Conditions: Dry Eye Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate the safety and effectiveness of OC-02 nasal spray compared to placebo on signs and symptoms of dry eye disease (DED).

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 subjects with dry eye disease. Approximately 45 subjects, at least 22 years of age, with a 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 twice daily (BID) for 4 weeks.

Arms:
arm 1: OC-02 (simpinicline) nasal spray, 11.1 mg/ml arm 2: Placebo (vehicle) nasal spray

Interventions: intervention 1: OC-02 (simpinicline) nasal spray intervention 2: Placebo (vehicle) nasal spray
Intervention descriptions: intervention 1: OC-02 (simpinicline) nasal spray, 11.1 mg/ml intervention 2: Placebo (vehicle) nasal spray

Protocol document:
Prot_000.pdf: 


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SYNOPSIS  
Protocol Title: 
A Multicenter, Randomized, Controlled, Double-Masked 
Clinical Trial to Evaluate the Efficacy of OC-02 Nasal 
Spray on Signs and Symptoms of Dry Eye Disease (The 
RAINIER Study) 
Protocol Number: 
OPP-003 
Investigational Product:  
2.0% OC-02 nasal spray  
Study Objective: 
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) 
 
Overall Study Design 
Structure: 
A Phase 2, multicenter, randomized, controlled, double-
masked study 
Duration: 
Five study visits over approximately four weeks 
Control: 
Placebo (OC-02 Vehicle Nasal Spray) 
Dosing Regimen:  
Intranasal delivery of OC-02 or Placebo twice daily 
(BID) for 4 weeks 
Summary of Visit 
Schedule: 
x Visit 1 = Day 1, Screening and Treatment (Schirmer’s 
Test Evaluation) 
x Visit 2 = 7 ± 2, Treatment (Schirmer’s Test 
Evaluation) 
x Visit 3 = 14 ± 2, Treatment (Schirmer’s Test 
Evaluation) 
x Visit 4 = 21 ± 2, Treatment (Eye Dryness Score  
Evaluation) 
x Visit 5 = 28 ± 2, Treatment (Schirmer’s Test 
Evaluation) 
Measures Taken to Reduce 
Bias: 
This is a randomized, double-masked study 
Study Population Characteristics 




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TABLE OF CONTENTS 
 
Synopsis ...............................................................................................................................3 
Secondary Efficacy Measure .........................................................................8 
Table of Contents ...............................................................................................................9 
List of Abbreviations .......................................................................................................12 
1 
Introduction .............................................................................................................13 
2 
Prior Clinical Experience .......................................................................................14 
3 
Study Objectives......................................................................................................20 
4 
Clinical Hypotheses .................................................................................................20 
5 
Overall Study Design ..............................................................................................20 
6 
Study Population .....................................................................................................21 
6.1 
Number of Subjects ......................................................................................21 
6.2 
Study Population Characteristics ...............................................................21 
6.3 
Inclusion Criteria .........................................................................................21 
6.4 
Exclusion Criteria .........................................................................................22 
6.5 
Withdrawal Criteria .....................................................................................24 
7 
Study Parameters ....................................................................................................24 
7.1 
Efficacy Measures .........................................................................................24 
7.1.1 
Primary Efficacy Measure ................................................................24 
7.1.2 
Secondary Efficacy Measure ............................................................24 
7.2 
Other Efficacy Measures .............................................................................24 
7.3 
Safety Measure .............................................................................................24 
7.4 
Other Measures ............................................................................................24 
8 
Study Materials .......................................................................................................25 
8.1 
Study Drug(s) ................................................................................................25 
8.1.1 
Regimens...........................................................................................25 
8.1.2 
Dispensation Schedule ......................................................................25 
8.1.3 
Instructions for Use ...........................................................................25 
8.2 
Other Study Supplies ...................................................................................33 
9 
Study Methods and Procedures .............................................................................33 
9.1 
Participant Entry Procedures .....................................................................33 
9.1.1 
Overview ...........................................................................................33 
9.1.2 
Informed Consent..............................................................................33 
9.1.3 
Washout Intervals .............................................................................33 
9.1.4 
Procedures for Final Study Entry ......................................................33 
9.1.5 
Methods for Assignment to Treatment Groups ................................33 
9.2 
Concurrent Therapies ..................................................................................34 
9.2.1 
Prohibited Medications/Treatments ..................................................34 
9.2.2 
Escape Medications ..........................................................................34 
9.2.3 
Special Diet or Activities ..................................................................34 
9.3 
Examination Procedures ..............................................................................34 


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9.3.1 
Procedures to be Performed at Each Study Visit with Regard to Study 
Objectives(s) ...................................................................................................34 
9.4 
Schedule of Visits, Measurements and Dosing ..........................................36 
9.4.1 
Scheduled Visits................................................................................36 
9.4.2 
Unscheduled Visits ...........................................................................36 
9.5 
Compliance with Protocol ............................................................................37 
9.6 
Subject Disposition .......................................................................................37 
9.6.1 
Completed Subjects ..........................................................................37 
9.6.2 
Discontinued Subjects .......................................................................37 
9.7 
Study Termination .......................................................................................38 
9.8 
Study Duration .............................................................................................38 
9.9 
Monitoring and Quality Assurance ............................................................38 
10 
safety definitions, safety monitoring and reporting .............................................38 
10.1 Adverse Event ...............................................................................................38 
10.1.1 Severity .............................................................................................38 
10.1.2 Relationship to Study Drug ...............................................................39 
10.1.3 Expectedness .....................................................................................39 
10.2 Serious Adverse Events ................................................................................40 
10.3 Procedures for Reporting Adverse Events .................................................40 
10.3.1 Reporting a Suspected Unexpected Adverse Reaction .....................41 
10.3.2 Reporting a Serious Adverse Event ..................................................41 
10.4 Procedures for Unmasking of Study Drug .................................................41 
10.5 Type and Duration of the Follow-up of Subjects after Adverse Events ..42 
11 
Statistical Analysis ..................................................................................................42 
11.1 Sample Size and Power Considerations .....................................................42 
11.2 Analysis Populations ....................................................................................42 
11.2.1 Intention-To-Treat Population ..........................................................42 
11.2.2 Safety Population ..............................................................................43 
11.3 Statistical Hypotheses ...................................................................................43 
11.4 Statistical Analysis ........................................................................................43 
11.4.1 General Considerations .....................................................................43 
11.4.2 Unit of Analysis ................................................................................43 
11.4.3 Subject Demographics and Baseline Characteristics ........................44 
11.4.4 Primary Efficacy Analysis ................................................................44 
11.4.5 Secondary Efficacy Analysis ............................................................44 
11.4.6 Other Efficacy Analysis ....................................................................44 
11.4.7 Safety Analysis .................................................................................44 
11.4.8 Interim Analysis ................................................................................45 
12 
Compliance with Good Clinical Practices, Ethical Considerations, and 
Administrative Issues..............................................................................................45 
12.1 Protection of Human Subjects.....................................................................45 
12.1.1 Subject Informed Consent.................................................................45 
12.1.2 Institutional Review Board Approval ...............................................46 
12.2 Ethical Conduct of Study .............................................................................46 


