Clinical trial NCT03688802
Conditions: Dry Eye Disease
Sponsor: Oyster Point Pharma, Inc.
Start date: 2018-09-25; Completion date: 2019-09-30
Enrollment: 18 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 in simulating Goblet Cell and Meibomian Gland function in adult subjects with DED.

Detailed description:
This was a Phase 2, single-center, randomized, masked (including all subjects, investigators, and study site personnel), placebo-controlled study designed to evaluate the safety and efficacy of OC-01 (varenicline) nasal spray in stimulating goblet cell and Meibomian gland function in in adult subjects with DED. Approximately 45 subjects at least 18 years of age with a physicians' diagnosis of DED and meeting all other study eligibility criteria were planned to be randomized to receive a single application of 0.2% (1.2 mg/mL) OC-01 or placebo

Arms: arm 1: OC-01 (varenicline) nasal spray, 1.2 mg/mL, one time dosing arm 2: Placebo (vehicle control) nasal spray, one time dosing
Interventions: intervention 1: OC-01 (varenicline) nasal spray intervention 2: Placebo (vehicle control) nasal spray
Intervention descriptions: intervention 1: OC-01 (varenicline) nasal spray intervention 2: Placebo

Protocol documents:
SAP_002.pdf: 
Page 1 of 27
Oyster Point Pharma, Inc.
Clinical Protocol: OPP-005:
A Single-Center, Randomized, Controlled, Masked
Clinical Trial to Evaluate the Efficacy of OC-01 Nasal
Spray on Goblet Cell and Meibomian Gland Stimulation
(The IMPERIAL Study)
Statistical Analysis Plan for Safety Data 
Version 1.0
Prepared 
Date: July 1, 2020


Page 2 of 27
Revision History


Page 3 of 27
Prepared by:


Page 4 of 27
Contents
1
Synopsis.................................................................................................................................. 5
2
Abbreviations.......................................................................................................................... 6
3
Introduction............................................................................................................................. 7
4
Study Objective....................................................................................................................... 7
5
Study Design........................................................................................................................... 7
6
Sample Size Determination and Power Calculation............................................................... 7
7
Statistical Analysis.................................................................................................................. 7
7.1
General Consideration .................................................................................................... 8
7.2
Analysis Populations....................................................................................................... 8
7.2.1
Safety population ........................................................................................................ 8
7.3
Definition of Study Day.................................................................................................. 8
7.4
Missing and Partial Data................................................................................................. 8
7.5
Protocol Deviations......................................................................................................... 9
7.6
Subject Disposition......................................................................................................... 9
7.7
Demographics and Baseline Characteristics................................................................. 10
7.8
Medical, Ocular and Dry Eye History .......................................................................... 10
7.9
Treatment Exposure...................................................................................................... 10
8
Intranasal Examination ......................................................................................................... 10
9
Safety Analysis ..................................................................................................................... 10
9.1
Adverse Events ............................................................................................................. 10
9.2
Prior and Concomitant Medications ............................................................................. 11
Appendix 1 Schedule of Visits and Measurements ...................................................................... 13
Appendix 2 Table of Contents...................................................................................................... 14
Appendix 3 Tableshell.................................................................................................................. 16


Page 5 of 27
1 Synopsis
Protocol Title:
A Single-Center, Randomized, Controlled, Masked Clinical Trial to Evaluate the 
Efficacy of OC-01 Nasal Spray on Goblet Cell and Meibomian Gland Stimulation 
(The IMPERIAL Study)
Protocol Number:
OPP-005
Investigational Product:
OC-01 (varenicline) Nasal Spray:
x
1.2 mg/mL
Study Objective:
The objective of this study is to evaluate the safety and effectiveness of OC-01 Nasal 
Spray as compared to placebo in simulating Goblet Cell and Meibomian Gland
function in adult subjects with DED.
Treatment Assignment
45 subjects will be randomized in a 2:1 ratio to the two treatment groups.
x
1.2 mg/mL
x
Placebo (vehicle)
Subjects who passed screening at Visit 1 will be randomized and administered study 
drug in office at Visit 2.
Sample Size and Power
The sample size for this study is not based on statistical power considerations.
Safety Endpoint
Safety Endpoint:
x
Adverse Events
Analysis Populations
The safety population will include all randomized subjects who received study drug. 
Analysis on the safety population will group subjects according to the treatment 
actually received.


Page 6 of 27
2 Abbreviations
AE
adverse event
CRF
case report form
DED
dry eye disease
FDA
Food and Drug Administration
HIPAA
Health Information Portability and Accountability Act
IB
Investigator’s Brochure
ICF
informed consent form
IRB
institutional review board
mg
Milligram
mL
Milliliter
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
TEAE
treatment-emergent adverse event


