Clinical trial NCT04957758
Conditions: Neurotrophic Keratopathy
Sponsor: Oyster Point Pharma, Inc.
Start date: 2021-06-17; Completion date: 2023-04-28
Enrollment: 113 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the safety and effectiveness of OC-01 (varenicline) nasal spray as compared to placebo nasal spray for mean change from baseline in corneal fluorescein staining in subjects with Stage 1 (corneal epithelial hyperplasia/punctate keratopathy) neurotrophic keratopathy (NK) in one or both eyes.

Detailed description:
Protocol OPP-102 is a Phase 2, multicenter, randomized, controlled, double- masked study designed to evaluate the safety and efficacy of OC-01 (varenicline) nasal spray in subjects with NK. Approximately 100 subjects at least 18 years of age with a physicians' diagnosis of Stage 1 NK as defined by the Mackie Criteria and meeting all other study eligibility criteria will be randomized 1:1 and will receive OC-01 (varenicline)/ nasal spray or placebo nasal spray for 8 weeks three times daily (TID) as follows:

* OC-01 (varenicline) nasal spray, 1.2 mg/mL
* Placebo (vehicle control) nasal spray All doses will be delivered as a 50 microliter (µL) nasal spray.

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

Protocol documents:
SAP_002.pdf: 
  
Page 1 of 25 
 
 
 
 
 
 
Oyster Point Pharma, Inc. 
 
Clinical Protocol: OPP-102: 
A Phase 2, Multicenter, Randomized, Controlled, Double- 
Masked, Clinical Trial to Evaluate the Efficacy and Safety 
of OC-01 (varenicline) Nasal Spray in Subjects with 
Neurotrophic Keratopathy (the Olympia Study) 
 
 
 
 
Statistical Analysis Plan 
Version 3.0 
 
 
 
Date: October 7, 2022 

















































Prot_000.pdf: 
OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
Confidential 
 
 
1 
 
Clinical Trial Protocol 
 
 
Protocol Title: 
A Phase 2, Multicenter, Randomized, Controlled, Double-
Masked, Clinical Trial to Evaluate the Efficacy and Safety 
of OC-01 (varenicline) Nasal Spray in Subjects with 
Neurotrophic Keratopathy (the Olympia Study) 
Protocol Number: 
OPP-102 
Study Phase:
2
Product Name: 
OC-01 (Varenicline) Nasal Spray 
IND Number: 
138645 
Indication: 
Neurotrophic Keratopathy
Investigators:
Multi-Center 
 
Sponsor:
Oyster Point Pharma, Inc. 
202 Carnegie Center, Suite 109 
Princeton, NJ 08540 
 
 
Date 
Original Protocol:
24 November 2020 
Amendment No. 1
08 February 2021
Amendment No. 2  
16 March 2021 
Amendment No. 3 
06 May 2021
Amendment No. 4 
22 Nov 2021 
Amendment No. 5 
03 Jun 2022 
Amendment No. 6 
17 Jun 2022 
Amendment No.7 
10 Nov 2022 
Confidentiality Statement  
This protocol contains confidential, proprietary information of Oyster Point Pharma, Inc. 
Further dissemination, distribution or copying of this protocol or its contents is strictly 
prohibited. 
 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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SPONSOR PERSONNEL 
 
 
 
 
 
 
 
 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
Confidential 
 
 
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SYNOPSIS  
Protocol Title:
A Phase 2, Multicenter, Randomized, Controlled, Double-Masked, 
Clinical Trial to Evaluate the Efficacy and Safety of OC-01 
(varenicline) Nasal Spray in Subjects with Neurotrophic 
Keratopathy (the Olympia Study) 
Protocol Number:
OPP-102
Investigational 
Product: 
OC-01 (varenicline) nasal spray, 1.2 mg/mL 
Study Objective:
The objective of this study is to evaluate the safety and 
effectiveness of OC-01 (varenicline) nasal spray as compared to 
placebo nasal spray for mean change from baseline in corneal 
fluorescein staining in subjects with Stage 1 (corneal epithelial 
hyperplasia/punctate keratopathy) neurotrophic keratopathy (NK)
in one or both eyes.
 
Overall Study Design 
Structure:
A Phase 2, multicenter, randomized, controlled and double-masked 
study 
Duration: 
Treatment: 8 weeks 
Follow-up: 1 Week post treatment and 6 months post treatment
Control:
Placebo (vehicle control) nasal spray 
Dosing Regimen:  
Subjects will receive OC-01 (varenicline)/ nasal spray or placebo 
nasal spray for 8 weeks three times daily (TID) as follows: 
 OC-01 (varenicline) nasal spray, 1.2 mg/mL  
 Placebo (vehicle control) nasal spray 
Summary of Visit 
Schedule:
Visit 1- Day 1 - Screening and Randomization  
Visit 2 (Week 1) - Day 7 ± 2, corneal assessment. 
Visit 3 (Week 2) - Day 14 ± 2, corneal assessment. 
Visit 4 (Week 4) - Day 28 ± 2, corneal assessment. 
Visit 5 (Week 6) - Day 42 ± 2, corneal assessment. 
Visit 6 (Week 8) - Day 56 ± 2, corneal assessment. 
Visit 7 (Week 9) - Day 63 ± 7, phone follow-up. 
Visit 8 (Week 24) - Day 168 ±7, safety follow-up 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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Measures Taken to 
Reduce Bias: 
This is a randomized and double-masked study 
Study Population Characteristics
Number of Subjects:
Approximately 100 subjects (50 subjects per treatment arm)
Condition/Disease:
Neurotrophic Keratopathy (NK)
Inclusion Criteria:  
Subjects must:
1. Be at least 18 years of age at Visit 1. 
2. Patients with Stage 1 (corneal epithelial 
hyperplasia/punctate keratopathy) NK in one or both eyes1, 
as defined by the Mackie Criteria.   
3. 
Cochet-Bonnet aesthesiometer) in at least 1 corneal 
quadrant.
4. Schirmer’s test without anesthesia 3 mm/ 5 minutes in the 
affected eye
 
 
 
 
 
 
 
 
 
 
 
 
 
12. If a female is of childbearing potential, they must: use an 
acceptable means of birth control (acceptable methods of 
contraception include hormonal – oral, implantable, 
injectable, or transdermal contraceptives, mechanical – 
spermicide in conjunction with a barrier such as a 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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diaphragm or condom, IUD, or surgical sterilization of 
partner), and have a negative urine pregnancy test on Day 1. 
1
 
. 
Exclusion Criteria: 
Subjects must not:
1. Have Stage 2 or Stage 3 NK affecting one or both eyes.
2. Have ocular graft versus host disease or Stevens-Johnson 
syndrome. 
3. Have any active ocular infection (COVID-19 conjunctivitis, 
bacterial, viral, fungal, or protozoal) or active ocular 
inflammation not related to NK in the affected eye. 
 
 
 
 
 
 
6. Be currently receiving autologous serum tears, amniotic 
membrane, cenegermin, Fresh Frozen plasma or cord blood 
derived tears. 
7. Have severe blepharitis and/or severe meibomian gland 
disease in the study eye.
 
 
 
 
 
 
 
 
 
 
 
 
 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
Confidential 
 
 
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OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
Confidential 
 
 
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Study Formulations: 
Subjects will be randomized 1:1 to receive as a 50 microliter (µL) 
spray in each nostril:  
 OC-01 (varenicline) nasal spray, 1.2 mg/mL  
 Placebo (vehicle control) nasal spray 
Randomization: 
Subjects who meet the eligibility requirements will be randomly 
assigned to 1 of 2 treatment groups. 
The randomization will be stratified by:: 
 Pre-procedure (baseline) non-anesthetized Schirmer’s 
score (<5, >5) measured at the screening/randomization 
visit. 
A central randomization list will be created using block 
randomization. Sites will be assigned entire blocks as needed. 
Evaluation Criteria 
Efficacy Measures: 
Primary Endpoint
 Mean change from baseline in corneal fluorescein
staining in subjects with Stage 1 NK at Week 8.   
Secondary Endpoints
 Mean change from baseline in visual acuity at Week 8
 