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12.3 Subject Confidentiality ................................................................................46 
12.4 Documentation ..............................................................................................46 
12.4.1 Retention of Documentation .............................................................46 
12.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ....................................................................................................47 
12.5.1 Labeling/Packaging...........................................................................47 
12.5.2 Storage of Investigational Drug / Placebo ........................................47 
12.5.3 Accountability of Study Drug ...........................................................47 
12.5.4 Return or Disposal of Study Drug ....................................................47 
12.6 Recording of Data on Source Documents and Electronic Case Reports 
Forms .............................................................................................................47 
12.7 Handling of Biological Specimens ...............................................................48 
12.8 Publications ...................................................................................................48 
13 
References ................................................................................................................49 
14 
Appendices ...............................................................................................................52 
Appendix 1: Schedule of Visits and Measurements ......................................................53 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ..............54 
Visual Acuity Procedures .......................................................................................54 
Slit Lamp Biomicroscopy .......................................................................................56 
Corneal Fluorescein Staining .................................................................................56 
Intranasal Examination ..........................................................................................57 
Schirmer’s Test with Topical Anesthesia .............................................................58 
Ocular Surface Disease Index© ..............................................................................59 
Eye Dryness Score (EDS) Using a Visual Analog Scale (VAS) ...........................62 
Ocular Discomfort Scale ................................................................63 
Appendix 3: Sponsor and 
Approvals .....................................................................64 
Appendix 4: Investigator’s Signature ............................................................................65 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
BCVA 
Best corrected visual acuity  
BID 
Two times a day 
CAE® 
Controlled adverse environment 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CRF 
Case report form 
EDS 
Eye Dryness Score 
DED 
Dry eye disease 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
logMAR 
Logarithm of the minimum angle of resolution 
LS 
Least Square 
MAD 
Mucosal Atomization Device 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
μL 
microliter 
mm 
Millimeter 
nAChR 
Nicotinic acetylcholine receptor 
OSDI© 
Ocular Surface Disease Index© 
PP 
Per Protocol 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-emergent adverse event 
US 
United States 
 
 
 
 
 








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6.4 
Exclusion Criteria  
Subjects must not:  
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 
 






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8 
STUDY MATERIALS 
8.1 
Study Drug(s) 
8.1.1 Regimens 
The study drug will be delivered as a 50 microliter (μL) intranasal spray in each 
nostril BID: 
 
 2.0% OC-02 nasal spray 
 Placebo nasal spray (OC-02 Vehicle Nasal Spray) 
8.1.2 Dispensation Schedule  
x At Visit 1, qualified subjects will be randomized and the first dose of study drug will 
be administered in office.  The second daily administration will happen at home. 
x At Visit 4 subjects will receive their first daily dose of study drug during CAE® 
exposure.  The second daily administration will happen at home. 
x At Visit 2, Visit 3, and Visit 5 the first daily dose of study drug will be administered 
in office concurrent with Schirmer’s testing.  The second daily administration will 
happen at home. 
x Between clinic visits, subjects will self-administer OC-02/Placebo BID as a 50 μL 
intranasal spray in each nostril. 
8.1.3 Instructions for Use 
General Appearance 
Preparation 


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Administration


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8.2 
Other Study Supplies  
x Urine pregnancy test kits  
x Fluorescein sodium solution or fluorescein strips 
x Schirmer’s test strips  
x Proparacaine  
9 
STUDY METHODS AND PROCEDURES 
9.1 
Participant Entry Procedures  
9.1.1 Overview  
Participants as defined by the criteria in Sections 6.2, 6.3, and 6.4 will be considered for 
entry into this study.  
9.1.2 Informed Consent  
Prior to a participant’s enrollment in the trial (i.e., prior to any study-related procedures), the 
study will be discussed with each potential participant and participants wishing to participate 
must be administered and provide written informed consent using an Institutional Review 
Board (IRB)-approved informed consent form (ICF). The ICF must be the most recent 
version that has received approval by a properly constituted IRB.  
9.1.3 Washout Intervals  
Prohibited medications, treatments, and activities are outlined in the Exclusion Criteria 
(Section 6.4).  
9.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion criteria and none of the exclusion criteria.  
9.1.5 Methods for Assignment to Treatment Groups 
Each subject who enters the screening period for the study (defined as the point at which the 
subject signs the informed consent form (ICF) receives a unique subject identification 
number before any study-related activities/procedures are performed.  This number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.   
The subject identification number must remain constant throughout the entire clinical study.  
This number will not necessarily be the same as the randomization number. 
Subjects who meet the eligibility requirements will be randomly assigned to 1 of 2 treatment 
groups. 


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9.2 
Concurrent Therapies  
9.3 
Examination Procedures  
9.3.1 Procedures to be Performed at Each Study Visit with Regard to Study Objectives(s) 
The following procedures will be performed (see Appendix 2 for description).  
Screening/Visit 1 (Day 1): Screening and Schirmer’s Test Evaluation  
x Informed consent/Health Information Portability and Accountability Act (HIPAA) 
consent 
x Demographic data, medical history, prior medication (s), and ocular history 
x Eligibility Criteria  
x Urine pregnancy test (if applicable) 
x OSDI© questionnaire 
x EDS (visual analog scale) 
x 
 Ocular Discomfort Scale 
x BCVA (pre-and post-treatment procedures) 
x Slit lamp biomicroscopy (pre-and post-treatment procedures) 
x Corneal fluorescein staining 
x Schirmer’s Test3 (pre- and post- treatment procedures) 
x Schirmer’s Test with nasal stimulation (cotton swab)4 
x Intranasal examination  
x Randomization 
                                                 
3 Procedure will occur after corneal fluorescein staining  
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x Dispense new study drug/placebo intranasal pump 
x Administration of study drug/placebo concurrently with Schirmer’s Test 
x Concomitant Medications 
x AE Query 
Visit 2 (Day 7 ±2): Schirmer’s Test Evaluation 
x BCVA (pre-and post-treatment) 
x Slit lamp biomicroscopy (pre-and post-treatment) 
x Administration of study drug/placebo 
x Schirmer’s Test (post-treatment) 
x Concomitant Medications 
x AE Query 
 
