Clinical trial NCT04576949
Conditions: Smoking Cessation
Sponsor: Achieve Life Sciences
Start date: 2020-10-13; Completion date: 2021-12-23
Enrollment: 810 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This placebo-controlled Phase 3 study is being conducted at sites within the United States to evaluate 3 mg cytisinicline 3 times daily (TID) for treatment duration of 42 days/6 weeks and evaluate 3 mg cytisinicline TID for treatment duration of 84 days/12 weeks.

Detailed description:

Arms: arm 1: one placebo tablet orally (PO) three times daily (TID) plus behavioral support for 12 weeks arm 2: one cytisinicline tablet PO TID plus behavioral support for 6 weeks followed by one placebo tablet PO TID plus behavioral support for 6 weeks arm 3: one cytisinicline tablet PO TID plus behavioral support for 12 weeks
Interventions: intervention 1: Cytisinicline intervention 2: Placebo intervention 3: Behavioral support
Intervention descriptions: intervention 1: film-coated oral tablets containing 3 mg cytisinicline intervention 2: film-coated oral tablets containing matched placebo intervention 3: Behavioral support sessions by a qualified study site staff member will be participant-driven and will include direct engagement with the subject about their attempt to quit smoking. Each session will last approximately 10 minutes.

Protocol documents:
Prot_000.pdf: 
 
 
 
Protocol ACH-CYT-03 (ORCA-2 Trial) 
 
A Multicenter, Double-blind, Randomized,  
Placebo-controlled Phase 3 Trial Evaluating the Efficacy 
and Safety of Cytisinicline in Adult Smokers  
 
 
 
March 8, 2021 
 
Version 4.0 
 
 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
   
. 
Achieve Life Sciences Technologies Inc.
Achieve Life Sciences, Inc. 
1040 West Geor
30
E, Suite 100 
Vancouver, Brit
nada   V6E 4H1 
021 
Tel: 425.686.1500    Fax: 425.686.1600 
Tel: 425.686.1500   Fax: 425.686.1600 




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SYNOPSIS . 
Protocol Number:  ACH-CYT-03 (ORCA-2 Trial) 
Sponsor: Achieve Life Sciences 
Title of Study: A Multicenter, Double-blind, Randomized, Placebo-controlled Phase 3 Trial 
Evaluating the Efficacy and Safety of Cytisinicline in Adult Smokers 
Clinical Phase: Phase 3 
Study Population: Male or female subjects ≥18 years who are daily cigarette smokers 
intending to make a quit attempt during the study. 
Rationale: (-)-Cytisine is a naturally occurring plant-based alkaloid that is believed to 
reduce the severity of nicotine withdrawal symptoms by targeting nicotinic acetylcholine 
receptors (nAChRs) in the brain. Cytisine administered using a 1.5 mg dose in a downward 
titration schedule over 25 days has been used as a smoking cessation drug since the 1980’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 or NRT in 
helping smokers to stop smoking. In 2018, the United States Adopted Names (USAN) 
Council adopted "cytisinicline" as the nonproprietary, or generic, name for cytisine. 
In the 2011 published Phase 3 study that evaluated cytisine versus placebo in 740 primarily 
moderate-to-heavy smokers treated for 25 days in Poland, the RR (relative risk) for 
sustained 6-month abstinence was 2.9 (10.0% cytisine arm compared to 3.5% placebo arm; 
P<0.001).1 In the 2014 published Phase 3 study that evaluated cytisine for 25 days versus 
nicotine replacement therapy (NRT) for 8 weeks in 1,310 adult daily smokers in New 
Zealand, the RR for continuous six-month abstinence was 1.4 for cytisine (22% cytisine 
arm compared to 15% in the NRT arm; P=0.002).2 
Data from the international EAGLES trial (N=8,120) were used to assess predictors for 
continuous smoking abstinence outcomes from Weeks 9-24.3 These analyses provided clear 
evidence that US origin was associated with lower success rates of stopping, regardless of 
treatment (varenicline, bupropion, or NRT). The continuous abstinence rates from 
9-24 weeks in the US were 16.1%, 11.4% and 10.6% for varenicline, bupropion, or NRT 
respectively, compared to 6.7% placebo treatment. The odds ratios (OR) for these 
treatments in the US were 2.66, 1.78, and 1.64 respectively. The lower success rate in US 
smokers supports the view that smokers in the US may have reached a point in the tobacco 
epidemic such that those who continue to smoke, despite strong cultural pressures not to, 
have particular characteristics that make it more difficult for them to stop smoking. This 
highlights the need for more effective treatments for treating smokers in the US. 
Studies have been conducted by Achieve Life Sciences evaluating cytisinicline at 1.5 mg 
and 3 mg dose levels in the downward 25-day titration schedule as well as in a simplified 
three times daily (TID) schedule. The 3 mg TID schedule for cytisinicline in the 
ACH-CYT-09 Phase 2b (ORCA-1) trial showed the highest level of prolonged abstinence 
starting from the End-of-Treatment (Week 4) through Week 8 (abstinence rate of 30% 
compared to 8% for placebo [p=0.005]). The 3 mg TID schedule also showed a well-


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tolerated safety profile and treatment compliance was high at 97.6%. Since the 3 mg TID 
schedule is a more simplified schedule and showed significantly higher abstinence at 30%, 
longer treatment could possibly increase the abstinence rate. This Phase 3 study will 
evaluate 3 mg cytisinicline TID for a slightly longer treatment duration of 42 days/6 weeks 
(instead of 25 days) as well as repeating that duration for a total of 84 days/12 weeks 
treatment (similar to the duration of varenicline treatment). 
All subjects will receive standard behavioral support for smoking cessation during the 
study. Subjects are to be randomized to one of three arms A, B, or C, where the intended 
interventions are placebo for 12 weeks plus behavioral support (Arm A), 3 mg cytisinicline 
TID for 6 weeks followed by placebo for 6 weeks plus behavioral support (Arm B), and 
3 mg cytisinicline TID for 12 weeks plus behavioral support (Arm C).  
The primary outcome measure is abstinence during the last 4 weeks of cytisinicline 
treatment compared to the placebo arm (Weeks 3-6 for comparison of Arm B vs Arm A; 
Weeks 9-12 for comparison of Arm C vs Arm A). The secondary outcome measure is 
abstinence continuing to Week 24 post randomization in the cytisinicline arms compared to 
the placebo arm (Weeks 6-24 for comparison of Arm B vs Arm A; Weeks 12-24 for 
comparison of Arm C vs Arm A). If the primary outcome of abstinence is significant for 
both 6 and 12 weeks of cytisinicline treatment, reduction in risk of relapse for those subjects 
achieving abstinence within a Week 3-6 period will be compared in Arm C vs Arm B from 
Week 7 to Week 24. 
In addition, the study will compare the safety profiles of 3 mg TID dosing for 6 weeks 
(Arm B) and 12 weeks (Arm C), relative to placebo (Arm A). 
Objectives:  
Multiple Primary Efficacy Objectives:  
The multiple primary objectives are based on two comparisons where study success can be 
based on success for either comparison: 
1. Assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 6 weeks 
followed by placebo TID for 6 weeks plus behavioral support) have a higher 
probability of abstinence from Week 3 to Week 6 post-randomization as compared to 
subjects randomized to Arm A (placebo TID plus behavioral support). 
2. Assess whether subjects randomized to Arm C (3 mg cytisinicline TID for 12 weeks 
plus behavioral support) have a higher probability of abstinence from Week 9 to 
Week 12 post-randomization as compared to subjects randomized to Arm A 
(placebo TID plus behavioral support). 
Secondary Efficacy Objectives:  
The analysis for secondary objectives 1 and 2 will be done only if the corresponding 
primary comparison passes statistical criterion. 
1. Assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 6 weeks 
followed by placebo TID for 6 weeks plus behavioral support) have a higher 
probability of continuous abstinence from Week 6 to Week 24 post-randomization 
as compared to subjects randomized to Arm A (placebo TID plus behavioral 
support).  


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2. Assess whether subjects randomized to Arm C (3 mg cytisinicline TID for 12 weeks 
plus behavioral support) have a higher probability of continuous abstinence from 
Week 12 to Week 24 post-randomization as compared to subjects randomized to 
Arm A (placebo TID plus behavioral support). 
The analysis for secondary objective 3 will be conditional and performed only if both 
primary comparisons 1 and 2 pass statistical criterion. 
3. Assess for a reduction in risk of relapse from Week 6 to Week 24 in subjects 
receiving 3 mg cytisinicline for 6 weeks and then either continue 3 mg cytisinicline 
from Week 6 to Week 12 (Arm C) or were switched to placebo from Week 6 to 
Week 12 (Arm B). Subjects not abstinent at Week 6 will be regarded as having 
relapsed. 
Other Objectives: 
1. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on 7-day point prevalence 
abstinence weekly at Week 2 to Week 12, then for Weeks 16, 20, and 24. 
2. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on serum cotinine levels 
every other week at Week 2 to Week 12, then at Weeks 16, 20, and 24. 
3. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on expired CO levels every 
week at Week 2 through Week 12, then at Weeks 16, 20, and 24. 
4. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on use of any non-cigarette 
nicotine products, including vaping, during study treatment (Week 2 through 
Week 12) and study follow-up (Week 16 through Week 24). 
5. Assess whether subjects randomized to Arm B have a higher probability of 
abstinence from Week 9 to Week 12 as compared to subjects randomized to Arm A 
(placebo).  
6. Assess among the subset of subjects who achieve abstinence from Week 3 to 
Week 6, whether subjects randomized to Arm B have a higher probability of 
continuous abstinence from Week 3 to Week 24 post-randomization as compared to 
subjects randomized to Arm A.  
7. Assess among the subset of subjects who achieve abstinence from Week 3 to 
Week 6, whether subjects randomized to Arm C have a higher probability of 
continuous abstinence at Week 24 post-randomization as compared to subjects 
randomized to Arm B. 
8. Assess among the subset of subjects who achieve abstinence from Week 9 to 
Week 12, whether subjects randomized to Arm C have a higher probability of 
continuous abstinence from Week 9 to Week 24 post-randomization as compared to 
subjects randomized to Arm A. 
9. Among subjects who achieve abstinence from Week 3 to Week 6, compare time to 
failure to maintain abstinence between arms (Arm B vs Arm A; Arm C vs Arm A) 
to Week 24. 


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10. To explore the magnitude of treatment effect between arms across various 
subgroups defined by demographic and baseline characteristics for the primary and 
secondary outcomes.  
11. To explore potential relationships between subject-reported outcomes (eg, anxiety, 
depression, withdrawal symptoms, tobacco craving) and the primary and secondary 
outcomes.   
12. To assess possible withdrawal symptoms at Week 7 in Arm B subjects who will 
have discontinued cytisinicline at Week 6, analyzing separately for nicotine status 
(eg, either smoking, abstinent, or if using other nicotine products including vaping 
or nicotine replacement therapy [NRT]) compared to Arms A and C.  
Safety Objectives:  
1. To evaluate the safety profile of 3 mg TID cytisinicline compared to placebo 
(Arm B vs Arm A; Arm C vs Arm A). 
2. To compare the safety profiles of Arm B subjects versus Arm C subjects with 
respect to adverse events occurring after Week 6 on the study. 
Study Design:  
This will be a multi-center, double-blind, randomized, placebo-controlled, Phase 3 study 
conducted in male or female adults who are daily cigarette smokers, intending to quit 
smoking, and are willing to set a quit date that is within 5-7 days of the start of treatment. 
Study treatment must start the day after randomization.  
Subjects must meet all requirements outlined in the inclusion and exclusion criteria. 
Approximately 750 subjects will be randomly assigned with equal probability to one of 
three Arms: (Arm A, 12 weeks placebo: N=250; Arm B, 6 weeks cytisinicline followed by 
6 weeks placebo: N=250; Arm C, 12 weeks of cytisinicline: N=250) as shown in the study 
design figure below. 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm A 
Placebo 
12 Weeks + Behavioral Support 
Arm B 
Cytisinicline 
6 Weeks + Behavioral Support, followed by 
Placebo 
6 Weeks + Behavioral Support 
 
 
 
 
S 
C 
R 
E 
E 
N 
F 
O 
L 
L 
O 
W 
 
U 
P 
Arm C 
Cytisinicline 
12 Weeks + Behavioral Support 


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Each randomized subject will receive 12 weeks of treatment using a TID dosing schedule. 
Smoking cessation assessments will begin on Week 2 (Day 14±1 post-randomization) and 
will continue weekly during the Treatment Period through the Weeks 16, 20 and 24 Follow-
up Period visits by the subject’s self-report of abstinence with carbon monoxide (CO) 
biochemical verification.  
All subjects will receive concurrent smoking cessation behavioral support during the study 
Treatment Period (Weeks 1-12). Additional behavioral support will be provided during the 
Follow-up Period based on issues/concerns/questions raised by the subject. 
Safety assessments at clinic visits will occur on Day 2 and Day 7 during 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 (EOT) during the Treatment 
Period. Any ongoing adverse events at Week 12 will be followed until resolved or 
determined to be chronic. The end of study is defined as the last follow-up visit (up to the 
Week 24 visit) for the last subject. 
Selection Criteria 
Inclusion Criteria: 
1. Male or female subjects, age ≥18 years.  
2. Current daily cigarette smokers (averaging at least 10 cigarettes per day upon 
completing a 7-day screening smoking diary) and who intend to quit smoking.  
3. Expired air carbon monoxide (CO) ≥10 ppm. 
4. Failed at least one previous attempt to stop smoking with or without therapeutic 
support. 
5. Willing to initiate study treatment on the day after randomization and set a quit date 
within 5-7 days of starting treatment. 
6. Willing to actively participate in the study’s smoking cessation behavioral support 
provided throughout the study. 
7. Able to fully understand study requirements, willing to participate, and comply with 
dosing schedule. 
8. Sign the Informed Consent Form. 
Exclusion criteria: 
1. More than 1 study participant in same household. 
2. Previous cytisinicline treatment in a prior clinical study or any other cytisine usage. 
3. Known hypersensitivity to cytisinicline or any of the excipients.  
4. Positive urinary drugs of abuse screen, determined within 28 days before the first 
dose of cytisinicline. 
5. Clinically significant abnormal serum chemistry or hematology values within 
28 days of randomization (ie, requiring treatment or monitoring).  


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6. Clinically significant abnormalities in 12-lead ECG determined after minimum of 
5 minutes in supine position within 28 days of randomization (ie, requiring 
treatment or further assessment). 
7. BMI classification for being underweight (<18.5 kg/m2) or having ≥Class 2 obesity 
(≥35 kg/m2). 
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.  
11. Currently having suicidal ideation or risk for suicide (“Yes” to question 4 or 
question 5 OR “Yes” to any suicidal behavior question on the C-SSRS). 
12. Current symptoms of moderate to severe depression (HADS score ≥11). 
13. Renal impairment defined as a creatinine clearance (CrCl) <60 mL/min (estimated 
with the Cockroft-Gault equation). 
14. Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2.0 x the upper limit of normal (ULN). 
15. Women who are pregnant or breast-feeding. 
16. Male or female subjects of childbearing potential who do not agree to use acceptable 
methods of birth control during the study treatment period. 
17. Participation in a clinical study with an investigational drug in the 4 weeks prior to 
randomization. 
18. Treatment with other smoking cessation medications (bupropion, varenicline, 
nortriptyline, or any nicotine replacement therapy [NRT]) in the 4 weeks prior to 
randomization or planned use of these other smoking cessation medications during 
the study. 
19. Use within the 2 weeks prior to randomization or planned use during the study of 
non-cigarette and/or noncombustible nicotine products (pipe tobacco, cigars, snuff, 
smokeless tobacco, hookah, e-cigarettes/vaping) or marijuana smoking or vaping.  
20. 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 750 subjects will be randomized at 15-19 sites in the United States, with 
250 subjects per arm. Subjects will be randomized within site. 
 
 
 


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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 (ie, 12 total packs for 12 weeks of study treatment). 
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, receive 
12 weeks of treatment, and will then be followed for up to 24 weeks post-randomization. 
Therefore, the duration of the study will be approximately 24 weeks post-randomization for 
a subject. 
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. If eligible, subjects will be required to attend a clinic 
visit prior to randomization in order to establish a quit date that will in turn determine the 
date of randomization. The quit date must be within 5-7 days of starting treatment and 
treatment must begin on the day after randomization. Subjects will be randomized in a 
blinded manner to receive Arm A, Arm B, or Arm C study drug for the 12-Week Treatment 
Period. Subjects will be provided with smoking cessation counseling beginning on the clinic 
visit during screening prior to randomization (setting quit date and plan), again on day of 
randomization, and continuing through the Week 12 visit. Additional counseling will also 
be provided during the Follow-up Period. 
Compliance will be assessed during the Treatment Period by reviewing subject’s treatment 
diary (date and time of dosing) as well as ongoing drug accountability at each weekly clinic 
visit. 
Subjects will be assessed for smoking cessation by self-report of abstinence with 
biochemical verification documented weekly starting at Week 2 through Week 12. 
Additional follow-up assessments will occur at Week 16, 20 and 24 to evaluate long-term 
continuous abstinence.  


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Subjects will be assessed for safety (vital signs, adverse event reporting and concomitant 
medications) on Day 2 and Day 7 during the first week of treatment (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 (EOT) during the Treatment 
Period. At Week 12 (EOT) 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. 
Follow-up visits will occur at Week 16, Week 20 and Week 24.  
 
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. 
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 
Primary efficacy outcomes: The primary efficacy outcome is binary and for each subject 
success is abstinence determined at Weeks 3, 4, 5, and 6 (Arm B) and Weeks 9, 10, 11, and 
12 (Arm C) post-randomization compared to the corresponding weekly assessments in the 
placebo arm (Arm A), with success defined as having reported abstinence in smoking by 
subject’s self-report with CO biochemical verification. Absence of success (non-success) is 
having been assessed but not meeting the criterion for success or not available for 
assessment per criteria. 
Secondary efficacy outcomes: The secondary outcome measure for the two comparison 
analyses associated with the secondary efficacy objectives 1 and 2 (Arm A versus Arm B 
and Arm A versus Arm C, respectively) is success with respect to continuous abstinence 
through Week 24. The secondary outcome measure for the comparison analysis associated 
with the secondary efficacy objective 3 (comparing Arm B to Arm C) is success with 
respect to being without relapse at Week 24. The considerations relative to the definition of 
these endpoints are similar. The analyses associated with these three objectives will be done 
as Intent-to-Treat (ITT) analyses. 
Subjects not observed to meet all success criteria will be regarded as non-success relative to 
secondary efficacy outcomes. Non-success will have two types: (1) subjects with adequate 
data that fail to meet the criteria, and (2) subjects having insufficient data to be assessed as a 
success. 


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The statistical model used for the secondary efficacy objectives 1 and 2 will be the same 
statistical model used for the analysis of the corresponding multiple primary objectives. 
Other outcomes: All other outcomes, including point prevalence abstinence, time to 
abstinence failure, magnitude of treatment effect across subsets defined by demographic and 
baseline characteristics, etc., will be considered exploratory outcomes. 
Statistical Methods 
Primary Analysis 
The primary analysis will include all randomized subjects by randomized arm (intent-to-
treat analysis). The multiple primary comparisons will be for 6 weeks cytisinicline (Arm B) 
vs placebo (Arm A) and for 12 weeks cytisinicline (Arm C) vs placebo (Arm A). If the 
primary efficacy comparison meets statistical criterion, then the corresponding secondary 
efficacy outcome analyses will have formal meaning. The primary comparisons will be 
comparing the arms based on the ratio of the odds of success in the experimental arm 
divided by the odds of success in the control arm (odds ratio) using exact computations for 
stratified 2x2 frequency tables. 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 also be reported.  
Trial Size 
The target accrual for each arm is planned for 250 (Approximately 750 for the study). The 
significance level to be used for the multiple primary comparisons is adjusted from the 
overall type I error probability of one-sided 0.025 to one-sided 0.0125 using the Bonferonni 
method to control for multiplicity. The assumed control arm probability of success (Weeks 
9-24 abstinence) is 0.07 (7%). The hypothesized experimental arm minus control arm 
probability difference is specified as 0.12 (12%), corresponding to a hypothesized odds ratio 
of 3.12 (7% for placebo vs 19% for cytisinicline treatment). The statistical operating 
characteristics for each comparison are illustrated using simulation with 10,000 replicates. 
These specifications are consistent with 95.7% power for each comparison with, conditional 
on 0.07 control arm probability outcome, an odds ratio critical region of ≥1.83, 
corresponding to a critical difference of ≥0.051 (7% for placebo vs 12% for cytisinicline 
treatment). 
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 . .....................................................................................................................................3 
LIST OF TABLES .........................................................................................................................16 
LIST OF FIGURES .......................................................................................................................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................17 
1. 
INTRODUCTION AND BACKGROUND ...............................................................19 
1.1. 
History of the Investigational Product ........................................................................19 
1.2. 
Nicotine Addiction and Impact on Health ..................................................................19 
1.3. 
Treatments for Smoking Cessation ..........................................................................19 
2. 
SAFETY OVERVIEW FOR CYTISINICLINE ........................................................21 
2.1. 
Non-Clinical Studies ...................................................................................................21 
2.1.1. 
Summary of 13-Week Toxicology Interim Substudy .................................................21 
2.1.2. 
Summary of 26-Week Chronic Toxicology Study .....................................................22 
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. 
PRIOR PHASE 3 EVIDENCE FOR CYTISINE AS A SMOKING 
CESSATION TREATMENT .....................................................................................25 
4. 
RECENT STUDIES COMPLETED BY SPONSOR .................................................26 
4.1. 
Summary from Study ACH-CYT-07 on the Effect of Food on Cytisinicline 
Bioavailability .............................................................................................................26 
4.2. 
Summary From Study ACH-CYT-08 on the Tolerability of Single 
Ascending Cytisinicline Dosing .................................................................................27 
4.3. 
Summary of the Multicenter, Double-blind, Randomized, Placebo-controlled 
ORCA-1 (ACH-CYT-09) Trial of Cytisinicline in Adult Smokers ...........................28 
5. 
RATIONALE FOR THE STUDY ..............................................................................31 
6. 
STUDY OBJECTIVES ..............................................................................................32 
6.1. 
Multiple Primary Efficacy Objectives ........................................................................32 
6.2. 
Secondary Efficacy Objectives ...................................................................................32 
6.3. 
Other Objectives .........................................................................................................32 
6.4. 
Safety Objectives ........................................................................................................33 
7. 
STUDY DESIGN OVERVIEW .................................................................................34 
7.1. 
Study Design ...............................................................................................................34 


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7.2. 
Treatment Period (12 Weeks) .....................................................................................35 
7.3. 
Discussion of Study Design ........................................................................................35 
7.3.1. 
Placebo Control ..........................................................................................................35 
7.3.2. 
Primary Endpoint ........................................................................................................35 
7.3.3. 
Blinding ......................................................................................................................36 
7.3.4. 
Unblinding ..................................................................................................................36 
7.4. 
Number of Subjects ....................................................................................................37 
7.5. 
Randomization ............................................................................................................37 
7.6. 
Number of Clinical Sites ............................................................................................37 
7.7. 
Estimated Duration/Completion of Study ..................................................................37 
8. 
SELECTION OF STUDY POPULATION ................................................................37 
8.1. 
Inclusion Criteria ........................................................................................................38 
8.2. 
Exclusion Criteria .......................................................................................................38 
8.3. 
Modifying or Discontinuing Study Treatment and/or Study Evaluations ..................39 
8.3.1. 
Study Treatment Modifications during the 12-Week Treatment Period ....................39 
8.3.2. 
Discontinuation of Study Drug Treatment during the 12-Week Treatment 
Period ..........................................................................................................................40 
8.3.3. 
Discontinuation of Follow-up Study Evaluations Prior to Week 24 
Assessment .................................................................................................................40 
8.3.4. 
Discontinuing from the Study (Withdrawal of Consent for Study 
Evaluations) ................................................................................................................40 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ..........................................41 
9.1. 
Cytisinicline Film-Coated Tablets ..............................................................................41 
9.2. 
Placebo Tablets ...........................................................................................................41 
9.3. 
Receipt and Storage ....................................................................................................41 
9.4. 
Administration ............................................................................................................41 
9.5. 
Return/Destruction ......................................................................................................41 
9.6. 
Method of Assigning Subjects to Arms ......................................................................41 
9.7. 
Study Drug Dosing Schedule ......................................................................................42 
9.8. 
Accountability .............................................................................................................42 
10. 
PREVIOUS AND CONCOMITANT MEDICATIONS ............................................42 
11. 
TREATMENT COMPLIANCE .................................................................................43 
12. 
STUDY PROCEDURES ............................................................................................43 


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12.1. 
Procedure Schedule ....................................................................................................43 
12.2. 
Detailed Description of Study Visits ..........................................................................47 
12.2.1. 
Screening Phase ..........................................................................................................47 
12.2.2. 
Randomization ............................................................................................................48 
12.2.3. 
Treatment Period ........................................................................................................49 
12.2.4. 
Follow Up Period for Smoking Cessation Assessments .............................................58 
12.2.5. 
Subject Diaries ............................................................................................................59 
12.2.6. 
Behavioral Support .....................................................................................................59 
13. 
EFFICACY CRITERIA ..............................................................................................60 
13.1. 
Laboratory Assessments for Efficacy .........................................................................60 
13.1.1. 
Expired Air Carbon Monoxide (CO) ..........................................................................60 
13.1.2. 
Serum Cotinine Levels ...............................................................................................61 
14. 
SAFETY ASSESSMENTS ........................................................................................61 
14.1. 
Definitions ..................................................................................................................61 
14.2. 
Recording of Adverse Events .....................................................................................63 
14.2.1. 
Grading Adverse Event Severity ................................................................................63 
14.2.2. 
Assessment of Attribution ..........................................................................................64 
14.2.3. 
Reporting of Serious Adverse Events .........................................................................64 
14.2.4. 
Reporting of a Pregnancy during Study Treatment ....................................................65 
14.2.5. 
Reporting of COVID-19 Positive cases as Adverse Events of Special Interest .........66 
14.3. 
Laboratory Assessments for Safety ............................................................................66 
14.3.1. 
Hematology and Chemistry Assessments ...................................................................66 
14.4. 
Vital Signs ..................................................................................................................66 
14.5. 
Physical Examination .................................................................................................66 
15. 
SAFETY MONITORING ..........................................................................................67 
15.1. 
Independent Data Safety Monitoring Committee .......................................................67 
16. 
STATISTICAL CONSIDERATIONS .......................................................................67 
16.1. 
Statistical Design ........................................................................................................68 
16.2. 
Primary Outcome for Subjects ....................................................................................68 
16.2.1. 
Analysis of Primary Outcome ....................................................................................68 
16.3. 
Secondary Outcome for Subjects ................................................................................69 
16.3.1. 
Analysis of Secondary Outcomes ...............................................................................69 
16.4. 
Study Size ...................................................................................................................70 