Safety Measures: 
 Adverse event (AE) query 
 Intranasal exam


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
Confidential 
 
 
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Slit lamp biomicroscopy 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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TABLE OF CONTENTS 
1.
INTRODUCTION.......................................................................................14
2. 
STUDY OBJECTIVES ...............................................................................15 
3. 
CLINICAL HYPOTHESES........................................................................15 
4. 
OVERALL STUDY DESIGN .................................................................... 15 
5.
STUDY POPULATION..............................................................................16
5.1. 
Number of Subjects .....................................................................................16 
5.2. 
Study Population Characteristics.................................................................16 
5.3. 
Inclusion Criteria .........................................................................................16 
5.4. 
Exclusion Criteria........................................................................................17 
5.5. 
Withdrawal Criteria .....................................................................................19 
6. 
STUDY PARAMETERS ............................................................................19 
6.1. 
Efficacy Measures .......................................................................................19 
6.1.1. 
Primary Efficacy Measure ...........................................................................19 
6.1.2. 
Secondary Efficacy Measure.......................................................................19 
6.2. 
Safety Measures ..........................................................................................19 
6.3. 
Other Measures............................................................................................19 
7. 
STUDY MATERIALS................................................................................20 
7.1. 
Study Drug ..................................................................................................20 
7.1.1. 
Regimens .....................................................................................................20 
7.1.2. 
Dispensation Schedule ................................................................................20 
7.1.3.
General Appearance ....................................................................................20
8. 
STUDY METHODS AND PROCEDURES ...............................................20 
8.1. 
Subject Entry Procedures ............................................................................ 20 
8.1.1. 
Overview .....................................................................................................20 
8.1.2. 
Informed Consent ........................................................................................21 
8.1.3. 
Washout Intervals........................................................................................21 
8.1.4. 
Procedures for Final Study Entry ................................................................21 
8.1.5. 
Methods for Assignment to Treatment Groups ...........................................21 
8.2. 
Concomitant Therapies ................................................................................21 
8.2.1. 
Prohibited Medications/Treatments ............................................................22 
8.2.2. 
Escape Medications .....................................................................................22 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
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8.2.3. 
Special Diet or Activities ............................................................................22 
8.3. 
Examination Procedures..............................................................................22 
8.3.1.
Procedures to be Performed at Each Study Visit with Regard to Study 
Objectives(s)................................................................................................22
8.4. 
Schedule of Visits, Measurements and Dosing ...........................................26 
8.4.1. 
Scheduled Visits ..........................................................................................26 
8.4.2. 
Unscheduled Visits ......................................................................................26 
8.5.
Compliance with Protocol...........................................................................26
8.6.
Subject Disposition......................................................................................26
8.6.1. 
Treatment Completed Subjects ...................................................................26 
8.6.2. 
Safety Follow up Completed Subjects ........................................................ 26 
8.6.3. 
Discontinued Subjects .................................................................................27 
8.7. 
Study Termination .......................................................................................27 
8.8. 
Study Duration ............................................................................................27 
8.9. 
Monitoring and Quality Assurance .............................................................27 
9. 
SAFETY DEFINITIONS, MONITORING AND REPORTING ............... 28 
9.1. 
Adverse Events............................................................................................28 
9.1.1. 
Severity ........................................................................................................28 
9.1.2. 
Relationship to Study Drug .........................................................................28 
9.1.3. 
Expectedness ...............................................................................................29 
9.2. 
Serious Adverse Events...............................................................................29 
9.3.
Procedures for Reporting Adverse Events ..................................................30
9.3.1. 
Reporting a Suspected Unexpected Adverse Reaction ............................... 30 
9.3.2. 
Reporting a Serious Adverse Event.............................................................30 
9.4. 
Procedures for Unmasking of Study Drug ..................................................31 
9.5. 
Type and Duration of the Follow-up of Subjects after Adverse Events .....31 
10. 
STATISTICAL ANALYSIS ....................................................................... 31 
10.1. 
Primary and Secondary Endpoints ..............................................................31 
10.1.1. 
Primary Endpoint ........................................................................................31 
10.1.2. 
Secondary Endpoints ...................................................................................32 
10.2. 
Analysis Populations ...................................................................................32 
10.2.1. 
Intention-To-Treat Population .....................................................................32 
10.2.2. 
Safety Population ........................................................................................32 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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10.3. 
Statistical Hypotheses ..................................................................................32 
10.4. 
Sample Size and Power Considerations ......................................................32 
10.5.
Statistical Analysis ......................................................................................32
10.5.1.
Randomization and Stratification................................................................32
10.5.2. 
General Considerations ...............................................................................33 
10.5.3. 
Unit of Analysis...........................................................................................33 
10.5.4. 
Subject Demographics and Baseline Characteristics .................................. 33 
10.5.5.
Primary Efficacy Analysis...........................................................................33
10.5.6.
Secondary Efficacy Analysis.......................................................................33
10.5.7. 
Safety Analysis ............................................................................................34 
10.5.8. 
Interim Analysis ..........................................................................................34 
11. 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ......................34 
11.1. 
Protection of Human Subjects .....................................................................34 
11.1.1. 
Subject Informed Consent...........................................................................34 
11.1.2. 
Institutional Review Board Approval..........................................................35 
11.2. 
Ethical Conduct of Study ............................................................................35 
11.3. 
Subject Confidentiality................................................................................35 
11.4. 
Documentation ............................................................................................35 
11.4.1. 
Retention of Documentation .......................................................................35 
11.5. 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ..................................................................................................36
11.5.1. 
Labeling/Packaging .....................................................................................36 
11.5.2. 
Storage of Study Drug/Placebo Nasal Spray ...............................................36 
11.5.3. 
Accountability of Study Drug .....................................................................36 
11.5.4. 
Return or Disposal of Study Drug ............................................................... 36 
11.6. 
Recording of Data on Source Documents and Electronic Case Reports 
Forms ...........................................................................................................36 
11.7. 
Handling of Biological Specimens..............................................................37 
11.8. 
Publications .................................................................................................37 
12. 
REFERENCES ............................................................................................38 
13. 
APPENDICES .............................................................................................40 
APPENDIX 1:
SCHEDULE OF VISITS AND MEASUREMENTS.........................41 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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APPENDIX 2: 
EXAMINATION PROCEDURES, TESTS, EQUIPMENT, AND 
TECHNIQUES ............................................................................................42 
GUIDELINES FOR MEASURING VISUAL ACUITY TO THE STANDARD 
PROCEDURE DEVELOPED FOR THE EARLY TREATMENT 
DIABETIC RETINOPATHY STUDY (ETDRS) .......................................43 
Visual Acuity Equipment and Facilities: ........................................................................43 
Visual Acuity Charts ......................................................................................................43 
Visual Acuity Box ..........................................................................................................43
Illumination ....................................................................................................................43
Marking the Distance......................................................................................................44 
Refraction Technique .....................................................................................................45 
Beginning Approximate Refraction................................................................................45 
Subjective Refraction .....................................................................................................47 
Determination of Spherical Refraction...........................................................................47 
Determination of Cylindrical Refraction ........................................................................ 48 
Refining Final of Spherical Power .................................................................................50 
Refraction for Subjects with Poor Visual Acuity...........................................................51 
Testing Best Corrected Visual Acuity............................................................................51 
Scoring Best-Corrected Visual Acuity ...........................................................................53 
Count Fingers Visual Acuity ..........................................................................................53 
Hand Motion Visual Acuity ...........................................................................................53 
Light Perception and No Light Perception.....................................................................54
Corneal Fluorescein Staining..........................................................................................54 
PAIN VISUAL ANALOG SCALE (VAS) ....................................................................60 
NATIONAL EYE INSTITUTE .....................................................................................61 
APPENDIX 3:
SPONSOR APPROVALS ..................................................................72 
APPENDIX 4: 
INVESTIGATOR’S SIGNATURE...................................................73 
 
LIST OF TABLES 
Table 1: 
Clinical Grading of Neurotrophic Keratopathy ...........................................42 
Table 2: 
Refraction Protocol Summary .....................................................................46 
Table 3: 
Axis Step Sizes for Refinement of Cylinder ...............................................47 
LIST OF ABBREVIATIONS 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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Abbreviation
Term
AE
Adverse event
ANCOVA
Analysis of covariance
BCDVA 
Best corrected distance visual acuity  
CAE® 
Controlled adverse environment
CFR
Code of Federal Regulations
CI 
Confidence interval 
CRF
Case report form
eCRF
Electronic Case Report Form
EDC 
Electronic Data Capture 
EGF
Epidermal Growth Factor
ETDRS 
Early Treatment Diabetic Retinopathy Study
HGF
Hepatocyte Growth Factor
HIPAA
Health Information Portability and Accountability Act
ICF 
Informed consent form 
ICH
International Conference on Harmonization 
IRB 
Institutional Review Board
ITT
Intention to Treat
IUD 
Intrauterine device
MedDRA 
Medical Dictionary for Regulatory Activities
NEI-VFQ 
National Eye Institute Visual Function Questionnaire
Mg 
Milligram 
NGF 
Nerve Growth Factor
NK
Neurotrophic Keratopathy
mL 
Milliliter
µL
Microliter
Mm 
Millimeter 
PED
Persistent Epithelial Defect 
PDGF 
Platelet Derived Growth Factor
SAE 
Serious adverse event 
SAP
Statistical Analysis Plan
STS
Schirmer’s Test Score
TEAE
Treatment-emergent adverse event
TID 
Three times daily
US 
United States 
VAS 
Pain Visual Analog Scale
VEGF
Vascular Endothelial Growth Factor 
 
 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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1. 
INTRODUCTION  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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2. 
STUDY OBJECTIVES  
The objective of this study is to evaluate the safety and effectiveness of OC-01 (varenicline) 
nasal spray as compared to placebo for mean change from baseline in corneal fluorescein 
staining in subjects with Stage 1 (corneal epithelial hyperplasia/punctate keratopathy) NK in 
one or both eyes.
3.
CLINICAL HYPOTHESES 
This study is testing the hypothesis that OC-01 (varenicline) nasal spray is superior to placebo 
nasal spray in treating subjects with Stage 1 NK.
4. 
OVERALL STUDY DESIGN  
Protocol OPP-102 is a Phase 2, multicenter, randomized, controlled, double- masked study 
designed to evaluate the safety and efficacy of OC-01 (varenicline) nasal spray in subjects with 
NK. Approximately 100 subjects at least 18 years of age with a physicians’ diagnosis of Stage 1 
NK, as defined by the Mackie Criteria and meeting all other study eligibility criteria will be 
randomized 1:1 and will receive OC-01 (varenicline)/ nasal spray or placebo nasal spray for 8 
weeks three times daily (TID) as follows:  
 OC-01 (varenicline) nasal spray, 1.2 mg/mL  
 Placebo (vehicle control) nasal spray
All doses will be delivered as a 50 microliter (µL) nasal spray. 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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Subjects who terminate early during the application period will be asked to complete safety 
and/or efficacy assessments (if the subjects agree) prior to study exit. Subjects who are 
terminated early from the study will not be replaced. 
5. 
STUDY POPULATION  
5.1. 
Number of Subjects 
Approximately 100 subjects (approximately 50 per arm) will be enrolled in approximately 40 
sites in the US.  
5.2.
Study Population Characteristics 
All subjects must be at least 18 years of age, of any gender and race and must meet all inclusion 
criteria and none of the exclusion criteria.  
5.3. 
Inclusion Criteria  
Subjects must: 
1. Be at least 18 years of age at Visit 1.
2. Patients with Stage 1 (corneal epithelial hyperplasia/punctate keratopathy) NK- in one or 
both eyes1, as defined by the Mackie Criteria.   
3. E
-Bonnet 
aesthesiometer) in at least 1 corneal quadrant. 
4. Schirmer’s test without anesthesia 3 mm/ 5 minutes in the affected eye
 
 
 
1
 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
Confidential 
 
 
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12. If a female is of childbearing potential, they must: use an acceptable means of birth control 
(acceptable methods of contraception include hormonal – oral, implantable, injectable, or 
transdermal contraceptives, mechanical – spermicide in conjunction with a barrier such 
as a diaphragm or condom, IUD, or surgical sterilization of partner), and have a negative 
urine pregnancy test on Day 1. 
5.4. 
Exclusion Criteria  
Subjects must not:
1. Have Stage 2 or Stage 3 NK affecting one or both eyes.
2. Have ocular graft versus host disease or Stevens-Johnson syndrome.
3. Have any active ocular infection (COVID-19 conjunctivitis, bacterial, viral, fungal, or 
protozoal) or active ocular inflammation not related to NK in the affected eye. 
 
 
 
 
6. Be currently receiving autologous serum tears, amniotic membrane, cenegermin, Fresh 
Frozen plasma or cord blood derived tears.
7. Have severe blepharitis and/or severe meibomian gland disease in the study eye.
 