Visit 3 (Day 14 ±2): Schirmer’s Test Evaluation 
 
x BCVA (pre-and post-treatment) 
x Slit lamp biomicroscopy (pre-and post-treatment) 
x Administration of study drug/placebo 
x Schirmer’s Test (concurrent with treatment) 
x Dispense new study drug/placebo intranasal pump 
x Concomitant Medications 
x AE Query 
 
Visit 4 (Day 21 ±2): CAE® Evaluation 
Pre- CAE® Procedures:  
x Urine pregnancy test (if applicable) 
x EDS (visual analog scale) 
x 
 Ocular Discomfort Scale 
x Concomitant Medications 
x AE Query 
Pre-Treatment CAE® Evaluation 
x EDS (visual analog scale) until threshold is met 
x 
Ocular Discomfort Scale until threshold is met 
ADMINISTRATION OF INVESTIGATIONAL DRUG/PLACEBO 
Treatment with Investigational drug/placebo will be administered upon a participant’s 
reporting an Ocular Discomfort score ≥ 3 at two or more consecutive time points in at 


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least one eye during CAE® exposure (participants with an Ocular Discomfort rating of 3 
or 4 at time = 0 for an eye must report an Ocular Discomfort rating of 4 for two 
consecutive measurements for that eye) using the 
Scale. Participants will 
resume symptom assessments every 5 minutes starting 1 minute after the application 
ends. 
Post-Treatment CAE® Evaluation 
x EDS (visual analog scale) 
x 
Ocular Discomfort Scale  
x BCVA (at investigator’s discretion as needed) 
x Slit lamp biomicroscopy (at investigator’s discretion as needed) 
x AE Query 
 
Visit 5 (Day 28 ±2): Schirmer’s Test Evaluation 
 
x BCVA (pre-and post-treatment) 
x Slit lamp biomicroscopy (pre-and post-treatment) 
x Intranasal examination  
x Administration of study drug/placebo 
x Corneal fluorescein staining (post-treatment) 
x Schirmer’s Test (concurrent with treatment) 
x EDS (visual analog scale; post-treatment) 
x Concomitant Medications 
x AE Query 
Early Termination (if applicable) 
x BCVA  
x Slit lamp biomicroscopy  
x Intranasal examination  
x Urine pregnancy test (if applicable) 
x Concomitant Medications 
x AE Query 
9.4 
Schedule of Visits, Measurements and Dosing 
9.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements.  
9.4.2 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 


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eCRF pages. Any procedure indicated in the eCRF that is not performed should be indicated 
as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
x Slit-lamp Biomicroscopy; 
x Visual Acuity; 
x Intranasal Examination; 
x Urine Pregnancy Test (if applicable); 
x Assessment of AEs; 
x Assessment of concurrent medications and/or treatments; and 
x Any other assessments needed in the judgment of the investigator. 
9.5 
Compliance with Protocol  
Subjects will be instructed on the proper use and storage of the study drug at Visits 1, 2, 3, 
and 4, and provided with written instructions upon dispensation of their study drug at Visit 1 
and Visit 3.  
9.6 
Subject Disposition  
9.6.1 Completed Subjects  
A completed subject is one who has completed 4 weeks of study visits.  
9.6.2 Discontinued Subjects  
Subjects may be discontinued from treatment, or from involvement in the study at any time 
prior to their completion of the study due to: 
x AEs; 
x unmasking when medically necessary; 
x protocol violations; 
x administrative reasons (e.g., inability to continue, lost to follow-up); 
x sponsor termination of study; 
x subject choice (e.g. withdrawal of consent); and 
x other 
Note: In addition, any subject may be discontinued from treatment or from study 
involvement from any sound medical reason at the discretion of the investigator (after 
consultation with the Sponsor) or Sponsor. 
Notification of a subject discontinuation and the reason for discontinuation will be made to 
Ora and/or Sponsor and will be clearly documented on the eCRF. 
Discontinued subjects will not be replaced. 


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9.7 
Study Termination  
The study may be stopped at any time by the Investigator and/or Ora after consultation with 
the Sponsor, with appropriate notification.  
9.8 
Study Duration  
An individual subject’s participation will involve 5 visits over approximately 4-weeks (28 
days) 
9.9 
Monitoring and Quality Assurance  
During the course of the study a monitor, or designee, will make routine site visits to review 
protocol compliance, assess study drug accountability, subject safety, and ensure the study is 
being conducted according to the pertinent regulatory requirements.  The review of the 
subjects’ medical records will be performed in a manner that adequately maintains subject 
confidentiality.  A monitoring plan will outline further details of the study monitoring. 
Regulatory authorities of domestic and foreign agencies, Sponsor quality assurance, 
 
quality assurance and or its designees may carry out on-site inspections and/or audits, which 
may include source data checks.  Therefore, direct access to the original source data will be 
required for inspections and/or audits.  All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that local, 
state, and federal laws apply. 
10 SAFETY DEFINITIONS, SAFETY MONITORING AND 
REPORTING 
10.1 Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not the event is considered drug-related.  An AE can 
therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease occurring after the subject started dosing with the study drug, without 
any judgment about causality.  Any pre-existing medical condition that worsens after 
administration of the study drug will also be considered a new AE.   
Study drug includes the investigational drug under evaluation and placebo. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to study drug, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the Investigator or reported by the subject upon indirect questioning. 
10.1.1 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 


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of severity is made irrespective of relationship to study drug or seriousness of the event and 
should be evaluated according to the following scale: 
x Mild:  
Event is noticeable to the subject, but is easily tolerated and does not 
interfere with the subject’s daily activities. 
x Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
x Severe: 
Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the subject’s daily activities. 
10.1.2 Relationship to Study Drug 
The relationship of each AE to the investigational product should be determined by the 
investigator (in a blinded manner) using these explanations: 
x Definite: When there are good reason and sufficient documentation to demonstrate a 
direct causal relationship between investigational product and AE 
x Probable: When there are good reasons and sufficient documentation to assume a 
causal relationship in the sense of plausible, conceivable, likely but not 
necessarily highly probable 
x Possible: When there is sufficient information to accept the possibility of a causal 
relationship in the sense of not impossible and not unlikely, although the 
connection is uncertain or doubtful, for example; due to missing data or 
insufficient evidence. 
x None: 
When there is sufficient information to accept a lack of a causal 
relationship, in the sense of impossible and improbable. 
x Unclassified: When the causal relationship is not assessable for whatever reason due 
to insufficient evidence, conflicting data or poor documentation. 
10.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the study drug using these explanations: 
x Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not 
listed at the specificity or severity that has been observed. 
x Expected: An AE that is listed in the IB at the specificity and severity that has been 
observed. 
x Not Applicable: Any AE that is unrelated to the study drug. 
AEs that are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug but are not specifically mentioned as occurring with 
the particular drug under investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 


