); and 
 Other 
Note: In addition, any subject may be discontinued from treatment or from study involvement for 
any sound medical reason at the discretion of the Investigator (after consultation with the 
Sponsor) or the Sponsor. 
Notification of a subject discontinuation and the reason for discontinuation will be made to the 
Sponsor and will be clearly documented on the eCRF. 
If a subject discontinues from treatment, the subject will be asked to be followed for safety for 
the duration of the study, unless they refuse to attend follow-up visits.  
Discontinued subjects may be replaced. 
8.7 Study Termination  
The study may be stopped at any time by the Investigator and/or Sponsor, with appropriate 
notification.  
8.8 Study Duration  
An individual subject’s participation will involve 2 visits over 7 days.   
8.9 Monitoring and Quality Assurance 
 
 
 
 


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Oyster Point Pharma, Inc. 
Clinical Trial Protocol: OPP-010 
 
21 Nov 2023 
 
CONFIDENTIAL 
 
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9  SAFETY DEFINITIONS, MONITORING AND REPORTING 
9.1 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
a drug or device in humans, whether the event is considered drug or device related or not. An AE 
can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease occurring after the subject started dosing with the device, without any 
judgment about causality. Any pre-existing medical condition that worsens after administration 
of Tyrvaya® will also be considered a new AE.  
AE collection will start following the first administration of Tyrvaya® with the additional 
silicone in the nasal pump until the last follow up visit of the study. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to study drug, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the Investigator or reported by the subject upon indirect questioning. 
9.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the Investigator or reported to him/her by the patient/subject. The assessment of 
severity is made irrespective of relationship to study drug or seriousness of the event and should 
be evaluated according to the following scale: 
 Mild:  
Event is noticeable to the subject but is easily tolerated and does not 
interfere with the subject’s daily activities. 
 Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
 Severe:  
Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the subject’s daily activities. 
9.1.2 Relationship  
The relationship of each AE to the investigational product should be determined by the 
Investigator (in a blinded manner) using these explanations: 
 Definite: When there are good reason and sufficient documentation to demonstrate a 
direct causal relationship between investigational product and AE 
 Probable: When there are good reasons and sufficient documentation to assume a 
causal relationship in the sense of plausible, conceivable, likely but not necessarily 
highly probable 
 Possible: When there is sufficient information to accept the possibility of a causal 
relationship in the sense of not impossible and not unlikely, although the connection 
is uncertain or doubtful, for example, due to missing data or insufficient evidence. 


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Clinical Trial Protocol: OPP-010 
 
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 None: 
When there is sufficient information to accept a lack of a causal 
relationship, in the sense of impossible and improbable. 
 Unclassified: When the causal relationship is not assessable for whatever reason due 
to insufficient evidence, conflicting data, or poor documentation. 
9.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information about 
the study drug using these explanations: 
 Unexpected: An AE that is not listed in the Package Insert (PI) or is not listed at the 
specificity or severity that has been observed. 
 Expected: An AE that is listed in the IB at the specificity and severity that has been 
observed. 
 Not Applicable: Any AE that is unrelated to the study drug. 
AEs that are mentioned in the PI as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug but are not specifically mentioned as occurring with the 
drug under investigation are to be considered unexpected. 
The Investigator should initially classify the expectedness of an AE, but the final classification is 
subject to the Medical Monitor’s determination. 
9.2 
Serious Adverse Events 
An AE is considered a serious adverse event (SAE) if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes: 
 Death 
 A life-threatening AE 
Note: An AE is considered “life-threatening” if, in the view of either the Investigator or Sponsor, 
its occurrence places the patient or subject at immediate risk of death. It does not include an AE 
that, had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if less than 24 
hours). For chronic or long-term inpatients, inpatient admission includes transfer within the 
hospital to an acute/intensive care inpatient unit. Inpatient hospitalization does not include 
emergency room visits; outpatient/same day/ambulatory procedures; observation/short stay units; 
rehabilitation facilities; hospice facilities; nursing homes; or clinical research/phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension of an inpatient 
hospitalization beyond the stay anticipated or required for the reason for the initial admission as 
determined by the Investigator or treating physician. 
Note: Planned hospital admissions or surgical procedures for an illness or disease that was 
present before the patient received any study drug are not to be considered SAEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier than planned). 


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Clinical Trial Protocol: OPP-010 
21 Nov 2023 
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
A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions.
Note: An SAE specifically related to visual threat would be interpreted as any potential 
impairment or damage to the subject’s eyes (e.g., hemorrhage, retinal detachment, central 
corneal ulcer, or damage to the optic nerve). 

