A Multicenter, Double-blind, Randomized, Placebo-controlled Phase 2 Trial Evaluating the Efficacy and Safety of Cytisinicline in Adults Using Nicotine-containing E-cigarettes
Phase: PHASE2
Conditions: Vaping, E-Cig Use
Sponsor: Achieve Life Sciences

 
 
 
 
 
 
 
Protocol ACH-CYT-10 (ORCA-V1 Trial) 
 
A Multicenter, Double-blind, Randomized,  
Placebo-controlled Phase 2 Trial Evaluating the Efficacy 
and Safety of Cytisinicline in Adults Using  
Nicotine-containing E-cigarettes  
 
 
 
May 4, 2022 
 
Version 3.0 
 
 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
   
. 
 
 
 
 
 
 
 
 

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SYNOPSIS  
Protocol Number: ACH-CYT-10 (ORCA-V1 Trial) 
Sponsor: Achieve Life Sciences, Inc 
Title of Study: A Multicenter, Double-blind, Randomized, Placebo-controlled Phase 2 Trial 
Evaluating the Efficacy and Safety of Cytisinicline in Adults Using Nicotine-containing 
E-cigarettes 
Clinical Phase: Phase 2 
Study Population: Male and female subjects ≥18 years who vape nicotine e-cigarettes daily 
and intend to make a quit attempt during the study. 
Rationale: (-)-Cytisine is a naturally occurring plant-based alkaloid, isolated from seeds of 
Cytisus laburnum (Golden chain acacia), and acts as a partial antagonist with high affinity 
and specificity for neuronal nicotinic (α4β2) receptors. Cytisine can reduce the severity of 
nicotine withdrawal symptoms as well as inhibiting nicotine reward effects by targeting 
nicotinic acetylcholine receptors (nAChRs) in the brain. Cytisine has been used as a 
smoking cessation drug since the 1960’s in Central and Eastern European countries, where 
initial clinical studies were conducted. Previous studies dating from decades ago and more 
recently two Phase 3 studies (published in 2011 and 2014) have shown that cytisine can be 
more effective than placebo as well as nicotine replacement therapy (NRT) in helping 
people to stop smoking. In 2018, the United States Adopted Names (USAN) Council 
adopted "cytisinicline" as the nonproprietary, or generic, name for cytisine. 
One increasingly popular alternative to smoking cigarettes is the use of electronic cigarettes 
(e-cigarettes), or vaping, which delivers liquid nicotine into a mist or aerosol which is 
inhaled. This method of consumption avoids or lowers exposure to many of the toxic 
chemicals associated with cigarette smoke but may have other associated health and safety 
issues. The emerging use of e-cigarettes is resulting in a population of people addicted to a 
new source of nicotine.  
According to the Annals of Internal Medicine, data reported in 2018 estimated that 
approximately 10.8 million American adults use e-cigarettes and half of these users are age 
18-34 years.1 The United States Food and Drug Administration, or FDA, considers 
e-cigarette use an epidemic, particularly in youth, and the National Institute on Drug Abuse, 
or NIDA, a division of the NIH, has tobacco/nicotine and vaping on their list of Drugs of 
Abuse. Not only does e-cigarette use come with risks of its own, but research has also 
shown that young adults who vape are more likely to start smoking combustible cigarettes 
later in life. This is an important area of focus given the increasing number of vaping-
related lung illnesses that have recently been reported. The number of e-cigarette users 
continues to grow and while e-cigarettes have been viewed as safer than combustible 
cigarettes, the long-term safety of e-cigarettes is still unproven and may sustain nicotine 
addiction. 

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Prior trials already have demonstrated cytisinicline’s efficacy in helping people quit 
smoking. This clinical study will evaluate the potential benefit of cytisinicline in treating 
nicotine addiction among users whose only source of nicotine is via the use of e-cigarettes. 
Given the mechanism of action of cytisinicline, this study will assess whether cytisinicline 
given to users of nicotine-containing e-cigarettes but not combustible tobacco products (i.e., 
conventional cigarettes) can reduce nicotine dependence and promote vaping cessation or 
reduction. As an added value, this study will evaluate the same safety parameters as the 
Phase 3 studies for cigarette smoking cessation and hence will add to the growing safety 
database for cytisinicline. 
In this study, all references to vaping means the use of nicotine-containing e-cigarettes or 
other nicotine-containing vaping devices. Subjects will be randomized 2:1 to receive either 
3 mg cytisinicline TID for 12 weeks plus standard behavioral support (Arm B: cytisinicline 
TID ) or placebo TID for 12 weeks plus standard behavioral support (Arm A: placebo TID). 
The primary outcome assessment will be nicotine vaping cessation during Weeks 9-12. 
Vaping cessation is defined as weekly nicotine vaping abstinence for 4 consecutive weeks. 
Other timing for weekly vaping abstinence/cessation (e.g., Weeks 3-6 or Weeks 6-9) and 
any reduction in nicotine vaping will be analyzed as secondary outcomes.  
This study will also assess the safety profile of 3 mg cytisinicline administered TID for 
12 weeks. 
Objectives:  
Primary Efficacy Objective:  
Assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 12 weeks plus 
behavioral support) have a higher probability of nicotine vaping cessation from Week 9 to 
Week 12 post-randomization as compared to subjects randomized to Arm A (placebo TID for 
12 weeks plus behavioral support). 
Secondary Efficacy Objectives:  
1) Assess whether subjects randomized to Arm B (cytisinicline TID) can achieve 
vaping abstinence/cessation at any time during treatment or reduce their daily 
vaping as objectively measured with biomarkers of nicotine exposure compared to 
subjects randomized to Arm A (placebo TID). Specific Secondary Efficacy 
Objectives related to this are described below: 
• Assess whether subjects randomized to Arm B have a higher probability of 
achieving vaping cessation between Week 3 and Week 9 post-randomization 
(e.g., Week 3-6 or Week 6-9,) as compared to subjects randomized to Arm A.  
• To compare arms (Arm A vs Arm B) on 7-day point prevalence rates for vaping 
abstinence on a weekly basis from Week 2 to Week 12. 
• To compare arms (Arm A vs Arm B) for a reduction in nicotine vaping using 
weekly quantitative cotinine levels from Week 2 to Week 12. 
2) Assess whether subjects randomized to Arm B have a higher probability for 
continuous vaping abstinence between Week 9 and Week 16 post-randomization 

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(i.e., subjects achieving primary endpoint abstinence with continued abstinence 
through follow-up). 
Other Objectives: 
Explore the magnitude of treatment effect between arms across various subgroups defined 
by demographic and baseline characteristics for the primary and secondary outcomes. 
Evaluate for nicotine withdrawal symptoms at Weeks 1-4 and again for any possible 
withdrawal symptoms due to study drug discontinuation pre- and post-Week 12. 
Safety Objectives: 
To evaluate the safety profile of 3 mg TID cytisinicline when administered for 12 weeks.  
Study Design:  
This will be a multi-center, double-blind, randomized, placebo-controlled, Phase 2 study 
conducted in male or female adults who are daily nicotine e-cigarette users only (i.e., 
vaping only subjects as confirmed with a positive salivary cotinine sample and a carbon 
monoxide [CO] breath sample <10 ppm), intending to try to quit vaping, and willing to set a 
quit date that is within 7-14 days from the start of cytisinicline treatment. Study treatment 
must start the day after randomization.  
Subjects must meet all requirements outlined in the inclusion and exclusion criteria. A total 
of approximately 150 subjects will be randomly assigned (2:1) to one of two Arms: (Arm B, 
12 weeks cytisinicline + behavior support: N=100 or Arm A, 12 weeks of placebo+ 
behavior support: N=50) as shown in the study design figure below. 
 
Vaping quit status (abstinence) will be assessed starting at Week 2 (Day 14±1) and 
assessments will continue weekly during the Treatment Period through to Week 12 and at 
Week 16 in the follow up period. In addition, assessments for cotinine in saliva and expired 
CO levels will be performed during the treatment period and will be compared to baseline 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm A 
N=50 
Placebo TID 12 Weeks  
+ Behavioral Support 
Arm B 
N=100 
3 mg Cytisinicline TID 12 Weeks 
+ Behavioral Support 
 
 
 
 
S 
C 
R 
E 
E 
N 
F 
O 
L 
L 
O 
W 
 
U 
P 

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measures. All subjects will receive concurrent nicotine cessation behavioral support during 
the study Treatment Period (Week 1-12). 
Safety assessments at clinic visits will occur weekly throughout the Treatment Period. 
Laboratory hematology and chemistry assessments will be made on Day 7, Week 6 and 
Week 12 during the Treatment Period. Adverse events will be monitored through the follow 
up period. Any ongoing adverse events at Week 16 will be followed until resolved or 
determined to be chronic. The end of study is defined as the last follow up visit (Week 16) 
for the last subject. 
Selection Criteria 
Inclusion Criteria: 
1. Male or female subjects, age ≥18 years.
2. Test positive for cotinine using the Alere iScreen® OFD Cotinine Oral Fluid
Screening Device (Positive testing at ≥30 ng/mL cotinine level).
3. Current daily nicotine-containing electronic cigarette usage as recorded in a
screening diary for at least 7 consecutive days. Willing to bring the e-cigarette or
nicotine device used to the clinical site so that the specific product type, flavor, and
nicotine level can be documented.
4. Willing to initiate study treatment on the day after randomization and set a quit date
within 7-14 days of starting treatment.
5. Willing to actively participate in the study’s vaping cessation behavioral support
provided throughout the study.
6. Able to fully understand study requirements, willing to participate, and comply with
dosing schedule.
7. Sign the Informed Consent Form.
Exclusion Criteria: 
1. Currently smoking, or having smoked within 4 weeks prior to study randomization,
any combustible cigarettes, other combustible tobacco products or non-combustible
tobacco products (such as heat not burn products) (i.e., dual users).
2. Expired Carbon Monoxide (CO) levels ≥10 ppm, indicating recent combustible
tobacco use.
3. More than 1 study participant in same household during the study treatment period.
4. Known hypersensitivity to cytisinicline or any of the excipients.
5. Positive urinary drugs of abuse screen determined within 28 days before the first
dose of cytisinicline (Note: THC is not part of the abuse screen).
6. Clinically significant abnormal serum chemistry or hematology values within
28 days of randomization (i.e., requiring treatment or monitoring).
7. Clinically significant abnormalities in 12-lead ECG determined after minimum of
5 minutes in supine position within 28 days of randomization (i.e., requiring
treatment or further assessment).

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8. Recent history (within 3 months) of acute myocardial infarction, unstable angina, 
stroke, cerebrovascular incident or hospitalization for congestive heart failure. 
9. Current uncontrolled hypertension (blood pressure ≥160/100 mmHg). 
10. Documented diagnosis of schizophrenia or bipolar psychiatric illness; currently 
psychotic; having suicidal ideation within the last 3 months (corresponding to 
question 4 or 5 on the C-SSRS); or current symptoms of moderate to severe 
depression (depression score ≥11 on the HADS) within the last 3 months. 
11. Renal impairment defined as a creatinine clearance (CrCl) <60 mL/min (estimated 
with the Cockroft-Gault equation). 
12. Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2.0 x the upper limit of normal (ULN). 
13. Recent history or symptoms (within 4 weeks of randomization) of unstable 
respiratory disease (e.g., pneumonia, product-use associated lung injury or EVALI, 
etc.) 
14. Women who are pregnant or breast-feeding. 
15. Male or female subjects of childbearing potential who do not agree to use acceptable 
methods of birth control starting at the time of consent, during the study treatment 
period, and continuing for one month after ending study treatment. 
16. Participation in a clinical study with an investigational drug in the 4 weeks prior to 
study randomization. 
17. Use of other smoking cessation medications (bupropion, varenicline, nortriptyline, 
or any nicotine replacement therapy [NRT]) in the 4 weeks prior to study 
randomization, any previous cytisine use or planned use of these or other nicotine 
replacement medications during the study. 
18. Any planned use during the study of combustible cigarettes or other nicotine-
containing, non-vaping products (e.g., pipe tobacco, cigars, snuff, smokeless 
tobacco, hookah, ZYN pouches, etc).  
19. Any other reason that the investigator views the subject should not participate or 
would be unable to fulfill the requirements for the study. 
Number of Subjects, Randomization, and Stratification: 
Approximately 150 subjects will be randomized (2:1) at 5-8 sites in the United States, with 
100 subjects in the cytisinicline arm and 50 subjects in the placebo arm. Subjects will be 
stratified on whether they have smoked >100 cigarettes in their lifetime (yes vs no). 
Study Treatments:  
Identical appearing tablets containing 3 mg cytisinicline or matched placebo will be 
administered orally. During the 12-week Treatment Period, subjects will take one tablet 
three times daily. Tablets will be blister sealed and configured into medication packs for 
one week of dosing. Each pack will contain 21 tablets for TID dosing for 7 days. Six weeks 
of dosing packs will be contained in a carton such that 2 cartons will be assigned to a 
subject during the study treatment (i.e., 12 total packs for 12 weeks of study treatment). 

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Clinic staff will distribute and collect packs as the subject progresses through the clinic 
visits and will conduct ongoing accountability during each weekly clinic visit by reviewing 
a subject’s treatment diary and associated blister packs. Used packs will be retained so that 
the Sponsor's monitoring staff can verify accountability records. 
Duration of Study:  
All randomized subjects will initiate study treatment the day after randomization and 
receive 12 weeks of treatment. Duration of this study is estimated to be approximately 
16 weeks for an individual subject (from randomization to Week 16 follow up visit).  
Study Procedures:  
Prior to taking part in the trial, subjects will be provided with an informed consent 
document outlining study requirements and procedures. Subjects will be given adequate 
time to review, discuss, and decide whether they wish to participate. 
Subjects providing signed informed consent will be assessed during the Screening Period to 
determine their eligibility for the trial and to complete their daily e-cigarette or device usage 
in the screening diary. Subjects must complete 7 consecutive days in the screening diary for 
confirmation of eligibility. If eligible, subjects will be required to attend a clinic visit prior 
to randomization and must bring to the clinic their e-cigarettes or devices that they used 
daily in the screening diary so that the clinical site can record specifically what they used 
(including product type, flavor, nicotine level, and average daily use). At this clinic visit, 
each subject must establish a quit date that will in turn determine the date of study 
randomization and initiation of treatment. The quit date must be within 7-14 days of starting 
treatment and treatment must begin on the day after randomization.  
Subjects will be provided with nicotine cessation counseling beginning on the clinic visit 
during screening prior to randomization (setting quit date and plan), again on the day of 
study randomization, and continuing weekly through the Week 12 visit.  
Compliance will be assessed during the Treatment Period by reviewing each subject’s diary 
(date and time of dosing) as well as ongoing drug accountability at each weekly clinic visit. 
Subjects will be assessed for vaping abstinence/cessation or reduction by self-report of 
vaping and with biochemical assessments documented weekly starting at Week 2 through 
Week 12 and at Week 16. Vaping cessation will be defined as weekly vaping abstinence for 
4 consecutive weeks documented by a subject self-report of not vaping and by biochemical 
verification of saliva cotinine <10 ng/mL by a central laboratory. Vaping reduction will be 
assessed by evaluating quantitative saliva cotinine levels relative to baseline screening 
levels. Measurements for expired CO levels will be monitored and are expected to stay at 
baseline levels of under 10 ppm. 
Subjects will be assessed for safety (vital signs, adverse event reporting and concomitant 
medications) on Day 7 (Week 1). Note: clinic will also contact subject via telephone on Day 
1 of treatment to assess for any initial reported adverse events) and then safety assessments 
will occur weekly at each clinic visit during the Treatment Period. In addition to the above 
safety assessments, hematology and chemistry assessments will be made on Day 7, Week 6 
and Week 12 during the Treatment Period. Adverse events will be monitored through the 
Follow Up period. Safety monitoring during the study will be performed by an independent 
Data Safety Monitoring Committee (DSMC) composed of at least 2 independent experts in 

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the relevant therapeutic field. At Week 16 any adverse event or abnormalities considered to 
be clinically significant by the investigating physician will be followed with appropriate 
medical management until values are considered to be clinically acceptable or deemed 
chronic. 
Statistical Considerations:  
Analysis Sets 
Screening Analysis Set: The Screening Analysis Set is defined as all subjects who give 
written informed consent and have entered screening but are not randomized. Analyses 
in this population will be restricted to presentation of baseline data and reasons for non-
participation only. 
Safety Analysis Set: The Safety Analysis Set (SAS) is defined as all randomized subjects 
who take at least one dose of study drug. All safety analyses will be performed on the 
Safety Analysis Set. 
Efficacy Analysis Set: The All Randomized Analysis Set (ARS) is based on the ‘intention-
to-treat’ principle and will include data from all randomized subjects. 
Efficacy Outcomes 
General efficacy outcomes will assess for vaping abstinence/cessation, or reduction in 
vaping.  
Weekly vaping assessments will start at Week 2 and continue weekly through Week 12.  
The primary efficacy measure will be the number of subjects who achieve vaping 
abstinence for 4 consecutive weeks from Week 9 to Week 12 by self-report of no vaping 
each week and supported by biochemical verification (saliva cotinine <10 ng/mL).  
Secondary efficacy outcomes: The number of subjects who achieve vaping abstinence at 
any time between Week 2 and Week 12 (e.g., self-report of no vaping in the past 7 days 
supported by biochemical verification) will also be reported as 7-day point prevalence rates. 
Other earlier time periods for achieving vaping cessation (e.g., vaping abstinence for 
4 consecutive weeks from Week 3 to 6 or from Week 6 to 9) will also be assessed. The 
number of subjects who achieve continuous vaping abstinence at Week 9 through Week 16 
(e.g., self-report of no vaping supported by biochemical verification).  
Measurements for CO levels will be monitored as a sensitivity test to assess that no 
concurrent combustible cigarette usage was used in those subjects reporting vaping 
abstinence or cessation.  
Other secondary efficacy outcomes for any reduction in vaping will be primarily assessed 
on a weekly basis between Week 2 and Week 12 using quantitative saliva cotinine levels 
when compared to baseline levels.  
Other Outcomes: All outcomes, including time to vaping abstinence, magnitude of 
treatment effect across subsets defined by demographic (e.g., gender, age) and/or baseline 
characteristics (e.g., e-cigarette product type, nicotine addiction severity), etc., will be 
performed as other exploratory assessments. In addition, the possible confounding effect of 
marijuana use on the ability to reduce nicotine vaping or cessation will be explored. 
 