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10.2 Serious Adverse Events 
An AE is considered “serious” (SAE) if, in the view of either the investigator or Sponsor, it 
results in any of the following outcomes: 
x Death 
 
x A life-threatening AE 
Note: An AE is considered “life-threatening” if, in the view of either the investigator 
or Sponsor, its occurrence places the patient or subject at immediate risk of death.  It 
does not include an AE that, had it occurred in a more severe form, might have 
caused death. 
x Inpatient hospitalization or prolongation of existing hospitalization 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if 
less than 24 hours).  For chronic or long-term inpatients, inpatient admission includes 
transfer within the hospital to an acute/intensive care inpatient unit.  Inpatient 
hospitalization does not include:  emergency room visits; outpatient/same-
day/ambulatory procedures; observation/short stay units; rehabilitation facilities; 
hospice facilities; nursing homes; or clinical research/phase 1 units. 
Note:  The term “prolongation of existing hospitalization” refers to any extension of 
an inpatient hospitalization beyond the stay anticipated or required for the reason for 
the initial admission as determined by the investigator or treating physician. 
x A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
Note:  An SAE specifically related to visual threat would be interpreted as any 
potential impairment or damage to the subject’s eyes (e.g., hemorrhage, retinal 
detachment, central corneal ulcer or damage to the optic nerve). 
x A congenital anomaly/birth defect in an offspring of a study subject. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
10.3 Procedures for Reporting Adverse Events  
All AEs and their outcomes must be reported to Ora, 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. 


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10.3.1 Reporting a Suspected Unexpected Adverse Reaction  
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the Sponsor and the 
IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities. 
10.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the study drug, must be 
immediately reported.  All information relevant to the SAE must be recorded on the 
appropriate CRFs.  The investigator is obligated to pursue and obtain information requested 
by 
 the Sponsor in addition to that information reported on the CRF.  All subjects 
experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the investigator must notify 
 the Sponsor immediately; obtain 
and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject; 
provide 
the Sponsor 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: 
 
 
 
 
 
 
10.4 Procedures for Unmasking of Study Drug 
All subjects, investigators, and study personnel involved with the conduct of the study will be 
masked with regard to treatment assignments. When medically necessary, the investigator 
may need to determine what treatment regimen has been assigned to a subject. When 
possible (i.e., in non-emergent situations), 
 the Sponsor should be notified before 
unmasking study drug. The unmasked subject will continue the study if warranted by the 
Investigator in consultation with the Medical Monitor.  




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11.2.2 Safety Population 
The safety population will include all randomized subjects who received at least one dose of 
the study drug. Analysis on the safety population will group subjects according to the 
treatment actually received.  
11.4.1 General Considerations 
Quantitative variables will be summarized using the number of subjects (n), mean, SD, 
median, 25th and 75th percentiles, and minimum and maximum. Qualitative variables will be 
summarized using counts and percentages. 
All summaries will be presented by treatment group. Summaries will be provided for 
demographics, medical history, concomitant medications, and subject disposition. 
For the summaries, medical history, concomitant medications, and AEs will be coded to 
MedDRA and World Health Organization Drug dictionaries, as appropriate. 
Baseline measures are defined as the last measure prior to the initiation of study treatment, 
usually at Visit 1 screening. 
11.4.2 Unit of Analysis 
For efficacy endpoints, the unit of analysis will be the study eye as defined as the eye that 
meets all inclusion and exclusion criteria. If both eyes qualify, then the study eye will be the 
eye with the greatest increase in tear production with stimulation by a cotton swab at the 
Screening Visit. 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. 
For safety endpoints, both eyes will be analyzed.  




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and the number of subjects with events (along with percentages) by treatment group for 
TEAEs in several categories base on seriousness, relationship to treatment, and severity.  
Other safety endpoints including visual acuity, slit-lamp biomicroscopy and intranasal 
examination will be summarized by treatment group and visit using descriptive statistics. 
Changes or shifts from baseline will be summarized where appropriate. For assessments 
performed by eye, study eye and fellow eye will be summarized separately. In addition, shifts 
from baseline to worst on-treatment value for ocular safety assessments will be summarized. 
The SAP will present methods of analysis of these defined parameters in detail. 
11.4.8 Interim Analysis 
No interim analysis planned for this study. 
12 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. 
12.1 Protection of Human Subjects 
12.1.1  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 Ora prior to submission to the governing IRB and that it is read, signed and 
dated by all subjects subsequently enrolled in the study as well as those currently enrolled in 
the study. 
If informed consent is taken under special circumstances (oral informed consent), then the 
procedures to be followed must be determined by 
Sponsor and provided in 
writing by 
 Sponsor prior to the consent process. 


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12.1.2 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. 
12.2 Ethical Conduct of Study  
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
12.3 Subject Confidentiality  
All personal study subject data collected and processed for the purposes of this study should 
be maintained by the investigator and his/her staff with adequate precautions as to ensure that 
the confidentiality of the data in accordance with local, state, and federal laws and 
regulations. 
Monitors, auditors and other authorized representatives of 
the Sponsor, the IRB 
approving this study, the Food and Drug Administration, the Department of Health and 
Human Services, other domestic government agencies, and other foreign regulatory agencies 
will be granted direct access to the study subject’s original medical and study records for 
verification of the data and/or clinical trial procedures.  Access to this information will be 
permitted to the aforementioned individuals to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
subject’s identity will not be disclosed in these documents. 
12.4 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. 
12.4.1  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 




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entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction.  
Data entry of all enrolled and randomized subjects will use software that conforms to 21 CFR 
Part 11 requirements, and will be performed only by staff who have been trained on the 
system and have access to the system. Data will not be entered for screen failure subjects. An 
audit trail will be maintained within the electronic system to capture all changes made within 
the eCRF database. After the end of the study and database lock, electronic copies of all 
applicable subjects’ eCRFs will be provided to each Investigator Site to be maintained on file 
by the Investigator. 
12.7 Handling of Biological Specimens  
Not applicable.  
12.8 Publications 
The study will be documented in a final report, which will contain appropriate statistical 
analysis and medical overview. No individual site or Investigator may publish or present any 
results from the study until the Sponsor completes a joint, multi-center publication of the trial 
results 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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14 APPENDICES 




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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 
letters on the last line should be attempted as letter difficulties vary and the last may be the 
only one read correctly. The number of letters missed or read incorrectly should be noted. 


