Open-Label, Single-Center, Randomized, 2-way Crossover Study Evaluating Relative Bioavailability of OC-01 (Varenicline) Nasal Spray as Compared to Orally Administered Varenicline (the Zen Study)
Phase: PHASE1
Conditions: Healthy Subjects
Sponsor: Oyster Point Pharma, Inc.

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Clinical Trial Protocol 
 
 
 
 
Protocol Title: 
An Open-Label, Single-Center, Randomized, 2-way 
Crossover Study to Evaluate the Relative Bioavailability 
of Varenicline Administered as OC-01 Nasal Spray as 
Compared to Varenicline Administered Orally as 
Chantix® (The ZEN Study) 
Protocol Number: 
OPP-100 
Study Phase: 
1 
Product Name: 
OC-01 (varenicline) Nasal Spray and Chantix® 
 
 
Indication: 
Healthy Volunteers 
Investigators: 
Single-Center 
Sponsor: 
Oyster Point Pharma, Inc. 
700 Alexander Park Drive 
Suite 301 
Princeton, NJ 08540 
 
 
Date 
Original Protocol: 
06 June 2019 
  
Amendment #1 
   28 June 2019 
 
Amendment #2 
   13 July 2019 
 
 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Oyster Point Pharma, Inc. Further 
dissemination, distribution or copying of this protocol or its contents is strictly prohibited. 

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SYNOPSIS 
Protocol Title: 
An Open-Label, Single-Center, Randomized, 2-way Crossover Study to 
Evaluate the Relative Bioavailability of Varenicline Administered as OC-01 
Nasal Spray as Compared to Varenicline Administered Orally as Chantix® 
Protocol Number: 
OPP-100 
Investigational Product: 
OC-01 (varenicline) Nasal Spray  
Study Objectives: 
Primary Objective: To assess the relative bioavailability of varenicline 
administered intranasally at its highest intended clinical strength 
compared to varenicline administered orally at its highest oral tablet 
strength. 
Secondary Objective: To assess the clinical and laboratory safety of 
varenicline administered as a single dose orally and intranasally. 
Overall Study Design 
Structure: 
This is an open label, single dose, randomized, 2-way crossover study. 
Subjects will attend the unit for a screening assessment up to 28 days 
prior to the first dose. 
Subjects who are eligible for the study will return to the unit for 2 in-unit 
treatment periods, each separated by a minimum of 14 days.  
An End of Study visit will occur 7-14 days after the final dose.  
The two study treatments are: 
• 
Single oral dose of 1 mg varenicline (Chantix®). 
• 
Intranasal dose of 0.12 mg OC-01 (varenicline)- delivered as a 
50 µL (0.06 mg) spray into each nostril 
Treatment Period 1: Subjects will be admitted and will be randomly 
assigned to receive a single dose of varenicline either orally or 
intranasally. The administration dose will be delivered after an overnight 
fast by the subject. 
PK samples will be collected pre-dose and in an intensive sampling 
regimen up to 120 hours post-dose to allow for the assay of varenicline.  
Treatment Period 2: This period will be identical to Treatment Period 
1 except that the administration of varenicline will be via the intranasal 

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route for those subjects that previously received varenicline via the oral 
route. Those subjects that were previously administered oral varenicline 
during Treatment Period 1 will receive varenicline via the intranasal 
route. 
End of Study Visit will occur 7-14 days after the final period’s dose of 
varenicline when follow-up assessments will be performed. 
Duration: 
10 study visits over a period of approximately 60 days:  
Screening: Day -28 to -2 
Period 1: Day 1-3 (In-Unit Subjects will be confined in the Clinical 
Research Unit (CRU) from the morning of Day -1 until at least 48 
hours post-dose (Day 3)); Day 4-6 (Out-Patient) 
Period 2: Day 15-17 (In-Unit Subjects will be confined in the Clinical 
Research Unit (CRU) from the morning of Day 14 until at least 48 
hours post-dose (Day 17)); Day 18-20 (Out-Patient) 
End of Study: Day 27 + 7 
Control: 
N/A 
Dosing Regimen: 
Treatment A: Single oral dose of 1 mg of Chantix® (varenicline) 
administered orally 
Treatment B: Intranasal dose of 0.12 mg OC-01 (varenicline)- delivered 
as a 50 µL (0.06 mg) spray into each nostril 
 
Collection Schedule: 
Treatment Period 1 and Treatment Period 2: 
All times are after study drug administration except for predose (time 0) 
In-Unit Blood PK Sampling  
Sample 1: Predose (time 0)  
Sample 2: 5 minutes  
Sample 3: 15 minutes  
Sample 4: 30 minutes  
Sample 5: 1 hour 
Sample 6: 2 hours 

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measures, safety parameters, and/or the general medical 
condition of the subject. 
 