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16.5. 
Other Objectives .........................................................................................................71 
16.6. 
Safety Objectives ........................................................................................................71 
17. 
REGULATORY AND ETHICS CONSIDERATIONS .............................................71 
17.1. 
Institutional Review Board (IRB) ...............................................................................71 
17.2. 
Ethical Conduct of the Study ......................................................................................72 
17.3. 
Informed Consent .......................................................................................................72 
17.4. 
Subject Confidentiality ...............................................................................................72 
18. 
DOCUMENTATION .................................................................................................73 
18.1. 
Study File and Site Documents ...................................................................................73 
18.2. 
Study Documents Supplied by the Sponsor ................................................................73 
18.3. 
Maintenance and Retention of Records ......................................................................73 
19. 
ADMINISTRATIVE PROCEDURES .......................................................................74 
19.1. 
Sponsor Responsibilities .............................................................................................74 
19.2. 
Investigator Responsibilities .......................................................................................74 
19.3. 
Regulatory Compliance ..............................................................................................75 
19.4. 
Protocol Modification/Premature Termination ...........................................................75 
19.5. 
Policy for Publication and Data Presentation .............................................................75 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................77 
21. 
REFERENCES ...........................................................................................................78 
APPENDIX 1. COLUMBIA - SUICIDE SEVERITY RATING SCALE (C-SSRS) ................80 
APPENDIX 2. FAGERSTRÖM TEST OF NICOTINE DEPENDENCE .................................87 
APPENDIX 3. SMOKING SELF-EFFICACY QUESTIONNAIRE (SEQ-12) .........................88 
APPENDIX 4. BRIEF QUESTIONNAIRE OF SMOKING URGES (QSU-BRIEF) ...............89 
APPENDIX 5. MINNESOTA WITHDRAWAL SCALE (MNWS) ..........................................90 
APPENDIX 6. HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) .......................91 
APPENDIX 7. BEHAVIORAL SUPPORT ...............................................................................93 
 


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LIST OF TABLES 
Table 1: 
Adverse Events Reported From the Sopharma Core Data Sheet for Cytisine ...........24 
Table 2:  
Summary of Statistical Analysis of Cytisinicline Cmax and AUC ..............................27 
Table 3: 
ORCA-1 Study: Most Common Treatment-emergent Adverse Events 
Experienced by ≥2% of Subjects ................................................................................30 
Table 4: 
Schedule of Study Procedures During Treatment Period ...........................................44 
Table 5: 
Schedule of Procedure During Follow-up Period .......................................................46 
Table 6: 
Adverse Event Severity ..............................................................................................63 
Table 7: 
Assessment of Attribution to Study Drug ...................................................................64 
 
LIST OF FIGURES 
Figure 1: 
ORCA-1 Study: CO-Verified Abstinence Results .....................................................29 
Figure 2: 
ACH-CYT-03 (ORCA-2) Study Design Overview ....................................................34 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABBREVIATION/TERM 
DEFINITION 
ACh 
Acetylcholine 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AUC 
Area Under the Curve 
ALT 
Alanine Aminotransferase 
ARS 
All Randomized Analysis Set 
AST 
Aspartate Aminotransferase 
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 
DPF 
Dose-Proportionality Factor 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
EOT 
End-of-Treatment 
FTND 
Fagerstrom Test of Nicotine Dependence 
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 
nAChRs 
Nicotinic Acetylcholine Receptors 
NMR 
Nicotine Metabolite Ratio 
NRT 
Nicotine Replacement Therapy 
NOAEL 
No-Observed-Adverse-Effect-Level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNWS 
Minnesota Nicotine Withdrawal Scale 
OR 
Odds Ratio 
PSUR 
Periodic Safety Update Reports 
PT 
Preferred Term 
QPPV 
Pharmacovigilance Qualified Person 
QSU-Brief 
Brief Questionnaire of Smoking Urges 
RR 
Relative Risk 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SAS 
Safety Analysis Set 
SD 
Standard Deviation 
SEQ 
Self-Efficacy Questionnaire 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 


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ABBREVIATION/TERM 
DEFINITION 
SmPC 
Summary of Product Characteristics 
SOC 
MedDRA System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TID 
Three Times a Day 
Tmax 
Time to Maximum Observed Concentration 
UADR 
Unexpected Adverse Drug Reaction 
UAE 
Unexpected Adverse Event 
ULN 
Upper Limit of Normal 
USAN 
United States Adopted Names 


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1. 
INTRODUCTION AND BACKGROUND 
1.1. 
History of the Investigational Product 
Cytisine is a plant-based alkaloid used as a smoking cessation drug since the 1980’s in Eastern 
and Central Europe, marketed by Sopharma, Sofia, Bulgaria.4 The molecular structure of cytisine 
has similarities to nicotine and acetylcholine (ACh). Nicotine addiction results, at least in part, 
from its interaction with neuronal nicotinic acetylcholine receptors (nAChRs). Both cytisine and 
nicotine compete for these receptors.5-7 Cytisine has high affinity and specificity for neuronal 
nicotinic (α4β2) receptors.  
Despite its widespread use, cytisine has not been market-approved for use outside Eastern and 
Central Europe. 
 
 
 
 
 
  
 
 
. In 2018, the United States Adopted Names (USAN) Council adopted 
"cytisinicline" as the nonproprietary, or generic, name for cytisine. This protocol uses the USAN 
cytisinicline nomenclature except when referring to previous published data using cytisine 
nomenclature. 
 
 
1.2. 
Nicotine Addiction and Impact on Health 
Nicotine is an addictive substance that is rapidly absorbed during cigarette smoking. The drug 
distributes quickly and is thought to interact with nAChRs in the central nervous system (CNS). 
Although many smokers attempt to quit smoking, few succeed without pharmacological 
supportive treatment. 
Tobacco smoking contributes to some 8 million premature deaths each year worldwide.8 It is 
highly addictive, with more than 95% of unaided attempts at cessation failing by 6 months.9 
Every year that a smoker delays quitting beyond the mid-30s, there is an estimated 3 months 
reduction in life expectancy.10 
Although nicotine is primarily responsible for the addictive properties of cigarette smoking, 
tobacco smoke also contains several hundred gaseous substances and several thousand 
compounds. There is increasing evidence that the presence of carbon monoxide in cigarette 
smoke plays a role in cardiovascular disease and that tar is a major factor in respiratory disease 
and cancer.11 Nicotine, of which 1 to 3 mg is typically absorbed from each cigarette, is a 
peripheral vasoconstrictor and a sympathomimetic stimulant, which also leads to improvement 
in mood and attention. 
1.3. 
Treatments for Smoking Cessation  
The pharmacotherapies currently available in the US and Western Europe to help smokers quit 
include nicotine replacement therapy (NRT) and two non-nicotine containing medications: 


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bupropion (Zyban®, Glaxo-SmithKline) and varenicline (Chantix®/Champix®, Pfizer). NRT 
and bupropion appear to have about equal efficacy.12,13 Varenicline is more effective than NRT 
and bupropion. A brief description of each pharmacotherapy is given below. 
Nicotine replacement therapy was first introduced in 1978. NRT replaces the nicotine absorbed 
from cigarettes and helps subjects stop smoking by reducing nicotine cravings, withdrawal 
symptoms, and mood changes. Available over-the-counter and prescription-only NRT products 
include: chewing gums, lozenges, transdermal patches, nasal sprays and inhalers. The purpose of 
all NRT products is to achieve a sufficient plasma concentration of nicotine (and hence 
concentration of nicotine at central nAChRs) and so reduce craving for nicotine derived from 
cigarette smoke. However, the efficacy of NRT (expressed as a pooled Relative Risk (RR) 
compared with placebo treatment) is limited (overall RR 1.60).13 In general, the delivery of 
nicotine from NRT products is relatively slow, and the pharmacokinetic profile does not 
resemble that of cigarettes: the time to peak plasma concentration (Tmax) tends to be longer for 
NRT, and the Cmax is not characterized by a sharp peak, but by a lower and flatter peak. Thus, the 
smoker does not have the same nicotine experience with NRT products that they do from 
smoking. Although there do not appear to be safety concerns for NRT usage, the relatively poor 
response to NRT products as aids to smoking cessation limits their effectiveness as treatment. 
Side effects of NRT products include: nausea, dizziness, weakness, vomiting, fast or irregular 
heartbeat, mouth problems with the lozenge or gum, and redness or swelling of the skin around 
the patch. 
Bupropion is one of the most frequently prescribed antidepressants in the US. Zyban is 
bupropion re-profiled as a smoking cessation medication in tablet form. Although it reduces 
nicotine withdrawal symptoms and craving and enhances tobacco cessation, the precise 
mechanism by which it aids smoking cessation is unknown. The efficacy of bupropion is similar 
to that of NRT (overall RR 1.62).12 Although the most commonly observed adverse events 
consistently associated with the use of bupropion are dry mouth and insomnia, the medication 
guide for bupropion cites other adverse events and risks related to this product, including 
seizures, high blood pressure, and allergic reactions. Because bupropion contains the same active 
substance as the antidepressant Wellbutrin®, users and potential users are urged to talk to their 
health care professional about risks of treatment with antidepressant medicines. 
Varenicline was synthetically developed as a new class of α4β2 nicotine receptor partial agonists, 
in part, using (-)-cytisine as the structural starting point.7 Varenicline is a partial agonist at 
nicotine receptors and acts as a nicotine substitute leading to a gradual decrease in the smoker's 
physical and psychological dependence on cigarettes. In a recent Cochrane analysis report 
detailing 6-month abstinence rates, varenicline was found to be more effective than placebo 
(overall RR=2.25) or bupropion (overall RR=1.39).14 The most common side effects of 
varenicline (>5% or twice the rate seen with placebo) include nausea, abnormal (vivid, unusual, 
or strange) dreams, constipation, flatulence, and vomiting. In addition, the Prescribing 
Information for varenicline cites other possible serious side effects and risks including new or 
worsening mental health problems such as changes in behavior, hostility, agitation, or depressed 
mood. Other warnings and precautions include new or worsening seizures, accidental injury (eg, 
trouble driving or operating heavy machinery), cardiovascular events (new or worsening 
cardiovascular symptoms), allergic hypersensitivity reactions, serious skin reactions, and nausea. 


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The recently published, international trial (referred as the EAGLES trial15) was a large 
randomized, double-blind, placebo-controlled and active-controlled (nicotine patch) trial 
comparing varenicline and bupropion at 140 centers in 16 countries between Nov 30, 2011, and 
Jan 13, 2015. The trial randomized 8,144 participants. The study did not show a significant 
increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to 
nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and 
bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were 
more effective than placebo. Across cohorts, the most frequent adverse events by treatment 
group were nausea (varenicline, 25%), insomnia (bupropion, 12%), abnormal dreams (nicotine 
patch, 12%), and headache (placebo, 10%). 
In summary, new treatments are still needed that are less costly, more effective, have an 
improved safety profile, or can more successfully treat individuals who have failed to quit using 
the above treatments.  
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 and in 
preparation for this Phase 3 study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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2.2. 
General Safety of Cytisine as a Marketed Product 
Cytisine has been marketed by Sopharma AD, or Sopharma, in Central and Eastern Europe for 
over 20 years and is estimated to have been administered to over 21 million subjects. 
 
 
 
 
 
 
 
 
 
 


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Thus, from marketing safety reporting for cytisine, the most frequent adverse effects include: 
nausea, gastrointestinal symptoms (including abdominal pain, dyspepsia, and dry mouth), sleep 
disorder, dizziness and headache. Most reported adverse effects appear mainly at the beginning 
of therapy, are short-lived, mild-to-moderate intensity, and resolved spontaneously. It is not 
possible to dissociate these effects due to cytisine and those related to nicotine withdrawal. 
2.3. 
Special Populations 
Safety or pharmacokinetic information for the administration of cytisinicline in subjects with 
coronary disease, cardiac insufficiency, arterial hypertension, cerebrovascular diseases, 
hyperthyroidism, peptic ulcer, diabetes, renal, or hepatic insufficiency have not yet been 
obtained. Exclusion criteria have therefore been developed with external clinical input to exclude 
subjects that may have, or are being treated for, these underlying medical conditions.
 
 
 
 
 
 


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3. 
PRIOR PHASE 3 EVIDENCE FOR CYTISINE AS A SMOKING 
CESSATION TREATMENT 
Cytisine was evaluated in two 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 (TASC1 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 
published in the New England Journal of Medicine in September 2011.1 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 (CASCAID2 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.2 


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4. 
RECENT STUDIES COMPLETED BY SPONSOR 
Achieve has sponsored and completed the following clinical studies: 
ACH-CYT-01 “A Phase 1 Open Label, Randomized, Two-Way Crossover Study in Healthy 
Volunteers to Investigate the Effect of Food on the Bioavailability of Cytisine”  
ACH-CYT-02 “Repeat-Dose Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine 
in Healthy Smokers” 
ACH-CYT-07 “A Phase 1 Open Label, Randomized, Two-Way Crossover Study in Healthy 
Smokers to Investigate the Effect of Food on the Bioavailability of Cytisine in a New 
Formulation” 
ACH-CYT-08 “A Phase I, Double-blind, Randomized, Placebo-controlled, Single Dose-
escalation Study to Evaluate the Tolerability and Safety of Cytisine in Adult Smokers” 
ACH-CYT-09 (ORCA-1) “A Multicenter, Double-blind, Randomized, Placebo-controlled 
Phase 2b Trial of Cytisine in Adult Smokers” 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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4.3. 
Summary of the Multicenter, Double-blind, Randomized, Placebo-
controlled ORCA-1 (ACH-CYT-09) Trial of Cytisinicline in Adult 
Smokers 
ORCA-1 “A Multicenter, Double-blind, Randomized, Placebo-controlled Phase 2b Trial of 
Cytisine in Adult Smokers” was a Phase 2b study evaluating cytisinicline doses using different 
administration schedules within a 25-day treatment period and was conducted at clinical sites 
within the US.  
The study was a Phase 2b, six-arm, multi-center, double-blind, randomized, placebo-controlled 
trial conducted in male or female adults who were daily cigarette smokers, intending to quit 
smoking, and were willing to set a quit date that was 5-7 days after the start of treatment. The 
study arms consisted of the 1.5 mg dose/downward titration schedule that is 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. The study was double-blinded to dose but not to the administration 
schedule. Study treatment started the day after randomization and was completed in 25 days. 
Follow-up assessments for smoking status and abstinence started at the End-of-Treatment visit 
(EOT: also defined as Week 4) and continued weekly to Week 8. 
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.  


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Below are the most relevant efficacy results for initial quit rates at Week 4 and continuous 
abstinence rates through Weeks 5-8. Initial quit rate at Week 4 was defined for a subject as 
having reported smoking no cigarettes from Day 21 to the Day 27 EOT visit, with an expired air 
carbon monoxide (CO) reading <10 ppm at the EOT visit. Continuous abstinence, defined as no 
cigarettes smoked from Week 5 to Week 8, was measured for a subject as having reported 
smoking abstinence (no cigarettes since the last clinic visit and over the past 7 days) at each 
clinic assessment from Weeks 5, 6, 7, to Week 8 with biochemical CO verification at each 
weekly assessment. 
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 
 
CO-verified 7-day point abstinence rates at EOT (Week 4) were statistically higher in all 
cytisinicline treatment arms compared to placebo: 45% and 42% for the 1.5 mg and 3 mg 
downward titration arms and 48% and 50% for the 1.5 mg and 3 mg TID arms, respectively, 
compared to 10% for the placebo arms (Figure 1).  
Continuous abstinence as of the Week 5 assessment through to the Week 8 assessment (total of 
4 weeks of continual abstinence after the end of treatment) is also shown in Figure 1. The TID 
schedule for cytisinicline had statistically higher continuous abstinence rates compared to 
placebo, with subjects in the 3 mg cytisinicline TID arm having the highest continuous 
abstinence rate at 30% compared to 8% for placebo. Subjects in the 3 mg TID arm also had 
higher odds for continuous abstinence from cigarettes from Week 5 to Week 8 compared with 
placebo (OR: 5.04, 95% CI: 1.42, 22.32). The OR for the 1.5 mg TID arm was 4.33 (95% CI: 


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1.21, 19.30). On the downward titration schedule, the ORs for the 1.5 mg and 3 mg arms were 
3.23 (95% CI: 0.86, 14.85) and 2.24 (95% CI: 0.55, 10.82), respectively.  
No subject experienced a serious adverse event. No new or unexpected adverse events were 
identified during the study. Most adverse events were mild or moderate in intensity; only 
2 (0.8%) were severe in intensity, and both were unrelated to study drug. About half of the 
adverse events (52.9%) were not related or unlikely to be related to the study drug. Most (95.3%) 
adverse events did not result in a change in dosing, and the subject was considered recovered 
(88.2%) during the study. A total of 3 subjects who received cytisinicline and 2 subjects who 
received placebo discontinued study treatment early due to an adverse event. Adverse events 
experienced by ≥2% of subjects in the trial are summarized in Table 3. 
Table 3: 
ORCA-1 Study: Most Common Treatment-emergent Adverse Events 
Experienced by ≥2% of Subjects 
 
Cytisinicline 
Downward Titration 
Schedule 
Cytisinicline TID 
Schedule 
 
All Subjects 
(N=254) 
n (%) 
 
 
1.5 mg  
(N=51) 
n (%) 
 
3 mg 
(N=50)  
n (%) 
 
1.5 mg 
(N=52) 
n (%) 
 
3 mg 
(N=50) 
n (%) 
Pooled 
Placebo 
(N=51) 
n (%) 
Upper respiratory tract infection 
3 (5.9) 
2 (4.0) 
5 (9.6) 
3 (6.0) 
7 (13.7) 
20 (7.9) 
Abnormal dreams 
4 (7.8) 
7 (14.0) 
4 (7.7) 
3 (6.0) 
1 (2.0) 
19 (7.5) 
Nausea 
5 (9.8) 
3 (6.0) 
1 (1.9) 
3 (6.0) 
5 (9.8) 
17 (6.7) 
Insomnia 
3 (5.9) 
4 (8.0) 
4 (7.7) 
3 (6.0) 
1 (2.0) 
15 (5.9) 
Headache 
1 (2.0) 
1 (2.0) 
6 (11.5) 
2 (4.0) 
2 (3.9) 
12 (4.7) 
Fatigue 
1 (2.0) 
2 (4.0) 
3 (5.8) 
1 (2.0) 
2 (3.9) 
9 (3.5) 
Nasopharyngitis  
2 (3.9) 
2 (4.0) 
0 
2 (4.0) 
1 (2.0) 
7 (2.8) 
Gastroenteritis 
1 (2.0) 
0 
2 (3.8) 
1 (2.0) 
2 (3.9) 
6 (2.4) 
Anxiety 
1 (2.0) 
1 (2.0) 
0 
1 (2.0) 
3 (5.9) 
6 (2.4) 
Vomiting 
2 (3.9) 
2 (4.0) 
0 
1 (2.0) 
 0 
5 (2.0) 
Constipation 
0 
0 
1 (1.9) 
3 (6.0) 
1 (2.0) 
5 (2.0) 
Diarrhoea 
2 (3.9) 
1 (2.0) 
0 
0 
2 (3.9) 
5 (2.0) 
Hypertension 
2 (3.9) 
0 
2 (3.8) 
0 
1 (2.0) 
5 (2.0) 
TID = 3 times daily 
N: Number of safety subjects in the specified treatment arm. 
n: Number of subjects with data available in the specified treatment arm. 
Treatment-emergent AE was defined as any AE that was new in onset or was aggravated in severity or frequency 
after the first dose of study drug up to and including the last visit of the study. 
Adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 21.0. 
If a subject experienced more than 1 finding within a given system organ class, that subject was counted only once 
for that system organ class. If a subject experienced more than 1 finding with a given preferred term, that subject 
was counted only once for that preferred term. 


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5. 
RATIONALE FOR THE STUDY 
Previous Phase 3 studies have shown that cytisine can be effective in helping smokers to stop 
smoking.1,2 These Phase 3 studies showed that cytisine was more effective than placebo as well 
as NRT for smoking cessation with an excellent safety profile that is consistent with the safety 
profile reported by Sopharma for cytisine. Since tobacco smoking contributes to some 9 million 
premature deaths each year worldwide,8 using cytisinicline as a smoking cessation aid could 
offer far more benefit with minor risks of treatment when compared to that of continued 
smoking.  
Data from the international EAGLES trial (N= 8120) were used to assess predictors for 
continuous smoking abstinence outcomes from weeks 9-24.3 These analyses provided clear 
evidence that US origin was associated with lower success rates of stopping, regardless of 
treatment (varenicline, bupropion, or NRT). The continuous abstinence rates from 9-24 weeks in 
the US were 16.1%, 11.4% and 10.6% for varenicline, bupropion, or NRT, respectively, 
compared to 6.7% placebo treatment. The odds ratios (OR) for these treatments in the US were 
2.66, 1.78, and 1.64, respectively. The lower success rate in US smokers support the view that 
smokers in the US may have reached a point in the tobacco epidemic such that those who 
continue to smoke, despite strong cultural pressures not to, have particular characteristics that 
make it more difficult for them to stop smoking. This highlights the need for more effective 
treatments for treating smokers in the US. 
In the ORCA-1 Trial, conducted only in the US, the study population represented highly addicted 
smokers who on average were 48.4 years old and had been smoking for 32 years, meaning that 
most of them had started smoking in their adolescent years. In addition, they had an average of 
4.5 prior quit attempts with the last quit attempt approximately 3.7 years prior to entering the 
study and were currently smoking an average of 1 pack of 20 cigarettes a day. Although the 3 mg 
TID schedule for cytisinicline showed significant abstinence rates starting from the End-of-
Treatment (Week 4) through Week 8 (continuous abstinence rate of 30% compared to 8% for 
placebo), comments from study investigators and smokers participating in the study stated that a 
longer treatment would have been preferred. Since the 3 mg TID schedule is a more simplified 
schedule with high treatment compliance and a well-tolerated safety profile, a slightly longer 
6-Week 3 mg cytisinicline treatment will be evaluated as well as another 6 weeks of treatment 
for a total of 12 weeks.  
This Phase 3 study will be conducted at sites within the US to evaluate the longer treatment 
duration of 6 weeks (instead of 25 days) as well as repeating that duration for a total of 12 weeks 
treatment (similar to the 12-Week duration of varenicline treatment). All subjects will receive 
standard behavioral support for smoking cessation during the study. Study treatment will be 
blinded and the 3 study treatment arms are defined below:  
• Arm A (placebo TID for 12 weeks plus behavioral support). 
• Arm B (3 mg cytisinicline TID for 6 weeks followed by placebo TID for 6 weeks plus 
behavioral support). 
• Arm C (3 mg cytisinicline TID for 12 weeks plus behavioral support). 


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6. 
STUDY OBJECTIVES 
6.1. 
Multiple Primary Efficacy Objectives 
The multiple primary objectives are based on two comparisons where study success can be based 
on success for either comparison: 
1. Assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 6 weeks 
followed by placebo TID for 6 weeks plus behavioral support) have a higher probability 
of abstinence from Week 3 to Week 6 post-randomization as compared to subjects 
randomized to Arm A (placebo TID plus behavioral support). 
2. Assess whether subjects randomized to Arm C (3 mg cytisinicline TID for 12 weeks plus 
behavioral support) have a higher probability of abstinence from Week 9 to Week 12 
post-randomization as compared to subjects randomized to Arm A (placebo TID plus 
behavioral support). 
6.2. 
Secondary Efficacy Objectives   
The analysis for secondary objectives 1 and 2 will be done only if the corresponding primary 
comparison passes statistical criterion. 
1. Assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 6 weeks 
followed by placebo TID for 6 weeks plus behavioral support) have a higher probability 
of continuous abstinence from Week 6 to Week 24 post-randomization as compared to 
subjects randomized to Arm A (placebo TID plus behavioral support).  
2. Assess whether subjects randomized to Arm C (3 mg cytisinicline TID for 12 weeks plus 
behavioral support) have a higher probability of continuous abstinence from Week 12 to 
Week 24 post-randomization as compared to subjects randomized to Arm A (placebo 
TID plus behavioral support). 
The analysis for secondary objective 3 will be conditional and performed only if both primary 
comparisons 1 and 2 pass statistical criterion. 
3. Assess for a reduction in risk of relapse from Week 6 to Week 24 in subjects receiving 
3 mg cytisinicline for 6 weeks and then either continue 3 mg cytisinicline from Week 6 to 
Week 12 (Arm C) or were switched to placebo from Week 6 to Week 12 (Arm B). 
Subjects not abstinent at Week 6 will be regarded as having relapsed. 
6.3. 
Other Objectives 
1. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on 7-day point prevalence 
abstinence weekly at Week 2 to Week 12, then for Weeks 16, 20, and 24. 
2. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on serum cotinine levels every 
other week at Week 2 to Week 12, then at Weeks 16, 20, and 24. 
3. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on expired CO levels every week 
at Week 2 through Week 12, then at Weeks 16, 20, and 24. 


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4. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on use of any non-cigarette 
nicotine products, including vaping during study treatment (Week 2 through Week 12) 
and study follow-up (Week 16 through Week 24). 
5. Assess whether subjects randomized to Arm B have a higher probability of abstinence 
from Week 9 to Week 12 as compared to subjects randomized to Arm A (placebo). 
6. Assess among the subset of subjects who achieve abstinence from Week 3 to Week 6, 
whether subjects randomized to Arm B have a higher probability of continuous 
abstinence from Week 3 to Week 24 post-randomization as compared to homologous 
subjects randomized to Arm A.  
7. Assess among the subset of subjects who achieve abstinence from Week 3 to Week 6, 
whether subjects randomized to Arm C have a higher probability of continuous 
abstinence at Week 24 post-randomization as compared to subjects randomized to 
Arm B. 
8. Assess among the subset of subjects who achieve abstinence from Week 9 to Week 12, 
whether subjects randomized to Arm C have a higher probability of continuous 
abstinence from Week 9 to Week 24 post-randomization as compared to homologous 
subjects randomized to Arm A. 
9. Among subjects who achieve abstinence from Week 3 to Week 6, compare time to failure 
to maintain abstinence between arms (Arm B vs Arm A; Arm C vs Arm A) to Week 24. 
10. To explore the magnitude of treatment effect between arms across various subgroups 
defined by demographic and baseline characteristics for the primary and secondary 
outcomes.  
11. To explore potential relationships between subject-reported outcomes (eg, anxiety, 
depression, withdrawal symptoms, tobacco craving) and the primary and secondary 
outcomes. 
12. To assess possible withdrawal symptoms at Week 7 in Arm B subjects who will have 
discontinued cytisinicline at Week 6, analyzing separately for nicotine status (eg, either 
smoking, abstinent, or if using other nicotine products including vaping or nicotine 
replacement therapy [NRT]) compared to Arms A and Arm C. 
6.4. 
Safety Objectives 
1. To evaluate the safety profile of 3 mg TID cytisinicline compared to placebo (Arm B vs 
Arm A; Arm C vs Arm A). 
2. To compare the safety profiles of Arm B subjects versus Arm C subjects with respect to 
adverse events occurring after Week 6 on the study. 