Page 7 of 27
3 Introduction
This statistical analysis plan (SAP) contains the detailed technical specifications for the 
safety data only described in the OPP-005 protocol Amendment #4 (26 March 2019). 
The reviewer can refer to the study protocol and the case report form (CRF) for details of 
study design, conduct and data collection. Specifications of tables and data listings are 
contained in a separate document.
The objective of this SAP is to evaluate the safety of OC-01 (varenicline) Nasal Spray as 
compared to placebo on incidence of treatment-emergent adverse event (TEAE) in adult 
participants with dry eye disease (DED).
If the analyses described in the protocols differ from those in this SAP, the methods of the 
SAP prevail.
4 Study Objective
The objective of this study is to evaluate the safety and effectiveness of OC-01 Nasal Spray 
as compared to placebo in simulating Goblet Cell and Meibomian Gland function in adult 
subjects with DED.
5 Study Design
Protocol OPP-005 is a Phase 2, single-center, randomized, masked, placebo-controlled study 
designed to evaluate the safety of OC-01 Nasal Spray as compared to in adult participants 
with DED. Approximately 45 subjects at least 18 years of age with a physicians’ diagnosis of 
dry eye disease and meeting all other study eligibility criteria will be randomized to receive 
an application of OC-01 or placebo at a single visit.
Appendix 1 describes the detailed study visits, measurements, and dosing information.
6 Sample Size Determination and Power Calculation
The sample size for this study is not based on statistical power considerations. The study
will randomize approximately 45 subjects in a 2:1 ratio to the two treatment groups. It is
expected that approximately 30 subjects will be enrolled in the investigational treatment arm 
and 15 subjects will be enrolled in the placebo arm. It is expected that all 45 subjects will be 
enrolled.
7 Statistical Analysis














Page 14 of 27
Appendix 2 Table of Contents
Table 14.1.1 Subjects Screened and Screen Failures (All Subjects)
Table 14.1.2 Subject Disposition (All Subjects)
Table 14.1.3 Demographics (Safety Population)
Table 14.1.4 Important Protocol Deviation (Safety Population)
Table 14.1.5.1 Ocular Medical History (Safety Population)
Table 14.1.5.2 Non-Ocular Medical History (Safety Population)
Table 14.1.6.1 Ocular Prior Medications (Safety Population)
Table 14.1.6.2 Non-Ocular Prior Medications (Safety Population)
Table 14.1.6.3 Ocular Concomitant Medications (Safety Population)
Table 14.1.6.4 Non-Ocular Concomitant Medications (Safety Population)
Table 14.3.1 Overall Summary of Treatment-Emergent Adverse Events (Safety Population)
Table 14.3.2.1 Ocular Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (Safety Population)
Table 14.3.2.2 Non-Ocular Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (Safety Population)
Table 14.3.3.1 Treatment-Emergent Adverse Events by Severity (Safety Population)
Table 14.3.3.2 Treatment-Emergent Adverse Events by Relationship (Safety Population)
Table 14.3.4 Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (Safety Population)
Table 14.3.5 Serious Treatment-Emergent Adverse Events Related to Study Drug (Safety Population)
Table 14.3.6 Treatment-Emergent Adverse Events Leading to Study Discontinuation (Safety Population)
Table 14.4.1 Intranasal Examination Results (Safety Population)
Listing 16.2.1 Demographics (All Subjects)
Listing 16.2.2 Subject Disposition at End of Study (All Population)
Listing 16.2.3 Protocol Deviations (Safety Population)
Listing 16.2.4 Inclusion/Exclusion Criterion Not Met (All Subjects)
Listing 16.2.5 Study Drug Exposure (Safety Population)
Listing 16.2.6 Prior and Concomitant Medications (Safety Population)
Listing 16.2.7 Medical History (Safety Population)


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Listing 16.2.8 Intranasal Examination (Safety Population)
Listing 16.2.9 Treatment-Emergent Adverse Events (Safety Population)


Page 16 of 27
Appendix 3 Tableshell
Table 14.1.1 Subjects Screened and Screen Failures (All Subjects)
Table 14.1.1
Subjects Screened and Screen Failures
All Subjects
Category
All Subjects
N=xx
n (%)
Number of subjects screened
xx
Number of subjects with screen failure
xx (xx.x)
Screen failure reason
Non-Fatal Adverse Event
xx (xx.x)
Protocol Violation
xx (xx.x)
Lost to Followup
xx (xx.x)
Pregnancy
xx (xx.x)
Physician Decision
xx (xx.x)
Subject non-compliance
xx (xx.x)
Death
xx (xx.x)
Study Terminated by Sponsor
xx (xx.x)
Withdraw by Subject
xx (xx.x)
Other
xx (xx.x)
Source: Listings 16….              O:\projects\ Oyster Point Pharma\OPP-005\tables\xxx.sas (ddmmmyyyy hh:mm)










Page 21 of 27
Table 14.1.6.1 Ocular Prior Medications (Safety Population)
Table 14.1.6.1 
Ocular Prior Medications
Safety Population
WHO Drug ATC2 
WHO Drug ATC4 
OC-01
1.2 mg/mL
N=xx
n (%)
Placebo
N=xx
n (%)
Total
N=xx
n (%)
Subjects with Any Ocular Prior Medications
xx (xx,x)
xx (xx,x)
xx (xx,x)
ATC2 1
xx (xx,x)
xx (xx,x)
xx (xx,x)
ATC4 1
xx (xx,x)
xx (xx,x)
xx (xx,x)
ATC4 2
xx (xx,x)
xx (xx,x)
xx (xx,x)
……
ATC2 xx
xx (xx,x)
xx (xx,x)
xx (xx,x)
ATC4 1
xx (xx,x)
xx (xx,x)
xx (xx,x)
ATC4 2
xx (xx,x)
xx (xx,x)
xx (xx,x)
……
Source: Listings 16….              O:\projects\ Oyster Point Pharma\OPP-005\tables\xxx.sas (ddmmmyyyy hh:mm)
Note: World Health Organization Drug Dictionary (WHO-DD) version WHODRUG GLOBAL B3 March 1, 2019 was used for medication coding. 
A prior medication is defined as any medication taken within 60 days before dosing on Day 1. Each subject could only contribute once to each of the incidence 
rates, regardless of the number of occurrences.