 
 
 
 
 
 
 
 
 
12. Be a female who is pregnant, nursing an infant, or planning a 
pregnancy at the Screening Visit. Be a woman of childbearing 
potential who is not using 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. 
13. Be currently enrolled in an investigational drug or device study 
or have used an investigational drug or device within 30 days or 
90 for investigational biologics prior to the Screening Visit.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Evaluation Criteria 
Pharmacokinetic 
Endpoints: 
Varenicline plasma AUC0-∞,  AUC0-t, Cmax, Tmax, T½, Kel 
Safety Measures: 
Adverse events, clinical chemistry, hematology and urinalysis, vital 
signs assessments, physical examinations, ECGs and intranasal 
examinations. 
Statistical Methods:  
Pharmacokinetics  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
SYNOPSIS… ...................................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF ABBREVIATIONS ........................................................................................................13 
1. 
INTRODUCTION ......................................................................................................15 
2. 
STUDY OBJECTIVES ..............................................................................................15 
3. 
CLINICAL HYPOTHESES .......................................................................................16 
4. 
OVERALL STUDY DESIGN ....................................................................................16 
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 ....................................................................................................18 
6. 
STUDY PARAMETERS ............................................................................................18 
6.1. 
Pharmacokinetic Parameters .......................................................................................18 
6.2. 
Safety Measures ..........................................................................................................19 
7. 
STUDY MATERIALS ...............................................................................................19 
7.1. 
Drug Supply ................................................................................................................19 
7.2. 
Other Study Supplies ..................................................................................................19 
8. 
STUDY METHODS AND PROCEDURES ..............................................................20 
8.1. 
Participant Entry Procedures ......................................................................................20 
8.2. 
Concomitant Therapies ...............................................................................................20 
8.3. 
Examination Procedures .............................................................................................21 
8.4. 
Pharmacokinetic Sampling Schedule .........................................................................23 
8.5. 
Schedule of Visits, Measurements and Dosing ..........................................................24 
8.6. 
Compliance with Protocol ..........................................................................................24 
8.7. 
Subject Disposition .....................................................................................................25 
8.8. 
Study Termination ......................................................................................................25 
8.9. 
Study Duration ............................................................................................................25 
8.10. 
Monitoring and Quality Assurance .............................................................................26 

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9. 
SAFETY DEFINITIONS, SAFETY MONITORING AND REPORTING ..............26 
9.1. 
Adverse Event .............................................................................................................26 
9.2. 
Serious Adverse Events ..............................................................................................28 
9.3. 
Procedures for Reporting Adverse Events ..................................................................29 
9.4. 
Type and Duration of the Follow-up of Subjects after Adverse Events .....................29 
10. 
STATISTICAL ANALYSIS ......................................................................................30 
10.1. 
Sample Size and Power Considerations ......................................................................30 
10.2. 
Analysis Populations ..................................................................................................30 
10.3. 
Statistical Hypotheses .................................................................................................30 
10.4. 
Statistical Analysis ......................................................................................................30 
11. 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES......................................32 
11.1. 
Protection of Human Subjects ....................................................................................32 
11.2. 
Ethical Conduct of Study ............................................................................................33 
11.3. 
Subject Confidentiality ...............................................................................................33 
11.4. 
Documentation ............................................................................................................33 
11.5. 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ..................................................................................................................34 
11.6. 
Recording of Data .......................................................................................................35 
11.7. 
Handling of Biological Specimens .............................................................................35 
11.8. 
Publications .................................................................................................................35 
12. 
REFERENCES ...........................................................................................................36 
13. 
APPENDICES ............................................................................................................38 
APPENDIX 1. SCHEDULE OF VISITS AND MEASUREMENTS ........................................39 
APPENDIX 2. EXAMINATION PROCEDURES, TESTS, EQUIPMENT, AND 
TECHNIQUES ...........................................................................................................40 
A1. 
Intranasal Examination ...............................................................................................40 
A2. 
Laboratory Samples ....................................................................................................40 
A3. 
Physical Examination .................................................................................................40 
A4. 
Vital Signs ..................................................................................................................41 
A5. 
Electrocardiogram .......................................................................................................41 
APPENDIX 3. SPONSOR APPROVALS ..................................................................................42 

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APPENDIX 4. INVESTIGATOR’S SIGNATURE....................................................................43 
APPENDIX 5. 
 