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7. 
STUDY DESIGN OVERVIEW 
7.1. 
Study Design 
This will be a multi-center, double-blind, randomized, placebo-controlled, Phase 3 study 
conducted in male or female adults who are ≥18 years age, current daily cigarette smokers, 
intending to quit smoking, and are willing to set a quit date within 5-7 days of being randomized 
on the study. Study treatment must start the day after randomization such that study treatment is 
initiated prior to the quit date.  
Subjects must meet all requirements outlined in the inclusion and exclusion criteria. 
Approximately 750 subjects will be randomly assigned with equal probability (1:1:1) to three 
arms: (Arm A, 12 weeks placebo: N=250; Arm B, 6 weeks cytisinicline followed by 6 weeks 
placebo:  N=250; Arm C, 12 weeks of cytisinicline) as shown in the study design figure below. 
Figure 2: 
ACH-CYT-03 (ORCA-2) Study Design Overview 
 
This study will be conducted at approximately 15-19 clinical sites across the US. Subjects will be 
randomized within site, with the goal of balancing between arm allocation within clinical sites in 
order to minimize imbalance for the assessment of evidence of heterogeneity of effect estimates 
across sites. Clinical sites will be used as a stratification factor in primary analyses. 
The study will be comprised of a pre-study screen, followed by 12 weeks of treatment, and post-
treatment follow up visits to 24 weeks post-randomization.  
Each randomized subject will receive 12 weeks of treatment using a TID dosing schedule. 
Determination of smoking cessation will be made from the subject’s self-report of abstinence 
accompanied by expired carbon monoxide (CO) biochemical verification. Assessments of 
smoking abstinence will begin on Week 2 (Day 14±1 post-randomization) and will continue 
weekly during the Treatment Period, then at the Weeks 16, 20 and 24 Follow-up Period visits.  
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm A 
Placebo 
12 Weeks + Behavioral Support 
Arm B 
Cytisinicline 
6 Weeks + Behavioral Support, followed by 
Placebo 
6 Weeks + Behavioral Support 
 
 
 
 
S 
C 
R 
E 
E 
N 
F 
O 
L 
L 
O 
W 
 
U 
P 
Arm C  
Cytisinicline 
12 Weeks + Behavioral Support 


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All subjects will receive concurrent smoking cessation behavioral support during the study 
Treatment Period (Weeks 1-12). Additional behavioral support will be provided during the 
Follow-up period based on issues/concerns/questions raised by the subject. 
Safety assessments at clinic visits will occur on Day 2 and Day 7 during 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 (EOT) during the Treatment Period. Adverse events will 
be monitored though the Follow-up Period. Any ongoing adverse events at Week 24 will be 
followed until resolved or determined to be chronic. The end of study is defined as the last 
follow-up visit (up to the Week 24 visit) for the last subject. 
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 7.3.4. 
7.2. 
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 A will take one placebo tablet at each dosing per day for 
12 weeks. Arm B subjects will take one cytisinicline tablet at each dosing per day for the first 
6 weeks followed by one placebo tablet at each dosing per day for the last 6 weeks. Arm C 
subjects will take one cytisinicline tablet at each dosing per day for 12 weeks.  
7.3. 
Discussion of Study Design 
7.3.1. 
Placebo Control 
A placebo control in this study design is necessary to control for response bias in evaluating 
cessation and safety. Behavioral support alone has been shown to be effective in helping 
smokers to quit and all subjects, including placebo control subjects, will receive behavioral 
support to aid their smoking cessation attempt. In addition, this study evaluates the effectiveness 
of cytisinicline when administered for either 6 weeks or 12 weeks compared to one placebo 
group, and the 1:1:1 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. 
7.3.2. 
Primary Endpoint 
Smoking abstinence during the last 4 weeks of treatment as the primary endpoint mirrors the 
prior varenicline Phase 3 trials and other smoking cessation trials for regulatory approval. Most 
of these prior Phase 3 trials had a “grace” period with success determined as having 4 weeks 
abstinence during the last 4 weeks of treatment. For varenicline, treatment was for 12 weeks with 
the first 8 weeks as a “grace” period and weekly assessments at Weeks 9-12 while on treatment 
was the primary endpoint assessment. Arm B in this study will assess the benefit of a shorter, 
6-Week cytisinicline treatment having the first 2 weeks as a “grace period” and weekly 
assessments at Weeks 3-6 while on treatment as the primary endpoint assessment. Arm C in this 
study will mirror that same treatment duration as varenicline with weekly assessments at 
Weeks 9-12 while on treatment as the primary endpoint assessment. 


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Cytisinicline treatment was developed as a shorter treatment for smoking cessation, especially 
for smokers who do not want to commit to 12 weeks of treatment. However, the commercial 
25-day treatment period may be too short on treatment, since smoking relapse appeared high in 
ORCA-1 from the end of treatment abstinence (Week 4) during the Weeks 5-8 assessment 
period. Therefore, this study will evaluate the benefit of a slightly longer 6-Week treatment 
period as well as repeating the treatment period for a 12-Week treatment duration. The 6-Week 
treatment period which is half in duration may still be beneficial and have a better safety profile 
due to less time on treatment.  
For the primary endpoint, success is defined as complete abstinence during the last 4 weeks of 
treatment with weekly expired CO measurements ≤10 ppm for both 6- and 12-Week cytisinicline 
treatment durations plus behavioral support (Arm B and Arm C, respectively) compared to 
placebo plus behavioral support (Arm A).  
7.3.3. 
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 7.3.4) 
until the database is locked and final study analysis at 24 weeks post-randomization has been 
performed. 
7.3.4. 
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 study drug 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; 


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• 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. 
7.4. 
Number of Subjects 
Approximately 750 subjects will be randomized to the study, with approximately 250 subjects 
per arm. Efforts will be taken to coordinate weekly limits to enrollment rates among the 
participating sites in order to ensure adequate subject management and timely study data entry. 
The maximum number of subjects that a single site may be allowed to enroll, is 10% of the study 
total.  
7.5. 
Randomization  
Sites will utilize an Interactive Response Technology (IRT) system for treatment arm assignment 
at randomization (Day 0). The IRT will randomize within site. Detailed instructions are provided 
in the Study Reference Manual. 
7.6. 
 Number of Clinical Sites 
This will be a multicenter clinical trial within the US. Approximately 15-19 clinical sites will 
participate.  
7.7. 
Estimated Duration/Completion of Study 
Duration of this study is estimated to be approximately 24 weeks for an individual subject (from 
randomization to Week 24 follow-up visit). Completion of the entire study is estimated at 
12 months 
 
8. 
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 Principal 
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. 


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Upon obtaining signed informed consent, each subject will undergo the screening procedures 
outlined in Section 12.2.1. 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.  
8.1. 
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. Current daily cigarette smokers (averaging at least 10 cigarettes per day upon completing 
a 7-day screening smoking diary) and who intend to quit smoking. 
3. Expired air carbon monoxide (CO) ≥10 ppm.  
4. Failed at least one previous attempt to stop smoking with or without therapeutic support. 
5. Willing to initiate study treatment on the day after randomization and set a quit date 
within 5-7 days of starting treatment. 
6. Willing to actively participate in the study’s smoking cessation behavioral support 
provided throughout the study. 
7. Able to fully understand all study requirements, willing to participate, and comply with 
dosing schedule. 
8.  Sign the Informed Consent Form. 
8.2. 
Exclusion Criteria 
Subjects meeting ANY of the following exclusion criteria will NOT be eligible for inclusion 
into the study. 
1. More than 1 study participant in same household. 
2. Previous cytisinicline treatment in a prior clinical study or any other cytisine usage. 
3. Known hypersensitivity to cytisinicline or any of the excipients. 
4. Positive urinary drugs of abuse screen, determined within 28 days before the first dose of 
cytisinicline.  
5. Clinically significant abnormal serum chemistry or hematology values within 28 days of 
randomization (ie, requiring treatment or monitoring).  
6. Clinically significant abnormalities in 12-lead ECG determined after minimum of 
5 minutes in supine position within 28 days of randomization (ie, requiring treatment or 
further assessment). 


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7. BMI classification for being underweight (<18.5 kg/m2) or having ≥Class 2 obesity 
(≥35 kg/m2). 
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. 
11.  Currently having suicidal ideation or risk for suicide (“Yes” to either question 4 or 
question 5 OR “Yes” to any suicidal behavior question on the C-SSRS). 
12. Current symptoms of moderate to severe depression (HADS score ≥11). 
13. Renal impairment defined as a creatinine clearance (CrCl) <60 mL/min (estimated with 
the Cockroft-Gault equation). 
14. Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2.0 x the upper limit of normal (ULN). 
15. Women who are pregnant or breast-feeding. 
16. Male or female subjects of childbearing potential who do not agree to use acceptable 
methods of birth control during the study treatment period. 
17. Participation in a clinical study with an investigational drug in the 4 weeks prior to 
randomization. 
18. Treatment with other smoking cessation medications (bupropion, varenicline, 
nortriptyline, or any nicotine replacement therapy [NRT]) in the 4 weeks prior to 
randomization or planned use of these other smoking cessation medications during the 
study. 
19. Use within the 2 weeks prior to randomization or planned use during the study of non-
cigarette and/or noncombustible nicotine products (pipe tobacco, cigars, snuff, smokeless 
tobacco, hookah, e-cigarettes/vaping) or marijuana smoking or vaping. 
20. Any other reason that the investigator views the subject should not participate or would 
be unable to fulfill the requirements for the study. 
8.3. 
Modifying or Discontinuing Study Treatment and/or Study 
Evaluations 
8.3.1. 
Study Treatment Modifications 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 (eg, 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 


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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. 
8.3.2. 
Discontinuation of Study Drug Treatment during the 12-Week Treatment 
Period 
Subjects can be discontinued from study drug treatment during the Treatment Period 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 (eg, 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 remain on the study for continued safety 
assessments and other study evaluations (See Section 12.2.4). 
4. At the request of the subject who does not want to continue study drug treatment. 
The reason for discontinuation of study drug treatment will be recorded in the CRF. Procedures 
outlined for the Week 12 (EOT) visit should be completed at the time of discontinuation and will 
be recorded in the CRF.  
Unless a subject withdraws consent to participate in the study, subjects who discontinue study 
drug treatment will continue study evaluations to the Week 24 follow-up assessment as outlined 
in the protocol. Week 12 (EOT) visit procedures must be repeated at the designated Week 12 
timepoint relative to start of treatment. 
If a subject discontinues study drug treatment 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. 
8.3.3. 
Discontinuation of Follow-up Study Evaluations Prior to Week 24 Assessment 
All subjects should remain in the study and provide the required follow-up visits until the 
Week 24 follow-up assessment is completed except if a subject is lost to follow-up (eg, moved to 
an untraceable address) or withdraws consent for the follow-up visits.  
8.3.4. 
Discontinuing from the Study (Withdrawal of Consent for Study Evaluations) 
Each subject will be informed of their right to discontinue from the study including any further 
study evaluations at any time and for any reason. 
If a subject requests to be discontinued from any further study evaluations, the reasons for 
the study discontinuation will be recorded on the study completion form of the CRF. 


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9. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
9.1. 
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. 
 
9.2. 
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. 
9.3. 
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. 
Drug supply will be managed via an IRT program to maintain predetermined stock levels at the 
sites and/or handle resupply using site initiated requests. Upon receipt, details of study drug 
supplied shall be documented using the IRT and/or internal site login procedures. 
The study drug shall be stored in a secure, temperature controlled location and only 
dispensed by suitably trained staff. 
9.4. 
Administration 
Study drug will be supplied as compressed tablets in blister packs. Tablets should be swallowed 
whole with water. Food does not influence the overall absorption of cytisinicline, so there are 
no restrictions on dosing with respect to the timing of meals.  
9.5. 
Return/Destruction 
At the end of the study, all unused study drug should be destroyed by the sites as directed by the 
Sponsor, unless a prearranged return to depot or to the Sponsor has been requested.  
9.6. 
Method of Assigning Subjects to Arms 
Subjects will be allocated to arms according to a predetermined randomization schedule and 
randomly assigned with equal probability (1:1:1) once all screening procedures are completed 
and verified. Randomization will be stratified by site.  
 
 


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The clinical research staff will record study drug (tablet) administration and all related 
information on the applicable source documents, to allow investigational product accountability 
and evaluation of subject compliance. 
9.7. 
Study Drug Dosing Schedule 
All subjects will receive 1 tablet for each of three dosing times, approximately every 5 hours per 
day. This 3 times a day (TID) schedule will be maintained for the 12-Week Treatment Period. 
Initial treatment Day 1 for the 12-Week Treatment Period must start on the day after 
randomization. 
9.8. 
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 treatment 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. 
10. 
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).  


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All concomitant medication(s) taken during the trial, and any changes (additions, deletions, dose 
changes) must be recorded in the CRF.  
11. 
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 treatment diary that 
will record the number of tablets taken and time taken. Subjects will be instructed to bring their 
medication packs (blister packs) to each clinic visit so that clinic staff can reconcile against the 
treatment 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. 
12. 
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 5-7 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 2, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77 and 86. Follow-up visits will be scheduled 
at Weeks 16, 20 and 24. 
12.1. 
Procedure Schedule  
Table 4 provides a summary of required study evaluations. Refer to Section 12.2 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 5-7 days of Day 1.


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Table 4: 
Schedule of Study Procedures During Treatment Period 
Study Assessment 
Screening 
Period 
(Day-28 to 
Rand) 
Randomizati
on 
 
Treatment Period 
Week 1 – Week 12 (Day 84) 
 
(Days 7-86 are ±1 Day) 
 
 
SV 
1 
SV 
21 
Day 
0 
D12 
D2 
W1 
(D7) 
W2  
(D14) 
W3  
(D21) 
W4  
(D28) 
W5  
(D35) 
W6  
(D42) 
W7  
(D49) 
W8  
(D56) 
W9  
(D63) 
W10  
(D70) 
W11 
(D77) 
EOT3 
(D86) 
Informed Consent 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Psychiatric 
History  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS Questionnaire4 
• 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
• 
Physical Exam 
•5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking History 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
for all Females6 
• 
 
• 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
• 
Drugs of Abuse Screen7 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs including 
weight  
•8 
 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Hematology and 
Chemistry 
• 
 
 
 
 
• 
 
 
 
 
• 
 
 
 
 
 
• 
12-lead ECG 
• 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
• 
Concomitant 
Medications 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Quit Date Set and 
Treatment Day 1 
Scheduled 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Smoking & 
Treatment Diary 
Completion 
Instructions9 
• 
 
• 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Smoking 
Diary10 
• 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Treatment 
Diary Entries for 
Completeness and 
Compliance11 
 
 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Adverse Event 
Reporting 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Study Drug 
Distribution, 
Accountability and 
Collection 
 
 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 


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Study Assessment 
Screening 
Period 
(Day-28 to 
Rand) 
Randomizati
on 
 
Treatment Period 
Week 1 – Week 12 (Day 84) 
 
(Days 7-86 are ±1 Day) 
 
 
SV 
1 
SV 
21 
Day 
0 
D12 
D2 
W1 
(D7) 
W2  
(D14) 
W3  
(D21) 
W4  
(D28) 
W5  
(D35) 
W6  
(D42) 
W7  
(D49) 
W8  
(D56) 
W9  
(D63) 
W10  
(D70) 
W11 
(D77) 
EOT3 
(D86) 
Behavioral Support 
 
•12 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Fagerström Test of 
Nicotine Dependence 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Self-Efficacy 
Questionnaire 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QSU-Brief  
Questionnaire 
 
 
• 
 
• 
• 
• 
• 
• 
• 
• 
 
 
 
 
 
 
MNWS Questionnaire13 
 
 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
 
 
 
 
 
HADS Questionnaire 
• 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
• 
Smoking Cessation 
Status 
 
 
 
 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Expired CO 
• 
 
• 
 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Use of any non-
cigarette nicotine 
products14 
 
 
 
 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Serum Cotinine 
•15 
 
 
 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
1Randomization may occur at the SV2 visit IF subject can commit to a quit date that allows start of treatment the following day. In such cases all Day 0 (Randomization) 
procedures must be completed at the SV2 clinic visit. 
2Clinic will telephone each subject towards the end of Day 1 (first day of treatment) to make sure subject has taken medication according to dosing schedule, answer any 
questions, assess for adverse events and any concomitant medications and confirm the Day 2 clinic appointment.  
3Procedures required at Day 86 or if subject discontinues treatment prior to Week 12. The final day of treatment should be on Day 84. In order to ensure subject 
completes all treatment prior to assessments, the End of Treatment visit is to be scheduled on Day 86±1 Day. 
4 The Screening assessment for suicidal ideation (questions 1-5) will be asked in the temporal context of “within the past 3 months” and the Suicidal Behavior questions 
will be asked within the temporal context of  “within lifetime” in order to fully evaluate current ideation or risk of suicide. Assessments conducted at Week 6 and EOT 
will ask all questions in the temporal context of “since last assessment” for suicidal ideation/risk. 
5Physical exam may be conducted at either the SV1 or the SV2. 
6 Urine pregnancy test kits supplied to site by central laboratory. All other testing performed by a central laboratory. Test results must be negative at the SV1 and D0 visit 
for inclusion into the study. 
7 Drugs of abuse to include at a minimum amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, ecstasy, opiates, and phencyclidine. 
8 To include height at screening for BMI calculation. 
9 There are two distinct diaries to be used: The screening smoking diary will capture daily cigarette consumption for 7 consecutive days so that an average can be 
obtained to assess Inclusion Criteria #2. The on-study treatment diary is to assess treatment compliance and will capture each study drug dose date and time. 
10Number of cigarettes smoked daily will be recorded in a 7-day smoking diary to be completed by the subject between SV1 and SV2. Adequate completion of the 7-day 
screening diary with an average of at least 10 cigarettes smoked per day is required for inclusion into the study.  
11Study subjects are to make daily diary entries noting date and time of each dose. Sites are to review these prior (via on-line access) and during clinic visits to ensure 
subject is completing entries in real-time and accurately. 
12Setting the quit date and plan is to be considered the first behavioral support counseling session. 


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13The MNWS questionnaire to assess withdrawal will be administered to all subjects on Day 0 and then weekly at Week 1 through Week 7 clinic visits.  
14 Although planned use during the study is an exclusion criteria, record any actual  use of non-cigarette nicotine products, including vaping. 
15Serum will be collected with other laboratory testing at SV#1 for cotinine testing and another sample will be frozen/stored for possible Nicotine Metabolite Ratio 
(NMR) testing at baseline only. Serum collected on subjects that are screen-failed will be destroyed. 
 
Table 5: 
Schedule of Procedure During Follow-up Period 
Study Assessment 
Follow-up Period 
Week 16–Week 241 
 (Week Visits ±3 Days) 
 
Week 16 
Week 20 
Week 24 
Behavioral Support2 
• 
• 
• 
Adverse Event Reporting 
• 
• 
• 
Smoking Cessation Status 
• 
• 
• 
Expired CO 
• 
• 
• 
Use of any non-cigarette nicotine products3 
• 
• 
• 
Serum Cotinine 
• 
• 
• 
1All subjects regardless of smoking status at Day 84/Week 12 will continue for follow-up at the Week 16, Week 20 and Week 24 clinic visits.  
2Behavioral support sessions during the Follow-up Period are abbreviated and based only on issues/concerns/questions raised by subject for Weeks 16, 20 and 24. 
3Record any actual use of non-cigarette nicotine products, including vaping.  
 
 
 


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12.2. 
Detailed Description of Study Visits 
12.2.1. 
Screening Phase 
Screening assessments used to evaluate inclusion and exclusion criteria can occur during 1 or 
more clinical visits over a 28-day period prior to randomization and must include a minimum of 
2 clinic visits.  
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/risk is to be determined and 
documented via administration and assessment of the Screening C-SSRS questionnaire 
(Appendix 1). Depression is to be assessed via subject’s completion of the HADS 
questionnaire (Appendix 6). 
4. Physical examination. 
5. Document any existing adverse events. 
6. Concomitant medications. 
7. Review of smoking history, to include year started smoking, information about previous 
quit attempts (and methods/treatments used), average number of cigarettes smoked per 
day over the past 30 days, and type of cigarettes typically smoked (regular vs menthol).  
8. Provide smoking diary instructions to capture number of cigarettes smoked for 7 
consecutive days. This diary will be reviewed at Screening Visit #2 to verify that 
Inclusion #2 is met (averaging at least 10 cigarettes per day over a 7 day period). 
9. Expired CO. 
10. Vital signs, including weight and height. 
11. Urine pregnancy for all female subjects. 
12. Drugs of abuse screen. 
13. Hematology and Chemistry testing. 
14. Serum collected and frozen for cotinine testing. Actual baseline cotinine testing will be 
completed only for subjects that are randomized (batch tested). NOTE: An additional 
minimum 1.0 mL serum will be frozen and stored by the central laboratory for possible 
Nicotine Metabolite Ratio (NMR) testing at baseline only. These serum samples will be 
destroyed for all subjects that are screen-fails. 
15. 12-lead ECG. 
16. Review all inclusion and exclusion criteria and if satisfied, schedule Screening Visit #2.  


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Screening Visit #2 
1. During the Screening Visit #2 document any existing adverse events and concomitant 
medications. Note: Subjects must have adequately completed the 7-day daily smoking 
diary and have reported smoking an average of at least 10 cigarettes on 7 consecutive 
days to be eligible for inclusion into the study. 
2. Each subject to provide their quit date, which must be 5-7 days after randomization 
(Treatment Day 5, 6 or 7) and the 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 12.2.2) must be completed. 
12.2.2. 
Randomization  
Randomization (Day 0) 
Randomization must be performed within 5-7 days prior to the agreed upon quit date. All other 
screening evaluations must be completed with 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. 
5. Expired CO. 
Upon completion of all procedures and final confirmation/verification of eligibility, complete the 
following: 
1. Subject to complete the following questionnaires: 
a. Fagerström Test for Nicotine Dependence (Appendix 2). 
b. Smoking Self-Efficacy questionnaire (SEQ-12) (Appendix 3). 
c. Brief Questionnaire of Smoking Urges (QSU-Brief) questionnaire (Appendix 4). 
d. Minnesota Nicotine Withdrawal Scale (MNWS) questionnaire (Appendix 5).  
2. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: it should be stressed to subjects that they must maintain their 
dosing schedule throughout the Treatment Period.  
3. Randomize according to a pre-determined, blinded, randomization schedule (see 
Section 7.5) and obtain the first study treatment carton (Carton #1) which will contain 
treatment packs for Weeks 1-6.  
4. Provide study treatment Week 1 pack for the first 7 days of dosing and review dosing 
requirements. Review the layout and dosing instructions printed on the study treatment 


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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. 
5. Develop an appointment schedule that includes dates and times for each required clinic 
visit during the trial, providing a copy to the subject. 
6. Provide study treatment diary instructions that require daily entries for both date and time 
of each dose taken. 
7. 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. 
8. Remind subject of appointment time for Day 2 clinic visit. 
12.2.3. 
Treatment Period 
Treatment Day 1  
All subjects must begin treatment on the morning of Day 1 and record all dosing in the 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 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 following day and that they must bring 
with them their study treatment pack.  
Treatment Day 2 
1. Subject to complete the QSU-Brief questionnaire (Appendix 4). 
2. Review 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 and provide a study treatment 
Week 2 pack. 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: it should be stressed to subjects that they must maintain their 
dosing schedule throughout the Treatment Period.  
7. Remind subject of their appointment date and time for the Day 7 (Week 1) visit and that 
they must bring with them their study treatment packs. 


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Treatment Day 7/Week 1 (±1 day) 
1. Reconfirm planned quit attempt on Treatment Day 5, 6, or 7. 
2. Subject to complete the following questionnaires:  
a. QSU-Brief questionnaire (Appendix 4). 
b. MNWS questionnaire (Appendix 5). 
3. Review study treatment diary to verify dosing up to time of visit. 
4. Assess for AEs and any changes to concomitant medications. 
5. Vital signs, including weight. 
6. 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. 
7. Provide subject with behavioral support information that includes counseling. (NOTE: it 
should again be stressed to subjects that even if they are smoking less or have quit 
smoking, they must maintain their dosing schedule throughout the Treatment Period.  
8. Blood for hematology and serum chemistry testing. 
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. Subject to complete the following questionnaires: 
a. QSU-Brief questionnaire (Appendix 4). 
b. MNWS questionnaire (Appendix 5). 
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 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. 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 7). 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 
smoking. In addition, subjects are to be encouraged to continue trying to quit even if they 
are smoking or have a lapse after they have quit smoking. 
7. Blood for cotinine testing.  
8. Expired CO. 


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9. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 7) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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. 
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. Subject to complete the following questionnaires: 
a. QSU-Brief questionnaire (Appendix 4). 
b. MNWS questionnaire (Appendix 5). 
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 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. 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 7). 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 
smoking. In addition, subjects must be counseled to be honest with their smoking status 
information and encouraged to continue trying to quit even if they are smoking or have a 
lapse after they have quit smoking. 
7. Expired CO. 
8. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 14) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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. 
9. Remind subject of their Day 28 (Week 4) appointment date and time and that they must 
bring with them their study treatment packs. 


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Treatment Day 28/Week 4 (±1 day) 
1. Subject to complete the following questionnaires: 
a. QSU-Brief questionnaire (Appendix 4). 
b. MNWS questionnaire (Appendix 5). 
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 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. 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: Again it should be stressed to subjects that they must maintain 
their dosing schedule throughout the Treatment Period even if they have quit smoking. In 
addition, subjects must be counseled to be honest with their smoking status information 
and encouraged to continue trying to quit even if they are smoking or have a lapse after 
they have quit smoking. 
7. Blood for cotinine testing. 
8. Urine pregnancy for all female subjects. 
9. Expired CO. 
10. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 21) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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. 
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. Subject to complete the following questionnaires: 
a. QSU-Brief questionnaire (Appendix 4). 
b. MNWS questionnaire (Appendix 5). 
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. 


