Clinical trial NCT03709823
Conditions: Smoking Cessation
Sponsor: Achieve Life Sciences
Start date: 2018-11-13; Completion date: 2019-04-23
Enrollment: 254 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This placebo-controlled Phase 2b trial is being conducted at sites within the United States (US) to evaluate the effectiveness cytisine dosage (1.5 mg, 3.0 mg) and administration schedule (commercial titration versus simplified 3 times daily \[TID\] schedule) within a 25-day treatment period.

Detailed description:

Arms: arm 1: 1.5 mg cytisine dose using the commercial 25-day titration schedule + behavioral support arm 2: 3.0 mg cytisine dose using the commercial 25-day titration schedule + behavioral support arm 3: Placebo tablets using the commercial 25-day titration schedule + behavioral support arm 4: 1.5 mg cytisine dose for 25 days using a simplified 3 times daily (TID) schedule + behavioral support arm 5: 3.0 mg cytisine dose for 25 days using a simplified TID schedule + behavioral support arm 6: Placebo tablets for 25 days using a simplified TID schedule + behavioral support
Interventions: intervention 1: Cytisine intervention 2: Placebo Comparator intervention 3: Behavioral support
Intervention descriptions: intervention 1: film coated tablet containing 1.5 mg cytisine in a single tablet intervention 2: 1.5 mg cellulose powder to match final weight of the cytisine tablet intervention 3: 12 behavioral support sessions by a qualified staff member plus supportive literature and online resources

Protocol documents:
Prot_000.pdf: 
Protocol ACH-CYT-09 
A Multicenter, Double-blind, Randomized,  
Placebo-controlled Phase 2b Trial of Cytisine in Adult 
Smokers  
April 15, 2019 
Version 3.0 
CONFIDENTIAL 
Achieve Life Sciences Technologies Inc. 
Achieve Life Sciences, Inc. 
1001 W. Broadway, Suite 400 
520 Pike Street, Suite 2250 
Vancouver, British Columbia, Canada   V6H 4B1 
Seattle, Washington, USA   98101 
Tel: 604.736.3678   Fax: 604.736.3687 
Tel: 425.686.1500   Fax: 425.686.1600 




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SYNOPSIS   . 
Protocol Number:  ACH-CYT-09 
Sponsor: Achieve Life Sciences 
Title of Study: A Multicenter, Double-blind, Randomized, Placebo-controlled Phase 2b 
Trial of Cytisine in Adult Smokers 
Clinical Phase: Phase 2b 
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, isolated from seeds of 
Cytisus laburnum (Golden chain), that is believed to reduce the severity of nicotine 
withdrawal symptoms while inhibiting nicotine’s effects by targeting nicotinic acetylcholine 
receptors (nAChRs) in the brain. Cytisine administered at the 1.5 mg dose has been used as 
a smoking cessation drug since the 1960’s in Central and Eastern European countries. 
Previous studies dating from decades ago to support use in Central and Eastern Europe, and 
more recent studies conducted to Good Clinical Practice (GCP), have shown that cytisine 
can be effective in helping smokers to stop smoking. The titration schedule for the 
commercial product comprises a gradual reduction in the number of tablets per day from 
6 tablets to 1 tablet over a 25-day treatment period. However, no studies are available 
evaluating how alternative dose exposure and administration impacts outcomes within the 
treatment period. The intent of this Phase 2b trial is to test the logistics and planned Phase 3 
procedures, including compliance using various blister packaging, as well as the general 
effectiveness of cytisine treatment and the intended behavioral support in overall smoking 
cessation rates for subsequent Phase 3 sample size determinations. 
This Phase 2b trial is being conducted at sites within the United States (US) to evaluate 
cytisine dosage and administration schedules within a 25-day treatment period. Study arms 
will consist of the commercial 1.5 mg dose/titration schedule that is marketed in European 
countries, a higher dose of 3.0 mg following the marketed titration schedule, 1.5 mg and 
3.0 mg doses using an initial three times a day (tid) schedule and respective placebo arms 
for either schedule. The study will evaluate efficacy based on the overall reduction in the 
number of cigarettes smoked during the various study treatment dosing/schedules as well as 
evaluate general compliance and safety profiles compared to the respective placebo arms 
(i.e. the marketed titration schedule or a simplified tid schedule). Results will also be used 
to aid defining Phase 3 sample size calculations when using the planned behavioral support 
and timing of study evaluations for the Phase 3 primary endpoint of abstinence from Week 
5 to Week 8 post-randomization. 
 
 
 
 


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Objectives:  
Efficacy Objectives:  
1. Assess whether subjects randomized to cytisine, administered using the commercial 
titration schedule, have a greater overall reduction in cigarette smoking during the 
study treatment period (Day 1 – 25) compared to subjects randomized to the same 
titration schedule of a placebo. 
2. Assess whether subjects randomized to cytisine, using a simplified tid schedule, 
have a greater overall reduction in cigarette smoking during the study treatment 
period (Day 1 - 25) compared to subjects randomized to the same tid schedule of a 
placebo. 
Other Efficacy Objectives  
(to include comparisons for 1.5 mg or 3.0 mg doses versus placebo when given as the 
commercial 25-day titration schedule and for the tid treatment schedule as well as 
comparisons between the commercial 25-day titration versus tid treatment schedules): 
1. Assess the probability of abstinence from Week 5 to Week 8 post-randomization in 
subjects randomized to cytisine as compared to subjects randomized to placebo. 
2. To compare cytisine and placebo arms on initial quit rates during study treatment, at 
Week 4 (End of Treatment) and on 7-day point prevalence abstinence at Week 5, 
Week 6, Week 7, and Week 8. 
3. Among subjects abstinent at Week 4, compare time to failure to maintain abstinence 
through Week 8 between arms. 
4. To explore potential relationships between subject-reported outcomes (e.g. anxiety, 
withdrawal symptoms, depression, tobacco craving, alcohol use) with the reduction 
in cigarette smoking during the study Treatment Period, as well as smoking 
cessation outcomes at Week 4 (End of Treatment) and from Week 5 to Week 8 post-
randomization. 
5. To explore a potential correlation for subject’s nicotine metabolite ratio (NMR) with 
the reduction in cigarette smoking and smoking cessation outcomes. 
Safety Objectives:  
To evaluate overall safety profiles of cytisine when administered at 1.5 mg or 
3.0 mg, using the 25-day commercial titration or simplified tid schedules, compared 
to placebo. 
Study Design:  
This will be a six-arm, multi-center, double-blind, randomized, placebo-controlled, Phase 
2b 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 5-7 days after the start of treatment. 
The study will be double-blinded to dose but not to the administration schedule. Study 
treatment will start the day after randomization. 