 
 
 
 
 
 
 
 


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
Confidential 
 
 
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OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
Confidential 
 
 
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5.5. 
Withdrawal Criteria  
If at any time during the study the Investigator determines that a subject’s safety has been 
compromised, the subject may be withdrawn from treatment, but will be followed for safety for 
the duration of the study, unless they refuse to attend follow-up visits.  
Additionally, if a subject should progress to Stage 2 NK while receiving the study drug, the
subject should remain in the study and receive treatment. If a subject should progress to Stage 3 
NK while receiving study treatment, the subject may be withdrawn from treatment at the 
discretion of the Investigator. The subject will continue to be followed for safety unless the 
subject refuses to attend the follow-up visits.   
A subject may withdraw consent from the study at any time.  
The Sponsor and/or the Investigator may discontinue any subject from study treatment for non-
compliance or for any valid medical reason during the study (see Section 8.6.2).  
6. 
STUDY PARAMETERS  
6.1. 
Efficacy Measures  
6.1.1. 
Primary Efficacy Measure 
The following primary endpoints will be tested:  
 Mean change from baseline in corneal fluorescein staining in subjects with Stage 1 
NK at Week 8.   
6.1.2. 
Secondary Efficacy Measure 
The following secondary endpoints will be tested: 
Mean change from baseline in visual acuity at Week 8
6.2. 
Safety Measures 
 Adverse events 
 Intranasal exam 
 Slit lamp biomicroscopy
6.3. 
Other Measures 
 Urine pregnancy test (Visit 1, Visit 4 and Visit 6)


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc. 
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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7. 
STUDY MATERIALS 
7.1. 
Study Drug 
7.1.1.
Regimens
The study drug will be delivered as a 50 microliter (µL) nasal spray in each nostril TID:
OC-01 (varenicline) nasal spray, 1.2 mg/mL 
Placebo (vehicle control) nasal spray
7.1.2.
Dispensation Schedule 
At Day 1, qualified subjects will be screened and randomized and the first dose of study drug 
will be administered in the clinic. The remaining administrations will happen at home after the 
clinic visit.
Between clinic visits, subjects will self-administer OC-01 (varenicline) nasal spray as a 50 µL 
dose in each nostril.
At Visit 2, the study drug/placebo nasal spray will be administered in the clinic to reinforce the 
proper use of the nasal pump. The remaining administrations will happen at home. 
At Week 8, the final study drug/placebo nasal spray administration will occur in the clinic. 
Subjects will self-administer OC-01 (varenicline) nasal spray as a 50 µL dose in each nostril up 
to 8 weeks. 
7.1.3. 
General Appearance 
OC-01 (varenicline)/placebo nasal spray will be formulated at the desired concentration in 
sodium phosphate buffers and sodium chloride as an aqueous solution and presented in a multi-
use preservative-free nasal pump. 
The product is preservative-free and intended for intranasal use only. The product should not be 
used if cloudy or if particulate matter is present. 
OC-01 (varenicline) solution must be administered without dilution.  
8. 
STUDY METHODS AND PROCEDURES 
8.1. 
Subject Entry Procedures  
8.1.1. 
Overview  
Subjects as defined by the criteria in Section 5.2, Section 5.3 and Section 5.4 will be considered 
for entry into this study.  


OC-01 (varenicline) Nasal Spray
Sponsor: Oyster Point Pharma, Inc.  
Clinical Trial Protocol # OPP-102 
10 Nov2022 
Amendment No. 7 
 
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8.1.2. 
Informed Consent  
Prior to a subject’s enrollment in the trial (i.e., prior to any study-related procedures), the study 
will be discussed with each potential subject and subject wishing to participate must be 
administered and provide written informed consent using an Institutional Review Board (IRB)-
approved informed consent form (ICF). The ICF must be the most recent version that has 
received approval by a properly constituted IRB.  
8.1.3. 
Washout Intervals  
Prohibited medications, treatments, and activities are outlined in the Exclusion Criteria (Section 
5.4).  
8.1.4. 
Procedures for Final Study Entry 
Subjects must meet all inclusion criteria and none of the exclusion criteria.  
8.1.5. 
Methods for Assignment to Treatment Groups 
Each subject who enters the screening period for the study (defined as the point at which the 
subject signs the informed consent form (ICF) receives a unique subject identification number 
before any study-related activities/procedures are performed.  This number will be used to 
identify the subject throughout the clinical study and must be used on all study documentation 
related to that subject.   
The subject identification number must remain constant throughout the entire clinical study.   
Subjects who meet the eligibility requirements will be randomly assigned to 1 of 2 treatment 
groups. 
The randomization will be stratified by:  
 Pre-procedure (Baseline) non-anesthetized Schirmer’s score (<5, >5) measured at 
the screening/randomization visit.  
A central randomization list will be created using block randomization. Sites will be assigned 
entire blocks as needed. 
8.2. 
Concomitant Therapies  
The use of any concurrent medication, prescription or over the counter, is to be recorded on the 
subject’s source document and corresponding eCRF along with the reason the medication was 
taken.
Concurrent enrollment in another investigational drug or device study during the treatment 
period is not permitted.  Any investigational therapies taken after the treatment period of the 
study must be recorded on the eCRF.     
Subjects on topical ophthalmic medications must have a stable medication regimen for at least 2 
weeks prior to enrollment and the regimen must remain unchanged during the treatment period 
of the study.   


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8.2.1. 
Prohibited Medications/Treatments  
Disallowed medications/treatments during the study are outlined below: 
 No concomitant use of a nicotinic acetylcholine receptor agonist [Nicoderm®, 
Nicorette®, Nicotrol NS® (nicotine), Tabex®, Desmoxan® (cytisine), and Chantix®
(varenicline)] during the treatment period (baseline to Day 56) of the study.
Topical ophthalmic medications, including preservative free artificial tears must not 
be utilized for 1 hour pre and post study drug administration.   
Other nasal sprays, including nasal steroids must not be utilized for 1 hour pre and 
post study drug administration 
  Autologous serum tears, amniotic membrane, cenegermin, Fresh Frozen plasma or 
cord blood derived tears during the study treatment period. 
8.2.2. 
Escape Medications 
If a subject should progress to Stage 2 NK while receiving the study drug, the subject should 
remain in the study and receive treatment. If a subject should progress to Stage 3 NK while 
receiving the study drug, the subject may be withdrawn from the study treatment at the 
discretion of the Investigator.  
8.2.3. 
Special Diet or Activities  
No special diets or activity is required for this study.  
8.3. 
Examination Procedures  
8.3.1. 
Procedures to be Performed at Each Study Visit with Regard to Study 
Objectives(s) 
The following procedures will be performed (see Appendix 2 for description)
Visit 1 (Day 1): Screening and Randomization
 Informed consent/Health Information Portability and Accountability Act (HIPAA) 
consent 
 Demographic data, medical history, prior medication (s), and ocular history 
 Eligibility criteria  
 Urine pregnancy test (if applicable) 
 NEI-VFQ-25 questionnaire 
 Pain Visual Analog Scale (VAS) 
 Best corrected distance visual acuity (BCDVA) 
 Slit lamp biomicroscopy (prior to Schirmer’s Test) 


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Corneal fluorescein staining (prior to Schirmer’s Test)
Slit lamp (cornea) photography (prior to Schirmer’s Test)
Corneal sensitivity (prior to Schirmer’s Test)
In-vivo Confocal Microscopy (prior to Schirmer’s Test) (select centers)
 Schirmer’s Test without anesthesia (pre- treatment) 
 Schirmer’s Test with anesthesia (concurrent with treatment) 
 Intranasal examination (pre- and post- treatment) 
 Randomization 
 Administration of the study drug/placebo nasal spray (concurrent with Schirmer’s 
test with anesthesia) 
 Dispense the study drug/placebo nasal spray  
 Concomitant medications 
 AE query 
Visit 2 (Week 1) - Day 7 ±2: 1 Week: Corneal Assessment  
 Slit lamp biomicroscopy 
 Corneal fluorescein staining assessment 
 Slit lamp (cornea) photography
 NK staging per Mackie Criteria
 Schirmer’s Test with anesthesia (concurrent with treatment)
 Intranasal examination  
 Administration of the study drug/placebo nasal spray (concurrent with Schirmer’s 
test) 
 Dispense the study drug/placebo nasal spray 
 Concomitant medications
 AE query 
Visit 3 (Week 2) - Day 14 ±2: 2 Week Corneal Assessment  
 VAS 
 Slit lamp biomicroscopy
 Corneal fluorescein staining
 Slit lamp (cornea) photography
 Intranasal Examination


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NK staging per Mackie Criteria
Dispense the study drug/placebo nasal spray
Concomitant medications
AE query
Visit 4 (Week 4) - Day 28 ± 2: 4 Week Corneal Assessment
NEI-VFQ-25 questionnaire
Urine pregnancy test (if applicable)
NK staging per Mackie Criteria
 VAS 
 BCDVA 
 Slit lamp biomicroscopy 
 Corneal fluorescein staining 
 Slit lamp (cornea) photography 
 Corneal sensitivity 
 Intranasal Examination 
 Dispense the study drug/placebo nasal spray 
 Concomitant medications 
 AE query 
Visit 5 (Week 6) - Day 42 ± 2: 6 Week Corneal Assessment 
 VAS 
 Slit lamp biomicroscopy 
 Intranasal Examination 
 NK staging per Mackie Criteria 
 Dispense the study drug/placebo nasal spray 
 Concomitant medications 
 AE query 
Visit 6 (Week 8) - Day 56 ± 2: corneal assessment 
 NEI-VFQ-25 questionnaire 
 VAS 
 Urine pregnancy test (if applicable) 


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NK staging per Mackie Criteria
BCDVA
Slit lamp biomicroscopy (prior to Schirmer’s Test)
Corneal fluorescein staining (prior to Schirmer’s Test)
 Slit lamp (cornea) photography (prior to Schirmer’s Test) 
 Corneal sensitivity (prior to Schirmer’s Test) 
 In-vivo Confocal Microscopy (prior to Schirmer’s Test) (select centers)
 Intranasal examination
 Schirmer’s Test with anesthesia (concurrent with treatment)
 Administration of the study drug/placebo nasal spray (concurrent with Schirmer’s 
test) 
 Concomitant medications
 AE query 
Visit 7 (Week 12) - Day 63 ± 7 Phone Visit Follow up
 Concomitant medications
 AE query 
Visit 8 (Week 24) _Day 168 ± 7: Safety Follow up  
 Intranasal Examination 
 Concomitant medications 
 AE query 
Early Termination 
 Urine pregnancy test (if applicable) 
 NEI-VFQ-25 questionnaire 
 VAS 
 BCDVA 
 Slit lamp biomicroscopy (prior to Schirmer’s Test) 
 Corneal fluorescein staining (prior to Schirmer’s Test) 
 Slit lamp (cornea) photography (prior to Schirmer’s Test) 
 Corneal sensitivity (prior to Schirmer’s Test) 
 In-vivo Confocal Microscopy (prior to Schirmer’s Test) (select centers) 


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NK staging per Mackie Criteria
Schirmer’s Test with anesthesia 
Intranasal examination
Administration of the study drug/placebo nasal spray (concurrent with Schirmer’s 
test if subject agrees)
Concomitant medications
AE query
8.4. 
Schedule of Visits, Measurements and Dosing 
8.4.1. 
Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2. 
Unscheduled Visits  
These visits may be performed 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 
 BCDVA 
 Intranasal examination 
 Assessment of AEs 
Assessment of concomitant medications and/or treatments
Any other assessments needed in the judgment of the Investigator.
8.5. 
Compliance with Protocol  
Subjects will be instructed on the proper use and storage of the study drug and provided with 
written instructions upon dispensation of their study drug at Visit 1. 
8.6. 
Subject Disposition  
8.6.1. 
Treatment Completed Subjects  
A Treatment Completed Subject is one who has completed 8 weeks of study visits (Visit 6).  
8.6.2. 
Safety Follow up Completed Subjects 
A Safety Follow up Completed Subjects is one who has completed all study visits up to Month 
6 (Visit 8). 