A congenital anomaly/birth defect in an offspring of a study subject.
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  
SAEs are collected at the time the subject signs the Informed Consent Form until the last follow 
up visit of the study.  
9.3 
Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to the Sponsor, and the IRB/IEC as required by the 
IRB/IEC, federal, state, or local regulations and governing health authorities and recorded on the 
appropriate eCRF. 
9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to the Sponsor and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health authorities. 
9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the device, must be reported 
within 24 hours of the Investigator’s knowledge. All information relevant to the SAE must be 
recorded on the appropriate CRFs. The Investigator is obligated to pursue and obtain information 
requested by the Sponsor in addition to that information reported on the CRF. All subjects 
experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the Investigator must obtain and maintain in his/her files all pertinent 
medical records, information, and medical judgments from colleagues who assisted in the 
treatment and follow-up of the subject; provide the Sponsor with a complete case history, which 
includes a statement as to whether the event was or was not suspected to be related to the use of 
the study drug; and inform the IRB of the SAE within their guidelines for reporting SAEs. 
Contact information for reporting SAEs: 
Name: 
Title: 
Company: 
Mobile Telephone: 
Email: 
 
 
 
 


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9.4 
Procedures for Unmasking  
Not applicable as this is an open label study. 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events 
The Investigator will follow unresolved AEs to resolution until the subject is lost to follow-up or 
until the AE is otherwise classified. Resolution means the subject has returned to baseline state 
of health or the Investigator does not expect any further improvement or worsening of the AE. If 
the patient is lost to follow-up, the Investigator should make 3 reasonable attempts to contact the 
patient via telephone, post, or certified mail. All follow-ups will be documented in the subject’s 
source document. Non-serious AEs identified on the last scheduled contact must be recorded on 
the AE eCRF with the status noted.  
New information relating to a previously reported serious adverse event must be submitted.  All 
new information for serious adverse events must be submitted within 24 hours following the 
investigator’s knowledge of new information.  The investigator may be asked to provide 
additional follow-up information, which may include discharge summary or extracts from the 
medical record.  
10 STATISTICAL METHODS 
Statistical considerations and methods of analyses for this study are provided below; the 
accompanying Statistical Analysis Plan (SAP) contains complete details of the planned analyses. 
10.1 Primary Endpoint 
10.1.1 Primary Endpoint 
 Incidence of Adverse Event 
10.2 Analysis Populations 
10.2.1 Safety Population 
The safety population will include all enrolled subjects who received at least one Tyrvaya® 
administered with the nasal pump with additional silicone. 
10.3 Statistical Analysis 
This section briefly outlines the planned analyses. The statistical analysis plan (SAP) describes 
the methods to be used in detail. If the SAP and the protocol disagree, the details and methods of 
the SAP will prevail.  
The AE data collected from this study will be compared with the historical AE data collected for 
Tyrvaya® alone from OC-01 (varenicline solution) nasal spray Integrated Summary of Safety 


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(ISS). The data comparison will be presented descriptively without inferential statistics 
comparison.   
10.3.1 General Considerations 
No formal sample size calculation will be made in this pilot study. All data, including 
demographic and baseline characteristics and endpoint measures, will be summarized 
descriptively. Continuous variables will be summarized with mean, median, standard deviation 
and range. Categorical variables will be summarized with frequency and percentage. 
10.3.2 Safety Analysis 
The investigator will promptly review each Adverse Event (AE) for accuracy and completeness, 
and classify each AE according to its intensity, its relationship to drug or administration 
procedure, and its seriousness. AEs will be coded using version 26.0 of the MedDRA dictionary. 
AEs will be monitored throughout the study and documented on the appropriate AE form. AEs 
will be categorized as ocular and non-ocular events as well as by system organ class (SOC) and 
preferred term (PT), seriousness, severity, and relation to study medications.  
All treatment-emergent adverse events (TEAEs) will be summarized.  A TEAE is defined as an 
AE that is new or worsened in severity compared to the first dose of study drug.  
TEAEs will be summarized by subject. In addition, the number of TEAE episodes that occurred 
during the study will be provided in the overall summary of AE table.  
The following presentations of TEAEs will be generated: 
 Overall adverse events summary (including any TEAEs, ocular TEAEs, resolved ocular 
TEAEs, non-ocular TEAEs, ocular TEAEs, non-ocular TEAEs, SAEs, treatment- 
emergent SAEs, treatment-related treatment emergent SAEs, TEAEs by maximum 
severity, TEAEs by relationship to study drug, AEs leading to treatment/study 
discontinuation) 
 Serious adverse events (SAE) by SOC and PT; 
 All ocular TEAEs by SOC and PT; 
 All non-ocular TEAEs by SOC and PT; 
 TEAEs leading to treatment discontinuation; 