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Subjects must meet all requirements outlined in the inclusion and exclusion criteria. 
Subjects will be stratified at randomization by BMI class (18.5 to <25 kg/m2; 
25 to <30 kg/m2; 30 to <35 kg/m2). A total of approximately 250 subjects will be randomly 
assigned 2:1 to cytisine treatment and the respective placebo treatment as designated by the 
defined schedule (i.e. the commercial titrated schedule or the simplified tid schedule). The 
intended six treatment arms are as follows: 
Arm A     N=50 
1.5 mg cytisine dose using the commercial 25-day titration schedule+behavioral 
support 
  
Arm B     N=50 
3.0 mg cytisine dose using the commercial 25-day titration schedule+behavioral 
support 
 
Arm C     N=25 
Placebo tablets using the commercial 25-day titration schedule+behavioral support 
  
Arm D     N=50 
1.5 mg cytisine dose for 25 days using a simplified tid schedule+behavioral support 
  
Arm E     N=50 
3.0 mg cytisine dose for 25 days using a simplified tid schedule+behavioral support 
  
Arm F     N=25 
Placebo tablets for 25 days using a simplified tid schedule+behavioral support 
 
Each randomized subject will receive twenty-five (25) days treatment either using the 
commercial titration schedule (i.e. decreasing daily tablets over the 25 days) or a simplified 
tid version of the schedule. Smoking status assessments will begin on Day 1 and will 
continue through study treatment by recording the number of cigarettes smoked daily during 
treatment and at the End-of-Treatment visit on Week 4 (Day 27±2 day post-randomization). 
Smoking cessation status will then be assessed weekly over a 4-week follow-up period by 
the subject’s self-report of abstinence with biochemical verification (expired CO) 
documented at Week 5, 6, 7 and 8. 
Safety assessments will occur during study treatment, at the Week 4 End-of-Treatment 
clinic visit, and at the Week 5, 6, 7 and 8 clinic visits. The end of study is defined as the last 
follow-up visit (at Week 8 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 diary) and who intend to quit smoking. 
3. Expired air carbon monoxide (CO) ≥10 ppm. 


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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 
that will be 5-7 days after 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, comply with 
dosing schedule, and sign the Informed Consent Form. 
Exclusion criteria: 
1. Known hypersensitivity to cytisine or any of the excipients. 
2. Positive urinary drugs of abuse screen, determined within 28 days before the first 
dose of cytisine. 
3. Clinically significant abnormal serum chemistry or hematology values within 
28 days of randomization (i.e. requiring treatment or monitoring). 
4. Clinically significant abnormalities in 12-lead ECG determined after minimum of 
5 minutes in supine position within 28 days of randomization (i.e. requiring 
treatment or further assessment). 
5. BMI classification for being underweight (<18.5 kg/m2) or having ≥Class 2 obesity 
(≥35 kg/m2). 
6. Recent history (within 3 months) of acute myocardial infarction, unstable angina, 
stroke, cerebrovascular incident or hospitalization for congestive heart failure. 
7. Current uncontrolled hypertension (blood pressure ≥160/100 mmHg). 
8. Documented diagnosis of schizophrenia or bipolar psychiatric illness; currently 
psychotic; having suicidal ideation (SBQ-R score ≥7); or current symptoms of 
moderate to severe depression (HAD score ≥11). 
9. Renal impairment defined as a creatinine clearance (CrCl) <60 mL/min (estimated 
with the Cockroft-Gault equation) or hepatic impairment defined as alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 x the upper limit 
of normal (ULN). 
10. Women who are pregnant or breast-feeding. 
11. Male or female subjects of child bearing potential who do not agree to use 
acceptable methods of birth control during the study treatment period. 
12. Participation in a clinical study with an investigational drug within 4 weeks of 
randomization. 
13. Treatment with other smoking cessation medications (bupropion, varenicline, 
nortriptyline, or any nicotine replacement therapy [NRT]) within 4 weeks of 
randomization or planned use of these other smoking cessation medications during 
the study. 


