Clinical trial NCT04036292
Conditions: Dry Eye Disease (DED)
Sponsor: Oyster Point Pharma, Inc.
Start date: 2019-07-23; Completion date: 2021-02-05
Enrollment: 758 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the safety and effectiveness of OC-01 Nasal Spray as compared to placebo on signs and symptoms of dry eye disease.

Detailed description:
This was a Phase 3, multicenter, randomized, controlled, double-masked (including subjects, Investigators, study site personnel, and Sponsor personnel) study designed to evaluate the safety and efficacy of OC-01 (varenicline) nasal spray 0.6 mg/mL and 1.2 mg/mL in adult participants with DED. The study randomized 758 subjects at least 22 years of age with a physicians' diagnosis of DED and meeting all other study eligibility criteria to receive OC-01 (varenicline) nasal spray or placebo twice daily (BID) for 28 days with three additional long-term follow-up visits at 6 weeks, 6 months, and 12 months. Participants who terminated from the study during the treatment period were asked to complete safety assessments (if the participants agree) prior to study exit. Participants who were terminated early from the study were not replaced

Arms: arm 1: OC-01 (varenicline) nasal spray, 0.6 mg/ML arm 2: OC-01 (varenicline) nasal spray, 1.2 mg/ML arm 3: Placebo (vehicle) nasal spray
Interventions: intervention 1: OC-01 (varenicline) nasal spray intervention 2: Placebo (vehicle) nasal spray
Intervention descriptions: intervention 1: OC-01 (varenicline) nasal spray intervention 2: Placebo (vehicle) nasal spray

Protocol documents:
Prot_002.pdf: 
OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
September 18, 2019 
Amendment #1 
 
 
CONFIDENTIAL 
Page 1 of 55 
 
Clinical Trial Protocol  
 
Protocol Title: 
A Phase 3, Multicenter, Randomized, Controlled, Double-
Masked, Clinical Trial to Evaluate the Efficacy and Safety 
of OC-01 (varenicline) Nasal Spray on Signs and 
Symptoms of Dry Eye Disease (The ONSET-2 Study) 
Protocol Number: 
OPP-101 
Study Phase: 
3 
Product Name: 
OC-01 (varenicline) Nasal Spray 
 
 
Indication: 
Dry Eye Disease  
Investigators: 
Multi-Center  
 
Sponsor: 
Oyster Point Pharma, Inc. 
202 Carnegie Center 
Suite 109 
Princeton, NJ 08540 
 
Contract Research 
Organization: 
 
 
 
 
 
 
Institutional Review 
Board: 
 
 
 
 
 
Date 
Original Protocol: 
June 3, 2019 
Amendment #1: 
September 18, 2019 
Confidentiality Statement  
This protocol contains confidential, proprietary information of
 and/or Oyster Point 
Pharma, Inc. Further dissemination, distribution or copying of this protocol or its contents is 
strictly prohibited. 


OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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SPONSOR PERSONNEL 
 
 
.  
 
  
MEDICAL MONITOR 
Medical Monitor: 
 
 
 
 
 
 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
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SYNOPSIS  
Protocol Title: 
A Phase 3, Multicenter, Randomized, Controlled, Double-Masked 
Clinical Trial to Evaluate the Efficacy and Safety of OC-01 
(varenicline) Nasal Spray on Signs and Symptoms of Dry Eye Disease 
(The ONSET-2 Study) 
Protocol Number: 
OPP-101 
Investigational 
Product:  
OC-01 (varenicline) Nasal Spray: 
x 0.6 mg/mL  
x 1.2 mg/mL  
Study Objective: 
The objective of this study is to evaluate the safety and effectiveness of 
OC-01 (varenicline) Nasal Spray as compared to placebo on signs and 
symptoms of dry eye disease (DED) 
 
Overall Study Design 
Structure: 
A Phase 3, multicenter, randomized, controlled, double- masked study 
Duration: 
Four (4) study visits over approximately 28 days during the treatment 
period with three (3) additional long-term follow-up visits at 6 weeks, 6 
months, and 12 months. 
Control: 
Placebo (OC-01 Vehicle Nasal Spray) 
Dosing Regimen:  
Intranasal delivery of OC-01 twice daily (BID) for 28 days of 
one of the following dose groups: 
x 0.6 mg/mL  
x 1.2 mg/mL  
x Placebo (vehicle) 
Summary of Visit 
Schedule: 
Visit 1- Screening and randomization (Day 1) 
Visit 2- Dosing Compliance Assessment (Week 1) 
Visit 3- Schirmer’s Score Assessment (Week 2) 
Visit 4- Primary and Secondary Endpoint Assessment 
x Symptom Assessment (EDS) in Controlled Adverse 
Environment (CAE) Chamber (Week 4) 
x Schirmer’s Score Assessment; Eye Dryness Score (EDS) 
Assessment (Week 4) 
Visit 5 – Safety Assessment (Week 6) 
Visit 6- Safety Assessment (Month 6) 
Visit 7- Safety Assessment (Month 12) 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
Page 8 of 55 
 
Study Formulations: 
Subjects will be randomized 1:1:1 to be treated with OC-01 
(varenicline) Nasal Spray delivered as a 50 microliter (μL) spray 
in each nostril at the following formulations: 
x 0.6 mg/mL  
x 1.2 mg/mL  
x Placebo (vehicle) 
 
Randomization: 
 The randomization will be stratified by three factors: 
x Pre-procedure (Baseline) anesthetized Schirmer’s score (<5, 
>5) measured the screening/randomization visit  
x Pre-procedure (Baseline) EDS (<60, >60) measured at the 
screening/randomization visit  
x Study site 
A central randomization list will be created using block randomization. 
Sites will be assigned entire blocks as needed. 
 