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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.  
Corneal Fluorescein Staining  
The examiner should instill 5 PL of 2% preservative-free sodium fluorescein solution into the 
inferior conjunctival cul-de-sac of each eye. Alternatively, corneal staining can be assessed 
using 1.0 mg sodium fluorescein strips. After moistening the tip of the strip with sterile 
buffered saline, the excess is shaken into a waste bin with a sharp flick. The lower lid is then 
pulled down and the flat end of the tip should be gently applied to the inferior tarsal 
conjunctiva with the intent of not inducing reflex tearing and instilling a very small volume 
of dye.  
The participant will be instructed to blink naturally several times without forced closure of 
the eyelid to distribute the fluorescein. In order to achieve maximum fluorescence, the 
examiner should wait at least two minutes after instillation before evaluating corneal 
fluorescein staining. A Wratten #12 yellow filter will be used to enhance the ability to grade 
fluorescein staining. The staining will be graded with the NEI Scale. The upper eyelid is 
lifted slightly to grade the entire corneal surface.  
 
 


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 0 
Intranasal Examination  
Qualified participants for the study must undergo an intranasal exam to make the final 
eligibility determination (e.g. severe nasal airway obstruction such as, severe septal deviation 
or inferior turbinate hypertrophy, or vascularized polyp seen on examination are reasons for 
exclusion).  To monitor nasal mucosal integrity during the study for participant safety, an 
examination of the nasal cavities via an intranasal exam will be performed at the Screening 
Visit(after all other screening procedures have been completed) and at Visit 5 or the Early 
Termination Visit.  This examination will be performed by an Ear Nose and Throat (ENT) 
specialist, otolaryngologist or other suitably qualified medical practitioner (i.e. one who has 
been trained to perform intranasal exam).  Still images or video may be captured.  The 
procedure used for the intranasal exam can be conducted either by endoscopic examination 
or nasal specula. 
 
 


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Schirmer’s Test with Topical Anesthesia  
At the Screening Visit, one basal Schirmer’s test will be performed followed by a Schirmer’s 
test with cotton swab nasal stimulation. The Schirmer’s test with topical anesthetic will be 
used to assess tear production using the following steps:   
1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride or equivalent should 
be instilled in both eyes of the participant. 
2. The participant will be instructed to keep the eyes gently closed for one minute.   
3. After opening the eyes and allowing the eyes to recover for approximately one additional 
minute, excess moisture in the inferior fornix is gently removed with a spear. 
4. Schirmer’s strips (35 mm x 5 mm size filter paper strip) will be placed in each eye at the 
junction of the middle and lateral thirds of the lower eye lid.  
5. Under ambient light, the participant will be instructed to look forward and to blink 
normally during the course of the test. The test should be performed in a room with no 
direct air on the participant’s face. 
6. The Schirmer’s strips should remain in place until five minutes have elapsed or both 
strips have reached maximum score. 
7. After five minutes, strips will be removed from both eyes and the amount of wetting will 
be recorded. The strips should be taped to the CRF.   
Schirmer’s test using cotton swab nasal stimulation   
At the Screening Visit, the Schirmer’s test should be performed using cotton swab nasal 
stimulation. New anesthetic drops should be instilled following the same procedure specified 
in steps #1 to 3 above. 
1. With new strips in place, the examiner should insert cotton swabs in the participant’s two 
nostrils simultaneously and gently probe both nasal middle turbinates for approximately 
30 seconds. After this, the examiner can simply hold the swabs in place, applying gentle 
pressure, and repeat probing intermittently as necessary.   
2. Alternatively, the participant can be instructed to hold the cotton swabs and gently probe 
both nasal turbinates simultaneously, resting intermittently before probing again.  The 
examiner should continuously coach the participant on how to perform this test properly.  
3. The Schirmer’s strips should remain in place until five minutes have elapsed or both 
strips have reached maximum score. 
Both Schirmer’s scores will be recorded and verified that they meet the inclusion criteria.   
 
 




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APPENDIX 3: SPONSOR AND 
APPROVALS 
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 
 
 


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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-003 
 
 
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 Ora 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: 
CONFIDENTIAL 
 
 
Oyster Point Pharma, Inc. 
Clinical Protocol: OPP-003: 
Multicenter, Randomized, Controlled, Double-Masked Clinical Trial  
to Evaluate the Efficacy of OC-02 Nasal Spray  
on Signs and Symptoms of Dry Eye Disease (The RAINIER Study) 
 
 
Statistical Analysis Plan 
Version 1.0 
 
October 4, 2018 
 
 


 




 




Protocol # OPP-003 - Statistical Analysis Plan 
October 4, 2018 
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Contents 
1. Introduction ....................................................................................................................................... 1 
2. Investigational plan .......................................................................................................................... 1 
 
Study design ............................................................................................................................ 1 
2.1.
 
Study objectives and outcome measures ............................................................................ 1 
2.2.
 
Randomization and masking ................................................................................................ 2 
2.3.
3. Study schedule .................................................................................................................................. 3 
 
Study days ............................................................................................................................... 3 
3.1.
 
Unscheduled visits ................................................................................................................. 3 
3.2.
4. Analysis populations ........................................................................................................................ 3 
 
Intent-To-Treat population ................................................................................................... 3 
4.1.
 
Safety population ................................................................................................................... 4 
4.2.
5. Sample size determination and power calculation ...................................................................... 4 
6. Protocol deviations ........................................................................................................................... 5 
7. Statistical analysis: general considerations and conventions ..................................................... 6 
 
Unit of analysis ....................................................................................................................... 6 
7.1.
 
Definition of time ................................................................................................................... 7 
7.2.
 
Missing and partial data ........................................................................................................ 7 
7.3.
8. Subject characteristics, disposition, and exposure to study drug .............................................. 7 
 
Demographic and baseline characteristics .......................................................................... 7 
8.1.
 
Subject disposition.................................................................................................................. 8 
8.2.
 
Treatment exposure ............................................................................................................... 9 
8.3.
 