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14. Use within 2 weeks of randomization or planned use during the study of non-
cigarette nicotine products (e-cigarettes, pipe tobacco, cigars, snuff, chewing 
tobacco, hookah) or marijuana vaping or smoking. 
15. 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 250 subjects will be randomized to the study. Subjects will be stratified at 
randomization by BMI class (18.5 to <25 kg/m2; 25 to <30 kg/m2; 30 to <35 kg/m2) in order 
to minimize imbalanced allocation to treatment arms. 
Study Treatment Dosing and Administration:  
Dosing:  
All subjects will receive 2 tablets at each dosing according to randomization as follows: 
Specified Tablets 
Cytisine 
1.5 mg Arms 
Cytisine 
3.0 mg Arms 
Placebo 
Arms 
Cytisine 1.5 mg tablets  
1 tablet 
2 tablets 
- 
Placebo tablets 
1 tablet 
- 
2 tablets 
Commercial Titration Schedule:  
During the 25-day Treatment Period, subjects will take 2 tablets as follows:  
25-day Schedule 
Number of Daily Treatments 
Days 1 - 3 
6 times daily 
Days 4 - 12 
5 times daily 
Days 13 - 16 
4 times daily 
Days 17 - 20 
3 times daily 
Days 21 - 24 
2 times daily 
Day 25 
1 time only  
Simplified TID Schedule:  
During the 25-day Treatment Period, subjects will take 2 tablets as follows: 
25-day Schedule 
Number of Daily Treatments 
Days 1 - 20 
3 times daily 
Days 21 - 24 
2 times daily 
Day 25 
1 time only  
The reduction in the frequency of administrations starting on Day 21 is intended to match 
the corresponding reduction in the commercial titration schedule. 
 


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Administration  
In order to facilitate accurate compliance and accountability within the clinic visit schedule, 
tablets will be blister packed and will be configured into 9 medication packs, regardless of 
the 25-day treatment scheduled assignment. Each of the 9 packs will contain the correct 
number of tablets for the days of treatment as follows: 
Pack Number 
Days of Treatment 
1 
1-2 
2 
3-4 
3 
5-7 
4 
8-10 
5 
11-13 
6 
14-15 
7 
16-17 
8 
18-21 
9 
22-25 
Clinic staff will distribute and collect packs as the subject progresses through the clinic 
visits and will conduct ongoing accountability during each clinic visit by reviewing a 
subject’s 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 
25 days of treatment and then be followed for up to 8 weeks post-randomization 
(approximately 31 days post-treatment). Therefore, the duration of the study will be 
approximately 8 weeks post-randomization for each 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 5-7 days after starting treatment and treatment 
must begin on the day after randomization. Subjects will be randomized 2:1 (active vs. 
placebo) in a blinded manner to either Arm A or Arm B, versus Arm C and similarly to 
either Arm D or Arm E versus Arm F. 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 at various scheduled 
times through the Week 8 Follow-Up Period. 
Compliance will be assessed during the treatment period by reviewing subject’s diary (date 
and time of dosing) as well as ongoing drug accountability at each clinic visit (Days 2, 3, 6, 
12, 16, 20, and 27). 


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Subjects will be assessed for efficacy (number of cigarettes smoked daily during treatment 
as well as smoking cessation status by self-report of abstinence with biochemical 
verification (expired CO) during the follow-up assessments at Week 5, 6, 7 and 8). 
Subjects will be assessed for safety (vital signs, adverse event reporting and concomitant 
medications) at each clinic visit, starting on Day 2 of treatment and ending at the Week 8 
visit (Note: clinic will contact subject via telephone on Day 1 of treatment to assess for 
reported adverse events). In addition to the above safety assessments, hematology and 
chemistry assessments will be made during treatment (Days 2, 3, 6, 12, 16, 20 and 27) and 
again at the Week 8 visit. Subjects presenting with clinically significant laboratory findings 
or any adverse event of moderate severity (or higher), regardless of attribution, on the Day 
16 visit must be scheduled for an additional safety visit on Day 21 (±1 Day). Any adverse 
event or abnormalities considered to be clinically significant by the investigating physician 
will be followed with appropriate medical management until values are considered to 
be clinically acceptable or deemed chronic. 
Statistical Considerations:  
Analysis Sets 
Screening Analysis Set: The Screening Analysis Set is defined as all subjects who give 
written informed consent and have entered screening. Analyses will be restricted to 
presentation of baseline data and reasons for non-participation as contrasted to those 
randomized. 
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 smokers. 
Efficacy outcomes 
The primary outcome Y is the percent of expected cigarettes smoked computed for each 
subject as follows: 
Let N=total of number of cigarettes smoked each day over period from 1 to 25 days. 
Let R=representation of the average number of cigarettes smoked daily over the 7-day 
screening period as baseline. 
Let T=number of post-randomization days where number of cigarettes smoked is recorded. 
Compute Y=100*N/(T*R) 
The denominator is the expected number of cigarettes that would have been smoked without 
intervention over the days where the number of cigarettes smoked is recorded, and the 
numerator is 100 times the actual number of cigarettes smoked (the purpose of the 100 
factor is to convert to a percent). 
Statistical methods 
This study will be analyzed without specific statistical criteria. The overall goal is to obtain 
effect and conduct estimates to inform the design of future studies. 