Page 22 of 27
Table 14.1.6.2 Non-Ocular Prior Medications (Safety Population)
Programming note: same format as Table 14.1.6.1.
Table 14.1.6.3 Ocular Concomitant Medications (Safety Population)
Programming note: same format as Table 14.1.6.1.
Footnote:
World Health Organization Drug Dictionary (WHO-DD) version WHODRUG GLOBAL B3 March 1, 2019 was used for medication coding. Concomitant 
medications are all medications taken from the day of first dose of the study treatment up to the day of last date of the study. 
Table 14.1.6.4 Non-Ocular Concomitant Medications (Safety Population)
Programming note: same format as Table 14.1.6.1.
Footnote:
World Health Organization Drug Dictionary (WHO-DD) version WHODRUG GLOBAL B3 March 1, 2019 was used for medication coding. Concomitant 
medications are all medications taken from the day of first dose of the study treatment up to the day of last date of the study. 






Page 25 of 27
Table 14.3.3.1 Treatment-Emergent Adverse Events by Severity (Safety Population)
Table 14.3.3.1
Treatment-Emergent Adverse Events by Severity
Safety Population
System Organ Class
Preferred Term
Severity 
OC-01 1.2 mg/mL
N=xx
n (%)
Placebo
N=xx
n (%)
Total
N=xx
n (%)
Any TEAEs
Mild
xx (xx.x)
xx (xx.x)
xx (xx.x)
Moderate
xx (xx.x)
xx (xx.x)
xx (xx.x)
Severe
xx (xx.x)
xx (xx.x)
xx (xx.x)
System Organ Class 1
Mild
xx (xx.x)
xx (xx.x)
xx (xx.x)
Moderate
xx (xx.x)
xx (xx.x)
xx (xx.x)
Severe
xx (xx.x)
xx (xx.x)
xx (xx.x)
Preferred Term 1
Mild
xx (xx.x)
xx (xx.x)
xx (xx.x)
Moderate
xx (xx.x)
xx (xx.x)
xx (xx.x)
Severe
xx (xx.x)
xx (xx.x)
xx (xx.x)
        
Source: Listings 16….              O:\projects\ Oyster Point Pharma\OPP-005\tables\xxx.sas (ddmmmyyyy hh:mm)
n (%) = number (percent) of subjects with events.
Note: A TEAE is defined as AE that is new or worsened in severity compared to the first dose of study drug. TEAEs were coded using MedDRA version 22.0.
[1] Subjects reporting more than one event are counted only once at the maximum severity reported.






Oyster Point Pharma, Inc.
Clinical Protocol: OPP-005:
A Single-Center, Randomized, Controlled, Masked 
Clinical Trial to Evaluate the Efficacy of OC-01 Nasal 
Spray on Goblet Cell and Meibomian Gland Stimulation 
(The IMPERIAL Study)
Abbreviated Statistical Analysis Plan
Version 1.0
Prepared by 
Date: February 14, 2020








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Page 6 of 8 
 


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Page 8 of 8 
 

Prot_000.pdf: 
OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 1 of 54 
 
 
 
Clinical Trial Protocol  
Protocol Title: 
A Single-Center, Randomized, Controlled, Masked 
Clinical Trial to Evaluate the Efficacy of OC-01 Nasal 
Spray on Goblet Cell and Meibomian Gland Stimulation 
(The IMPERIAL Study) 
Protocol Number: 
OPP-005 
Study Phase: 
2 
Product Name: 
OC-01 Nasal Spray 
 
 
Indication: 
Dry Eye Disease  
Investigators: 
Single Center  
 
Sponsor: 
Oyster Point Pharma, Inc. 
700 Alexander Park 
Suite 301 
Princeton, NJ 08540 
 
 
Date 
Original Protocol: 
June 14, 2018 
Amendment 1: 
July 11, 2018 
Amendment 2: 
October 23, 2018 
Amendment 3: 
January 21, 2019 
Amendment 4: 
March 26, 2019 
Confidentiality Statement  
This protocol contains confidential, proprietary information of Oyster Point Pharma, Inc. 
Further dissemination, distribution or copying of this protocol or its contents is strictly 
prohibited. 
 
 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 2 of 54 
 
SPONSOR PERSONNEL 
Chief Executive Officer: 
 
  
 
  
 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 3 of 54 
 
SYNOPSIS  
Protocol Title: 
A Single-Center, Randomized, Controlled, Masked 
Clinical Trial to Evaluate the Efficacy of OC-01 Nasal 
Spray on Goblet Cell and Meibomian Gland Stimulation 
(The IMPERIAL Study) 
Protocol Number: 
OPP-005 
Investigational Product:  
0.2% OC-01 (varenicline tartrate) nasal spray   
Study Objective: 
The objective of this study is to evaluate the safety and 
effectiveness of OC-01 Nasal Spray as compared to 
placebo in simulating Goblet Cell and Meibomian Gland 
function in adult subjects with DED. 
 