Concomitant medications and therapies ............................................................................. 9 
8.4.
9. Baseline, post-baseline, and unscheduled measurements .......................................................... 9 
 
Ocular assessments .............................................................................................................. 10 
9.1.
9.1.1. 
Schirmer’s Test ........................................................................................................ 10 
9.1.2. 
Eye Dryness Score ................................................................................................... 10 
9.1.3. 
BCVA ........................................................................................................................ 10 


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9.1.4. 
 Ocular Discomfort Scale ................................................................. 11 
9.1.5. 
Ocular Surface Disease Index© .............................................................................. 11 
9.1.6. 
Corneal Fluorescein Staining ................................................................................. 11 
9.1.7. 
Slit Lamp Biomicroscopy ....................................................................................... 12 
 
Intranasal assessments ......................................................................................................... 12 
9.2.
10. Efficacy analyses ............................................................................................................................. 12 
 Primacy efficacy analysis .................................................................................................... 12 
10.1.
 Exploratory efficacy analyses ............................................................................................. 13 
10.2.
10.2.1. Exploratory efficacy endpoints ............................................................................. 13 
10.2.2. Exploratory efficacy analysis methods ................................................................ 14 
11. Safety analyses ................................................................................................................................ 15 
12. Subgroup analysis .......................................................................................................................... 16 
13. Appendices ...................................................................................................................................... 17 
14. Reference .......................................................................................................................................... 22 
 
Appendices 
Appendix 1. Schedule of visits and measurements ......................................................................... 17 
Appendix 2. Analysis for primary efficacy outcome with multiple imputation ......................... 18 
Appendix 3. Sensitivity analysis using a mixed model for repeated measures .......................... 21 
Appendix 4. Winsorized mean approach ......................................................................................... 21 
 
Exhibit 
Exhibit 1. Sample SAS code for assessing missing data patterns ................................................. 19 
Exhibit 2. Sample SAS code for creating a dataset that satisfies the monotone 
missingness ........................................................................................................................ 19 
Exhibit 3. Sample SAS code for standard multiple imputation for primary analysis ............... 20 
Exhibit 4. Sample SAS code for MMRM .......................................................................................... 21 


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Abbreviations 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BCVA 
best corrected visual acuity 
BID 
twice daily 
CAE® 
Controlled Adverse Environment® 
CRF 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
DED 
dry eye disease 
EDS 
Eye Dryness Score 
FDA 
Food and Drug Administration 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IRB 
institutional review board 
ITT 
intent-to-treat 
logMAR 
logarithm of the minimum angle of resolution 
LS 
least square 
MAD 
mucosal atomization device 
MedDRA 
medical dictionary for regulatory activities 
MI 
multiple imputation 
MMRM 
mixed model for repeated measures 
μL 
microliter 
mm 
millimeter 
nAChR 
nicotinic acetylcholine receptor 
OSDI© 
Ocular Surface Disease Index© 
PP 
per protocol 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
STS 
Schirmer’s Test Score 
TEAE 
treatment-emergent adverse event 
US 
United States 
 
 
 


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1. 
Introduction 
This statistical analysis plan (SAP), which is based on Amendment 1.0 of the study protocol 
dated 11 July 2018, defines the methods and analyses that Oyster Point Pharma, Inc, 
(henceforth, Oyster Point) plans to use to analyze the data from Protocol OPP-003. This SAP 
complies with guidance promulgated by the International Conference on Harmonization 
(ICH) and the US Food and Drug Administration (FDA). If the protocol is subsequently 
amended, this SAP may be amended as well. Should the SAP and the protocol be inconsistent 
with respect to the planned analyses, the language of the SAP is governing. 
2. 
Investigational plan 
 
Study design 
2.1.
Oyster Point’s protocol OPP-003 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 dry eye disease (DED). Subjects with DED who provide signed 
informed consent and meet enrollment criteria (that is, all inclusion criteria and none of the 
exclusion criteria) will be randomized in a 2:1 ratio to be treated with OC-02 nasal solution 
delivered as a 50 microliter (μL) intranasal spray in each nostril BID for a total of 4 weeks: 
x 
Placebo (vehicle) nasal spray[control] 
x 
2.0% OC-02 nasal spray[treatment] 
All enrolled subjects will receive treatment according to the protocol’s schedule of visits and 
procedures (see Appendix 1). 
 
 
 
 
Study objectives and outcome measures 
2.2.
The Protocol OPP-003 is designed to evaluate the safety and efficacy of 2.0% OC-02 nasal spray 
compared to placebo in subjects with DED. See Table 1 for the study objectives and outcome 
measures. 




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(eCRF). The Sponsor, Investigators, and study staff will be masked during the randomization 
process and throughout the study. 
3. 
Study schedule 
Subjects are expected to attend 5 visits over the study period of approximately 4 weeks (28 
days) of participation in the study. They are examined at screening (Day 1, randomization), 
Visit 2 (Day 7), Visit 3 (Day 14), Visit 4 (Day 21), and Visit 5 (Day 28). See Appendix 1 for the 
schedule of visits.  
 
Study days 
3.1.
Study days will be calculated from the date of randomization, which will be designated as Day 
1 (Visit 1). Positive study days will be measured forward in time from randomization while 
negative study days will be measured backward from randomization (e.g., Day 2 will 
represent the day after randomization while Day -1 will represent the day before 
randomization). 
 
Unscheduled visits 
3.2.
Unscheduled visits may be performed to ensure safety of the subject. The study investigator or 
designee should record all information gathered at unscheduled visits on the Unscheduled 
Visit/Early Exit Visit pages of the Source Document and corresponding electronic Case Report 
Form (eCRF). If a randomized subject does not attend a scheduled visit, the eCRF pages for the 
missed visit will be skipped. All reasonable efforts should be made to schedule subjects for an 
Exit Visit to complete Exit Procedures. 
4. 
Analysis populations 
 
Intent-To-Treat population 
4.1.
The Intent-To-Treat (ITT) population will include all randomized subjects. Analyses using the 
ITT population will group subjects according to the treatment to which they were randomized. 
The ITT analyses will be considered the primary analysis population for efficacy outcomes. 


