Conditions: Dry Eye Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 165
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate the safety and effectiveness of OC-02 Nasal Spray as compared to placebo on signs and symptoms of dry eye disease.

Detailed description:
This was a Phase 2, multicenter, randomized, double-masked, placebo controlled study designed to evaluate the safety and efficacy of OC 02 Nasal Spray in adult participants with dry eye disease. Approximately 160 subjects, at least 22 years of age, with a subject-reported history of dry eye disease and meeting all other study eligibility criteria were planned to be randomized to receive an application of OC-02 or placebo at Visit 1 and Visit 2.

Arms:
arm 1: 0.2 % hemigalactarate (0.11% free base) 0.2 % OC-02 Low Dose (1.1 mg/mL) arm 2: 1.0 % hemigalactarate (0.11% free base) 1.0 % OC-02 Mid Dose (5.5 mg/mL) arm 3: 2.0 % hemigalactarate (0.11% free base) 2.0 % OC-02 High Dose (11.1 mg/mL) arm 4: Placebo (vehicle) nasal spray

Interventions: intervention 1: 0.2 % hemigalactarate (0.11% free base) 0.2 % OC-02 Low Dose (1.1 mg/mL) intervention 2: 1.0 % hemigalactarate (0.11% free base) 1.0 % OC-02 Mid Dose (5.5 mg/mL) intervention 3: 2.0 % hemigalactarate (0.11% free base) 2.0 % OC-02 High Dose (11.1 mg/mL) intervention 4: Placebo (vehicle) nasal spray
Intervention descriptions: intervention 1: 0.2 % hemigalactarate (0.11% free base) 0.2 % OC-02 Low Dose (1.1 mg/mL) intervention 2: 1.0 % hemigalactarate (0.11% free base) 1.0 % OC-02 Mid Dose (5.5 mg/mL) intervention 3: 2.0 % hemigalactarate (0.11% free base) 2.0 % OC-02 High Dose (11.1 mg/mL) intervention 4: Placebo (vehicle) nasal spray

Protocol document:
Prot_000.pdf: 
OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
CONFIDENTIAL 
Page 1 of 57 
 
Clinical Trial Protocol  
Protocol Title: 
Multicenter, Randomized, Controlled, Double-Masked 
Clinical Trial to Evaluate the Efficacy of OC-02 Nasal 
Spray on Signs and Symptoms of Dry Eye Disease 
Protocol Number: 
OPP-001 
Study Phase: 
2 
Product Name: 
OC-02 Nasal Spray 
 
 
Indication: 
Dry Eye Disease  
Investigators: 
Multi-Center  
 
Sponsor: 
Oyster Point Pharma, Inc. 
One Sansome Street, Suite #3630 
San Francisco, CA  94104 
 
Contract Research 
Organization: 
 
 
 
 
 
 
Institutional Review 
Board: 
Alpha IRB 
1001 Avenida Pico 
Suite C, #497 
San Clemente, CA 92673 
 
 
 
 
 
 
Date 
Original Protocol: 
11 October 2017 
Amendment 1: 
N/A 
Confidentiality Statement  
This protocol contains confidential, proprietary information of 
. and/or Oyster Point 
Pharma, Inc. Further dissemination, distribution or copying of this protocol or its contents is 
strictly prohibited. 
 
 


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Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
CONFIDENTIAL 
Page 2 of 57 
 
SPONSOR PERSONNEL 
 
 
  
 
  
MEDICAL MONITOR 
 
 
 
 
 
  
 PERSONNEL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 










OC-02 Nasal Spray 
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Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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 1.1% OC-02 (2.0% hemigalactarate salt) [high 
dose] 
 Placebo (OC-02 Vehicle Nasal Spray) 
Evaluation Criteria 
 
Efficacy Measures:  
Primary Efficacy Measures: 
 Schirmer’s Test at Visit 1 
 Eye Dryness Score (EDS) at Visit 2 
Safety Measures: 
 Adverse Event (AE) Query 
Other Measures: 
 Ora Calibra® Ocular Discomfort Scale 
 Urine pregnancy test (if applicable) 
General Statistical Methods and Types of Analyses 
Analysis Populations: 
 Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. Subjects in the ITT population will be analyzed as 
randomized. 
 Per Protocol Population – The per protocol (PP) population includes subjects in the 
ITT population who do not have significant protocol deviations and who complete 
the study. Protocol deviations will be assessed prior to database lock and 
unmasking. Subjects in the PP population will be analyzed as treated. randomized. 
 Safety Population – The safety population includes all subjects who have received 
at least one dose of the investigational product. Subjects in the Safety population 
will be analyzed as treated. 
Sample Size: 
The sample size for this study is not based on statistical power considerations. It is 
expected that approximately 40 subjects will be enrolled in each of the four treatment arms, 
for a total of approximately 160 randomized subjects. Assuming a 5% drop out rate, 
approximately 38 subjects per group are expected to complete the study.  
Multiplicity Consideration: 
Adjustments for multiple testing will not be implemented for this early phase study. 
Primary Efficacy Analyses: 
Schirmer’s Test and EDS will be summarized by visit, time point (where appropriate) and 
treatment with descriptive statistics (n, mean, median, standard deviation, minimum and 
maximum).  
An analysis of covariance (ANCOVA) model will be used to compare results from 
Schirmer’s Test concurrent with treatment between each dose of OC-02 Nasal Spray and 
placebo treatment groups. The ANCOVA model will include baseline Schirmer’s Test 
(captured at Screening), treatment and study site as covariates. Least Squares Means (LS 
Means) for each treatment, the corresponding 95% confidence intervals (CIs), and the 


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Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
CONFIDENTIAL 
Page 8 of 57 
 
estimated treatment differences between each dose of OC-02 Nasal Spray and placebo will 
be calculated from this ANCOVA model. In addition, the study site by treatment 
interaction will be explored in a separate model to evaluate how the treatment effect may 
differ across study sites. 
The change in EDS from pre- to post-treatment will be analyzed using an ANCOVA model 
with pre-treatment EDS as a covariate and with treatment and time point as fixed effects 
(accounting for repeated measures). LS means for each treatment, the corresponding 95% 
CIs, and the estimated treatment difference between each dose of OC-02 Nasal Spray and 
placebo will be calculated from this ANCOVA model. A study site by treatment interaction 
will also be explored in a separate model to evaluate how the treatment effect may differ 
across study sites. 
The primary analyses will be performed on the ITT population on observed data. Two-
sample t-tests and non-parametric Wilcoxon rank sum tests will be used to compare 
treatments as unadjusted sensitivity analyses. Sensitivity analyses will also be performed 
on the ITT population with multiple imputation (MI) to impute missing data, as well as the 
PP population with observed data only. 
Other Efficacy Analyses: 
Change from pre to post-treatment in EDS will also be analyzed at each individual time 
point in a manner similar to the primary analysis for Schirmer’s Test. These ANCOVA 
models will include pre-treatment EDS, treatment and study site as covariates.  
Change from pre-to post-treatment in 
 Ocular Discomfort Scale results will be 
summarized by visit, time point (where appropriate) and treatment with quantitative 
descriptive statistics and will be analyzed at each individual time point in a manner similar 
to EDS.  
The analyses will be performed for observed data only for the ITT and PP populations. 
Safety Variables: 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. Frequencies and percentages of subjects with treatment-emergent AEs 
(TEAEs), serious TEAEs, and TEAEs causing premature discontinuation will be provided 
by treatment group. An AE is treatment emergent if it occurs or worsens after the first dose 
of study treatment. Furthermore, frequencies will be given of subjects with TEAEs by 
system organ class, by system organ class and preferred term, by system organ class, 
preferred term and maximal severity, by system organ class, preferred term and strongest 
relationship, and by system organ class, preferred term, maximal severity, and strongest 
relationship. Separate analyses will be performed for ocular specific and all AEs (including 
systemic).  
Other safety endpoints including visual acuity, slit-lamp biomicroscopy and intranasal 
endoscopic examination will be summarized by treatment group and visit using descriptive 
statistics. Changes or shifts from baseline will also be summarized where appropriate. For 
assessments performed by eye, study eye and fellow eye will be summarized separately. In 
addition, shifts from baseline to worst on-treatment value for ocular safety assessments will 
be summarized. 