Overall Study Design 
Structure: 
A Phase 2, single-center, randomized, controlled, masked 
study 
Duration: 
A single study visit 
Control: 
Placebo (OC-01 Vehicle Nasal Spray) 
Dosing Regimen:  
Intranasal delivery of OC-01 at a single visit 
Summary of Visit 
Schedule: 
x Screening 
x Visit 1 (Meibomian Gland and Goblet Cell 
Evaluation) 
 
Measures Taken to Reduce 
Bias: 
This is a randomized, masked study 
Study Population Characteristics 
Number of Subjects: 
Approximately 45 (30 subjects in the OC-01 nasal spray 
arm; and 15 subjects in the placebo (vehicle) nasal spray 
arm) 
Condition/Disease: 
Dry Eye Disease  
Inclusion Criteria:  
Subjects must: 
1. 
 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 4 of 54 
 
2. Have used and/or desired to use an artificial tear 
substitute for dry eye symptoms within 6 months 
prior to Visit 1 
3. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
1 The study eye will be defined as the eye that meets all inclusion criteria; if both eyes qualify then the eye with 
the greatest increase in tear production with stimulation by a cotton swab at the Screening Visit or, if there is no 
difference in stimulated tear production, the eye with the lower basal Schirmer’s score at screening. If there is 
no difference for either measure, the right eye will be used as the study eye.  


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 5 of 54 
 
 
 
 
 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 6 of 54 
 
Exclusion Criteria:  
Subjects must not: 
1. 
 
  
 
  
 
 
 
5. Have had any intraocular surgery (such as cataract 
surgery), extraocular surgery (such as blepharoplasty) 
in either eye within three months or refractive surgery 
(e.g. laser-assisted in-situ keratomileusis, laser 
epithelial keratomileusis, photorefractive keratectomy 
or corneal implant) within twelve months of Visit 1 
 
 
 
8. Have a history or presence of any ocular disorder or 
condition in either eye that would, in the opinion of 
the Investigator, likely interfere with the 
interpretation of the study results or participant safety 
such as significant corneal or conjunctival scarring; 
pterygium or nodular pinguecula; current ocular 
infection, conjunctivitis, or inflammation not 
associated with dry eye; anterior (epithelial) 
basement membrane corneal dystrophy or other 
clinically significant corneal dystrophy or 
degeneration; ocular herpetic infection; evidence of 
keratoconus; etc.  
 
d. 
10. Have a systemic condition or disease not stabilized or 
judged by the Investigator to be incompatible with 
participation in the study or with the lengthier 
assessments required by the study (e.g., current 
systemic infection, uncontrolled autoimmune disease, 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 7 of 54 
 
uncontrolled immunodeficiency disease, history of 
myocardial infarction or heart disease, etc.)   
11. Have a known hypersensitivity to any of the 
procedural agents or study drug components  
 
 
 
 
 
 
 
 
  
 
  
 
  
 Have any condition or history that, in the opinion of 
the investigator, may interfere with study compliance, 
outcome measures, safety parameters, and/or the 
general medical condition of the subject 
 
 
 
 
 
 
 
 
  
 
 
 
Study Formulations: 
Subjects will be randomized 2:1 to be treated with OC-01 
nasal solution delivered as a 50 microliter (μL)-intranasal 
spray in each nostril at the following formulations: 
x 0.2% OC-01 (varenicline tartrate) nasal spray 
x Placebo nasal spray (OC-01 Vehicle Nasal Spray) 
Evaluation Criteria 
Efficacy Measures:  
Primary Efficacy Measures: 
x Change in Pre- vs, Post-Treatment Goblet cell area 
at Visit 2 
x Change in Pre- vs, Post-Treatment Goblet cell 
perimeter at Visit 2 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 8 of 54 
 
x Change in Pre- vs, Post-Treatment Meibomian 
gland area lower lids at Visit 2 
 
Safety Measures: 
x Adverse Event (AE) Query 
Summary of Known and Potential Risks and Benefits to Human Subjects 
There are no known risks with the instillation of OC-01 (varenicline tartrate) nasal spray.  
 