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8.6.3. 
Discontinued Subjects  
Subjects may be discontinued from treatment, or from involvement in the study at any time 
prior to their completion of the study due to:
 Non-fatal adverse event
 Protocol violations
 Disease progression 
 Lost to follow-up. 
Physician decision
Subject non-compliance
Death
 Study terminated by the Sponsor 
 Withdraw by subject (e.g., withdrawal of consent); and 
 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 the Sponsor. 
Notification of a subject discontinuation and the reason for discontinuation will be made to the 
Sponsor and will be clearly documented on the eCRF. 
If a subject discontinues from treatment, the subject will be asked to be followed for safety for 
the duration of the study, unless they refuse to attend follow-up visits. A subject will be asked 
to attend Visit 8 and have all scheduled assessments performed as per the Schedule of Visits 
and Measurements (Appendix 1)
Discontinued subjects will not be replaced.
8.7. 
Study Termination  
The study may be stopped at any time by the Investigator and/or Sponsor, with appropriate 
notification.  
8.8. 
Study Duration  
An individual subject’s participation will involve 8 visits over 6 months.
8.9. 
Monitoring and Quality Assurance  
 
 
 
 
 


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9. 
SAFETY DEFINITIONS, MONITORING AND REPORTING 
9.1. 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use 
of a drug in humans, whether the event is considered drug related or not. 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/placebo nasal spray will also be considered a new AE. 
AE collection will start following the first administration of the study drug/placebo nasal spray
until the last follow up visit of the study.
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to study drug, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the Investigator or reported by the subject upon indirect questioning. 
9.1.1. 
Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the Investigator or reported to him/her by the patient/subject. The assessment of 
severity is made irrespective of relationship to study drug or seriousness of the event and should 
be evaluated according to the following scale: 
 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


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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: 
 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 
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 a serious adverse event (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 


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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. 
Note: Planned hospital admissions or surgical procedures for an illness or disease that was 
present before the patient received any study drug are not to be considered SAEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier than planned). 
 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 in an offspring of a study subject. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
SAEs are collected at the time the subject signs the Informed Consent Form until the last follow 
up visit of the study.  
9.3. 
Procedures for Reporting Adverse Events  
All AEs and their outcomes must be reported to the Sponsor, and the IRB/IEC as required by 
the IRB/IEC, federal, state, or local regulations and governing health authorities and recorded 
on the appropriate eCRF.
9.3.1.
Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to the Sponsor and the 
IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities. 
9.3.2. 
Reporting a Serious Adverse Event
To ensure subject safety, all SAEs, regardless of relationship to the study drug, must be 
reported within 24 hours of the Investigator’s knowledge. 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 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 


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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. 
An SAE will be reported through the electronic data capture (EDC) system.  If the EDC system 
is unavailable to the site staff to report the serious adverse event, the information is to be 
reported to the sponsor via the SAE Form and submitted to safety@oysterpointrx.com.  The 
data must be entered into the EDC system when the system is again available.  If requested, 
medical records may be provided at safety@oysterpointrx.com. 
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 regards 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. 
Unmasking will be performed utilizing the randomization system. The unmasked subject will 
continue the study if warranted by the Investigator in consultation with the Medical Monitor.  
9.5. 
Type and Duration of the Follow-up of Subjects after Adverse 
Events 
The Investigator will follow unresolved AEs to resolution until the subject is lost to follow-up 
or until the AE is otherwise classified. Resolution means the subject has returned to baseline 
state of health or the Investigator does not expect any further improvement or worsening of the 
AE. If the patient is lost to follow-up, the Investigator should make 3 reasonable attempts to 
contact the patient via telephone, post, or certified mail. All follow-ups 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.  
New information relating to a previously reported serious adverse event must be submitted.  All 
new information for serious adverse events must be submitted within 24 hours following the 
investigator’s knowledge of new information.  The investigator may be asked to provide 
additional follow-up information, which may include discharge summary or extracts from the 
medical record.  
10. 
STATISTICAL ANALYSIS  
Statistical considerations and methods of analyses for this study are provided below; the 
accompanying Statistical Analysis Plan (SAP) contains complete details of the planned 
analyses.
10.1. 
Primary and Secondary Endpoints  
10.1.1. 
Primary Endpoint 
 Mean change from baseline in corneal fluorescein staining in subjects with Stage 1 
NK at Week 8.   


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10.1.2. 
Secondary Endpoints 
 Mean change in baseline in visual acuity at Week 8 
10.2. 
Analysis Populations 
 
 
 
10.2.2. 
Per Protocol 
The per-protocol (PP) population will include all ITT subjects with baseline corneal fluorescein 
 in subjects with Stage I (corneal epithelial hyperplasia/punctate keratopathy) NK in 
one or both eyes.  Analysis using the PP population will group subjects according to the 
treatment to which they were randomized.
10.2.3. 
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 
received.  
10.3. 
Statistical Hypotheses 
Let µh, and µp denote the mean change in corneal fluorescein staining from baseline to Week 8 
(1.2 mg/mL OC-01 and placebo, respectively) in subjects with Stage 1 NK
H0: µh - µp = 0
H1: µh - µp
10.4.
Sample Size and Power Considerations
 
 
10.5. 
Statistical Analysis 
This section briefly outlines the planned efficacy analyses. The statistical analysis plan (SAP) 
describes the methods to be used in detail. If the SAP and the protocol disagree, the details and 
methods of the SAP will prevail. 
10.5.1. 
Randomization and Stratification 
Subjects will be randomized 1:1 to receive either OC-01 nasal spray or vehicle control. 
The randomization will be stratified by:  
Pre-procedure (Baseline) non-anesthetized Schirmer’s score (<5, >5) measured at 
the screening/randomization visit  


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A central randomization list will be created using block randomization. Sites will be assigned 
entire blocks as needed. 
10.5.2. 
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 the 
Medical Dictionary for Regulatory Activities (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. 
10.5.3. 
Unit of Analysis 
 
 
 
 
For safety endpoints, both eyes will be analyzed. 
10.5.4.
Subject Demographics and Baseline Characteristics 
Continuous summary statistics will be generated for age in years by treatment group and for all 
subjects. Discrete summary statistics will be generated for the following qualitative 
demographic variables: age category, gender, ethnicity, race, and other baseline intranasal 
examination results, tabulated by treatment group and for all subjects. Individual subject data 
listings will support the summary tables.
10.5.5.
Primary Efficacy Analysis
The primary efficacy endpoint will be analyzed on the 
 
comparing the treatment group to placebo with the randomization strata, 
Baseline Schirmer’s Test Score as the covariate and Mackie Classification Stage as an 
independent variable.   The primary endpoint will be the mean change from baseline in corneal 
fluorescein staining at Week 8.  The analysis using the PP population will be treated as the 
primary analysis.   
10.5.6. 
Secondary Efficacy Analysis 
The secondary efficacy endpoints are as follows:
 Mean change from baseline in visual acuity at Week 8 


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The secondary efficacy endpoint will be analyzed on the PP population using an analysis of 
covariance model comparing the treatment group to placebo with randomization strata, baseline 
Schirmer’s Test Score and the baseline ETDRS visual acuity as covariates.   
10.5.7. 
Safety Analysis 
All safety analyses will be performed on the safety population. 
The safety of OC-01 (varenicline) will be assessed primarily by the incidence of AEs. An AE 
will be considered a treatment-emergent AE (TEAE) if it occurs or worsens on or after 
initiation of treatment. An overall summary of TEAEs will be presented including the number 
of events and the number of subjects with events (along with percentages) by treatment group 
for TEAEs in several categories base on seriousness, relationship to treatment, and severity. 
Other safety endpoints including visual acuity, slit lamp bio microscopy and intranasal 
examination will be summarized by treatment group and visit using descriptive statistics. 
Changes or shifts from baseline will be summarized where appropriate. For assessments 
performed by eye, study eye and fellow eye will be summarized separately.  
The SAP will present methods of analysis of these defined parameters in detail.
10.5.8. 
Interim Analysis
No interim analysis is planned for this study.  
11. 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES  
This study will be conducted in compliance with this protocol, Good Clinical Practices, 
including the International Conference on Harmonization (ICH) Guidelines, and in general, 
consistent with the Declaration of Helsinki. In addition, all applicable local, state, and federal 
requirements relevant to the use of study drugs in the countries involved will be adhered to.
11.1. 
Protection of Human Subjects 
11.1.1. 
 Subject Informed Consent  
Informed consent/assent must take place before any study specific procedures are initiated. 
Signed and dated written informed consent must be obtained from each subject and/or from the 
subject’s parent or legal guardian prior to enrollment into the study. If the subject is under the 
legal age of consent, the consent form must be signed by a legal guardian or as required by state 
and/or local laws and regulations.
All informed consent/assent forms must be approved for use by the Sponsor and receive 
approval/favorable opinion from an IRB prior to their use. If the consent form requires revision 
(e.g., due to a protocol amendment or significant new safety information), it is the 
Investigator’s responsibility to ensure that the amended informed consent is reviewed and 
approved by Sponsor prior to submission to the governing IRB and that it is read, signed and 


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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.
11.1.2. 
Institutional Review Board Approval  
This study is to be conducted in accordance with IRB regulations [U.S. 21 Code of Federal 
regulations (CFR) Part 56.103]. The Investigator must obtain appropriate IRB approval before 
initiating the study and re-approval at least annually. 
Only an IRB-approved version of the informed consent form will be used. 
11.2. 
Ethical Conduct of Study  
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki.
11.3. 
Subject Confidentiality  
All personal study subject data collected and processed for the purposes of this study should be 
maintained by the Investigator and his/her staff with adequate precautions so as to ensure the 
confidentiality of the data in accordance with local, state, and federal laws and regulations. 
Monitors, auditors and other authorized representatives of the Sponsor, the IRB approving this 
study, the Food and Drug Administration, the Department of Health and Human Services, other 
domestic government agencies, and other foreign regulatory agencies will be granted direct 
access to the study subject’s original medical and study records for verification of the data 
and/or clinical trial procedures. Access to this information will be permitted to the above listed 
individuals to the extent permitted by law.
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents.
11.4. 
Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
Investigator’s study subject files, as well as the results of diagnostic tests such as photographs, 
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 


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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 
The study drug/placebo nasal spray will be provided in multi-use intranasal applicator that will 
be assigned at randomization for use during study. 
11.5.2. 
Storage of Study Drug/Placebo Nasal Spray
The study drug/placebo nasal spray must be stored in accordance with the pharmacy manual for 
this study, which contains detailed information regarding the storage and administration. 
11.5.3. 
Accountability of Study Drug
The study drug/placebo nasal spray is only prescribed by the principal Investigator or his/her 
named sub investigator(s) and is to only be used in accordance with this protocol. The study 
drugs must only be distributed to subjects properly qualified under this protocol to receive study 
drug. The Investigator must keep an accurate accounting of the study drugs by maintaining a 
detailed inventory. This includes the amount of study drugs received by the site, amount 
dispensed to subjects, amount returned to the site by the subjects, and the amount returned to 
the Sponsor upon the completion of the study.  
11.5.4.
Return or Disposal of Study Drug
You may be requested to destroy study drug or study drug kits on-site that are expired, not 
acceptable for use due to a temperature deviation, or at the end of the study. If site regulations 
do not permit destruction, study drugs will be returned to the Sponsor or their designee for 
destruction. 
11.6. 
Recording of Data on Source Documents and Electronic Case 
Reports Forms 
All subject data will be captured in the subject source documents which will be transcribed in 
the eCRFs. The Investigator is responsible for ensuring that study data is completely and 
accurately recorded on each subject’s eCRF, source documents, and all study-related materials. 
All study data should also be attributable, legible, contemporaneous, and original. A recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or 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 


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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. Minimal data will be entered for screen failure subjects. An audit 
trail will be maintained within the electronic system to capture all changes made within the 
eCRF database. After the end of the study and database lock, electronic copies of all applicable 
subjects’ eCRFs will be provided to each Investigator Site to be maintained on file by the 
Investigator. 
11.7. 
Handling of Biological Specimens  
Not applicable. 
11.8. 
Publications 
The study will be documented in a final report, which will contain appropriate statistical 
analysis and medical overview. No individual site or Investigator may publish or present any 
results from the study until the Sponsor completes a joint, multi-center publication of the trial 
results in conjunction with various participating Investigators and appropriate sites contributing 
data and comments. Subsequently, individual Investigators may request to publish or present 
results from the trial; however, approval will be at the sole discretion of the Sponsor. Should the 
foregoing language 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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13. 
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: 
Table 1:
Clinical Grading of Neurotrophic Keratopathy
Stage
Clinical Findings
I
Corneal epithelial hyperplasia and irregularity
Scattered small facets of dried epithelium (Gaule 
spots) 
Superficial punctate keratopathy 
Rose bengal staining of inferior conjunctiva 
Increased viscosity of tear mucus
Decreased breakup time
Superficial neovascularization
Stromal Scarring
Dellen 
II
Persistent corneal epithelial defect with smooth and 
rolled edges 
Descemet’s membrane folds and stromal swelling 
Anterior chamber inflammatory reaction with 
hypopyon (rare) 
III 
Corneal ulcer 
Corneal perforation
Corneal stromal melting


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GUIDELINES FOR MEASURING VISUAL ACUITY TO THE 
STANDARD PROCEDURE DEVELOPED FOR THE EARLY 
TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS)  
Visual Acuity Equipment and Facilities:  
The procedure described in this section utilizes the following equipment:  
 Set of three ETDRS Distance Visual Acuity Test charts which are modified 
ETDRS Charts 1, 2 and R for testing visual acuity at 4 meters 
 Retro-illuminated box providing standardized chart illumination 
Visual acuity testing is required at a distance of 4 meters and, for subjects with sufficiently 
reduced vision, at 1 meter. The 4-meter distance should be marked clearly and permanently. 
The 1-meter distance must be measured with a 1-meter stick when the subject is seated (see 
below) 
Visual Acuity Charts  
Charts 1 and 2 are used for testing the right and left eye, respectively, and Chart R is used for 
entering acuity measurements and refraction for each eye.  The features of the charts are high 
contrast Sloan Letters in each of 14 lines, lines of equal difficulty, and a geometric 
progression of letter size (and, thus, an arithmetic progression of the logarithm of minimum 
angle of resolution) from line to line.  Charts 1, 2, and R have different letter sequences.  
Subjects should be prevented from seeing Charts 1 and 2 until refraction has been completed 
and the visual acuity test begins.
Visual Acuity Box 
The dimensions of the light box are 24 ¾ inches by 7 inches. The box can be mounted on a 
wall or on a cylindrical stand. The stand is mounted on a five-pronged wheelbase, with each 
prong about 14 inches long; two of the five wheels are lockable. When the box is mounted on 
the stand, its height can be varied.
The light box should be mounted at a height such that the top of the third row of letters (0.8 log 
MAR) is 49 (2 inches +/-) from the floor. The rear of the box provides storage space for the 
two charts not being used.
Illumination 
Most of the room lights should be turned off during the visual acuity test.  The box itself 
provides sufficient illumination for the examiner to record the test results.  Additional light 


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can have an adverse effect.  With the light box off, the light box should appear uniformly dark 
with no specular reflections visible to the subject sitting in the examination chair. 
The visual acuity light box is equipped with two General Electric Cool Daylight 20-watt 
fluorescent tubes and a ballast.  Because the illumination of fluorescent tubes diminishes by 
 
 New Tubes should be kept “on” for about 4 days (96 hours, does not have to be 
continuous). A note should be kept on the back of the light box, indicating the date 
and time when new tubes were replaced.
 No testing will be done with the light box during the initial 4-day period.
 All tubes should be replaced once a year. 
Each tube is partly covered by a 14-inch fenestrated sleeve, open in the back, which serves as 
a baffle to reduce illumination.  Each sleeve should be centered on the tube such that an equal 
length of tube (4 3/16 inches) is left uncovered to the right and left of the sleeve.  The 
openings in the backs of the sleeves should be oriented to point directly toward the back of 
the box (i.e., the sleeves should not be tilted up or down).  Also, the lower sleeve has a cutout 
that should point toward the ballast. 
4- and 1- Meter Visual Acuity Lanes 
A distance of exactly 4 meters (13 feet and 1 1/2 inches, or 157.5 inches) is required between 
the subject’s eyes and the visual acuity chart for the 4-meter test, and a distance of exactly 1 
meter (39 and 3/8 inches) is required for the 1-meter test. 
The room for visual acuity testing must have, in addition to the 4-meter lane, space for the 
visual acuity box (and possibly a stand) and space for the seated subject.  Minimum room-
length requirements vary according to how the box is mounted: 
 Wall-mounted box: In addition to the 4-meter lane, 7 inches must be allowed for 
the depth of the box plus space for the seated subject.
Stand-mounted box: In addition to the 4-meter lane, 13 inches must be allowed for 
two of the stand’s casters to touch the rear wall (or a line marked on the floor 
when there is no wall) plus space for the seated subject. 
Marking the Distance 
4 Meters 
If the chair and visual acuity box are permanently affixed, distance measurements need to be 
made only once and no floor marks are needed to ensure the correct distance. 
If the box is mounted on the wall but the subjects chair is not permanently affixed, the 4-
meter distance of the subject’s eye from the chart must be marked clearly and permanently.  


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The room lights should be reduced to a maximum of 15 foot-candles during the visual acuity 
test. The box itself provides sufficient illumination for the examiner to record the test results. 
Additional light can have an adverse effect.  With the light box off, the light box should 
appear uniformly dark with no specular reflections visible to the subject sitting in the 
examination chair.
If the box is mounted on a moveable stand, the 4-meter distance must be marked clearly and 
permanently on the floor.  The location and orientation of the box must be rechecked each 
time a new chart is put in place.  When the stand touches the rear wall of the room, two of the 
five casters should touch the wall. 
1 Meter 
The 1-meter distance is measured from the eye of the subject, seated comfortably in a chair 
with his or her back firmly placed against the back of the chair, to the center of the second or 
fourth letter on the third line of the chart. A non-flexible measuring device should be used for 
this measurement such as a yardstick, a dowel or a rod purchased at a local hardware store. 
Refraction Technique 
The technique described below is recommended for all study subjects whenever a manifest 
refraction and best-corrected visual acuity measurement is indicated by the protocol. 
Refraction Chart R must be used for determining the best lens correction in each eye. Charts 1 
and 2 are not used for refraction, only for visual acuity testing. The right eye is refracted first 
and then the left eye. Chart 1 will be used to test visual acuity in the right eye, Chart 2 to test 
visual acuity in the left eye, and the Chart 1 will be also used to test binocular vision. 
Beginning Approximate Refraction 
The lens correction recorded should be the final correction in the trial frame at the end of 
refraction and spherical refinement in the visual acuity lane.  Corrected aphakic patients, 
including those with intraocular lenses, should undergo subjective refraction as specified 
below. For uncorrected aphakic patients, a +10.00-diopter sphere should be added to the trial 
frame as the beginning approximate refraction.
The beginning approximate refraction is the result of the subjective refraction on the previous 
visit.
At Visit 1, if the visual acuity is 20/100 (2/10) or better, and the subject does not wear glasses 
for distance, the beginning approximate refraction is plano.
If he or she does wear glasses for distance, the beginning approximate refraction is the 
measured power of those glasses (using a lensometer).
Before the subjective refraction, visual acuity is measured using the beginning approximate 
refraction and Chart R.


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If the subject’s visual acuity is <20/200 (2/20) in either eye with the subject’s present distance 
glasses (or without correction, if the subject does not have glasses), retinoscopy should be 
performed by an examiner proficient in this procedure.
An acceptable alternative is to use an automated refractor.  The refraction steps below are 
recommended for visual acuities of 20/20 through 20/80 with the beginning approximate 
refraction.  For visual acuities worse than 20/80, refer to the refraction table for the 
appropriate sphere and cylinder powers and testing distance (see Table 2) and follow a similar 
procedure using steps in power that are equal to the power of the lens being presented. 
NOTE: Whenever the visual acuity improves to a higher range by improved correction, for 
example, from the 20/80 to 20/160 range to the 20/20 to 20/80 range, refinement should be 
performed with the smaller sphere and cylinder powers given for the better visual acuity. 
Table 2:
Refraction Protocol Summary 
Vision with 
Best 
Correction 
(Refraction 
Distance) 
 
Sphere 
 
Cylinder 
 
Sphere Refinement 
 
Power 
 
Increment 
 
Axis 
 
Power 
 
Increment 
 
Power 
 
Increment 
20/10-20/100 
(4 meters) 
+0.50             +0.50 
-0.37               -0.25 
+0.50              +0.50 
0.50              0.25             +0.25 
JCC              JCC             -0.25 
 
+0.25           +0.25 
-0.37            -0.25 
+0.25           +0.25 
<20/125-20/200  
(4 meters) 
+1.00              +1.00 
-0.75              -0.75 
+1.00             +1.00 
1.00                1.00             +1.00 
JCC                 JCC             -1.00 
+0.50            +0.50 
-0.37             -0.25 
+0.50            +0.50 
20/250 - 20/400 
(4 meters) 
+1.50               +1.50 
-1.00                -1.00 
+1.50               +1.50 
1.00                1.00              +1.00 
JCC                 JCC              JCC            
+0.75             +0.75 
-0.50              -0.50 
+0.75             +0.75 
<20/400 
(1 meter) 
+2.00                  +2.00 
-1.50                   -1.50 
-2.00                  +2.00 
No Cylinder Test 
No refinement 


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Table 3:
Axis Step Sizes for Refinement of Cylinder 
Cylinder Power
Axis Step Sizes
<1.00 D
1.00 - <2.00 D
2.00 - <3.00 D
3.00 - <5.00 D
5.00 - <8.00 D
Subjective Refraction 
The trial frame is placed and adjusted on the subject’s face so that the lens cells are level and 
parallel to the anterior plane of the orbits and centered in front of the pupils.  The left eye is 
occluded (by lightly patching with an eye pad or folded tissue with tape) and the beginning 
approximate refraction, as determined above, is placed in the right lens cells with the 
cylindrical correction anterior. Chart R should be read at a distance of 4 meters.
Determination of Spherical Refraction 
The visual acuity of the right eye is assessed and noted. A +0.50 sphere is then held in front of 
the right eye and the subject is asked if the vision is “better,” “worse,” or “no different” while 
he or she is looking at the smallest line read well.
 If vision is improved, the subject is requested to read the chart and if at least one 
more letter is read, the sphere in the trial frame is replaced by a sphere that is 0.25 
diopter less plus.  If vision is improved or there is no change, the sphere in the 
frame is replaced with one that is one-half diopter more plus.  The +0.50 sphere is 
held in front of the right eye again and the subject is asked again if the vision is 
“better”, “worse” or “no different”.  This process of increasing the plus sphere in 
the trial frame is repeated until the subject says that the +0.50-sphere held in front 
of the trial frame makes the vision worse.  When the subject responds that the 
vision is made “worse”, the lens should be left in place for 10 to 15 seconds to 
evaluate whether the subject is accommodating (an unlikely situation in a 
population over age 60).  If the vision clears during this period, the +0.50 sphere 
may be added again and succeeding attempts to evaluate additional plus lenses 
should be accompanied with a 10 to 15 second delay.  If there is no evidence of 
unrelaxed accommodation, the delay period while assessing plus lenses is not 
necessary at any time further in the examination.


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 Whenever the subject says that the vision is “worse” and remains worse, the +0.50 
sphere is removed from in front of the trail frame.
By this process, the highest-plus or least-minus sphere that is tolerated without blurring the 
subject’s vision is determined.  After determining this highest-plus or least–minus sphere, the 
subject is asked to read the smallest line possible.
Next, a –0.37 sphere is held in front of the trial frame and the subject is asked if the vision is 
“better”, “worse”, or “no different”.
 If vision is improved, the subject is requested to read the chart and if at least one 
more letter is read, the sphere in the trial frame is replaced by a sphere that is 0.25 
diopter less plus. 
 In certain situations, the subject may be unable to read more letters, but is 
convinced that the vision is improved.  If the examiner believes this is the case, the 
additional minus lens can be added.  At any stage in the examination, no more than 
0.25 diopters of minus should be added without an increase in the number of 
letters read correctly.  The additional minus lens should not be added if the subject 
reads fewer letters but states that the acuity is better.  There is a general attempt in 
this refraction protocol to avoid “over-minusing” the subjects. However, when 
plus cylinders are in the refraction, one must be careful not to unnecessarily 
withhold minus which may be necessary for the subject to accept the needed plus 
cylinders later in the refraction.  Minus spherical power is added in –0.25 diopter 
increments until the subject shows no further improvement in vision.  If minus 
power is added, a +0.50 sphere is tried again to determine if more plus will be 
accepted. 
 If the subject says the vision is “no different” or “worse”, no minus power should 
be added, and the spherical determinations are completed.
Determination of Cylindrical Refraction 
For purposes of this discussion only plus cylinder techniques are presented. 
Cylinder axis determination
If the approximate refraction contains a cylinder correction, changes in cylindrical axis are 
tested by adding a 0.25, 0.37, or 0.50 diopter cross-cylinder, first with the positive axis 45 
degrees to one side of the cylinder axis, and then with positive axis 45 degrees to the opposite 
side of the cylinder axis.  Since neither position may produce a clear image, the subject is 
encouraged to select the position producing “less blur” while fixating on a single round letter 
on the line above the lowest line on the chart he or she is able to read when the cross-cylinder 
is not held up before the trial frame.  If the subject cannot choose between the two positions 
of the cross cylinder at the beginning of this test, the axis of the cylinder is moved 5 to 15 


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degrees, first in one direction and then in the other, with the cross-cylinder being checked in 
each position to confirm that the original axis was indeed correct.  If the subject prefers one 
position of the cross-cylinder to the other and the cylinder in the trial frame is plus the axis of 
the cylinder is moved 5 to 15 degrees toward the positive axis of the cross-cylinder when it is 
in the position found to be less. 
(When the power of the cylinder is low or if the subject’s discrimination is poor; larger shifts 
will produce more clear-cut answers.) The cross-cylinder is tried again with the positive axis 
45 degrees first to one side and then to the opposite side of the new cylinder axis to determine 
which position is producing less blur. 
If the subject finds one position less blurry, the axis of the plus cylinder is moved toward the 
positive axis of the cross-cylinder. Testing for change of axis is repeated until the subject 
finds neither position better than the other. 
 
Cylinder Power determination
Change in cylinder power is tested by adding the cross-cylinder, first with the positive axis 
and then with the negative axis coincident with the cylinder axis.  For this test, the subject is 
requested to focus attention on a round letter on the lowest line on the chart he or she is able 
to read.  If the subject prefers the position axis coincident with the cylinder axis, the power of 
the correcting plus cylinder is increased by an additional +0.25 diopter.  If the subject prefers 
the negative axis coincident with the cylinder axis, the total power of the correcting plus 
cylinder is reduced by 0.25 diopter.  The process is repeated until the subject finds neither 
position definitely better than the other.  As plus cylinders are added, the examiner should 
recognize that the spherical equivalent of the refraction is being changed.  More minus 
spheres may be needed as plus cylinders are added. When using plus cylinders for every 0.50 
diopter of cylinder power added, the sphere should be changed by –0.25 diopter.  If, at any 
time, the preference with the cross-cylinder indicates that cylinder power should be removed 
entirely, the 0.25 cylinder should be rotated 90 degrees from its original position.  The axis 
should be refined, and the power should be tested again. If the beginning refraction is a 
“pure” sphere, the presence of astigmatism is tested by arbitrarily placing a +0.25 cylinder at 
180 degrees in the trial frame, after having determined the highest-plus or least-minus sphere 
producing minimal blurring of vision, as described above.  The refraction is then continued by 
using the cross-cylinder to test for cylinder axis and then cylinder power using the cross-
cylinder technique outlined above.  If, at any time, the preference with the cross-cylinder 
indicates that cylinder power should be removed entirely, the 0.25 cylinder should be rotated 
90 degrees from its original position and the power should be tested again.  At this point, if 
the subject prefers additional power, it should be added. If, on the other hand the subject 
prefers to remove the +0.25, it should be removed and the final refraction is then purely 
spherical. An example of this procedure follows:


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Beginning refraction: -2.50 + 0.25 axis 37 degrees.  Use of the cross-cylinder to check 
cylinder axis indicates that the subject prefers the 37-degree axis.  If, upon using the cross-
cylinder to check cylinder power, the subject wants the 0.25 cylinder removed, rotate the 
cylinder to 127 degrees and test for cylinder power again. If additional power is preferred, add 
it. 
If the preference with the cylinder at 127 degrees is to remove the 0.25 cylinder, this should 
be done, and the resulting refraction is 2.50. 
Minus cylinders may be used instead of plus cylinders to determine the best correction for the 
cylinder power and axis. If minus cylinders are used, the above procedure must be revised to 
reflect the change in sign (+ or -). 
When using minus cylinder correcting lenses, the preferred orientation of the cross cylinder is 
determined in the same way as when using plus cylinder lenses.  When determining cylinder 
axis however, the correcting minus cylinder axis is rotated toward the minus cylinder axis of 
the cross cylinder (not the cylinder axis as it is when a plus cylinder correcting lens is used).  
When determining cylinder power, the correcting minus cylinder power is increased when, in 
the preferred orientation, the minus axis of the cross cylinder coincides with the minus 
cylinder axis of the correcting lens. 
Refining Final of Spherical Power 
When neither the power nor the axis of the cylinder can be improved, the power of the sphere 
is refined by testing with +0.25 sphere and –0.37 sphere and changing the spherical power 
(see below). If the sphere is changed at this point, the cylinder should be rechecked. This 
process is repeated until no further significant lens changes are made.
This refraction protocol can be summarized as follows: First, having eliminated any possible 
accommodation with plus spheres, the best spherical equivalent power is found, which places 
the circle of least confusion on the retina. Then the cylinder power and cylinder axis are 
assessed. This process of checking sphere, cylinder axis, and cylinder power is repeated until 
there are no changes that result in an increased number of letters being read. Ideally, at the 
end of the refraction, the sphere is checked and the subject neither tolerates increased plus nor 
improves with increased minus spheres. Then the axis is checked and no change in axis is 
indicated. Finally, the cylindrical power is checked and no change in this is indicated. At this 
point, the refraction is completed. Sometimes this endpoint cannot be reached because there is 
an unending number of small corrections at each repetition of the process. When it becomes 
clear that these small changes are not resulting in an increased number of letters read 
correctly, the examiner may terminate the refraction.
The lens corrections obtained in this way for the right eye are recorded on the BCdVA 
Assessment Form as the corrections obtained by subjective refraction for the right eye. The 


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entire process is repeated for the left eye, and these lens corrections are recorded on the 
BCdVA Assessment Form as the corrections obtained by subjective refraction for the left eye.
Refraction for Subjects with Poor Visual Acuity 
If it is not possible to perform a subjective refraction at 4 meters because visual acuity is too 
poor and the patient reads less than 20 letters correct on the refraction chart at this distance, 
the refraction should be attempted at 1 meter. If the subjective refraction can be performed 
successfully at 1 meter, a +0.75 sphere should be subtracted from the results of the 1- meter 
refraction to make the correction appropriate for the 4-meter distance. This correction should 
be entered on the BCdVA Assessment Form in the space provided for distance subjective 
refraction. (NOTE: Visual acuity will be tested first at the 4-meter distance even if the subject 
cannot be refracted at this distance. If the patient reads less than 20 letters correctly at 4 
meters, visual acuity must also be tested at 1 meter, in which case the +0.75 sphere should be 
added to the 4-meter refraction.) 
Testing Best Corrected Visual Acuity 
4-Meter Test
Testing of all eyes begins at 4 meters. First, the right eye is tested with Chart 1 and then the 
left eye is tested with Chart 2.  Each Chart should remain hidden from view until the eye in 
question is ready for testing.  For the binocular BCDVA testing the Chart 1 should be used.
The distance from the subject’s eyes to the visual acuity chart must be exactly 4 meters (13 
feet and 1 ½ inches, or 157.5 inches).  The subject must sit for the 4-meter visual acuity test. 
As indicated previously, the subject should be seated comfortably with his or her back firmly 
placed against the back of the chair.  The examiner should ensure that the subject is seated 
comfortably, that the head does not move forward or backward during the test, and that the 
subject’s eyes remain at the 4- meter distance.
The testing procedure for visual acuity is based on the principle that the objective is to test 
visual acuity and not intelligence or the ability to concentrate or follow or remember 
instructions (although all of these factors are involved).  The subject should be told that the 
chart has five letters in each line, and has letters only and no numbers.  If the subject forgets 
this instruction and reads a number, he or she should be reminded that the chart contains no 
numbers and the examiner should request a letter in lieu of the number. 
The subject should be asked to read slowly (at a rate not faster than about one letter per 
second) to achieve the best identification of each letter and to not proceed until they have 
given a definite response.  It may be useful for the examiner to demonstrate the letter-a-
second place by reciting “A, B, C,…”.  If, at any point, the subject reads too quickly, he or 
she should be asked to stop and read slowly.  If the subject loses his or her place in reading or 
the examiner loses his or her place (possibly because the letters are read too quickly), the 


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examiner should ask the subject to go back to where the place was lost.  Examiners should 
never point to the chart or to specific letters on the chart or read any of the letters during the 
test; instead, a sheet of white paper may be used to guide the subject to the proper location on 
the chart.  Each letter is scored as right or wrong (see below).  Once a subject has identified a 
letter with a definite single-letter response and has read the next letter, a correction of the 
previous letter cannot be accepted.  If the subject changes a response aloud (e.g., That was a 
“C”, not an “O”) before he or she has read aloud the next letter then the change should be 
accepted.  If the subject changes a response after beginning to read the next letter, the change 
is not accepted.
When the subject says he or she cannot read a letter, he or she should be encouraged to guess. 
If the subject identifies a letter as one of two or more letters, he or she should be asked to 
choose one letter and if necessary, to guess even if the next letter has already been read. The 
examiner may suggest that the subject turn his or her head or eye in any manner if this 
improves visual acuity.  If the subject does this, care must be taken to ensure that the fellow 
eye remains covered.  If testing the right eye, the left eye must be occluded by lightly 
patching with an eye pad or a folded tissue with tape.  The subject should be encouraged to 
read as many letters as possible. 
There are several reasons for encouraging subjects to guess:
 Subject’s statements that they cannot identify a letter are often unreliable.
 Encouraging them to guess helps to maximize the subject’s effort. 
 It helps to assure uniformity among procedures performed in different clinics.
 It may help to prevent subject bias (malingering).
1-Meter Test 
At 4 meters, if less than 20 letters on the chart are read correctly then visual acuity must also 
be tested at 1 meter.  If the trial frame is to be removed when changing the test distance from 
4 meters to 1 meter, the testing chart (Chart 1 and 2) should first be removed from view to 
prevent the subject from reading the chart with the fellow eye.
Before testing at 1 meter, a +0.75 sphere should be added to the 4-meter correction already in 
the trial frame to compensate for the closer testing distance. (As previously indicated, the 
subject should be seated comfortably with his or her back firmly placed against the back of 
the chair).  The distance of 1 meter should be confirmed with a rigid measuring device. The 
avoidance of any head movement forward or backward is particularly important during the 1-
meter test.  The subject should be asked to read only the first six lines at 1 meter, making 30 
the maximum score attainable at that distance. 
After the test of the right eye is completed, switch the occlusion from the left to the right eye 
and replace Chart 1 by Chart 2.  The test is repeated for the left eye, starting at 4 meters.  


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When testing of the left eye is completed Chart 2 should be removed from view.  Once each 
eye, right eye and left eye, have been tested, then Chart 1 should be mounted again and, after 
giving a patient a rest of few minutes, then binocular vision with this Chart 1 should be 
undertaken.
Scoring Best-Corrected Visual Acuity
On the BCDVA Assessment Form, the total number of letters read correctly in each row of 
letters should be written down.  Visual acuity will be measured once for each eye, using Chart 
1 for the right eye, Chart 2 for the left eye, and Chart 1 for binocular vision testing.  After 
each measurement of visual acuity, the visual score for the visit is calculated. The visual 
acuity score is defined as follows:
 If 20 or more letters are read correctly at the 4-meter test distance, the visual 
acuity score is equal to the numbers of letters read correctly at 4 meters, plus 30; 
or 
 If less than 20 letters are read correctly at the 4-meter test distance, the visual 
acuity score is equal to the number of letters read correctly at 1 meter plus the 
number at 4 meters: or 
 If no letters are read correctly at either the 4-meter distance or the 1-meter 
distance, the visual acuity score is 0. 
Count Fingers Visual Acuity 
If visual acuity is so poor that the subject cannot read any of the largest letters at 1 meter (i.e. 
number of letters read correctly at 1 meter is zero), count fingers vision (CF), the examiner’s 
hand holding 1, 2, or 5 fingers is held steady at a distance of two feet directly in front of the 
eye being examined.  If testing the right eye, the left eye must be occluded by lightly patching 
with an eye pad or a folded tissue with tape.  A light should be shone directly on the hand 
from behind the patient.  The examiner’s fingers should be presented in random order and 
repeated 5 times.  Eccentric fixation, if present, should be encouraged.  If the subject correctly 
identifies three of the five presentations, then count fingers (CF) is noted as “yes.”  If not, the 
subject should be tested for hand motion vision.
Hand Motion Visual Acuity 
The examiner’s hand with all fingers spread out should be extended two feet directly in front 
of the eye being examined.  The fellow eye should be occluded.  If testing the right eye, the 
left eye must be occluded by lightly patching with an eye pad or a folded tissue with tape. A 
light should be shone directly on the hand from behind the subject.  The examiner’s hand 
should be moved in an up and down direction (vertically) or in a side-to-side direction 
(horizontally) at a constant speed of approximately one back and forth presentation per 


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second. The subject is instructed that the examiner’s hand will be presented, and they will 
have to respond to the question: “What am I doing with my hand?”  This should be repeated 
five times. Four out of five correct responses indicate that hand motion vision is present.  If 
the subject does not correctly identify four of five, then light perception must be tested. 
Light Perception and No Light Perception
Light perception should be tested with an indirect ophthalmoscope in a darkened room.  The 
fellow eye should be well occluded, ideally with a taped tissue behind the trial frame as well 
as the occlude lens in the trial frame.  The indirect ophthalmoscope light should be in focus at 
3 feet with the rheostat set at maximum voltage.  From a distance of 3 feet, the beam should 
be directed in and out of the eye being examined at least four times, and the subject should be 
asked to respond when he or she sees the light.  If the examiner is convinced that the subject 
perceives the light, vision should be recorded as “light perception”; if not, vision should be 
recorded as “no light perception.” 
When examiners conclude that the final visual acuity score is totally unreliable because of the 
subject’s decreased mental ability, the visual acuity score must still be entered on the 
appropriate form. 
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 subject broke his/her glasses), the reason for the change in 
correction should be documented. 
from Visit 1 should be evaluated by the Investigator as a potential AE. 
Slit Lamp Bio microscopy  
Slit lamp bio microscopy will be performed during the study. Observations will be graded as 
Normal or Abnormal. Abnormal findings, which are clinically significant, will be described.  
Cornea Photography 
Details instructions will be provided in the photography manual.
Corneal Fluorescein Staining  
The examiner should instill 5 
-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 


OC-01 (varenicline) Nasal Spray
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Clinical Trial Protocol # OPP-102 
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Amendment No. 7 
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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 subject will be instructed to blink naturally several times without forced closure of the 
eyelid to distribute the fluorescein. 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 modified Oxford Grading Scale.
Modified Oxford Grading Scale 
The examiner compares the overall appearance of the patient's corneal staining with the 
reference figure (below) and selects the appropriate grade that best represents the state of 
corneal staining. 
For subjects that progress to Stage 2, graders will assess the following: 
 Lesion size
 Is any residual staining present (Yes/No)? 
 If residual staining is present, is the staining persistent (Yes/No)?


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Corneal Sensitivity
Cochet-Bonnet Aesthesiometer
Corneal sensation is measured in the affected eye of the patient at all applicable visits using a 
Cochet Bonnet aesthesiometer. The measurements taken from the affected eye are as follows:
Sensitivity in each of the 4 quadrants of the cornea:
 Superior nasal (cm) 
 Inferior nasal (cm) 
 Superior temporal (cm)
 Inferior temporal (cm) 
Steps for using the handheld aesthesiometer: 
Note: Cochet Bonnet aesthesiometer measurements MUST be performed prior to 
administration of Topical Anesthesia 
 Sterilize the filament, by wiping only the tip with an alcohol pad, do not wipe the 
entire length of the filament or pull on the filament. 
 Extend the filament to full length of 6 cm. 
 Perform sensitivity in each of the 4 quadrants of the cornea: 
 Superior nasal (cm) 
 Inferior nasal (cm) 
Superior temporal (cm)
Inferior temporal (cm)
Retract the filament incrementally in 0.5 cm steps until the patient can feel its 
contact.
Record the length (NOTE: The shorter the length indicates decreased sensation.)
Compare the fellow eye cornea.
Repeat steps 1-4 in each quadrant: superior nasal, inferior nasal, superior temporal, 
and inferior nasal.
Sterilize the filament tip by gently wiping with an alcohol pad and retract back 
into the device to protect it from damage.


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For Stage 1 subjects, corneal sensitivity is defined as the mean of the 4 quadrants (four 
measurements) 
 
Intranasal Examination 
Qualified subjects 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 subject safety, an 
examination of the nasal cavities via an intranasal exam will be performed at Visit 1 (after all 
other screening procedures have been completed). This examination will be performed by an 
Ear Nose and Throat (ENT) specialist, otolaryngologist or other suitably qualified medical 
practitioner (i.e. one who has been trained to perform intranasal exam). Still images or video 
may be captured. The procedure used for the intranasal exam can be conducted either by 
endoscopic examination or nasal specula.
Schirmer’s Test without Anesthesia  
1. Excess moisture in the inferior fornix is gently removed with a sponge spear. 
 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.  
 Under ambient light, the subject will be instructed to look forward and to blink 
normally during the test. The test should be performed in a room with no direct air 
or sunlight on the subject’s face.
The Schirmer’s strips should remain in place until five minutes have elapsed or 
both strips have reached maximum score.
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 source document. 
Schirmer’s Test with Topical Anesthesia  
The Schirmer’s test will be performed concurrent with the study drug/placebo nasal spray 
treatment be used to assess tear production using the following steps:  
1. 
should be instilled in both eyes of the subject.
 The subject will be instructed to keep the eyes gently closed for one minute.   


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Clinical Trial Protocol # OPP-102 
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 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 
sponge spear.
 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.  
 Under ambient light, the subject will be instructed to look forward and to blink 
normally during the test. The test should be performed in a room with no direct air 
or sunlight on the subject’s face. 
 The Schirmer’s strips should remain in place until five minutes have elapsed or 
both strips have reached maximum score. 
 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.   


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PAIN VISUAL ANALOG SCALE (VAS)
 
 
 
 


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NATIONAL EYE INSTITUTE
Visual Functioning Questionnaire - 25 
(NEI-VFQ-25)2 
Version 2000
(SELF-ADMINISTERED FORMAT)
January 2000 
The following is a survey with statements about problems which involve your vision or 
feelings that you have about your vision condition.  After each question, please choose the 
response that best describes your situation. 
Please answer all the questions as if you were wearing your glasses or contact lenses (if any).
Please take as much time as you need to answer each question.  All your answers are 
confidential.  In order for this survey to improve our knowledge
about vision problems and how they affect your quality of life, your answers must be as 
accurate as possible.  Remember, if you wear glasses or contact lenses, please answer all of 
the following questions as though you were wearing them.
 
INSTRUCTIONS:
2. In general we would like to have people try to complete these forms on their own. If 
you find that you need assistance, please feel free to ask the project staff and they will 
assist you.
 
2 NEI-VFQ-25 is reproduced here (in part or in its entirety) with permission from the RAND Corporation. 
Copyright © the RAND Corporation. RAND's permission to reproduce the survey is not an endorsement of the 
products, services, or other uses in which the survey appears or is applied. 


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3. Please answer every question (unless you are asked to skip questions because they 
don’t apply to you). 
4. Answer the questions by circling the appropriate number. 
5. If you are unsure of how to answer a question, please give the best answer you can 
and make a comment in the left margin.
6. Please complete the questionnaire before leaving the center and give it to a member of 
the project staff.  Do not take it home. 
7. If you have any questions, please feel free to ask a member of the project staff, and 
they will be glad to help you.
STATEMENT OF CONFIDENTIALITY:
All information that would permit identification of any person who completed this 
questionnaire will be regarded as strictly confidential.  Such information will be used only for 
the purposes of this study and will not be disclosed or released for any other purposes without 
prior consent, except as required by law
 
 


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Clinical Trial Protocol # OPP-102 
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Visual Functioning Questionnaire - 25 
PART 1 - GENERAL HEALTH AND VISION
1.    In general, would you say your overall health is:
(Circle One)
Excellent............................... 1
Very Good ............................ 2
Good ...................................... 3
Fair ......................................... 4
Poor........................................ 5
2.
At the present time, would you say your eyesight using both eyes (with 
glasses or contact lenses, if you wear them)  is excellent, good, fair, 
poor, or very poor or are you completely blind?
(Circle One)
Excellent............................... 1
Good ...................................... 2
Fair ......................................... 3
Poor........................................ 4
Very Poor.............................. 5
Completely Blind ................ 6


OC-01 (varenicline) Nasal Spray
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3.    How much of the time do you worry about your eyesight?
(Circle One)
None of the time ............................. 1
A little of the time........................... 2
Some of the time ............................ 3
Most of the time.............................. 4
All of the time?................................ 5
4.    How much pain or discomfort have you had in and around your eyes
(for example, burning, itching, or aching)?  Would you say it is:
(Circle One)
None....................................... 1
Mild......................................... 2
Moderate............................... 3
Severe, or ............................. 4
Very severe?........................ 5
PART 2 - DIFFICULTY WITH ACTIVITIES 
The next questions are about how much difficulty, if any, you have doing 
certain activities wearing your glasses or contact lenses if you use them for 
that activity.
5.
How much difficulty do you have reading ordinary print in 
newspapers? Would you say you have:
(Circle One) 
No difficulty at all .........................................................  1 
A little difficulty.............................................................  2 
Moderate difficulty .......................................................  3 
Extreme difficulty .........................................................  4 
Stopped doing this because of your eyesight .....  5


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Clinical Trial Protocol # OPP-102 
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Stopped doing this for other reasons or not 
interested in doing this........................................... 6
6.
How much difficulty do you have doing work or hobbies that require 
you to see well up close, such as cooking, sewing, fixing things 
around the house, or using hand tools? Would you say:
(Circle One)
No difficulty at all .........................................................  1 
A little difficulty.............................................................  2 
Moderate difficulty .......................................................  3 
Extreme difficulty .........................................................  4 
Stopped doing this because of your eyesight .....  5
Stopped doing this for other reasons or not 
interested in doing this........................................... 6
7.
Because of your eyesight, how much difficulty do you have finding
something on a crowded shelf?
(Circle One) 
No difficulty at all .........................................................  1 
A little difficulty.............................................................  2 
Moderate difficulty .......................................................  3 
Extreme difficulty .........................................................  4 
Stopped doing this because of your eyesight .....  5
Stopped doing this for other reasons or not 
interested in doing this........................................... 6
8.
How much difficulty do you have reading street signs or the names of
stores? 
(Circle One) 
No difficulty at all .........................................................  1 
A little difficulty.............................................................  2 
Moderate difficulty .......................................................  3 


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Extreme difficulty.........................................................  4
Stopped doing this because of your eyesight .....  5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
9.
Because of your eyesight, how much difficulty do you have going
down steps, stairs, or curbs in dim light or at night? 
(Circle One)
No difficulty at all .........................................................  1
A little difficulty.............................................................  2
Moderate difficulty.......................................................  3
Extreme difficulty .........................................................  4 
Stopped doing this because of your eyesight .....  5
Stopped doing this for other reasons or not 
interested in doing this........................................... 6
10. Because of your eyesight, how much difficulty do you have noticing 
objects off to the side while you are walking along? 
(Circle One) 
No difficulty at all .........................................................  1 
A little difficulty.............................................................  2 
Moderate difficulty .......................................................  3 
Extreme difficulty .........................................................  4 
Stopped doing this because of your eyesight .....  5
Stopped doing this for other reasons or not 
interested in doing this........................................... 6
11. Because of your eyesight, how much difficulty do you have seeing
how people react to things you say? 
(Circle One) 
No difficulty at all .........................................................  1 


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A little difficulty.............................................................  2 
Moderate difficulty .......................................................  3 
Extreme difficulty .........................................................  4 
Stopped doing this because of your eyesight .....  5 
Stopped doing this for other reasons or not 
interested in doing this ........................................... 6 
12. Because of your eyesight, how much difficulty do you have picking out 
and matching your own clothes?
(Circle One)
No difficulty at all .........................................................  1 
A little difficulty.............................................................  2
Moderate difficulty .......................................................  3 
Extreme difficulty .........................................................  4 
Stopped doing this because of your eyesight .....  5 
Stopped doing this for other reasons or not 
interested in doing this ...........................................6 
13. Because of your eyesight, how much difficulty do you have visiting 
with people in their homes, at parties, or in restaurants ? 
(Circle One) 
No difficulty at all .........................................................  1 
A little difficulty.............................................................  2 
Moderate difficulty.......................................................  3
Extreme difficulty.........................................................  4
Stopped doing this because of your eyesight .....  5
Stopped doing this for other reasons or not 
interested in doing this ...........................................6 
14. Because of your eyesight, how much difficulty do you have going out
to see movies, plays, or sports events?
(Circle One) 


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No difficulty at all .........................................................  1 
A little difficulty.............................................................  2 
Moderate difficulty .......................................................  3 
Extreme difficulty .........................................................  4 
Stopped doing this because of your eyesight .....  5 
Stopped doing this for other reasons or not 
interested in doing this ..........................................6 
15.  Are you currently driving, at least once in a while?
(Circle One) 
Yes........................ 1 Skip To Q 15c 
No .........................  2 
15a.
IF NO: Have you never driven a car or have you given up 
driving?
(Circle One) 
 
Never drove........  1  Skip To Part 3, Q 17 
Gave up...............  2 
15b.
IF YOU GAVE UP DRIVING:  Was that mainly because of your eyesight, 
mainly for some other reason, or because of both your eyesight and 
other reasons? 
(Circle One) 
Mainly eyesight..................................... 1 
 
Skip To Part 3, Q 17
Mainly other reasons........................... 2
Skip To Part 3, Q 17
Both eyesight and other reasons .... 3
Skip To Part 3, Q 17


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No difficulty at all ................................. 1
A little difficulty..................................... 2
Moderate difficulty............................... 3
Extreme difficulty................................. 4
15c.
IF CURRENTLY DRIVING:  How much difficulty do you have driving 
during the daytime in familiar places?  Would you say you have:
(Circle One) 
16. How much difficulty do you have driving at night?  Would you say you 
have: 
(Circle One)
No difficulty at all .......................................  1 
A little difficulty...........................................  2 
Moderate difficulty .....................................  3 
Extreme difficulty .......................................  4 
Have you stopped doing this because 
of your eyesight ....................................  5 
Have you stopped doing this for other 
reasons or are you not interested in 
doing this................................................  6
16A.How much difficulty do you have driving in difficult conditions, such as 
in bad weather, during rush hour, on the freeway, or in city traffic? 
Would you say you have:
(Circle One)
No difficulty at all .......................................  1 
A little difficulty...........................................  2 
Moderate difficulty .....................................  3 
Extreme difficulty .......................................  4 
Have you stopped doing this because 
of your eyesight ....................................  5 


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Have you stopped doing this for other 
reasons or are you not interested in 
doing this ................................................  6 
 
PART 3: RESPONSES TO VISION PROBLEMS 
The next questions are about how things you do may be affected by your
vision. For each one, please circle the number to indicate whether for 
you the statement is true for you all, most, some, a little, or none of the
time.
(Circle One On Each Line) 
 
READ CATEGORIES:
All of
the
time
Most of
the 
time
Some
of the 
time 
A little
of the 
time 
None of
the
time 
17. Do you accomplish less 
than you would like 
because of your vision? 
 
1 
2 
3 
 
4 
5 
18. Are you limited in how 
long you can work or do 
other activities because of 
 
 
1 
2 
3 
 
 
4 
5 
your vision?....................... 
 
 
19. How much does pain or
discomfort in or around
your eyes, for example,
burning, itching, or
aching, keep you from
doing what you’d like to
be doing? Would you say:
 
 
 
 
1 
2 
3 
 
 
 
 
4 
5 


OC-01 (varenicline) Nasal Spray
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Clinical Trial Protocol # OPP-102 
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Amendment No. 7 
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71 
 
 
 
 
For each of the following statements, please circle the number to indicate 
whether for you the statement is definitely true, mostly true, mostly false, 
or definitely false for you or you are not sure.
(Circle One On Each Line)
Definitely
Mostly
Not
Mostly
Definitely
True
True
Sure
False
False
20. I stay home most of the time
because of my eyesight. ....
1
 
2
3
4
 
5
21. I feel frustrated a lot of the 
time because of my 
eyesight. ................................. 
1
 
 
2
3
4
 
 
5
 
22. 
 
I have much less control
over what I do, because of 
my eyesight. ..........................
1
 
 
2
3
4
 
 
5
 
23. 
 
Because of my eyesight, I 
have to rely too much on 
what other people tell me... 
1
 
 
2
3
4
 
 
5
 
24. 
 
I need a lot of help from 
others because of my 
eyesight. ................................. 
1
 
 
2
3
4
 
 
5
25. I worry about doing things
that will embarrass myself 
or others, because of my 
eyesight. ................................. 
1
 
 
 
2
3
4
 
 
 
5


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APPENDIX 3: SPONSOR APPROVALS
Protocol Title:
A Phase 2, Multicenter, Randomized, Controlled, Double-Masked, 
Clinical Trial to Evaluate the Efficacy and Safety of OC-01 
(Varenicline) Nasal Spray in Subjects with Neurotrophic Keratopathy 
(the Olympia Study) 
Protocol Number: 
OPP-102 


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APPENDIX 4:  
INVESTIGATOR’S SIGNATURE  
 
Protocol Title:
A Phase 2, Multicenter, Randomized, Controlled, Double-Masked, 
Clinical Trial to Evaluate the Efficacy and Safety of OC-01 
(varenicline) Nasal Spray in Subjects with Neurotrophic Keratopathy
(the Olympia Study)
Protocol Number:
OPP-102
 
 
I agree to implement and conduct the study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. I agree to maintain all 
information supplied by the Sponsor in confidence and, when this information is submitted to an 
Institutional Review Board (IRB) or another group, it will be submitted with a designation that 
the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all aspects.
 
 
Signed: ____________________________ 
Date: _____________________________ 
 
Name: _____________________________ 
 
 
Title: ______________________________
Site: _______________________________ 
 
 
Address: ____________________________ 
 
 
Phone Number: _______________________