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5. 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. 
6. Obtain the study treatment carton #2 via IRT, which will contain study treatment packs 
for Weeks 7-12. Provide subject with a Week 7 pack from Carton #2. 
7. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: Again it should be stressed to subjects that they must maintain 
their dosing schedule throughout the Treatment Period even if they have quit smoking. In 
addition, subjects must be counseled to be honest with their smoking status information 
and encouraged to continue trying to quit even if they are smoking or have a lapse after 
they have quit smoking. 
8. Expired CO. 
9. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 28) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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 following questionnaires: 
a. QSU-Brief questionnaire (Appendix 4). 
b. MNWS questionnaire (Appendix 5). 
c. HADS questionnaire (Appendix 6). 
3. Review study treatment diary to verify dosing up to time of visit. 
4. Assess for AEs and any changes to concomitant medications. 
5. Vital signs, including weight. 
6. 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. 
7. Provide subject with behavioral support information that includes counseling 
(Appendix 7). 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 
smoking status information. 
8. Blood for hematology, serum chemistry and cotinine testing.  


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9. 12-lead ECG. 
10. Expired CO. 
11. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 35) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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. 
12. 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. Subject to complete the MNWS questionnaire (Appendix 5). 
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 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. 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 7). 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 
smoking status information. 
7. Expired CO. 
8. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 42) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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. 


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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. 
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 7). 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. Blood for cotinine testing.  
7. Urine pregnancy for all female subjects. 
8. Expired CO. 
9. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 49) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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 7). NOTE: Stress to subjects that they must maintain their dosing schedule 
for the remaining Treatment Period and to be honest with their smoking status 
information. 


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6. Expired CO. 
7. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 56) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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. 
8. 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 7). NOTE: Stress to subjects that they must maintain their dosing schedule 
for the remaining Treatment Period and to be honest with their smoking status 
information. 
6. Blood for cotinine testing.  
7. Expired CO. 
8. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 63) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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. 
 


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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 7). NOTE: Stress to subjects that they must maintain their dosing schedule 
for the remaining week and to be honest with their smoking status information. 
6.  Expired CO. 
7. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 70) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, 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. 
8. Remind subject of their Day 84 (Week 12) appointment date and time and that they must 
bring with them their study treatment packs. 
Treatment Day 84/ Week 12 (Assessment Day 86 ±1) 
Note: The final day of treatment should be on Day 84. In order to ensure all subjects have 
completed treatment prior to assessments, the End of Treatment 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 6). 
3. Review study treatment diary to verify dosing through Week 12. 
4. Assess for AEs and any changes to concomitant medications. 
5. Vital signs, including weight. 
6. Review study treatment Week 12 pack for compliance and collect both Weeks 11 and 
12 packs (which should be empty if all doses were taken as expected). 
7. Provide subject with behavioral support information that includes counseling 
(Appendix 7).  
8. Blood for hematology, serum chemistry and cotinine testing.  
9. Urine pregnancy for all female subjects. 
10. 12-lead ECG. 


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11. Expired CO. 
12. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Day 77) visit?  
b. If subject has smoked, subject should report the total number of cigarettes smoked 
since the last clinic visit. 
c. Has the subject used any non-cigarette nicotine products, including vaping, since 
the last clinic (Day 77) visit? If yes, record what was used and remind subject such 
products should not be used during the study. 
13. All subjects, regardless of smoking status, are to be scheduled for their Week 16 
(±3 days) follow-up visit. 
12.2.4. 
Follow Up Period for Smoking Cessation Assessments 
Week 16 (±3 days) 
1. Record the following:  
a. Has the subject smoked any cigarettes since the last (Day 86/Week 12) clinic visit?  
b. Has the subject smoked any cigarettes over the past 7 days?  
c. If subject has smoked, subject should report the total number of cigarettes smoked. 
d. Has the subject used any non-cigarette nicotine products, including vaping, since the 
last clinic (Day 86/Week 12) visit? If yes, record what was used and remind subject 
such products should not be used during the study. 
2. Assess for AEs.  
3. Blood for cotinine testing.  
4. Expired CO. 
5. Provide subject with abbreviated behavioral support based on issues/concerns/questions 
raised (Appendix 7). 
6. All subjects regardless of smoking status are to be scheduled for their Week 20 (±3 days) 
follow-up visit. 
Week 20 (±3 days) 
1. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Week 16) visit?  
b. Has the subject smoked any cigarettes over the past 7 days?  
c. If subject has smoked, subject should report the total number of cigarettes smoked. 
d. Has the subject used any non-cigarette nicotine products, including vaping, since the 
last clinic (Week 16) visit? If yes, record what was used and remind subject such 
products should not be used during the study. 
2. Assess for AEs.  
3. Blood for cotinine testing.  
4. Expired CO. 


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5. Provide subject with abbreviated behavioral support based on issues/concerns/questions 
raised (Appendix 7). 
6. All subjects, regardless of their smoking status, should be scheduled for their 
Week 24 (±3 days) follow-up visit. 
Week 24 (± 3 days) 
1. Record the following:  
a. Has the subject smoked any cigarettes since the last clinic (Week 20) visit?  
b. Has the subject smoked any cigarettes over the past 7 days?  
c. If subject has smoked, subject should report the total number of cigarettes smoked. 
d. Has the subject used any non-cigarette nicotine products, including vaping, since the 
last clinic (Week 20) visit? If yes, record what was used and remind subject such 
products should not be used during the study. 
2. Assess for AEs.  
3. Blood for cotinine testing.  
4. Expired CO. 
5. Provide subject with abbreviated behavioral support based on issues/concerns/questions 
raised (Appendix 7). 
6. Discharge subject from study. 
12.2.5. 
Subject Diaries 
A 7-day smoking diary will be collected during the screening period in order to capture the 
number of cigarettes smoked daily for 7 consecutive days. These data will be used to calculate 
the average number of cigarettes smoked per day in order to support Inclusion Criteria #2.  
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 for 
completeness with the subject at each clinic visit.  
12.2.6. 
Behavioral Support 
Each participating site must have at least two or more staff members experienced and qualified 
to provide smoking cessation counseling. For this study, site counselors are required to have 
either a master’s level or higher degree in a counseling profession (eg, health educator, chemical 
dependence counselor) or completed a tobacco treatment training course of at least 4 hours. 
Evidence of the above qualification(s) must be provided during the site qualification process. 
The site counselors will be provided additional study-specific training prior to or during site 
initiation that reviews validated counseling techniques and how to implement them. 
All subjects will receive up to 15 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 4. Each behavioral session will be subject-driven and must include direct 


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engagement with the subject about their attempt to quit smoking. Each session should last 
approximately 10 minutes (Refer to Appendix 7). 
Site counselor(s) are to encourage subjects to continue study drug as scheduled even if they quit 
smoking as planned or if they lapse and have a cigarette after their quit date during the Treatment 
Period. It is important during the Week 2 to Week 8 “grace” period for subjects to keep trying to 
quit as planned. It is also important to stress to subjects that they should be honest when 
reporting cigarette smoking status and to remind them that all timepoints from Week 2 through 
Week 12 during the Treatment Period will be verified using CO.  
Subjects will receive additional abbreviated support (based on issues/concerns/questions raised 
by the subject) during the Follow-up Period.  
13. 
EFFICACY CRITERIA 
This study will follow general criteria that are applicable to previous and current trials of 
cessation aids where participants have a defined target quit date and there is face-to-face contact 
with researchers or clinic staff.16 Endpoint analyses for abstinence (4 weeks abstinence 
documented during the last 4 weeks of treatment) and continuous abstinence (continually 
documented to Week 24 post-randomization) will include the following criteria:  
1. Self-report of smoking abstinence since the last clinic visit at each clinic assessment.  
2. Biochemical verification of abstinence by expired CO at each clinic visit. 
3. Use of an ‘intention-to-treat’ approach in which data from all randomized smokers are 
included in the analysis. 
4. Subjects with an unknown smoking status at the Week 6, Week 12 and Week 24 
assessments or lost to follow up will be classified as failed to quit.  
5. Self-report of smoking abstinence during the follow up period only (Week 12 to 
Week 24) will follow the Russell Standard.16 
6. Continually blinded to treatment allocation during collection of follow-up data to 
Week 24. 
Refer to Section 16.2 and Section 16.3 for the specific criteria in determining the primary and 
secondary efficacy outcomes, respectively. 
13.1. 
Laboratory Assessments for Efficacy 
13.1.1. 
Expired Air Carbon Monoxide (CO) 
Expired CO will be obtained using a calibrated instrument (eg, the Bedfont Micro+ 
Smokerlyzer®) provided and maintained by the clinical site. Each clinical site must have 
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 Weeks 16, 20 and 24.  


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13.1.2. 
Serum Cotinine Levels 
Serum samples will be collected as additional laboratory efficacy assessments with cotinine 
levels determined at Weeks 2, 4, 6, 8, 10, 12, 16, 20 and 24. Baseline cotinine testing will use 
frozen serum collected at the SV1 visit for subjects that are randomized. Cotinine levels will be 
determined at a central laboratory. 
14. 
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 2 and Day 7 during Week 1, then weekly 
throughout the Treatment Period (Weeks 2 through 12/EOT) and monthly during the Follow-up 
Period (see Table 4 and Table 5). 12-lead ECG evaluations will be obtained on Week 6 and 
Week 12. 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 clinically significant abnormalities detected on 12-lead ECG or 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 Principal 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 randomization (prior to dosing) 
through the Week 24 visit will be recorded in the subject’s CRF. 
14.1. 
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, ie, the relationship cannot be ruled out 
and is judged by the investigator as at least possible (see definition below). 


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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 
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 (eg, 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 (ie, is not consistent with the applicable product information eg, 
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 


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treatment of a pre-existing condition that has not significantly worsened, or to diagnostic 
procedures. 
14.2. 
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 24 visit must be 
followed until final resolution or until it is medically justifiable to stop further follow up (eg, a 
chronic condition has been reached.) Documentation of adverse events should be updated as 
necessary. 
14.2.1. 
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 6. Only 1 severity grade will 
be used for each AE (eg, mild - moderate is not acceptable). 
Table 6: 
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 in 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. 


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14.2.2. 
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 7.  
Table 7: 
Assessment of Attribution to Study Drug  
Category 
Description 
Not Related 
The event is definitely not associated with study drug.  
Unlikely 
The event was most probably produced by other factors such as the subject’s 
clinical state, therapeutic intervention or concomitant therapy, and does not 
follow a known response pattern to study drug.  
Possible 
The event follows a reasonable temporal sequence from the time of study drug 
administration, and/or follows a known response pattern to the investigational 
product, but could have been produced by other factors such as the subject’s 
clinical state, therapeutic intervention or concomitant therapy. 
Probable 
The event follows a reasonable temporal sequence from the time of study drug 
administration, and/or follows a known response pattern to the investigational 
product, and could not have been produced by other factors such as the 
subject’s clinical state, therapeutic intervention or concomitant therapy. 
Definite 
The event follows a reasonable temporal sequence from the time of study drug 
administration, and/or follows a known response pattern to the investigational 
product, and could not have been produced by other factors such as the 
subject’s clinical state, therapeutic intervention or concomitant therapy, and 
either occurs immediately following study drug administration, or improves on 
stopping the study drug. 
14.2.3. 
Reporting of Serious Adverse Events 
Any SAE that occurs during the AE reporting period (randomization to Week 24) must be 
recorded and reported immediately. All SAEs including those that are ongoing at the end of the 
Week 24 visit will be followed until each event resolves or is assessed as chronic.  
In order to satisfy regulatory requirements, any Serious Adverse Event, whether deemed study 
drug-related or not, must be reported to the Sponsor or designee as soon as possible after the 
Investigator (or delegate) has become aware of its occurrence. SAE form completion and 
reporting must not be delayed, even if all of the information is not available at the time of the 
initial contact. 
SAEs must be reported within 24 h of knowledge of the event by submitting an initial SAE 
report via email, telephone or fax. 
 
 
 
 
 
 


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Additional information (follow-up) about any SAE unavailable at the initial reporting should be 
forwarded by the site within 24 hours of the information becoming available.  
The following information should be provided to accurately and completely record the event: 
• Investigator name and center number. 
• Subject number. 
• Subject initials. 
• 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 (randomization through to 
Week 24 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.  
14.2.4. 
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 period, the Investigator must complete the Pregnancy Notification Form and 
submit to the 
Pharmacovigilance Associate. Although not considered an SAE, the 
 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) 


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within 24 hours of receipt to the site with a copy to the Medical Monitor and Sponsor for their 
awareness].  
Although non-clinical assessments have shown no treatment-related toxicity in pregnant rabbits 
and rats, the pregnant subject should discontinue study drug treatment while remaining on the 
study for continued safety assessments and other study evaluations.  
The 
 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 
born. Any serious adverse events of the subject during the pregnancy or of the child at birth need 
to be recorded and 
 notified accordingly.  
14.2.5. 
Reporting of COVID-19 Positive cases 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. Any effects of the COVID-19 pandemic on the 
conduct of the study or any specific effects of COVID-19 infections on treatment arm results will 
be assessed. 
14.3. 
Laboratory Assessments for Safety 
14.3.1. 
Hematology and Chemistry Assessments  
Routine laboratory safety samples will be analyzed at screening and at clinic visits as identified 
in Table 4 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 CRF. The reference ranges for laboratory parameters will also 
be entered in the database and filed in 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. 
14.4. 
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. Clinically significant abnormalities 
occurring during the study will be recorded on the AE CRF. Height is to be recorded at 
Screening Visit #1 for BMI calculation. 
14.5. 
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. 


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15. 
SAFETY MONITORING 
15.1. 
 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 
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 (eg, moderate or severe 
adverse events). 
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. 
16. 
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 (ie, 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. 


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16.1. 
Statistical Design 
The overall study type I error probability will be one-sided 0.025 conditional on evidence of a 
favorable outcome for cytisinicline. Subjects will be randomized with equal probability to one of 
three arms (groups), one of two experimental arms or a control arm. The intended dosing 
regimens in these three arms are placebo for 12 weeks (Arm A), 3 mg cytisinicline for 6 of 
12 weeks (Arm B) and 3 mg cytisinicline for 12 weeks (Arm C). The details of the interventions 
are specified in Section 7.1 and Section 7.2. 
Two primary study objectives are specified in Section 6.1. These two primary objectives specify 
that the outcomes for each of the two experimental arms are to be compared to the control arm. 
The study size is based on a one-sided type I error probability of 0.0125 for each comparison of 
an experimental arm to the control (placebo) arm. Study success will be assessed using the 
Hochberg method for the two comparisons and the overall study type I error probability of one-
sided 0.025; the outcomes are assumed to be positively correlated.  
16.2. 
Primary Outcome for Subjects 
The primary efficacy outcome (biochemically verified abstinence for the last 4 weeks of 
cytisinicline treatment) for each subject is binary: success versus failure. Success is defined for 
the subject as having reported smoking abstinence (no cigarettes since the last clinic visit) at 
each clinic assessment from Week 3 to Week 6 (Arm B) and Week 9 to Week 12 (Arm C) with 
biochemical verification at each assessment. Biochemical verification will be defined by a 
carbon monoxide concentration in exhaled breath of less than 10 ppm. Similar timeframe and 
analyses will occur for Arm A placebo subjects. 
Any other outcome is regarded as a failure. There are therefore two types of failure for the 
subject: (1) subjects with adequate data that they are smoking at any time (either by the subject’s 
self-report or CO ≥10 ppm) and (2) subjects having insufficient data to be determined as a 
success for smoking 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. 
16.2.1. 
Analysis of Primary Outcome 
The outcome for each arm will be the proportion of subjects classified as a success. Each of the 
two experimental arms will be compared separately to the control arm (Arm A) at the 
appropriate timeframes. All randomized subjects will be included in the comparisons according 
to their randomized arm (ITT analysis). The statistical significance of each comparisons 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 clinical site, with the possibility of 
pooling clinical sites having a small contribution. 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. 


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The exact difference in proportion confidence interval is derived using the method of Thomas 
(1971 and 1977).17,18 
The primary comparisons will be presented in the context of a tipping point analysis.19 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. 
16.3. 
Secondary Outcome for Subjects 
The secondary efficacy outcome 1 and 2 (continued biochemically verified abstinence to 
Week 24) for each subject is binary: success versus failure. Success is defined for the subject as 
having reported smoking abstinence since the last clinic visit at each clinic assessment from 
Week 6 (Arm B) or Week 12 (Arm C) to Week 24 with biochemical verification at each 
assessment. Biochemical verification will be defined by a carbon monoxide concentration in 
exhaled breath of less than 10 ppm. During the Follow-up Smoking Cessation Assessment Period 
between Weeks 12 to 24, self-report of smoking abstinence will be according to the Russell 
Standard.16 
The secondary efficacy outcome 3 is success with respect to being without relapse at Week 24. 
The secondary efficacy outcome 3 (reduction in risk of relapse from Week 6 to Week 24 in 
Arm C vs Arm B) will be assessed in each subject (in both Arms C and B). Subjects not 
abstinent at Week 6 will be regarded as having relapsed. 
The considerations relative to the definition of these secondary efficacy endpoints are similar. 
The analyses associated with these three objectives will be done as Intent-to-Treat (ITT) 
analyses. The statistical model used for secondary objectives will be the same statistical model 
used for the analysis of the primary objectives. 
16.3.1. 
Analysis of Secondary Outcomes 
There are 3 secondary efficacy objectives, 2 objectives for continuous abstinence and 1 objective 
for reduction in risk of relapse. The continuous abstinence through Week 24 success outcome 
(secondary objectives 1 and 2) and relapse-free through Week 24 (secondary objective 3) must 
be defined separately for each of the three associated comparisons because of differences in the 
primary evaluation timing, that is, Weeks 3-6 for the Arm A versus Arm B comparison and 
Weeks 9-12 for Arm A versus Arm C comparison, and a mixed primary evaluation time for the 
Arm B versus Arm C comparison. It is important to note that the data collected and the schedule 
of collection are identical for all arms. 
The following operational details are applicable to these secondary comparisons: 
• Being abstinent requires meeting both a self-reported criterion and a biochemical 
verification. The beginning of self-reported abstinence is Week 3 to Week 6 for 
comparisons of Arm A and Arm B and Week 9 to Week 12 for comparison of Arm A 
and Arm C. For comparison of Arm B to Arm C, the failure of self-reported 
abstinence starts at Week 6 for both Arms B and C. 
• Self-reported abstinence over the Follow-up Weeks 16-24 period will be assessed 
using the Russell Standard16 to be regarded as abstinent or without relapse. 


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• Biochemical verification of non-smoking status is defined by a carbon monoxide 
concentration in exhaled breath of less than 10 ppm. 
Subjects not observed to meet all success criteria will be regarded as non-success relative to the 
secondary efficacy outcome. Non-success will have two types: (1) subjects with adequate data 
that fail to meet the above criteria, and (2) subjects having insufficient data to be assessed as a 
success. 
16.4. 
Study Size 
In the 2011 published TASC Phase 3 study that evaluated cytisine versus placebo in 
740 primarily moderate-to-heavy smokers treated for 25 days in Poland, the sustained 6-month 
abstinence rate was 10.0% in the cytisinicline arm compared to 3.5% in the placebo arm 
(P<0.001). In the 2014 published Phase 3 study that evaluated cytisinicline for 25 days versus 
nicotine replacement therapy (NRT) for 8 weeks in 1,310 adult daily smokers in New Zealand, 
the continuous six-month abstinence rate was 22% in the cytisinicline arm compared to 15% in 
the NRT arm (P=0.002).  
Data from the international EAGLES trial (N=8120) were used to assess predictors for 
continuous smoking abstinence outcomes from Weeks 9-24. These analyses provided clear 
evidence that US origin was associated with lower success rates of stopping, regardless of 
treatment (varenicline, bupropion, or NRT). The continuous abstinence rates from 9-24 weeks in 
the US were 16.1%, 11.4% and 10.6% for varenicline, bupropion, or NRT, respectively, 
compared to 6.7% (95% CI: 5.3-8.4%) for placebo treatment. The odd ratios (OR) for these 
treatments in the US were 2.66, 1.78, and 1.64, respectively. The lower success rate in US 
smokers supports the view that smokers in the US may have particular characteristics that make 
it more difficult for them to stop smoking.  
The trial size for this study is specified as 250 subjects per arm. The assumed control arm 
probability of success (continued abstinence to Week 24) is 0.07 (7%). The hypothesized 
experimental arm minus control arm probability difference is specified as 0.12 (12 points), 
corresponding to a hypothesized odds ratio of 3.116 (eg, 7% for placebo vs 19% for cytisinicline 
treatment). The significance level to be used is adjusted from the overall type I error probability 
of one-sided 0.025 to one-sided 0.0125 using the Bonferonni method to control for multiplicity. 
The statistical operating characteristics for each comparison are illustrated using simulation of 
Fisher’s exact test with 10,000 replicates. These specifications are consistent with 95.7% power 
for each comparison with, conditional on 0.07 control arm probability outcome, an odds ratio 
critical region of ≥1.83, corresponding to a critical difference of ≥0.051 (7% for placebo vs 12% 
for cytisinicline treatment). 
The study size is designated for approximately 750 subjects (250 subjects per arm). However, if 
higher than expected early treatment discontinuations (>5% to 10%) occur before completion of 
6 weeks study treatment due to reasons other than adverse events, additional enrollment may be 
allowed up to 10% or 75 subjects. 


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16.5. 
Other Objectives 
Other objectives beyond the designated primary and secondary objectives will be exploratory. 
There will be no multiplicity protection scheme for these analyses, and the results of these 
analyses will be labeled as exploratory. 
16.6. 
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. 
17. 
REGULATORY AND ETHICS CONSIDERATIONS 
17.1. 
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 can begin, all required regulatory documents 
(Section 18.1) must be in place. In addition, 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 
version that was reviewed, as well as any associated documents. The Investigator also must 
forward copies of subsequent amendment approval letters upon receipt.  


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17.2. 
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. Study plans may 
be adjusted in response to COVID-19 public health control measures and in accordance with 
regulatory guidelines to ensure subject safety, data integrity and study continuity occurs.  
17.3. 
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 (ie, 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. 
17.4. 
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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18. 
DOCUMENTATION  
18.1. 
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 Principal Investigator’s curriculum vitae and current medical license. Note: Principal 
Investigator or a Co-Investigator must be a medical doctor (MD). 
4. Documentation of required training for designated smoking cessation behavioral 
counselors. 
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 
18.2. 
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) 
18.3. 
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. 
19. 
ADMINISTRATIVE PROCEDURES 
19.1. 
Sponsor Responsibilities 
The study will be monitored by representatives of the Sponsor and/or designated contract 
research organizations (CROs). On-site monitoring is preferred and will be performed. However, 
should circumstances arise that prohibit routine travel (eg, in response to COVID-19 public 
health control measures), remote monitoring will be conducted as needed. 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. 
19.2. 
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. 
19.3. 
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. 
19.4. 
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 Principal 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 
Principal 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.  
19.5. 
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 
Principal 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 


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reviewed to 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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Protocol No. ACH-CYT-03 (ORCA-2) 
20. 
INVESTIGATOR’S AGREEMENT  
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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21. 
REFERENCES 
 
1. 
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. 
2. 
Walker N, Howe C, Glover M, et al. Cytisine versus nicotine for smoking cessation. The 
New England journal of medicine 2014;371:2353-62. 
3. 
West R, Evins AE, Benowitz NL, et al. Factors associated with the efficacy of smoking 
cessation treatments and predictors of smoking abstinence in EAGLES. Addiction (Abingdon, 
England) 2018;113:1507-16. 
4. 
Etter J. Cytisine for smoking cessation: A literature review and a meta-analysis. Archives 
of Internal Medicine 2006;166:1553-9. 
5. 
Papke RL, Heinemann SF. Partial agonist properties of cytisine on neuronal nicotinic 
receptors containing the beta 2 subunit. Molecular pharmacology 1994;45:142-9. 
6. 
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. 
7. 
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. 
8. 
WHO Report on the Global Tobacco Epidemic, 2019. 2019.  
9. 
Hughes JR, Keely J, Naud S. Shape of the relapse curve and long-term abstinence among 
untreated smokers. Addiction (Abingdon, England) 2004;99:29-38. 
10. 
Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years' 
observations on male British doctors. BMJ (Clinical research ed) 2004;328:1519. 
11. 
Foulds J, Burke M, Steinberg M, Williams JM, Ziedonis DM. Advances in 
pharmacotherapy for tobacco dependence. Expert opinion on emerging drugs 2004;9:39-53. 
12. 
Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. Antidepressants for 
smoking cessation. The Cochrane database of systematic reviews 2014:Cd000031. 
13. 
Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. 
The Cochrane database of systematic reviews 2012;11:Cd000146. 
14. 
Cahill K, Lindson-Hawley N, Thomas KH, Fanshawe TR, Lancaster T. Nicotine receptor 
partial agonists for smoking cessation. The Cochrane database of systematic reviews 
2016:Cd006103. 
15. 
Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of 
varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders 
(EAGLES): a double-blind, randomised, placebo-controlled clinical trial. The Lancet 
2016;387:2507-20. 
16. 
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. 
17. 
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. 
18. 
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. 
19. 
Yan X, Lee S, Li N. Missing data handling methods in medical device clinical trials. 
Journal of biopharmaceutical statistics 2009;19:1085-98. 


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20. 
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. 
21. 
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The Fagerstrom Test for 
Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. British journal of 
addiction 1991;86:1119-27. 
22. 
Etter JF, Bergman MM, Humair JP, Perneger TV. Development and validation of a scale 
measuring self-efficacy of current and former smokers. Addiction (Abingdon, England) 
2000;95:901-13. 
23. 
Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges 
(QSU-brief) in laboratory and clinical settings. Nicotine & tobacco research : official journal of 
the Society for Research on Nicotine and Tobacco 2001;3:7-16. 
24. 
West R, Ussher M. Is the ten-item Questionnaire of Smoking Urges (QSU-brief) more 
sensitive to abstinence than shorter craving measures? Psychopharmacology 2010;208:427-32. 
25. 
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. 
26. 
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. 
27. 
Stern AF. The hospital anxiety and depression scale. Occupational medicine (Oxford, 
England) 2014;64:393-4. 
 
 


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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.20 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 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 at the Week 6 (Day 42) or End of Treatment (Day 86) study visits 
requires reporting as an AE as well as referral to a qualified Mental Health Professional for 
followup. 
*Training by study staff is to be documented via certification in past 1 year on the C-SSRS. 
Training can be obtained on-line (www.cssrs.columbia.edu/training/training-research-setting). 
 


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APPENDIX 2. FAGERSTRÖM TEST OF NICOTINE DEPENDENCE  
 
The Fagerström Test of Nicotine Dependence (FTND) has been shown to be a reliable and valid 
measure of nicotine dependence21 and will be administered at the randomization visit only. 
Analysis of results is outlined in the study Statistical Analysis Plan. 
 