Evaluation Criteria 
Efficacy Measures:  
Primary Endpoint: 
x Percent of subjects who achieve ≥10 mm improvement in 
Schirmer’s Test Score from baseline at Visit 4 (Day 28) 
Secondary Endpoints 
x Mean change from Baseline in Eye Dryness Score (EDS) at 5 
minutes after threshold defined treatment administration in the 
Controlled Adverse Environment® Chamber at Visit 4 (Day 28) 
x Mean change from Baseline in Eye Dryness Score (EDS) at 
Visit 4 (Day 28) (Post STS) 
x Mean change from Baseline in Schirmer’s Test Score (STS) at 
Visit 4 (Day 28). 
x Mean change from Baseline in Corneal Fluorescein Staining at 
Visit 4 (Day 28) 
Safety Measures: 
x Adverse Event (AE) Query 
x Intranasal Exam 
x Slit Lamp Biomicroscopy 
Other Efficacy 
Measures: 
 N/A 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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Summary of Known and Potential Risks and Benefits to Human Subjects 
 
The administration of OC-01 0.6 mg/mL and 1.2 mg/mL (varenicline) Nasal Spray was safe, well 
tolerated, and efficacious as assessed in the ONSET-1 study. The study met the primary endpoint 
(Schirmer’s Test) for both the 0.6 mg/mL and 1.2 mg/mL dose groups. It also met the secondary 
symptom endpoints (EDS) for 0.6 mg/mL OC-01 (varenicline) Nasal Spray. There was not a 
statistically significant improvement in EDS in the normal environment at Day 28 for the 1.2 
mg/mL dose, although there was a numerical benefit as compared to placebo.  Because of the 
pre-specified hierarchical approach to multiplicity for the secondary outcomes, the EDS 
symptoms within the CAE® environment at Day 21 could not be formally tested; however, the 
data strongly suggest benefit on that outcome as well. Although the low dose of 0.12 mg/mL OC-
01 (varenicline) Nasal Spray demonstrated statistical significance in Schirmer’s Score in 
exploratory analyses, this dose did not yield statistically significant difference in the symptom 
endpoint in exploratory analyses as measured by EDS.   
Showing statistical significance in both signs and symptoms of DED in the same study population 
is a goal seldom before achieved in the treatment of the disease.  Importantly, after treatment with 
OC-01 (varenicline) Nasal Spray, improvements in EDS were seen as early as 5 minutes after 
administration in the CAE® in the 0.6 mg/mL and 1.2 mg/mL OC-01 (varenicline) Nasal Spray 
dose groups.  Exploratory analyses of fluorescein corneal staining indicate a benefit in subjects 
treated with OC-01 (varenicline) Nasal Spray compared to those subjects treated with placebo.   
 
OC-01 (varenicline) Nasal Spray was safe and well-tolerated at all concentrations assessed in the 
ONSET-1 clinical study.  Most TEAEs were mild to moderate in severity, with only 1 subject 
reporting a severe TEAE. 
 
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 TEAEs 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, intranasal examination, and pupil diameter did 
not indicate clinically significant changes from baseline. These data from the ONSET-1 study 
suggest that 28 days of BID delivery of OC-01 (varenicline) Nasal Spray is safe and efficacious in 
subjects with DED.  
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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Table of Contents 
 