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 TEAEs leading to study discontinuation 
10.3.3 Interim Analysis 
No interim analysis is planned for this study.  
11 Compliance with Good Clinical Practices, Ethical Considerations, and 
Administrative Issues  
This study will be conducted in compliance with this protocol, Good Clinical Practices, 
including the International Conference on Harmonization (ICH) Guidelines, and in general, 
consistent with the Declaration of Helsinki. In addition, all applicable local, state, and federal 
requirements relevant to the use of study drugs/devices in the countries involved will be adhered 
to. 
11.1 Protection of Human Subjects 
11.1.1 Subject Informed Consent  
Informed consent/assent must take place before any study specific procedures are initiated. 
Signed and dated written informed consent must be obtained from each subject and/or from the 
subject’s parent or legal guardian prior to enrollment into the study. If the subject is under the 
legal age of consent, the consent form must be signed by a legal guardian or as required by state 
and/or local laws and regulations. 
All informed consent/assent forms must be approved for use by the Sponsor and receive 
approval/favorable opinion from an IRB prior to their use. If the consent form requires revision 
(e.g., due to a protocol amendment or significant new safety information), it is the Investigator’s 
responsibility to ensure that the amended informed consent is reviewed and approved by Sponsor 
prior to submission to the governing IRB and that it is read, signed and dated by all subjects 
subsequently enrolled in the study as well as those currently enrolled in the study. 
If informed consent is taken under special circumstances (oral informed consent), then the 
procedures to be followed must be determined by Sponsor and provided in writing by Sponsor 
prior to the consent process. 


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11.1.2 Institutional Review Board Approval 
This study is to be conducted in accordance with IRB regulations [U.S. 21 Code of Federal 
regulations (CFR) Part 56.103]. The Investigator must obtain appropriate IRB approval before 
initiating the study and re-approval at least annually. 
Only an IRB-approved version of the informed consent form will be used. 
11.2 Ethical Conduct of Study  
 
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
11.3 Subject Confidentiality  
All personal study subject data collected and processed for the purposes of this study should be 
maintained by the Investigator and his/her staff with adequate precautions so as to ensure the 
confidentiality of the data in accordance with local, state, and federal laws and regulations. 
Monitors, auditors and other authorized representatives of the Sponsor, the IRB approving this 
study, the Food and Drug Administration, the Department of Health and Human Services, other 
domestic government agencies, and other foreign regulatory agencies will be granted direct 
access to the study subject’s original medical and study records for verification of the data and/or 
clinical trial procedures. Access to this information will be permitted to the above listed 
individuals to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health authorities 
in any country in which the study drug may ultimately be marketed, but the subject’s identity 
will not be disclosed in these documents. 
11.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
Investigator’s study subject files, as well as the results of diagnostic tests such as photographs, 
X-rays, laboratory tests, and electrocardiograms. The Investigator’s copy of the CRFs serves as 
the Investigator’s record of a subject’s study-related data. 
11.4.1 Retention of Documentation  
All study related correspondence, subject records, consent forms, record of the distribution and 
use of all study drug and copies of CRFs should be maintained on file for at least two years after 


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the last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region; or until at least two years have elapsed 
since the formal discontinuation of clinical development of the study drug. These documents will 
be retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will accept 
the responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal  
11.5.1 Labeling and Packaging  
Tyrvaya® will be provided in multi-use intranasal applicator with additional silicone lubricant 
added to the nasal pump.   
Additionally, the nasal guide will be provided individually wrapped and sealed in plastic storage 
bag.  Please refer to the nasal guide package insert for additional information.    
11.5.2 Storage of Tyrvaya® and the Nasal Guide 
Tyrvaya® can be stored ambient temperature at 20°C to 25°C (68°F to 77°F).   
The nasal guide can be stored ambient temperature at 20°C to 25°C (68°F to 77°F).   
 