Question 
Response 
How soon after you wake up do you smoke your 
first cigarette? 
Within 5 minutes 
 
6-30 minutes 
 
31-60 minutes 
 
After 60 minutes 
 
 
Do you find it difficult to refrain from smoking in 
places where it is forbidden (for example in church, 
at the library, in a cinema, etc.)? 
Yes 
 
No 
 
 
Which cigarette would you hate most to give up? 
The first one in the 
morning 
 
All others 
 
 
How many cigarettes/day do you smoke? 
10 or less 
 
11-20 
 
21-30 
 
31 or more 
 
 
Do you smoke more frequently during the first 
hours after waking than during the rest of the day? 
Yes 
 
No 
 
 
Do you smoke if you are so ill that you are in bed 
most of the day? 
Yes 
 
No 
 
 


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APPENDIX 3. SMOKING SELF-EFFICACY QUESTIONNAIRE (SEQ-12) 
The Smoking Self-Efficacy Questionnaire (SEQ-12)22 is a validated instrument to assess baseline 
situations in which people might be tempted to smoke and will be administered at the 
randomization visit only. Analysis of results is outlined in the study Statistical Analysis Plan. 
 
The following are some situations in 
which certain people might be tempted to 
smoke. Please indicate whether you are 
sure that you could refrain from smoking 
in each situation using one of the 
following answers: 
1 = 
Not at 
all sure 
2 =  
Not Very 
Sure 
3= 
More or 
less sure 
4 = 
Fairly 
Sure 
5 = 
Absolutely 
Sure 
1. When I feel nervous 
1 
2 
3 
4 
5 
2. When I feel depressed 
1 
2 
3 
4 
5 
3. When I am angry 
1 
2 
3 
4 
5 
4. When I feel very anxious 
1 
2 
3 
4 
5 
5. When I want to think about a 
difficult problem 
1 
2 
3 
4 
5 
6. When I feel the urge to smoke 
1 
2 
3 
4 
5 
7. When having a drink with 
friends 
1 
2 
3 
4 
5 
8. When celebrating something 
1 
2 
3 
4 
5 
9. When drinking beer, wine, or 
other spirits 
1 
2 
3 
4 
5 
10. When I am with other 
smokers 
1 
2 
3 
4 
5 
11. After a meal 
1 
2 
3 
4 
5 
12. When having coffee or tea 
1 
2 
3 
4 
5 
 


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89 
APPENDIX 4. BRIEF QUESTIONNAIRE OF SMOKING URGES 
(QSU-BRIEF) 
The 10-question Brief Questionnaire of Smoking Urges (QSU-Brief) has been validated as a 
self-report instrument to measure tobacco craving/urges23,24 and will be administered to study 
subjects at randomization and clinic visits on Day 2, 7, 14, 21, 28, 35, and 42. Analysis of results 
is outlined in the study Statistical Analysis Plan. 
We are interested in how you are thinking or feeling right now as you are filling out the 
questionnaire: 
Question 
Response 
 
Strongly Disagree……..Strongly Agree 
 
1 
2 
3 
4 
5 
6 
7 
I have a desire for a cigarette right now. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
Nothing would be better than smoking a cigarette 
right now. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
If it were possible, I probably would smoke now. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
I could control things better right now if I could 
smoke. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
All I want right now is a cigarette. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
I have an urge for a cigarette. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
A cigarette would taste good now. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
I would do almost anything for a cigarette now. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
Smoking would make me less depressed. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
I am going to smoke as soon as possible. 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
 
 


Protocol ACH-CYT-03, March 8, 2021, Ver 4.0 
 
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90 
APPENDIX 5. 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.25,26 The questionnaire will be administered to all study subjects at 
randomization and then weekly starting on Week 1 through Week 7 clinic visits. 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 smoke 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 
 
 


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91 
APPENDIX 6. HOSPITAL ANXIETY AND DEPRESSION SCALE 
(HADS) 
The HADS questionnaire27 has been validated as a self-report instrument to measure levels of 
anxiety and depression and will be administered to study subjects. This questionnaire must be 
completed by all potential study subjects (completed = each of the 14 questions must be 
answered by the subject) during screening. The HADS questionnaire must be reviewed by clinic 
staff and a summation score calculated by totalling the numbers circled for each question at 
Screening Visit #1. A score >11 (total of Depression “D” Questions only) indicates current 
symptoms of moderate to severe depression and will be considered exclusionary for this study. 
The HADS questionnaire is to also be completed at Day 42 (Week 6) and again at Day 86 
(Week 12/EOT). Analysis of results is outlined in the study Statistical Analysis Plan. 
 
A 
I feel tense or 'wound up': 
 
D 
I feel as if I am slowed down: 
3 
Most of the time 
 
3 
Nearly all the time 
2 
A lot of the time 
 
2 
Very often 
1 
From time to time, occasionally 
 
1 
Sometimes 
0 
Not at all 
 
0 
Not at all 
 
 
 
 
 
D 
I still enjoy the things I used to enjoy: 
 
A 
I get a sort of frightened feeling like 
'butterflies' in the stomach: 
0 
Definitely as much 
 
0 
Not at all 
1 
Not quite so much 
 
1 
Occasionally 
2 
Only a little 
 
2 
Quite Often 
3 
Hardly at all 
 
3 
Very Often 
 
 
 
 
 
A 
I get a sort of frightened feeling as if 
something awful is about to happen: 
 
D 
I have lost interest in my appearance: 
3 
Very definitely and quite badly 
 
3 
Definitely 
2 
Yes, but not too badly 
 
2 
I don't take as much care as I should 
1 
A little, but it doesn't worry me 
 
1 
I may not take quite as much care 
0 
Not at all 
 
0 
I take just as much care as ever 
 
 
 
 
 
D 
I can laugh and see the funny side of 
things: 
 
A 
I feel restless as I have to be on the 
move: 
0 
As much as I always could 
 
3 
Very much indeed 
1 
Not quite so much now 
 
2 
Quite a lot 
2 
Definitely not so much now 
 
1 
Not very much 
3 
Not at all 
 
0 
Not at all 
 
 
 
 
 
A 
Worrying thoughts go through my 
mind: 
 
D 
I look forward with enjoyment to 
things: 
3 
A great deal of the time 
 
0 
As much as I ever did 
2 
A lot of the time 
 
1 
Rather less than I used to 
1 
From time to time, but not too often 
 
2 
Definitely less than I used to 
0 
Only occasionally 
 
3 
Hardly at all 
 
 
 
 
 
D 
I feel cheerful: 
 
A 
I get sudden feelings of panic: 
3 
Not at all 
 
3 
Very often indeed 
2 
Not often 
 
2 
Quite often 
1 
Sometimes 
 
1 
Not very often 
0 
Most of the time 
 
0 
Not at all 
 
 
 
 
 


Protocol ACH-CYT-03, March 8, 2021, Ver 4.0 
 
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92 
A 
I can sit at ease and feel relaxed: 
 
D 
I can enjoy a good book or radio or TV 
program: 
0 
Definitely 
 
0 
Often 
1 
Usually 
 
1 
Sometimes 
2 
Not Often 
 
2 
Not often 
3 
Not at all 
 
3 
Very seldom 
Note: The actual questionnaire will not indicate the category (A=anxiety, D=depression) or the points, which are 
provided here to show how responses will be scored for analysis. 


Protocol ACH-CYT-03, March 8, 2021, Ver 4.0 
 
Cytisinicline  
 CONFIDENTIAL 
 
 
93 
APPENDIX 7. BEHAVIORAL SUPPORT 
Each participating site must have at least two or more staff members experienced and qualified 
to provide smoking 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 (eg, health educator, chemical dependence counselor) or completed a 
tobacco treatment training course of at least 4 hours. 
All subjects will receive up to 15 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 smoking. Each session should last approximately 10 minutes. 
Ideally, one counselor should be assigned to support a given subject throughout their smoking 
cessation journey during the study in order to establish a trusting and supportive relationship.  
Site counselor(s) are to encourage subjects to continue study drug as scheduled even if they quit 
smoking as planned or if they lapse and have a 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 cigarette smoking status and to remind 
them that all timepoints from Week 2 through Week 12 during the Treatment Period will be 
verified using CO.  
Subjects will be given the National Cancer Institute, “Clearing the Air” booklet, American Heart 
Associate “Managing Stress” handout, and the American Thoracic Society, “What is Second and 
Third Hand Smoking?” handout at the randomization visit. 
Subjects will be given a list of 2-3 U.S. websites (eg, www.smokefree.gov, 
www.cancer.org/healthy/stay-away-from-tobacco/guide-quitting-smoking, 
www.heart.org/en/healthy-living/healthy-living-lifestyle/quit-smoking-tobacco) as resources.  
Subjects may 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 smoking. 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 approximately 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.  


Protocol ACH-CYT-03, March 8, 2021, Ver 4.0 
 
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94 
• Anticipate triggers or challenges in the upcoming attempt–Discuss challenges/triggers 
and how the subject will successfully overcome them (eg, 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 in the household–Quitting is more difficult when there is another 
smoker in the household. Subjects should encourage housemates to quit with them or 
to not smoke in their presence. 
• Recognize danger situations–Identify events, internal states, or activities that increase 
the risk of smoking or relapse (ie, smoking cues and availability of cigarettes, 
experiencing urges) 
• Develop coping skills–Identify and practice coping or problem solving skills. 
Typically, these skills are intended to cope with danger situations (ie, learning to 
avoid temptation and triggers) 
• Provide basic information–Provide basic information about smoking 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 a cigarette? 
• What are some alternatives I can do when I face these barriers instead of smoking? 
• What are my stress triggers for cravings? 
• How will I deal with these stressors instead of smoking? 
• What are your biggest concerns/fears about quitting smoking? 
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.  
 

SAP_001.pdf: 
Statistical Analysis Plan:
PROTOCOL ACH-CYT-03 (ORCA-2 Trial)
A Multicenter, Double-blind, Randomized, 
Placebo-controlled Phase 3 Trial Evaluating the Efficacy 
and Safety of Cytisinicline in Adult Smokers
March 25, 2022
Version 1.0
CONFIDENTIAL
Achieve Life Sciences Technologies Inc.
Achieve Life Sciences, Inc.
1040 W. Georgia S
22722 29th D
0
Vancouver, Brit
   V6E 4H1
Bothell, Was
  98021
Tel: 425.686.1500 Fax: 425.686.1600
Tel: 425.686.1500   Fax: 425.686.1600
A 
ACHIEVE 
LIFE SCIENCES 
1-55


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Version 1.0 – March 25, 2022
Cytisinicline
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APPROVAL SIGNATURES
Protocol
ACH-CYT-03
Document Title 
Statistical Analysis Plan: Protocol ACH-CYT-03 (ORCA-2 Trial)
Document Version
Version 1.0
Document Date
March 25, 2022
By signing this section, the individuals below agree that they have reviewed the scope of the 
effort described in this Statistical Analysis Plan for the ACH-CYT-03 (ORCA-2) study. The 
signatures below represent the approval and acceptance of this document by V
tat and 
Achieve
nces, Inc.
Approved By:
Yicheng Ma, PhD
Seni
tician
Veristat, LLC.
Renee J Perdok, MS, MBA
Senior D
ometrics
Achiev
ces, Inc.
Cindy Jacobs, PhD, MD
Chief M
Achieve L
es, Inc.
Signing 
document 
Signing Time: 29-Mar-2022 I 2:05:04 PM EDT 
7EEBF0268D244F6CB80E97273E9428FA 
Signing 
document 
Signing Time: 29-Mar-2022 12:51 :16 PM EDT 
B 18EA62D4DE04 77896EDC7 4EF90D228A 
11 :58:01 AM PDT 
FC1674605FD64D5881230485455561D7 
2-55


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GLOSSARY OF ABBREVIATIONS
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CDISC
Clinical Data Interchange Standards Consortium
CO
Carbon Monoxide
CRF
Case Report Form
C-SSRS
Columbia - Suicide Severity Rating Scale
DTS
Data Transfer Specification
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA
Effect Modification Analyses
eCRF
Electronic Case Report Form
EOT
End of Treatment
FTND
Fagerstrom Test of Nicotine Dependence
HADS
Hospital Anxiety and Depression Scale
ICH
International Conference on Harmonization
IRT
Interactive Response Technology
ITT
Intent-to-Treat
MedDRA
Medical Dictionary for Regulatory Activities
MNWS
Minnesota Nicotine Withdrawal Scale
NMR
Nicotine Metabolite Ratio
NRT
Nicotine Replacement Therapy
PCS
Potentially Clinically Significant
PT
Preferred Term
QSU-Brief
Brief Questionnaire of Smoking Urges
RTF
Rich Text Format
SAP
Statistical Analysis Plan
SDTM
Study Data Tabulation Model
SI
Système International
SOC
MedDRA System Organ Class
SV1
Screening Visit #1
TEAE
Treatment Emergent Adverse Event
TID
Three Times Daily
WHODrug
World Health Organization Drug Dictionary
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TABLE OF CONTENTS
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY DESCRIPTION..............................................................................................7 
2.1. 
Study Design.................................................................................................................7 
2.2. 
Determination of Sample Size......................................................................................9 
2.3. 
Treatment Assignment................................................................................................10 
2.4. 
Administration of Study Medication ..........................................................................10 
3. 
STUDY OBJECTIVES ..............................................................................................10 
3.1. 
Multiple Efficacy Objectives......................................................................................10 
3.2. 
Secondary Efficacy Objectives...................................................................................10 
3.3. 
Other Objectives.........................................................................................................11 
3.4. 
Safety Objectives........................................................................................................12 
4. 
EFFICACY AND SAFETY ENDPOINTS................................................................12 
4.1. 
Efficacy Endpoints......................................................................................................12 
4.1.1. 
Primary Efficacy Endpoints........................................................................................12 
4.1.2. 
Secondary Efficacy Endpoints....................................................................................13 
4.1.2.1. 
Continuous Abstinence...............................................................................................13 
4.1.2.2. 
Risk of Relapse (Free of  Relapse) .............................................................................14 
4.1.3. 
Other Efficacy Endpoints ...........................................................................................15 
4.2. 
Safety Endpoints.........................................................................................................16 
4.2.1. 
Definitions ..................................................................................................................16 
4.2.1.1. 
Treatment-emergent Adverse Event...........................................................................16 
4.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................16 
4.2.1.3. 
Other Significant Adverse Events ..............................................................................17 
4.2.1.4. 
End of Treatment (EOT) Visit....................................................................................17 
4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations................................................18 
5. 
TRIAL CONDUCT CONSIDERATIONS.................................................................18 
5.1. 
Changes in Inclusion and Exclusion Criteria..............................................................18 
5.2. 
Interim Analysis and Early Stopping..........................................................................18 
5.3. 
Sample Size Adjustment.............................................................................................18 
6. 
DATA ANALYSIS CONSIDERATIONS.................................................................18 
6.1. 
Clinical Databases ......................................................................................................18 
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6.2. 
General Considerations...............................................................................................18 
6.3. 
Definition of Analysis Timepoints .............................................................................19 
6.4. 
Data Handling Rules...................................................................................................20 
6.4.1. 
Missing Dates .............................................................................................................20 
6.4.2. 
Questionnaire Scoring ................................................................................................21 
6.5. 
Analysis Sets...............................................................................................................24 
7. 
SUBJECT DISPOSITION..........................................................................................24 
7.1. 
Protocol Deviations ....................................................................................................25 
8. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....................25 
8.1. 
Demographics.............................................................................................................25 
8.2. 
Medical and Psychiatric History.................................................................................25 
8.3. 
Prior Medications........................................................................................................26 
8.4. 
Smoking History.........................................................................................................26 
8.5. 
Baseline Smoking and Nicotine Testing.....................................................................26 
8.6. 
Baseline Questionnaires..............................................................................................27 
8.7. 
Other Baseline Characteristics....................................................................................27 
9. 
EXPOSURE TO STUDY TREATMENT..................................................................27 
9.1. 
Duration of Study Drug Treatment.............................................................................28 
9.2. 
Study Drug Compliance .............................................................................................28 
9.3. 
Behavioral Support Compliance.................................................................................29 
10. 
EFFICACY ANALYSIS ............................................................................................29 
10.1. 
Analyses of Primary and Secondary Efficacy Endpoints...........................................29 
10.1.1. 
General Considerations...............................................................................................29 
10.1.2. 
Primary Efficacy Analysis..........................................................................................30 
10.1.2.1. 
Sensitivity Analyses....................................................................................................32 
10.1.3. 
Secondary Efficacy Analysis......................................................................................33 
10.2. 
Analyses of Other Efficacy Endpoints .......................................................................34 
10.2.1. 
7-day Point Prevalence Abstinence ............................................................................34 
10.2.2. 
Serum Cotinine Levels ...............................................................................................34 
10.2.3. 
Expired CO Levels .....................................................................................................35 
10.2.4. 
Use of Non-cigarette Nicotine Products.....................................................................35 
10.2.5. 
Abstinence from Week 9 to Week 12: Arm B vs. Arm A..........................................35 
10.2.6. 
Continuous Abstinence from Week 3 to Week 24 (Subset Analysis)........................36 
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10.2.7. 
Continuous Abstinence from Week 9 to Week 24 (Subset Analysis)........................36 
10.2.8. 
Time to Failure to Maintain Abstinence.....................................................................36 
10.2.9. 
Relationship Between Treatment Effect and Demographic and Baseline 
Characteristics.............................................................................................................36 
10.2.10. 
Relationship Between Subject-Reported Outcomes and Primary and 
Secondary Efficacy Endpoints....................................................................................37 
10.2.11. 
Questionnaires ............................................................................................................37 
10.3. 
Other Analyses Not Specified ....................................................................................37 
11. 
SAFETY ANALYSIS ................................................................................................38 
11.1. 
Adverse Events...........................................................................................................38 
11.1.1. 
Serious Adverse Events..............................................................................................40 
11.1.2. 
Other Significant Adverse Events ..............................................................................40 
11.2. 
Hematology and Chemistry Data................................................................................40 
11.3. 
Vital Signs and Weight...............................................................................................41 
11.4. 
12-Lead ECG Interpretation .......................................................................................41 
11.5. 
Concomitant Medications...........................................................................................41 
12. 
PHARMACOKINETIC ANALYSES........................................................................42 
13. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ...............................................................................................................42 
14. 
REFERENCES ...........................................................................................................43 
APPENDIX 1. RANDOMIZATION PLAN...............................................................................44 
LIST OF FIGURES
Figure 1: 
Study Design Overview................................................................................................8 
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1.
INTRODUCTION
The purpose of this Statistical Analysis Plan (SAP) is to provide a thorough description of 
statistical methods and presentation of the study data to be used for the analysis of data generated 
from the clinical trial described in protocol ACH-CYT-03 (ORCA-2 Trial): “A Multicenter, 
Double-blind, Randomized, Placebo-controlled Phase 3 Trial Evaluating the Efficacy and Safety 
of Cytisinicline in Adult Smokers”, Version 3.0 (September 10, 2020).
This SAP was prepared by Achieve Life Sciences Inc. (Achieve) and reviewed by Veri
LLC 
(V
tat). It includes details of data handling procedures and statistical methodology. The final 
statistical analyses will proceed in accordance with this SAP. Any deviation from this SAP will 
be documented in the final CSR. 
For this study, Ve
tat is responsible for programming of datasets. Ve
tat will provide to 
Achieve the Study Data Tabulation Model (SDTM) as well as Analysis Data Model (ADaM) 
dataset specifications based on:
x
SDTM Model 1.4 and SDTM Implementation Guide (SDTM IG) Version 3.2.
x
ADaM Model 2.1 and ADaM Implementation Guide (ADaM IG) Version 1.1.
It is essential that the user of this document also be familiar with the contents of the protocol. 
The protocol is the designated place where background, operational, and procedural details 
necessary for the understanding of this trial can be found to supplement this SAP. In addition to 
the protocol, the following study documents were reviewed in preparation of this SAP:
x
Electronic Case Report Form (eCRF): Version 4.0, 01-Oct-2020
x
Case Report Form Completion Guidelines (CCGs): Version 1.0, 01-Oct-2020
x
Data Management Plan for EDC Studies: Version 1.0, 02-Oct-2020
x
Data Transfer Specification (DTS) for Achieve ACH-CYT-03 IRT to eCRF:
Version 1.2, 18-Aug-2020
2.
STUDY DESCRIPTION
2.1.
Study Design
Study ACH-CYT-03 will be a multi-center, double-blind, randomized, placebo-controlled, 
Phase 3 study conducted in male or female aGXOWVZKRDUH years age, current daily cigarette 
smokers, intending to quit smoking, and willing to set a quit date within 5-7 days of being 
randomized on the study. Study treatment must start the day after randomization such that study 
treatment is initiated prior to the quit date.
Subjects must meet all requirements outlined in the inclusion and exclusion criteria. A total of 
approximately 750 subjects will be randomly assigned with equal probability (1:1:1) to one of 
three arms as summarized below and shown in more detail in the study design figure: 
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x
Arm A (N=250; placebo three times daily (TID) for 12 weeks plus behavioral 
support)
x
Arm B (N=250; 3 mg cytisinicline TID for 6 weeks followed by placebo TID for 
6 weeks plus behavioral support)
x
Arm C (N=250; 3 mg cytisinicline TID for 12 weeks plus behavioral support)
For brevity, the arms may be described as follows:
x
Arm A (placebo)
x
Arm B (cytisinicline 6 weeks)
x
Arm C (cytisinicline 12 weeks)
All subjects are to receive behavioral support during the 12-week treatment period with 
additional behavioral support during the follow-up period.
Figure 1:
Study Design Overview
This study will be conducted at approximately 12-16 clinical sites across the US. Subjects will be 
randomized within site (see Randomization Plan, Appendix 1), with the goal of balancing 
between arm allocation within clinical sites in order to minimize imbalance for the assessment of 
evidence of heterogeneity of effect estimates across sites. Clinical site will be used as a 
stratification factor in primary analyses.
The study will be comprised of a pre-study screen, followed by 12 weeks of treatment, and 
12 weeks of post-treatment follow up visits to 24 weeks post-randomization. 
Each randomized subject will receive 12 weeks of treatment using a TID dosing schedule. 
Determination of smoking cessation will be made from the subject’s self-report of abstinence 
accompanied by expired carbon monoxide (CO) biochemical verification. Assessments of
R
A
N
D
O
M
I
Z
E
Arm A
Placebo
12 Weeks + Behavioral Support
Arm B
Cytisinicline
6 Weeks + Behavioral Support, followed by
Placebo
6 Weeks + Behavioral Support
S
C
R
E
E
N
F
O
L
L
O
W
U
P
Arm C
Cytisinicline
12 Weeks + Behavioral Support
----+L___I ___ 
I-. 
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smoking abstinence will begin on Week 2 (Day 14 ±1 post-randomization) and will continue
weekly during the Treatment Period, then at the Weeks 16, 20 and 24 Follow-up Period visits.
All subjects will receive concurrent smoking cessation behavioral support during the treatment 
period (Weeks 1-12). Additional behavioral support will be provided during the Follow-Up 
period based on issues/concerns/questions raised by the subject.
Safety assessments at clinic visits will occur on Day 2 and Day 7 during Week 1 and then weekly 
throughout the treatment period. Adverse events will also be assessed through the Follow-up
period. Any adverse events at Week 24 will be followed until resolved or determined to be 
chronic. The end of study will be defined as the last follow-up visit (up to the Week 24 visit) for 
the last subject.
2.2.
Determination of Sample Size
In the 2011 published TASC Phase 3 study that evaluated cytisine versus placebo for 25 days in 
740 primarily moderate-to-heavy smokers in Poland, the sustained 6-month abstinence rate was 
10.0% in the cytisine arm compared to 3.5% in the placebo arm (P<0.001). In the 2014 published 
Phase 3 study that evaluated cytisine for 25 days versus nicotine replacement therapy (NRT) for 
8 weeks in 1,310 adult daily smokers in New Zealand, the continuous six-month abstinence rate 
was 22% in the cytisine arm compared to 15% in the NRT arm (P=0.002). 
Data from the international EAGLES trial (N=8,120) were used to assess predictors for 
continuous smoking abstinence outcomes from Weeks 9-24. These analyses provided evidence 
that subjects treated in the US had lower success rates of quitting, regardless of treatment 
(varenicline, bupropion, or NRT). The continuous abstinence rates from 9-24 weeks in the US 
were 16.1%, 11.4% and 10.6% for varenicline, bupropion, or NRT, respectively, compared to 
6.7% for placebo treatment. The odd ratios (OR) for these treatments in the US were 2.66, 1.78, 
and 1.64, respectively. The lower success rate in US smokers supports the view that smokers in 
the US may have particular characteristics that make it more difficult for them to stop smoking. 
The trial size for this study is specified as 250 subjects per arm. The assumed control arm 
probability of success (continued abstinence to Week 24) is 0.07 (7%). The hypothesized 
experimental arm minus control arm probability difference is specified as 0.12 (12 points),
corresponding to a hypothesized odds ratio of 3.116 (eg, 7% for placebo vs 19% for cytisinicline 
treatment). The significance level to be used is adjusted from the overall type I error probability 
of one-sided 0.025 to one-sided 0.0125 using the Bonferroni method to control for multiplicity.
The statistical operating characteristics for each comparison are illustrated using simulation of
Fisher’s exact test with 10,000 replicates. These specifications are consistent with 95.7% power 
for each comparison with, conditional on 0.07 control arm probability outcome, an odds ratio 
FULWLFDOUHJLRQRIFRUUHVSRQGLQJWRDFULWLFDOdifference RIIRUSODFHERYV
for cytisinicline treatment). The trial sizing simulations were not done using the Hochberg 
method for controlling inferential multiplicity for the two primary comparisons. (The use of the 
Hochberg methods is described subsequently.) The statistical power estimated from simulation 
therefore should be regarded as an underestimate of power because the Hochberg method is 
slightly less conservative relative to the Bonferroni method.
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2.3.
Treatment Assignment
A total of approximately 750 subjects will be randomized with equal probability (1:1:1) to 
three arms (Arm A, Arm B, Arm C). Refer to Section 2.1.
2.4.
Administration of Study Medication
Tablets with identical appearance 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. 
3.
STUDY OBJECTIVES
3.1.
Multiple Efficacy Objectives
The multiple objectives are based on two comparisons where study success can be based on 
success for either comparison:
1. Assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 6 weeks 
followed by placebo TID for 6 weeks plus behavioral support) have a higher probability 
of abstinence from Week 3 to Week 6 post-randomization as compared to subjects 
randomized to Arm A (placebo TID plus behavioral support).
2. Assess whether subjects randomized to Arm C (3 mg cytisinicline TID for 12 weeks plus 
behavioral support) have a higher probability of abstinence from Week 9 to Week 12
post-randomization as compared to subjects randomized to Arm A (placebo TID plus 
behavioral support).
3.2.
Secondary Efficacy Objectives
The analysis for secondary objectives 1 and 2 will be done only if the corresponding primary 
comparison passes statistical criterion.
1. Assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 6 weeks
followed by placebo TID for 6 weeks plus behavioral support) have a higher probability 
of continuous abstinence from Week 6 to Week 24 post-randomization as compared to 
subjects randomized to Arm A (placebo TID plus behavioral support).
2. Assess whether subjects randomized to Arm C (3 mg cytisinicline TID for 12 weeks plus 
behavioral support) have a higher probability of continuous abstinence from Week 12 to 
Week 24 post-randomization as compared to subjects randomized to Arm A (placebo
TID plus behavioral support).
The analysis for secondary objective 3 will be conditional and performed only if both primary
comparisons 1 and 2 pass statistical criterion.
3. Assess for a reduction in risk of relapse from Week 6 to Week 24 in subjects receiving
3 mg cytisinicline for 6 weeks and then either continue 3 mg cytisinicline from Week 6 to 
Week 12 (Arm C) or were switched to placebo from Week 6 to Week 12 (Arm B).
Subjects not abstinent at Week 6 will be regarded as having relapsed.
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3.3.
Other Objectives
1. To compare arms (Arm B vs Arm A, Arm C vs Arm A) on 7-day point prevalence 
abstinence weekly at Week 2 through Week 12, then at Weeks 16, 20, and 24.
2. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on serum cotinine levels every 
other week at Week 2 through Week 12, then at Weeks 16, 20, and 24.
3. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on expired CO levels every week 
at Week 2 through Week 12, then at Weeks 16, 20, and 24.
4. To compare arms (Arm B vs Arm A; Arm C vs Arm A) on use of any non-cigarette
nicotine products, including vaping, during study treatment (Week 2 through Week 12) 
and study follow-up (Week 16 through Week 24).
5. Assess whether subjects randomized to Arm B have a higher probability of abstinence 
from Week 9 to Week 12 as compared to subjects randomized to Arm A (placebo).
6. Assess among the subset of subjects who achieve abstinence from Week 3 to Week 6, 
whether subjects randomized to Arm B have a higher probability of continuous 
abstinence from Week 3 to Week 24 post-randomization as compared to homologous
subjects randomized to Arm A.
7. Assess among the subset of subjects who achieve abstinence from Week 3 to Week 6,
whether subjects randomized to Arm C have a higher probability of continuous 
abstinence at Week 24 post-randomization as compared to subjects randomized to 
Arm B.
8. Assess among the subset of subjects who achieve abstinence from Week 9 to Week 12,
whether subjects randomized to Arm C have a higher probability of continuous 
abstinence from Week 9 to Week 24 post-randomization as compared to homologous
subjects randomized to Arm A.
9. Among subjects who achieve abstinence from Week 3 to Week 6, compare time to failure 
to maintain abstinence between arms (Arm B vs Arm A, Arm C vs Arm A) to Week 24.
10. To explore the magnitude of treatment effect between arms across various subgroups 
defined by demographic and baseline characteristics for the primary and secondary 
outcomes.
11. To explore potential relationships between subject-reported outcomes (eg, anxiety, 
depression, tobacco craving) and the primary and secondary outcomes.
12. To assess possible withdrawal symptoms at Week 7 in Arm B subjects who will have 
discontinued cytisinicline at Week 6, analyzing separately for nicotine status (eg, either 
smoking, abstinent, or if using other nicotine products including vaping or nicotine 
replacement therapy [NRT]) compared to Arms A and C.
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3.4.
Safety Objectives
1. To evaluate the safety profile of 3 mg TID cytisinicline compared to placebo (Arm B vs 
Arm A; Arm C vs Arm A).
2. To compare the safety profiles of Arm B subjects versus Arm C subjects with respect to 
adverse events occurring after Week 6 on the study.
4.
EFFICACY AND SAFETY ENDPOINTS
4.1.
Efficacy Endpoints 
Efficacy endpoints will be based on a subject’s self-reported cigarette smoking data with 
biochemical verification at each assessment. Biochemical verification of smoking abstinence will 
be defined by a CO concentration in exhaled breath of less than 10 ppm.
4.1.1.
Primary Efficacy Endpoints
The comparisons for the primary efficacy objectives will be between experimental arms and the 
placebo arm, for the following endpoints: 
x
Abstinence from Week 3 to Week 6: Arm B (cytisinicline 6 weeks) vs Arm A 
(placebo)
x
Abstinence from Week 9 to Week 12: Arm C (cytisinicline 12 weeks) vs Arm A 
(placebo)
The smoking abstinence endpoint for each subject is binary: success versus failure. Success is 
biochemically verified smoking abstinence documented at Weeks 3, 4, 5, and 6 (Arm B) or 
Weeks 9, 10, 11, and 12 (Arm C), compared to the corresponding weekly assessments in the 
placebo arm (Arm A). At each visit, success will be defined for an individual subject as having 
reported smoking abstinence (no cigarettes since the last clinic visit) and having CO
concentration in exhaled breath of less than 10 ppm. For subjects that say no to the question 
‘Has the subject smoked any cigarettes since the last clinical visit’ and number of cigarettes 
smoked is missing this will be imputed to 0. Subjects will be allowed only 1 missed visit 
(smoking status unknown) for analysis of the primary endpoint (ie, one of Week 4 or Week 5 for 
the comparison of Arm B vs Arm A; one of Week 10 or Week 11 for the comparison of Arm C 
vs Arm A).
Any other outcome will be regarded as a failure. There are therefore two types of failure for a
subject: (1) subjects with adequate data that they are smoking at any time (either by the subject’s 
self-report or &2 ppm) and (2) subjects having insufficient data to be determined as a 
success for smoking abstinence. Examples of subjects with insufficient data include the 
following:
x
Smoking status unknown at more than 1 of the interim visits listed above. A smoking 
status is unknown when data are missing for either the number of cigarettes smoked 
since the last clinic visit or CO reading or both.
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x
Smoking status unknown at key visits for the endpoint. For the Week 3 to Week 6 
endpoint, subjects with smoking status unknown at either Week 3 or Week 6 will be 
regarded as failures. Likewise, for the Week 9 to Week 12 endpoint, subjects with 
smoking status unknown at either Week 9 or Week 12 will be regarded as failures.
This definition of the primary endpoint means that all subjects will have a realization of the 
primary outcome and therefore this endpoint is amenable to intent-to-treat (ITT) analyses.
Statistical methods for the primary efficacy endpoints are described in Section 10.1.
4.1.2.
Secondary Efficacy Endpoints
There are 3 secondary efficacy objectives, 2 objectives for continuous abstinence and 1 objective 
for reduction in risk of relapse.
The continuous abstinence through Week 24 success endpoint (secondary objectives 1 and 2) 
and the reduction in risk of relapse through Week 24 endpoint (secondary objective 3) must be 
defined separately for each of the three secondary efficacy comparisons because of differences in 
the primary evaluation timing, that is, Weeks 3-6 for the Arm A versus Arm B comparison and 
Week 9-12 for Arm A versus Arm C comparison, and a mixed primary evaluation time for the 
Arm B versus Arm C comparison of reduction in risk of relapse. It is important to note that the 
data collected, and the schedules of collection, are identical for all arms.
The following operational details are applicable to these secondary efficacy comparisons:
x
Being abstinent requires meeting both a self-reported criterion and a biochemical 
verification. The beginning of self-reported abstinence is Week 3 to Week 6 for 
comparisons of Arm A and Arm B and Week 9 to Week 12 for comparison of Arm A 
and Arm C. For comparison of Arm B to Arm C, the failure of self-reported 
abstinence starts at Week 6 for both Arms B and C.
x
Self-reported abstinence over the Week 16 to Week 24 Follow-up period will be 
assessed using the Russell Standard1 which allows up to a total of 5 cigarettes to be 
smoked in order to be regarded as abstinent or without relapse.
x
Biochemical verification of non-smoking status is defined by a carbon monoxide 
concentration in exhaled breath of less than 10 ppm.
Subjects not observed to meet all success criteria will be regarded as non-success relative to the 
secondary efficacy outcome. Non-success will have two types: (1) subjects with adequate data 
that fail to meet the above criteria, and (2) subjects having insufficient data to be assessed as a 
success.
4.1.2.1.
Continuous Abstinence
The comparisons for the 2 continuous abstinence efficacy objectives will be between 
experimental arms and the placebo arm, as follows: 
x
Continuous abstinence from Week 6 to Week 24: Arm B (cytisinicline 6 weeks)
vs Arm A (placebo)
x
Continuous abstinence from Week 12 to Week 24: Arm C (cytisinicline 12 weeks)
vs Arm A (placebo).
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For the comparison of Arm A to Arm B (secondary objective 1), success for the continuous 
abstinence from Week 6 to Week 24 endpoint will be defined as having all of the following 
observed:

Abstinence determined at the primary evaluation (Weeks 3-6), and

At the Week 7 to Week 11 visits, subject self-report of abstinence since the last 
clinic visit together with biochemical verification of abstinence, and

At the Week 12 visit, subject self-report of abstinence since the last clinic visit 
together with biochemical verification of abstinence, and 

Self-reported abstinence during the Week 16 to Week 24 Follow-up period,
defined as smoking up to a total of 5 cigarettes at the attended Week 16, Week 20,
and Week 24 visits together with biochemical verification of abstinence at each 
attended visit. (Only one visit, either Week 16 or Week 20, is allowed to be 
missing.)
For the comparison of Arm A to Arm C (secondary objective 2), success for the continuous 
abstinence from Week 12 to Week 24 endpoint will be defined as having all of the following 
observed:

Abstinence determined at the primary evaluation (Weeks 9-12), and

Self-reported abstinence during the Week 16 to Week 24 Follow-up period, 
defined as smoking up to a total of 5 cigarettes at the attended Week 16, Week 20, 
and Week 24 visits together with biochemical verification of abstinence at each 
attended visit. (Only one visit, either Week 16 or Week 20, is allowed to be 
missing.)
Any other outcome will be regarded as a failure. There are therefore two types of failure for the 
subject: (1) subjects with adequate data that they are not abstinent at any time (either by the 
subject’s self-report or &2 ppm) and (2) subjects having insufficient data to be determined 
as a success for continuous abstinence.
Statistical methods for the continuous abstinence endpoints are described in Section 10.1.3.
4.1.2.2.
Risk of Relapse (Free of  Relapse)
For the comparison of Arm B to Arm C (secondary objective 3), free of relapse (success of not 
having relapsed) from Week 6 to Week 24 will be defined as having the following observed after 
initial abstinence is determined from Weeks 3-6 (primary success criteria defined for 
Weeks 3-6):

At the Week 9-12 visit, subject self-report of abstinence since the last clinic visit 
together with biochemical verification of abstinence, and

Self-reported abstinence during the Week 16 to Week 24 Follow-up period, 
defined as smoking up to a total of 5 cigarettes at the attended Week 16, Week 20, 
and Week 24 visits together with biochemical verification of abstinence at each 
attended visit. (Only one visit, either Week 16 or Week 20, is allowed to be 
missing.)
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Subjects not observed to meet the above success criteria will be regarded as having relapsed to 
the secondary efficacy 3 outcome. Non-success or relapse will have two types: (1) subjects with
adequate data that fail to meet the above criteria, and (2) subjects having insufficient data to be 
assessed as a success. Note: subjects not abstinent at Week 6 (eg, Weeks 3-6) will be regarded as
having already relapsed.
Statistical methods for the risk of relapse endpoint are described in Section 10.1.3. 
4.1.3.
Other Efficacy Endpoints
In general, the other efficacy endpoints defined in this section are associated with tertiary
efficacy objectives. The other efficacy endpoints are:
7-day point prevalence abstinence is a binary endpoint (success, failure) at each visit from 
Week 2 through Week 24. At each visit, success will be defined for a subject as having reported 
smoking abstinence with biochemical verification (CO<10 ppm). 7-day point prevalence for 
smoking abstinence will be defined as reporting no smoking since the last clinic visit at each 
weekly clinic visit from Week 2 through Week 12 and over the past 7 days during Follow-up
visits at Weeks 16, 20 and 24. Any other outcome will be regarded as a failure. All subjects will 
have a realization of this endpoint, thereby enabling analyses that follow the ITT principle 
without imputation.
Serum cotinine levels (ng/mL) are a continuous endpoint measured every other week from 
Week 2 to Week 12, then at Week 16, Week 20, and Week 24. 
Expired CO levels (ppm) are a continuous endpoint measured at each visit from Week 2 
through Week 24. 
Use of non-cigarette nicotine products, including vaping, will be assessed at each visit from 
Week 2 to Week 24. Subjects report whether they have used any non-cigarette nicotine products 
since the last visit (yes, no) and report all products used during the interval (eg, pipe tobacco, 
e-cigarettes/vaping, marijuana smoking/vaping). 
Continuous abstinence from Week 3 to Week 24 (subset analysis): Assess among the subset 
of subjects who achieve abstinence from Week 3 to Week 6 in Arm A and Arm B (ie, are a 
success on the primary efficacy endpoint for primary objective 1). Success will be defined for a 
subject following the same rules as the continuous abstinence endpoint (see Section 4.1.2.1).
Continuous abstinence from Week 9 to Week 24 (subset analysis): Assess among the subset 
of subjects who achieve abstinence from Week 9 to Week 12 in Arm A and Arm C (ie, are a 
success on the primary efficacy endpoint for primary objective 2). Success will be defined for a 
subject following the same rules as the continuous abstinence endpoint (see Section 4.1.2.1).
Time to failure to maintain abstinence will be evaluated for the subset of subjects who were 
classified as a success for abstinence at Weeks 3-6. Time to failure to maintain abstinence (days) 
will be calculated as end date of abstinence minus start date of abstinence +1. The start date of 
abstinence will be defined as the date of the Week 6 visit. The end date of abstinence will be 
defined as the earliest date that the subject was known to have resumed smoking, or will be 
censored, as described below:  
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x
At a visit during the treatment period, if a subject reported smoking since the last visit 
(either by the subject’s self-report or CO  ppm), the end date of abstinence will be 
the earliest of the following dates: the date the subject reported resuming smoking, or 
the date of CO  ppm.
x
During the follow-up period, if a subject reported smoking a total of more than 
5 cigarettes at the attended Week 16, Week 20, and Week 24 visits, RU&2 ppm at 
a visit, the end date of abstinence will be the earliest of the following dates: the date 
the subject reported smoking the 6th cigarette, or the date of &2 ppm.
x
Subjects who have not resumed smoking at their final visit will have end date of 
abstinence censored at the date of that final visit. (The final visit is expected to be the 
Week 24 visit.)
4.2.
Safety Endpoints
The safety endpoints are:
x
adverse events, including serious adverse events and other significant adverse events
x
laboratory assessment