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Safety population 
4.2.
The safety population will include all randomized subjects who received at least one dose of 
the study drug. Analysis using the safety population will group subjects according to the 
treatment actually received. The safety analysis will not exclude any data because of protocol 
violations. 
5. 
Sample size determination and power calculation 
The study will randomize approximately 45 subjects in a 2:1 ratio to the two treatment groups. 
Approximately 28 subjects of the 30 subjects in the 2.0% OC-02 treatment group and 13 of the 
15 subjects in the placebo (OC-02 vehicle) nasal spray are expected to complete their assigned 
treatment and have endpoint assessments at Visit 5. 
The primary hypothesis underlying the study is that 2.0% OC-02 nasal spray is superior to the 
placebo group with respect to mean change in STS from baseline to Visit 
 
 


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6. 
Protocol deviations 


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Prior to database lock, masked members of study team will review the data for each subject to 
assess whether an important deviation has occurred. The data management plan will describe 
the process planned for those reviews. 
7. 
Statistical analysis: general considerations and conventions 
Descriptive and inferential statistics will be used to summarize results of Protocol OPP-003. 
Continuous variables will be summarized using the number of subjects (n), mean, SD, median, 
25th and 75th percentiles, and minimum and maximum. Discrete variables will be 
summarized using counts and percentages. Baseline measures will be defined as the last 
measure prior to the initiation of study treatment, usually at Visit 1 screening. 
All summaries will be presented by treatment group. Summaries will be provided for 
demographics, medical history, concomitant medications, and subject disposition. For the 
summaries of medical history, concomitant medications, and AEs, Medical Dictionary for 
Regulatory Activities (MedDRA®) and World Health Organization Drug dictionaries, as 
appropriate, will be used. 
All data listings, summaries, and statistical analyses will be generated using SAS® Version 9.4 
or higher or other validated software. 
The following sections describe the analyses to be used for the study. 
 
Unit of analysis 
7.1.
For efficacy endpoints, the unit of analysis will be the study eye defined as the eye that meets 
all inclusion and exclusion criteria. If both eyes qualify, then the study eye will be the eye with 
the greatest increase in tear production with stimulation by a cotton swab at the Screening 
Visit. If there is no difference in stimulated tear production, the eye with the lower basal 
Schirmer’s score at screening will be the study eye. If there is no difference for either measure, 
the right eye will be used as the study eye. 
Both eyes will be analyzed for safety variables. 


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Definition of time 
7.2.
For visits (or events) that occur on or after randomization, time is calculated in days as: 
Time = Visit (or event) date – Date of randomization + 1 
For visits (or events) that occur prior to randomization, time is calculated in days as: 
Time = Visit (or event) date – Date of randomization 
For listings (e.g., for adverse events), the number of days since first (or last) dose is defined as: 
Days since first (or last) dose = Visit (or event) date – Date of randomization + 1 
For summaries that present distribution of time expressed in weeks and months, weeks will be 
defined as days divided by 7 and months as days divided by 30.4375. 
 
Missing and partial data 
7.3.
8. 
Subject characteristics, disposition, and exposure to study drug 
 
Demographic and baseline characteristics 
8.1.
Quantitative variables will be summarized using the number of subjects (n), mean, SD, 
median, 25th and 75th percentiles, and minimum and maximum. Qualitative variables will be 
summarized using counts and percentages.  
The following demographic and baseline characteristics will be summarized: age, gender, 
ethnicity, race, and ocular history. 
Age in years will be calculated as the integer portion of the following: 
[(Date of randomization- Date of birth) + 1] / 365.25. 


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Unless otherwise stated, percentages will be calculated relative to the number of subjects 
randomized. All demographic data will be presented.  
Summary tables will describe baseline ocular characteristics for each treatment group. 
Medical history will be coded using the MedDRA and summarized, for each treatment group, 
by system organ class (SOC) and preferred term (PT). Medical history may also be listed for all 
subjects in the ITT. Medical history may be sorted by treatment group and descending overall 
frequency, by SOC and PT, in the summary tables. Medical history will be presented 
separately for ocular and non-ocular events. 
 
Subject disposition 
8.2.
The study has four times of evaluation after baseline: Visit 2 (Day 7), Visit 3 (Day 14), Visit 4 
(Day 21), and Visit 5 (Day 28). At each of these times, the disposition of all subjects will be 
listed and summarized by treatment group. Tables will present the number and percentage of 
subjects who were screened, randomized, received treatment, or withdrew from the study 
early by treatment group and overall. For subjects who were randomized but withdrew from 
the study early, the number and percentage withdrawing by reason will be presented by 
treatment group and overall. 
The Case Report Form (CRF) lists the following reasons why subjects may discontinue 
treatment before completing of the study: 
x 
Adverse event (AE) or serious adverse event (SAE) 
x 
Protocol deviation 
x 
Administrative reason (e.g.: inability to continue, lost to follow-up) 
x 
Sponsor termination of study 
x 
Voluntary withdrawal or withdrawal of consent 
In addition, a subject may be discontinued for any sound medical reason at the discretion of 
the Investigator. 


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Treatment exposure 
8.3.
Duration of exposure to study treatment, in weeks, will be summarized for all randomized 
subjects. Summary statistics for duration of exposure will be presented by visit and treatment 
group. 
 
Concomitant medications and therapies 
8.4.
9. 
Baseline, post-baseline, and unscheduled measurements 
Baseline is defined as the last non-missing measurement prior to randomization (Visit 1). 
Unless otherwise specified, if a subject has more than one baseline value, the value recorded 
closest to the date and time of randomization prior to the first dose of study treatment will be 
used as the baseline measurement. 
The clinical study report (CSR) will include listings of all repeated measurements collected 
prior to first dose indicating whether they were included in the calculation of baseline. 
If a laboratory result is retested and the laboratory subsequently considers the original result 
valid, the original result will be used and the second (i.e., ‘retested’) result will be ignored. 
Otherwise, if the laboratory detects an error through the retesting, the retested result will be 
used as the scheduled measurement and the original result will be ignored. 
For post-baseline measures, specific time points will be calculated relative to randomization, 
rather than solely on the visit labels in the clinical database. 


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Results of unscheduled tests will be presented in data listings, but they will not be included in 
summaries of safety for the analysis of change in STS unless otherwise specified. 
 
Ocular assessments 
9.1.
Ocular assessments, which will occur at baseline and each study visit, collect results in terms 
of grade, clinical significance, and relatedness to administration procedure and study drug. 
These results will be listed, summarized in tables, and presented in figures as appropriate. 
9.1.1. 
Schirmer’s Test 
The Schirmer’s Test with topical anesthetic will be used to assess tear production. At Visit 1, 
the first Schirmer’s Test, which should be performed after corneal fluorescein staining, will be 
used as the baseline Schirmer’s Test score. A second Schirmer’s Test with nasal stimulation 
using cotton swab will occur 10 minutes after the first Schirmer’s Test. An additional 
Schirmer’s Test with topical anesthetic will be assessed after the first treatment at Visit 1. At 
Visits 2, 3, and 5, the Schirmer’s Tests will be performed concurrent with treatment.  
9.1.2. 
Eye Dryness Score 
The Eye Dryness Score (EDS) will be assessed using a Visual Analog Scale (VAS). EDS scoring 
is performed by subjects at Visit 1 (baseline), Visit 4 (pre-CAE®), Visit 4 (pre-treatment CAE® 
exposure, post-treatment CAE® exposure every 5 minutes within the CAE® for a total of 120 
minutes), and Visit 5.  Participants will be asked to rate their ocular symptoms (both eyes 
simultaneously) due to eye dryness every 5 minutes during CAE® exposure. At Visit 4, EDS 
from multiple time points and change in EDS from pre- to post-treatment will be collected and 
summarized by CAE® exposure period and by treatment group. 
 