 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 9 of 54 
 
TABLE OF CONTENTS 
 
Synopsis ...............................................................................................................................3 
Table of Contents ...............................................................................................................9 
List of Abbreviations .......................................................................................................12 
1 
Introduction .............................................................................................................13 
2 
Study Objectives......................................................................................................14 
3 
Clinical Hypotheses .................................................................................................15 
4 
Overall Study Design ..............................................................................................15 
5 
Study Population .....................................................................................................15 
5.1 
Number of Subjects ......................................................................................15 
5.2 
Study Population Characteristics ...............................................................15 
5.3 
Inclusion Criteria .........................................................................................15 
5.4 
Exclusion Criteria .........................................................................................17 
5.5 
Withdrawal Criteria .....................................................................................18 
6 
Study Parameters ....................................................................................................18 
6.1 
Efficacy Measures .........................................................................................18 
6.1.1 
Primary Efficacy Measure ................................................................18 
6.2 
Safety Measure .............................................................................................18 
7 
Study Materials .......................................................................................................19 
7.1 
Study Drug(s) ................................................................................................19 
7.1.1 
Regimens...........................................................................................19 
7.1.2 
Dispensation Schedule ......................................................................19 
7.1.3 
Instructions for Use ...........................................................................19 
8 
Study Methods and Procedures .............................................................................27 
8.1 
Participant Entry Procedures .....................................................................27 
8.1.1 
Overview ...........................................................................................27 
8.1.2 
Informed Consent..............................................................................27 
8.1.3 
Washout Intervals .............................................................................27 
8.1.4 
Procedures for Final Study Entry ......................................................27 
8.1.5 
Methods for Assignment to Treatment Groups ................................27 
8.2 
Concurrent Therapies ..................................................................................27 
8.2.1 
Prohibited Medications/Treatments ..................................................28 
8.2.2 
Escape Medications ..........................................................................28 
8.2.3 
Special Diet or Activities ..................................................................28 
8.3 
Examination Procedures ..............................................................................28 
8.3.1 
Imaging Procedures ..........................................................................28 
8.3.2 
Procedures to be Performed at Each Study Visit with Regard to Study 
Objectives(s) ...................................................................................................28 
8.4 
Compliance with Protocol ............................................................................29 
8.5 
Subject Disposition .......................................................................................30 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 10 of 54 
 
8.5.1 
Completed Subjects ..........................................................................30 
8.5.2 
Discontinued Subjects .......................................................................30 
8.6 
Study Termination .......................................................................................30 
8.7 
Study Duration .............................................................................................30 
8.8 
Monitoring and Quality Assurance ............................................................30 
9 
safety definitions, safety monitoring and reporting .............................................31 
9.1 
Adverse Event ...............................................................................................31 
9.1.1 
Severity .............................................................................................31 
9.1.2 
Relationship to Study Drug ...............................................................31 
9.1.3 
Expectedness .....................................................................................32 
9.2 
Serious Adverse Events ................................................................................32 
9.3 
Procedures for Reporting Adverse Events .................................................33 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................33 
9.3.2 
Reporting a Serious Adverse Event ..................................................33 
9.4 
Procedures for Unmasking of Study Drug .................................................34 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ..34 
10 
Statistical Analysis ..................................................................................................34 
10.1 Sample Size and Power Considerations .....................................................34 
10.2 Analysis Populations ....................................................................................35 
10.2.1 Intention-To-Treat Population ..........................................................35 
10.2.2 Safety Population ..............................................................................35 
10.3 Statistical Hypotheses ...................................................................................35 
10.4 Statistical Analysis ........................................................................................36 
10.4.1 General Considerations .....................................................................36 
10.4.2 Unit of Analysis ................................................................................36 
10.4.3 Subject Demographics and Baseline Characteristics ........................36 
10.4.4 Efficacy Analysis ..............................................................................36 
10.4.5 Safety Analysis .................................................................................37 
10.4.6 Interim Analysis ................................................................................37 
11 
Compliance with Good Clinical Practices, Ethical Considerations, and 
Administrative Issues..............................................................................................37 
11.1 Protection of Human Subjects.....................................................................37 
11.1.1 Subject Informed Consent.................................................................37 
11.1.2 Institutional Review Board Approval ...............................................38 
11.2 Ethical Conduct of Study .............................................................................38 
11.3 Subject Confidentiality ................................................................................38 
11.4 Documentation ..............................................................................................38 
11.4.1 Retention of Documentation .............................................................38 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ....................................................................................................39 
11.5.1 Labeling/Packaging...........................................................................39 
11.5.2 Storage of Investigational Drug / Placebo ........................................39 
11.5.3 Accountability of Study Drug ...........................................................39 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 11 of 54 
 
11.5.4 Return or Disposal of Study Drug ....................................................39 
11.6 Recording of Data on Source Documents and Electronic Case Reports 
Forms .............................................................................................................39 
11.7 Handling of Biological Specimens ...............................................................40 
12 
References ................................................................................................................41 
13 
Appendices ...............................................................................................................44 
Appendix 1: Schedule of Visits and Measurements ......................................................45 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ..............46 
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 
Appendix 3: Sponsor and Approvals .............................................................................53 
Appendix 4: Investigator’s Signature ............................................................................54 
 
 
 
 
 


OC-01 (varenicline tartrate) Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-005 
March 26, 2019 
 
Amendment 4 
 
CONFIDENTIAL 
Page 12 of 54 
 
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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1 
INTRODUCTION  
Dry eye disease (DED) is a multifactorial, age-related disorder of the ocular surface resulting 
in severe pain, visual impairment, tear film hyperosmolarity and instability, inflammation, 
and corneal wounding. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 


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2 
STUDY OBJECTIVES  
The objective of this study is to evaluate the safety and effectiveness of OC-01 Nasal Spray 
as compared to placebo in simulating goblet cell and meibomian gland function in adult 
participants with DED.  