Synopsis ...............................................................................................................................3 
List of Abbreviations .......................................................................................................13 
1 
Introduction .............................................................................................................14 
2 
Study Objectives......................................................................................................15 
3 
Clinical Hypotheses .................................................................................................16 
4 
Overall Study Design ..............................................................................................16 
5 
Study Population .....................................................................................................16 
5.1 
Number of Subjects ......................................................................................16 
5.2 
Study Population Characteristics ...............................................................16 
5.3 
Inclusion Criteria .........................................................................................16 
5.4 
Exclusion Criteria .........................................................................................18 
5.5 
Withdrawal Criteria .....................................................................................19 
6 
Study Parameters ....................................................................................................20 
6.1 
Efficacy Measures .........................................................................................20 
6.1.1 
Primary Efficacy Measure ................................................................20 
6.1.2 
Secondary Efficacy Measure ............................................................20 
6.2 
Safety Measures ............................................................................................20 
6.3 
Other Measures ............................................................................................20 
7 
Study Materials .......................................................................................................20 
7.1 
Study Drug(s) ................................................................................................20 
7.1.1 
Regimens...........................................................................................20 
7.1.2 
Dispensation Schedule ......................................................................21 
7.1.3 
General Appearance ..........................................................................21 
7.2 
Other Study Supplies ...................................................................................21 
8 
Study Methods and Procedures .............................................................................21 
8.1 
Participant Entry Procedures .....................................................................21 
8.1.1 
Overview ...........................................................................................21 
8.1.2 
Informed Consent..............................................................................21 
8.1.3 
Washout Intervals .............................................................................22 
8.1.4 
Procedures for Final Study Entry ......................................................22 
8.1.5 
Methods for Assignment to Treatment Groups ................................22 
8.2 
Concomitant Therapies ................................................................................22 
8.2.1 
Prohibited Medications/Treatments ..................................................22 
8.2.2 
Escape Medications ..........................................................................23 
8.2.3 
Special Diet or Activities ..................................................................23 
8.3 
Examination Procedures ..............................................................................23 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to Study 
Objectives(s) ...................................................................................................23 
8.4 
Schedule of Visits, Measurements and Dosing ..........................................26 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
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8.4.1 
Scheduled Visits................................................................................26 
8.4.2 
Unscheduled Visits ...........................................................................26 
8.5 
Compliance with Protocol ............................................................................26 
8.6 
Subject Disposition .......................................................................................26 
8.6.1 
Treatment Completed Subjects .........................................................26 
8.6.2 
Safety Follow up Completed Subjects ..............................................26 
8.6.3 
Discontinued Subjects .......................................................................27 
8.7 
Study Termination .......................................................................................27 
8.8 
Study Duration .............................................................................................27 
8.9 
Monitoring and Quality Assurance ............................................................27 
9 
safety definitions, safety monitoring and reporting .............................................28 
9.1 
Adverse Event ...............................................................................................28 
9.1.1 
Severity .............................................................................................28 
9.1.2 
Relationship to Study Drug ...............................................................28 
9.1.3 
Expectedness .....................................................................................29 
9.2 
Serious Adverse Events ................................................................................29 
9.3 
Procedures for Reporting Adverse Events .................................................30 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................30 
9.3.2 
Reporting a Serious Adverse Event ..................................................30 
9.4 
Procedures for Unmasking of Study Drug .................................................31 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ..31 
10 
Statistical Analysis ..................................................................................................32 
10.1 Primary and Secondary Endpoints .............................................................32 
10.2 Analysis Populations ....................................................................................32 
10.2.1 Intention-To-Treat Population ..........................................................32 
10.2.2 Safety Population ..............................................................................32 
10.3 Statistical Hypotheses ...................................................................................33 
10.4 Sample Size and Power Considerations .....................................................33 
10.5 Statistical Analysis ........................................................................................33 
10.5.1 General Considerations .....................................................................33 
10.5.2 Unit of Analysis ................................................................................34 
10.5.3 Subject Demographics and Baseline Characteristics ........................34 
10.5.4 Primary Efficacy Analysis ................................................................34 
10.5.5 Secondary Efficacy Analysis ............................................................34 
10.5.6 Safety Analysis .................................................................................35 
10.5.7 Interim Analysis ................................................................................35 
11 
Compliance with Good Clinical Practices, Ethical Considerations, and 
Administrative Issues..............................................................................................35 
11.1 Protection of Human Subjects.....................................................................35 
11.1.1 Subject Informed Consent.................................................................35 
11.1.2 Institutional Review Board Approval ...............................................36 
11.2 Ethical Conduct of Study .............................................................................36 
11.3 Subject Confidentiality ................................................................................36 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
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11.4 Documentation ..............................................................................................36 
11.4.1 Retention of Documentation .............................................................36 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ....................................................................................................37 
11.5.1 Labeling/Packaging...........................................................................37 
11.5.2 Storage of Investigational Drug / Placebo ...........................................37 
11.5.3 Accountability of Study Drug ...........................................................37 
11.5.2 Return or Disposal of Study Drug ....................................................37 
11.6 Recording of Data on Source Documents and Electronic Case Reports 
Forms .............................................................................................................37 
11.7 Handling of Biological Specimens ...............................................................38 
11.8 Publications ...................................................................................................38 
12 
References ................................................................................................................39 
13 
Appendices ...............................................................................................................42 
Appendix 1: Schedule of Visits and Measurements ......................................................43 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ..............44 
Visual Acuity Procedures .......................................................................................44 
Slit Lamp Biomicroscopy .......................................................................................46 
Corneal Fluorescein Staining .................................................................................46 
Intranasal Examination ..........................................................................................47 
Schirmer’s Test with Topical Anesthesia .............................................................48 
Ocular Surface Disease Index© ..............................................................................49 
Eye Dryness Score (EDS) Using a Visual Analog Scale (VAS) ...........................52 
Ocular Discomfort Scale ................................................................53 
Appendix 3: Sponsor 
Approvals .....................................................................54 
Appendix 4: Investigator’s Signature ............................................................................55 
 
 
 
 
 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
BCVA 
Best corrected visual acuity  
BID 
Two times a day 
CAE® 
Controlled adverse environment 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CRF 
Case report form 
eCRF 
Electronic Case Report Form 
EDS 
Eye Dryness Score 
DED 
Dry eye disease 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
logMAR 
Logarithm of the minimum angle of resolution 
LS 
Least Square 
MAD 
Mucosal Atomization Device 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
mg 
Milligram 
mL 
Milliliter 
μL 
microliter 
mm 
Millimeter 
nAChR 
Nicotinic acetylcholine receptor 
OSDI© 
Ocular Surface Disease Index© 
PP 
Per Protocol 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
STS 
Schirmer’s Test Score 
TEAE 
Treatment-emergent adverse event 
US 
United States 
 
 
 
 
 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
Page 20 of 55 
 
6 
STUDY PARAMETERS  
6.1 
Efficacy Measures  
6.1.1 Primary Efficacy Measure 
The following primary endpoints will be tested:  
x Percent of subjects who achieve ≥10 mm improvement in Schirmer’s Test Score 
(STS) from baseline at Visit 4 (Day 28) 
6.1.2 Secondary Efficacy Measure 
x Mean Change from Baseline in Eye Dryness Score (EDS) at 5 minutes after threshold 
defined treatment administration in the Controlled Adverse Environment® Chamber 
at Visit 4 (Day 28) 
x Mean Change from Baseline in Eye Dryness Score (EDS) at Visit 4 (Day 28) (Post 
STS) 
x Mean Change from Baseline in Schirmer’s Test Score (STS) at Visit 4 (Day 28) 
x Mean Change from Baseline in Corneal Fluorescein Staining at Visit 4 (Day 28) 
6.2 
Safety Measures 
x Adverse Events 
x Intranasal Exam 
x Slit Lamp Biomicroscopy 
6.3 
Other Measures 
x Urine pregnancy test (Visit 1 and Visit 4a/ET) 
7 
STUDY MATERIALS 
7.1 
Study Drug(s) 
7.1.1 Regimens 
The study drug will be delivered as a 50 microliter (μL) intranasal spray in each nostril BID: 
x OC-01 (varenicline) Nasal Spray, 0.6 mg/mL  
x OC-01 (varenicline) Nasal Spray, 1.2 mg/mL  
x Placebo (vehicle) 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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7.1.2 Dispensation Schedule  
x At Visit 1, qualified subjects will be randomized and the first dose of study drug will 
be administered in office concurrent with Schirmer’s test.  The second daily 
administration will happen at home. 
x At Visit 2, study drug/placebo will not be administered in office. Subject will self-
administer study drug/placebo following their routine schedule. 
x At Visit 3 the first daily dose of study drug will be administered in office concurrent 
with Schirmer’s testing.  The second daily administration will happen at home. 
x At Visit 4a subjects will receive their first daily dose of study drug during CAE® 
exposure. The second daily administration will happen at home.   
x At Visit 4b the first daily dose of study drug will be administered in office concurrent 
with Schirmer’s testing.   
x Between clinic visits, subjects will self-administer OC-01 (varenicline) Nasal Spray 
BID as a 50 μL dose in each nostril. 
7.1.3 General Appearance 
x OC-01 (varenicline) /Placebo Nasal Spray 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. 
x 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. 
x OC-01 (varenicline) solution must be administered without dilution.  
 
7.2 
Other Study Supplies  
For all other study supplies refer to the Non-IP supplies list. 
8 
STUDY METHODS AND PROCEDURES 
8.1 
Participant Entry Procedures  
8.1.1 Overview  
Participants as defined by the criteria in Sections 5.2, 5.3, and 5.4 will be considered for 
entry into this study.  
8.1.2 Informed Consent  
Prior to a participant’s enrollment in the trial (i.e., prior to any study-related procedures), the 
study will be discussed with each potential participant and participants 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.  
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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8.1.3 Washout Intervals  
Prohibited medications, treatments, and activities are outlined in the Exclusion Criteria 
(Section 5.4).  
8.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion criteria and none of the exclusion criteria.  
8.1.5 Methods for Assignment to Treatment Groups 
Each subject who enters the screening period for the study (defined as the point at which the 
subject signs the informed consent form (ICF) receives a unique subject identification 
number before any study-related activities/procedures are performed.  This number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.   
The subject identification number must remain constant throughout the entire clinical study.   
Subjects who meet the eligibility requirements will be randomly assigned to 1 of 3 treatment 
groups. 
The randomization will be stratified by three factors: 
x Pre-procedure (Baseline) anesthetized Schirmer’s score (<5, >5) measured the 
screening/randomization visit  
x Pre-procedure (Baseline) EDS (<60, >60) measured at the screening/randomization 
visit  
x Study site 
A central randomization list will be created using block randomization. Sites will be assigned 
entire blocks as needed. 
 
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.  
Concurrent enrollment in another investigational drug or device study during the treatment 
period is not permitted.  
8.2.1 Prohibited Medications/Treatments  
Disallowed medications/treatments during the study are outlined in the Exclusion Criteria 
below: 
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OC-01 (varenicline) Nasal Spray 
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Clinical Trial Protocol # OPP-101 
 
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x No concomitant use of a nicotinic acetylcholine receptor agonist [Nicoderm®, 
Nicorette®, Nicotrol NS® (nicotine), Tabex®, Desmoxan® (cytisine), and Chantix® 
(varenicline)] during the treatment period (Baseline to Day 28) of the study. 
x No concomitant use of Restasis® or Xiidra® during the treatment period (Baseline to 
Day 28) of the study. 
8.2.2 Escape Medications 
No escape medication is required for this study.  
8.2.3 Special Diet or Activities  
No special diets or activity is required for this study.  
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 2 for description).  
Screening/Visit 1 (Day 1): Screening and Randomization   
x Informed consent/Health Information Portability and Accountability Act (HIPAA) 
consent 
x Demographic data, medical history, prior medication (s), and ocular history 
x Eligibility Criteria  
x Urine pregnancy test (if applicable) 
x OSDI© questionnaire 
x Eye Dryness Scale (EDS) (visual analog scale) (pre-treatment) 
x 
 Ocular Discomfort Scale (pre-treatment) 
x BCVA (pre-and post-treatment procedures) 
x Slit lamp biomicroscopy (pre-and post-treatment procedures) 
x Corneal fluorescein staining 
x Baseline Schirmer’s Test 
x Schirmer’s Test with nasal stimulation (cotton swab)3 
x Intranasal examination (pre-and post-treatment procedures) 
x Randomization 
x Dispense study drug/placebo  
x Schirmer’s Test (concurrent with treatment)2 
x Administration of study drug/placebo concurrently with Schirmer’s Test 
x Concomitant Medications 
x AE Query 
2 Procedure will occur after corneal fluorescein staining 
3 Schirmer’s test with nasal stimulation will occur ≥10 minutes after the Baseline Schirmer’s test 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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Visit 2 (Day 7 ±2): Dosing Compliance Assessment  
 
x BCVA  
x EDS (visual analog scale) 
x Slit lamp biomicroscopy  
x Intranasal exam  
x Concomitant Medications 
x AE Query 
 
Visit 3 (Day 14 ±3): Schirmer’s Test Assessment  
 
x EDS (visual analog scale) 
x BCVA (pre-and post-treatment) 
x Slit lamp biomicroscopy (pre-and post-treatment) 
x Administration of study drug/placebo 
x Schirmer’s Test (concurrent with treatment) 
x Dispense study drug/placebo  
x Concomitant Medications 
x AE Query 
 
Visit 4 (Day 28 ±4): Primary and Secondary Endpoint Assessment  
Visit 4 CAE® and Schirmer’s Test Evaluation procedures are conducted on different days 
within the visit window. The Schirmer’s Test Evaluation and all assessments should be 
performed after the CAE® visit assessments. 
Visit 4a 
Pre- CAE® Procedures:  
 
x Urine pregnancy test (if applicable) 
x EDS (visual analog scale) 
x 
 Ocular Discomfort Scale 
x BCVA 
x Dispense study drug/placebo   
x Concomitant Medications 
x AE Query 
Pre-Treatment CAE® Evaluation 
x EDS (visual analog scale)  
x 
 Ocular Discomfort Scale until threshold is met 
ADMINISTRATION OF INVESTIGATIONAL DRUG/PLACEBO 
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Treatment with Investigational drug/placebo will be administered upon a participant’s 
reporting an Ocular Discomfort score ≥ 3 at two or more consecutive time points in at 
least one eye during CAE® exposure (participants with an Ocular Discomfort rating of 3 
at time = 0 for an eye must report an Ocular Discomfort rating of 4 for two consecutive 
measurements for that eye (i.e. Threshold). Participants with an Ocular Discomfort rating 
of 4 at time = 0 for an eye must report an Ocular Discomfort rating of 4 for two 
additional consecutive measurements for that eye, not including time = 0 measurement) 
using the 
 Scale. Participants will resume symptom assessments (EDS and 
ODS) every 5 minutes starting 1 minute after the application ends. 
Post-Treatment CAE® Evaluation 
x EDS (visual analog scale) 
x 
 
Ocular Discomfort Scale 
Visit 4b (Minimum +3 Days after Visit 4a) 
Schirmer’s Test Evaluation: 
 
x EDS (visual analog scale) (post treatment) 
x BCVA (pre and post treatment) 
x Slit lamp biomicroscopy (pre and post treatment) 
x Corneal fluorescein staining (post treatment) 
x Intranasal examination (pre and post treatment) 
x Administration of study drug/placebo 
x Schirmer’s Test (concurrent with treatment) 
x Concomitant medications 
x AE Query 
 
Visit 5 (Day 42 ± 3): 6 Week Safety Assessment 
x Slit lamp biomicroscopy  
x Intranasal examination 
x Concomitant Medications 
x AE Query 
 
Visit 6 (Day 168 ± 7): 6 Month Safety Assessment 
x Slit lamp biomicroscopy  
x Intranasal examination 
x Concomitant Medications 
x AE Query 
 
 
 
Visit 7 (Day 336 ±7): 12 Month Safety Assessment 
x Urine pregnancy test (if applicable) 
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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x Slit lamp biomicroscopy  
x Intranasal examination 
x Concomitant Medications 
x AE 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 in order 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: 
x Slit-lamp Biomicroscopy; 
x EDS 
x BCVA 
x Intranasal Examination; 
x Corneal Fluorescein staining  
x Urine Pregnancy Test (if applicable); 
x Assessment of AEs; 
x Assessment of concomitant medications and/or treatments; and 
x 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 the study drug at Visits 1, 2, 3 
and 4a, and provided with written instructions upon dispensation of their study drug at Visit 
1.. 
8.6 
Subject Disposition  
8.6.1 Treatment Completed Subjects  
A Treatment Completed Subject is one who has completed the first 4 weeks of study visits.    
8.6.2 Safety Follow up Completed Subjects 
A Safety Follow up Completed Subjects is one who has completed all study visits up to Visit 
7.   
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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8.6.3 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: 
x Non-Fatal Adverse Event; 
x Protocol Violations; 
x Lost to Follow-up;  
x Physician Decision; 
x Subject Non-compliance; 
x Death; 
x Study Terminated by sponsor; 
x Withdraw by Subject (e.g. withdrawal of consent); and 
x Other 
Note: In addition, any subject may be discontinued from treatment or from study 
involvement from any sound medical reason at the discretion of the investigator (after 
consultation with the Sponsor) or Sponsor. 
Notification of a subject discontinuation and the reason for discontinuation will be made to 
and/or Sponsor and will be clearly documented on the eCRF. 
If the subject discontinues from treatment, they will be asked to be followed for safety for the 
duration of the study, unless they refuse to attend follow-up visits.  Subjects will be asked to 
attend Visit 4b, Visit 5, Visit 6 and Visit 7 and have all scheduled assessments performed as 
per the Schedule of Visits and Measurements (Appendix 1) 
Discontinued subjects will not be replaced. 
8.7 
Study Termination  
The study may be stopped at any time by the Investigator and/or 
 after consultation with 
the Sponsor, with appropriate notification.  
8.8 
Study Duration  
An individual subject’s participation will involve 7 visits over approximately 48-weeks (336 
days) 
8.9 
Monitoring and Quality Assurance  
During the course of the study a monitor, or designee, will make routine site visits to review 
protocol compliance, assess study drug accountability, subject safety, and ensure the study is 
being conducted according to the pertinent regulatory requirements.  The review of the 
subjects’ medical records will be performed in a manner that adequately maintains subject 
confidentiality.  A monitoring plan will outline further details of the study monitoring. 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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Regulatory authorities of domestic and foreign agencies, Sponsor quality assurance,
. 
quality assurance and or its designees may carry out on-site inspections and/or audits, which 
may include source data checks.  Therefore, direct access to the original source data will be 
required for inspections and/or audits.  All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that local, 
state, and federal laws apply. 
9 
SAFETY DEFINITIONS, SAFETY MONITORING AND REPORTING 
9.1 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not the event is considered drug-related.  An AE can 
therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease occurring after the subject started dosing with the study drug, without 
any judgment about causality.  Any pre-existing medical condition that worsens after 
administration of the study drug will also be considered a new AE.   
Study drug includes the investigational drug under evaluation and placebo. 
AE collection will start following the first administration of study drug 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: 
x Mild:  
Event is noticeable to the subject but is easily tolerated and does not 
interfere with the subject’s daily activities. 
x Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
x Severe: 
Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the subject’s daily activities. 
9.1.2 Relationship to Study Drug 
The relationship of each AE to the investigational product should be determined by the 
investigator (in a blinded manner) using these explanations: 
x Definite: When there are good reason and sufficient documentation to demonstrate a 
direct causal relationship between investigational product and AE 
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
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x 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 
x 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. 
x None: 
When there is sufficient information to accept a lack of a causal 
relationship, in the sense of impossible and improbable. 
x 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: 
x Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not 
listed at the specificity or severity that has been observed. 
x Expected: An AE that is listed in the IB at the specificity and severity that has been 
observed. 
x Not Applicable: Any AE that is unrelated to the study drug. 
AEs that are mentioned in the IB 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 particular 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 “serious” (SAE) if, in the view of either the investigator or Sponsor, it 
results in any of the following outcomes: 
x Death 
 
x 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. 
x Inpatient hospitalization or prolongation of existing hospitalization 
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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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. 
x 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). 
x 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 study drug, must be 
immediately reported.  All information relevant to the SAE must be recorded on the 
appropriate CRFs.  The investigator is obligated to pursue and obtain information requested 
by 
 and/or the Sponsor in addition to that information reported on the CRF.  All subjects 
experiencing a SAE must be followed up and the outcome reported. 
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Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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In the event of a SAE, the investigator must notify 
 and the Sponsor immediately; obtain 
and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject; 
provide
 and 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: 
Office Telephone: 
Mobile Telephone: 
Office Facsimile: 
 
Clinical Project Manager
 
 
 
 
 
Name: 
Title: 
Office Telephone: 
Mobile Phone: 
Office Facsimile: 
 
Medical Monitor 
 
 
 
 
9.4 
Procedures for Unmasking of Study Drug 
All subjects, investigators, and study personnel involved with the conduct of the study will be 
masked with regard to treatment assignments. When medically necessary, the investigator 
may need to determine what treatment regimen has been assigned to a subject. When 
possible (i.e., in non-emergent situations), 
 and/or the Sponsor should be notified before 
unmasking study drug. Unmasking will be performed utilizing the randomization system.  
The unmasked subject will continue the study if warranted by the Investigator in consultation 
with the Medical Monitor.  
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-up 
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
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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.  
If the Investigator becomes aware of any new information regarding an existing SAE (i.e., 
resolution, change in condition, or new treatment), a new SAE/Unanticipated Report Form 
must be completed and faxed to 
 within 24 hours of the site’s awareness of the new 
information. The original SAE form is not to be altered. The report should describe whether 
the event has resolved or continues and how the event was treated. 
10 
STATISTICAL ANALYSIS  
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 and Secondary Endpoints  
Primary Endpoint: 
x Percent of subjects who achieve ≥10 mm improvement in Schirmer’s Test Score from 
baseline at Visit 4 (Day 28) 
Secondary Endpoints 
x Mean change from Baseline in Eye Dryness Score (EDS) at 5 minutes after threshold 
defined treatment administration in the Controlled Adverse Environment® Chamber 
at Visit 4 (Day 28) 
x Mean change from Baseline in Eye Dryness Score (EDS) at Visit 4 (Day 28) (Post 
STS) 
x Mean change from Baseline in Schirmer’s Test Score (STS) at Visit 4 (Day 28) 
x Mean change from Baseline in Corneal Fluorescein Staining at Visit 4 (Day 28) 
10.2 
Analysis Populations 
10.2.1 Intention-To-Treat Population  
The intent-to-treat (ITT) population will include all randomized subjects. Analyses using the 
ITT population will group subjects according to the treatment to which they were 
randomized.  
10.2.2 Safety Population 
The safety population will include all randomized subjects who received at least one dose of 
the study drug. Analysis on the safety population will group subjects according to the 
treatment actually received.  
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
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10.3 
Statistical Hypotheses 
Let pl, ph, and pp denote the percent of subjects in each group (low dose, high dose, and 
placebo, respectively) who have ≥ 10mm change from baseline to Visit 4 in STS. 
 
H0: pl – pp = 0 or ph – pp = 0 
 
H1: pl – pp ≠ 0 or ph – pp ≠ 0 
10.4 
Sample Size and Power Considerations 
The study will randomize approximately 750 subjects in a 1:1:1 ratio to the three treatment 
groups. Approximately 250 subjects in each treatment group are expected to complete their 
assigned treatment and have endpoint assessments at Visit 4. 
For the primary endpoint, the percent of subjects achieving > 10 mm improvement from 
Baseline in STS at Visit 4, the ONSET-1 study had roughly 15% of subjects in the placebo 
group and 50% in each of the 0.6 mg/ml and 1.2 mg/ml groups.  If the true proportion 
achieving at least a 10 mm improvement is 15% in the placebo group and, conservatively, 
40% in each of the active arms, the power for each dose would be greater than 99%. 
The secondary endpoint is the EDS test. The ONSET-1 study showed a roughly 12 unit 
difference between placebo and each active treatment group in mean change from baseline to 
day 28 with a standard deviation (SD) of roughly 26 units. If these estimates apply to the 
Phase III ONSET-2 study and the data are analyzed with an analysis of variance, the study 
will have approximately 99% power for each dose. 
 