 

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LIST OF ABBREVIATIONS 
Term 
Description 
AE 
adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BID 
two times a day 
BUN 
blood urea nitrogen 
CAE® 
controlled adverse environment 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration observed 
CRF 
case report form 
ECG 
electrocardiogram 
EDS 
eye dryness score 
EDTA 
ethylenediaminetetraacetic acid 
ENT 
ear nose and throat 
DED 
dry eye disease 
GGT 
gamma-glutamyl transferase  
HIPAA 
health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ID 
identification 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
intention to treat 
Kel 
elimination rate constant 
Kg 
kilograms 
logMAR 
logarithm of the minimum angle of resolution 
LS 
least square 
M2 
meter square 

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Term 
Description 
MAD 
mucosal atomization device 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
µL 
microliter 
mL 
milliliter 
mm 
millimeter 
nAChR 
nicotinic acetylcholine receptor 
PCSA 
potentially clinically significant abnormalities 
PK 
pharmacokinetic 
PP 
per protocol 
RBC 
red blood cell count 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SGOT 
serum glutamic oxalocaetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach the maximum concentration observed 
US 
United States 
WBC 
white blood cell count 
WHO 
World Health Organization 

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3. 
CLINICAL HYPOTHESES 
No formal hypothesis testing will be performed.  
4. 
OVERALL STUDY DESIGN 
Protocol OPP-100 is a Phase 1, open-label, randomized, 2-way crossover study to evaluate the 
relative bioavailability of OC-01 (varenicline) Nasal Spray compared to varenicline administered 
orally as Chantix®. Approximately 22 healthy volunteer subjects between 18-65 years of age 
meeting all other study eligibility criteria will be randomized (Treatment Period 1) to receive an 
intranasal dose of 0.12 mg OC-01 (50 µL spray of 0.06 mg into each nostril) or a single 1 mg oral 
dose of Chantix®. Both administrations will be delivered while subject is in an overnight fasted 
state. Subjects then will return at least 14 days later (Treatment Period 2) to receive the alternate 
dose of varenicline that was delivered at Treatment Period 1. Again, this delivery will be performed 
while subject is in an overnight fasted state.  
Participants who terminate early during the application period will be asked to complete safety 
assessments (if the participants agree) prior to study exit. Participants who are terminated early 
from the study will not be replaced. 
5. 
STUDY POPULATION 
5.1. 
Number of Subjects 
Approximately 22 healthy volunteer participants will be enrolled at one site in the US. Subjects 
who are eligible for the study will return to the unit for two in-unit treatment periods, each 
separated by at least 14 days. The two study treatments are: 
• Treatment A: Single oral dose of 1 mg varenicline (Chantix®) administered orally 
• Treatment B: Intranasal dose of 0.12 mg OC-01 (varenicline)- delivered as a 50 µL 
(0.06 mg) spray into each nostril 
5.2. 
Study Population Characteristics 
All subjects must be between 18-65 years of age, inclusive of either gender, and of any race, and 
must meet all inclusion criteria and none of the exclusion criteria. 
5.3. 
Inclusion Criteria 
Subjects must: 
 
. 

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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. 
13. Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 30 days or 90 for investigational biologics prior to 
the Screening Visit.  
 