11.5.3 Accountability of Tyrvaya® and the Nasal Guide 
Tyrvaya® and the nasal guide utilized in this study is only to be prescribed by the principal 
Investigator or his/her named sub investigator(s) and can only be used in accordance with this 
protocol. Tyrvaya® and the nasal guide must only be distributed to subjects properly qualified 
under this protocol. The Investigator must keep an accurate accounting by maintaining a detailed 
inventory. This includes the amount received by the site, amount dispensed to subjects, amount 
returned to the site by the subjects, and the amount returned to the Sponsor upon the completion 
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11.5.4 Return or Disposal of Tyrvaya® and the Nasal Guide 
You may be requested to destroy Tyrvaya® and/or the nasal guide on-site that are expired, not 
acceptable for use due to a temperature deviation, or at the end of the study. If site regulations do 
not permit destruction, study drugs will be returned to the Sponsor or their designee for 
destruction. 
11.6 Recording of Data on Source Documents and Electronic Case Reports Forms 
All subject data will be captured in the subject source documents which will be transcribed in the 
eCRFs. The Investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s eCRF, source documents, and all study-related materials. All study 
data should also be attributable, legible, contemporaneous, and original. A recorded datum 
should only be corrected in a manner that does not obliterate, destroy, or render illegible the 
previous entry (e.g., by drawing a single line through the incorrect entry and writing the revision 
next to the corrected data). An individual who has corrected a data entry should make clear who 
made the correction and when, by adding to the correction his/her initials as well as the date of 
the correction.  
Data entry of all enrolled and randomized subjects will use software that conforms to 21 CFR 
Part 11 requirements and will be performed only by staff who have been trained on the system 
and have access to the system. Minimal data will be entered for screen failure subjects. An audit 
trail will be maintained within the electronic system to capture all changes made within the 
eCRF database. After the end of the study and database lock, electronic copies of all applicable 
subjects’ eCRFs will be provided to each Investigator Site to be maintained on file by the 
Investigator. 
11.7 Handling of Biological Specimens  
All Schirmer’ test strip samples and associated results will be coded prior to being shipped from 
the site for analysis or storage.  Schirmer’s test strips will be tracked using a unique identifier 
that is assigned to the samples for the study.  Results will be stored in a secure database to ensure 
confidentiality.   
11.8 Publications 
The study will be documented in a final report, which will contain appropriate statistical analysis 
and medical overview. No individual site or Investigator may publish or present any results from 


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the study until the Sponsor has completed a joint, multi-center publication of the study results in 
conjunction with various participating Investigators and appropriate sites contributing data and 
comments. Subsequently, individual Investigators may request to publish or present results from 
the study; however, approval will be at the sole discretion of the Sponsor. Should the foregoing 
language conflict with the language addressing publication in the clinical trial agreement, the 
language in the clinical trial agreement will prevail.  
 


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12 
REFERENCES 
 
 


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13. Appendices  
 
  
 
 
 
 
 


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APPENDIX 2:  
EXAMINATION PROCEDURES, TESTS, EQUIPMENT, 
AND TECHNIQUES  
Tear Film Break-Up Time (TFBUT) 
One to 2 drops of ophthalmic saline will be used to wet a standard fluorescein strip (without 
anesthesia), which the examiner will gently touch to the inferior conjunctival cul-de-sac of each 
eye. The subject will be instructed to blink several times to mix the fluorescein with the tear film 
thoroughly. In order to achieve maximum fluorescence, the examiner should wait approximately 
30 seconds after instillation before evaluating TFBUT. 
With the aid of a slit lamp, the examiner will monitor the integrity of the tear film, noting the 
time it takes to form micelles from the time that the eye is opened. TFBUT will be measured in 
seconds using a stopwatch for the right eye followed by the left eye. A Wratten #12 yellow filter 
will be used to enhance the ability to grade TFBUT.  For each eye, 2 measurements will be taken 
and averaged unless the 2 measurements are > 2 seconds apart and are each < 10 seconds, in 
which case, a third measurement would be taken, and the 2 closest of the 3 would be averaged. 
 
Eye Dryness Score (EDS) Using a Visual Analog Scale (VAS) 
Participants will be asked the following question regarding eye dryness every 5 minutes during 
CAE® exposure.  
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)   
 
 
 
No 
Discomfort 
Maximal 
Discomfort 


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Appendix 3: 
TYRVAYA® Instructions for Use 
 


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Appendix 4: 
TYRVAYA® Nasal Guide Instructions for Use 
 
 


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Appendix 5: 
Sponsor Approvals 
 
Protocol Title: 
A Phase 4, Single-Center, Open-Label Study Evaluating the Safety of 
the Tyrvaya® Nasal Pump  
Protocol Number: 
OPP-010 


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Appendix 6:  
Investigator’s Signature  
 
Protocol Title: 
A Phase 4, Single-Center, Open-Label Study Evaluating the Safety of 
the Tyrvaya® Nasal Pump 
Protocol Number: 
OPP-010 
I agree to implement and conduct the study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. I agree to maintain all 
information supplied by the Sponsor in confidence and, when this information is submitted to an 
Institutional Review Board (IRB) or another group, it will be submitted with a designation that 
the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all aspects. 
 
 
Signed: ____________________________ 
Date: _____________________________ 
 
Name: _____________________________ 
 
 
Title: ______________________________ 
 
 
Site: _______________________________ 
 
 
Address: ____________________________ 
 
 
Phone Number: _______________________