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Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
CONFIDENTIAL 
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Summary of Known and Potential Risks and Benefits to Human Subjects 
There are no known risks with the instillation of OC-02 Nasal Spray.  
 
 


OC-02 Nasal Spray 
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Clinical Trial Protocol #OPP-001 
11 October 2017 
 
CONFIDENTIAL 
Page 10 of 57 
 
TABLE OF CONTENTS 
 
Synopsis ...............................................................................................................................3 
Table of Contents .............................................................................................................10 
List of Abbreviations .......................................................................................................13 
1 
Introduction .............................................................................................................14 
2 
Study Objectives......................................................................................................15 
3 
Clinical Hypotheses .................................................................................................15 
4 
Overall Study Design ..............................................................................................15 
5 
Study Population .....................................................................................................17 
5.1 
Number of Subjects ......................................................................................17 
5.2 
Study Population Characteristics ...............................................................17 
5.3 
Inclusion Criteria .........................................................................................17 
5.4 
Exclusion Criteria .........................................................................................18 
5.5 
Withdrawal Criteria .....................................................................................20 
6 
Study Parameters ....................................................................................................20 
6.1 
Efficacy Measures .........................................................................................20 
6.1.1 
Primary Efficacy Measures ...............................................................20 
6.2 
Safety Measure .............................................................................................20 
6.3 
Other Measures ............................................................................................20 
7 
Study Materials .......................................................................................................20 
7.1 
Study Drug(s) ................................................................................................20 
7.1.1 
Formulations .....................................................................................20 
7.1.2 
Dispensation Schedule ......................................................................20 
7.1.3 
Instructions for Use ...........................................................................21 
7.2 
Other Study Supplies ...................................................................................26 
8 
Study Methods and Procedures .............................................................................26 
8.1 
Participant Entry Procedures .....................................................................26 
8.1.1 
Overview ...........................................................................................26 
8.1.2 
Informed Consent..............................................................................26 
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 ..................................................27 
8.2.2 
Escape Medications ..........................................................................27 
8.2.3 
Special Diet or Activities ..................................................................27 
8.3 
Examination Procedures ..............................................................................28 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to Study 
Objectives(s) ...................................................................................................28 
8.4 
Schedule of Visits, Measurements and Dosing ..........................................30 
8.4.1 
Scheduled Visits................................................................................30 


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Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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8.4.2 
Unscheduled Visits ...........................................................................30 
8.5 
Compliance with Protocol ............................................................................30 
8.6 
Subject Disposition .......................................................................................30 
8.6.1 
Completed Subjects ..........................................................................30 
8.6.2 
Discontinued Subjects .......................................................................30 
8.7 
Study Termination .......................................................................................31 
8.8 
Study Duration .............................................................................................31 
8.9 
Monitoring and Quality Assurance ............................................................31 
9 
Adverse Events ........................................................................................................31 
9.1 
Adverse Event ...............................................................................................31 
9.1.1 
Severity .............................................................................................32 
9.1.2 
Relationship to Study Drug ...............................................................32 
9.1.3 
Expectedness .....................................................................................32 
9.2 
Serious Adverse Events ................................................................................33 
9.3 
Procedures for Reporting Adverse Events .................................................34 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................34 
9.3.2 
Reporting a Serious Adverse Event ..................................................34 
9.4 
Procedures for Unmasking of Study Drug .................................................35 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ..35 
10 
Statistical Hypotheses and Methods of Analyses .................................................35 
10.1 Analysis Populations ....................................................................................35 
10.2 Statistical Hypotheses ...................................................................................36 
10.3 Sample Size ...................................................................................................36 
10.4 Statistical Analysis ........................................................................................36 
10.4.1 General Considerations .....................................................................36 
10.4.2 Unit of Analysis ................................................................................36 
10.4.3 Missing Data .....................................................................................37 
10.4.4 Multiplicity Consideration ................................................................37 
10.4.5 Primary Efficacy Analyses ...............................................................37 
10.4.6 Other Efficacy Analyses ...................................................................38 
10.4.7 Safety Variables ................................................................................38 
10.4.8 Interim Analyses ...............................................................................38 
11 
Compliance with Good Clinical Practices, Ethical Considerations, and 
Administrative Issues..............................................................................................38 
11.1 Protection of Human Subjects.....................................................................39 
11.1.1 Subject Informed Consent.................................................................39 
11.1.2 Institutional Review Board Approval ...............................................39 
11.2 Ethical Conduct of Study .............................................................................39 
11.3 Subject Confidentiality ................................................................................39 
11.4 Documentation ..............................................................................................40 
11.4.1 Retention of Documentation .............................................................40 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ....................................................................................................40 
11.5.1 Labeling/Packaging...........................................................................40 


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Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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11.5.2 Storage of Investigational Drug / Placebo ........................................40 
11.5.3 Accountability of Study Drug ...........................................................40 
11.5.4 Return or Disposal of Study Drug ....................................................41 
11.6 Recording of Data on Source Documents and Electronic Case Reports 
Forms .............................................................................................................41 
11.7 Handling of Biological Specimens ...............................................................41 
11.8 Publications ...................................................................................................41 
12 
References ................................................................................................................42 
13 
Appendices ...............................................................................................................45 
Appendix 1: Schedule of Visits and Measurements ......................................................45 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ..............46 
Visual Acuity Procedures .......................................................................................46 
Slit Lamp Biomicroscopy .......................................................................................48 
Corneal Fluorescein Staining .................................................................................48 
Intranasal Examination ..........................................................................................49 
Schirmer’s Test with Topical Anesthesia .............................................................50 
Ocular Surface Disease Index© ..............................................................................51 
Eye Dryness Score (EDS) Using a Visual Analog Scale (VAS) ...........................54 
 Ocular Discomfort Scale ................................................................55 
Appendix 3: Sponsor and 
 Approvals .....................................................................56 
Appendix 4: Investigator’s Signature ............................................................................57 
 
 
 
 
 


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Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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Page 13 of 57 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
BCVA 
Best corrected visual acuity  
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 
TEAE 
Treatment-emergent adverse event 
US 
United States 
 
 
 
 
 








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Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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5 STUDY POPULATION  
5.1 
Number of Subjects 
It is estimated that approximately 160 participants (approximately 40 per arm) will be 
enrolled at up to 3 sites in the US. Subjects will be randomized to receive one of the 
following four dose assignments: 
 Placebo (vehicle) delivered as a 100 microliter (µL) intranasal spray in each nostril 
 0.11% OC-02 (0.2% hemigalactarate salt) delivered as a 100 µL intranasal spray in 
each nostril 
 0.55% OC-02 (1.0% hemigalactarate salt) delivered as a 100 µL intranasal spray in 
each nostril 
 1.1% OC-02 (2.0% hemigalactarate salt) delivered as a 100 µL intranasal spray in 
each nostril 
Subjects will be administered OC-02/Placebo at Visit 1 and Visit 2.  
5.2 
Study Population Characteristics  
All subjects must be at least 22 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. 
 