 
 
 
 
 
 
 
 
 
 
 
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 should attend the final follow up 
visit for safety evaluation.   
Subjects may withdraw consent from the study at any time. 
Sponsor and/or Investigator may discontinue any subject from study treatment for non- compliance 
or any valid medical reason during the course of the study (see Section 8.7.2 Discontinued 
Subjects). 
6. 
STUDY PARAMETERS 
6.1. 
Pharmacokinetic Parameters 
The follow pharmacokinetic parameters will be calculated on the varenicline plasma levels: 
 
 
 
 
 
 

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8. 
STUDY METHODS AND PROCEDURES 
8.1. 
Participant Entry Procedures 
8.1.1. 
Overview  
Participants as defined by the criteria in Sections 5.2 , 5.3, and 5.4 will be considered for entry into 
this study. 
8.1.2. 
Informed Consent 
Prior to a participant’s enrollment in the trial (i.e., prior to any study-related procedures), the study 
will be discussed with each potential participant and participants wishing to participate must be 
administered and provide written informed consent using an Institutional Review Board (IRB)-
approved informed consent form (ICF). The ICF must be the most recent version that has received 
approval by a properly constituted IRB. 
8.1.3. 
Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the Exclusion Criteria 
(Section 5.4). 
8.1.4. 
Procedures for Final Study Entry 
Subjects must meet all inclusion criteria and none of the exclusion criteria. 
8.1.5. 
Methods for Assignment to Treatment Groups 
Each subject who enters the screening period for the study (defined as the point at which the subject 
signs the informed consent form (ICF) receives a unique subject identification number before any 
study-related activities/procedures are performed. This number will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical study.  
Subjects who meet the eligibility requirements will be randomly assigned to receive Treatment A 
or Treatment B during Treatment Period 1. For Treatment Period 2, subjects will receive the 
alternate treatment not received during Treatment Period 1.   
8.2. 
Concomitant Therapies 
 
 
 

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• Urinalysis 
• Intranasal Examination 
Period 1 Check-In (Day -1) 
• Serum pregnancy test (if applicable) 
• Drug and Alcohol Screen 
• Intranasal Examination 
• Concomitant Medications 
Period 1 (Day 1-6):  
• Vital Signs (pre-treatment and 2 hours post treatment administration) 
• Laboratory Samples (chemistry 2 hours post treatment administration) 
• Randomization 
• Administration of OC-01 (varenicline) Nasal Spray or Chantix®   
• PK Sample Collection 
• Concomitant Medications 
• AE Query 
Period 2 Check-In (Day 14) 
• Serum Pregnancy Test (if applicable) 
• Drug and Alcohol Screen 
• Intranasal Examination  
• Concomitant Medications 
• AE Query 
Period 2 (Day 15-20):  
• Vital Signs (pre-treatment and 2 hours post treatment administration) 
• Laboratory Samples (chemistry 2 hours post treatment administration)) 
• Administration of OC-01 (varenicline) Nasal Spray or Chantix® 
• PK Sample Collection 
• Concomitant Medications 
• AE Query 

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End of Study/Early Termination (Day 27 + 7): 
• Urine pregnancy test (if applicable) 
• Physical Examination 
• 12-lead ECG 
• Vital Signs 
• Laboratory Samples (hematology, chemistry) 
• Urinalysis 
• Intranasal Examination 
• Concomitant Medications 
• AE Query 
8.4. 
Pharmacokinetic Sampling Schedule 
PK samples should be collected according to the following schedule during Treatment Period 1 
and Treatment Period 2: 
All times are after study drug administration except for predose (time 0) 
In-Unit Blood PK Sampling  
Sample 1: Predose (time 0)  
Sample 2: 5 minutes  
Sample 3: 15 minutes  
Sample 4: 30 minutes  
Sample 5: 1 hour 
Sample 6: 2 hours 
Sample 7: 3 hours 
Sample 8: 4 hours 
Sample 9: 6 hours 
Sample 10: 8 hours 
Sample 11: 12 hours 
Sample 12: 24 hours 
Sample 13: 36 hours 
Sample 14: 48 hours 
Out-Patient Blood PK Sampling 
Sample 15: 72 hours 
Sample 16: 96 hours 

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Sample 17: 120 hours 
8.5. 
Schedule of Visits, Measurements and Dosing 
8.5.1. 
Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.5.2. 
Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All procedures performed at an 
unscheduled visit will be recorded in the source.  
Evaluations that may be conducted at an Unscheduled Visit include: 
• Intranasal Examination 
• Physical Examination 
• Vital Signs 
• 12 lead ECG 
• Laboratory assessments/urinalysis 
• Urine pregnancy test (if applicable) 
• Assessment of AEs 
• Assessment of concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the investigator 
8.6. 
Compliance with Protocol 
Oyster Point Pharma, Inc. will not compensate the Investigator for evaluation of cases in which 
the procedures and evaluations are conducted in a manner other than that specified in the protocol.  
The investigator will conduct the trial in compliance with the protocol and approved by the 
IRB/IEC and the appropriate regulatory authority(ies). Modifications to the protocol are not to be 
made without agreement of both the investigator and Oyster Point Pharma, Inc. Changes to the 
protocol will require written IRB/IEC approval prior to implementation, except when the 
modification is needed to eliminate an immediate hazard(s) to subjects. When immediate deviation 
from the protocol is required to eliminate an immediate hazard(s) to patients, the investigator will 
contact Oyster Point Pharma, Inc. Any departures from the protocol must be documented.  

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8.7. 
Subject Disposition 
8.7.1. 
Completed Subjects 
A completed subject is one who has completed both the Period 1 and Period 2 study visits and has 
received treatment with both OC-01 (varenicline) Nasal Spray and Chantix®.  
8.7.2. 
Discontinued Subjects 
Subjects may be discontinued from treatment, or from involvement in the study at any time prior 
to their completion of the study due to: 
• AEs 
• Protocol violations 
• Lost to follow-up 
• Pregnancy 
• Physician decision 
• Subject non-compliance 
• Sponsor termination of study 
• Withdrawal by subject  
• Other reasons 
Note: In addition, any subject may be discontinued from treatment or from study involvement from 
any sound medical reason at the discretion of the investigator (after consultation with the Sponsor) 
or Sponsor. 
Notification of a subject discontinuation and the reason for discontinuation will be made to the 
Sponsor and/or its designee and will be clearly documented.  
Discontinued subjects will not be replaced.  
8.8. 
Study Termination 
The study may be stopped at any time by the Investigator and/or after consultation with the 
Sponsor, with appropriate notification. 
8.9. 
Study Duration 
An individual subject’s participation will involve ten visits over approximately 60 days.   

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8.10. 
Monitoring and Quality Assurance 
 
 
 
 
 
 
 
 
 
 
9. 
SAFETY DEFINITIONS, SAFETY MONITORING AND 
REPORTING 
9.1. 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
a drug in humans, whether or not the event is considered drug-related. An AE can therefore be any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
occurring after the subject started dosing with the study drug, without any judgment about 
causality. Any pre-existing medical condition that worsens after administration of the study drug 
will also be considered a new AE. 
Study drug includes the investigational drug under evaluation. Documentation regarding the AE 
should be made as to the nature, date of onset, end date, severity, expectedness 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. AE collection will start following 
the first administration of study drug until the last follow up visit of the study.   
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. 

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• 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 
using these explanations: 
• Definite: When there are good reasons and/or sufficient documentation to demonstrate 
a direct causal relationship between investigational product and AE 
• Probable: When there are good reasons and/or 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 
particular drug under investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final classification is 
subject to the Medical Monitor’s determination. 

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9.2. 
Serious Adverse Events 
An AE is considered “serious” (SAE) if, in the view of either the investigator or Sponsor, it results 
in any of the following outcomes: 
• Death 
• A life-threatening AE 
Note: An AE is considered “life-threatening” if, in the view of either the investigator 
or Sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if 
less than 24 hours). For chronic or long-term inpatients, inpatient admission includes 
transfer within the hospital to an acute/intensive care inpatient unit. Inpatient 
hospitalization does not include: emergency room visits; outpatient/same- 
day/ambulatory procedures; observation/short stay units; rehabilitation facilities; 
hospice facilities; nursing homes; or clinical research/phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the 
initial admission as determined by the investigator or treating physician. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
Note: An SAE specifically related to visual threat would be interpreted as any potential 
impairment or damage to the subject’s eyes (e.g., hemorrhage, retinal detachment, 
central corneal ulcer or damage to the optic nerve). 
• A congenital anomaly/birth defect in an offspring of a study subject. 
• Other medically important event 
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.  

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9.3. 
Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to the Sponsor and/or its designee, and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health authorities 
and recorded on the appropriate source documents. 
9.3.1. 
Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to the Sponsor and/or its designee 
and the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and governing 
health authorities. 
9.3.2. 
Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the study drug, must be 
immediately reported. All information relevant to the SAE must be recorded. The investigator is 
obligated to pursue and obtain information requested by the Sponsor and/or its designee. All 
subjects experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the investigator must notify the Sponsor and/or it’s designee immediately; 
obtain and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject; provide the 
Sponsor and/or its designee with a complete case history, which includes a statement as to whether 
the event was or was not suspected to be related to the use of the study drug; and inform the IRB 
of the SAE within their guidelines for reporting SAEs. 
Refer to the SAE form for additional reporting instructions.  
9.4. 
Type and Duration of the Follow-up of Subjects after Adverse Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to follow- up or 
until the AE is otherwise classified. Resolution means the subject has returned to baseline state of 
health or the Investigator does not expect any further improvement or worsening of the AE. If the 
patient is lost to follow-up, the Investigator should make 3 reasonable attempts to contact the 
patient via telephone, post, or certified mail. All follow-up will be documented in the subject’s 
source document.  
If the Investigator becomes aware of any new information regarding an existing SAE (i.e., 
resolution, change in condition, or new treatment), a new SAE/Unanticipated Report Form must 
be completed and faxed to the Sponsor and/or its designee within 24 hours of the site’s awareness 
of the new information. The original SAE form is not to be altered. The report should describe 
whether the event has resolved or continues and how the event was treated. 

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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. 
Sample Size and Power Considerations 
 
 
 
 
 
 
 
 
 
 
10.2. 
Analysis Populations 
• Pharmacokinetics 
• Safety Population 
10.3. 
Statistical Hypotheses 
No formal hypothesis will be tested.  
10.4. 
Statistical Analysis 
This section briefly outlines the planned analyses. The 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. 
10.4.1. 
General Considerations 
 
 
 
 
Table 1: 
Interim Analysis Matrix 
Outcome 
Action 
 
  
 

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Outcome 
Action 
 
  
 
 
 
 
  
 
 
 
 
10.4.1.1. Subject Demographics and Baseline Characteristics 
Continuous summary statistics will be generated for age in years by treatment group and for all 
subjects. Discrete summary statistics will be generated for the following qualitative demographic 
variables: age category, gender, ethnicity, race, and other baseline intranasal examination results, 
tabulated by treatment group and for all subjects. Individual subject data listings will support the 
Summary tables. 
10.4.2. 
Pharmacokinetic Analysis 
 
 
 
 
  
 
 
 
 
 
 
10.4.2.1. Safety Analysis 
 
 
 
  
 
 
 
 
 
 

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10.4.3. 
Interim Analysis 
 
 
 
 
11. 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, Good Clinical Practices, including 
the International Conference on Harmonization (ICH) Guidelines, and in general, consistent with 
the Declaration of Helsinki. In addition, all applicable local, state, and federal requirements 
relevant to the use of study drugs in the countries involved will be adhered to. 
11.1. 
Protection of Human Subjects 
11.1.1. 
Subject Informed Consent 
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study. 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. A copy of the signed informed consent form will be given to the subject and the 
original will be placed in the subject’s medical record. 
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 the 
Sponsor and/or it’s designee prior to submission to the governing IRB and that it is read, signed 
and dated by all subjects subsequently enrolled in the study as well as those currently enrolled in 
the study. 
If informed consent is taken under special circumstances (oral informed consent), then the 
procedures to be followed must be determined by the Sponsor and provided in writing by prior to 
the consent process. 

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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 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 aforementioned individuals to 
the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health authorities 
in any country in which the study drug may ultimately be marketed, but the subject’s identity will 
not be disclosed in these documents. 
11.4. 
Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
investigator’s study subject files, as well as the results of diagnostic tests such as X-rays, laboratory 
tests, and electrocardiograms. The investigator’s copy of the CRFs serves as the investigator’s 
record of a subject’s study-related data. 
11.4.1. 
Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the distribution and 
use of all study drug and copies of CRFs should be maintained on file for at least two years after 
the last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region; or until at least two years have elapsed 
since the formal discontinuation of clinical development of the study drug. These documents will 

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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 
 
 
 
 
  
11.5.2. 
Storage of Investigational Drug / Placebo 
 
 
  
 
 
 
   
11.5.3. 
Accountability of Study Drug 
OC-01/Chantix® must only be 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 
OC-01 (varenicline) Nasal Spray will be returned to the Sponsor or their designee for destruction. 

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11.6. 
Recording of Data  
All subject data will be captured in the subject source documents. The investigator is responsible 
for ensuring that study data is completely and accurately recorded on each subject’s source 
documents, and all study-related materials. All study data should also be attributable, legible, 
contemporaneous, and original 
Data capture of all enrolled and randomized subjects will use software that conforms to 21 CFR 
Part 11 requirements, and will be performed only by staff who have been trained on the system 
and have access to the system. Data will not be analyzed for screen failure subjects. An audit trail 
will be maintained within the electronic system to capture all changes made within the database. 
After the end of the study and database lock, electronic copies of all applicable subjects’ source 
documents will be provided to each Investigator Site to be maintained on file by the Investigator. 
11.7. 
Handling of Biological Specimens 
Blood samples (4 mL in K2EDTA tubes) are collected from an arm vein or catheter into Vacutainer 
tubes containing K2EDTA. Blood samples are mixed gently and maintained chilled until 
centrifuged within 2 hours of collection.  
Plasma samples are separated into two equivalent aliquots and labeled appropriate with subject ID, 
site and nominal time point 
  
All samples and associated results will be coded prior to being shipped from the site for analysis. 
Samples will be tracked using the unique identification number that is assigned to the subject.  
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 publication of the trial in conjunction with various 
participating Investigators and appropriate sites contributing data and comments. Subsequently, 
individual Investigators may request to publish or present results from the trial; however, approval 
will be at the sole discretion of the Sponsor. Should the foregoing language be in conflict with the 
language addressing publication in the clinical trial agreement, the language in the Clinical Trial 
Agreement will prevail. 

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12. 
REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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: 
A1. 
Intranasal Examination  
Qualified participants for the study must undergo an intranasal exam to make the final eligibility 
determination (e.g. severe nasal airway obstruction such as, severe septal deviation or inferior 
turbinate hypertrophy, or vascularized polyp seen on examination are reasons for exclusion). To 
monitor nasal mucosal integrity during the study for participant safety, an examination of the nasal 
cavities via an intranasal exam will be performed at the Screening Visit (after all other screening 
procedures have been completed), Periods 1 and 2 Check-in, and at the End of Study/Early 
Termination Visit. This examination will be performed by an Ear Nose and Throat (ENT) 
specialist, otolaryngologist or other suitably qualified medical practitioner (i.e. one who has been 
trained to perform intranasal exam). The procedure used for the intranasal exam can be conducted 
either by endoscopic examination or nasal specula. 
A2. 
Laboratory Samples 
The Schedule of Visits and Measurements (Appendix 1) defines the timepoints when each analyte 
should be collected. Table 2 below outlines the specific analytes to be tested: 
Table 2: 
Laboratory Analytes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
A3. 
Physical Examination 
A physical examination will be conducted as per Standard of Care (SOC). Breast, genital and rectal 
examinations are not required unless specific evaluation is warranted. Physical examination 
findings should be recorded on the appropriate source document (e.g., medical history). Body 

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height and weight will be collected at screening. Height should be measured in centimeters 
(without shoes). Weight should be measured in kilograms (without shoes).  
A4. 
Vital Signs 
Vital signs, including heart rate, respiratory rate and blood pressure will be obtained. Subjects must 
be in supine or sitting position in a rested and calm state for at least 5 minutes before blood pressure 
assessments are conducted. If the subject is unable to be in the supine position, the subject should 
be in the most recumbent position possible. The position selected for a subject should be the same 
that is used throughout the study.  Vital sign assessments should be performed prior to blood 
sample collection.    
A5. 
Electrocardiogram 
A 12-lead ECG will be obtained during Screening and End of Study/Early Termination. Subject 
must be in a supine position in a rested and calm state for at least 5 minutes before ECG assessment 
is conducted. If the subject is unable to be in the supine position, the subject should be in the most 
recumbent position as possible.  
The principal investigator or designated site physician will review all ECGs. Once signed, the 
original ECG tracing will be retained with the subject’s source documents.  ECG should be 
performed prior to blood sample collection. 

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APPENDIX 4. INVESTIGATOR’S SIGNATURE 
Protocol Title: 
An, Open-Label, Single-Center, Randomized, 2-way Crossover Study to 
Evaluate the Relative Bioavailability of Varenicline Administered as OC-
01 Nasal Spray as Compared to Varenicline Administered Orally as 
Chantix® (The ZEN Study) 
Protocol Number: 
OPP-100 
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:  
 

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APPENDIX 5.