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3 
CLINICAL HYPOTHESES  
This study is testing the hypothesis that OC-01 nasal spray is superior to placebo in 
stimulating goblet cell and meibomian gland function as assessed by pre- vs. post-treatment 
change in goblet cell area, pre- vs. post-treatment change in goblet cell perimeter, and pre- 
vs. post-treatment change in meibomian gland area within the region of the lower lids. 
  
4 
OVERALL STUDY DESIGN  
Protocol OPP-005 is a Phase 2, single-center, randomized, masked, placebo-controlled study 
designed to evaluate the safety and effectiveness of OC-01 Nasal Spray as compared to 
placebo in simulating goblet cell and meibomian gland function in adult participants with 
DED.  Approximately 45 subjects at least 18 years of age with a physicians’ diagnosis of dry 
eye disease and meeting all other study eligibility criteria will be randomized to receive an 
application of OC-01 or placebo at a single visit and have pre- and post-treatment images 
acquired.  
Participants who terminate early during the application period will be asked to complete 
safety assessments (if the participants agree) prior to study exit. Participants who are 
terminated early from the study will not be replaced. 
5 
STUDY POPULATION  
5.1 
Number of Subjects 
Approximately 45 subjects will be enrolled at a single center in the US. Subjects will be 
randomized 2:1 to receive one of the two dose assignments. All doses will be delivered as a 
50 microliter (μL) intranasal spray in each nostril at a single visit. 
x 30 subjects- 0.2% OC-01 (varenicline tartrate) nasal spray 
x 15 subjects- Placebo (vehicle) nasal spray [control] 
5.2 
Study Population Characteristics  
All subjects must be at least 18 years of age, of either gender, and of any race, and must meet 
all inclusion criteria and none of the exclusion criteria.  
5.3 
Inclusion Criteria  
Subjects must:  
1. 
 


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2. 
Have used and/or desired to use an artificial tear substitute for dry eye symptoms 
within 6 months prior to Visit 1 
3. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
2 The study eye will be defined as the eye that meets all inclusion criteria; if both eyes qualify then the eye with 
the greatest increase in tear production with stimulation by a cotton swab at the Screening Visit or, if there is no 
difference in stimulated tear production, the eye with the lower basal Schirmer’s score at screening. If there is 
no difference for either measure, the right eye will be used as the study eye.  


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5.4 
Exclusion Criteria  
Subjects must not:  
1. 
 
  
 
 
 
 
5. Have had any intraocular surgery (such as cataract surgery), extraocular surgery (such 
as blepharoplasty) in either eye within three months or refractive surgery (e.g. laser 
epithelial keratomileusis, laser-assisted in-situ keratomileusis, photorefractive 
keratectomy or corneal implant) within twelve months of Visit 1 
 
  
8. Have a history or presence of any ocular disorder or condition in either eye that 
would, in the opinion of the Investigator, likely interfere with the interpretation of the 
study results or participant safety such as significant corneal or conjunctival scarring; 
pterygium or nodular pinguecula; current ocular infection, conjunctivitis, or 
inflammation not associated with dry eye; anterior (epithelial) basement membrane 
corneal dystrophy or other clinically significant corneal dystrophy or degeneration; 
ocular herpetic infection; evidence of keratoconus; etc.  
 
10. Have a systemic condition or disease not stabilized or judged by the Investigator to be 
incompatible with participation in the study or with the lengthier assessments 
required by the study (e.g., current systemic infection, uncontrolled autoimmune 
disease, uncontrolled immunodeficiency disease, history of myocardial infarction or 
heart disease, etc.)   
11. Have a known hypersensitivity to any of the procedural agents or study drug 
components  
 
 
 
 
  
  


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14. Have any condition or history that, in the opinion of the investigator, may interfere 
with study compliance, outcome measures, safety parameters, and/or the general 
medical condition of the subject 
 
 
 
 
 
 
5.5 
Withdrawal Criteria  
If at any time during the study the Investigator determines that a subject’s safety has been 
compromised, the subject may be withdrawn from treatment. 
Subjects may withdraw consent from the study at any time.  
Sponsor or designee and/or Investigator may discontinue any subject from study treatment 
for non-compliance or any valid medical reason during the course of the study (see Section 
8.5.2).  
6 
STUDY PARAMETERS  
6.1 
Efficacy Measures  
6.1.1 Primary Efficacy Measure 
The following efficacy measures will be tested:  
x Change in Pre- vs, Post-Treatment Goblet cell area at Visit 2 
x Change in Pre- vs, Post-Treatment Goblet cell perimeter at Visit 2 
x Change in Pre- vs, Post-Treatment Meibomian gland area lower lids at Visit 2 
6.2 
Safety Measure 
x Adverse Events 


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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 at Visit 2:: 
 Placebo (vehicle) 
 0.2% OC-01 (varenicline tartrate) nasal spray 
7.1.2 Dispensation Schedule  
Qualified subjects will be randomized and the first dose of study drug will be 
administered in office at Visit 2.   
  
7.1.3 Instructions for Use 
General Appearance 
 
 
 
 
 
  
Preparation 
  
 
 
 


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Figure 1 
3. 
 
Figure 2 


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4. 
 
 
Figure 3 
 


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Figure 4 
 


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Administration 
7. 
 
 
 
 


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11. 
 