2. 
Have used and/or desired to us an artificial tear substitute for dry eye symptoms 
within 6 months prior to Visit 1 
3. 
 
4. 
 
 
  
 
 
s 
                                                 
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.  


OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
CONFIDENTIAL 
Page 18 of 57 
 
 
 
 
 
5. 
 
 
 
6. 
 
 
7. 
 
 
8. 
 
9. 
 
 
10. 
 
 
11. 
 
12. 
   
 
5.4 
Exclusion Criteria  
Subjects must not:  
1. 
 
  
2. 
 
 
 
3. 
 
  
4. 
  
 
 
5. 
 
6. 
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 
7. 
 


OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
CONFIDENTIAL 
Page 19 of 57 
 
8. 
 
od 
9. 
  
10. 
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. Blepharitis not requiring 
treatment and mild meibomian gland disease that are typically associated with DED 
are allowed. 
11. 
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.)   
12. 
Have a known hypersensitivity to any of the procedural agents or study drug 
components  
13. 
 
 
14. 
 
 
 
15. 
  
 
  
 
 
 
 
 
 
  
16. 
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 
17. 
 
18. 
 
 












OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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 
 


OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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 
 
 
7.2 
Other Study Supplies  
 
Urine pregnancy test kits  
 
Fluorescein sodium solution or fluorescein strips 
 
Schirmer’s test strips  
 
Proparacaine  
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 participation in the trial (i.e., prior to study-related procedures), the 
study will be discussed with each potential participant and participants wishing to participate 


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Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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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 qualifies will be assigned a screening number. All screening numbers will 
be assigned in strict numerical sequence at a site and no numbers will be skipped or omitted. 
If all inclusion and exclusion criteria are met at Visit 1, each qualifying subject will then be 
assigned a randomization number. 
A randomization schedule will be provided to each investigational site. The randomization 
schedule will be stratified by site, such that there will be an approximate equal number of 
subjects assigned to each of the four treatment arms at each site. The site staff will dispense 
to the patient the study kit labeled with the corresponding randomization number. The 
randomization number will be recorded on the patient’s source document and electronic case 
report form (eCRF). The Sponsor, Investigators, and study staff will be masked during the 
randomization process and throughout the study.  
8.2 
Concurrent Therapies  
 
 
  
  
 
  
 
 
 
 
  
 
  
.  


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Clinical Trial Protocol #OPP-001 
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8.3 
Examination Procedures  
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study Objectives(s) 
The following procedures will be performed (see Appendix 2 for description).  
Visit 1 (Day 1): Screening and Schirmer’s Test Evaluation  
Screening 
 
Informed consent/Health Information Portability and Accountability Act 
(HIPAA) consent 
 
Demographic data, medical/medication, and ocular history 
 
Eligibility Criteria  
 
OSDI© 
 
EDS (visual analog scale) 
 
Ocular Discomfort Scale 
 
BCVA  
 
Slit lamp biomicroscopy  
 
Corneal fluorescein staining 
 
Schirmer’s Test3  
 
Schirmer’s Test with nasal stimulation (cotton swab)4 
 
Intranasal examination  
 
Urine Pregnancy Test (if applicable) 
 
Concomitant Medications 
 
AE Query 
Treatment (Schirmer’s Test Evaluation) 
Pre-Treatment Procedures:  
 
Randomization: Qualified participants will be assigned to one of the 
following treatment groups: 
o Placebo (vehicle) delivered as a 100 µL intranasal spray in each 
nostril 
o 0.11% OC-02 (0.2% hemigalactarate salt) delivered as a 100 µL 
intranasal spray in each nostril 
                                                 
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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Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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o 0.55% OC-02 (1.0% hemigalactarate salt) delivered as a 100 µL 
intranasal spray in each nostril 
o 1.1% OC-02 (2.0% hemigalactarate salt) delivered as a 100 µL 
intranasal spray in each nostril 
Treatment Procedures:  
 
Instruct subjects on investigational drug / placebo administration  
 
Treatment with investigational drug/placebo 
Post-Treatment Procedures:  
 
Post-treatment Schirmer’s test (performed immediately after investigational 
drug administration) 
 
BCVA 
 
Slit lamp biomicroscopy 
 
Intranasal endoscopic examination  
 
Concomitant Medications 
 
AE Query 
 
Schedule participant for Visit 2 
Visit 2 (Day 15+4):  CAE 
 
Medical/medication and ocular history updates 
 
EDS 
 
Ora Calibra® Ocular Discomfort Scale  
 
Approximately 120 minutes of CAE® Exposure 
 
EDS collected upon entering the CAE® and every 5 minutes thereafter.  
 
 Ocular Discomfort Scale upon entering the CAE® and every 5 
minutes thereafter. 
 
Instruct subjects on investigational drug/placebo administration  
 
Treatment with investigational drug/placebo 
o Treatment with Investigational drug/placebo will be administered 
upon participant reporting an Ocular Discomfort score ≥ 3 at two 
or more consecutive time points in at least one eye during CAE® 
exposure (if a participant has an Ocular Discomfort rating of 3 at 
time = 0 for an eye, s/he must report an Ocular Discomfort rating 
of 4 for two consecutive measurements for that eye) using the 
 
Scale. Participant will resume symptom assessments 1 
minute after the application ends every 5 minutes. 
 