hematology

chemistry
x
vital signs
x
12-lead ECG results
x
concomitant medications
4.2.1.
Definitions
4.2.1.1.
Treatment-emergent Adverse Event
A TEAE is any AE that is new in onset or was aggravated in severity or frequency following the 
first dose of study drug, up to and including the last visit of the study. Treatment emergence will 
be determined by comparing the AE start date/time with the actual date/time of first dose of
study drug. TEAEs are defined as events with start date/time on or after the date/time of first 
dose of study drug. If either the AE start date or start time is unknown, treatment-emergent 
events will be defined based on a “Yes” response to the CRF item “Did the AE start after the 
first dosing?” 
4.2.1.2.
Serious Adverse Event (SAE)
An SAE is defined as an AE that: 
x
Results in death. 
x
Is life-threatening. 
x
Requires hospitalization or prolongs existing inpatient hospitalization. 
x
Results in persistent or significant disability or incapacity. 
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x
Results in a congenital abnormality or birth defect. 
x
Is an important medical event that requires medical intervention to prevent any of the 
above outcomes. 
4.2.1.3.
Other Significant Adverse Events
The following events will be reported as “other significant adverse events”:
x
Treatment-emergent suicidal ideation or risk, as measured by responses on the C-SSRS 
on or after first dose of study drug. Suicidal ideation or risk will be defined as a response 
of “Yes” to either question 4 or question 5 or “Yes” to any suicidal behavior question on 
the C-SSRS.
Note: Suicidal ideation or risk for suicide prior to randomization (“Yes” to either 
question 4 or question 5 OR “Yes” to any suicidal behavior question on the C-SSRS) is 
an exclusion criterion.
x
Treatment-emergent moderate to severe depression, as measured by a HADS depression 
score  on or after first dose of study drug.
Note: Current symptoms of moderate to severe depression prior to randomization (HADS 
depression VFRUHLVDQH[FOXVLRQFULWHULRQ.
x
New pregnancy documented by a positive pregnancy test on or after first dose of study 
drug.
Note: Pregnancy is an exclusion criterion.
x
Treatment-emergent COVID-19, defined as adverse events with MedDRA lower-level 
term containing the phase “COVID-19” or preferred term of “Immunisation Reaction” 
will be included.
4.2.1.4.
End of Treatment (EOT) Visit
As specified in the protocol, post-treatment assessments will be done for all subjects
approximately 1 – 3 days after the last dose of study drug (the EOT assessments).
The timing of EOT assessments will be different for subjects who complete treatment and 
subjects who discontinue treatment early. Subjects that complete treatment will have EOT 
assessments done at the Week 12 (Day 86/EOT) visit. Subjects who discontinue treatment early, 
will have EOT assessments done at an earlier visit that coincides with their date of treatment 
discontinuation. The visit at which EOT safety assessments were done will be documented in 
study datasets. 
Subjects who discontinue treatment early are expected to continue in the study through Week 24.
Therefore, it is expected that the procedures outlined under the Week 12 (Day 86/EOT) visit will 
be repeated at that time.
In order to accurately summarize changes from baseline to EOT in safety endpoints, the EOT 
safety assessments for all subjects will be combined into a derived visit named “EOT”. That visit 
will be included in summary tables of safety endpoints.
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4.3.
Pharmacokinetic and Pharmacodynamic Evaluations
None planned.
5.
TRIAL CONDUCT CONSIDERATIONS
5.1.
Changes in Inclusion and Exclusion Criteria
No changes are planned.
5.2.
Interim Analysis and Early Stopping
None planned.
5.3.
Sample Size Adjustment
Not applicable.
6.
DATA ANALYSIS CONSIDERATIONS
6.1.
Clinical Databases
There will be two clinical data sources for this study: a web-based interactive response 
technology (IRT) application and an eCRF database. 
IRT will be used to collect subject diary data, randomize subjects, and allocate study drug. In
general, data collected in the IRT application will be transferred to the eCRF database. The 
following data will not be transferred to the eCRFs but will be extracted from the IRT 
application after the eCRF database is locked:
x
Subject randomization data: date randomized, value of stratification factor at 
randomization, treatment arm assignment.
x
Subject treatment-diary data: date and time of each dose (or indication if dose was 
missed) as recorded by subjects each day during the treatment period.
All other subject data will be entered into the eCRF database and will be extracted from that 
application after the eCRF database is locked. 
6.2.
General Considerations
Statistical analyses will be performed at the end of the study after the last subject has completed 
the Week 24 visit, all data have been reported, cleaned, and the eCRF database has been locked.
Medical history events and adverse events will be coded to standard “preferred terms” and 
“system organ classifications (SOC)” using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.1 or higher. Concomitant medications will be coded using the World 
Health Organization Drug Dictionary (WHODrug) Version Mar-2020 B2 or higher.
All statistical programming will be done using SAS® Version 9.4 or higher (SAS® Institute, 
Cary, North Carolina). All tables, figures and listings will be produced in landscape format. 
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In general, all data will be listed by treatment arm, subject and visit/time point where 
appropriate. The summary tables will have columns corresponding to, or be stratified by, 
treatment arm. In listings and summary tables the treatment arms will be ordered and labelled as 
follows: Placebo, Cytisinicline 6 Weeks, Cytisinicline 12 Weeks.
The total number of subjects under the stated analysis set in each treatment arm (N) will be 
displayed in the header of summary tables. 
Data will be summarized using descriptive statistics for continuous variables. Unless otherwise 
specified, descriptive statistics will include number of subjects (n), mean, standard deviation, 
minimum, median and maximum. In case of n<2, where n indicates the number of subjects with 
evaluable data at the particular time point, the standard deviation will be empty. The statistic 
“Missing” will also be presented as the number of missing entries/subjects, if any at that 
visit/timepoint, and presented as a summary statistic only when non-zero. The minimum and 
maximum statistics will be presented to the same number of decimal places as the original data. 
The mean and median will be presented to one more decimal place than the original data, 
whereas the standard deviation will be presented to two more decimal places than the original 
data. 
In summary tables of categorical variables, counts and percentages will be used. The count [n]
indicates the actual number of subjects with a particular value of a variable or event, which 
should always be less than or equal to the total number of subjects with non-missing value of the 
variable or event [M]. Percentage will be obtained by: %=(n/M) × 100. Unless otherwise stated, 
all percentages will be expressed to one decimal place. 
In by-visit summary tables only scheduled visits/timepoints will be summarized. In listings all 
visits and timepoints with any data collected, including both scheduled and unscheduled ones, 
will be included. 
All dates in tables, figures and listings will be displayed in DDMMMYYYY format.
All outputs will be sent to Achieve as electronic files in RTF format documents.
6.3.
Definition of Analysis Timepoints
x
Baseline: The last non-missing observation prior to the first dose of study drug 
(cytisinicline and/or placebo), unless otherwise specified. The last non-missing 
observation prior to the first dose of study drug (cytisinicline and/or placebo), unless 
for randomized subjects who do not receive study drug then baseline is defined prior 
to date of randomization. If both a planned assessment and repeat assessment (eg, 
retest) meet the above criteria and were collected on the same date and time, the 
repeat assessment will be used as baseline.
x
Change from Baseline: The change from baseline values will be derived for each 
subject as the post-baseline value minus the baseline value.
x
End of Treatment (EOT) Visit: The last clinic visit during the treatment period. 
Expected to occur at Week 12 (Day 86/EOT visit) for subjects who complete the 
12-week treatment period. Subjects who discontinue treatment prior to 12 weeks will 
have the EOT visit when treatment is discontinued. (See Section 4.2.1.4.)
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x
Pre-treatment Period: Prior to first dose of study drug on Day 1.
x
Treatment Period: The treatment period is expected to be 84 days (12 weeks) in 
duration. For an individual subject, the treatment period starts on the date of the first 
dose of study drug (Day 1), continues through the date of the last dose of study drug,
and ends on the date of the Week 12 (Day 86/EOT) visit.
x
Follow-up Period: The follow-up period is expected to be 12 weeks in duration, and 
includes the monthly visits at Week 16, Week 20, and Week 24.
x
Study Day: Study day will be calculated for all assessment dates relative to the first 
dose of study drug (cytisinicline and/or placebo). The first dose of study drug will be 
Day 1, and the date preceding Day 1 will be Day –1 which is consistent with the 
Submission Data Standards (Version 3.1) from Clinical Data Interchange Standards 
Consortium (CDISC).
6.4.
Data Handling Rules
Dropouts (ICH E3/11.4.2.2) will not be replaced during the study, but will be included in the 
data analysis to the extent that evaluable data are present. 
For qualitative parameters, a category with the number of subjects with missing values will be 
presented where applicable.
6.4.1.
Missing Dates
Partial or missing dates will be imputed only if a date is required to derive a study endpoint 
(eg, time to failure, duration of AE) or a variable used in study analyses. Otherwise no date 
imputation will be done. Date imputation will follow the rules below.
Efficacy Related Dates 
Partial or missing dates required to compute efficacy endpoints will be imputed as follows:
x
Missing day only: For partial dates with only the day of the month missing, the day 
will be imputed as the 15th day of the month, provided that a preceding date of 
interest does not occur in the same month. If the preceding date does occur in the 
same month, then the missing day will be imputed as half the distance between the 
preceding date and the end of the month.
x
Missing month and day: For partial dates with the month and day missing, the month 
and day will be imputed as July 1st, provided that a preceding date of interest does not 
occur in the same year. If the preceding date occurs in the same year, then the month 
and day will be imputed as half the distance from the preceding date to the end of the 
known year.
x
Missing month, day, and year: Missing dates will be imputed as the date of first dose.
x
In situations where the above rules result in an illogical time (eg, negative study day, 
negative time to failure, etc.) the date will be imputed as the date half the distance 
between the preceding date of interest and the partial date.
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Safety Related Dates
For prior and concomitant medications see Sections 8.3 and 11.5 for more specific rules. For
safety data besides medications where the date of onset is during or after administration of the 
first dose of study drug, missing or partial start dates will be imputed as the earliest possible date 
that is on or after the date of the first dose of study drug. For events occurring prior to first dose 
of study drug, missing or partial dates will not be imputed. 
x
Missing day only: If the start date and date of first dose share the same month and 
year, the missing start day will be imputed as the day of first dose. If the start date 
month is after the month of first dose, day will be imputed as the 1st (ie, 01-Jan-2019).
x
Missing month only: If the start date and date of first dose share the same year, month 
will be imputed as the month of the first dose. If the start date year is after the year of 
the first dose, the month will imputed as Jan.
x
Missing month and day: If the start date and date of first dose share the same year, 
day and month will be imputed as the day and month of first dose. If the start date 
year is after the year of first dose, the month and day will be imputed as January 1st
(ie, 01-Jan-2019).
x
Missing month, day, and year: Missing start dates will be imputed as the date of first 
dose.
x
For partial end dates: Missing month and day: if year matches the year of the last date 
of study( date of last contact if subject  lost to follow-up; date of completion or early 
termination), then impute as the month and day of the last date of the study, otherwise 
assign 31 December.
x
Missing month only: if year matches the year of the last date in the study (date of last 
contact if subject  lost to follow-up; date of completion or early termination), then 
impute as the month of the last date of the study, otherwise assigned December. 
x
Missing day only: if the month and year match the month and year of the last date of 
study, then impute as the day of the last date of the study; otherwise assign the last 
day of the month.
6.4.2.
Questionnaire Scoring
This section describes scoring for the questionnaires that will be used in the study. No imputation 
will be done for missing item responses on the questionnaires. Total scores will only be 
computed if there are no missing item scores. 
Fagerstrom Test of Nicotine Dependence (FTND)
The FTND is a 6-item multiple-choice questionnaire (see Appendix 2 of the study protocol). It 
will be administered at SV1. An FTND total score will be derived for each subject providing all 
questions have been answered, using the scoring key that follows: 
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Item #
Item Text
Item Response
Item Score
1
How soon after you wake up do you smoke 
your first cigarette?
Within 5 minutes
3
6–30 minutes
2
31–60 minutes
1
After 60 minutes
0
2
Do you find it difficult to refrain from 
smoking in places where it is forbidden 
(eg, in church, at the library, in the cinema, 
etc.)?
Yes
1
No
0
3
Which cigarette would you hate most to 
give up?
The first one in the morning
1
All others
0
4
How many cigarettes/day do you smoke?
10 or less
0
11 – 20
1
21 – 30
2
31 or more
3
5
Do you smoke more frequently during the 
first hours after waking than during the rest 
of the day?
Yes
1
No
0
6
Do you smoke if you are so ill that you are 
in bed most of the day?
Yes
1
No
0
Smoking Self-efficacy Questionnaire (SEQ-12)
The SEQ-12 is a 12-item questionnaire that will be administered at the Day 0 visit. Item scores 
will be assigned using the scoring key pre-printed on the questionnaire (see Appendix 3 of the 
study protocol). Three scores will be derived for each subject providing there are no missing 
questions: SEQ-12 internal stimuli score (items 1-6), external stimuli score (items 7-12) and a
total score (items 1-12).
Hospital Anxiety and Depression (HADS)
The HADS questionnaire will be administered at SV1, Week 6 and Week 12. Item scores will be 
assigned using the scoring key pre-printed on the questionnaire (see Appendix 6 of the study 
protocol). Providing there are no missing questions, total scores for depression and anxiety and 
overall will be derived for each subject.
Brief Questionnaire of Smoking Urges (QSU-Brief)
The QSU-Brief is a 10-item questionnaire that will be administered Day 0, and at various visits 
during the treatment period (Day 2, Week 1 through Week 6). Item scores will be assigned using 
the scoring key pre-printed on the questionnaire (see Appendix 4 of the study protocol). A total 
QSU-Brief score will be derived for each subject, providing all questions have been answered.
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Minnesota Withdrawal Scale (MNWS)
The MNWS is a 9-item questionnaire that will be administered at Day 0, and at various visits 
during the treatment period (Week 1 through Week 7). Item scores will be assigned using the 
scoring key pre-printed on the questionnaire (see Appendix 5 of the study protocol). A total 
MNWS score will be derived for each subject, providing all questions have been answered.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS (see Appendix 1 of the study protocol) is an assessment of both suicidal ideation 
and behavior. Suicidal ideation or risk for suicide (“Yes” to either question 4 or question 5 OR 
“Yes” to any suicidal behavior question on the C-SSRS) is an exclusion criterion.
The “Screening” version of the C-SSRS assesses suicidal ideation over the past 3 months, and 
suicidal behavior over the subject’s lifetime. The “Screening” version of the C-SSRS will be 
administered at SV1. The “Since Last Visit” version of the C-SSRS evaluates both suicidal 
ideation and behavior since the last assessment. This version of the C-SSRS will be administered 
at Week 6 and Week 12.
C-SSRS Suicidal Ideation: In both the “Screening” and “Since Last Visit” forms, there are 
5 items that assess suicidal ideation. Subjects indicate (Yes/No) whether each of the following 
applies: 
1. Wish to be dead
2. Non-specific active suicidal thoughts
3. Active suicidal ideation with any methods, without intent to act
4. Active suicidal ideation with some intent to act, without specific plan
5. Active suicidal ideation with specific plan and intent.
Each item will be assigned a numeric score (0=No, 1=Yes).
C-SSRS Suicidal Behavior: In both the “Screening” and “Since Last Visit” forms, there are 
5 items that assess suicidal behavior. Subjects indicate (Yes/No) whether each of the following 
applies: 
1. Actual attempt (non-fatal)
2. Interrupted attempt
3. Aborted attempt
4. Preparatory acts or behavior
5. Completed suicide
Each item will be assigned a numeric score (0=No, 1=Yes).
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6.5.
Analysis Sets 
Three analysis sets will be used.
Screening Set: all subjects who give written informed consent and enter screening. The 
Screening Set consists of two mutually exclusive subgroups: 
x
subjects who were not randomized at completion of screening, generally due to 
failure of one or more of the study entry criteria (ie, the inclusion/exclusion criteria) 
and 
x
subjects who were randomized at completion of screening
All Randomized Set: all randomized subjects. Subjects will be evaluated by their randomized 
treatment arm (‘intent-to-treat’ analysis) unless otherwise specified. The All Randomized Set 
will be the primary set for efficacy analyses. 
Safety Set: all randomized subjects who take at least one dose of study drug. Subjects will be 
evaluated by their randomized treatment arm (‘intent-to-treat’ analysis) unless otherwise
specified. The Safety Set will be the primary set for safety summaries. Safety summaries may 
also be provided based on the treatment actually received.
Achieve will approve the list of subjects to be excluded from the Safety Set after database lock. 
Achieve must approve this list before any analysis is to be performed.
7.
SUBJECT DISPOSITION 
The number of subjects who were screened, screen failures, randomized and treated will be 
summarized overall for the Screening Set. The reason for failing screening will also be 
summarized.
The number of subjects who were screened, randomized, treated, completed or discontinued 
study drug, completed or withdrew from study, as well as the number of subjects in each analysis 
set will be summarized for each treatment arm. In addition, the number of subjects randomized 
and treated will be summarized by investigational site for each treatment arm.
For subjects who discontinued study drug, the reasons for discontinuation (eg, adverse event, 
withdrawal by subject, physician decision) will be summarized for each treatment arm. The list 
of subjects who discontinued study drug will be reported, along with the reason for 
discontinuation.
For subjects who did not complete the study, the reasons for withdrawal (eg, adverse event, 
withdrawal by subject, lost to follow-up) will be summarized for each treatment arm. The list of 
subjects who withdrew from the study will be reported, along with the reason for withdrawal.
A listing will be provided of subjects who were excluded from either the All Randomized Set or 
the Safety Set. The listing will include the reason for exclusion. 
Attendance at each study visit will be reported with the number and percentage of subjects who 
attended each visit (ie, Screening #1, Screening #2, Day 0 (randomization), Day 1 (treatment 
start), etc.). Similarly, the last study visit attended will be reported with the number and 
percentage of subjects having their last study visit at Week 24, Week 20, etc. 
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The number and percentage of subjects who completed the treatment period, and enter the 
follow-up period (ie, attended the Week 16 or Week 20 or Week 24 visit) will be reported.
A Kaplan-Meier figure will be produced by treatment arm of time to last recorded data related to 
the abstinence endpoints (ie, time from date of randomization to date of last smoking cessation 
data recorded at or prior to the Week 24 visit). Smoking cessation data includes the self-reports 
of cigarette smoking since the last clinic visit (yes, no) or over the past 7 days (yes, no) and 
expired CO levels.
7.1.
Protocol Deviations
Protocol deviations will be reported as outlined in the ACH-CYT-03 Monitoring Plan and 
documented in the CRF. Each deviation will be classified as either “major” or “minor”. Major 
deviations are defined in the monitoring plan as those requiring direct/immediate escalation to 
the Sponsor/Medical Monitor in order to determine if the deviation could affect study results or 
the subject’s study participation. These include deviations in the following categories: 
x
Inadequate informed consent procedures,
x
Violations of inclusion/exclusion criteria,
x
Errors in randomization/stratification,
x
Errors in study drug administration such that the planned and actual treatment are 
discrepant (eg, subject assigned to Arm A [placebo] receiving treatment prescribed 
for Arm B [cytisinicline 6 weeks]),
x
Missing results from screening assessments used for determining subject eligibility.
The number and percentage of subjects with at least one deviation (major or minor) and with at 
least one major deviation will be summarized by treatment arm. For major deviations, the 
number and percentage of subjects with each type of deviation (eg, informed consent, 
inclusion/exclusion violation, etc.) will be summarized by treatment arm. 
8.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographic and other baseline characteristics will be listed and summarized.
8.1.
Demographics 
Demographic data (gender, age at randomization, race, ethnicity, body weight, height, and BMI) 
will be summarized for each of the subgroups (Randomized, Not Randomized) in the Screening 
Set, and overall. 
Demographic data will also be summarized by treatment arm and overall for both the All 
Randomized Set and the Safety Set.
8.2.
Medical and Psychiatric History
A medical and psychiatric history summary will be provided for both the All Randomized Set
and the Safety Set. The number and percentage of subjects with events will be summarized for 
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each treatment arm by MedDRA SOC and preferred term. Multiple occurrences of the same 
event within a subject will be counted only once. 
Medical and psychiatric history conditions will be coded using MedDRA version 23.1.
8.3.
Prior Medications
Concomitant medications will be recorded beginning at the Screening #1 (SV1) visit. Prior 
medications will be defined as medications with a stop date prior to the first dose of study drug. 
For medication start or end dates with unknown month or day, month will be imputed to JAN 
and day to 01 and for medication start or end dates with unknown month, month will be imputed 
as JAN for purposes of identifying prior medications. Prior medications will be summarized for 
both the All Randomized Set and the Safety Set. The number and percentage of subjects with 
each prior medication will be summarized for each treatment arm by highest available 
Anatomical Therapeutic Chemical (ATC) class and preferred name. Multiple occurrences of the 
same medication within a subject will be counted only once.
Prior medications will be coded using WHO Drug Dictionary March 2021.
8.4.
Smoking History
Smoking history will be summarized for both the All Randomized Set and the Safety Set.
At SV1 the following subject-reported smoking history variables will be summarized by
treatment arm.
x
Duration of smoking (years)
x
Average number of cigarettes the subject reported smoking per day over the past 
30 days
x
Type of cigarettes typically smoked (regular vs menthol)
x
Number (%) of subjects who attempted to quit in the past
x
Number of previous quit attempts
x
Time from last quit attempt to date of SV1 visit (months)
In addition, the number (%) of subjects reporting past use of various smoking cessation 
treatments will be summarized separately for the most recent quit attempt and all quit attempts.
For each of these summaries, multiple occurrences of the same treatment within a subject will be 
counted only once.
8.5.
Baseline Smoking and Nicotine Testing
The following baseline data related to smoking will be summarized by treatment arm for both the 
All Randomized Set and the Safety Set:
x
Average number of cigarettes smoked per day over 7 consecutive days, as reported in the 
subject diary 
x
Expired CO (ppm) at SV1
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x
Expired CO (ppm) at Day 0
x
Cotinine result (ng/mL) at SV1. 
If nicotine metabolism ratio (NMR) testing is done at SV1 then NMR will be derived as the ratio 
of the results for 3-hydroxycotinine (3-OH cotinine) and cotinine (ie, 3-OH cotinine / cotinine)
and summarized by treatment arm.
8.6.
Baseline Questionnaires
Questionnaire scores will be derived as described in Section 6.4.2.
The following will be summarized at baseline by treatment arm for both the All Randomized Set 
and the Safety Set:
x
FTND: total score
x
HADS: total score, anxiety score, depression score
x
SEQ-12: internal stimuli score, external stimuli score, and total score.
x
QSU-Brief: total score
x
MNWS: total score.
8.7.
Other Baseline Characteristics
Vital signs (body temperature, heart rate, and systolic and diastolic blood pressure) will be 
assessed at two timepoints prior to randomization: SV1 and Day 0. Baseline vital signs will be 
summarized by treatment arm for both the All Randomized Set and the Safety Set.
Serum chemistry and hematology testing will be performed at SV1. Baseline laboratory test 
results will be summarized by treatment arm for both the All Randomized Set and the Safety Set.
Separate summaries will be provided for hematology tests (hemoglobin, red blood cells, white 
blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets), serum 
chemistry tests (total protein, albumin, total bilirubin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, glucose, sodium, potassium, calcium, creatinine 
and urea) and creatinine-clearance.
Urine pregnancy testing will be performed for all female subjects at SV1 and Day 0. Test results 
will be summarized by treatment arm and visit for all females in both the All Randomized Set 
and the Safety Set.
A 12-lead ECG will be performed at SV1. Baseline ECG findings (normal, abnormal – not 
clinically significant, abnormal – clinically significant) will be summarized by treatment arm for
both the All Randomized Set and the Safety Set.
9.
EXPOSURE TO STUDY TREATMENT
Study treatment consists of administration of study drug in combination with behavioral support.
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9.1.
Duration of Study Drug Treatment
The time (days) from randomization to first dose of study drug will be derived and summarized 
by treatment arm for the Safety Set.
Duration of study drug treatment (days) will be calculated as date of last dose of study drug 
minus date of first dose of study drug +1. Duration of study drug treatment will be summarized 
by treatment arm for the Safety Set. The number (%) of subjects who had duration of 84 days 
will also be summarized by treatment arm. 
9.2.
Study Drug Compliance
All subjects are planned to receive 3 doses of study drug each day for 84 days, for a total of 252 
prescribed doses. There are some subjects that inadvertently enter in their patient diary taking 
more than the 252 prescribed doses, for the analysis 252 doses will be used. Under version 4 of 
the protocol, on a case-by-case basis, the study treatment may be reduced to twice a day. These 
dose reductions will only be allowed for subjects who experience moderate or severe adverse 
events that might be attributed to study drug and who would otherwise discontinue study 
treatment due to the adverse event. For subjects with a dose reduction, #  doses prescribed is 
based on the number of days with 3 doses  prescribed as well as the number days with 2 doses 
prescribed.
Each dose contains study drug (3 mg cytisinicline or placebo) in a single tablet. 
For each dosing day (Day 1 to Day 84) subjects will record a diary entry for each dose: whether 
the dose was taken by the subject or missed and, for doses taken, the date and time of each dose.
The following variables will be calculated for each subject from the diary data and summarized 
by treatment arm for the Safety Set: 
x
total number of doses taken by the subject,
x
total number of doses that were not taken (ie, missed) 
x
percentage of doses missed: (#doses missed / # doses prescribed) × 100
x
study drug compliance: [(# doses taken) / # doses prescribed] × 100
x
total dose of study drug, calculated as number of doses taken × 3 mg per dose
x
Number and percentage of subjects with a dose reduction
Compliance with study drug will be summarized both as a continuous variable and as a
categorical variable (<80%, 80-<90%, 90-<100%, 100%). 
In addition to summary tables, details of study drug compliance will be listed. The listing will 
include the total dose of study drug (mg), total number of doses taken by the subject, total 
number of doses missed, percentage of doses missed, and percentage of doses taken (ie,
compliance with study drug).
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9.3.
Behavioral Support Compliance
Thirteen (13) behavioral support sessions are planned during the treatment period, at the Day 2,
and Week 1 to Week 12 visits. Additional behavioral support will be provided during the 
follow-up period based on issues/concerns/questions raised by the subject.
The total number of behavioral support sessions received during the treatment period will be 
calculated for each subject and summarized by treatment arm for the Safety Set. Summaries will 
also be provided for compliance with behavioral support, derived as:
x
[(# behavioral support sessions received) / (13)] × 100.
10.
EFFICACY ANALYSIS
The efficacy analyses will be conducted using subjects in the All Randomized Set. Unless 
otherwise specified, all randomized subjects will be included in efficacy analyses. Subjects will 
be evaluated by their randomized treatment arm (‘intent-to-treat’ analysis).
For qualitative endpoints, summary tables will present the number and percentage of subjects for
each class of the endpoint. Quantitative endpoints will be summarized by presenting the mean, 
SD, minimum, median and maximum values. All summary statistics will be presented by 
treatment arm.
10.1.
Analyses of Primary and Secondary Efficacy Endpoints
10.1.1.
General Considerations
In general, the implementation of familywise error protection for a family of comparisons is 
most logically implemented using one-sided hypothesis testing because the tests must be 
interchangeable with respect to the goal of the research. The P values reported by statistical 
programs, unless otherwise indicated, will always be two-sided. A two-sided P value associated 
with a one-sided hypothesis is converted to a one-sided P-value for that hypothesis as follows: 
Let P be the two-sided P value. If the estimate associated with the hypothesis is consistent with 
the one-sided alternative hypothesis the one-sided P value is P/2, otherwise the one-sided P value 
is 1 – P/2. Unless otherwise stipulated, one-sided P values will be used only to execute the 
Hochberg procedures for passing statistical criterion.
The overall Type I error probability for the trial is specified to be one-sided 0.025 (overall 
one-sided alpha). The primary objective has two endpoints therefore the interpretation of these 
analyses must protect the overall one-sided alpha of 0.025. The primary objective analyses will 
provide two one-sided P values. Assessing whether the primary objective meets statistical 
criterion will be implemented using the Hochberg procedure as follows. If neither one-sided 
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whereas if both one-VLGHG3YDOXHVDUHWKHQERWKQXOOK\SRWKHVHVFDQEHUHMHFWHGDQGWKH
primary objective will have met statistical criterion. If one of the one-sided P values is >0.025 
then in order for the primary objective to meet statistical criterion the other one-sided P value 
must be 0.0125 (= 0.025/2).
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Secondary objectives will be analyzed only if a statistical criterion for the primary objective is 
met. Specifically, the amount of alpha passed to the secondary objectives will depend on the one-
sided P values associated with the primary analyses (See FDA Guidance: Multiple Endpoints in 
Clinical Trials). There are three possibilities: (1) If the primary objective statistical criterion is 
not met then no alpha is left for the secondary analysis and the associated analyses of those 
endpoints cannot be associated with specified significance testing. (2) If both one-sided P values 
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VLGHG3YDOXHVLV!DQGWKHRWKHULVWKHQWKHDPRXQWRIDOSKDLVEDVHGRQWKH
Hochberg procedures having been truncated and the amount of alpha that can be passed to the 
secondary analyses is 0.0125. (Note on truncated Hochberg when there are two hypotheses, the 
alpha to be passed is invariant to the fraction specification to be used in the computing of the 
alpha passed per FDA Guidance).
If case (2) happens (both primary comparisons are successful) then the Hochberg procedure 
based on one-sided 0.025 as described above can be used for secondary endpoints 1 and 2. 
Secondary endpoint 3 can be analyzed with multiplicity protection only if both secondary 
endpoints 1 and 2 are successful, and can be analyzed using one-sided significance level 0.025.
If case (3) happens (only one of the primary comparisons is successful) then the corresponding 
secondary endpoint can be analyzed using significance level one-sided 0.0125, and secondary 
endpoint 3 cannot be analyzed with multiplicity protection.
10.1.2.
Primary Efficacy Analysis
The primary efficacy endpoint (abstinence) is described in Section 4.1.1. Two primary objectives 
are described in Section 3.1. Two between-arm comparisons are planned, corresponding to the 
two objectives:
x
Abstinence from Week 3 to Week 6: Arm B (cytisinicline 6 weeks) vs Arm A 
(placebo)
x
Abstinence from Week 9 to Week 12: Arm C (cytisinicline 12 weeks) vs Arm A 
(placebo)
The abstinence endpoint is binary (success, failure). For each of the comparisons listed above, 
the two treatment arms will be compared in terms of the proportion of subjects classified as a 
success. All randomized subjects will be included in the comparisons according to their randomized 
arm (ITT analysis).
The statistical significance of each comparisons 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 clinical site, with the possibility of pooling clinical sites having a small contribution,
as described below. 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 (CI) will be reported. Also, 
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.
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The exact difference in proportion confidence interval will be derived using the method of 
Thomas (1971 and 1977).2,3
Following is template SAS code for doing each of the statistical comparisons using SAS PROC 
FREQ:
proc freq data=data;
exact fisher or comor eqor;
table s*x*y / nopercent nocol;
run;
Where
s: site designator (with the possibility of pooling)
x: Two-level arm designator with x=0 for control arm and x=1 for experimental arm.
y: Indicator of success(y=1) or nonsuccess (y=0).
The coding of x and y assures that an estimated odd ratio >1 indicates favorable outcome 
for experimental arm.
The output from SAS PROC FREQ for the above template will have three tables of interest for
assessing success of the comparison, with the following steps to be used to extract relevant items 
and assess whether the statistical criterion has been met:
1. Table “Tests for Homogeneity of the Odds Ratios”: The P value preferred for the test of 
homogeneity is “Exact Pr <=P” (Zelen exact test). If the Zelen exact test is not 
computable (it is known to be susceptible to memory exhaustion), then use the Breslow-
Day P value indicated as "Pr > Chisq".  
2. Table “Common Odds Ratio”: Extract from this table the “Mantel-Haenszel Estimate” of 
the odds ratio and the “Exact Conf Limits” of this odds ratio estimate.
3. Table “Exact Test of H0: Common Odds Ratio=1”: Extract “One-Sided Pr>=S” as the 
one-sided P value for the between-arm comparison. If this one-sided P value is less than 
or equal to the applicable one-sided favorable direction significance level specified above 
then statistical criterion for the between-arm comparison will have been met, and not met 
otherwise. Report whether significance has been met and the two-sided P value 
“Sum<=Point.” The two-sided P value is to be reported because it is conventional (and 
less confusing). Reporting the one-sided P value is optional but not recommended; if 
reported it requires an explicit labeling as one-sided.
If the number of subjects within a stratum (clinical site) is small, then clinical sites stratification 
may require pooling to create a pseudo-site. The criterion for pooling will be to pool clinical sites 
with fewer than 2 subjects in any treatment arm. The pseudo site will represent the effect of sites 
with relatively small contribution. For purposes of statistical analysis, a unique site identification 
number will be assigned to the pseudo-site; the original clinical site identification number will be 
used for the remaining sites (ie, sites that did not meet the criterion for pooling). If no clinical 
sites meet the criterion for pooling, the original clinical site identification number will be used in 
the statistical analysis.
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10.1.2.1.
Sensitivity Analyses
The sensitivity analyses described in this section will be performed separately for each of the 
primary efficacy endpoints (abstinence from Week 3 to Week 6, abstinence from Week 9 to 
Week 12). Sensitivity analyses for each endpoint will include the treatment arms of interest for 
that endpoint. That is, the sensitivity analyses for the abstinence from Week 3 to Week 6 
endpoint will include the cytisinicline 6 weeks (Arm B) and placebo (Arm A) treatment arms and 
the analyses for the abstinence from Week 9 to Week 12 endpoint will include the cytisinicline
12 weeks (Arm C) and placebo (Arm A) treatment arms.
When there is evidence of material non-homogeneity of odds ratio across clinical sites then the 
interpretation of the results will be evaluated for each clinical site. The results of each clinical 
site can be assessed using Fisher’s exact test for the 2x2 table specific to that site, including the 
site specific odds ratio estimate and its confidence interval. The above code template for Fisher’s 
exact test and odds ratio confidence interval is modified as follows: (1) Delete “comor eqor” in 
the exact statement. (2) Add  “or(cl=midp)” following the slash in the table statement. These 
modifications will produce a separate 2x2 table analysis for each site. Extract odds ratio 
confidence interval for each table from the “Confidence Limits for the Odds Ratio” table with 
“Mid-p” in the line of the output. Note: The assessment of the degree of variability of the site-
specific odds ratio estimates is also specified as a planned sensitivity analysis and is somewhat 
informative even if the interaction is not material.
Due to the study being conducted during the stress of the pandemic, a sensitivity analysis will 
explore implementing the Russell standard for each of the primary efficacy endpoints (abstinence 
from Week 3 – 6 and abstinence from Weeks 9 -12), which allows up to a total of 5 cigarettes
during each period (week 3 – 6, week 9 -12) and still be regarded as abstinent/success.
Another sensitivity analysis will be performed for the primary efficacy endpoint of abstinence 
from Week 3 to Week 6, where Arm B (cytisinicline 6 weeks) and Arm C (cytisinicline 
12 weeks) will be combined versus Arm A (placebo).
The analyses described below as Effect Modification Analyses and Tipping Point Analyses will 
be conducted by an independent statistician (Brent A. Blum
Arc Consulting)
who will document the results of these analyses in a statistical report that will be included as an 
appendix to the clinical study report.
Effect Modification Analyses (EMA)
The goal of the EMA will be to evaluate the degree to which arm effects estimated for discrete 
values of a baseline attribute differ. For example, an EMA of sex estimates sex-specific arm 
effects and evaluates whether these estimates differ. If a baseline attribute to be evaluated using 
EMA is not discrete, the attribute is made discrete by specifying cutpoints based on external 
criteria or using percentiles computed from the pooled data (median, tertiles, or quartiles), for 
example, baseline CO split at below 10 or not, or using pooled quartile values.
For each of the primary efficacy endpoints, the relationship between treatment arm and the 
proportion of subjects with abstinence will be evaluated within stratum defined by the effect 
modifier. Evidence of effect modification will be indicated by a material interaction between the 
EDVHOLQHDWWULEXWHDQGDUPZLWKWKHFULWHULRQIRUDPDWHULDOLQWHUDFWLRQVHWDW7KH
interaction P value is a measure of the contribution to the statistical model of the interaction, and 
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will be reported. For each stratum, the number (%) of subjects within each stratum with 
abstinence will be reported for each treatment arm. Odds ratios and their 95% CIs will also be 
reported. Forest plots will be used to display the stratum-specific 95% CIs. 
Tipping Point Analyses
A tipping point analysis4 will be performed for each of the primary efficacy endpoints, including 
sensitivity analyses if applicable.
The goal of each tipping point analysis will be to assess the degree to which the assignment of 
cases defined as failure due to inability to assess for success would influence results. The tipping 
point evaluation will re-analyze the data for all possible reversals of the failure assignment to a 
success, and present the results in a graph.
10.1.3.
Secondary Efficacy Analysis
The three secondary efficacy objectives are stated in Section 3.2. The secondary efficacy 
endpoints (continuous abstinence, risk of relapse) are described in Section 4.1.2.
The analysis for secondary objectives 1 and 2 will be done only if the corresponding primary 
comparison passes statistical criterion.
Two between-arm comparisons are planned for secondary objectives 1 and 2:
x
Continuous abstinence from Week 6 to Week 24: Arm B (cytisinicline 6 weeks)
vs Arm A (placebo)
x
Continuous abstinence from Week 12 to Week 24: Arm C (cytisinicline 12 weeks)
vs Arm A (placebo)
Each continuous abstinence endpoint is binary (success, failure). Note: For the secondary 
analyses, smoking abstinence during the follow up period only (Week 16 to Week 24) followed
the Russell Standard of allowing up to 5 cigarettes and still be regarded as abstinent/success.
Each analysis will then compare the treatment arms in terms of the proportion of subjects 
classified as a success using the same statistical methods as described above for the primary 
endpoint. 
The analysis for secondary objective 3 will be conditional and performed only if both primary
comparisons 1 and 2 pass statistical criterion. One between-arm comparison is planned for 
secondary objective 3.
x
Relapse from Week 6 to Week 24: Arm B (cytisinicline 6 weeks) vs Arm C 
(cytisinicline 12 weeks)
The relapse endpoint is binary (relapsed, without relapse). The treatment arms will be compared 
in terms of the proportion of subjects without relapse using the same statistical methods as 
described above for the primary endpoint.
Sensitivity analyses will be performed for each of the 3 secondary endpoints (continuous 
abstinence week 6 to week 24, continuous abstinence week 12 to week 24, and risk of relapse). 
Sensitivity analyses for each endpoint will include the treatment arms of interest for that 
endpoint. That is, the sensitivity analyses for continuous abstinence from Week 6 to Week 24 
endpoint will include the cytisinicline 6 weeks (Arm B) and placebo (Arm A) treatment arms, the 
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analyses for continuous abstinence from Week 12 to Week 24 endpoint will include the 
cytisinicline 12 weeks (Arm C) and placebo (Arm A) treatment arms and analyses for relapse 
from Week 6 to 24 endpoint will include the cytisinicline 6 weeks (Arm B) and cytisinicline
12 weeks (Arm C).
Sensitivity analyses will not implement the Russell standard during the follow up period (Week 
16 to Week 24) when it has already been implemented for the primary sensitivity analyses during 
Week 3 – 6 or Weeks 9 -12. Another sensitivity analyses will implement the Russell standard 
during the Week 3 – 24 or Week 9 – 24 period. Other implementation timing for the Russell 
standard may be explored.
10.2.
Analyses of Other Efficacy Endpoints
The other efficacy objectives are stated in Section 3.3. The other efficacy endpoints are defined 
in Section 4.1.3. Analyses of the other efficacy endpoints will be exploratory. There will be no 
multiplicity protection scheme for these analyses, and the results of these analyses will be 
labeled as exploratory.
The results for each endpoint will be displayed graphically by treatment arm. Side-by-side bar 
charts may be used to display categorical endpoints, Kaplan-Meier figures will be used for 
time-to-event endpoints. For binary endpoints, forest plots may be used to display 95% CIs for 
the odds ratio. 
For each of the other efficacy endpoints identified below, 3 between arm comparisons will be 
performed, where appropriate:
x
Arm B (cytisinicline 6 weeks) vs Arm A (placebo)
x
Arm C (cytisinicline 12 weeks) vs Arm A (placebo)
x
Arm C (cytisinicline 12 weeks) vs Arm B (cytisinicline 6 weeks) (this comparison 
will be two-sided)
The statistical analyses that will be performed for binary endpoints will follow the specification 
as described for the secondary objectives according to whether the comparison is one-or
two-sided. For other than binary endpoints, the analysis methodologies are described below.  
10.2.1.
7-day Point Prevalence Abstinence
The 7-day point prevalence abstinence endpoints are binary (success, failure) endpoints defined 
at each of the following visits: Weeks 2 to Week 12, Week 16, Week 20, and Week 24. The 
analyses of point prevalence abstinence endpoints will be conducted using all subjects in the All 
Randomized Set. The analysis methodology for binary endpoints was described in 
Section 10.1.2.
10.2.2.
Serum Cotinine Levels
Serum cotinine levels will be measured every other week from Week 2 to Week 12, then at
Week 16, Week 20, and Week 24.
Serum cotinine levels may be reported by the central laboratory as less than the lower limit of 
quantitation (eg, result reported as “<10 ng/mL”) or greater than the upper limit of quantitation 
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(eg, result reported as “>2000 ng/mL”). Results reported as “<X” will be converted to a numeric 
result of “X – 1” prior to statistical analysis (eg, <10 ng/mL will be converted to 9 ng/mL). 
Results reported as “>X” will be converted to a numeric result of “X+1” prior to statistical 
analysis (eg, >2000 ng/mL will be converted to 2001 ng/mL).
Summary tables and figures of serum cotinine levels by treatment arm and visit will be provided 
for the All Randomized Set. 
The treatment arms will be compared (cytisinicline 6 weeks vs placebo, cytisinicline 12 weeks 
vs placebo) using repeated-measures analysis of variance models with fixed effect term for 
treatment arm. The between-arm difference in means, their respective 95% CIs and p-values 
will be reported. Forest plots may be used to display 95% CIs for the differences of the means. 
10.2.3.
Expired CO Levels
Expired CO levels (ppm) will be measured every week from Week 2 to Week 12, then at
Week 16, Week 20, and Week 24.
Summary tables and figures of expired CO levels by treatment arm and visit will be provided for 
the All Randomized Set. 
The treatment arms will be compared (cytisinicline 6 weeks vs placebo, cytisinicline 12 weeks 
vs placebo) using repeated-measures analysis of variance models with fixed effect term for 
treatment arm. The between-arm difference in means, their respective 95% CIs and p-values will 
be reported. Forest plots may be used to display 95% CIs for the differences of the means.
10.2.4.
Use of Non-cigarette Nicotine Products
At each study visit from Week 2 through Week 24, subjects will be asked whether they have 
used (yes, no) any non-cigarette nicotine products since the previous clinic visit. The name of 
any product used during the interval will be recorded in the CRF (eg, pipe tobacco, smokeless 
tobacco, e-cigarettes/vaping). 
The number (%) of subjects reporting use of non-cigarette nicotine product will be summarized
by treatment arm and visit for the All Randomized Set. The summary table will report both the 
number (%) of subjects using any non-cigarette nicotine product and the number (%) of subjects 
using each specific product. The summary table will include visits from Week 2 to Week 24, as 
well as the following study periods: Week 2 to Week 24 (Entire Study Period), Week 2 to 
Week 12 (Treatment Period), and Week 16 to Week 24 (Follow-up Period). For the summary by 
study periods, multiple occurrences of the same nicotine product within a subject will be counted 
only once.
Statistical comparisons between treatment arms (Arm B vs Arm A; Arm C vs Arm A) will be 
performed for the Treatment Period and the Follow-up Period. For each period, Fisher’s Exact 
Tests will be used to compare treatment arms in terms of the incidence of using any non-cigarette
nicotine products.
10.2.5.
Abstinence from Week 9 to Week 12: Arm B vs. Arm A
The statistical methods for this binary endpoint will follow the specifications as described for the 
secondary objectives.
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10.2.6.
Continuous Abstinence from Week 3 to Week 24 (Subset Analysis)
The summaries and statistical analyses of the continuous abstinence from Week 3 to Week 24 
binary endpoint will include the subset of subjects who achieve abstinence from Week 3 to 
Week 6 (ie, subset of subjects who are a success on the primary efficacy endpoint for primary 
objective 1) and have continuous abstinence to Week 24. The statistical methods for binary 
endpoints will follow the specifications as described for the secondary objectives.
10.2.7.
Continuous Abstinence from Week 9 to Week 24 (Subset Analysis)
The summaries and statistical analyses of the continuous abstinence from Week 9 to Week 24 
binary endpoint will include the subset of subjects who achieve abstinence from Week 9 to 
Week 12 (ie, subset of subjects who are a success on the primary efficacy endpoint for primary 
objective 2) and have continuous abstinence to Week 24. The statistical methods for binary 
endpoints will follow the specifications as described for the secondary objectives.
10.2.8.
Time to Failure to Maintain Abstinence 
Time to failure to maintain abstinence will be evaluated for the subset of subjects who were 
classified as a success for abstinence from Week 3 to Week 6. Time to failure (days) will be 
calculated for individual subjects as described in Section 4.1.3. Subjects who are still abstinent at 
Week 24 will have time to failure censored at the date of the Week 24 visit. 
Time to failure will be summarized by treatment arm; the minimum, maximum, median and 95% 
confidence interval for the median time to failure reported by the LIFETEST procedure will be 
reported. A Kaplan-Meier figure of treatment arm by time to failure will be produced.
10.2.9.
Relationship Between Treatment Effect and Demographic and Baseline 
Characteristics
The analyses described below will only be performed for the primary efficacy endpoint 
(biochemically verified abstinence). The objective of these analyses is to assess the homogeneity
of treatment effect within strata (subgroups) defined by potential effect-modifying variables. If
both primary comparisons (Arm A vs Arm B, Arm A vs Arm C) performed for the primary 
efficacy endpoint do not meet statistical criterion (ie, are not statistically significant) then the 
statistical analyses described below will not be performed. If only one of the comparisons meets 
statistical criterion then the analyses described below will be performed using data from only two 
of the treatment arms. 
Strata for continuous effect modifiers will be defined by either logical considerations (eg, age 
>65 years) or statistical criteria (eg, quantile (median, tertile or quartile) split). The variables 
(factors) that will be evaluated as effect modifiers include, but are not limited to: 
x
demographic characteristics (eg, sex, age, race, BMI), 
x
smoking history variables (eg, duration of smoking, average number of cigarettes the 
subject reported smoking per day over the past 30 days, number of previous quit 
attempts, type of cigarettes typically smoked: regular vs menthol, prior smoking 
cessation treatment with varenicline, bupropion, nicotine patch),
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x
baseline smoking variables (eg, average number of cigarettes smoked per day over 
7 consecutive days as reported in the subject diary, baseline CO (ppm), baseline 
cotinine (ng/mL)),
For each stratum, the number (%) of subjects within each stratum with biochemically verified
abstinence will be reported for each treatment arm. Odds ratios (Arm A vs Arm B, Arm A 
vs Arm C) and their 95% CIs will also be reported. Forest plots will be used to display the 
stratum-specific 95% CIs. 
10.2.10.
Relationship Between Subject-Reported Outcomes and Primary and Secondary 
Efficacy Endpoints
The correlation of subject-reported outcomes (eg, anxiety, withdrawal symptoms, tobacco 
craving) with the primary and secondary efficacy endpoints (abstinence, continuous abstinence) 
will be explored. Descriptive statistics for each of the subject-reported outcome variables will be 
produced for subgroups defined by success/failure on those endpoints.
10.2.11.
Questionnaires
The HADS, QSU-Brief, and MNWS questionnaires will be administered at baseline and after the 
start of treatment. Scores for each questionnaire will be derived as described in Section 8.6.
Questionnaire scores will be summarized using descriptive statistics. For each score, the actual 
value, change from baseline and percent change from baseline will be summarized by treatment 
arm and visit. Only subjects with non-missing results at both the baseline and post-baseline visit 
will be summarized at each time point. 
10.3.
Other Analyses Not Specified
Other analyses not detailed in this SAP are anticipated and will be conducted by an independent 
statistician (Brent A. Blume
Arc Consulting). These analyses fall into the class of 
being “data-directed” and will be labeled as such. Explanations of objectives, details of 
methodology, identification of limitations, any known/anticipated biases, and known/anticipated 
threats to validity will accompany each analysis. Here are examples:
x
Additional sensitivity analyses that have the potential to provide alternative 
explanations for observed between-arm differences or lack thereof.
x
Analyses of observed trial conduct anomalies and the relationship of these to 
understanding the observed results.
x
Fitting of multiple explanatory variable models of outcomes including and especially 
including interactions.
x
Analyses designed to explore the associations between outcomes.
x
Analyses designed to explore the relationship between safety and efficacy.
x
Analyses illustrating consistency across multiple outcomes measures.
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11.
SAFETY ANALYSIS 
Safety objectives are described in Section 3.4. All safety analyses described below will be 
presented for each treatment arm using the Safety Set (see Section 6.5).
Safety analyses that are presented “by visit” will include a derived visit named EOT (see 
Section 4.2.1.4).
No statistical comparisons between treatment arms are planned for safety endpoints; thus, no 
statistical test results will be reported. 
11.1.
Adverse Events 
Per the study protocol all adverse events (AE) occurring during the study, whether or not 
attributable to study drug, will be recorded in the subject’s source documents and CRF. The 
adverse event reporting period will start at the date of informed consent and continue through the 
end of the study (Week 24 visit). Treatment emergent adverse events (TEAE) are defined in 
Section 4.2.1.
AE severity will be assessed by the Investigator as mild, moderate or severe. The Investigator 
will also assess the relationship of each AE to study drug (none, unlikely, possible, probable,
definite). Treatment-related AEs are defined as events the Investigator considers to be possibly, 
probably, or definitely related to study drug, as well as events with “unknown” relationship.
Adverse event summaries will present data for the 3 treatment arms. An overall summary of 
adverse events will be provided that reports, for each treatment arm, both the number (%) of 
events meeting a specific criterion and the number (%) of subjects with at least one event 
meeting that criterion during the AE reporting period. Events meeting the following specific 
criteria will be presented in this table: 
x
Any reported adverse event (ie, both pre-existing and treatment-emergent events)
x
For treatment-emergent AEs:

Any TEAE

Any serious TEAE

Any related serious TEAE

TEAEs by severity (mild, moderate, severe)

TEAEs by relationship (none, unlikely, possible, probable, definite)

TEAEs by relationship (not related, related)

TEAEs by action taken with study drug (dose increased, dose not changed, dose 
reduced, dose interrupted, drug withdrawn, not applicable, unknown)

TEAEs by outcome (Fatal, Not recovered/Not resolved, Recovered/Resolved, 
Recovered/Resolved with sequelae, Recovering/Resolving )
Three overall summary tables will be provided, as follows:
x
all AEs during the study
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x
all AEs occurring after Week 6 on the study, defined as AEs with start date after the 
date of the Week 7 Day 1 dose.
x
All AEs occurring after Week 6 of the study defined as AEs with start date after the 
date of the Week 7 Day 1 dose, or AEs that are ongoing (ie, not resolved) on the date 
of the Week 7 Day 1 dose.
Dosing dates will be obtained from subject treatment diaries. 
In addition to the overall summaries described above, the following summaries of TEAEs
occurring anytime during the study will be produced:
x
Incidence by SOC and preferred term (PT), in alphabetical order of SOC and PT, for 
both all TEAE and related TEAE
x
Incidence by PT, in decreasing frequency of PT, for both all TEAE and related TEAE
x
Incidence of TEAEs that resulted in dose reduction or discontinuation of study drug 
(ie, action taken with study drug reported as dose reduced, dose interrupted, or drug 
withdrawn), in decreasing frequency of PT
x
Incidence of TEAE by PT and severity (mild, moderate, severe), in alphabetical order 
of PT
x
Incidence of TEAE by PT and relationship (related, not related ), in alphabetical order 
of PT
x
Incidence of TEAE by PT for events of special interest: COVID-19
The following summaries will also be produced of TEAEs occurring after Week 6 on the study 
(see definitions above):
x
Incidence by SOC and PT, in alphabetical order of SOC and PT
x
Incidence by PT, in decreasing frequency of PT
x
Incidence of TEAEs that resulted in dose reduction or discontinuation of study drug 
(ie, action taken with study drug reported as dose reduced, dose interrupted, or drug 
withdrawn), in decreasing frequency of PT
In summaries of AE incidence, if a subject experiences the same AE (preferred term) multiple 
times that subject will be counted only once for that preferred term. Similarly, if a subject 
experiences multiple AEs (preferred terms) within the same SOC then that subject will be 
counted only once for that SOC. When summarizing by severity and relationship, only the AE 
with the highest severity or relationship will be counted.
A Kaplan-Meier figure of time to first TEAE (ie, time from date of randomization to earliest 
TEAE start date) will be provided by treatment arm.
In addition to summary tables, the following listings will be produced.
x
All AEs
x
AEs which resulted in dose reduction or discontinuation of study drug (ie, action 
taken with study drug reported as dose reduced, dose interrupted, or drug withdrawn)
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11.1.1.
Serious Adverse Events 
Serious adverse events (SAEs) will be summarized by SOC and PT for each treatment arm using 
counts and percentages. The followings summaries of SAEs will be produced.
x
Incidence by SOC and PT, in alphabetical order of SOC and PT
x
Incidence by PT, in decreasing frequency of PT
In addition to summary tables, a listing of SAEs will be produced.
11.1.2.
Other Significant Adverse Events 
Other significant adverse events were defined in Section 4.2.1.3 as the following events:
x
treatment-emergent suicidal ideation or behavior
x
treatment-emergent moderate to severe depression
x
new pregnancy.
The number (%) of subjects with each event will be summarized by treatment arm. 
11.2.
Hematology and Chemistry Data
Hematology and chemistry samples will be collected at SV1, Week 1, Week 6, and at Week 12
(Day 86/EOT).
The protocol-specified hematology tests are hemoglobin, red blood cells (erythrocytes), platelets, 
white blood cells (leukocytes), and absolute counts for neutrophils, lymphocytes, monocytes, 
eosinophils and basophils. The protocol-specified serum chemistry tests are total protein, 
albumin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST),
alkaline phosphatase, glucose, sodium, potassium, calcium, creatinine, creatinine 
clearance/glomerular filtration rate and blood urea nitrogen (BUN). Samples will be analyzed by
a central laboratory. If the central laboratory does not provide results in Système International 
(SI) units then the designated Clinical Research Organization (CRO) will convert all laboratory 
results to SI units prior to analysis. The SI unit values will be derived from CDISC controlled 
terminology. 
The following laboratory summaries will be provided for the protocol-specified tests by
treatment arm and visit:
x
Actual value and change from baseline will be summarized using descriptive 
statistics, by laboratory test and visit.
x
Shift tables will be used to summarize the number (%) of subjects with changes from 
baseline in normal range flag (L=low, N=within normal limits, H=high), by 
laboratory test and visit.
Separate summary tables will be produced for serum chemistry tests and hematology tests. In
addition to summary tables, separate listings of protocol-specified laboratory test results will be 
produced.
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11.3.
Vital Signs and Weight
Vital signs, including weight, will be assessed at SV1, Day 0 (Randomization), at each clinic 
visit during the treatment period.
For each test (oral temperature, pulse rate, systolic and diastolic blood pressure, weight), the 
actual value and change from baseline will be summarized by treatment arm and visit using 
descriptive statistics. For change from baseline, only subjects with non-missing results at both
the baseline and post-baseline visit will be summarized at each time point. 
The number and percentages of subjects reporting potentially clinically significant (PCS) vital 
signs at any time post-baseline will be summarized by treatment arm, where PCS will be defined 
as follows:
PCS – Low if:
PCS – High if:
Observed 
Value is:
AND
Decrease from 
Baseline is:
Observed 
Value is:
AND
Increase from 
Baseline is:
Systolic Blood Pressure
<85 mmHg
PP+J
>160 mmHg
PP+J
Diastolic Blood Pressure
<40 mmHg
PP+J
>90 mmHg
PP+J
Heart Rate
<35 bpm
ESP
>100 bpm
ESP
11.4.
12-Lead ECG Interpretation
A 12-lead ECG will be done at the SV1, Week 6 and Week 12 (Day 86/EOT) visits.
An overall interpretation (normal, abnormal – not clinically significant, abnormal – clinically 
significant) will be recorded in the CRF for each assessment.
The number (%) of subjects with shifts in overall interpretation (eg, normal to abnormal – NCS,
normal to abnormal - CS) will be summarized by visit and treatment arm. The number (%) of 
subjects with at least one shift from a baseline result of “normal” or “abnormal – not clinically 
significant” to a post-treatment result of “abnormal – clinically significant” will also be reported.
In addition, an ECG listing will be provided. 
11.5.
Concomitant Medications
All medications taken during the trial will be recorded in the CRF. Concomitant medications will 
be defined as any medication (other than study drug) taken during the course of treatment (ie,
with medication start date on or after the date of the first dose of study drug). Additionally, 
medications will be considered concomitant if the medication started prior to the first dose of 
study drug and the stop date is either on or after the first dose of study drug, missing (not 
available) or reported as ongoing. For medication start and end dates with unknown month or 
day, month will be imputed to JAN and day to 01 and for medication start or end dates with 
unknown month, month will be imputed as JAN for purposes of identifying concomitant
medications. The number and percentage of subjects with each concomitant medication will be 
summarized for each treatment arm by highest available ATC class and preferred name. Multiple 
occurrences of the same medication within a subject will be counted only once.
Concomitant medications will be coded using WHO Drug Dictionary March 2021.
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12.
PHARMACOKINETIC ANALYSES
None planned.
13.
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES 
There are no changes in the planned analyses described in this SAP from the planned analyses
outlined in the study protocol.
Any changes that might need to be made to this document after database lock will be 
documented in the Clinical Study Report.
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14.
REFERENCES
1.
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.
2.
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.
3.
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.
4.
Yan X, Lee S, Li N. Missing data handling methods in medical device clinical trials. 
Journal of biopharmaceutical statistics 2009;19:1085-98.
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APPENDIX 1.
RANDOMIZATION PLAN
ical 
Rcmdomization Schedule Requirement5 for Achieve ACH•CYT •03 Project. 
Document Version 1.0 
10 September 2020 
author: Ian Davison 
L 
Operat i ons Director 
w 
Director 
Senior Biostat istician 
Resetrch 
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Randomization Schedule Requirements - Achieve ACH-CYT--03 
confidential 
Contents 
Revi$ion Hi5tory 
I ntroduction 
P\Jrpose 
Scope 
HMO clinical Generated Randomi:zation Lists 
File Specification 
Subject Randomization Schedule 
Requirements 
Schedule Generation 
Sllmma,y: 
Melllod 
Sample 
Restriction on o lsdosure statement 
3 
4 
4 
4 
5 
5 
6 
6 
6 
6 
6 
7 
All information in this document is confidential and shall be used only for ct1stomer or 
regulatory authority evaluation purposes. 
Author
Davison 
2 of 7 
Vl.0 
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Randomization Schedule Requirements- Achieve ACH-CYT--03 
confidential 
Revision History 
The following text describes content changes made between versions of this document. 
Version 
Summary of Change 
Reason for 
Date 
Chanae 
1.0 
Initial Version 
10-2020 
Author
Davison 
3 of 7 
Vl.0 
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ACH-CYT-03 Statistical Analysis Plan
Version 1.0 – March 25, 2022
Cytisinicline
CONFIDENTIAL
Page 47 of 50
l 
Randomization Schedule Requirements - Achieve ACH-CYT--03 
confidential 
Introduction 
Achieve are planning a Phase 3 trial: 
Product: 
3mg cytisinicline tablet 
Protocol Number: 
ACH·CYT-03 
study Title: 
A Multieenter, Double~blind, Randomized, Placebo~controUed 
Phase 3 Trial Evaluating the Efficacy and Safety of Cytisinicline 
In Adult Smokers 
Development Phase: 
Phase 3 
HMO 
l here describes the productk>n of a peimuted blod< randomization scheme to: 
A 
Assign Subjects to the next available treatment arm 
Purpose 
The l)\lrpose of tills document is to define the meioods used to generate the subject 
randomization schedules used within the IRT system for the study. 
Scope 
Tols document Is the nnal spectflcatloa for the randomlzacion lists to be generated by 
l '°'' the study. 
Author
Davison 
Vl.0 
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ACH-CYT-03 Statistical Analysis Plan
Version 1.0 – March 25, 2022
Cytisinicline
CONFIDENTIAL
Page 48 of 50
Randomization Schedule Requirements- Achieve ACH-CYT--03 
confidential 
nical Generated Randomization Lists 
l wlD produce test randomlz;atlon !.dledules for Achieve's approval, system 
validation and user acceptance testing (UAT). 
HMO dinical will generate the live Randomization schedules as specified below. 
HMO dinic.al will verify RandO('l'li:zation schedules per SoP 'POS • Randofni:ation Schedule 
Management'. The Project Manager verifies lllat Ille appropriate tests will be perf0<med 
and that the correct schedules will be loaded into the Test and Live environments. 
File Specification 
Structured text files will be generated as 
• comma separated values (csv files) 
Flies will be packaged In a passwor~ protected zip file. The oota columns for the subject 
schedule ate described In ttlel.r respective 'sample' sections of this document. 
Author: 
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ACH-CYT-03 Statistical Analysis Plan
Version 1.0 – March 25, 2022
Cytisinicline
CONFIDENTIAL
Page 49 of 50
HMD 
Randomization Schedule Requirements- Achieve ACH-CYT--03 
confidential 
Subject Randomization Schedule 
Requirements 
A target of 750 wbjects are randomized to one of three treatment grouPS, stratified by 
site. On randomization, each Subject Number is assigned the next available randomization 
record and treatment group for their stratum (le, site). Treatment groups are: 
1. Arm A; 12 weeks placebo 
2. Arm 8, 6 weeks cytisinicline Follov,ed by 6 weeks placebo 
3. Arm C, 12 weeks ot cytlsinicline 
Sobjects .are asslgnoo to treatment anms In a ratio ol I: I: 1. 
Schedulce Ge.neration 
The Randomization schedule wlll be generated using varying blod< sizes of 6 and 9. 200 
blocks ol 6 and 200 blocks of 9 randomization records will be generated producing a total 
of 3,000 records, which comfortably exceeds the trial target of 750 randomized subjects, 
providing1 a safe contingency buffer for any partially used blocks, randomization errors or a 
moderate over-recruitment. 
Randomization will be stratified by the following factof(s): 
• sue 
There are no strata pre·defined In this schedule as stratification will be handled 
dynamically by tile IRT application. Blocks will be assigned to each strata (site) during the 
shipment generation process in order to ensure tfle correct ratio of IQts are sent to the site, 
or at time of randomization if no records are available. 
Stratum details (i.e., which site the block was assigned to) will be ineluded in the 
unblinding file downloaded from tile !RT system at the end of Ule trial. 
To avoid any possible confusion beM-een the 6 digit subject numbers and! 5 digit kit 
numbers, a 4 digit number will be used in this sdledule starting from 1001 <ensuring no 
leading zeros), 
Summary: 
Block size 
6and9 
Numberoftreatme!ltanms 
3 
Ratio 
1:1:1 
Number of blocks 
200of6 200019 
Total codes oroduced 
3000 
Starti....., value of randomization number 
l001 
Method 
Using PL/SQL: 
A 
a table of all possible permutations of treatment arm IO's (l,2,3) are generated 
for each block size a.nd each unique permutation assigned a permutation number. 
Author
Davison 
6of 7 
Vl.0 
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ACH-CYT-03 Statistical Analysis Plan
Version 1.0 – March 25, 2022
Cytisinicline
CONFIDENTIAL
Page 50 of 50
HMD 
l 
Randomization Schedule Requirements- Achieve ACH-CYT--03 
confidential 
For example, '123312'. {see sample section below for mapping between 
treatment arm ID and description) 
,,. 
Orade's built in random fun<:Uon iS used with a seed strlt1g to generate a list of 
pseu(l()oranclom numbers rrom tile pool ol assigned permutation numbers. 
A 
a randomization schedule Is aeated by concatenating the randomized 
permutations. 
Sample 
The following sample schedule illustrates the SQL output. 
R_ID • randomi?ation number 
BLOCK_ID = block number 
RG_ID = treatment ann - decode according to: 
1. Arm A, 12 weeks plaoebo 
2. Arm 8, 6 weeks cytisinicline followed by 6 weeks placebo 
3. Arm C, 12 weeks of cytlsinktlne 
R IO 
1001 
1002 
1003 
1004 
1005 
1006 
1001 
1008 
1009 
1010 
1011 
1012 
1013 
1014 
1015 
BLOCK ID 
1 
-
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
2 
2 
RG_rD 
I 
2 
3 
2 
3 
1 
3 
2 
1 
1 
3 
2 
3 
l 
2 
Note - only 2 blocks have been shown for this illustrative schedule. 
Author
7of 7 
Vl.0 
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