 
9.1.3. 
BCVA 
Visual function of the study and fellow eye will be assessed using the best corrected ETDRS 
protocol starting at 10 feet. Visual acuity examiners must be certified to ensure consistent 
measurement of BCVA. In order to provide standardized and well-controlled assessments of 


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visual acuity during the study, all visual acuity assessments at a single site must be performed 
consistently using the same lighting conditions and same correction, if possible, during the 
entire study. If the same correction cannot be used (e.g., a subject broke his/her glasses), the 
reason for the change in correction should be documented. BCVA will be summarized by visit 
and by treatment group for both study and fellow eyes. 
9.1.4. 
Ocular Discomfort Scale 
Participants will grade themselves on the 
Ocular Discomfort Scale (ODS) with 
scores from 0 to 4 to indicate the level of discomfort: 0 corresponds to “No discomfort”, 1 to 
“Intermittent awareness”, 2 to “Constant awareness”, 3 to “Intermittent discomfort”, and 4 to 
“Constant discomfort”. The ODS collected at Visit 4 will be used to determine treatment 
administration. Treatment of investigational drug or placebo will be administered upon a 
participant’s reporting an ODS ≥ 3 at two or more consecutive time points in at least one eye 
during CAE® exposure (participants with an ODS of 3 at time 0 for an eye must report an ODS 
of 4 for two consecutive measurements for that eye) using 
Scale. ODS will be 
summarized by visit, pre-CAE® and every 5 minutes in CAE® at Visit 4, and treatment group 
for both the study and fellow eye.  
9.1.5. 
Ocular Surface Disease Index© 
The Ocular Surface Disease Index© (OSDI©) will be collected at screening. The protocol 
provides the questionnaire, calculation, and details of categorization. The OSDI© score will be 
summarized by treatment with quantitative descriptive statistics (n, mean, median, standard 
deviation, 25th quartile, 75th quartile, minimum, and maximum). 
9.1.6. 
Corneal Fluorescein Staining 
Corneal fluorescein staining will be assessed for both the study and fellow eye. Staining will 
be graded using the National Eye Institute (NEI)/Industry Workshop Scale. Examiners will 
score each of five areas on the cornea of each eye: 1 – Central; 2 – Superior; 3 – Temporal; 4 – 
Nasal; 5 – Inferior. A standardized grading system of 0-3 will be used for each of the five areas. 
The corneal fluorescein staining score will be described by visit, treatment, study eye, and 


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fellow eye with summary statistics. Specifically, scores will be presented by each of the five 
cornea areas and total scores for all corneal areas. 
9.1.7. 
Slit Lamp Biomicroscopy 
A slit lamp will be used for external examination and biomicroscopy. The eyelids, cornea, 
conjunctiva, anterior chamber, iris, and lens will be examined at each visit. Slit lamp 
biomicroscopy results will be summarized for each treatment group for the study and fellow 
eye by visit using discrete summary statistics. Abnormal clinically significant findings will be 
described. Shifts from baseline including normal to abnormal (not clinically significant), and 
normal to abnormal (clinically significant) will be presented using counts and percentages. 
 
Intranasal assessments 
9.2.
Intranasal assessments collected at the screening visit, the post-treatment CAE® evaluation at 
Visit 4, and the early termination visit will be summarized by treatment group with counts 
and percentages. Shifts from baseline of normal to abnormal (not clinically significant) and 
normal to abnormal (clinically significant) will be presented using counts and percentages. 
10. 
Efficacy analyses 
 Primacy efficacy analysis 
10.1.


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Appendix 2 provides details of the planned methodology, including sample SAS code. 
 Exploratory efficacy analyses 
10.2.
10.2.1. Exploratory efficacy endpoints 


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10.2.2. Exploratory efficacy analysis methods 


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11. 
Safety analyses 
The safety population will be used for all safety analyses. All recorded safety parameters will 
be listed. 
The investigator will promptly review each Adverse Event (AE) for accuracy and 
completeness, and classify each AE according to its intensity, its relationship to study drug or 
administration procedure, and its seriousness. AE will be coded using version 20.1 or later of 
the MedDRA dictionary. AEs will be monitored throughout the study and documented on the 
appropriate AE form. AEs will be categorized as ocular and non-ocular as well as by system 
organ class (SOC) and preferred term (PT), seriousness, severity, and relation to study 
medications. AEs will be summarized by subject, not event. 
All AE presentations will summarize treatment-emergent adverse events (TEAEs) defined as 
AEs with onset on or after first dose of investigational drug or placebo. 
The following presentations of AEs will be generated: 
x 
Overall adverse events summary (including any AEs, ocular AEs, resolved ocular 
AEs, non-ocular AEs, TEAEs, ocular TEAEs, non-ocular TEAEs, SAEs, treatment-
emergent SAEs, treatment-related treatment emergent SAEs, TEAEs by maximum 
severity, TEAEs by relationship to study drug, AEs leading to treatment/study 
discontinuation); 
x 
Serious adverse events (SAE) by SOC and PT; 
x 
All ocular AEs by SOC and PT; 
x 
All non-ocular AEs by SOC and PT; 
x 
AEs suspected to be related to the study medication; 
x 
AEs leading to treatment discontinuation. 
x 
AEs leading to study discontinuation. 


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All AE data will be presented in listings. Selected AEs will be listed for ocular TEAEs, AEs 
leading to treatment discontinuation, AEs leading to study discontinuation, and AEs related to 
the study medication. In addition, for the safety population “traffic light” plots will present 
reported AEs by severity over time by treatment group. 
BCVA will be summarized by treatment group and study visit for both study and fellow eyes. 
12. 
Subgroup analysis 




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Appendix 2. 
Analysis for primary efficacy outcome with multiple imputation 


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Exhibit 1. Sample SAS code for assessing missing data patterns 
 


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Appendix 3. 
Sensitivity analysis using a mixed model for repeated measures 
 
 
 
Appendix 4. 
Winsorized mean approach 
 


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