BCVA 
 
Slit lamp biomicroscopy  


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Clinical Trial Protocol #OPP-001 
11 October 2017 
 
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 
Intranasal Examination  
 
Urine Pregnancy Test (if applicable) 
 
Concomitant Medications 
 
AE Query 
 
Study exit 
8.4 
Schedule of Visits, Measurements and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements.  
8.4.2 Unscheduled Visits  
These visits may be performed in order to ensure subject safety. All procedures performed at 
an unscheduled visit will be recorded in the source documents and on the Unscheduled Visit 
eCRF pages. Any procedure indicated in the eCRF that is not performed should be indicated 
as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
 
Slit-lamp Biomicroscopy; 
 
Visual Acuity; 
 
Intranasal Examination; 
 
Urine Pregnancy Test (if applicable); 
 
Assessment of AEs; 
 
Assessment of concurrent medications and/or treatments; and 
 
Any other assessments needed in the judgment of the investigator. 
8.5 
Compliance with Protocol  
Subjects will be instructed on how study drug will be administered at Visits 1 and 2 and 
provided detailed written instructions to review.  
Dosing compliance will be based on used/unused study drug at Visits 1 and 2. 
8.6 
Subject Disposition  
8.6.1 Completed Subjects  
A completed subject is one who has not be discontinued from the study.  
8.6.2 Discontinued Subjects  
Subjects may be discontinued at any time prior to their completion of the study due to: 
 
AEs; 
 
unmasking when medically necessary; 
 
protocol violations; 


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 
administrative reasons (e.g., inability to continue, lost to follow up); 
 
sponsor termination of study; 
 
subject choice (e.g. withdrawal of consent); and 
 
other 
Note: In addition, any subject may be discontinued for 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 
Ora and/or Sponsor and will be clearly documented on the eCRF. 
Discontinued subjects will not be replaced. 
8.7 
Study Termination  
The study may be stopped at any time by the investigator, the Sponsor, and/or Ora with 
appropriate notification.  
8.8 
Study Duration  
An individual subject’s participation will involve 2 visits over approximately 2-weeks (14 
days) 
8.9 
Monitoring and Quality Assurance  
 
 
 
 
 
 
 
 
 
 
 
9 ADVERSE EVENTS 
9.1 
Adverse Event  
An 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 


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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: 
 
Mild:  Event is noticeable to the subject, but is easily tolerated and does not 
interfere with the subject’s daily activities. 
 
Moderate:  
Event is bothersome, possibly requiring additional therapy, and 
may interfere with the subject’s daily activities. 
 
Severe: 
Event is intolerable, necessitates additional therapy or 
alteration of therapy, and interferes with the subject’s daily activities. 
9.1.2 Relationship 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: 
 
Definite: When there are good reason and sufficient documentation to 
demonstrate a direct causal relationship between investigational product and 
AE 
 
Probable: When there are good reasons and sufficient documentation to 
assume a causal relationship in the sense of plausible, conceivable, likely but 
not necessarily highly probable 
 
Possible: When there is sufficient information to accept the possibility of a 
causal relationship in the sense of not impossible and not unlikely, although 
the connection is uncertain or doubtful, for example; due to missing data or 
insufficient evidence. 
 
None: When there is sufficient information to accept a lack of a causal 
relationship, in the sense of impossible and improbable. 
 
Unclassified: When the causal relationship is not assessable for whatever 
reason due to insufficient evidence, conflicting data or poor documentation. 
9.1.3 Expectedness  
The expectedness of an AE should be determined based upon existing safety information 
about the study drug using these explanations: 


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 
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. 
 
Expected: An AE that is listed in the IB at the specificity and severity that 
has been observed. 
 
Not Applicable: Any AE that is unrelated to the study drug. 
AEs that are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
9.2 
Serious Adverse Events  
An AE is considered serious (SAE) if, in the view of either the investigator or Sponsor, it 
results in any of the following outcomes: 
 
Death 
 
A life-threatening AE 
Note:  An AE is considered “life-threatening” if, in the view of either the investigator or 
Sponsor, its occurrence places the patient or subject at immediate risk of death.  It does not 
include an AE that, had it occurred in a more severe form, might have caused death. 
 
Inpatient hospitalization or prolongation of existing hospitalization 
Note:  The term “inpatient hospitalization” refers to any inpatient admission (even if less than 
24 hours).  For chronic or long-term inpatients, inpatient admission includes transfer within 
the hospital to an acute/intensive care inpatient unit.  Inpatient hospitalization does not 
include:  emergency room visits; outpatient/same-day/ambulatory procedures; 
observation/short stay units; rehabilitation facilities; hospice facilities; nursing homes; or 
clinical research/phase 1 units. 
Note:  The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the initial 
admission as determined by the investigator or treating physician. 
 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
Note:  An SAE specifically related to visual threat would be interpreted as any potential 
impairment or damage to the subject’s eyes (e.g., hemorrhage, retinal detachment, central 
corneal ulcer or damage to the optic nerve). 
 
A congenital anomaly/birth defect. 


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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, and the IRB/IEC as 
required by the IRB/IEC, federal, state, or local regulations and governing health authorities 
and recorded on the appropriate eCRF. 
9.3.1 Reporting a Suspected Unexpected Adverse Reaction  
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to 
, the Sponsor and the 
IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities. 
9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the study drug, must be 
immediately reported.  All information relevant to the SAE must be recorded on the 
appropriate CRFs.  The investigator is obligated to pursue and obtain information requested 
by 
 and/or the Sponsor in addition to that information reported on the CRF.  All subjects 
experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the investigator must notify 
 and the Sponsor immediately; obtain 
and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject; 
provide 
 and the Sponsor with a complete case history, which includes a statement as to 
whether the event was or was not suspected to be related to the use of the study drug; and 
inform the IRB of the SAE within their guidelines for reporting SAEs. 
Contact information for reporting SAEs:  
Name: 
Title: 
Company: 
Office Telephone: 
Alternative Telephone: 
Office Facsimile: 
 
 
 
 
 
 
Name: 
Title: 
Office Telephone: 
Mobile Phone: 
Office Facsimile: 
 
 
 
 
 


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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 arm has been assigned to a subject. When possible 
(i.e., in non-emergent situations), 
 and/or the Sponsor should be notified before 
unmasking study drug. The unmasked subject will be discontinued from the study.  
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to follow-
up or until the AE is otherwise classified. Resolution means the subject has returned to 
baseline state of health or the Investigator does not expect any further improvement or 
worsening of the AE. If the patient is lost to follow-up, the Investigator should make 3 
reasonable attempts to contact the patient via telephone, post, or certified mail. All follow-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 to Ora 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 HYPOTHESES AND METHODS OF ANALYSES  
10.1 
Analysis Populations 
The following analysis populations will be considered: 
 
Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. Subjects in the ITT population will be analyzed as 
randomized. 
 
Per Protocol Population – The per protocol (PP) population includes subjects 
in the ITT population who do not have significant protocol deviations and 
who complete the study. Protocol deviations will be assessed prior to 
database lock and unmasking. Subjects in the PP population will be analyzed 
as treated. 
 
Safety Population – The safety population includes all subjects who have 
received at least one dose of the investigational product. Subjects in the 
Safety population will be analyzed as treated. 
The statistical analysis of safety data will be performed for the safety population. The 
analysis of baseline and efficacy data will be performed for the ITT population. Efficacy 
analyses will also be performed for the PP population as sensitivity analyses. 