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Statistical Methods 
The overall study intent is to obtain effect outcomes and conduct additional safety 
assessments for efficacy and safety endpoints that will be used to inform the design of 
future studies. Thus, this study will be analyzed without specific statistical criteria. That is, 
no formal statistical hypothesis testing will be conducted, and consequently, a level of 
significance (α level) is not specified in the Statistical Analysis Plan (SAP). There will be 
statistical testing performed with p-values, and confidence intervals (CIs) to be computed. 
The p-values will be interpreted as an assessment of consistency with the play of chance 
(small p-values indicating a small likelihood that the observed effect was due to chance) and 
will be used qualitatively in decisions concerning next steps. 
Trial Size 
The target accrual is for approximately 150 subjects (100 subjects treated with cytisinicline 
and 50 subjects treated with placebo) which should be adequate to obtain additional safety 
assessments as well as explore various measures of cytisinicline effect outcomes compared 
to placebo.  
Safety 
The profiles of adverse events for the arms with regard to incidences of treatment 
emergent adverse events will be assessed. Treatment emergent adverse events are defined 
as those events that appear during treatment or are present before treatment and 
subsequently worsen. Laboratory, vital signs and ECG data will primarily be assessed for 
clinical safety. Data will be listed and summarized for each treatment according to 
measurement time. 

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TABLE OF CONTENTS 
SYNOPSIS . .....................................................................................................................................2 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................14 
1. 
INTRODUCTION AND BACKGROUND ...............................................................16 
1.1. 
History of the Investigational Product ........................................................................16 
1.2. 
Nicotine Addiction, Vaping, and Impact on Health ...................................................16 
1.3. 
Cytisinicline for Treatment of Nicotine Addiction ..................................................17 
2. 
SAFETY OVERVIEW FOR CYTISINICLINE ........................................................20 
2.1. 
Non-Clinical Studies ...................................................................................................20 
2.1.1. 
Summary of 26-Week Chronic Toxicology Study .....................................................21 
2.1.2. 
Summary of 39-Week Chronic Toxicology Study .....................................................21 
2.1.3. 
Summary of Reproductive/Developmental Studies ....................................................22 
2.2. 
General Safety of Cytisine as a Marketed Product .....................................................23 
2.3. 
Special Populations .....................................................................................................24 
3. 
RATIONALE FOR THE STUDY ..............................................................................24 
4. 
STUDY OBJECTIVES ..............................................................................................25 
4.1. 
Primary Efficacy Objective ........................................................................................25 
4.2. 
Secondary Efficacy Objectives ...................................................................................26 
4.3. 
Other Objectives .........................................................................................................26 
4.4. 
Safety Objectives ........................................................................................................26 
5. 
STUDY DESIGN OVERVIEW .................................................................................26 
5.1. 
Study Design ...............................................................................................................26 
5.2. 
Treatment Period (12 Weeks) .....................................................................................28 
5.3. 
Discussion of Study Design ........................................................................................28 
5.3.1. 
Placebo Control ..........................................................................................................28 
5.3.2. 
Primary Endpoint ........................................................................................................28 
5.3.3. 
Blinding ......................................................................................................................29 
5.3.4. 
Unblinding ..................................................................................................................29 
5.4. 
Number of Subjects ....................................................................................................30 
5.5. 
Randomization ............................................................................................................30 

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5.6. 
Number of Clinical Sites ............................................................................................30 
5.7. 
Estimated Duration/Completion of Study ..................................................................30 
6. 
SELECTION OF STUDY POPULATION ................................................................30 
6.1. 
Inclusion Criteria ........................................................................................................31 
6.2. 
Exclusion Criteria .......................................................................................................31 
6.3. 
Modifying or Discontinuing Study Drug and/or Study Evaluations ..........................32 
6.3.1. 
Study Drug Modification during the 12-Week Treatment Period ..............................32 
6.3.2. 
Study Discontinuation ................................................................................................33 
7. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ..........................................33 
7.1. 
Cytisinicline Film-Coated Tablets ..............................................................................33 
7.2. 
Placebo Tablets ...........................................................................................................33 
7.3. 
Receipt and Storage ....................................................................................................33 
7.4. 
Administration ............................................................................................................34 
7.5. 
Return/Destruction ......................................................................................................34 
7.6. 
Method of Assigning Subjects to Arms ......................................................................34 
7.7. 
Study Drug Dosing Schedule ......................................................................................34 
7.8. 
Accountability .............................................................................................................35 
8. 
PREVIOUS AND CONCOMITANT MEDICATIONS ............................................35 
9. 
TREATMENT COMPLIANCE .................................................................................35 
10. 
STUDY PROCEDURES ............................................................................................36 
10.1. 
Procedure Schedule ....................................................................................................36 
10.2. 
Detailed Description of Study Visits ..........................................................................40 
10.2.1. 
Screening Phase (SV1-SV2) .......................................................................................40 
10.2.2. 
Randomization ............................................................................................................42 
10.2.3. 
Treatment Period ........................................................................................................43 
10.2.4. 
Follow-up Assessment ................................................................................................51 
10.2.5. 
Subject Diaries ............................................................................................................51 
10.2.6. 
Behavioral Support .....................................................................................................51 
11. 
EFFICACY CRITERIA ..............................................................................................52 
12. 
SAFETY ASSESSMENTS ........................................................................................53 
12.1. 
Definitions ..................................................................................................................53 
12.2. 
Recording of Adverse Events .....................................................................................55 
12.2.1. 
Grading Adverse Event Severity ................................................................................55 

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12.2.2. 
Assessment of Attribution ..........................................................................................55 
12.2.3. 
Reporting of Serious Adverse Events .........................................................................56 
12.2.4. 
Reporting of a Pregnancy during Study Treatment ....................................................57 
12.2.5. 
Reporting of COVID-19 Positive cases and COVID-19 vaccinations as 
Adverse Events of Special Interest .............................................................................58 
12.3. 
Laboratory ...................................................................................................................58 
12.3.1. 
Routine Laboratory Assessments ...............................................................................58 
12.3.2. 
Monitoring of Expired Air Carbon Monoxide (CO) ..................................................58 
12.3.3. 
Cotinine Levels ...........................................................................................................59 
12.4. 
Vital signs ...................................................................................................................59 
12.5. 
Physical Examination .................................................................................................59 
13. 
SAFETY MONITORING ..........................................................................................59 
13.1. 
Independent Data Safety Monitoring Committee .......................................................59 
14. 
STATISTICAL CONSIDERATIONS .......................................................................60 
14.1. 
Statistical Design ........................................................................................................60 
14.2. 
Analysis Sets ...............................................................................................................61 
14.3. 
Primary Efficacy Outcome .........................................................................................61 
14.4. 
Analysis of Primary Outcome ....................................................................................61 
14.5. 
Secondary Efficacy Outcomes ....................................................................................62 
14.6. 
Analysis of Secondary Outcomes ...............................................................................62 
14.7. 
Study Size ...................................................................................................................62 
14.8. 
Other Objectives .........................................................................................................63 
14.9. 
Safety Objectives ........................................................................................................63 
15. 
REGULATORY AND ETHICS CONSIDERATIONS .............................................63 
15.1. 
Institutional Review Board (IRB) ...............................................................................63 
15.2. 
Ethical Conduct of the Study ......................................................................................64 
15.3. 
Informed Consent .......................................................................................................64 
15.4. 
Subject Confidentiality ...............................................................................................64 
16. 
DOCUMENTATION .................................................................................................65 
16.1. 
Study File and Site Documents ...................................................................................65 
16.2. 
Study Documents Supplied by the Sponsor ................................................................65 
16.3. 
Maintenance and Retention of Records ......................................................................65 
17. 
ADMINISTRATIVE PROCEDURES .......................................................................66 

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17.1. 
Sponsor Responsibilities .............................................................................................66 
17.2. 
Investigator Responsibilities .......................................................................................66 
17.3. 
Regulatory Compliance ..............................................................................................67 
17.4. 
Protocol Modification/Premature Termination ...........................................................67 
17.5. 
Policy for Publication and Data Presentation .............................................................67 
18. 
INVESTIGATOR’S AGREEMENT ..........................................................................69 
19. 
REFERENCES ...........................................................................................................70 
APPENDIX 1. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) ..................72 
APPENDIX 2. HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) .......................79 
APPENDIX 3. PENN STATE ELECTRONIC CIGARETTE DEPENDENCE INDEX ..........81 
APPENDIX 4. MARIJUANA CRAVING QUESTIONNAIRE (MCQ-SHORT 
FORM) ........................................................................................................................82 
APPENDIX 5. BEHAVIORAL SUPPORT ...............................................................................83 
APPENDIX 6. MINNESOTA WITHDRAWAL SCALE (MNWS) ..........................................85 
 
LIST OF TABLES 
Table 1: 
ORCA-1 Study: Most Common Adverse Events .......................................................20 
Table 2: 
Adverse Events Reported From Sopharma Core Data Sheets for Cytisine ................23 
Table 3: 
Schedule of Study Procedures During Treatment Period ...........................................37 
Table 4: 
Adverse Event Severity ..............................................................................................55 
Table 5: 
Assessment of Attribution to Study Drug ...................................................................56 
 
LIST OF FIGURES 
Figure 1: 
ORCA-1 Study: CO-Verified Abstinence Results .....................................................19 
Figure 2: 
ACH-CYT-10 (ORCA-V1) Study Design Overview .................................................27 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABBREVIATION/TERM 
DEFINITION 
ACh 
Acetylcholine 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ARS 
All Randomized Analysis Set 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BID 
Twice a Day 
BMI 
Body Mass Index 
CI 
Confidence Interval 
Cmax 
Maximum Observed Plasma Concentration 
CO 
Carbon Monoxide 
CrCl 
Creatinine Clearance  
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DDI 
Drug-to-Drug Interaction 
DSMC 
Data Safety Monitor Committee 
ECG 
Electrocardiogram 
EVALI 
e-cigarette or vaping use-associated lung injury 
ET 
Early Termination 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
HADS 
Hospital Anxiety and Depression Scale 
HED 
Human Equivalent Dose 
ICH 
International Conference on Harmonization 
I.D. 
Identification 
IMP 
Investigational Medicinal Product (for this protocol indicates 
cytisinicline 3 mg film coated tablet) 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNWS 
Minnesota Nicotine Withdrawal Scale 
nAChRs  
Nicotinic Acetylcholine Receptors 
NRT 
Nicotine Replacement Therapy 
NOAEL 
No-Observed-Adverse-Effect-Level 
OR 
Odds Ratio 
PSUR 
Periodic Safety Update Reports 
RR 
Relative Risk 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 

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ABBREVIATION/TERM 
DEFINITION 
SAS 
Safety Analysis Set 
SD 
Standard Deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SmPC 
Summary of Product Characteristics 
SOC 
MedDRA System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TID 
Three Times a Day 
UADR 
Unexpected Adverse Drug Reaction 
UAE 
Unexpected Adverse Event 
ULN 
Upper Limit of Normal 
USAN 
United States Adopted Names 

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In 2019, the Center for Disease Control (CDC), the U.S. Food and Drug Administration (FDA), 
state and local health departments, and other clinical and public health partners were 
investigating a national outbreak of severe cases of lung illnesses referred to as “e-cigarette, or 
vaping, product use-associated lung injury (EVALI)”. The number of EVALI cases reported to 
CDC peaked during the week of September 15, 2019, with the weekly number of hospitalized 
patients steadily declining as of February 2020 (refer to: www.cdc.gov/lunginjury). As of 
February 18, 2020, a total of 2,807 hospitalized EVALI cases or deaths were reported to CDC 
from all 50 states, the District of Columbia, and two U.S. territories (Puerto Rico and U.S. Virgin 
Islands). Laboratory data showed that vitamin E acetate, an additive in some THC-containing 
e-cigarette, or vaping, products, was strongly linked to the EVALI outbreak. However, evidence 
was not sufficient to rule out the contribution of other chemicals of concern, including chemicals 
in either THC or non-THC vaping products, in some of the reported EVALI cases. Although 
there is currently no molecular mechanism of nicotine involvement in causing EVALI cases, 
other chemical components in nicotine-containing vaping products can also not be ruled out. 
Cigarette smoking has long been a known risk factor for cardiovascular and pulmonary diseases 
(CVPD), even though direct effects and molecular mechanisms of nicotine in the pathogenesis of 
these diseases have not been elucidated. There is evidence that cigarette smoke or direct nicotine 
inhalation has a role in disrupting the homeostasis of the renin-angiotensin system (RAS), which 
impacts the regulation of blood pressure and the development of CVPD. The literature suggests 
that nicotine alters the homeostasis of the RAS by upregulating the detrimental angiotensin-
converting enzyme (ACE)/angiotensin (ANG)-II/ANG II type 1 receptor axis and 
downregulating the compensatory ACE2/ANG-(1-7)/MAS receptor axis.10 
Other publications have shown various direct and indirect effects of nicotine on the immune 
system which may result in increased pulmonary inflammation or risk of pulmonary infections in 
smokers and possibly vapers.11-14 Recent hypotheses that smoking or vaping nicotine may result 
in more susceptibility to the effects of coronavirus infections will warrant further investigations 
for either a possible direct nicotine effect or due to underlying CVPD as a risk factor.  
Regardless of the various risks, outcomes, or direct mechanisms, nicotine addiction remains a 
public health concern.  
1.3. 
Cytisinicline for Treatment of Nicotine Addiction 
Prior trials have demonstrated cytisinicline’s efficacy in helping people deal with nicotine 
addiction and to quit smoking. Cytisine was evaluated in three large, randomized Phase 3 clinical 
trials that were conducted according to Good Clinical Practice (GCP) in more than 
2,000 participants. The overall objectives in these trials were to confirm the efficacy and safety 
of cytisine according to current clinical development standards.  
The Phase 3 trial (TASC6 trial) was sponsored by the UK Centre for Tobacco Control Studies 
and evaluated cytisine versus placebo in 740 primarily moderate-to-heavy smokers treated for 
25 days in a single center in Warsaw, Poland. The primary outcome measure was sustained, 
biochemically-verified smoking abstinence for 12 months after the End-of-Treatment. The 
TASC trial was conceived by Professor Robert West (Department of Epidemiology and Public 
Health, University College London) and was funded by a grant from the National Prevention 
Research Initiative, including contributions from Cancer Research UK, Medical Research 
Council, United Kingdom Department of Health, and others. The results of the TASC trial were 