 
 
Figure 9 
 
 
 
 
 
 
 


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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.  
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.  
This number will not necessarily be the same as the randomization number. 
Subjects who meet the eligibility requirements will be randomly assigned to 1 of 2 treatment 
groups. 
8.2 
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.  
Concurrent enrollment in another investigational drug or device study is not permitted.  


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8.2.1 Prohibited Medications/Treatments  
Disallowed medications/treatments during the study are outlined in the Exclusion Criteria 
(Section 5.4) 
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 Imaging Procedures 
Imaging procedures will begin first prior to bilateral intranasal delivery of drug/placebo. 
Meibography will be performed first followed by in vivo confocal goblet cell imaging. 
Approximately 10 minutes after the delivery of bilateral intranasal drug/placebo delivery, 
imaging procedures will be repeated.  Meibography will be performed first followed by in 
vivo confocal goblet cell imaging. 
8.3.1.1 Meibomian Gland Imaging 
Meibomian glands will be imaged by the keratography 5M® and Meibomian gland area will 
be assessed using the MeiboScan digital measurement software. 
8.3.1.2 Goblet Cells Imaging 
Goblet cells will be imaged by In vivo confocal microscopy (Heidelberg Retinal Tomograph 
3/Rostock cornea module; Heidelberg Engineering). 
8.3.2 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): Screening  
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 EDS (visual analog scale) 
x Slit-lamp biomicroscopy 
x Corneal fluorescein staining 


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x Schirmer’s Test3 (pre-treatment) 
x Schirmer’s Test with nasal stimulation (cotton swab) [pre-treatment ]4 
x Intranasal examination  
x Concomitant Medications 
x AE Query 
 
Treatment and Imaging Visit (Visit 2) [Meibomian Gland and Goblet Cell Evaluation] 
Pre-treatment Assessments (prior to administration of study drug/placebo) 
x Concomitant Medications 
x AE Query 
x Slit-lamp biomicroscopy 
x Randomization 
x Dispense study drug/placebo intranasal applicator 
x Imaging of conjunctival inferonasal goblet cells with Heidelberg Retinal Tomograph 
3®/Rostock cornea module  
x Meibography assessment by infrared imaging with Oculus Keratograph 5M® 
ADMINISTRATION OF STUDY DRUG/PLACEBO 
Post-treatment Assessments (after administration of study drug/placebo) 
x Imaging of conjunctival inferonasal goblet cells with Heidelberg Retinal Tomograph 
3®/Rostock cornea module  
x Meibography assessment by infrared imaging with Oculus Keratograph 5M® 
x AE Query 
8.4 
Compliance with Protocol  
As subjects will be treated at a single visit at the clinic, it is expected that compliance with 
the protocol will be excellent. 
                                                 
3 Procedure will occur after corneal fluorescein staining  
4 Schirmer’s test with nasal stimulation will occur 10 minutes after the first Schirmer’s test  


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8.5 
Subject Disposition  
8.5.1 Completed Subjects  
A completed subject is one who has completed Visit 2, been administered investigational 
therapy, and completed all imaging exams.  
8.5.2 Discontinued Subjects  
As subjects will be treated at a single visit at the clinic, it is expected that a minimal amount 
of subjects will be discontinued from the study. 
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 unmasking when medically necessary; 
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 
Notification of a subject discontinuation and the reason for discontinuation will be made to 
Sponsor or designee and will be clearly documented on the CRF. 
Discontinued subjects will not be replaced. 
8.6 
Study Termination  
The study may be stopped at any time by the Investigator after consultation with the Sponsor 
or designee, with appropriate notification.  
8.7 
Study Duration  
An individual subject’s participation will involve 2 visits. 
8.8 
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. 
Regulatory authorities of domestic and foreign agencies, Sponsor or designee quality 
assurance and or its designees may carry out on-site inspections and/or audits, which may 


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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. 
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 
x Probable: When there are good reasons and sufficient documentation to assume a 
causal relationship in the sense of plausible, conceivable, likely but not 
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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 or 
designee, 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 
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 


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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. 
9.3 
Procedures for Reporting Adverse Events  
All AEs and their outcomes must be reported to the Sponsor or designee, and the IRB/IEC as 
required by the IRB/IEC, federal, state, or local regulations and governing health authorities 
and recorded on the appropriate CRF. 
9.3.1 Reporting a Suspected Unexpected Adverse Reaction  
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to the Sponsor or designee 
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 the Sponsor or designee 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 the Sponsor or designee 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 the Sponsor or designee 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. 


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Contact information for reporting SAEs:  
Name: 
Title: 
Company: 
Office Telephone: 
Alternative Telephone: 
 
 
 
 
 
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), the Sponsor or designee 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.  
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 
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/email to Sponsor or designee 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. 
10.1 Sample Size and Power Considerations 
The sample size for this study is not based on statistical power considerations.  The study 
will randomize approximately 45 subjects in a 2:1 ratio to the two treatment groups. It is 
expected that approximately 30 subjects will be enrolled in the investigational treatment arm 


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and 15 subjects will be enrolled in the placebo arm.  It is expected that all 45 subjects will be 
enrolled. 
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.  
10.3 Statistical Hypotheses 
Meibomian Gland Area 
The mean change in meibomian gland area from Pre-Treatment to Post-Treatment is denoted 
as μp, μv for placebo and 0.2% OC-01, respectively. 
H01: μp = μv 
H11: μp Į μv   
Goblet Cell Area 
The mean change in goblet cell area from Pre-Treatment to Post-Treatment is denoted as μp, 
μv for placebo and 0.2% OC-01, respectively. 
H01: μp = μv 
H11: μp Į μv   
 
Goblet Cell Perimeter 
The mean change in goblet cell perimeter from Pre-Treatment to Post-Treatment is denoted 
as μp, μv for placebo and 0.2% OC-01, respectively. 
H01: μp = μv 
H11: μp Į μv   
 
A successful outcome will be one that rejects the null hypothesis. 
 