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10.2 
Statistical Hypotheses 
H01: There is no difference between OC-02 Nasal Spray (Low Dose, Medium Dose, or High 
Dose), and placebo in the change from baseline in Schirmer’s Test results. 
H11: There is a difference between OC-02 Nasal Spray (Low Dose, Medium Dose, or High 
Dose) and placebo in the change from baseline in Schirmer’s Test results.  
H02: There is no difference between OC-02 Nasal Spray (Low Dose, Medium Dose, or High 
Dose) and placebo in the change from pre- to post-treatment in EDS. 
H12: There is a difference between OC-02 Nasal Spray (Low Dose, Medium Dose, or High 
Dose) and placebo in the change from pre- to post-treatment in EDS.  
A successful outcome will be one that rejects both null hypotheses (H01 and H02). 
10.3 
Sample Size 
The sample size for this study is not based on statistical power considerations. It is expected 
that approximately 40 subjects will be enrolled in each of the four treatment arms, for a total 
of approximately 160 randomized subjects. Assuming a 5% drop out rate, approximately 38 
subjects per group are expected to complete the study.  
10.4 
Statistical Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.4.3 Missing Data 
The primary analyses will be performed using observed data (without imputing missing 
data). Sensitivity analyses for the primary efficacy analysis will be performed using Markov 
Chain Monte Carlo multiple imputation methodology to impute missing data. The rate of 
missing data is expected to be low; however, if the missing data rate exceeds 5%, additional 
missing data imputation methods (such as tipping point analyses) will be employed to 
understand the potential impact of missing data on the primary outcomes. 
Other efficacy analyses will be performed using observed data only. 
10.4.4 Multiplicity Consideration 
Adjustments for multiple testing will not be implemented for this early phase study. 
10.4.5 Primary Efficacy Analyses 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.4.6 Other Efficacy Analyses 
 
 
  
 
 
 
 
  
. 
10.4.7 Safety Variables 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
10.4.8 Interim Analyses 
 
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. 


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11.1 
Protection of Human Subjects 
11.1.1  Subject Informed Consent  
Informed consent/assent must take place before any study specific procedures are initiated.  
Signed and dated written informed consent must be obtained from each subject and/or from 
the subject’s parent or legal guardian prior to enrollment into the study.  If the subject is 
under the legal age of consent, the consent form must be signed by a legal guardian or as 
required by state and/or local laws and regulations. 
All informed consent/assent forms must be approved for use by the Sponsor and receive 
approval/favorable opinion from an IRB prior to their use.  If the consent form requires 
revision (e.g., due to a protocol amendment or significant new safety information), it is the 
investigator’s responsibility to ensure that the amended informed consent is reviewed and 
approved by 
 prior to submission to the governing IRB and that it is read, signed and 
dated by all subjects subsequently enrolled in the study as well as those currently enrolled in 
the study. 
If informed consent is taken under special circumstances (oral informed consent), then the 
procedures to be followed must be determined by 
 and/or Sponsor and provided in 
writing by 
 and/or Sponsor prior to the consent process. 
11.1.2  Institutional Review Board Approval  
This study is to be conducted in accordance with IRB regulations [U.S. 21 Code of Federal 
regulations (CFR) Part 56.103].  The investigator must obtain appropriate IRB approval 
before initiating the study and re-approval at least annually. 
Only an IRB-approved version of the informed consent form will be used. 
11.2 
Ethical Conduct of Study  
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
11.3 
Subject Confidentiality  
All personal study subject data collected and processed for the purposes of this study should 
be maintained by the investigator and his/her staff with adequate precautions 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. 


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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 
years have elapsed since the formal discontinuation of clinical development of the study 
drug. These documents will be retained for a longer period if required by the applicable 
regulatory requirements or by an agreement with the Sponsor.  It is the responsibility of the 
Sponsor to inform the investigator/institution as to when these documents no longer need to 
be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility.  The Sponsor must be notified in writing of the name and address of 
the new custodian. 
11.5 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug 
11.5.1 Labeling/Packaging 
Investigational drug will be provided in single-use vials and assigned prior to each treatment 
at Visit 1 and Visit 2.  
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 


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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 or their designee for destruction. 
11.6 
 Recording of Data on Source Documents and Electronic Case Reports 
Forms 
All subject data will be captured in the subject source documents which will be transcribed in 
the eCRFs. The investigator is responsible for ensuring that study data is completely and 
accurately recorded on each subject’s eCRF, source documents, and all study-related 
materials. All study data should also be attributable, legible, contemporaneous, and original. 
Recorded datum should only be corrected in a manner that does not obliterate, destroy, or 
render illegible the previous entry (e.g., by drawing a single line through the incorrect entry 
and writing the revision next to the corrected data). An individual who has corrected a data 
entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction.  
Data entry of all enrolled and randomized subjects will use software that conforms to 21 CFR 
Part 11 requirements, and will be performed only by staff who have been trained on the 
system and have access to the system. 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, compact discs (CDs) 
containing copies of all applicable subjects’ eCRFs will be provided to each Investigator Site 
to be maintained on file by the Investigator. 
11.7 
Handling of Biological Specimens  
Not applicable.  
11.8 
Publications 
The study will be documented in a final report, which will contain appropriate statistical 
analysis and medical overview. No individual site or Investigator may publish or present any 
results from the study until 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.  
 
 


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12 REFERENCES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 2: EXAMINATION PROCEDURES, TESTS, EQUIPMENT, 
AND TECHNIQUES  
The following examination procedures, tests, equipment and techniques are listed in this 
Appendix:  
Visual Acuity Procedures  
LogMAR visual acuity must be assessed using an ETDRS chart. The procedure used will be 
consistent with the recommendations provided for using the ETDRS eye chart. Visual acuity 
should be evaluated at the beginning of each visit in the study (i.e., prior to slit lamp 
examination). Participants should use the most recent correction to attain their corrected 
distance visual acuity (CDVA); if they forget their spectacles, this prescription can be placed 
in a trial frame. 
Equipment 
The visual acuity chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", 
e.g., from Prevent Blindness) wall charts are used, the participant viewing distance should be 
exactly 10 feet (or as specified by the manufacturer). In ALL cases, for purposes of 
standardizing the testing conditions during the study, all sites must use only ETDRS Series 
2000 Chart 1 & 2, and the right eye should be tested first. For reflectance (wall) charts, the 
chart should be placed frontally and be well illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. The 
participant should attempt to read each letter, line-by-line, left to right, beginning with line 1 
at the top of the chart. The participant should be told that the chart has letters only, no 
numbers. If the participant reads a number, s/he should be reminded that the chart contains 
no numbers, and the examiner should then request a letter in lieu of the number. The 
participant should be asked to read slowly, so as to achieve the best identification of each 
letter. S/he is not to proceed to the next letter until s/he has given a definite response. 
If the participant changes a response (e.g., 'that was a "C" not an "O"') before s/he has read 
aloud the next letter, then the change must be accepted. If the participant changes a response 
having read the next letter, then the change is not accepted. The examiner should never point 
to the chart or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the participant 
says s/he cannot read a letter, s/he should be encouraged to guess. If the participant identifies 
a letter as one of two letters, s/he should be asked to choose one letter and, if necessary, to 
guess. When it becomes evident that no further meaningful readings can be made, despite 
encouragement to read or guess, the examiner should stop the test for that eye. However, all 


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letters on the last line should be attempted as letter difficulties vary and the last may be the 
only one read correctly. The number of letters missed or read incorrectly should be noted. 
LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. To 
this value will be added the number "N x 0.02" where 'N' represents the total number of 
letters missed up to and including the last line read. This total sum represents the logMAR 
visual acuity for that eye. 
Example: Participant correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 
line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR visual acuity 
= 0.18 
 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of visual acuity during the 
study, all visual acuity assessments at a single site must be consistently done using the same 
lighting conditions and same correction if possible during the entire study. If the same 
correction cannot be used (i.e., a participant broke his/her glasses), the reason for the change 
in correction should be documented. 
Note: A clinically significant visual acuity decrease (defined as an increase of 0.22 or greater 
in logMAR score) from the Screening Visit (Visit 1) should be evaluated by the Investigator 
as a potential AE. 
 
 


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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. 
The following will be examined at each visit: 
 
Cornea  
 
Conjunctiva  
 
Anterior Chamber 
 
Lid 
Corneal Fluorescein Staining  
The examiner should instill 5 L 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 a nasal endoscopy 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 endoscopic camera 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 
nasal endoscopy).  Still images or video may be captured.  Participants should be instructed 
not to perform nasal stimulation on the day nasal endoscopy will be performed. 
 
 


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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.   
 
 


OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
 
CONFIDENTIAL 
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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.  
 
 


OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
 
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OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
 
CONFIDENTIAL 
Page 54 of 57 
 
Eye Dryness Score (EDS) Using a Visual Analog Scale (VAS) 
Participants will be asked the following question regarding eye dryness every 5 minutes 
during CAE® exposure.  
The participant will be asked to rate their ocular symptoms (both eyes simultaneously) due to 
eye dryness by placing a vertical mark on the horizontal line to indicate the level of 
discomfort; 0 corresponds to “no discomfort” and 100 corresponds to “maximal discomfort.” 
The assessment line length of the scale will be 100 mm. 
Please rate your current eye dryness by drawing a vertical line on the line 
below: 
                                               
 
 
 
   
 
 
No 
Discomfort 
Maximal 
Discomfort 


OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
 
CONFIDENTIAL 
Page 55 of 57 
 
 Ocular Discomfort Scale  
Ocular discomfort scores will be subjectively graded by the participants according to the 
following scale, rating each eye separately.   
0 = No discomfort 
1 = Intermittent awareness 
2 = Constant awareness 
3 = Intermittent discomfort 
4 = Constant discomfort 
 
 
 




OC-02 Nasal Spray 
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol #OPP-001 
11 October 2017 
 
 
CONFIDENTIAL 
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APPENDIX 4: INVESTIGATOR’S SIGNATURE  
Protocol Title: 
Multicenter, Randomized, Controlled, Double-Masked Clinical 
Trial to Evaluate the Efficacy of OC-02 Nasal Spray on Signs and 
Symptoms of Dry Eye Disease 
Protocol Number: 
OPP-001 
 
 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to maintain 
all information supplied by 
 and the Sponsor in confidence and, when this information is 
submitted to an Institutional Review Board (IRB) or another group, it will be submitted with 
a designation that the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
 
Name:  
 
 
 
Title:  
 
 
 
Site:  
 
 
 
Address:  
 
 
 
Phone Number:  
 
 
 
 
 
 

SAP_001.pdf: 


 
 
STATISTICAL ANALYSIS PLAN  
Multicenter, Randomized, Controlled, Double-Masked Clinical Trial to 
Evaluate the Efficacy of OC-02 Nasal Spray on Signs and Symptoms 
of Dry Eye Disease 
 
Sponsor:   
 
 Oyster Point Pharma, Inc. 
700 Alexander Park Dr., Suite #301 
Princeton, NJ 08540 
 
 
 
 
 
 
Protocol Number: 
OPP-001 
 
 
Author:   
 
 
 
 
 
 
 
 
Date:    
 
10-May-2018 
Version:  
 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Table of Contents 
1. 
Introduction .............................................................................................................................. 7 
2. 
Study Objectives ...................................................................................................................... 7 
3. 
Study Variables ........................................................................................................................ 7 
3.1 Efficacy Measures .................................................................................................................... 7 
3.2 Safety Measures ...................................................................................................................... 7 
3.3 Other Measures ....................................................................................................................... 8 
3.4 Statistical Hypotheses .............................................................................................................. 8 
4. 
Study Design and Procedures ................................................................................................. 8 
4.1 General Study Design .............................................................................................................. 8 
4.2 Schedule of Visits and Assessments ....................................................................................... 9 
5. 
Study Treatments ................................................................................................................... 10 
5.1 Method of Assigning Subjects to Treatment Groups ............................................................. 10 
5.2 Unmasking ............................................................................................................................. 10 
6. 
Sample Size and Power Considerations ............................................................................... 10 
7. 
Data Preparation .................................................................................................................... 11 
8. 
Analysis Populations .............................................................................................................. 11 
8.1 Intent-to-Treat ........................................................................................................................ 11 
8.2 Per Protocol ........................................................................................................................... 11 
8.3 Safety ..................................................................................................................................... 12 
9. 
General Statistical Considerations ......................................................................................... 12 
9.1 Unit of Analysis ...................................................................................................................... 12 
9.2 Missing or Inconclusive Data Handling .................................................................................. 12 
9.3 Definition of Baseline ............................................................................................................. 12 
9.4 Data Analysis Conventions .................................................................................................... 12 
9.5 Adjustments for Multiplicity .................................................................................................... 13 
10. 
Disposition of Subjects ........................................................................................................... 13 
11. 
Demographic and Pretreatment Variables ............................................................................. 14 
11.1 Demographic Variables .......................................................................................................... 14 
11.2 Baseline Variables ................................................................................................................. 14 
11.2.1 
Ocular Surface Disease Index© ................................................................................. 15 
11.2.2 
Corneal Fluorescein Staining ..................................................................................... 15 
11.2.3 
Schirmer’s Test with Cotton Swab Stimulation .......................................................... 16 
12. 
Medical History and Concomitant Medications ...................................................................... 16 
12.1 Medical History ...................................................................................................................... 16 


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12.2 Prior and Concomitant Medications ....................................................................................... 16 
13. 
Treatment Exposure .............................................................................................................. 17 
13.1 Treatment Exposure .............................................................................................................. 17 
14. 
Efficacy Analyses ................................................................................................................... 17 
14.1 Primary Analysis .................................................................................................................... 17 
14.1.1 
Schirmer’s Test .......................................................................................................... 17 
14.1.2 
Eye Dryness Score as the Primary Analysis ............................................................. 20 
14.2 Other Efficacy Analyses ......................................................................................................... 22 
14.2.1 
Eye Dryness Score .................................................................................................... 22 
14.2.2 
 Ocular Discomfort Scale ....................................................................... 23 
15. 
Safety Analyses ..................................................................................................................... 24 
15.1 Adverse Events ...................................................................................................................... 24 
15.2 Best-Corrected Visual Acuity (BCVA) .................................................................................... 26 
15.3 Slit-Lamp Biomicroscopy Examination .................................................................................. 26 
15.4 Intranasal Examination .......................................................................................................... 26 
15.5 Pupil Diameter ....................................................................................................................... 27 
16. 
Other Analyses ...................................................................................................................... 27 
16.1 Urine Pregnancy Test ............................................................................................................ 27 
17. 
Interim Analyses .................................................................................................................... 27 
18. 
Changes from Protocol-Stated Analyses ............................................................................... 27 
19. 
Revision History ..................................................................................................................... 27 
20. 
Tables .................................................................................................................................... 27 
21. 
Listings ................................................................................................................................... 30 
22. 
Figures ................................................................................................................................... 32 
 
 
 
 
 
 
 
 
 






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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol OPP-001, dated 11OCT2017. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports (CSR). 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol. If additional analyses are required to supplement 
the planned analyses described in this SAP they may be completed and will be identified in the CSR. 
2. Study Objectives 
The objective of this study is to evaluate the safety and effectiveness of OC-02 Nasal Spray as compared 
to placebo on signs and symptoms of dry eye disease (DED). 
3. Study Variables 
3.1 Efficacy Measures 
The primary efficacy measures are: 
• 
Schirmer’s Test at Visit 1 
• 
Eye Dryness Score (EDS) at Visit 2 
An additional efficacy measure is the 
 Ocular Discomfort Scale at Visit 2. 
3.2 Safety Measures 
The safety measures include the following: 
• 
Adverse Event (AE) query 
• 
Visual Acuity 
• 
Slit-lamp biomicroscopy 
• 
Intranasal examination 
• 
Pupil diameter 


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3.3 Other Measures 
Other measures include the urine pregnancy test (if applicable).  
3.4 Statistical Hypotheses 
The statistical hypotheses are stated in terms of one-sided hypotheses, although statistical testing will 
be two-sided. 
H01: There is no difference between OC-02 Nasal Spray (Medium Dose or High Dose), and placebo 
in the change from baseline in Schirmer’s Test results. 
H11: There is a difference between OC-02 Nasal Spray Medium Dose or High Dose) and placebo in 
the change from baseline in Schirmer’s Test results. 
H02: There is no difference between OC-02 Nasal Spray (Medium Dose or High Dose) and placebo 
in the change from pre- to post-treatment in EDS. 
H12: There is a difference between OC-02 Nasal Spray (Medium Dose or High Dose) and placebo in 
the change from pre- to post-treatment in EDS. 
A successful outcome will be one that rejects both null hypotheses (H01 and H02), although these 
hypotheses are exploratory as the study-wide Type I and II errors are not controlled. 
4. Study Design and Procedures 
4.1 General Study Design 
This is a Phase 2, multicenter, randomized, double-masked, placebo-controlled study designed to 
evaluate the safety and efficacy of OC-02 nasal spray in adult participants with DED. Approximately 
160 subjects at least 22 years of age with a subject-reported history of dry eye and meeting all other 
study eligibility criteria will be randomized to receive an application of OC-02 or placebo at Visit 1 and 
Visit 2. 
OC-02 nasal solution is delivered as a 100 microliter (μL)-intranasal spray in each nostril. The subjects 
will be randomized to one of the following treatment arms: 
• 
0.11% OC-02 (0.2% hemigalactarate salt) [low dose] 
• 
0.55% OC-02 (1.0% hemigalactarate salt) [medium dose] 
• 
1.1% OC-02 (2.0% hemigalactarate salt) [high dose] 
• 
Placebo (OC-02 Vehicle Nasal Spray) 




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Randomization  
  
X  
  
  
Administer investigational 
drug / placebo  
  
X2  
X  
  
AE Query  
X  
X1  
X  
X  
Exit from study  
  
  
  
X  
X1 = Post-treatment procedures; X2 = Concurrent with Schirmer’s Test; X3 = For females of childbearing potential; 
X4 = Procedure started at time 0 and then conducted every 5 minutes thereafter during the 120 minute CAE® 
exposure; X5 = Procedure may be performed after CAE® exit at the Investigator’s discretion as needed    
 
5. Study Treatments 
5.1 Method of Assigning Subjects to Treatment Groups 
Each subject who qualifies will be assigned a screening number. All screening numbers will be 
assigned in strict numerical sequence at a site and no numbers will be skipped or omitted. If all 
inclusion and exclusion criteria are met at Visit 1, each qualifying subject will then be assigned a 
randomization number.  
A randomization schedule will be provided to each investigational site. The randomization schedule 
will be stratified by site, such that there will be an approximate equal number of subjects assigned to 
each of the four treatment arms at each site. The site staff will dispense to the patient the study kit 
labeled with the corresponding randomization number. The randomization number will be recorded on 
the patient’s source document and electronic case report form (eCRF). The Sponsor, Investigators, 
and study staff will be masked during the randomization process and throughout the study.   
5.2 Unmasking 
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 arm has been assigned to a subject. When possible (i.e., in non-emergent 
situations), 
 and/or the Sponsor should be notified before unmasking study drug. Scratch off labels 
will be used to facilitate unmasking.  The unmasked subject will be discontinued from the study.   
6. Sample Size and Power Considerations 
 
 
 
   
 
 


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7. Data Preparation 
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 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, compact discs containing copies of all applicable subjects’ eCRFs will be provided 
to each Investigator Site to be maintained on file by the Investigator. 
8. Analysis Populations 
Analysis populations include the intent-to-treat (ITT) population, the per-protocol (PP) population, and 
the Safety population. The statistical analysis of safety data will be performed for the safety population. 
The analysis of baseline and efficacy data will be performed for the ITT population. Efficacy analyses 
will also be performed for the PP population as sensitivity analyses.  
8.1 Intent-to-Treat 
The ITT population includes all randomized subjects. Subjects in the ITT population will be analyzed as 
randomized.  
8.2 Per Protocol 
The PP population includes subjects in the ITT population who do not have significant protocol 
deviations and who complete the study. Protocol deviations will be assessed prior to database lock and 
unmasking. Subjects in the PP population will be analyzed as treated.  


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8.3 Safety 
The Safety population includes all randomized subjects who have received at least one dose of the 
investigational product. Subjects in the Safety population will be analyzed as treated.  
9. General Statistical Considerations 
9.1 Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints, the unit of analysis will be the 
study eye as defined by the following:  
The study eye is defined as the eye that meets all inclusion/exclusion 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.  
9.2 Missing or Inconclusive Data Handling 
 
 
 
 
 
  
  
9.3 Definition of Baseline 
Baseline measures are defined as the last measure prior to the initiation of study treatment, usually at 
Visit 1 screening.  
9.4 Data Analysis Conventions 
All data analysis will be performed by Statistics & Data Corporation (SDC) after the study is completed 
and the database has been locked and released for unmasking.  Statistical programming and analyses 
will be performed using SAS® Version 9.4 or higher.  Output will be provided in RTF (Rich Text Format) 
for tables and PDF (Portable Document Format) for tables, listings, and figures using landscape 
orientation.  All study data will be listed by subject, treatment, and visit (as applicable) based on all 
enrolled subjects unless otherwise specified. 