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published in the New England Journal of Medicine in September 2011.6 The Relative Risk (RR) 
for sustained 12-month abstinence was 3.4 for cytisine compared to placebo (8.4% cytisine arm 
compared to 2.4% placebo arm; P<0.001). The RR for sustained 6-month abstinence was 2.9 
(10.0% cytisine arm compared to 3.5% placebo arm; P<0.001). Cytisine was well tolerated with 
an increase in all-combined gastrointestinal (GI) adverse events (although there was no 
significant difference in individual GI events between the arms). The safety profile of cytisine 
was similar to that of a placebo, with no overall difference in the rate of side effects in the two 
arms.  
The second Phase 3 trial (CASCAID7 trial) was conducted by the Health Research Council of 
New Zealand and was an open-label trial that randomized 1,310 adult daily smokers. Subjects 
were randomized to receive either cytisine for 25 days or NRT for 8 weeks. Both treatment 
groups were offered low-intensity telephone behavioral support during trial treatment. The 
primary outcome measure was continuous self-reported abstinence from smoking one month 
after a quit date. The RR for continuous one-month abstinence was 1.3 for cytisine (40% cytisine 
arm compared to 31% in the NRT arm; P<0.001). A secondary outcome included the RR for 
continuous six-month abstinence which was 1.4 for cytisine (22% cytisine arm compared to 15% 
in the NRT arm; P=0.002). Cytisine was generally well tolerated, although self-reported adverse 
events were higher in the cytisine arm compared with the NRT arm. The most frequent adverse 
events were nausea and vomiting and sleep disorders. The results of the CASCAID trial, which 
were published in the New England Journal of Medicine in December 2014, showed that cytisine 
was superior to NRT for smoking cessation and, specifically, that cytisine was 1.43 times more 
likely than nicotine gums or patches to help participants stop smoking and remain non-smokers 
for six months.7 
A recent third Phase 3 trial (RAUORA8 trial) was conducted by Natalie Walker in New Zealand 
to determine whether cytisine was at least as effective as varenicline in supporting smoking 
abstinence for ≥6 months in the New Zealand indigenous Māori or whānau (extended-family) of 
Māori, given the high smoking prevalence in this population. The study design was a pragmatic, 
open-label, randomized, community-based non-inferiority trial. Adult daily smokers who 
identified as Māori or whānau of Māori, motivated to quit in within 2 weeks, aged ≥18 years, 
and eligible for subsidized varenicline were enrolled and 679 people were randomly assigned 
(1:1) to receive a prescription for 12-weeks of cytisine or varenicline, plus low-intensity 
cessation behavioral support. Cytisine was administered first via the 25-day downward titration 
regimen followed by a daily maintenance of 1.5mg cytisine twice a day for the remaining 
12 weeks and varenicline was administered for 12 weeks per market approved prescription. The 
primary outcome was carbon-monoxide verified continuous abstinence at 6 months, analyzed as 
intention to treat (with multiple imputation for missing data). Secondary outcomes included 
adverse event analyses. Verified continuous abstinence rates at 6 months post-quit date were 
12.1% (41 of 337) for cytisine vs 7.9% (27 of 342) for varenicline (risk difference 4.29%, 95% 
confidence interval [CI] -0.22 to 8.79; relative risk 1.55; 95% CI 0.97 to 2.46). Sensitivity 
analyses confirmed the findings were robust. Self-reported adverse events over 6 months 
occurred significantly more frequently in the varenicline group (cytisine: 313 events in 
111 participants; varenicline: 509 events in 138 participants, incidence rate ratio 0.56, 95% CI 
0.49 to 0.65, p<0.001) compared with the cytisine group. Common adverse events were 
headache, nausea, and difficulty sleeping. The results of the RAUORA trial, which were 
published in Addiction in March 2021, showed that cytisine was at least as effective as 

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varenicline at supporting smoking abstinence in New Zealand indigenous Māori or whānau 
(extended-family) of Māori, with significantly fewer adverse events. 
Achieve recently conducted a Phase 2b study that evaluated cytisinicline dosing using different 
administration schedules within the 25-day treatment period.15 The Phase 2b study arms 
consisted of the 1.5 mg dose/downward titration schedule (used in the above Phase 3 studies and 
currently marketed in European countries), a higher dose of 3 mg using the same downward 
titration schedule, as well as a 1.5 mg and 3 mg dose using a simplified three times a day (TID) 
schedule, and respective placebo arms. Of the 254 subjects enrolled in the study, 121 (47.6%) 
were men and 133 (52.4%) were women. The mean (SD) age was 48.4 (13.0) years. For all 
Subjects, the mean (SD) number of years as a smoker was 32.1 (13.7), with an average of 
18.2 (6.0) cigarettes smoked per day. All subjects in the study attempted to quit smoking in the 
past, with an average (SD) of 4.5 (4.8) previous quit attempts. The mean (SD) number of years 
from the last quit attempt to the first screening visit was 3.7 (5.1). 
Below are the most relevant efficacy results for abstinence rates at Week 4 and prolonged 
abstinence (smoking cessation) through Week 5-8. The respective titration placebo and TID 
placebo arms were pooled based on demonstrating the same efficacy outcome measures. 
Treatment compliance was high for all arms with >94% mean compliance for study drug 
administration. 
Figure 1: 
ORCA-1 Study: CO-Verified Abstinence Results 
 
 

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Results for the initial quit rate at Week 4 demonstrated both arms of the TID schedule had 
significantly higher odds of success of quitting smoking compared with placebo; subjects in the 
3 mg cytisine arm had the best odds of success for quitting smoking: OR: 6.31 (95% CI: 2.28, 
18.45). The OR for the 1.5 mg cytisine arm on the TID schedule was 5.81 (95% CI: 2.12, 16.87). 
On the commercial schedule, the ORs for the 1.5 and 3 mg cytisine arms were 5.59 (95% CI: 
2.03, 16.29) and 5.38 (95% CI: 1.95, 15.72), respectively.  
For smoking cessation from Week 5 to Week 8, both arms of the TID schedule had higher odds 
of success for abstinence compared with placebo; subjects in the 3 mg cytisine arm had the best 
odds of success for abstinence from Weeks 5 to 8, with an OR of 5.04 (95% CI: 1.42, 22.32). 
The OR for the 1.5 mg cytisine arm on the TID schedule was 4.33 (95% CI: 1.21, 19.30). On the 
commercial schedule, the ORs for the 1.5 mg cytisine and 3 mg arms were 3.23 (95% CI: 0.86, 
14.85) and 2.24 (95% CI: 0.55, 10.82), respectively.  
Subjects in the cytisine arms on the TID schedule also had higher odds of smoking abstinence at 
the Week 6, 7, and 8 timepoints compared with subjects in the corresponding arms on the 
commercial schedule versus placebo, as demonstrated by higher ORs at each timepoint. 
All safety profiles appeared acceptable, especially for the 3mg TID schedule as shown below for 
the most common (>5%) adverse events. 
Table 1: 
ORCA-1 Study: Most Common Adverse Events 
Downward Titration 
TID 
1.5 mg 
(n=51) 
3 mg 
(n=50) 
1.5 mg 
(n=52) 
3 mg 
(n=50) 
Pooled Placebo 
(n=51) 
At least 1 AE 
29 (57%) 
23 (46%) 
20 (39%) 
21 (42%) 
24 (47%) 
Nausea 
5 (10%) 
3 (6%) 
1 (2%) 
3 (6%) 
5 (10%) 
Abnormal dreams 
4 (8%) 
7 (14%) 
4 (8%) 
3 (6%) 
1 (2%) 
Insomnia 
3 (6%) 
4 (8%) 
4 (8%) 
3 (6%) 
1 (2%) 
Headache 
1 (2%) 
1 (2%) 
6 (12%) 
2 (4%) 
2 (4%) 
URTI 
3 (6%) 
2 (4%) 
5 (10%) 
3 (6%) 
7 (14%) 
Refer to the Investigator’s Brochure for more detail on GCP-conducted clinical studies by 
Achieve Life Sciences. 
2. 
SAFETY OVERVIEW FOR CYTISINICLINE 
2.1. 
Non-Clinical Studies 
The US National Center for Complementary and Integrative Health (NCCIH) designated cytisine 
as “a drug of national Public Health importance” and, in collaboration, has sponsored a series of 
recent pharmacology and toxicology studies in support of the cytisinicline IND. In that regard, 
NCCIH has sponsored non-clinical GLP studies that have included 28-day repeat dosing for 
toxicology assessments in rats and dogs as well as reproductive/developmental studies in rats and 
rabbits. Achieve has also completed a 26-week chronic toxicology study in rats and a 39-week 
chronic toxicology study in dogs.  

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The number of e-cigarette users continues to grow and while e-cigarettes have been viewed as 
safer than combustible cigarettes, e-cigarettes may sustain nicotine addiction and the long-term 
safety of and addiction to e-cigarettes is still unknown. While developing a questionnaire for 
assessing dependence to e-cigarettes,16 a multivariate analysis showed that individuals who had 
used e-cigarettes longer had higher dependence scores, as did those using more advanced 
e-cigarette devices that were larger than a cigarette and had a manual button. Those using zero 
nicotine liquid had significantly lower e-cigarette dependence scores than those using 
1-12 mg/ml nicotine and those using 1-12 mg/ml nicotine also scored significantly lower than 
those using 13 or greater mg/ml nicotine liquid (p <.003). Thus, e-cigarette dependence appeared 
to vary by product characteristics, liquid nicotine concentration, and length of time using 
e-cigarettes. 
Prior trials have demonstrated cytisinicline’s efficacy in helping people quit smoking. This 
clinical study will evaluate the potential benefit of cytisinicline in treating nicotine addiction 
among users whose only source of nicotine is via the use of e-cigarettes. Given the mechanism of 
action of cytisinicline, this study will assess whether cytisinicline given to users of nicotine-
containing e-cigarettes but not combustible tobacco products (i.e., conventional cigarettes) can 
reduce nicotine dependence and promote vaping cessation or reduction. The study population of 
e-cigarette users only, not dual users who are also smoking combustible cigarettes, is intentional 
for this study in order to monitor expired CO levels for any reverting to combustible cigarette 
smoking, which would be viewed as increasing harm while reducing e-cigarette usage.  
As an added value, this study will evaluate the same safety parameters as the planned Phase 3 
studies to be conducted for regulatory approval of cytisinicline as an aid for cigarette smoking 
cessation and hence will add to the growing safety database for cytisinicline in subjects addicted 
to nicotine either via combustible or e-cigarettes. 
Thus, in this study, subjects will be randomized 2:1 to receive either 3 mg cytisinicline TID for 
12 weeks plus standard behavioral support (Arm B: cytisinicline TID ) or placebo TID for 
12 weeks plus standard behavioral support (Arm A: placebo TID). The primary outcome 
assessment will be nicotine vaping cessation during Weeks 9-12. In this study, all references to 
vaping means the use of nicotine-containing e-cigarettes or other nicotine-containing vaping 
devices. Vaping cessation is defined as weekly nicotine vaping abstinence for 4 consecutive 
weeks. Other timing for weekly vaping abstinence/cessation (e.g., Weeks 3-6 or Weeks 6-9) and 
any reduction in nicotine vaping will be analyzed as secondary outcomes. The safety profile for 
3 mg cytisinicline administered TID for 12 weeks will also be evaluated. 
4. 
STUDY OBJECTIVES 
4.1. 
Primary Efficacy Objective 
Assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 12 weeks plus 
behavioral support) have a higher probability of nicotine vaping cessation from Week 9 to Week 
12 post-randomization as compared to subjects randomized to Arm A (placebo TID for 12 weeks 
plus behavioral support). 

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4.2. 
Secondary Efficacy Objectives   
1) Assess whether subjects randomized to Arm B (cytisinicline TID) can achieve vaping 
abstinence/cessation at any time during treatment or reduce their daily vaping as 
objectively measured with biomarkers of nicotine exposure compared to subjects 
randomized to Arm A (placebo TID). Specific Secondary Efficacy Objectives related to 
this are described below: 
• Assess whether subjects randomized to Arm A have a higher probability of achieving 
vaping cessation between Week 3 and Week 9 post-randomization (e.g., Week 3-6 or 
Week 6-9,) as compared to subjects randomized to Arm B.  
• To compare arms (Arm A vs Arm B) on 7-day point prevalence rates for vaping 
abstinence on a weekly basis from Week 2 to Week 12. 
• To compare arms (Arm A vs Arm B) for a reduction in nicotine vaping using weekly 
quantitative cotinine levels from Week 2 to Week 12.  
2) Assess whether subjects randomized to Arm A have a higher probability for continuous 
vaping abstinence between Week 9 and Week 16 post-randomization (i.e., subjects 
achieving primary endpoint abstinence with continued abstinence through follow-up). 
4.3. 
Other Objectives 
Explore the magnitude of treatment effect between arms across various subgroups defined by 
demographic and baseline characteristics for the primary and secondary outcomes. 
Evaluate for nicotine withdrawal symptoms at Weeks 1-4 and again for any possible withdrawal 
symptoms due to study drug discontinuation pre- and post-Week 12. 
4.4. 
Safety Objectives 
To evaluate the safety profile of 3 mg TID cytisinicline when administered for 12 weeks. 
5. 
STUDY DESIGN OVERVIEW 
5.1. 
Study Design 
This will be a multi-center, double-blind, randomized, placebo-controlled, Phase 2 study 
conducted in male or female adults who are ≥18 years age and are daily nicotine e-cigarette users 
(i.e., vaping only subjects as confirmed with a positive cotinine sample >30 ng/mL and a carbon 
monoxide [CO] breath sample <10 ppm), intending to try to quit vaping, and willing to set a quit 
date that is within 7-14 days from the start of study treatment. Study treatment must start the day 
after study randomization.  
Subjects must meet all requirements outlined in the inclusion and exclusion criteria. A total of 
approximately 150 subjects will be randomly assigned (2:1) to one of two arms: (Arm B, 
cytisinicline plus behavioral support: N=100 or Arm A placebo plus behavioral support: N=50) 
as shown in the study design figure below. 
  

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Figure 2: 
ACH-CYT-10 (ORCA-V1) Study Design Overview 
 
The study will be conducted at approximately 5-8 clinical sites across the United States. Subjects 
will be randomized and stratified based on whether they have smoked >100 cigarettes in their 
lifetime (yes vs no). 
The study will be comprised of a pre-study screen, followed by 12 weeks of treatment, and one 
post-treatment follow up visit at 16 weeks post-randomization.  
Each randomized subject will receive 12 weeks of treatment using a TID dosing schedule. 
Vaping quit status (abstinence) will be assessed starting at Week 2 (Day 14±1) and assessments 
will continue weekly during the Treatment Period through to Week 12 and at Week 16. In 
addition, periodic assessments for cotinine in saliva and expired CO levels will be performed 
during the treatment period and will be compared to baseline (Day 0) measures. All subjects will 
receive concurrent nicotine cessation behavioral support during the study Treatment Period 
(Week 1-12).  
Determination of vaping abstinence will be made from the subject’s self-report of no vaping in 
the past 7 days with biochemical cotinine verification (cotinine <10 ng/mL). Weekly vaping 
assessments will start at Week 2 and continue weekly through Week 12. At the Week 16 follow 
up visit, expired CO will be measured and for those subjects reporting vaping abstinence, a 
saliva sample for cotinine testing will be assessed.  
The primary efficacy measure will be the number of subjects who achieve nicotine vaping 
abstinence for 4 consecutive weeks from Week 9 to Week 12 (i.e., vaping cessation). The 
number of subjects who achieve vaping abstinence at any time between Week 2 and Week 12 
will also be reported as 7-day point prevalence rates. Other secondary efficacy outcomes for 
achieving earlier vaping cessation (e.g., vaping abstinence for 4 consecutive weeks from Week 3 
to 6 or from Week 6 to 9) will be assessed. Measurements for CO levels will be used as a 
sensitivity test to assess for concurrent combustible cigarette usage in those subjects reporting 
vaping abstinence or cessation. The number of subjects who achieve continuous vaping 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm A 
N=50 
Placebo TID 12 Weeks  
+ Behavioral Support 
Arm B 
N=100 
Cytisinicline 3 mg TID 12 Weeks 
+ Behavioral Support 
 
 
 
 
S 
C 
R 
E 
E 
N 
F 
O 
L 
L 
O 
W 
 
U 
P 

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abstinence at Week 9 through Week 16 (e.g., self-report of no vaping supported by biochemical 
verification).  
Additional secondary efficacy outcomes for any reduction in vaping will be assessed on a weekly 
basis between Week 2 and Week 12 of cytisinicline treatment using quantitative saliva cotinine 
levels compared to baseline levels, as conducted by the central lab.  
Subjects will be instructed to complete the Minnesota Nicotine Withdrawal Scale (MNWS) 
questionnaire (Appendix 6) electronically at the Week 1, 2, 3, 4 clinic visits and again at 3 (±1) 
days prior to the Week 12 clinic visit and 3 (±1) days after the Week 12 clinic visit. 
Safety assessments at clinic visits will occur on Day 7 (Week 1) and then weekly throughout the 
Treatment Period. Laboratory hematology and chemistry assessments will be made on Day 7, 
Week 6, and Week 12 during the treatment period. Adverse events will be monitored through the 
Follow-up Period. Any ongoing adverse events at Week 16 will be followed until resolved or 
determined to be chronic.  
Treatment assignment unblinding for subjects will not occur until the end of the study has been 
reached, the database has been locked, and final study analyses have been performed, unless 
defined as an unblinding exception in Section 5.3.4. 
5.2. 
Treatment Period (12 Weeks) 
Treatment Period must begin on the day after randomization. Study treatment will be blinded, 
and subjects will take one study tablet three times during the day, approximately 5 hours apart. 
Subjects randomly assigned to Arm B will take one cytisinicline tablet at each dosing per day for 
12 weeks. Arm A subjects will take one placebo tablet at each dosing per day for 12 weeks.  
5.3. 
Discussion of Study Design 
5.3.1. 
Placebo Control 
A placebo control in this study design is necessary to control for response bias in evaluating for 
vaping abstinence and safety. Behavioral support alone has been shown to be effective in 
helping cigarette smokers to quit their nicotine addiction. Therefore all subjects in this study will 
receive behavioral support to aid their attempt to quit their nicotine vaping addiction. In addition, 
this study evaluates the effectiveness of cytisinicline when administered for 12 weeks compared 
to one placebo group, and the 2:1 randomization schedule means that subjects have a 2 in 3 
chance of receiving active study drug. The use of a placebo group is therefore considered 
justified. 
5.3.2. 
Primary Endpoint 
The primary endpoint mirrors that used for smoking cessation trials. Smoking abstinence during 
the last 4 weeks of treatment with biochemically-verified CO levels has been the established 
primary endpoint for smoking cessation trials in regulatory approvals. Most Phase 3 trials had a 
“grace” period with success then determined by having 4 weeks abstinence during the last 
4 weeks of treatment.  