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10.4 Statistical Analysis 
This section briefly outlines the planned efficacy analyses. 
10.4.1 General Considerations 
 
 
 
 
 
 
10.4.2 Unit of Analysis 
 
 
 
 
 
 
 
  
10.4.3 Subject Demographics and Baseline Characteristics 
Continuous summary statistics will be generated for age in years by treatment group and for 
all subjects. Discrete summary statistics will be generated for the following qualitative 
demographic variables: age category, gender, ethnicity, race, and other baseline intranasal 
examination results, tabulated by treatment group and for all subjects. Individual subject data 
listings will support the Summary tables. 
10.4.4 Efficacy Analysis 
The efficacy endpoints will be the mean change in meibomian cell area, goblet cell area, and 
goblet cell perimeter from Pre-Treatment to Post-Treatment. 
 
 
 
  


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10.4.5 Safety Analysis 
 
 
 
 
  
10.4.6 Interim Analysis 
 
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 or designee or 
designee and receive approval/favorable opinion from an IRB prior to their use.  If the 
consent form requires revision (e.g., due to a protocol amendment or significant new safety 
information), it is the investigator’s responsibility to ensure that the amended informed 
consent is reviewed and approved by Sponsor or designee 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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If informed consent is taken under special circumstances (oral informed consent), then the 
procedures to be followed must be determined by Sponsor or designee and provided in 
writing by 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 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 or designee, 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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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 or designee 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. 
11.5.2 Storage of Investigational Drug / Placebo 
The investigational drug / placebo must be stored in a secure area accessible only to the 
investigator and his/her designee(s). Study drug(s) must be refrigerated (2-8°C, Do Not 
Freeze), protected from light, and secured at the investigational site in a locked container.  
11.5.3 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.  
11.5.4 Return or Disposal of Study Drug 
All study drugs will be returned to the Sponsor for destruction. 
11.6 Recording of Data on Source Documents and Electronic Case Reports 
Forms 
If applicable, 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 


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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.  
 
 


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12 REFERENCES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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. 
 
 
 
 
 
 
 
 
 
 
 


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13 APPENDICES 


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APPENDIX 2: EXAMINATION PROCEDURES, TESTS, EQUIPMENT, 
AND TECHNIQUES  
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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NEI/Industry Workshop Scale 
Score each of five areas on the cornea of each eye. 
Diagram of the division of the corneal surface for measuring fluorescein uptake. A 
standardized grading system of 0-3 is used for each of the five areas on each cornea. Grade 0 
will be specified when no staining is present. The maximum score is 15. 
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. 
 
 


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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 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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Ocular Surface Disease Index©  
To minimize bias, participants will be asked to complete the OSDI questionnaire 
independently and in private after instructions have been provided by site personnel. 
The OSDI is a 12-item questionnaire generated by the Outcomes Research Group at Allergan 
(Irvine, CA),(Walt JG 1997) which asks participants to describe the severity and the nature of 
their irritation symptoms.  The participant will answer the 12 questions by circling the 
number that best represents each answer:  4 (all of the time), 3 (most of the time), 2 (half of 
the time), 1 (some of the time), or 0 (none of the time).  The final score for the questionnaire 
is calculated as follows: 
Add subtotals from Sections I, II, and III =  A 
Determine total number of questions answered from Sections I, II, and III (do not include 
N/A) = B 
Final OSDI score = A x 25 divided by B   
 
An example of the questionnaire follows.  
 
 


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Eye Dryness Score (EDS) Using a Visual Analog Scale (VAS) 


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APPENDIX 3: SPONSOR AND APPROVALS 
Protocol Title: 
A Single-Center, Randomized, Controlled, Masked Clinical Trial 
to Evaluate the Efficacy of OC-01 Nasal Spray on Goblet Cell and 
Meibomian Gland Stimulation (The IMPERIAL Study) 
Protocol Number: 
OPP-005 
 
Date: 
 
 
 
 
 
 
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APPENDIX 4: INVESTIGATOR’S SIGNATURE  
Protocol Title: 
A Single-Center, Randomized, Controlled, Masked Clinical Trial 
to Evaluate the Efficacy of OC-01 Nasal Spray on Goblet Cell and 
Meibomian Gland Stimulation (The IMPERIAL Study) 
Protocol Number: 
OPP-005 
 
 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to maintain 
all information supplied by the Sponsor in confidence and, when this information is 
submitted to an Institutional Review Board (IRB) or another group, it will be submitted with 
a designation that the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
 
Name:  
 
 
 
Title:  
 
 
 
Site:  
 
 
 
Address:  
 
 
 
Phone Number: