Conditions: Long Term Follow up Dry Eye Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 101
Healthy volunteers: no

Brief summary:
The objective of this safety long-term follow-up study was to evaluate the safety of OC-01 Nasal Spray at 6 months and 12 months post treatment in the OPP-002 study (NCT03636061).

Detailed description:
Study OPP-002-01 was a long-term follow-up study of those subjects who had previously participated in the OPP-002 study (NCT03636061). The OPP-002 study is a Phase 2, multicenter, randomized, double-masked, placebo-controlled study designed to evaluate the safety and efficacy of OC-01 nasal spray in adult participants with dry eye disease.

The first scheduled visit occurs 6 months after the first treatment of OC-01 nasal spray/placebo in the OPP-002 study. The second scheduled visit occurs 12 months after the first treatment of OC-01 nasal spray/placebo in the OPP-002 study.

Arms:
arm 1: OC-01 (varenicline) nasal spray, 0.12 mg/mL arm 2: OC-01 (varenicline) nasal spray, 0.60 mg/mL arm 3: OC-01 (varenicline) nasal spray, 1.2 mg/mL arm 4: Placebo (vehicle) nasal spray

Interventions: intervention 1: OC-01 Low Dose, 0.12 mg/mL intervention 2: OC-01 Mid Dose, 0.6 mg/mL intervention 3: OC-01 High Dose, 1.2 mg/mL intervention 4: Placebo (vehicle) nasal spray
Intervention descriptions: intervention 1: OC-01 (varenicline) nasal spray intervention 2: OC-01 (varenicline) nasal spray intervention 3: OC-01 (varenicline) nasal spray intervention 4: Placebo (vehicle) nasal spray

Protocol document:
Prot_000.pdf: 


OC-01 (varenicline tartrate) Nasal Spray 
Clinical Trial Protocol #OPP-002-01EXT 
Sponsor: Oyster Point Pharma, Inc. 
January 21, 2019 
CONFIDENTIAL 
Page 2 of 32 
  
 
SPONSOR PERSONNEL 
 
 
 
Chief Executive Officer: 
 
 
MEDICAL MONITOR 
 
 
 
 
Medical Monitor: 


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Sponsor: Oyster Point Pharma, Inc. 
January 21, 2019 
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SYNOPSIS 
 
 
Protocol Title: 
Multicenter, Randomized, Controlled, Double-Masked 
Clinical Trial to Evaluate the Efficacy of OC-01 Nasal 
Spray on Signs and Symptoms of Dry Eye Disease (The 
ONSET Study)-Long Term Safety Follow-up 
Protocol Number: 
OPP-002-01 
Investigational Product: 
Subjects were previously treated in the OPP-002 
study with one of the following formulations of OC-
01 (varenicline tartrate) nasal spray: 0.02% (low 
dose), 0.1% (medium dose), 0.2% (high dose) or 
placebo 
Study Objective: 
The objective of this safety long-term follow-up study is 
to evaluate the safety of OC-01 Nasal Spray at 6 months 
and 12 months post treatment in the OPP-002 study.   
Overall Study Design 
Structure: 
A Phase 2 safety follow up extension study of the OPP-
002 study. 
Duration: 
Two study visits over approximately 6 months 
Control: 
N/A 
Dosing Regimen: 
N/A 
Summary of Visit 
Schedule: 
x Visit 1 = Month 6 (± 7 days) 
x Visit 2 = Month 12 (± 7 days) 
Study Population Characteristics 
Number of Subjects: 
Approximately 180 subjects previously enrolled in the 
OPP-002 study 
Condition/Disease: 
Dry Eye Disease 


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Inclusion Criteria: 
Subjects must: 
1. Have been enrolled in the OPP-002 study 
2. Have received at least one dose of the study 
drug/placebo in OPP-002 study 
3. Completed the OPP-002 study to Visit 5   
4. Have provided verbal and written informed consent 
 


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January 21, 2019 
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Exclusion Criteria: 
Subjects must not: 
1. Have discontinued prior to Visit 5 in the OPP-002 
study.   
 




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TABLE OF CONTENTS 
 
SYNOPSIS ................................................................................................................................. 3 
TABLE OF CONTENTS ......................................................................................................... 7 
LIST OF ABBREVIATIONS .................................................................................................. 9 
1 
INTRODUCTION.......................................................................................................... 10 
2 
STUDY OBJECTIVES .................................................................................................. 11 
3 
CLINICAL HYPOTHESES ......................................................................................... 11 
4 
OVERALL STUDY DESIGN ....................................................................................... 12 
5 
STUDY POPULATION ................................................................................................ 12 
5.1 
Number of Subjects ............................................................................................. 12 
5.2 
Study Population Characteristics ....................................................................... 12 
5.3 
Inclusion Criteria ................................................................................................ 12 
5.4 
Exclusion Criteria ................................................................................................ 13 
5.5 
Withdrawal Criteria ............................................................................................ 13 
6 
STUDY PARAMETERS ............................................................................................... 13 
6.1 
Primary Safety Measure ..................................................................................... 13 
7 
STUDY METHODS AND PROCEDURES ................................................................ 13 
7.1 
Participant Entry Procedures ............................................................................ 13 
7.2 
Concurrent Therapies ......................................................................................... 14 
7.2 
Examination Procedures ..................................................................................... 14 
7.3 
Schedule of Visits, Measurements and Dosing.................................................. 15 
7.4 
Subject Disposition .............................................................................................. 15 
7.5 
Study Termination .............................................................................................. 15 
7.6 
Study Duration .................................................................................................... 16 
7.7 
Monitoring and Quality Assurance ................................................................... 16 
8 
SAFETY DEFINITIONS, SAFETY MONITORING AND REPORTING ............. 16 
8.1 
Adverse Event ...................................................................................................... 16 
8.2 
Serious Adverse Events ....................................................................................... 17 
8.3 
Procedures for Reporting Adverse Events ........................................................ 18 
8.4 
Procedures for Unmasking of Study Drug ........................................................ 19 
8.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ......... 19 
8.6 
Compliance with Protocol ................................................................................... 20 
8.7 
Subject Disposition .............................................................................................. 20 
8.8 
Study Termination .............................................................................................. 20 
8.9 
Study Duration .................................................................................................... 20 
8.10 Monitoring and Quality Assurance ................................................................... 20 
9 
STATISTICAL ANALYSIS ......................................................................................... 21 
9.1 
Analysis Populations ........................................................................................... 21 
9.2 
Statistical Analysis ............................................................................................... 21 
10 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................... 22 
10.1 Protection of Human Subjects............................................................................ 22 
10.2 Ethical Conduct of Study .................................................................................... 23 


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10.3 Subject Confidentiality ....................................................................................... 23 
10.4 Documentation ..................................................................................................... 23 
10.5 Recording of Data on Source Documents and Electronic Case Report     
Forms…………………………………………………………………………….24 
10.6 Handling of Biological Specimens ...................................................................... 24 
10.7 Publications .......................................................................................................... 24 
11 
REFERENCES ............................................................................................................... 25 
12 
APPENDICES ................................................................................................................ 46 
APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS ................................. 47 
APPENDIX 2: EXAMINATION PROCEDURES, TESTS, EQUIPMENT, AND 
TECHNIQUES ............................................................................................................... 48 
APPENDIX 3: SPONSOR AND 
APPROVALS ......................................................... 49 
APPENDIX 4: INVESTIGATOR’S SIGNATURE ............................................................. 50 
 


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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 
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 
μL 
microliter 
mm 
Millimeter 
nAChR 
Nicotinic acetylcholine receptor 
OSDI© 
Ocular Surface Disease Index© 
PP 
Per Protocol 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-emergent adverse event 
US 
United States 








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5.4 
Exclusion Criteria 
Subjects must not: 
 
1. Have discontinued prior to Visit 5 in the OPP-002 study   
 
 
5.5 
Withdrawal Criteria 
Subjects may withdraw consent from the study at any time. 
Sponsor and/or Investigator may discontinue any subject for non- compliance or any 
valid medical reason during the course of the study (see Section 8.6.2). 
 
6 
STUDY PARAMETERS 
6.1 
Primary Safety Measure 
 
x Intranasal Exam at Months 6 and 12 
x Slit Lamp Examination at Months 6 and 12 
x Adverse Events (AE) at Months 6 and 12 
7 
STUDY METHODS AND PROCEDURES 
7.1 
Participant Entry Procedures 
7.1.1 
Overview 
Participants as defined by the criteria in Sections 5.2, 5.3, and 5.4 will be considered for 
entry into this study.  Only subjects that were previously enrolled in the OPP-002 study 
will be eligible for participation in this long-term follow-up study.   
7.1.2 
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. 
7.1.3 
Washout Intervals 
There are no washout intervals required for this study.   
7.1.4 
Procedures for Final Study Entry 
Subjects must meet all inclusion criteria and none of the exclusion criteria. 
7.1.5 
Subject Enrollment 
Each subject who agrees to participate in the study (defined as the point at which the subject 
signs the informed consent form (ICF)) receives a unique subject identification number 


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January 21, 2019 
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before any study-related activities/procedures are performed. 
 
   
 
7.2 
Concurrent 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. 
7.1.6 
Prohibited Medications/Treatments 
There are no disallowed medications/treatments during the study.   
7.1.7 
Escape Medications 
No escape medication is required for this study. 
7.1.8 
Special Diet or Activities 
No special diets or activity is required for this study. 
 
7.2 
Examination Procedures 
7.2.1 
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).  
Visit 1 (Month 6 ±7 days) 
x Informed consent/Health Information Portability and Accountability Act (HIPAA) 
consent 
x Eligibility Criteria 
x Slit lamp biomicroscopy  
x Intranasal examination 
x Concomitant Medications 
x AE Query 
 
Visit 2 (Month 12 ±7 days) 
 
x Slit lamp biomicroscopy  
x Intranasal examination 
x Concomitant Medications 
x AE Query 
x Study Exit 
 
Early Termination (if applicable) 
 
x Slit lamp biomicroscopy 
x Intranasal examination 


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x Concomitant Medications 
x AE Query 
7.3 
Schedule of Visits, Measurements and Dosing 
7.3.1 
Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
7.3.2 
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 Intranasal Examination; 
x Assessment of AEs; 
x Assessment of concurrent medications and/or treatments; and 
x Any other assessments needed in the judgment of the investigator. 
 
7.4 
Subject Disposition 
7.4.1 
Completed Subjects 
A completed subject is one who has completed all study visits (Visit 1 and Visit 2).   
7.4.2 
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: 
x AEs; 
x protocol violations; 
x administrative reasons (e.g., inability to continue, lost to follow-up); 
x sponsor termination of study; 
x subject choice (e.g. withdrawal of consent); and 
x other 
Note: In addition, any subject may be discontinued 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 
 Sponsor and will be clearly documented on the eCRF. 
Discontinued subjects will not be replaced. 
7.5 
Study Termination 


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The study may be stopped at any time by the Investigator 
 after consultation with 
the Sponsor, with appropriate notification. 
 
7.6 
Study Duration 
An individual subject’s participation will involve 2 visits over approximately 6 months.  
 
7.7 
Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to review 
protocol compliance, assess 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. 
Regulatory authorities of domestic and foreign agencies, Sponsor 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. 
8 
SAFETY DEFINITIONS, SAFETY MONITORING AND 
REPORTING 
8.1 
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. 
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. 
8.1.1 
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 


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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. 
 
8.1.2 
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 
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. 
 
8.1.3 
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.  
 
8.2 
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 


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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 
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. 
 
 
8.3 
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. 
8.3.1 
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. 
8.3.2 
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 


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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 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: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
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), 
 the Sponsor should be notified before 
unmasking study drug. The unmasked subject will continue the study if warranted by the 
Investigator in consultation with the Medical Monitor. 
8.5 
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 
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 


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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. 
8.6 
Compliance with Protocol 
Subjects will be instructed on the necessity to attend Visit 1 and Visit 2 to be examined and 
to have their adverse event information collected. 
 
8.7 
Subject Disposition 
8.7.1 
Completed Subjects 
A completed subject is one who has completed both study visits (Visit 1 and Visit 2). 
8.7.2 
Discontinued Subjects 
Subjects may be discontinued from involvement in the study at any time prior to their 
completion of the study due to: 
x AEs; 
x protocol violations; 
x sponsor termination of study; 
x non-compliance 
x withdraw by subject 
x other 
Note: In addition, any subject may be discontinued from 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 
 Sponsor and will be clearly documented on the eCRF. 
Discontinued subjects will not be replaced.  
 
8.8 
Study Termination 
The study may be stopped at any time by the Investigator 
after consultation with 
the Sponsor, with appropriate notification. 
 
8.9 
Study Duration 
An individual subject’s participation will involve 2 study visits over approximately 6 
months 
 
8.10 Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to review 




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For safety endpoints, both eyes will be analyzed. 
 
10 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. 
 
10.1 Protection of Human Subjects 
10.1.1  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. 
If informed consent is taken under special circumstances (oral informed consent), then the 


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procedures to be followed must be determined by 
 Sponsor and provided in 
writing by 
 Sponsor prior to the consent process. 
10.1.2 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. 
 
10.2 Ethical Conduct of Study 
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
 
10.3 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 as to ensure that 
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. 
 
10.4 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. 
10.4.1  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 
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 


OC-01 (varenicline tartrate) Nasal Spray 
Clinical Trial Protocol #OPP-002-01EXT 
Sponsor: Oyster Point Pharma, Inc. 
January 21, 2019 
CONFIDENTIAL 
Page 24 of 32 
  
 
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. 
 
10.5 Recording of Data on Source Documents and Electronic Case Report 
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. 
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 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. 
 
10.6 Handling of Biological Specimens 
Not applicable. 
 
10.7 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 is made by Sponsor 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. 








OC-01 (varenicline tartrate) Nasal Spray 
Clinical Trial Protocol #OPP-002-01EXT 
Sponsor: Oyster Point Pharma, Inc. 
January 21, 2019 
 
 
CONFIDENTIAL 
 
Page 28 of 32 
 
 
 
12 APPENDICES 




OC-01 (varenicline tartrate) Nasal Spray 
Clinical Trial Protocol #OPP-002-01EXT 
Sponsor: Oyster Point Pharma, Inc. 
January 21, 2019 
 
 
CONFIDENTIAL 
 
Page 30 of 32 
 
 
APPENDIX 2: EXAMINATION PROCEDURES, TESTS, EQUIPMENT, 
AND TECHNIQUES 
The following examination procedures, tests, equipment and techniques are listed in this 
Appendix: 
 
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. 
 
Intranasal Examination 
Qualified participants for the study must undergo an intranasal exam to make the final 
eligibility determination (e.g. severe nasal airway obstruction such as, severe septal deviation 
or inferior turbinate hypertrophy, or vascularized polyp seen on examination are reasons for 
exclusion). To monitor nasal mucosal integrity during the study for participant safety, an 
examination of the nasal cavities via an intranasal exam will be performed at the Screening 
Visit (after all other screening procedures have been completed). This examination will be 
performed by an Ear Nose and Throat (ENT) specialist, otolaryngologist or other suitably 
qualified medical practitioner (i.e. one who has been trained to perform intranasal exam). 
Still images or video may be captured. The procedure used for the intranasal exam can be 
conducted either by endoscopic examination or nasal specula. 
 
 
 
 
 


OC-01 (varenicline tartrate) Nasal Spray 
Clinical Trial Protocol #OPP-002-01EXT 
Sponsor: Oyster Point Pharma, Inc. 
January 21, 2019 
 
 
CONFIDENTIAL 
 
Page 31 of 32 
 
APPENDIX 3: SPONSOR AND 
 APPROVALS 
Protocol Title: 
Multicenter, Randomized, Controlled, Double-Masked Clinical 
Trial to Evaluate the Efficacy of OC-01 Nasal Spray on Signs and 
Symptoms of Dry Eye Disease (The ONSET study) – Long Term 
Safety Follow-up 


OC-01 (varenicline tartrate) Nasal Spray 
Clinical Trial Protocol #OPP-002-01EXT 
Sponsor: Oyster Point Pharma, Inc. 
January 21, 2019 
 
 
CONFIDENTIAL 
 
Page 32 of 32 
 
 
 
APPENDIX 4: INVESTIGATOR’S SIGNATURE 
Protocol Title: 
Multicenter, Randomized, Controlled, Double-Masked Clinical 
Trial to Evaluate the Efficacy of OC-01 Nasal Spray on Signs and 
Symptoms of Dry Eye Disease (The ONSET Study) – Long Term 
Safety Follow-up 
 
Protocol Number: 
OPP-002-01 
 
 
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 
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:   
 

SAP_001.pdf: 




Page 3 of 13
Contents 
1 
Synopsis.................................................................................................................................. 4 
2 
Abbreviations.......................................................................................................................... 5 
3 
Introduction............................................................................................................................. 7 
4 
Study objective ....................................................................................................................... 7 
5 
Study Design........................................................................................................................... 7 
6 
Primary Safety Measures........................................................................................................ 7 
7 
Statistical Analysis.................................................................................................................. 7 
7.1 
General Consideration...................................................................................................... 7 
7.2 
Unit of Analysis ............................................................................................................... 8 
7.3 
Analysis Populations........................................................................................................ 8 
 
Safety population ...................................................................................................... 8 
7.4 
Missing and Partial Data.................................................................................................. 8 
7.5 
Definition of Study Day or Dosing Day .......................................................................... 9 
7.6 
Protocol Deviation ........................................................................................................... 9 
7.7 
Subjects Disposition......................................................................................................... 9 
7.8 
Demographics ................................................................................................................ 10 
8 
Ocular Assessments .............................................................................................................. 10 
8.1 
Slit Lamp Biomicroscopy .............................................................................................. 10 
9 
Intranasal Examination ......................................................................................................... 10 
10 Safety Analysis ..................................................................................................................... 10 
10.1 
Adverse Events........................................................................................................... 11 
10.2 
Prior and Concomitant Medications........................................................................... 11 
Appendix 1   Schedule of Visits and Measurements .................................................................... 13 


Page 4 of 13
1 Synopsis
Protocol Title:
Multicenter, Randomized, Controlled, Double-Masked Clinical Trial to 
Evaluate the Efficacy of OC-01 Nasal Spray on Signs and Symptoms of Dry 
Eye Disease (The ONSET Study)-Long Term Safety Follow-up
Protocol Number:
OPP-002-01EXT
Investigational Product:
Subjects were previously treated in the OPP-002 study with one of the 
following formulations of OC- 01 (varenicline tartrate) nasal spray: 0.12
mg/mL (low dose), 0.6 mg/mL (medium dose), 1.2 mg/mL (high dose) or 
Placebo.
Study Objective:
The objective of this safety long-term follow-up study is to evaluate the 
safety of OC-01 Nasal Spray at 6 months and 12 months post treatment in 
the OPP-002 study.
Treatment Assignment
180 subjects were randomized in a 1:1:1:1 into one of four treatment groups in 
OPP-002:
x
OC-01 (varenicline) Nasal Spray, 0.12 mg/mL [low dose]
x
OC-01 (varenicline) Nasal Spray, 0.6 mg/mL [medium dose]
x
OC-01 (varenicline) Nasal Spray, 1.2 mg/mL [high dose]
x
Placebo (vehicle) [control]
Sample Size
Approximately 100 subjects previously enrolled in the OPP-002 study


Page 5 of 13
2 Abbreviations
AE
adverse event
ANCOVA
analysis of covariance
BCVA
best corrected visual acuity
BID
twice daily
CAE®
Controlled Adverse Environment®
CMH
Cochran-Mantel-Haenszel
CFR
Code of Federal Regulations
eCRF
Electronica case report form
CI
confidence interval
CRF
case report form
DED
dry eye disease
EDS
Eye Dryness Score
FDA
Food and Drug Administration
HIPAA
Health Information Portability and Accountability Act
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
IRB
institutional review board
ITT
intent-to-treat
logMAR
logarithm of the minimum angle of resolution
LS
least square
MAD
mucosal atomization device
MAR
missing at random
MCAR
missing completely at random
MedDRA
medical dictionary for regulatory activities
MI
multiple imputation
MMRM
mixed model for repeated measures
MNAR
missing not at random
μL
microliter
mm
millimeter
nAChR
nicotinic acetylcholine receptor
OSDI©
Ocular Surface Disease Index©
PP
per protocol
SAE
serious adverse event
SAP
Statistical Analysis Plan




Page 7 of 13
3 Introduction
This statistical analysis plan (SAP), which is based on the original study protocol dated 
January 21, 2019, defines the methods and analyses that Oyster Point Pharma, Inc. 
(henceforth, Oyster Point) plans to use to analyze the data from Protocol OPP-002-01EXT.
This SAP complies with guidance promulgated by the International Conference on 
Harmonization (ICH) and the US Food and Drug Administration (FDA). If the protocol is 
subsequently amended, this SAP may be amended as well. Should the SAP and the protocol 
be inconsistent with respect to the planned analyses, the language of the SAP prevails.
4 Study objective
The objective of this safety long-term follow-up study is to evaluate the safety of OC-01
Nasal Spray at 6 months and 12 months post treatment in the OPP-002 study.
5 Study Design
Protocol OPP-002-01EXT is a long-term follow-up study of those subjects that have 
previously participated in the OPP-002 study. The OPP-002 study was a Phase 2,
multicenter, randomized, double-masked, placebo-controlled study designed to evaluate the 
safety and efficacy of OC-01 nasal spray in adult participants with DED. The first scheduled 
visit will occur 6 months after the first treatment of OC-01 Nasal Spray/Placebo in the OPP-
002 study. The second scheduled visit will occur 12 months after the first treatment of OC-01
Nasal Spray/Placebo in the OPP-002 study.
6 Primary Safety Measures
•
Intranasal Exam at Months 6 and 12
•
Slit Lamp Examination at Months 6 and 12
•
Adverse Events (AE) at Months 6 and 12
7 Statistical Analysis
7.1 General Consideration
Descriptive and inferential statistics will be used to summarize results of Protocol OPP-002-
01EXT. Continuous variables will be summarized using the number of subjects (n), mean, 
SD, median, 25th and 75th percentiles, and minimum and maximum. Categorical variables 
will be summarized using frequency counts and percentages. Baseline measures are defined 
in the OPP-002 protocol as the last measure prior to the initiation of study treatment.
All summaries for safety data will be presented by treatment group. For the subject
characteristics at Visit 1, all summaries will be presented by treatment group and overall. All 






Page 10 of 13
x
Subject non-compliance
x
Death
x
Study terminated by sponsor
x
Withdraw by subject
7.8 Demographics
Continuous variables will be summarized using the number of subjects (n), mean, SD, 
median, 25th and 75th percentiles, and minimum and maximum. Categorical variables will be 
summarized using counts and percentages. Summary data will be presented by treatment 
group and overall.
The following demographic at Visit 1 will be summarized: age and gender.
Age in years will be calculated as the integer portion of the following:
[(Date of informed consent - Date of birth) + 1] / 365.25.
8 Ocular Assessments
Ocular assessments will occur at Visit 1 and Visit 2, the results will be collected in terms of 
grade, clinical significance, and relatedness to administration procedure and study drug. 
These results will be listed, summarized in tables.
8.1 Slit Lamp Biomicroscopy
The slit lamp biomicroscope will be performed at Visit 1, Visit 2, and the early termination.
A slit lamp will be used for external examination and biomicroscopy. The eyelids, cornea, 
conjunctiva, anterior chamber, iris, and lens will be examined at each visit. Slit lamp 
biomicroscopy results will be summarized for each treatment group for the study by visit 
using discrete summary statistics. Abnormal clinically significant findings will be described. 
Shifts from baseline including normal to abnormal (not clinically significant), and normal to 
abnormal (clinically significant) will be presented using counts and percentages
9 Intranasal Examination
Intranasal assessments collected at Visit 1, Visit 2, and the early termination visit will be 
summarized by treatment group with counts and percentages. Shifts from baseline of normal 
to abnormal (not clinically significant) and normal to abnormal (clinically significant) will be 
presented using counts and percentages.
10 Safety Analysis






Page 13 of 13
Appendix 1 Schedule of Visits and Measurements