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For the primary endpoint, success is defined as vaping abstinence during the last 4 weeks of the 
12 week treatment period (Week 9 through Week 12) using quantitative saliva cotinine levels at 
<10 ng/mL for biochemical verification and subject’s self-report of no vaping in the past 7 days.  
5.3.3. 
Blinding 
This double-blind study design protects against subjective bias in reporting both efficacy and 
safety. Blinding will occur by coding the individual study drug cartons and packs by an 
independent vendor assigned to the trial. The Sponsor and site personnel will not have access to 
the treatment assignment for individual subjects (except as an emergency; refer to Section 5.3.4) 
until the database is locked and final study analysis has been performed. 
5.3.4. 
Unblinding  
There is no intention to routinely unblind individual subjects at any time. During the study, 
emergency unblinding for treatment or regulatory reporting of adverse events might need to be 
performed as described below.  
Unblinding may be done if the subject's well-being or treatment of adverse events requires 
knowledge of study drug assignment. The investigator must first contact the Study Medical 
Monitor, or representative, who will coordinate access to the treatment assignment code via the 
independent vendor.  
Examples of unblinding for treatment emergencies include:  
• A life-threatening, unexpected adverse event that is thought to be related to study 
drug and for which unblinding would change or influence treatment decisions. 
• Medication error, such as an accidental overdose, that would warrant unblinding in 
order to more effectively manage toxicity. 
Unblinding by the Sponsor may also be necessary to determine whether a serious and unexpected 
suspected adverse reaction (SUSAR) requires expedited reporting to FDA. Per FDA guidance, 
the sponsor must report an adverse event as a SUSAR only if there is evidence to suggest a 
causal relationship between the investigational drug and the adverse event such as: 
• A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure; 
• One or more occurrences of an event that is not commonly associated with the 
investigational drug exposure, but is otherwise uncommon in the population exposed 
to the drug; 
• An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the study population independent of drug therapy) that 
indicates those events occur more frequently in the investigational drug treatment 
group than in the concurrent control group. 
Any unblinding of specific subjects by the Sponsor or required at the site level must be 
documented by the Sponsor. 

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5.4. 
Number of Subjects 
A total of 150 subjects will be randomized to the study, with approximately 100 subjects in the 
cytisinicline arm and 50 subjects in the placebo arm. Efforts will be taken to coordinate weekly 
limits to enrollment rates and total enrollment numbers among the participating sites in order to 
ensure adequate subject management and similar enrollment distribution among sites. The 
maximum number of subjects that a single site may be allowed to enroll is 30% of the study 
total.  
5.5. 
Randomization  
Sites will utilize an Interactive Response Technology (IRT) system for treatment arm assignment 
at randomization (Day 0). The IRT will randomize and stratify subjects (lifetime >100 cigarettes 
smoked; yes vs no) across the study. Detailed instructions are provided in the Study Reference 
Manual.  
5.6. 
 Number of Clinical Sites 
This will be a multicenter clinical trial within the US. Approximately 5-8 clinical sites will 
participate.  
5.7. 
Estimated Duration/Completion of Study 
Duration of this study is estimated to be approximately 16 weeks for an individual subject (from 
randomization to Week 16 visit). Completion of the entire study is dependent on accrual and is 
currently estimated at 8 months with ~2 months accrual ramp-up, an additional 2 months to 
complete accrual and 4 months for the last randomized subject to complete the study. 
6. 
SELECTION OF STUDY POPULATION 
Each potential subject will be provided with an informed consent form that has been reviewed 
and approved by the site’s governing institutional review board (IRB). In accordance with the 
International Conference on Harmonization (ICH) guidelines on informed consent, the 
Investigator (or designee) will provide potential subjects with a verbal description of the study 
including, but not limited to, study purpose, study procedures, risks and duration. Potential 
subjects will be asked to read the consent form and to sign and date it once all of their questions 
have been answered and they voluntarily agree to participate in the study. A copy of the signed 
informed consent form will be provided to the subject. 
Upon obtaining signed informed consent, each subject will undergo the screening procedures 
outlined in Section 10.2.1. A screening log will be maintained by the site and will include 
documentation for screening failures. Subjects meeting all inclusion/exclusion criteria will then 
be randomized to treatment and begin the study procedures. All subjects are considered enrolled 
once randomized.  
This clinical trial can fulfill its objectives only if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom protocol treatment and procedures are 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.  

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6.1. 
Inclusion Criteria 
Subjects must meet ALL of the following criteria to be eligible for inclusion into the study:  
1. Male or female subjects, age ≥18 years.  
2. Test positive for cotinine using the Alere iScreen® OFD Cotinine Oral Fluid Screening 
Device (Positive testing at ≥30 ng/mL cotinine level). 
3. Current daily nicotine-containing electronic cigarette usage as recorded in a screening 
diary for at least 7 consecutive days. Willing to bring the e-cigarette or nicotine device 
used to the clinical site so that the specific product type, flavor, and nicotine level can be 
documented. 
4. Willing to initiate study treatment on the day after randomization and set a quit date 
within 7-14 days of starting treatment. 
5. Willing to actively participate in the study’s vaping cessation behavioral support 
provided throughout the study. 
6. Able to fully understand study requirements, willing to participate, and comply with 
dosing schedule. 
7. Sign the Informed Consent Form. 
6.2. 
Exclusion Criteria 
Subjects meeting ANY of the following exclusion criteria will NOT be eligible for inclusion 
into the study. 
1. Currently smoking, or having smoked within 4 weeks prior to study randomization, any 
combustible cigarettes, other combustible tobacco products or non-combustible tobacco 
products (such as heat not burn products) (i.e., dual users). 
2. Expired Carbon Monoxide (CO) levels ≥10 ppm, indicating recent combustible tobacco 
use. 
3. More than 1 study participant in same household during the study treatment period. 
4. Known hypersensitivity to cytisinicline or any of the excipients.  
5. Positive urinary drugs of abuse screen determined within 28 days before the first dose of 
cytisinicline (Note: THC is not part of the abuse screen). 
6. Clinically significant abnormal serum chemistry or hematology values within 28 days of 
randomization (i.e., requiring treatment or monitoring).  
7. Clinically significant abnormalities in 12-lead ECG determined after minimum of 
5 minutes in supine position within 28 days of randomization (i.e., requiring treatment or 
further assessment). 
8. Recent history (within 3 months) of acute myocardial infarction, unstable angina, stroke, 
cerebrovascular incident or hospitalization for congestive heart failure. 
9. Current uncontrolled hypertension (blood pressure ≥160/100 mmHg). 
 

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10. Documented diagnosis of schizophrenia or bipolar psychiatric illness; currently 
psychotic; having suicidal ideation within the last 3 months (corresponding to question 4 
or 5 on the C-SSRS); or current symptoms of moderate to severe depression (depression 
score ≥11 on the HADS) within the last 3 months. 
11. Renal impairment defined as a creatinine clearance (CrCl) <60 mL/min (estimated with 
the Cockroft-Gault equation). 
12. Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2.0 x the upper limit of normal (ULN). 
13. Recent history or symptoms (within 4 weeks of randomization) of unstable respiratory 
disease (e.g., pneumonia, product-use associated lung injury or EVALI, etc.) 
14. Women who are pregnant or breast-feeding. 
15. Male or female subjects of childbearing potential who do not agree to use acceptable 
methods of birth control starting at the time of consent, during the study treatment period, 
and continuing for one month after ending study treatment. 
16. Participation in a clinical study with an investigational drug in the 4 weeks prior to study 
randomization. 
17. Use of other smoking cessation medications (bupropion, varenicline, nortriptyline, or any 
nicotine replacement therapy [NRT]) in the 4 weeks prior to study randomization, any 
previous cytisine use, or planned use of these or other nicotine replacement medications 
during the study. 
18. Any planned use during the study of combustible cigarettes or other nicotine-containing, 
non-vaping products (e.g., pipe tobacco, cigars, snuff, smokeless tobacco, hookah, ZYN 
pouches, etc).  
19. Any other reason that the investigator views the subject should not participate or would 
be unable to fulfill the requirements for the study. 
6.3. 
Modifying or Discontinuing Study Drug and/or Study Evaluations 
6.3.1. 
Study Drug Modification during the 12-Week Treatment Period 
Dose modifications in general are not allowed. On a case by case exception, the study treatment 
may be reduced to a twice a day (BID) schedule. These exceptions are only allowed for subjects 
who experience moderate or severe AEs (e.g., nausea, insomnia, nightmares, anxiety) that might 
be attributed to study drug and would otherwise discontinue study treatment due to the AE. The 
reduction of one dose from a TID to a BID schedule should be related to the timing of the 
moderate or severe AE. For example, removing the evening dose for AEs related to insomnia or 
nightmares OR removing the morning dose for nausea or other gastrointestinal symptoms related 
to possible fasting conditions. Any dose reductions need to be discussed and coordinated with 
the Study Medical Monitor, or representative, prior to any dose reduction. Once a dose reduction 
to a BID schedule occurs, no re-escalation back to a TID schedule is allowed. If the dose 
reduction to a BID schedule does not improve the AE symptoms to a tolerable level, then further 
dose reductions should not occur and the subject should discontinue study treatment. 
 

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6.3.2. 
Study Discontinuation  
Subjects can be discontinued from study for the reasons below:  
1. If a subject experiences a serious or intolerable adverse event that prevents the subject 
from continuing study drug.  
2. At the Investigator’s request (e.g., if the Investigator considers that the subject’s health 
might be compromised by continuing study drug). Non-compliance should not be a 
reason for discontinuing treatment. 
3. If a subject becomes pregnant during the study treatment period, study drug should be 
discontinued; however, the subject should be followed during the pregnancy for safety 
assessments. 
4. At the request of the subject who does not want to continue study drug treatment or study 
evaluations. 
The reason for discontinuation from study will be recorded in the CRF. If the subject 
discontinues prior to the Week 12 visit, safety assessments outlined for the Week 12 visit 
(C-SSRS, hematology and chemistry labs, ECG, HADS and urine pregnancy test if applicable) 
should be completed at the time of discontinuation.  
If a subject discontinues study due to any adverse event or any abnormalities considered to 
be clinically significant by the investigating physician, the subject will be followed until 
values are considered to be clinically acceptable or deemed chronic. 
7. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
7.1. 
Cytisinicline Film-Coated Tablets 
Cytisinicline will be supplied by the Sponsor. The cytisinicline drug product is formulated as a 
compressed film-coated tablet containing 3 mg cytisinicline in a single tablet. Each tablet is 
composed of cytisinicline active substance (as the base) and well-established tablet-forming 
excipients. 
  
 
 
 
. 
7.2. 
Placebo Tablets 
Placebo tablets will contain the same excipients as in the cytisinicline tablet formulation plus 
additional cellulose powder in order to match final weight of the cytisinicline tablet. Placebo 
tablets will be identical in size, shape, color, and packaging in order to preserve the double-blind 
design of the study. 
7.3. 
Receipt and Storage  
The Study Drug will be supplied in 1-week treatment blister packs with 6 individual weekly 
blister packs in a carton (6 weeks of treatment). Each subject will be assigned 2 cartons for 
completing the 84 days (12 weeks) of study treatment. The first carton will be assigned on Day 0 
and the second carton will be assigned on Day 35 (Week 5) so that treatment can follow assigned 
treatment arm (Figure 2). A clinical supplies management vendor will label, package, and 
distribute study drug to the sites. 

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7.8. 
Accountability 
The pharmacist or pharmacist designee will maintain records of study drug receipt at the trial 
site, inventory at the site, dispensing for each subject, and any destruction or possible return of 
unused doses to the site for investigational product accountability.  
Study drug for each subject will be configured into 2 coded study drug cartons, one of which will 
be assigned at randomization and the other will be assigned just prior to the Day 42 (Week 6) 
visit. Each carton will in turn contain 6 study drug packs and each pack will contain 21 tablets to 
cover 7 days (1 week) dosing. Clinic staff will distribute and collect the 7-day packs as the 
subject progresses through the clinic visits and will conduct ongoing accountability during each 
clinic visit by reviewing each subject’s dosing timing in the diary and associated blister packs. 
Used packs will be retained so that the Sponsor's monitoring staff can verify accountability 
records. 
Upon completion of the study, all the investigational study drug product that has not been used 
and all the empty containers of the used investigational product at the sites will be destroyed or 
returned to the depot or Sponsor. 
8. 
PREVIOUS AND CONCOMITANT MEDICATIONS 
All subjects will continue to receive any existing prescription medication. Every effort should be 
made to ensure that the regimen of existing medications remain stable during the study.  
At the discretion of the Investigator, the use of non-study drug medications (either prescription 
or over-the-counter) may be given if clinically-indicated during the study. Full details of any new 
medications must be recorded in the subject’s Case Report Form (CRF).  
All concomitant medication(s) taken during the trial, and any changes (additions, deletions, dose 
changes) must be recorded in the CRF.  
9. 
TREATMENT COMPLIANCE 
Treatment compliance will be monitored during the 84 day (12 week) Treatment Period via 
review of dose timing and drug accountability. Subjects will have a daily diary that will record 
the number and time of tablets taken. Subjects will be instructed to bring their medication packs 
(blister packs) to each clinic visit so that clinic staff can reconcile against the diary, recording the 
number of tablets taken and the number of missed tablets. In addition, an optional text messaging 
system will be implemented that will provide each subject with reminder texts corresponding to 
the approximate time of dosing. 
 
 
 

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10. 
STUDY PROCEDURES 
After providing signed informed consent, all subjects will be evaluated for inclusion in the study 
within a 28 day Screening Period. Subjects who meet inclusion criteria will be required to 
provide a quit date that must be within 7-14 days after the start of treatment and agree to 
initiating study treatment the day after randomization. Both planned quit and treatment start dates 
must be documented to confirm inclusion. Once all eligibility criteria are confirmed, 
randomization can occur. Study Day 1 will be defined as the first day of treatment. Subjects will 
complete a clinic visit on Day 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77 and 86, plus one follow-up 
visit 4-weeks after completing study drug treatment. 
10.1. 
Procedure Schedule  
Table 3 provides a summary of required study evaluations. Refer to Section 10.2 for a detailed 
description of each study visit. Screening evaluations are to occur within a 28 day interval from 
initiation of screening evaluations to randomization. Subjects must initiate study treatment the 
day after randomization, such that study treatment is initiated on Day 1 prior to the quit date, 
within 7-14 days of Day 1.

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13Saliva will be collected for cotinine determination. Screening will be based on the point-of-care Alere iScreen® OFD Cotinine Oral Fluid Screening Device (Positive 
testing at ≥30 ng/mL cotinine level). On-study cotinine determinations will be sent to a central laboratory for analysis. A post-treatment cotinine sample will be 
obtained at the Week 16 follow up visit.  
14Any subjects with an expired CO level ≥10 ppm will be asked about combustible cigarette smoking as well as any cannabis smoking (see Section 12.3.2).  
15Record any use of non-combustible nicotine products (other than vaping) and/or cigarette smoking.  
16 Subjects will be instructed to complete the Minnesota Nicotine Withdrawal Scale (MNWS) questionnaire (Appendix 6) electronically at the clinic visit at Week 1, 2, 3, 
and 4 to determine any nicotine withdrawal symptoms. At the Week 11 clinic visit, subjects will be instructed that the MNWS questionnaire will also be administered 
electronically to all subjects 3 (±1) days prior to the Week 12 clinic visit and then 3 (±1) days after the Week 12 clinic visit to determine any similar withdrawal 
symptoms after completing cytisinicline.  
 
 

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10.2. 
Detailed Description of Study Visits 
10.2.1. 
Screening Phase (SV1-SV2) 
Screening assessments used to evaluate inclusion and exclusion criteria (SV1) can occur during 1 
or more clinic visits over a 28-day period prior to randomization.  
Screening (Day -28 to Randomization Day 0) 
Study procedures include: 
1. Written informed consent obtained. 
2. Demographic data. 
3. Medical and psychiatric history. Suicidal ideation is to be determined and documented 
via administration and assessment of the screening C-SSRS questionnaire (Appendix 1). 
Depression is to be assessed via the HADS questionnaire using the total for all 
depression-related questions (Appendix 2). 
4. Physical examination. 
5. Document any existing adverse events. 
6. Document concomitant medications. 
7. Review e-cigarette/vape use history, to include age started and number of days a nicotine 
vaping product was used in the past 30 days. In addition, identify all e-cigarette or vaping 
products used in the past 30 days and if more than one, the one most used, as well as the 
flavors used. Details about the specific products used, including nicotine concentration 
and typical weekly usage will be recorded.  
8. Record if subject has attempted to quit e-cigarette smoking in the past and if they have, 
the number of times they had stopped vaping at least 1 day because they were trying to 
quit and the method(s) used in their quit attempt(s).  
9. Record subject’s reason for wanting to quit e-cigarettes, their level of desire to quit, and 
confidence in their ability to quit, as well as their perceived level of health risks from e-
cigarettes compared to smoking cigarettes.  
10. Identify if the subject has ever smoked a tobacco cigarette or smoked >100 cigarettes in 
their lifetime (Stratification Factor: “yes” versus “no”). Collect information about any 
previous use of combustible cigarettes (age started, average number of cigarettes smoked 
per day, how long since last smoked and methods/treatments used to quit). Inquire if the 
subject switched to nicotine-containing e-cigarettes in order to quit smoking cigarettes 
and how confident they are that they can continue to abstain from cigarettes in the future. 
11. Record any other nicotine use, past and present.  
12. Obtain saliva sample for cotinine level using the point-of-care Alere iScreen® OFD 
Cotinine Oral Fluid Screening Device to assess Inclusion Criteria #2 (Positive testing at 
≥30 ng/mL cotinine).  
13. Expired CO. 

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14. Vital signs, including weight and height for BMI calculation. 
15. Urine pregnancy for all female subjects, excluding those who are surgically 
sterile (hysterectomy or tubal ligation) or are >2 years post-menopausal. 
16. Drugs of abuse screen. 
17. Hematology and Chemistry testing. 
18. 12-lead ECG. 
19. Provide diary instructions to capture specific type of daily e-cigarette use or vaping 
devices (e.g., types of pods, cartridges, single-use devices, etc.) for 7 consecutive days. 
This diary will be reviewed and recorded at Screening Visit #2 to verify that Inclusion #3 
is met and document routine use. Note: Instruct subject to also bring into the clinic at 
Screening Visit #2, their device(s) and product(s) used during the 7-day screening diary 
period for further documentation. 
20. Review all inclusion and exclusion criteria and if satisfied, schedule Screening Visit #2.  
Screening Visit #2 
1. Review all inclusion and exclusion criteria and if satisfied, continue with Screening Visit 
#2 procedures.  
2. During the Screening Visit #2 document any existing adverse events and concomitant 
medications.  
3. Subject to complete the Penn State Electronic Cigarette Dependence Index (Appendix 3) 
and the Short Form of the Marijuana Craving Questionnaire (Appendix 4). 
4. Each subject is to complete an e-cigarette/vaping use diary and bring into the clinic their 
e-cigarette or device (including product type, flavor, product nicotine level) that they 
used on a daily basis during the 7-day screening diary. Clinic site personnel are to record 
the daily use for the 7 consecutive days and specifically what the subject used during the 
7-day screening diary. 
5. Each subject to provide their targeted quit date, which must be 7-14 days after 
randomization (Any Treatment Day between Day 7 to Day 14) and the targeted quit date 
must be documented. Setting a quit date and plan will be considered as the initial 
behavioral support session with the subject. The quit date will then determine the date for 
randomization. If a subject can commit to a quit date that allows for treatment to start the 
following day, the Screening Visit #2 may be treated as Day 0 and the subject can be 
randomized. In such cases, all procedures outlined in (Section 10.2.2 ) must be 
completed. 
 
 
 
 

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10.2.2. 
Randomization  
Randomization (Day 0) 
Randomization must be performed within 7-14 days prior to the agreed upon quit date. All other 
screening evaluations must be completed within 28 days prior to the Randomization Day. Study 
treatment must start on the day after randomization. 
Study procedures include: 
1. Update concomitant medication(s). 
2. Document any existing adverse events. 
3. Vital signs, including weight. 
4. Urine pregnancy for all female subjects, excluding those who are surgically 
sterile (hysterectomy or tubal ligation) or are >2 years post-menopausal. 
5. Obtain saliva sample for cotinine testing by central laboratory. 
6. Expired CO. 
Upon completion of procedures 1-6 above, assess for final confirmation/verification of eligibility  
If confirmation supports inclusion, complete the following:  
1. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: it should be stressed to subjects that they must maintain their 
dosing schedule throughout the Treatment Period.  
2. Randomize according to a pre-determined, blinded, randomization schedule (see 
Section 5.5) and obtain the first study treatment carton (Carton #1) which will contain 
treatment packs for Weeks 1-6.  
3. Provide study treatment Week 1 and Week 2 packs for the first 14 days of dosing and 
review dosing requirements. Review the layout and dosing instructions printed on the 
study treatment packs. Although packs will be marked with the week designation and 
dates, there will be times during the Treatment Period where a subject has multiple packs 
on hand. Review this with the subject and make sure it is understood that each pack must 
be completed for the designated time period before moving on to the next. Instruct 
subject that any/all packs in their possession must be brought back to the clinic at each 
visit and should never be thrown away. Used packs will be collected and all cartons and 
packs must be maintained by the site for drug accountability by the assigned study 
monitor. 
4. Develop an appointment schedule that includes dates and times for each required clinic 
visit during the trial, providing a copy to the subject. 
5. Provide study treatment diary instructions. 
6. Schedule a time on the following day (Day 1 of treatment, late in the day) when clinic 
will contact subject to assess compliance, any possible adverse events and any 
changes/additions in concomitant medications. 

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10.2.3. 
Treatment Period 
Treatment Day 1  
All subjects must begin treatment on the morning of Day 1 and record all dosing in the treatment 
diary. 
Clinic to contact subject via telephone call in afternoon or evening of Treatment Day 1 to: 
1. Verify subject is taking treatment (one tablet three times a day), review treatment diary 
completion requirements and answer any questions. 
2. Ask subject if any adverse events have occurred and/or any changes in concomitant 
medications. 
3. Remind subject of their appointment time for the Week 1 study visit and that they must 
bring with them their study treatment packs.  
Treatment Day 7/Week 1 (±1 day) 
1. Reconfirm planned quit attempt date, which must be between Treatment Day 7 to 14. 
2. Review study treatment diary to verify dosing up to time of visit. 
3. Assess for AEs and any changes to concomitant medications. 
4. Vital signs, including weight. 
5. Review study treatment Week 1 pack for compliance. Ensure that subject has study 
treatment Week 2 pack covering the next 7 days and provide a study treatment Week 3 
pack. 
6. Provide subject with behavioral support information that includes counseling. (NOTE: it 
should again be stressed to subjects that even if they are vaping less or have quit vaping, 
they must maintain their dosing schedule throughout the Treatment Period.  
7. Blood for hematology and serum chemistry testing. 
8. Have each subject complete the Minnesota Nicotine Withdrawal Scale (MNWS) 
questionnaire electronically at the clinic (Appendix 6). 
9. Remind subject of their Day 14 (Week 2) appointment date and time and that they must 
bring with them all study treatment packs. 
Treatment Day 14/Week 2 (±1 day) 
1. Review study treatment diary to verify dosing up to time of visit. 
2. Assess for AEs and any changes to concomitant medications.  
3. Vital signs, including weight. 
4. Review study treatment Week 2 pack for compliance and collect the Week 1 pack (which 
should be empty if all doses were taken as expected). Confirm that the subject has the 
Week 3 pack and provide a study treatment Week 4 pack. 
 

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5. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: At this time, it should be stressed to subjects that they must 
maintain their dosing schedule throughout the Treatment Period even if they have quit 
vaping. In addition, subjects are encouraged to continue trying to quit even if they are 
vaping or have a lapse after they have quit vaping. 
6. Obtain saliva sample for cotinine testing by central laboratory.  
7. Expired CO. 
8. Record the following:  
a. Has the subject vaped since the last clinic (Day 7) visit?  
b. If subject has vaped, record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 7) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 
9. Have each subject complete the MNWS questionnaire electronically at the clinic 
(Appendix 6). 
10. Remind subject of their Day 21 (Week 3) appointment date and time and that they must 
bring with them all study treatment packs. 
Treatment Day 21/Week 3 (±1 day) 
1. Review study treatment diary to verify dosing up to time of visit. 
2. Assess for AEs and any changes to concomitant medications. 
3. Vital signs, including weight. 
4. Review study treatment Week 3 pack for compliance and collect the Week 2 pack (which 
should be empty if all doses were taken as expected). Confirm that the subject has the 
Week 4 pack and provide a study treatment Week 5 pack. 
5. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: At this time, it should be stressed to subjects that they must 
maintain their dosing schedule throughout the Treatment Period even if they have quit 
vaping. In addition, subjects must be counseled to be honest with their vaping status 
information and encouraged to continue trying to quit even if they are vaping or have a 
lapse after they have quit vaping. 
6. Obtain saliva sample for cotinine testing by central laboratory.  
7. Expired CO. 
8. Record the following:  
a. Has the subject vaped since the last clinic (Day 14) visit?  
b. If subject has vaped, record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 14) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 

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9. Have each subject complete the MNWS questionnaire electronically at the clinic 
(Appendix 6). 
10. Remind subject of their Day 28 (Week 4) appointment date and time and that they must 
bring with them their study treatment packs. 
Treatment Day 28/Week 4 (±1 day) 
1. Review study treatment diary to verify dosing up to time of visit. 
2. Assess for AEs and any changes to concomitant medications. 
3. Vital signs, including weight. 
4. Review study treatment Week 4 pack for compliance and collect Week 3 pack (which 
should be empty if all doses were taken as expected). Confirm that the subject has the 
Week 5 pack and provide a study treatment Week 6 pack, which will be the last pack in 
first carton (Carton #1) assigned at randomization. 
5. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: Again it should be stressed to subjects that they must maintain 
their dosing schedule throughout the Treatment Period even if they have quit vaping. In 
addition, subjects must be counseled to be honest with their vaping status information and 
encouraged to continue trying to quit even if they are vaping or have a lapse after they 
have quit vaping. 
6. Obtain saliva sample for cotinine testing by central laboratory. 
7. Urine pregnancy for all female subjects, excluding those who are surgically 
sterile (hysterectomy or tubal ligation) or are >2 years post-menopausal. 
8. Expired CO. 
9. Record the following:  
a. Has the subject vaped since the last clinic (Day 21) visit?  
b. If subject has vaped, record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 21) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 
10. Have each subject complete the MNWS questionnaire electronically at the clinic 
(Appendix 6). 
11. Remind subject of their Day 35 (Week 5) appointment date and time and that they must 
bring with them their study treatment packs. 
Treatment Day 35/Week 5 (±1 day) 
1. Review study treatment diary to verify dosing up to time of visit. 
2. Assess for AEs and any changes to concomitant medications. 
3. Vital signs, including weight. 

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4. Review study treatment Week 5 pack for compliance and collect Week 4 pack (which 
should be empty if all doses were taken as expected). Confirm that the subject has the 
Week 6 pack. 
5. Obtain the study treatment carton #2 via IRT, which will contain study treatment Weeks 
7-12 packs. Provide subject with a Week 7 pack from Carton #2. 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: Again, it should be stressed to subjects that they must maintain 
their dosing schedule throughout the Treatment Period even if they have quit vaping. In 
addition, subjects must be counseled to be honest with their vaping status information and 
encouraged to continue trying to quit even if they are vaping or have a lapse after they 
have quit vaping. 
7. Obtain saliva sample for cotinine testing by central laboratory. 
8. Expired CO. 
9. Record the following:  
a. Has the subject vaped since the last clinic (Day 28) visit?  
b. If subject has vaped, record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 28) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 
10. Remind subject of their appointment date and time for the Day 42 (Week 6) visit and that 
they must bring with them their study treatment packs. 
Treatment Day 42/Week 6 (±1 day) 
1. Administer and assess suicidal ideation/risk using the “Since Last Visit” C-SSRS 
questionnaire (refer to Appendix 1). 
2. Subject to complete the HADS questionnaire (Appendix 2). 
3. Subject to complete the Penn State Electronic Cigarette Dependence Index (Appendix 3) 
4. Review study treatment diary to verify dosing up to time of visit. 
5. Assess for AEs and any changes to concomitant medications. 
6. Vital signs, including weight. 
7. Review study treatment Week 6 pack for compliance and collect the Week 5 pack (which 
should be empty if all doses were taken as expected). Confirm that the subject has the 
Week 7 pack and provide a study treatment Week 8 pack from Carton #2. 
8. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: Again it should be stressed to subjects that they must maintain 
their dosing schedule throughout the Treatment Period and to be honest with their vaping 
status information. 
9. Blood for hematology and serum chemistry testing.  
10. 12-lead ECG. 

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11. Obtain saliva sample for cotinine testing by central laboratory. 
12. Expired CO. 
13. Record the following:  
a. Has the subject vaped since the last clinic (Day 35) visit?  
b. If subject has vaped, record number of days subject vaped since the last visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 35) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 
14. Remind subject of their Day 49 (Week 7) appointment date and time and that they must 
bring with them their study treatment packs. 
Treatment Day 49/Week 7 (±1 day) 
1. Review study treatment diary to verify dosing up to time of visit. 
2. Assess for AEs and any changes to concomitant medications. 
3. Vital signs, including weight. 
4. Review study treatment Week 7 pack for compliance and collect the Week 6 pack (which 
was the last pack in Carton #1 and should be empty if all doses were taken as expected). 
Retain Carton #1 and all weekly packs for drug accountability by the study monitor. 
Confirm that the subject has the Week 8 pack and provide a study treatment Week 9 pack 
from Carton #2. 
5. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: Again it should be stressed to subjects that they must maintain 
their dosing schedule throughout the Treatment Period and to be honest with their vaping 
status information. 
6. Obtain saliva sample for cotinine testing by central laboratory. 
7. Expired CO. 
8. Record the following:  
a. Has the subject vaped since the last clinic (Day 42) visit?  
b. If subject has vaped, record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 42) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 
9. Remind subject of their Day 56 (Week 8) appointment date and time and that they must 
bring with them their study treatment packs. 
Treatment Day 56/Week 8 (±1 day) 
1. Review study treatment diary to verify dosing up to time of visit. 
2. Assess for AEs and any changes to concomitant medications. 
3. Vital signs, including weight. 

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4. Review study treatment Week 8 pack for compliance and collect Week 7 pack (which 
should be empty if all doses were taken as expected). Confirm that the subject has the 
Week 9 pack and provide a study treatment Week 10 pack from Carton #2. 
5. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: it should be stressed to subjects that they must maintain their 
dosing schedule throughout the Treatment Period and to be honest with their smoking 
status information. 
6. Obtain saliva sample for cotinine testing by central laboratory. 
7. Urine pregnancy for all female subjects, excluding those who are surgically 
sterile (hysterectomy or tubal ligation) or are >2 years post-menopausal. 
8. Expired CO. 
9. Record the following:  
a. Has the subject vaped since the last clinic (Day 49) visit?  
b. If subject has vaped, record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 49) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 
10. Remind subject of their Day 63 (Week 9) appointment date and time and that they must 
bring with them their study treatment packs. 
Treatment Day 63/Week 9 (±1 day) 
1. Review study treatment diary to verify dosing up to time of visit. 
2. Assess for AEs and any changes to concomitant medications. 
3. Vital signs, including weight. 
4. Review study treatment Week 9 pack for compliance and collect the Week 8 pack (which 
should be empty if all doses were taken as expected). Confirm that the subject has the 
Week 10 pack and provide a study treatment Week 11 pack from Carton #2. 
5. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: Stress to subjects that they must maintain their dosing schedule for 
the remaining Treatment Period and to be honest with their vaping status information. 
6. Obtain saliva sample for cotinine testing by central laboratory. 
7. Expired CO. 
8. Record the following:  
a. Has the subject vaped since the last clinic (Day 56) visit?  
b. If subject has vaped, record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 56) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 

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9. Remind subject of their Day 70 (Week 10) appointment date and time and that they must 
bring with them their study treatment packs. 
Treatment Day 70/Week 10 (±1 day) 
1. Review study treatment diary to verify dosing up to time of visit. 
2. Assess for AEs and any changes to concomitant medications. 
3. Vital signs, including weight. 
4. Review study treatment Week 10 pack for compliance and collect the Week 9 pack 
(which should be empty if all doses were taken as expected). Confirm that the subject has 
the Week 11 pack and provide the last study treatment Week 12 pack from Carton #2. 
5. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: Stress to subjects that they must maintain their dosing schedule for 
the remaining Treatment Period and to be honest with their vaping status information. 
6. Obtain saliva sample for cotinine testing by central laboratory.  
7. Expired CO. 
8. Record the following:  
a. Has the subject vaped since the last clinic (Day 63) visit?  
b. If subject has vaped, record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 63) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 
9. Remind subject of their Day 77 (Week 11) appointment date and time and that they must 
bring with them their study treatment packs. 
Treatment Day 77/Week 11 (±1 day) 
1. Review study treatment diary to verify dosing up to time of visit. 
2. Assess for AEs and any changes to concomitant medications. 
3. Vital signs, including weight. 
4. Review study treatment Week 11 pack for compliance and collect the Week 10 pack 
(which should be empty if all doses were taken as expected). Confirm that the subject has 
the last Week 12 pack. 
5. Provide subject with behavioral support information that includes counseling 
(Appendix 5). NOTE: Stress to subjects that they must maintain their dosing schedule for 
the remaining week and to be honest with their vaping status information. 
6. Obtain saliva sample for cotinine testing by central laboratory. 
7.  Expired CO. 
 
 

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8. Record the following:  
a. Has the subject vaped since the last clinic (Day 70) visit?  
b. If subject has vaped,  record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 70) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 
9. Remind subject of their Day 84 (Week 12) appointment date and time and that they must 
bring with them their study treatment packs. 
10. Instruct subject that they will be notified to complete the MNWS questionnaire 
electronically 3 (±1) days prior to the Week 12 clinic visit (Appendix 6).  
Treatment Day 84/ Week 12 (Day 86±1) 
Note: The final day of treatment should be on Day 84. In order to ensure all subjects have 
completed treatment, the Week 12 visit is to be scheduled on Day 86±1 day. 
1. Administer and assess suicidal ideation/risk using the “Since Last Visit” C-SSRS (refer to 
Appendix 1). 
2. Subject to complete the HADS questionnaire (Appendix 2). 
3. Subject to complete the Penn State Electronic Cigarette Dependence Index (Appendix 3) 
and the Short Form of the Marijuana Craving Questionnaire (Appendix 4). 
4.  Review study treatment diary to verify dosing through Week 12. 
5. Assess for AEs and any changes to concomitant medications. NOTE: Any ongoing 
adverse events must be followed until resolved or determined to be chronic. 
6. Vital signs, including weight. 
7. Review study treatment Week 12 pack for compliance and collect both Week 11 and 
12 packs (which should be empty if all doses were taken as expected). 
8. Provide subject with behavioral support information that includes counseling 
(Appendix 5).  
9. Blood for hematology and serum chemistry testing.  
10. Urine pregnancy for all female subjects, excluding those who are surgically 
sterile (hysterectomy or tubal ligation) or are >2 years post-menopausal. 
11. 12-lead ECG. 
12. Obtain saliva sample for cotinine testing by central laboratory.  
13. Expired CO. 
14. Record the following:  
a. Has the subject vaped since the last clinic (Day 77) visit?  
b. If subject has vaped, record number of days subject vaped since the last clinic visit. 
c. Has the subject used any other combustible or non-combustible nicotine products 
since the last clinic (Day 77) visit?  

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15. Instruct subject that they will be notified to complete the MNWS questionnaire 
electronically 3 (±1) days after this Week 12 clinic visit and remind subject of their 
Week 16 Follow-up appointment date and time. 
10.2.4. 
Follow-up Assessment 
Week 16 (±3 days) 
1. Assess for any AEs over the 4 weeks since completing study drug treatment. 
2. Vital signs, including weight. 
3. Urine pregnancy for all female subjects, excluding those who are surgically 
sterile (hysterectomy or tubal ligation) or are >2 years post-menopausal. 
4. Expired CO. 
5. Record the following:  
a. Has the subject vaped since completing study drug treatment?  
b. If not, has the subject used any other combustible or non-combustible nicotine 
products? 
6. Obtain saliva sample. Samples will be sent to a central laboratory for cotinine testing 
only for those subjects that have reported not vaping since completing the study treatment 
period. 
10.2.5. 
Subject Diaries 
A vaping diary will be collected during the screening period in order to capture daily e-cigarette 
use. These data will be used to support Inclusion Criteria #3 and document daily usage for at 
least 7 consecutive days on an individual basis.  
In addition, a study treatment diary must be maintained by each subject to record date and timing 
of study drug administrations during the Treatment Period. The diary will be configured into 
specific sections to support the above reporting by the subject. Staff must review entries with the 
subject at each clinic visit and document on CRF. Data from the study treatment diary will be 
reviewed at all clinic visits. 
10.2.6. 
Behavioral Support 
Each participating site must have at least two or more staff members experienced and qualified 
to provide nicotine cessation counseling. For this study, site counselors are required to have 
either a master’s level or higher degree in a counseling profession (e.g., health educator, 
chemical dependence counselor) or completed a nicotine treatment training course of at least 
4 hours. Evidence of the above qualification(s) must be provided during the site qualification 
process.  
All subjects will receive up to 14 behavioral support sessions by a qualified study site staff 
member, starting prior to randomization at the Screening Visit #2 when the subject sets their Quit 
Date, again at randomization and continuing through the End of Treatment (Day 86±1 day) visit 
as outlined in (Table 3). Each behavioral session will be subject-driven and must include direct 

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engagement with the subject about their attempt to quit vaping. Each session should last up to 
10 minutes (Refer to Appendix 5). 
Site counselor(s) are to encourage subjects to continue study drug as scheduled even if they quit 
vaping as planned or if they lapse and have a puff after their quit date during the Treatment 
Period. It is also important to stress to subjects that they should be honest when reporting their 
vaping status and to remind them that all timepoints from Week 2 through Week 12 during the 
Treatment Period will be verified using cotinine levels.  
11. 
EFFICACY CRITERIA 
This study will follow general criteria that have been used in registration trials for smoking 
cessation where participants have a defined target quit date and there is face-to-face contact with 
researchers or clinic staff.17 This vaping study will mirror criteria used for smoking cessation 
trials where smoking abstinence has been defined during the last 4 weeks of treatment with self-
reported abstinence and verified by biochemical testing.  
Vaping abstinence will be defined as a self-report of no nicotine-containing vaping in the past 
7 days with biochemical saliva cotinine verification (cotinine <10 ng/mL). Weekly vaping 
assessments will start at Week 2 and continue weekly through Week 12.  
The primary efficacy measure of nicotine vaping cessation will be the number of subjects who 
achieve vaping abstinence for 4 consecutive weeks from Week 9 to Week 12 by self-report of no 
vaping each week and supported by biochemical verification (saliva cotinine <10 ng/mL). 
Efficacy analyses for vaping abstinence will include the following criteria:  
1. Self-report of vaping abstinence since the last clinic visit at each weekly clinic 
assessment starting after the targeted quit week (Week 2 or Day 7-14).  
2. Biochemical verification of nicotine abstinence by saliva cotinine levels at each clinic 
visit. 
3. Use of an ‘intention-to-treat’ approach in which data from all randomized vapers are 
included in the analysis. 
4. Subjects with an unknown vaping status at the Week 9 to 12 assessments or lost to follow 
up will be classified as failed to quit.  
5. Continually blinded to treatment allocation during collection of all data and prior to 
database lock and final analyses. 
Refer to Section 14.3 and Section 14.5 for the specific criteria in determining the primary and 
secondary efficacy outcomes, respectively. 
 
 

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12. 
SAFETY ASSESSMENTS 
All subjects will be monitored for adverse events starting at screening (pre-existing), by 
telephone contact on Day 1, at clinic visits on Day 7 (Week 1), then weekly throughout the 
Treatment Period (Weeks 2 through 12). Adverse events will be monitored though the Follow-up 
Period. Any ongoing adverse events at Week 16 will be followed until resolved or determined to 
be chronic. Laboratory (hematology and chemistry) evaluations will be performed at the Week 1, 
Week 6, and Week 12 clinic visits using a central laboratory.  
Safety will be assessed by consideration of all adverse events reported by or elicited from the 
subject and abnormalities detected on hematology and serum chemistry tests. Worsening of other 
preexisting medical conditions and any changes to concomitant medications/treatments will also 
be taken into account in this evaluation.  
In addition to the planned times, safety procedures can be performed at any time when 
considered necessary by the Investigator or attending Research Physician.  
In the event of any clinically significant abnormalities identified by the investigating physician, 
subjects will be followed until: 
• It has resolved/returned to normal or baseline. 
• The event has stabilized at a level acceptable to the Investigator and is not considered 
to be clinically significant. 
• It has been shown to be chronic during follow-up assessment. 
All adverse events (serious and non-serious) beginning at screening (prior to dosing) through the 
Week 16 visit will be recorded in the subject’s CRF. 
12.1. 
Definitions 
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical trial subject 
administered a medicinal product and which does not necessarily have attribution with the 
treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational medicinal 
product, whether or not considered related to the investigational medicinal product. 
An Adverse Drug Reaction (ADR) means all untoward and unintended responses to a 
medicinal product related to any dose administered. The phrase ‘response to a medicinal product’ 
means that attribution has at least a reasonable possibility, i.e., the relationship cannot be ruled 
out and is judged by the investigator as at least possible (see definition below). 
An Unexpected Adverse Drug Reaction (UADR)/Unexpected Adverse Event (UAE) means 
an adverse reaction/event, the nature or severity of which is not consistent with the applicable 
product information, namely in the Investigator Brochure for an unauthorized investigational 
product or in the SmPC for an authorized product. 
The expected/unexpected status should be evaluated and assessed, by the Sponsor, based on the 
reference safety information available since expectedness in Pharmacovigilance refers strictly to 
the information listed or mentioned in the applicable reference safety information and not to 

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event(s) that might be anticipated from knowledge of the pharmacological properties of a 
substance or because it was foreseeable due to the health status (e.g., age, medical history) of the 
study subjects. 
A Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) is defined as an AE that 
results in any of the following: 
• Results in death. 
• Is life-threatening.  
• Requires hospitalization or prolongs existing inpatient’s hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Results in a congenital abnormality or birth defect. 
• Is an important medical event which requires medical intervention to prevent any of 
the above outcomes. 
SUSARs: AEs which meet all of the following criteria will be classified as suspected unexpected 
serious adverse reactions (SUSARs): 
• Serious. 
• Unexpected (i.e., is not consistent with the applicable product information e.g., 
Investigator's brochure for an unapproved IMP or SmPC for an authorised product). 
• There is at least a reasonable possibility that there is attribution between the event and 
the medicinal product. 
Important medical events are those which may not be immediately life-threatening, but may 
jeopardize the subject and may require intervention to prevent one of the other serious outcomes 
listed above. Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm, or blood dyscrasias or convulsions that do not result in 
hospitalization. 
The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe. For example, drug-induced hepatitis that 
resolves without evidence of hepatic failure would not be considered life threatening even 
though drug-induced hepatitis can be fatal. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital inpatient 
admission and/or prolongation of hospital stay were required for treatment of AE or occurred as 
a consequence of the event. It does not refer to pre-planned elective hospital admission for 
treatment of a pre-existing condition that has not significantly worsened, or to diagnostic 
procedures. 
 
 

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12.2. 
Recording of Adverse Events 
All of the following details will be recorded in the subject’s CRF for each AE: 
• Full description of AE. 
• Date and time of onset. 
• Date and time of resolution. 
• Severity of event, to be assessed by an Investigator, or their delegate, in accordance 
with the definitions below. 
• Relationship to study drug to be assessed by an Investigator, or their delegate, in 
accordance with the definitions below. 
• Action taken (if any). 
• Outcome and details of any further follow-up. 
Adverse events documented in the CRF without a stop date at the Week 16 visit must be 
followed until final resolution or until it is medically justifiable to stop further follow up (e.g., a 
chronic condition has been reached.) Documentation of adverse events should be updated as 
necessary. 
12.2.1. 
Grading Adverse Event Severity 
The following grades will be used by an Investigator to describe the severity of all AEs 
(including clinically-significant laboratory AEs) as shown in Table 4. Only 1 severity grade will 
be used for each AE (e.g., mild - moderate is not acceptable). 
 
Table 4: 
Adverse Event Severity 
Severity of AE 
Definition 
Mild 
No interference with activity 
Moderate 
Some interference with activity requiring no or minimal medical intervention  
Severe 
Prevents daily activity and requires medical intervention 
If an adverse event has multiple aspects, the aspect with the highest intensity will be graded. It is 
emphasized that the term severe is a measure of intensity; thus a severe AE is not necessarily 
serious. For example, itching for several days may be rated as severe; however, may not be 
clinically serious. 
12.2.2. 
Assessment of Attribution 
The attribution between an adverse event and study drug will be determined and documented by 
the responsible Investigator, or their delegate, according to best medical judgment as shown in 
Table 5.  
 
 

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•
Subject demographics.
•
Clinical event:
−
description.
−
date of onset.
−
severity.
−
treatment.
−
relationship to study drug (attribution).
−
action taken regarding study drug.
•
If the AE resulted in death:
−
cause of death (whether or not the death was related to study drug).
−
autopsy findings (if available).
•
Medical history case report form (copy).
•
Concomitant medication case report form (copy).
•
Any relevant reports (laboratory, discharge, x-ray, etc.).
Subjects who have had an SAE during the AE reporting period (Screening through to Week 16 
visit) must be followed clinically until all parameters (including laboratory) have either resolved 
or been assessed as chronic.  
SUSARs should be reported to the IRB (if applicable) and to the FDA in accordance with 
applicable regulatory requirements for expedited reporting. It is the Site’s responsibility to report 
any SUSAR to their IRB and it is the Sponsor’s responsibility to report any SUSAR to the FDA.  
Full details of SAE handling and SUSAR reporting will be documented in a study specific 
reference manual prior to the start of dosing.  
12.2.4. 
Reporting of a Pregnancy during Study Treatment 
If a pregnancy occurs in a randomized subject (or the partner of an enrolled subject) during the 
study treatment or follow-up period, the Investigator must complete the Pregnancy Notification 
Form and submit to the CRO Pharmacovigilance Associate. Although not considered an SAE, 
the CRO PV Group will process pregnancy notifications using the same guidelines as for SAE 
reports above [i.e., will acknowledge receipt of any pregnancy notification (initial or follow up) 
within 24 hours of receipt to the site with a copy to the Medical Monitor and Sponsor for their 
awareness].  
Since there may be unknown risks to a pregnancy, embryo, or fetus (Section 2.1.3), the pregnant 
subject should discontinue study drug treatment however the subject should be followed during 
the pregnancy for safety assessments.  
The CRO PV Group will also follow up with the Investigator after completion of the study on 
the monitoring of the subject for the duration of the pregnancy and until 28 days after the child is 

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born. Any serious adverse events of the subject during the pregnancy or of the child at birth need 
to be recorded and CRO PV Group notified accordingly.  
12.2.5. 
Reporting of COVID-19 Positive cases and COVID-19 vaccinations as Adverse 
Events of Special Interest 
Subjects known to be COVID-19 positive during the study will be documented under adverse 
event reporting as AEs of special interest. In addition, any COVID-19 vaccinations should be 
documented during the study and any side effects immediately following a COVID-19 
vaccination should be documented under adverse event reporting as AEs of special interest.  
Any effects of the COVID-19 pandemic on the conduct of the study or any specific effects of 
COVID-19 infections or vaccinations on treatment arm results will be assessed. 
12.3. 
Laboratory 
12.3.1. 
Routine Laboratory Assessments 
Routine laboratory safety samples will be analyzed at screening and at clinic visits as identified 
in (Table 3) for each subject by a central laboratory. A decision regarding whether a result 
outside the reference range is of clinical significance or not shall be made by an Investigator and 
the report will be annotated accordingly. Clinically significant abnormalities occurring during the 
study will be recorded on the AE page. The reference ranges for laboratory parameters should be 
filed in the TMF and the Investigator site file. 
Hematology: Hemoglobin, red blood cells, white blood cells, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils and platelets.  
Chemistry: Total protein, albumin, total bilirubin, SGPT (ALT), SGOT (AST), alkaline 
phosphatase, glucose, sodium, potassium, calcium, creatinine and urea. 
12.3.2. 
Monitoring of Expired Air Carbon Monoxide (CO) 
Expired CO will be obtained using a calibrated instrument (e.g., the Bedfont Micro+ 
Smokerlyzer®) provided and maintained by the clinical site. Each clinical site must have a 
minimum of 2 devices on hand, documentation of instrument used and current calibration. CO 
values are to be reported in parts per million (ppm) at Week 2, weekly through Week 12 and at 
Week 16.  
This study excludes dual users (smoking and vaping nicotine) because smoking oversight is 
difficult to monitor for increased use of combustible smoking while reducing nicotine vaping. 
Nonsmoking at screening in this study is confirmed by standard expired CO levels <10 ppm. 
Ongoing monitoring for expired CO levels is included in this study to assess for the potential risk 
of a subject to start, or relapse into, smoking combustible cigarettes while trying to reduce or 
stop nicotine vaping. If smoking appears to become an issue, the Data Safety Monitoring 
Committee can recommend amending study procedures or close the study if the risk appears 
greater than the benefit of stopping nicotine vaping (see Section 13.1). 
If expired CO levels ≥10 ppm are detected, the subject should be asked about combustible 
cigarette smoking including the start date of smoking. If the subject reports smoking combustible 
cigarettes, the total number of cigarettes smoked since the last clinic visit should be reported in 

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the CRF. If expired CO levels ≥10 ppm are detected and the subject reports not to have smoked 
combustible cigarettes, they should be asked about any cannabis smoking. If they report 
concomitant cannabis smoking, the number of days used since the last clinic visit should be 
reported in the CRF. 
12.3.3. 
Cotinine Levels 
Saliva samples will be collected for determining cotinine levels at Day 0 and again starting at 
Week 2 and weekly through Week 12 and at Week 16. Cotinine will be assessed using a 
quantitative saliva cotinine assay performed by a central laboratory and reported in ng/mL. 
12.4. 
Vital signs 
Systolic/diastolic blood pressure, pulse rate, and oral temperature measurements will be recorded 
in a seated position. Body weight will also be recorded. Height is to be recorded at Screening 
Visit #1 for BMI calculation. 
12.5. 
Physical Examination 
A physical examination will be performed by an Investigator. The examination will include 
general appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory 
system, gastrointestinal system, central nervous system, lymph nodes and musculoskeletal. An 
Investigator can examine other body systems if required, at their discretion. 
13. 
SAFETY MONITORING 
13.1. 
 Independent Data Safety Monitoring Committee 
Safety monitoring will be performed by an independent Data Safety Monitoring Committee 
(DSMC) who will be appointed for this study. The DSMC will be composed of at least 2 
independent experts in the relevant therapeutic field and a third relevant expert such as a 
statistician.  
The DSMC governance and operating procedures are described in a separate DSMC Charter. 
Meetings will be held via telecommunications equipment and will meet regularly in order to 
assess safety and trial status. Regular DSMC meetings will be planned during enrollment and 
while treatment is ongoing. Additional meetings will be at the discretion of the DSMC, and the 
meeting schedule may be altered at the request of the Sponsor or at the discretion of the DSMC 
Chairperson. Meetings will typically begin with an open session. DSMC members, 
representatives of the Sponsor and other individuals as needed may be present during the open 
session. The open session will be followed by a closed session. Only DSMC members, and other 
individuals, as needed by the DSMC, will be in attendance at the closed session.  
The primary responsibility of the DSMC will be to monitor for any unexpected safety risk for 
subjects on the protocol. The DSMC will:  
• Review all SUSARs and SAEs reported to the Sponsor. The Sponsor will provide the 
DSMC with a copy of any unexpected study drug-related SAE Report Form within 
7 business days of receipt by the Sponsor. The Medical Monitor (or designee) will 

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also provide the DSMC with copies of all expedited SAE reports submitted to 
regulatory agencies.  
• Perform periodic reviews of overall safety data for the study (e.g., moderate or severe 
adverse events).  
NOTE: Any respiratory symptoms, including cough, shortness of breath, or chest pain 
that are reported as moderate or severe will be reported to the DSMC within 7 
business days of being reported to the Sponsor. The DSMC will review for possible 
further EVALI assessment or further follow-up. 
• Specific reviews for subjects who may start or revert to smoking combustible 
cigarettes during study treatment will be assessed by the DSMC for any increased 
harm or risk to subjects. The timing of these reviews will be determined by the 
DSMC based on rate of enrollment and status of concern upon reviewing CO reports 
or reporting of combustible cigarettes by subjects during the study. 
The DSMC may request unblinding of study treatment based on a safety concern or specific 
SUSARs or SAE. All unblinding and the reason for unblinding will be documented by the 
DSMC. The Sponsor and sites will not be unblinded unless the DSMC requests that individual or 
other unblinding occurs due to a safety concern. 
The DSMC Chairperson will communicate with the sponsor in regard to issues resulting from the 
conduct and clinical aspects of the trial. The sponsor will work closely with the committee to 
provide the necessary data for review. 
14. 
STATISTICAL CONSIDERATIONS 
A major design feature of this study is blinding. The study will be unblinded only after database 
lock and at the time of final study analyses (i.e., when unblinding cannot induce bias in 
collection of data and interpretation of results).  
Detailed statistical specifications are documented in the Statistical Analysis Plan (SAP) and the 
SAP will be final prior to initiation of any study unblinding. 
14.1. 
Statistical Design 
The overall study design is to obtain effect outcomes and conduct additional safety assessments 
and endpoints that will be used to inform the design of future studies. Thus, this study will be 
analyzed without specific statistical criteria. That is, no formal statistical hypothesis testing will 
be conducted, and consequently, a level of significance (α level) is not specified in the Statistical 
Analysis Plan (SAP). There will be statistical testing performed with p-values, and confidence 
intervals (CIs). The p-values will be interpreted as an assessment of consistency with the play of 
chance (small p-values indicating a small likelihood that the observed effect was due to chance) 
and will be used qualitatively in decisions concerning next steps.  

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14.2. 
Analysis Sets 
Screening Analysis Set: The Screening Analysis Set is defined as all subjects who give written 
informed consent and have entered screening but are not randomized. Analyses in this population 
will be restricted to presentation of baseline data and reasons for non-participation only. 
Safety Analysis Set: The Safety Analysis Set (SAS) is defined as all randomized subjects who 
take at least one dose of study drug. All safety analyses will be performed on the Safety Analysis 
Set. 
Efficacy Analysis Set: The All Randomized Analysis Set (ARS) is based on the ‘intention-to-
treat’ principle and will include data from all randomized subjects. 
14.3. 
Primary Efficacy Outcome  
The primary efficacy outcome for vaping cessation (defined as biochemically verified vaping 
abstinence for the last 4 weeks of cytisinicline treatment) for each subject is binary: success 
versus failure will be analyzed using the Efficacy Analysis Set. Success is defined for the subject 
as having reported vaping abstinence (no vaping since the last clinic visit) at each clinic 
assessment from Week 9 to Week 12 with biochemical cotinine verification at each assessment. 
Biochemical verification will be defined by saliva cotinine levels of less than 10 ng/mL. Similar 
timeframe and analyses will occur for both Arm A and Arm B subjects. 
Any other outcome is regarded as a failure. There are two types of failure for a subject: 
(1) subjects with adequate data that they are vaping (either by the subject’s self-report or cotinine 
levels ≥10 ng/mL) and (2) subjects having insufficient data to be determined as a success for 
vaping cessation. This definition of primary outcome means that all subjects will have a 
realization of the primary outcome and therefore this endpoint is amenable to intent-to-treat 
(ITT) analyses. 
Measurements of CO levels will also be used for sensitivity testing to assess for any concurrent 
combustible cigarette usage in those subjects reporting successful vaping cessation. 
14.4. 
Analysis of Primary Outcome 
The outcome for each arm will be the proportion of subjects classified as a success. The 
experimental arm (Arm B) will be compared to the control arm (Arm A) at the appropriate 
timeframes. All randomized subjects will be included in the comparison according to their 
randomized arm (ITT analysis). The statistical significance of each comparison will be based on 
the odds ratio using exact computations for stratified 2×2 frequency tables and using Monte 
Carlo estimation if necessary. The stratifier will be whether subjects have smoked >100 
cigarettes in their lifetime (yes vs no). If cytisinicline is not favored by the effect size point 
estimate then the comparison will be designated as not statistically significant.  
The estimated common odds ratio and its exact confidence interval will be reported. In addition, 
the estimated odds ratio and exact confidence interval for the marginal 2x2 table across sites 
(unadjusted odds ratio), and the estimated difference in proportions and the associated derived 
exact confidence interval using the exact confidence interval on the odds ratio will be reported. 
The exact difference in proportion confidence interval is derived using the method of Thomas 
(1971 and 1977).18,19 

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In addition, the primary comparisons will be presented in the context of a tipping point 
analysis.20 Other supporting and sensitivity analyses challenging the results as well as analyses 
designed to assess homogeneity of effect are planned and described in the SAP. 
14.5. 
Secondary Efficacy Outcomes  
Secondary efficacy outcomes will assess for weekly vaping abstinence, earlier vaping cessation 
timing, any reduction in vaping during the treatment period, and continued vaping abstinence 
during the 4 week follow-up period for those subjects who achieved vaping abstinence at Week 9 
to 12 and through week 16.  
Vaping abstinence will be generally defined as a self-report of no vaping in the past 7 days with 
biochemical cotinine verification (saliva cotinine <10 ng/mL). Weekly vaping assessments for 
vaping abstinence will start at Week 2 and continue weekly through Week 12.  
As stated above, the primary efficacy measure of nicotine vaping cessation will be the number of 
subjects who achieve vaping abstinence for 4 consecutive weeks from Week 9 to Week 12 by 
self-report of no vaping each week and supported by biochemical verification (saliva cotinine 
<10 ng/mL). For the secondary analyses, the number of subjects who achieve vaping abstinence 
at any week between Week 2 and Week 12 (e.g., self-report of no vaping in the past 7 days 
supported by biochemical verification) will be reported as weekly point prevalence rates. 
Additional analyses will be done for earlier 4-week periods in achieving vaping cessation (e.g., 
vaping abstinence for 4 consecutive weeks from Week 3 to 6 or from Week 6 to 9).  
Measurements for CO levels will also be used for sensitivity testing to assess that no concurrent 
combustible cigarette usage was used in those subjects reporting weekly vaping abstinence or 
vaping cessation.  
Other secondary efficacy outcomes for any reduction in vaping will be assessed on a weekly 
basis between Week 2 and Week 12 of cytisinicline treatment using the quantitative saliva 
cotinine levels compared to baseline levels, as determined by the central lab.  
14.6. 
Analysis of Secondary Outcomes 
For the secondary endpoints of weekly vaping abstinence and earlier vaping cessation timing 
these will be analyzed the same as the primary endpoint analysis. For  the reduction in vaping 
during the treatment period, this will be analyzed using an analysis of variance.  
14.7. 
Study Size 
The target accrual is for approximately 150 subjects (100 subjects treated with cytisinicline and 
50 subjects treated with placebo) which should be adequate to obtain additional safety 
assessments as well as explore various measures of cytisinicline effect outcomes compared to 
placebo. Although no formal statistical hypothesis testing will be conducted, the sample size will 
have 95% power to detect a 57 ng/mL reduction in cotinine levels at baseline levels of 
300 ng/mL (e.g., approx. 19% reduction from baseline). 

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14.8. 
Other Objectives 
Other objectives beyond the designated primary and secondary objectives will be exploratory. 
All outcomes, including time to vaping abstinence, magnitude of treatment effect across subsets 
defined by demographic (e.g., gender, age) and/or baseline characteristics (e.g., e-cigarette 
product type, nicotine addiction severity), etc., will be performed as other exploratory 
assessments. In addition, possible confounding effects of marijuana use on the ability to reduce 
nicotine vaping or cessation will be explored as well as any withdrawal symptoms from 
discontinuing cytisinicline after 12 weeks of administration. 
14.9. 
Safety Objectives 
Safety assessments include reported adverse events, laboratory tests results, and vital signs. 
Safety variables will be summarized for the Safety Analysis Set (SAS), defined as all 
randomized subjects who take at least one dose of study drug.  
Adverse events will be coded using the MedDRA dictionary. Coding includes system organ class 
(SOC) and preferred term (PT). All verbatim descriptions and coded terms will be listed for all 
AEs.  
Safety summaries are described in the SAP. 
15. 
REGULATORY AND ETHICS CONSIDERATIONS 
15.1. 
Institutional Review Board (IRB) 
This study protocol must be submitted to an IRB for review and approval prior to initiation. As 
this study will be conducted at multiple sites, it is expected that each site must submit and obtain 
approval from their designated IRB with preference towards use of a central IRB when at all 
possible. Before the investigational product can be shipped to the investigative site and before 
the consenting and screening of subjects at the site, the protocol, any protocol amendments, the 
consent form, any advertising materials, any materials to be provided to the subjects for the 
proposed clinical study, and any other documents required by the IRB must be submitted by the 
Investigator (or representative) for review and approval by the IRB. The Investigator must also 
ensure that the IRB reviews the progress of the study, if necessary, and renews its approval of the 
study (if ongoing) on an annual basis. Any member of the IRB who is directly affiliated with this 
study as an Investigator or as participating site personnel must abstain from the IRB vote on the 
approval of the protocol and associated documents. 
All amendments or revisions to the protocol must undergo review by appropriate IRBs. 
Amendments/revisions will be circulated to all participating sites with clear instructions 
regarding IRB review. Amendments will be submitted by the Sponsor to the Food and Drug 
Administration (FDA) prior to central implementation to the study, and by IRBs prior to local 
implementation, EXCEPT when the amendment eliminates an immediate hazard to clinical trial 
subjects or is of a purely administrative nature. 
A copy of the IRB approval letter must be forwarded to the Sponsor or Sponsor’s representative 
before the study is implemented. The approval letter must clearly state the protocol title and 

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version that was reviewed, as well as any associated documents. The Investigator also must 
forward copies of subsequent amendment approval letters upon receipt.  
15.2. 
Ethical Conduct of the Study 
This trial will be conducted in accordance with the Declaration of Helsinki, as well as the ICH 
Guidelines on GCP, the US Code of Federal Regulations, and local requirements regarding IRB 
committee review, informed consent, and other statutes or regulations regarding the protection of 
the rights and welfare of human subjects participating in biomedical research. 
15.3. 
Informed Consent 
The informed consent forms used for the study must comply with the Declaration of Helsinki 
and its updates and the International Conference on Harmonization (ICH) Guidelines and must 
have been approved by the Sponsor or Sponsor’s representatives (prior to review by the site’s 
IRB) and the Investigator’s IRB. The Investigator or an authorized associate, must explain the 
nature of the study and the treatment in such a manner that the subject is aware of his/her rights 
and responsibilities, as well as potential benefits and risks. The Investigator is also responsible 
for answering any questions the subject may have throughout the study and sharing any new 
information, in a timely manner, that may be relevant to the subject’s willingness to continue 
his/her participation in the trial.  
Subjects must also be informed that participation is voluntary and that they may withdraw from 
the study at any time, without prejudice to their current or future care. Documentation of the 
discussion and the date of informed consent should be recorded in the subject’s medical record 
or a study/clinic chart. Once all of their questions have been answered and they have voluntarily 
agreed to participate in the study, subjects will be asked to sign and date the Informed Consent 
Form.  
Subjects, or their legally authorized representatives, must give informed consent in writing prior 
to the performance of any protocol-specific procedure. Subjects who cannot give informed 
consent (i.e., mentally incompetent subjects or those physically incapacitated such as comatose 
subjects) are not to be recruited into the study. Subjects who are competent but physically unable 
to sign the consent form may have the document signed by their nearest relative or legal 
guardian. A copy of the signed Informed Consent Form will be provided to the subject. 
15.4. 
Subject Confidentiality 
The Investigator must attempt to assure that the subjects’ confidentiality will be maintained 
within the limit of the law. Subjects will be identified by subject number and initials (or other 
code) on all documents submitted to the Sponsor. Subjects will not be identified by name.  
All records will be kept in a secure place in the clinical research site. Computer data entry and 
data review programs will be done using subject numbers and initials (or other code) only. 
Clinical information will not be released without written permission of the subject, as outlined in 
the subject consent form. 
The Investigator must maintain a log of subject names and identification codes. 

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16. 
DOCUMENTATION  
16.1. 
Study File and Site Documents 
Prior to the activation of the study, at a minimum, the following items must be received by the 
Sponsor from the site: 
1. Confidential Disclosure Agreement. 
2. Signed protocol, and amendment(s) page(s).  
3. The Investigator’s curriculum vitae and current medical license. Note: Investigator or a 
Co-Investigator must be a medical doctor (MD). 
4. Documentation of required training for designated behavioral counselors (e.g., nicotine or 
smoking cessation). 
5. Signed Clinical Study Agreement/Contract. 
6. Signed Financial Disclosure Form from the relevant site personnel. 
7. IRB written approval for the protocol, amendment(s), Informed Consent Form, Smoking 
cessation information and advertisements (if applicable). 
8. IRB Membership list or an official statement from the IRB stating the IRB is in 
compliance with Good Clinical Practice (GCP). 
9. FDA Form 1572 
16.2. 
Study Documents Supplied by the Sponsor 
The Sponsor will supply the investigator with the following items: 
1. Current version of the Investigator’s Brochure. 
2. Current version of study protocol. 
3. Master CRF. 
4. Informed Consent Form template. 
5. Study Procedure Manual. 
6. Laboratory Manual (if applicable). 
16.3. 
Maintenance and Retention of Records 
It is the responsibility of the investigator to maintain a comprehensive and centralized filing 
system of all relevant documentation. 
Investigators will be instructed to retain all study records required by the Sponsor and regulatory 
authorities in a secure and safe facility with limited access for one of the following time periods 
based on notification from the Sponsor: 
1. For a period of at least 2 years from the last marketing approval worldwide.  
2. Or a period of at least two years after discontinuation of clinical development of the 
investigational product as confirmed by the Sponsor. 

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The investigator will be instructed to consult with the Sponsor before disposal of any study 
records and to provide written notification to the Sponsor of any change in the location, 
disposition, or custody of the study files. 
17. 
ADMINISTRATIVE PROCEDURES 
17.1. 
Sponsor Responsibilities 
The study will be monitored by representatives of the Sponsor and/or designated contract 
research organizations (CROs). Routine monitoring visits will be conducted to (at a minimum): 
1. Assure compliance with the study protocol. 
2. Verify that the research facilities, including laboratories and equipment, are adequate to 
safely and properly conduct the study. 
3. Verify that the investigational product is stored properly and under the proper conditions, 
is in sufficient supply, and that receipt, use, and destruction or return of investigational 
product at the study sites are controlled and documented adequately. 
4. Verify that written informed consent was obtained before any protocol-specific screening 
procedures are performed solely for the purpose of determining eligibility for the clinical 
study and/or prior to the provision of study drug. 
5. Review the subject CRFs and source documents to ensure that reported study data are 
accurate, complete, and verifiable from source documents. 
6. Verify that the Investigator and study site personnel are adequately qualified throughout 
the study. 
7. Verify that the safety information and amendments are submitted to the IRBs. 
17.2. 
Investigator Responsibilities 
All requested study data must be entered on the CRFs for the study. An explanation should be 
provided for all missing data. Correction of data on a CRF will be made with identification of the 
individual making the correction and date of the correction. Only individuals who are identified 
on the Delegation of Responsibility Form(s) may correct data on the CRF. For those subjects 
who withdraw before completion of their specified treatment regimen, all available efficacy and 
safety data must be entered in the CRF. The reason for withdrawal must be specified. Incomplete 
or inconsistent data on the CRFs will result in data queries that will be returned to the 
Investigator for resolution. 
The Investigator must maintain adequate and accurate source documents upon which CRFs for 
each subject are based. The source documents are to be separate and distinct from the CRFs, 
except for cases in which the Sponsor has predetermined that direct entry into specified pages of 
the subject’s CRF is appropriate. The documents to be maintained must include, but are not 
limited to, detailed notes on: 
 
 

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1. The medical history prior to participation in the study. 
2. The basic identifying information, such as demographics, that link the subject’s source 
documents with the CRFs. 
3. The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject. 
4. The subject’s exposure to study treatment. 
5. All AEs. 
6. The subject’s exposure to any concomitant therapy, including dates of administration. 
7. All relevant observations and data on the condition of the subject throughout the study. 
8. The oral and written communication with the subject regarding the study treatment, 
including the risks and benefits of the study. The date of informed consent must be 
recorded in the source documentation. 
17.3. 
Regulatory Compliance 
Quality Assurance representatives from the Sponsor or their delegate, and the FDA as required 
will be allowed to periodically visit the Investigators to discuss the conduct of the trial and, upon 
request, to inspect the records of the trial. These reviews are necessary to ensure that the study is 
conducted according to standards consistent with the ICH GCP Guidelines. 
The Investigator agrees to discuss and correct, if necessary, any problems or deficiencies that are 
found during the course of these reviews. 
17.4. 
Protocol Modification/Premature Termination 
All protocol amendments must be written and approved by the Sponsor. Each IRB will review 
and approve amendments prior to their implementation in the study. IRB approval need not be 
obtained prior to removal of an immediate hazard to subjects. 
The Sponsor may suspend or terminate the protocol early if safety or other issues occur. 
Furthermore, the study may also be terminated prematurely by the Sponsor for important 
corporate reasons, or due to instruction of the FDA due to safety reasons.  
The Investigator may terminate participation at his/her site at any time but must provide all study 
data for subjects randomized.  
Following a decision of temporary suspension or discontinuation, it is a responsibility of the 
Investigator to inform the study subjects and IRB stating the reasons for premature termination. 
The Sponsor shall be responsible for expedited reporting and/or notification to the FDA, as 
applicable.  
17.5. 
Policy for Publication and Data Presentation 
The Sponsor encourages the scientific publication of data from clinical research trials. However, 
Investigators may not present or publish partial or complete study results individually. The 
Investigators and the Sponsor may propose appropriate scientific manuscripts or abstracts from 
the study data. Any manuscript or abstract proposed by the Investigators must be reviewed to 

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ensure accuracy of data represented and commented upon in writing by the Sponsor prior to 
submission for publication. Investigators agree to consider the comments of the Sponsor in good 
faith and the Sponsor agrees in good faith not to impose limitations on access to the complete 
study data or unreasonable or inappropriate restrictions on publication of the study results. In 
case of publication, confidentiality of the study volunteers will be maintained. 

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18. 
INVESTIGATOR’S AGREEMENT 
 
Protocol No. ACH-CYT-10 (ORCA-V1) 
 
I have carefully read the foregoing protocol including all appendices and agree that it contains all 
the necessary information for conducting the study safely. 
I will conduct this study in strict accordance with this protocol and according to the current GCP 
guidelines and will attempt to complete the study within the time designated. 
I will provide copies of the protocol and all other information submitted by the Sponsor relating 
to non-clinical and prior clinical experience to all personnel for whom I am responsible that 
participate in the study. I will discuss this information with them to assure that they are 
adequately informed regarding the drug and conduct of the study. 
I agree to keep records on all subject information (case report forms, shipment and drug 
return/destruction forms and all other information collected during the study) in accordance with 
the current GCP and local regulations. 
 
 
Site Principal Investigator’s name 
 
 
 
Signature 
 
Date  
 
Institution 

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19. 
REFERENCES 
 
1. 
Mirbolouk M, Charkhchi P, Kianoush S, et al. Prevalence and distribution of e-cigarette 
use among U.S. adults: Behavioral Risk Factor Surveillance System, 2016. Annals of internal 
medicine 2018;169:429-38. 
2. 
Etter J. Cytisine for smoking cessation: A literature review and a meta-analysis. Archives 
of Internal Medicine 2006;166:1553-9. 
3. 
Papke RL, Heinemann SF. Partial agonist properties of cytisine on neuronal nicotinic 
receptors containing the beta 2 subunit. Molecular pharmacology 1994;45:142-9. 
4. 
Parker MJ, Beck A, Luetje CW. Neuronal nicotinic receptor beta2 and beta4 subunits 
confer large differences in agonist binding affinity. Molecular pharmacology 1998;54:1132-9. 
5. 
Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic receptor 
partial agonist for smoking cessation. Journal of medicinal chemistry 2005;48:3474-7. 
6. 
West  R, Zatonski  W, Cedzynska  M, et al. Placebo-Controlled Trial of Cytisine for 
Smoking Cessation. New England Journal of Medicine 2011;365:1193-200. 
7. 
Walker N, Howe C, Glover M, et al. Cytisine versus nicotine for smoking cessation. The 
New England journal of medicine 2014;371:2353-62. 
8. 
Walker N, Smith B, Barnes J, et al. Cytisine versus varenicline for smoking cessation in 
New Zealand indigenous Māori: a randomized controlled trial. Addiction (Abingdon, England) 
2021. 
9. 
WHO report on the global tobacco epidemic, 2019. 2019.  
10. 
Oakes JM, Fuchs RM, Gardner JD, Lazartigues E, Yue X. Nicotine and the renin-
angiotensin system. American journal of physiology Regulatory, integrative and comparative 
physiology 2018;315:R895-r906. 
11. 
Bagaitkar J, Zeller I, Renaud DE, Scott DA. Cotinine inhibits the pro-inflammatory 
response initiated by multiple cell surface Toll-like receptors in monocytic THP cells. Tobacco 
induced diseases 2012;10:18. 
12. 
Hamano R, Takahashi HK, Iwagaki H, Yoshino T, Nishibori M, Tanaka N. Stimulation 
of alpha7 nicotinic acetylcholine receptor inhibits CD14 and the toll-like receptor 4 expression in 
human monocytes. Shock (Augusta, Ga) 2006;26:358-64. 
13. 
Takbiri Osgoei L, Parivar K, Ebrahimi M, Mortaz E. Nicotine modulates the release of 
inflammatory cytokines and expression of TLR2, TLR4 of cord blood mononuclear cells. Iranian 
journal of allergy, asthma, and immunology 2018;17:372-8. 
14. 
McElroy JP, Carmella SG, Heskin AK, Tang MK. Effects of cessation of cigarette 
smoking on eicosanoid biomarkers of inflammation and oxidative damage. PloS one 
2019;14:e0218386. 
15. 
Nides M, Rigotti NA, Benowitz N, Clarke A, Jacobs C. A multicenter, double-blind, 
randomized, placebo-controlled phase 2b trial of cytisinicline in adult smokers (The ORCA-1 
trial). Nicotine & tobacco research : official journal of the Society for Research on Nicotine and 
Tobacco 2021. 
16. 
Foulds J, Veldheer S, Yingst J, et al. Development of a questionnaire for assessing 
dependence on electronic cigarettes among a large sample of ex-smoking E-cigarette users. 
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and 
Tobacco 2015;17:186-92. 

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17. 
West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking cessation trials: 
proposal for a common standard. Addiction (Abingdon, England) 2005;100:299-303. 
18. 
Thomas DG. Algorithm AS 36: Exact confidence limits for the odds ratio in a 2 × 2 table. 
Journal of the Royal Statistical Society Series C (Applied Statistics) 1971;20:105-10. 
19. 
Thomas DG, Gart JJ. A table of exact confidence limits for differences and ratios of two 
proportions and their odds ratios. Journal of the American Statistical Association 1977;72:73-6. 
20. 
Yan X, Lee S, Li N. Missing data handling methods in medical device clinical trials. 
Journal of biopharmaceutical statistics 2009;19:1085-98. 
21. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with adolescents and 
adults. The American journal of psychiatry 2011;168:1266-77. 
22. 
Stern AF. The Hospital Anxiety and Depression Scale. Occupational medicine (Oxford, 
England) 2014;64:393-4. 
23. 
Heishman SJ, Evans RJ, Singleton EG, Levin KH, Copersino ML, Gorelick DA. 
Reliability and validity of a short form of the Marijuana Craving Questionnaire. Drug and 
alcohol dependence 2009;102:35-40. 
24. 
Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. 
Revealing the multidimensional framework of the Minnesota nicotine withdrawal scale. Current 
medical research and opinion 2005;21:749-60. 
25. 
Foulds J, Russ C, Yu CR, et al. Effect of varenicline on individual nicotine withdrawal 
symptoms: a combined analysis of eight randomized, placebo-controlled trials. Nicotine & 
tobacco research : official journal of the Society for Research on Nicotine and Tobacco 
2013;15:1849-57. 
 

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APPENDIX 1. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) provides a standardized method to assess 
both suicidal ideation and behaviour to identify those at risk for suicide.21 The questionnaire 
must be administered by trained study staff at Screening and again at the Week 6 (Day 42) and 
End of Treatment (Day 86) study visits. Assessments at Screening will utilize the “Screening” 
version of the form with ideation to be assessed in the past 3 months and suicidal behaviour 
within lifetime (the later assessment timing helps to discern if later positive assessments are 
possibly treatment emergent). Any “Yes” to question 4 or 5 at screening or “Yes” to any suicidal 
behaviour question will be considered exclusionary for this study. Assessments at Week 6 (Day 
42) and End of Treatment (Day 86) study visits will utilize the “Since Last Visit” version of the
form with timeframe to be “since last assessment”. Any “Yes” to question 4 or 5 or “Yes” to any
suicidal behaviour question requires reporting as an AE as well as referral to a qualified Mental
Health Professional for follow up.
*Training is to be documented via certification in past 1 year on the C-SSRS and may be updated
or by reviewing the on-line training module provided by the developing author.

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APPENDIX 3. PENN STATE ELECTRONIC CIGARETTE 
DEPENDENCE INDEX 
 
The PennState Electronic Cigarette Dependence index (PSECD) -10 questions,16 must be 
administered at Screening, Week 6, and Week 12 and completed by the study subject. 
1. How many times per day do you usually use your electronic cigarette? (assume one 
“time” consists of around 15 puffs, or lasts around 10 minutes)  
_______ per day  
2. On days that you can use your electronic cigarette freely, how soon after you wake up do 
you first use your electronic cigarette?    _______ minutes   
3. Do you sometimes awaken at night to use your electronic cigarette? 
 
□   Yes 
□   No  
4. If yes, how many nights per week do you typically awaken to do so?   _______ nights 
5. Do you use an electronic cigarette now because it is really hard to quit (using e-cigs)?    
□   Yes 
□   No 
6. Do you ever have strong cravings to use an electronic cigarette? 
□   Yes 
□   No 
7. Over the past week, how strong have the urges to use an electronic cigarette been? (check 
one)  
□   No urges  
□   Slight  
□   Moderate  
□   Strong  
□   Very strong  
□   Extremely strong  
8. Is it hard to keep from using an electronic cigarette in places where you are not supposed 
to?  
□   Yes 
□   No 
When you have not used an electronic cigarette for a while, OR when you tried to stop 
using one:  
9. Did you feel more irritable because you couldn’t use an electronic cigarette?  
□   Yes 
□   No 
10. Did you feel nervous, restless, or anxious because you couldn’t use an electronic 
cigarette? 
□   Yes 
□   No 
 

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APPENDIX 5. BEHAVIORAL SUPPORT 
Each participating site must have at least two or more staff members experienced and qualified 
to provide nicotine cessation counseling. Study site counselors who provide behavioral support 
during this study are required to have either a master’s level or higher degree in some sort of 
counseling profession (e.g., health educator, chemical dependence counselor) or completed a 
nicotine treatment training course of at least 4 hours. 
All subjects will receive up to 14 behavioral support sessions by a qualified study site staff 
member, starting prior to randomization at the Screening Visit #2 when the subject sets their Quit 
Date, again at randomization and continuing through the End of Treatment (Day 86±1 day) visit. 
Each behavioral session will be subject-driven and must include direct engagement with the 
subject about their attempt to quit nicotine vaping. Each session should last up to 10 minutes. 
Site counselor(s) are to encourage subjects to continue study drug as scheduled even if they quit 
vaping as planned or if they lapse and use an e-cigarette after their quit date during the Treatment 
Period. It is important for subjects to keep trying to quit as planned. It is also important to stress 
to subjects that they should be honest when reporting their e-cigarette status and to remind them 
that all timepoints from Week 2 through Week 12 during the Treatment Period will be verified 
using cotinine levels.  
Subjects will receive additional abbreviated support (based on issues/concerns/questions raised 
by the subject) during the Follow-up Period. 
Each behavioral session will be subject-driven and must include direct engagement with the 
subject about their attempt to quit vaping. Counselors must be warm, empathetic, and genuine so 
that the subject is comfortable and will share issues and challenges that can be discussed further. 
In addition, the counselor is to be well-versed on study drug administration and expected side 
effects of cytisinicline and able to clearly review and discuss these topics with the study subject. 
Subjects will be encouraged to “keep trying” if they experience set-backs or a “lapse” during 
treatment. Each session should last up to 10 minutes. 
Practical counseling (problem solving/skills training) should be given. Topics include, but are 
not limited to, the following: 
• Abstinence–Striving for total abstinence is essential. Not even a single puff after the 
quit date. 
• Past quit experience–Identify what helped and what hurt in previous quit attempts. 
Build on past success.  
• Anticipate triggers or challenges in the upcoming attempt–Discuss challenges/triggers 
and how the subject will successfully overcome them (e.g., avoid triggers, alter 
routines). 
• Alcohol–Because alcohol is associated with relapse, the subject should consider 
limiting/abstaining from alcohol while quitting. (Note that reducing alcohol intake 
could precipitate withdrawal in alcohol-dependent persons).  
• Other smokers or vapers in the household–Quitting is more difficult when there is 
another smoker/vaper in the household. Subjects should encourage housemates to quit 
with them or to not smoke/vape in their presence. 

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• Recognize danger situations–Identify events, internal states, or activities that increase 
the risk of vaping or relapse (i.e., e-cigarette cues and availability of e-cigarettes or 
other nicotine-containing vaping devices, experiencing urges). 
• Develop coping skills–Identify and practice coping or problem solving skills. 
Typically, these skills are intended to cope with danger situations (i.e., learning to 
avoid temptation and triggers). 
• Provide basic information–Provide basic information about nicotine addiction and 
successful quitting. 
Worksheets containing questions will be provided and may be administered by the counselor to 
initiate/foster open conversation with the subject and may be used at the start or during the study. 
These questions do not need to be used at every visit. They are provided as guidance if the 
subject has difficulty opening up a discussion.  
Potential questions are: 
• What is my motivation for quitting?  
• Why is it important for me to quit right now? 
• What are the biggest barriers I will encounter without an e-cigarette? 
• What are some alternatives I can do when I face these barriers instead of using 
nicotine? 
• What are my stress triggers for cravings? 
• How will I deal with these stressors instead of vaping or using nicotine? 
• What are your biggest concerns/fears about quitting vaping or using nicotine? 
At the end of each visit, the subject will be reminded of supplementary information for additional 
support including: study staff contact information, Quitline information (1-800-QUIT-NOW), or 
additional websites.  
Any questions regarding the medication or protocol must be answered by qualified study staff. 
Documentation of the behavioral support must be captured in the subject’s source document.  
 

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APPENDIX 6. MINNESOTA WITHDRAWAL SCALE (MNWS) 
Several versions of the Minnesota Withdrawal Scale (MNWS) have been used since 1986. The 
version used in this study has been shown to provide specific assessment of nicotine withdrawal 
using 9 specific items.24,25 The questionnaire will be administered to all study subjects on Week 
1, Week 2, Week 3, Week 4, and twice around the Week 12 visit (first to be 3 days (+/- 1 day) 
prior to the Week 12 visit and again 3 days (+/- 1 day) after the Week 12 visit).  Analysis of 
results is outlined in the study Statistical Analysis Plan. 
For each of the following, please rate yourself on how you have been feeling over the past 
24 hours. Mark the number that applies to you: 
Question 
Response 
 
Not at all Slight 
Moderate 
Quite a bit 
Extreme 
Urge to vape item 1 
0 
1 
2 
3 
4 
Depressed mood item 2 
0 
1 
2 
3 
4 
Irritability, frustration, or anger item 3 
0 
1 
2 
3 
4 
Anxiety item 4 
0 
1 
2 
3 
4 
Difficulty concentrating item 5 
0 
1 
2 
3 
4 
Restlessness item 6 
0 
1 
2 
3 
4 
Increased appetite item 7 
0 
1 
2 
3 
4 
Difficulty going to sleep item 8   
0 
1 
2 
3 
4 
Difficulty staying asleep item 9 
0 
1 
2 
3 
4