10.5 
Statistical Analysis 
This section briefly outlines the planned efficacy 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. 
10.5.1 General Considerations 
Quantitative variables will be summarized using the number of subjects (n), mean, SD, 
median, 25th and 75th percentiles, and minimum and maximum. Qualitative variables will be 
summarized using counts and percentages. 
All summaries will be presented by treatment group. Summaries will be provided for 
demographics, medical history, concomitant medications, and subject disposition. 
For the summaries, medical history, concomitant medications, and AEs will be coded to 
MedDRA and World Health Organization Drug dictionaries, as appropriate. 
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
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10.5.6 Safety Analysis 
All safety analyses will be performed on the safety population. 
The safety of OC-01 (varenicline) will be assessed primarily by the incidence of AEs. An AE 
will be considered a treatment-emergent AE (TEAE) if it occurs or worsens on or after 
initiation of treatment. An overall summary of TEAEs will be presented including the 
number of events and the number of subjects with events (along with percentages) by 
treatment group for TEAEs in several categories base on seriousness, relationship to 
treatment, and severity.  
Other safety endpoints including visual acuity, slit-lamp biomicroscopy and intranasal 
examination will be summarized by treatment group and visit using descriptive statistics. 
Changes or shifts from baseline will be summarized where appropriate. For assessments 
performed by eye, study eye and fellow eye will be summarized separately.  
The SAP will present methods of analysis of these defined parameters in detail. 
10.5.7 Interim Analysis 
No interim analysis planned for this study. 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES  
This study will be conducted in compliance with the protocol, Good Clinical Practices, 
including the International Conference on Harmonization (ICH) Guidelines, and in general, 
consistent with the Declaration of Helsinki.  In addition, all applicable local, state, and 
federal requirements relevant to the use of study drugs in the countries involved will be 
adhered to. 
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 
 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. 
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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If informed consent is taken under special circumstances (oral informed consent), then the 
procedures to be followed must be determined by 
and/or Sponsor and provided in 
writing by
 and/or Sponsor prior to the consent process. 
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 aforementioned individuals to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
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 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 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 
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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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 of Study 
Drug 
11.5.1 Labeling/Packaging 
Investigational drug will be provided in multi-use intranasal applicator that will be assigned 
at randomization for use during the first 28 days of study.  
11.5.2 Storage of Investigational Drug / Placebo  
The investigational drug / placebo must be stored in accordance with the pharmacy manual 
for this study, which contains detailed information regarding the storage and administration.  
1.1.3 Accountability of Study Drug 
The investigational drug / placebo is only prescribed by the principal investigator or his/her 
named sub investigator(s) and is to only be used in accordance with this protocol. The study 
drugs must only be distributed to subjects properly qualified under this protocol to receive 
study drug.  The investigator must keep an accurate accounting of the study drugs by 
maintaining a detailed inventory. This includes the amount of study drugs 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 of the study.  
11.5.2 Return or Disposal of Study Drug 
You may be requested to destroy study drug or study drug kits 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 
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Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
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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. Data will not 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  
Not applicable.  
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 the study until the Sponsor completes a joint, multi-center publication of the trial 
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 trial; however, approval will be at the sole discretion of 
the Sponsor. Should the foregoing language be in conflict with the language addressing 
publication in the clinical trial agreement, the language in the Clinical Trial Agreement will 
prevail.  
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma  Inc   
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
CONFIDENTIAL 
Page 42 of 55 
 
 
13 
APPENDICES  
Appendix 1: Schedule of Visits and Measurements 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques 
Appendix 3: Sponsor and 
 Approvals 
Appendix 4: Investigator’s Signature 
 
 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
Page 44 of 55 
 
APPENDIX 2: EXAMINATION PROCEDURES, TESTS, EQUIPMENT, AND 
TECHNIQUES  
The following examination procedures, tests, equipment and techniques are listed in this 
Appendix:  
Visual Acuity Procedures  
LogMAR visual acuity must be assessed using an ETDRS chart. The procedure used will be 
consistent with the recommendations provided for using the ETDRS eye chart. Visual acuity 
should be evaluated at the beginning of each visit in the study (i.e., prior to slit lamp 
examination). Participants should use the most recent correction to attain their corrected 
distance visual acuity (CDVA); if they forget their spectacles, this prescription can be placed 
in a trial frame. 
Equipment 
The visual acuity chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", 
e.g., from Prevent Blindness) wall charts are used, the participant viewing distance should be 
exactly 10 feet (or as specified by the manufacturer). In ALL cases, for purposes of 
standardizing the testing conditions during the study, all sites must use only ETDRS Series 
2000 Chart 1 & 2, and the right eye should be tested first. For reflectance (wall) charts, the 
chart should be placed frontally and be well illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. The 
participant should attempt to read each letter, line-by-line, left to right, beginning with line 1 
at the top of the chart. The participant should be told that the chart has letters only, no 
numbers. If the participant reads a number, s/he should be reminded that the chart contains 
no numbers, and the examiner should then request a letter in lieu of the number. The 
participant should be asked to read slowly, so as to achieve the best identification of each 
letter. S/he is not to proceed to the next letter until s/he has given a definite response. 
If the participant changes a response (e.g., 'that was a "C" not an "O"') before s/he has read 
aloud the next letter, then the change must be accepted. If the participant changes a response 
having read the next letter, then the change is not accepted. The examiner should never point 
to the chart or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the participant 
says s/he cannot read a letter, s/he should be encouraged to guess. If the participant identifies 
a letter as one of two letters, s/he should be asked to choose one letter and, if necessary, to 
guess. When it becomes evident that no further meaningful readings can be made, despite 
encouragement to read or guess, the examiner should stop the test for that eye. However, all 
letters on the last line should be attempted as letter difficulties vary and the last may be the 
only one read correctly. The number of letters missed or read incorrectly should be noted. 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
Page 45 of 55 
 
LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. To 
this value will be added the number "N x 0.02" where 'N' represents the total number of 
letters missed up to and including the last line read. This total sum represents the logMAR 
visual acuity for that eye. 
Example: Participant correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 
line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR visual acuity 
= 0.18 
 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of visual acuity during the 
study, all visual acuity assessments at a single site must be consistently done using the same 
lighting conditions and same correction if possible during the entire study. If the same 
correction cannot be used (i.e., a participant broke his/her glasses), the reason for the change 
in correction should be documented. 
Note: A clinically significant visual acuity decrease (defined as an increase of 0.32 or greater 
in logMAR score) from the Screening Visit (Visit 1) should be evaluated by the Investigator 
as a potential AE. 
 
 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
Page 46 of 55 
 
Slit Lamp Biomicroscopy  
Slit lamp biomicroscopy will be performed during the study. Observations will be graded as 
Normal or Abnormal. Abnormal findings, which are clinically significant, will be described.  
Corneal Fluorescein Staining  
The examiner should instill 5 PL of 2% preservative-free sodium fluorescein solution into the 
inferior conjunctival cul-de-sac of each eye. Alternatively, corneal staining can be assessed 
using 1.0 mg sodium fluorescein strips. After moistening the tip of the strip with sterile 
buffered saline, the excess is shaken into a waste bin with a sharp flick. The lower lid is then 
pulled down and the flat end of the tip should be gently applied to the inferior tarsal 
conjunctiva with the intent of not inducing reflex tearing and instilling a very small volume 
of dye.  
The participant will be instructed to blink naturally several times without forced closure of 
the eyelid to distribute the fluorescein. In order to achieve maximum fluorescence, the 
examiner should wait at least two minutes after instillation before evaluating corneal 
fluorescein staining. A Wratten #12 yellow filter will be used to enhance the ability to grade 
fluorescein staining. The staining will be graded with the NEI Scale. The upper eyelid is 
lifted slightly to grade the entire corneal surface.  
 
 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
Page 47 of 55 
 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
Page 48 of 55 
 
Schirmer’s Test with Topical Anesthesia  
At the Screening Visit, one basal Schirmer’s test will be performed followed by a Schirmer’s 
test with cotton swab nasal stimulation. The Schirmer’s test with topical anesthetic will be 
used to assess tear production using the following steps:   
1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride or equivalent should 
be instilled in both eyes of the participant. 
2. The participant will be instructed 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, excess moisture in the inferior fornix is gently removed with a spear. 
4. Schirmer’s strips (35 mm x 5 mm size filter paper strip) will be placed in each eye at the 
junction of the middle and lateral thirds of the lower eye lid.  
5. Under ambient light, the participant will be instructed 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, strips will be removed from both eyes and the amount of wetting will 
be recorded. The strips should be taped to the CRF.   
Schirmer’s test using cotton swab nasal stimulation   
At the Screening Visit, the Schirmer’s test should be performed using cotton swab nasal 
stimulation. New anesthetic drops should be instilled following the same procedure specified 
in steps #1 to 3 above. 
1. With new strips in place, the examiner should insert cotton swabs in the participant’s two 
nostrils simultaneously and gently probe both nasal middle turbinates for approximately 
30 seconds. After this, the examiner can simply hold the swabs in place, applying gentle 
pressure, and repeat probing intermittently as necessary.   
2. Alternatively, the participant can be instructed to hold the cotton swabs and gently probe 
both nasal turbinates simultaneously, resting intermittently before probing again.  The 
examiner should continuously coach the participant on how to perform this test properly.  
3. The Schirmer’s strips should remain in place until five minutes have elapsed or both 
strips have reached maximum score. 
Both Schirmer’s scores will be recorded and verified that they meet the inclusion criteria.   
 
 
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CONFIDENTIAL 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
Page 51 of 55 
 
 
 
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OC-01 (varenicline) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-101 
 
Amendment #1 
 
 
CONFIDENTIAL 
Page 55 of 55 
 
APPENDIX 4: INVESTIGATOR’S SIGNATURE  
Protocol Title: 
A Phase 3, Multicenter, Randomized, Controlled, Double-Masked, 
Clinical Trial to Evaluate the Efficacy and Safety of OC-01 
(varenicline)  Nasal Spray on Signs and Symptoms of Dry Eye 
Disease (The ONSET-2 Study) 
Protocol Number: 
OPP-101 
 
 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to maintain 
all information supplied by 
 and the Sponsor in confidence and, when this information is 
submitted to an Institutional Review Board (IRB) or another group, it will be submitted with 
a designation that the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
 
Name:  
 
 
 
Title:  
 
 
 
Site:  
 
 
 
Address:  
 
 
 
Phone Number:  
 
 
 
 
 
 
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SAP_003.pdf: 
 
 
 
Page 1 of 34 
 
 
 
 
Oyster Point Pharma, Inc. 
 
Clinical Protocol: OPP-101: 
 
A Phase 3, Multicenter, Randomized, Controlled, Double-
Masked, Clinical Trial to Evaluate the Efficacy of OC-01 
(varenicline)Nasal Spray on Signs and Symptoms of Dry 
Eye Disease (The ONSET-2 Study) 
 
 
 
 
 
Statistical Analysis Plan 
Version 3.0 
 
 
 
Date: April 29, 2020