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11.2.1 OCULAR SURFACE DISEASE INDEX© 
The OSDI© is assessed on a scale of 0 to 100, with higher scores representing greater disability.  The 
OSDI© asks the following 12 questions at the subject level: 
Have you experienced any of the following during the last week: 
1) Eyes that are sensitive to light? 
2) Eyes that feel gritty? 
3) Painful or sore eyes? 
4) Blurred vision? 
5) Poor vision? 
Have problems with your eyes limited you in performing any of the following during the last week: 
6) Reading? 
7) Driving at night? 
8) Working with a computer or bank machine (ATM)? 
9) Watching TV? 
Have your eyes felt uncomfortable in any of the following situations during the last week: 
10) Windy conditions? 
11) Places or areas with low humidity (very dry)? 
12) Areas that are air conditioned? 
OSDI© will be collected for both eyes pre- treatment at Visit 1.  The 5-unit scale for responses to the 
OSDI© is given by the following:  0=None of the time, 1=Some of the time, 2=Half of the time, 3=Most of 
the time and 4=All of the time.  The total OSDI© score is calculated by the following: 
OSDI© = 
(sum of scores) x 25 
# of questions answered 
Note that the number of questions answered in the denominator should exclude those questions with a 
response of “N/A”.  
11.2.2 CORNEAL FLUORESCEIN STAINING 
Corneal fluorescein staining will be performed on both eyes and graded using the National Eye Institute 
(NEI)/Industry Workshop Scale. The scale will grade the cornea by five regions: inferior, superior, 
central, temporal, and nasal. The scale ranges from 0 to 3.  Grade 0 indicates no staining is present.  
The maximum total score is 15. 
Fluorescein staining scores will be summarized by region (5 regions, plus total score) for the study eye 
using quantitative summary statistics.  










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- 
  
 
 
 
 
 
 
 
 
 
 
 
 
Schirmer’s test will also be analyzed in the fellow eye using the ITT and PP populations with observed 
data only. 
Stratified analyses of Schirmer’s test will include 
 analysis, t-tests and Wilcoxon rank sum tests 
using the ITT population with observed data only, in the study eye and fellow eye, separately.  The 
following strata will be used: 
• 
Inferior corneal staining < 1.5 
• 
Inferior corneal staining ≥ 1.5 
• 
Baseline EDS  < 60 
• 
Baseline EDS  ≥ 60 
14.1.2 EYE DRYNESS SCORE AS THE PRIMARY ANALYSIS  
Eye dryness will be assessed pre-treatment at Visit 1, pre-CAE at Visit 2, and every 5 minutes during 
CAE® exposure at Visit 2.  For each assessment, the participant will be asked to rate their ocular 
symptoms (both eyes simultaneously) due to eye dryness by placing a vertical mark on a 100 mm 
horizontal line to indicate the level of discomfort; 0 corresponds to “no discomfort” and 100 corresponds 
to “maximal discomfort”.    
Treatment with study drug will be administered upon the participant reporting an Ocular Discomfort (
 
Scale) score ≥ 3 at two or more consecutive timepoints in at least one eye during CAE® 
exposure.  If a participant has an Ocular Discomfort rating of 3 at time = 0 for an eye, s/he must report 
an Ocular Discomfort rating of 4 for two consecutive measurements for that eye.  Participant will resume 
symptom assessments 1 minute after the application ends every five minutes.   
The primary analysis will be a one-timepoint analysis in which the pre-treatment EDS will be the EDS at 
the timepoint that the subject first qualifies for study drug administration during the CAE® and post-
treatment EDS will be the EDS at the first timepoint following qualification.  If a participant fails to qualify 








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in a line plot by treatment group.  Two sample t-tests and non-parametric Wilcoxon rank sum tests will 
be used to compare treatments as unadjusted sensitivity analyses. 
15. Safety Analyses 
All safety analyses will be conducted using the Safety population.   
15.1 Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. An AE can therefore be any unfavorable and unintended sign 
(eg, 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.  All AEs will be coded using MedDRA Version 20.1.   
Treatment-emergent adverse events (TEAEs) are defined as any AE that occurs or worsens after the 
first dose of study treatment.  AEs recorded in the eCRF which began prior to treatment will not be 
included in the summary tables but will be included in the AE data listings. 
An overall summary will be presented that includes the number of AEs, TEAEs, serious AEs (SAE), and 
serious TEAEs (TE-SAE).  The summary will also include the number and percentage of subjects 
withdrawn due to an AE, the number and percentage of subjects with an AE resulting in death, and the 
number and percentage of subjects who experienced at least one AE, TEAE, SAE and TE-SAE, by 
treatment group and for all subjects.  This summary will include breakdowns of AEs further categorized 
as ocular or non-ocular. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE.  These summaries will be presented by SOC and PT.  Non-ocular 
TEAEs will be summarized using discrete summary statistics and presented by treatment group at the 
subject and event level by SOC and PT.  Ocular TEAEs will be similarly summarized at the subject and 
event level as well as for study and fellow eyes separately.  If a subject reports the same PT multiple 
times within the same SOC, that PT will only be reported once within that SOC.  As with the PT, if a 
subject reports multiple conditions within the same SOC, that SOC will only be reported once.  In the 
summary, SOC will be listed in order of descending frequency for all subjects; PTs will be listed in order 
of descending frequency for all subjects within each SOC.  The occurrence of non-ocular and ocular 
TEAEs will also be tabulated by SOC, PT, and maximal severity. 
The relationship of each adverse event to the investigational product should be determined by the 
Investigator (in a blinded manner) using these explanations: 




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All AEs will be presented in a subject listing that classifies each AE as ocular or non-ocular and indicates 
whether it is a TEAE.  Separate listings will be produced for AEs leading to study discontinuation,  AEs 
leading to death and SAEs. 
15.2 Best-Corrected Visual Acuity (BCVA) 
The visual acuity procedure will be performed at pre- and post-treatment at Visit 1 and may be performed 
post-CAE® at Visit 2 at the Investigator’s discretion as needed. The logarithm of the minimum angle of 
resolution (logMAR) VA must be assessed using an ETDRS chart. The procedure used will be consistent 
with the recommendations provided for using the ETDRS eye chart. Subjects should use their most 
recent correction to attain their corrected distance visual acuity (CDVA). 
The observed and change from baseline visual acuity will be summarized for each eye (study eye and 
fellow eye) using continuous descriptive statistics by visit for each treatment group. A subject listing of 
visual acuity will also be produced.  This listing will also include values used in the calculation of BCVA 
including base logMAR, which is the last line in which a letter is read correctly, N, which is the number 
of letters missed up to and including the last line read, and T, which is a multiplier equal to 0.02. 
15.3 Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination of the cornea, conjunctiva, anterior chamber, iris, lens, lid, motility 
and pupil will be performed at pre- and post-treatment at Visit 1 and may be performed post-CAE® at 
Visit 2 at the Investigator’s discretion as needed. The results will be graded as Normal, Abnormal Not 
Clinically Significant (NCS) or Abnormal Clinically Significant (CS).  Abnormal findings will be described. 
The results will be summarized using counts and percentages for each treatment group at each visit for 
each eye (study eye and fellow eye). Percentages will be based on the number of subjects in each 
treatment group with responses. Shift tables for the slit-lamp biomicroscopy parameters will also be 
provided comparing post-treatment at Visit 1 and post-CAE® at Visit 2 to baseline. A subject listing of 
the slit-lamp biomicroscopy parameters will also be produced. 
15.4 Intranasal Examination 
The intranasal examination will be performed as needed pre-treatment at Visit 1 and post-CAE® at Visit 
2. The results in terms of Normal, Abnormal (NCS), and Abnormal (CS) will be summarized using counts 
and percentages for each treatment group for each nasal cavity (right and left). Percentages will be 
based on the number of subjects in each treatment group with responses. Shift tables will also be 
provided comparing results post-treatment at Visit 1 to pre-treatment at Visit 1. A subject listing will also 
be produced.