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The primary comparisons are: A versus C, B versus C, D versus F, and E versus F 
(comparison of active arms to the associated placebo arm). 
The primary analyses will include all randomized subjects by randomized arm (intent-to-
treat analysis). The four primary comparisons will be based on analysis of variance with 
main effects arm (2 levels for the arms to be compared) and BMI class (3 level stratification 
as previously specified), and with covariate of baseline cigarettes. Sensitivity analyses will 
include the assessment of the contribution of interaction terms and effect modification 
analyses.  
Analyses of data associated with other objectives will be detailed in a statistical analysis 
plan (SAP) and will include comparisons for 1.5 mg or 3.0 mg doses versus placebo when 
given as the commercial 25-day titration schedule and for the tid treatment schedule as well 
as comparisons between the commercial 25-day titration versus tid treatment schedules. 
The trial size was computed based on previous data from a Phase 1/2 trial and for achieving 
narrow confidence intervals for the primary comparison estimates in this trial. 
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 adverse event 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 ABBREVIATIONS AND DEFINITION OF TERMS ..................................................16 
1. 
INTRODUCTION AND BACKGROUND ...............................................................17 
1.1. 
History of the Investigational Product ........................................................................17 
1.2. 
Nicotine Addiction and Impact on Health ..................................................................17 
1.3. 
Treatments for Smoking Cessation ..........................................................................17 
2. 
RECENT EVIDENCE FOR CYTISINE AS A SMOKING CESSATION 
TREATMENT ............................................................................................................19 
3. 
SAFETY OVERVIEW FOR CYTISINE ...................................................................20 
3.1. 
Non-Clinical Studies ...................................................................................................20 
3.1.1. 
Summary of 28-Day Repeat Toxicology Studies .......................................................20 
3.1.2. 
Summary of Reproductive/Developmental Studies....................................................21 
3.2. 
General Safety of Cytisine as a Marketed Product .....................................................22 
3.2.1. 
Summary of Safety Profile .........................................................................................22 
3.2.2. 
Tabulated List of Adverse Reactions ..........................................................................23 
4. 
RECENT STUDIES COMPLETED BY SPONSOR .................................................24 
4.1. 
Preliminary Results from Study ACH-CYT-02 on Safety and 
Pharmacodynamics of Cytisine Using the Commercial 25-Day Titration 
Schedule ......................................................................................................................24 
4.2. 
Results from Study ACH-CYT-01 on the Effect of Food on Cytisine 
Bioavailability .............................................................................................................28 
5. 
RATIONALE FOR THE STUDY ..............................................................................29 
6. 
STUDY OBJECTIVES ..............................................................................................30 
6.1. 
Efficacy Objectives .....................................................................................................30 
6.2. 
Other Efficacy Objectives ...........................................................................................30 
6.3. 
Safety Objectives ........................................................................................................30 
7. 
STUDY DESIGN OVERVIEW .................................................................................31 
7.1. 
Study Design ...............................................................................................................31 
7.2. 
Treatment Schema ......................................................................................................32 
7.3. 
Discussion of Study Design ........................................................................................33 
7.3.1. 
Placebo Control ..........................................................................................................33 
7.3.2. 
Efficacy Objectives .....................................................................................................33 
7.3.3. 
Blinding ......................................................................................................................33 


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7.3.4. 
Unblinding ..................................................................................................................34 
7.4. 
Number of Subjects ....................................................................................................34 
7.5. 
Randomization and Stratification ...............................................................................34 
7.6. 
Number of Clinical Sites ............................................................................................34 
7.7. 
Estimated Duration/Completion of Study ..................................................................34 
8. 
SELECTION OF STUDY POPULATION ................................................................34 
8.1. 
Inclusion Criteria ........................................................................................................35 
8.2. 
Exclusion Criteria .......................................................................................................35 
8.3. 
Discontinuation of Study Drug or Study Withdrawal Prior to Week 8 
Assessment .................................................................................................................36 
8.3.1. 
Discontinuation of Study Drug ...................................................................................36 
8.3.2. 
Withdrawal from Study ..............................................................................................37 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT 
(IMP)INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ................................37 
9.1. 
Cytisine 1.5 mg Film-Coated Tablets .........................................................................37 
9.2. 
Placebo Tablets ...........................................................................................................37 
9.3. 
Receipt and Storage ....................................................................................................37 
9.4. 
Administration ............................................................................................................37 
9.5. 
Return/Destruction ......................................................................................................38 
9.6. 
Method of Assigning Subjects to Arms ......................................................................38 
9.7. 
Study Drug Dosing Schedule ......................................................................................38 
9.8. 
Accountability .............................................................................................................39 
10. 
PREVIOUS AND CONCOMITANT MEDICATIONS ............................................40 
11. 
TREATMENT COMPLIANCE .................................................................................40 
12. 
STUDY PROCEDURES ............................................................................................40 
12.1. 
Procedure Schedule ....................................................................................................40 
12.2. 
Detailed Description of Study Visits ..........................................................................43 
12.2.1. 
Screening Phase ..........................................................................................................43 
12.2.2. 
Randomization ............................................................................................................44 
12.2.3. 
Treatment Period ........................................................................................................45 
12.2.4. 
Follow-up Assessment Period ....................................................................................48 
12.2.5. 
Subject Diary ..............................................................................................................50 
12.2.6. 
Behavioral Support .....................................................................................................50 


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13. 
EFFICACY CRITERIA..............................................................................................50 
14. 
SAFETY ASSESSMENTS ........................................................................................51 
14.1. 
Definitions ..................................................................................................................52 
14.2. 
Recording of Adverse Events .....................................................................................53 
14.2.1. 
Grading Adverse Event Severity ................................................................................53 
14.2.2. 
Assessment of Attribution ..........................................................................................54 
14.2.3. 
Reporting of Serious Adverse Events .........................................................................54 
14.3. 
Laboratory ...................................................................................................................55 
14.3.1. 
Routine Laboratory Assessments ...............................................................................55 
14.3.2. 
Expired Air Carbon Monoxide (CO) and Cotinine ....................................................56 
14.4. 
Vital signs ...................................................................................................................56 
14.5. 
Physical Examination .................................................................................................56 
15. 
SAFETY MONITORING ..........................................................................................56 
15.1. 
Independent Data Safety Monitor ...............................................................................56 
16. 
STATISTICAL CONSIDERATIONS .......................................................................57 
16.1. 
Statistical Design ........................................................................................................57 
16.2. 
Efficacy Outcomes ......................................................................................................57 
16.3. 
Study Size ...................................................................................................................57 
16.4. 
Safety Objective ..........................................................................................................58 
17. 
REGULATORY AND ETHICS CONSIDERATIONS .............................................58 
17.1. 
Institutional Review Board (IRB) ...............................................................................58 
17.2. 
Ethical Conduct of the Study ......................................................................................59 
17.3. 
Informed Consent .......................................................................................................59 
17.4. 
Subject Confidentiality ...............................................................................................59 
18. 
DOCUMENTATION .................................................................................................60 
18.1. 
Study File and Site Documents...................................................................................60 
18.2. 
Study Documents Supplied by the Sponsor ................................................................60 
18.3. 
Maintenance and Retention of Records ......................................................................60 
19. 
ADMINISTRATIVE PROCEDURES .......................................................................61 
19.1. 
Sponsor Responsibilities .............................................................................................61 
19.2. 
Investigator Responsibilities .......................................................................................61 
19.3. 
Regulatory Compliance ..............................................................................................62 
19.4. 
Protocol Modification/Premature Termination ...........................................................62 


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19.5. 
Policy for Publication and Data Presentation .............................................................62 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................63 
21. 
REFERENCES ...........................................................................................................64 
APPENDIX 1. SUICIDAL BEHAVIORS QUESTIONNAIRE-REVISED (SBQ-R) ...............66 
APPENDIX 2. FAGERSTRÖM TEST OF NICOTINE DEPENDENCE .................................67 
APPENDIX 3. SMOKING SELF-EFFICACY QUESTIONNAIRE (SEQ-12) .........................68 
APPENDIX 4. SHORT FORM OF THE TOBACCO CRAVING QUESTIONNAIRE ...........69 
APPENDIX 5. HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) .......................70 
APPENDIX 6. ALCOHOL USE QUESTIONNAIRE ...............................................................71 
APPENDIX 7. BEHAVIORAL SUPPORT................................................................................72 
 


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LIST OF TABLES 
Table 1: 
Calculation of Margin of Safety based on Rat and Dog Toxicology Studies .............21 
Table 2: 
Adverse Events Reported From the Recent 
 Core Data Sheet ..........................23 
Table 3:  
ACH-CYT-02: Dose Timing and Total Daily Dose ...................................................24 
Table 4: 
ACH-CYT-02: Subject Demographics (Aged 18-65) ................................................25 
Table 5: 
ACH-CYT-02: Overall Summary of TEAEs by Severity and Relationship – 
18 to 65 Years Old (Safety Set) ..................................................................................26 
Table 6: 
ACH-CYT-02: Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term – 18 to 65 Years Old (Safety Set) ...............................................27 
Table 7: 
ACH-CYT-01: Summary of Statistical Analysis of Cytisine Cmax and AUC ..........29 
Table 8: 
Scheduled Dosing and Total Daily Cytisine Dosing for Arm A and Arm B 
(Commercial Titration Schedule) ...............................................................................32 
Table 9: 
Scheduled Dosing and Total Daily Cytisine Dosing for Arm D and Arm E 
(Simplified TID Schedule) .........................................................................................32 
Table 10: Schedule of Study Procedures ....................................................................................41 
Table 11: Adverse Event Severity ..............................................................................................53 
Table 12: Assessment of Attribution to Study Drug ...................................................................54 
 
LIST OF FIGURES 
Figure 1: 
ACH-CYT-02: Percent of Cigarettes Smoked Daily During Study Treatment 
Compared to Baseline Number of Cigarettes Smoked (N=24) ..................................28 
Figure 2: 
Study Design Overview ..............................................................................................31 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION/TERM 
DEFINITION 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
Cmax 
Maximum Observed Plasma Concentration 
CrCl 
Creatinine Clearance  
CRF 
Case Report Form 
DSM 
Data Safety Monitor 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product (for this protocol indicates 
cytisine 1.5 mg film coated tablet) 
MedDRA 
Medical Dictionary for Regulatory Activities 
NMR 
Nicotine Metabolite Ratio  
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SOC 
MedDRA System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Events 
tid 
Three Times Daily 
Tmax 
Time to Maximum Observed Concentration 
UADR 
Unexpected Adverse Drug Reaction 
UAE 
Unexpected Adverse Event 
ULN 
Upper Limit of Normal 


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1. 
INTRODUCTION AND BACKGROUND 
1.1. 
History of the Investigational Product 
(-)-Cytisine (cytisinicline) is a plant-based alkaloid isolated from seeds of Cytisus laburnum L. 
(Golden chain) and has been used as a smoking cessation drug since the 1960’s in Central and 
Eastern Europe, marketed as 
 
).1 It is estimated that over 
20 million smokers have been treated with 
 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.2-4 Cytisine has high affinity and specificity for neuronal 
nicotinic (α4β2) receptors. 
Despite its widespread use, cytisine has not been market-approved for use outside Central and 
Eastern Europe. This may, in part, be explained by 
 focus on clinical development of 
cytisine in its traditional markets in Central and Eastern Europe countries where the initial 
clinical studies were conducted and published, although not in English.1 Two more recent 
Phase 3 studies have been conducted and published in 2011 and 2014 in the New England 
Journal of Medicine.5,6 
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 7 million premature deaths each year worldwide.7 It is 
highly addictive, with more than 95% of unaided attempts at cessation failing by 6 months.8 
Every year that a smoker delays quitting beyond the mid-30s, there is an estimated 3 months 
reduction in life expectancy.9 
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.10 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: 
bupropion (Zyban®, Glaxo-SmithKline) and varenicline (Chantix®/Champix®, Pfizer). NRT and 
bupropion appear to have about equal efficacy.11,12 Varenicline is more effective than single 
NRT and bupropion, although combination NRT is comparable in efficacy.13 A brief description 
of each pharmacotherapy is given below. 


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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).12 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. 
Combining NRT (e.g. oral and patch) has been shown to increase effectiveness.13 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).11 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.4 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 
(e.g., trouble driving or operating heavy machinery), cardiovascular events (new or worsening 
cardiovascular symptoms), allergic hypersensitivity reactions, serious skin reactions, and nausea. 
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 


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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. 
RECENT EVIDENCE FOR CYTISINE AS A SMOKING 
CESSATION TREATMENT 
Cytisine has recently been evaluated using the commercial 25-day titration schedule 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 (
 Smoking Cessation, or TASC5 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 2011.5 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. Compliance (assessed at End of Treatment visit) showed that 44% of subjects 
randomized to cytisine took all doses as directed and 33% of subjects randomized to placebo 
were compliant with all doses. 
The second Phase 3 trial (Cytisine As a Smoking Cessation Aid, or CASCAID6 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 by 
the commercial 25-day titration schedule or vouchers for low-cost combination NRT (patch plus 
gum or lozenges) 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 


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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. Overall, 53% of subjects randomized to receive cytisine were in compliance with the 
treatment schedule (had taken 80 or more of the required 100 tablets). Subjects in the NRT group 
showed 67% compliance (using NRT at both 1 week and 1 month). 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 patches with gum or lozenges to help participants stop 
smoking and remain non-smokers for six months.6 
Both studies are described in more detail within the Investigator’s Brochure. 
3. 
SAFETY OVERVIEW FOR CYTISINE 
3.1. 
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 
more recent pharmacology and toxicology studies in support of the cytisine IND and in 
preparation for formal Phase 3 evaluation. In that regard, NCCIH has sponsored new non-clinical 
studies to current Good Laboratory Practice (GLP) that have included 28-day repeat dosing for 
toxicology assessments in rats and dogs as well as two reproductive/developmental studies in 
rats. 
3.1.1. 
Summary of 28-Day Repeat Toxicology Studies 
Daily oral dose administration of cytisine in Sprague Dawley rats at 5 or 20 mg/kg/day for 28 
consecutive days resulted in clinical signs, such as drooling, in a dose dependent manner. Other 
clinical signs were only seen in the 20 mg/kg group including ruffled fur, hypoactivity, shoveling 
behaviors, and ataxia. Decreases in food consumption and body weight gain were observed in 
animals treated with 20 mg/kg of cytisine. No cytisine-related macroscopic and microscopic 
findings were observed. The no observed adverse effect level (NOAEL) of cytisine is considered 
to be approximately 2 mg/kg/day when given orally for 28 consecutive days in rats. This would 
calculate to an estimated Human Equivalent Dose (HED) of 0.3 mg/kg (i.e. 21 mg for a 70 kg 
human) when cytisine is administered for 28 consecutive days. 
Daily oral dose administration of cytisine via capsules in Beagle dogs at 0.5, 1, or 2 mg/kg/day 
for 28 consecutive days resulted in adverse effects. The maximum tolerated dose (MTD) was 
considered to be greater than 1 mg/kg/day but less than 2 mg/kg/day. Although emesis, drooling 
and diarrhea were observed in some animals treated with 0.5 mg/kg cytisine, the severities were 
mostly slight and not dose-limiting clinically; therefore, the NOAEL was slightly less or at 
approximately 0.5 mg/kg/day following 28 days oral administration. This gives an estimated 
HED of 0.28 mg/kg (i.e. 20 mg for a 70 kg human) should cytisine be administered for 28 
consecutive days (Note: cytisine is administered for 25 days using a descending dose titration 
schedule). 
Based on the findings in both the 28-day rat and 28-day dog toxicology studies, the established 
commercial dose of 1.5 mg × 6 doses/day (maximum total exposure of 9 mg/day for the first 


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3 days of treatment) is approximately half that of the estimated HED of ~20 mg/day for humans. 
The planned higher 3 mg/dose for this study yields a maximum total exposure of 18 mg/day for 
the first 3 days of treatment. This again is below the calculated HED based on all of the studies 
as shown in Table 1.  
Table 1: 
Calculation of Margin of Safety based on Rat and Dog Toxicology Studies 
NOAEL 
Cmax 
(ng/mL) 
AUClast 
(ng*h/mL) 
HEDa 
(mg/kg/day) 
HEDa 
(mg/day) 
Human 
Doseb 
Margin of 
Safety based 
on BSA 
7-day rat study: 
5 mg/kg 
383.5 
2926 
0.8 
56 
9 mg/day 
~6X 
7-day dog study: 
2 mg/kg 
317.5 
708.5 
1.1 
77 
9 mg/day 
~8X 
28-day rat study: 
2 mg/kg 
292.6 
1071.7 
0.3 
21 
9 mg/day 
~2X 
28-day dog study: 
0.5 mg/kg 
TBD 
TBD 
0.28 
20 
9 mg/day 
~2X 
a HED = Human Equivalent Dose 
b Human commercial dose is 9 mg/day for the first 3 days in the 25-day schedule per commercial use. 
Notes: Cmax and AUC are determined from the NOAEL data.  
HED (mg/kg/day) = rat dose divided by 6.2 and dog dose divided by 1.8. 
HED (mg/day) = HED dose (mg/kg/day) x 70 kg. 
 
3.1.2. 
Summary of Reproductive/Developmental Studies 
The study titled “Combined Fertility and Embryofetal Development Toxicity Study in Rats with 
Toxicokinetics” administered oral cytisine once daily to males for 10 weeks (initiating 28 days 
prior to mating) and to females for 14 days prior to mating, during mating, and through Gestation 
Day (GD) 17. Reproductive assessment for 10 males/group included sperm assessments with 
sample collection for evaluation of motility and total sperm count. Females were sacrificed with 
caesarian section on GD 21 with uterine contents examined and any grossly abnormal cervical, 
thoracic and abdominal viscera noted. The placenta, amniotic sac, number of live fetuses, 
number of early or late resorptions, and number of corpora lutea and any abnormalities were also 
recorded. Fetuses were evaluated for gross, visceral, and skeletal abnormalities. This study has 
been completed and no treatment-related mortality or clinical signs of toxicity were observed. 
There was also no evidence of treatment-related effects on mating, cyclicity, impaired fertility or 
embryofetal development. 
The study titled “Pre- and Postnatal Development Toxicity Study in Rats, Including Maternal 
Function” administered daily cytisine to time-mated females on Gestation Days 6 through 
Lactation Day (LD) 20. Once daily, during the dosing interval (GD 6 through LD 20), detailed 
observations were done for each maternal animal at 4 hours post-dosing. Prior to and after the 
dosing interval, detailed observations were done at the same time that body weights were taken. 
On LD 0, date of delivery, litter size, and the sex, weight, and observations of individual 
offspring were recorded. During lactation on LD 4, 7, 14, and 21 (weaning), general 
development was recorded daily for individual offspring. Maturation phase procedures on 
LD 22-63 were also evaluated and recorded for development of each offspring. This study has 
been completed. No treatment-related mortality or clinical signs of toxicity were observed, and 


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no evidence of treatment-related effects on mating, cyclicity, impaired fertility or embryofetal 
development. A slight treatment-related effect on body weight/body weight gain was seen at the 
10.0 mg/kg dose level in both males and females. Systemic exposure was generally higher in 
females than in males regardless of dose, and Cmax was slightly higher in females at the 10 mg/kg 
compared to males at the 10 mg/kg dose level. 
The non-GLP study titled “Embryotoxicity and Teratogenicity Study of Cytisine 
 in 
Rabbits” administered cytisine in sexually mature female rabbits. After fertilization by a male, 
female rabbits were treated with cytisine daily. Fertilized animals were observed for symptoms 
of toxicity and weight gain. Female animals were sacrificed by anesthesia on day 28 of 
pregnancy and were subjected to macroscopic examination of internal organs and Caesarean 
section of the uterus. After visual examination of fetuses, placentas and fetal resorption remains, 
fetuses were weighed, examined for external anomalies as well as skeleton and brain structure 
development were evaluated. Treatment with cytisine did not cause clinical symptoms, death or 
negative influence on weight gain of pregnant rabbits. Unsuccessful pregnancies, loss of 
offspring or abortion associated with the effect of cytisine were not found. Increased pre- and 
post-implantation death of the developing fetus, as well as reduced fetal weight, was not 
observed. No cases of external or visceral malformations and defects in fetal development were 
found. Malformations in the development of the skeleton and cranial bones as well as higher 
incidence rate of delayed ossification and variants in groups exposed to cytisine were also not 
observed. 
Refer to the Investigator’s Brochure for more detail on GLP-conducted, non-clinical studies. 
3.2. 
General Safety of Cytisine as a Marketed Product 
Cytisine (Generic designation cytisinicline) has been marketed by 
, 
in Central and Eastern Europe for over 20 years under the brand name 
 is 
currently marketed in 20 countries and is estimated to have been administered to over 21 million 
subjects. 
 maintains an independently-audited pharmacovigilance system overseen by a 
pharmacovigilance Qualified Person (QPPV). Periodic Safety Update Reports (PSURs) have 
been regularly provided to the relevant European authorities since 2005 (
 
). It is estimated that the cumulative 
number of exposures to cytisine since 2005, and forming the denominator in the cumulative 
PSURs is over 15 million cases. 
The safety information in the 
 Core Data Sheet is regularly reviewed against new PSUR 
information. Sections 3.2.1 and 3.2.2 summarize the section titled “Undesirable Effects” in the 
latest 
 Core Data Sheet. 
3.2.1. 
Summary of Safety Profile 
Since cytisine has a structural similarity to nicotine and is a partial agonist of nicotine 
acetylcholine receptors, the possible pharmacodynamic undesirable effects are manifested 
mainly as nicotine effects. 
In 6 placebo-controlled clinical trials (N=2,844) 1,389 subjects received cytisine. The most 
commonly reported adverse events in the cytisine group involved the gastro-intestinal system: 


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upper abdominal pain, nausea, dyspepsia, dry mouth, vomiting, constipation and diarrhea. 
Nervous system and psychiatric disorders were also common, most frequently headache and 
dizziness, as well as somnolence and insomnia. However, statistical analysis did not reveal any 
significant difference in the nervous system adverse events between the cytisine and placebo 
groups (P=0.12). 
3.2.2. 
Tabulated List of Adverse Reactions 
Adverse reactions are listed according to MedDRA system organ class (SOC) and frequency 
category. Frequency categories are defined using the following convention: very common 
(>1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). 
Table 2: 
Adverse Events Reported From the Recent 
Core Data Sheet 
System Organ 
Class 
Very 
Common 
Common 
Uncommon 
 
Rare 
 
Very 
rare 
 
Not known 
 
Cardiac disorders 
 
 
 
 
 
Tachycardia 
Palpitations 
Vascular 
disorders 
 
 
 
 
 
Slight increase in 
blood pressure 
Nervous system 
disorders 
 
Headachea 
Dizzinessa 
Insomniaa 
Drowsinessa 
 
 
Increased 
irritability 
Respiratory, 
thoracic and 
mediastinal 
disorders 
 
 
 
 
 
Dyspnea 
Gastrointestinal 
disorders 
 
Upper 
abdominal 
paina 
Nauseaa 
Dry moutha 
Dyspepsiaa 
Constipationa 
Diarrheaa 
Vomitinga 
 
 
Changes in taste 
and appetite 
Abdominal pain 
Musculoskeletal 
and connective 
tissue disorders 
 
 
 
 
 
Myalgia 
Metabolism and 
nutrition disorders 
 
 
 
 
 
Hyperhidrosis 
Weight 
decreased 
General disorders 
and 
administration 
site conditions 
 
 
 
 
 
Chest pain 
aThe frequency was estimated based on data from 6 randomized clinical trials. 
Thus, from marketing safety reporting for 
, 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. 


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4. 
RECENT STUDIES COMPLETED BY SPONSOR 
4.1. 
Preliminary Results from Study ACH-CYT-02 on Safety and 
Pharmacodynamics of Cytisine Using the Commercial 25-Day 
Titration Schedule  
ACH-CYT-02 titled “Repeat-Dose Pharmacokinetic and Pharmacodynamic Evaluation of 
Cytisine in Healthy Smokers” is an open-label, randomized, multi-dose study to evaluate the PK 
profile and PD effect of cytisine when administered at doses of 1.5 mg and 3.0 mg following the 
commercialized 25-day schedule as shown in Table 3.  
Table 3:  
ACH-CYT-02: Dose Timing and Total Daily Dose 
Treatment 
Day 
Schedule 
Total Daily Dose 
Approximate Interval 
 
1.5 mg Dose 
3.0 mg Dose 
 
1-3 
6 times daily 
9.0 mg 
18.0 mg 
2 hours 
4-12 
5 times daily 
7.5 mg 
15.0 mg 
2.5 hours 
13-16 
4 times daily 
6.0 mg 
12.0 mg 
3 hours 
17-20 
3 times daily 
4.5 mg 
9.0 mg 
4-5 hours 
21-24 
2 times daily 
3.0 mg 
6.0 mg 
6 hours 
25 
Once daily 
1.5 mg 
3.0 mg 
- 
A total of 36 subjects (24 subjects aged 18-65 years and 12 subjects aged >65 years) are planned 
for enrollment in the study. Twenty-four (24) subjects aged 18-65 have completed the study with 
safety and pharmacodynamics results presented in this section. 
Subject demographics are summarized for the 24 subjects (18-65 years) in Table 4. Twelve (12) 
(8 male: 4 female) were randomized to 1.5 mg cytisine doses and 12 (7 male: 5 female) were 
randomized to 3 mg cytisine doses. All 12 subjects in the 1.5 mg and all 12 subjects in the 3 mg 
dose groups received cytisine over a 25 day period, with 98.4% and 99.1% of planned doses 
administered respectively. 


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Table 4: 
ACH-CYT-02: Subject Demographics (Aged 18-65) 
Parameter 
Statistic 
18-65 Years 
1.5 mg Cytisine 
(N=12) 
3.0 mg Cytisine 
(N=12) 
Overall 
(N=12) 
Age (yrs) 
n 
12 
12 
24 
Mean 
34.5 
38.6 
36.5 
SD 
9.60 
10.25 
9.93 
Height (m) 
n 
12 
12 
24 
Mean 
1.723 
1.701 
1.712 
SD 
0.0763 
0.1083 
0.0924 
Weight (kg) 
n 
12 
12 
24 
Mean 
84.87 
75.53 
80.20 
SD 
15.115 
14.704 
15.343 
Body Mass Index (kg/m2) 
n 
12 
12 
24 
Mean 
28.47 
25.98 
27.23 
SD 
3.922 
3.699 
3.938 
Race:   
 - White 
 
n (%) 
 
12 (100.0) 
 
11 (91.7) 
 
23 (95.8) 
 - Other 
n (%) 
0 (0.0) 
1 (8.3) 
1 (4.2) 
Gender:  
 - Male 
 
n (%) 
 
8 (66.7) 
 
7 (58.3) 
 
15 (62.5) 
 - Female 
n (%) 
4 (33.3) 
5 (41.7) 
9 (37.5) 
 
A total of 42 treatment-emergent adverse events (TEAEs) were reported by 16 (66.7%) subjects 
during the study; the severity was mild or moderate for all events, the majority of which were 
related to cytisine (Table 5).  
When the number of subjects reporting TEAEs were compared, the same number of subjects 
reported at least 1 TEAE in each dose group (66.7%). However, there was a slight tendency for a 
greater number of TEAE’s to be reported for 3.0 mg cytisine versus 1.5 mg cytisine (24 events 
vs 18 events, respectively). There was also a tendency for more subjects reporting moderate 
events with 3.0 mg cytisine when compared to 1.5 mg cytisine (41.7% vs 16.7% respectively) 
(Table 5).  
There were no SAEs or suspected unexpected serious adverse reactions (SUSAR). All TEAEs 
resolved. 


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Table 5: 
ACH-CYT-02: Overall Summary of TEAEs by Severity and Relationship – 
18 to 65 Years Old (Safety Set) 
 
18-65 Years 
1.5 mg Cytisine 
(N=12) 
3.0 mg 
Cytisine 
(N=12) 
Overall 
(N=24) 
Number of TEAEs 
18 
24 
42 
  Mild 
13 
16 
29 
  Moderate 
5 
8 
13 
  Severe 
0 
0 
0 
Number(%) of Subjects Reporting at Least 1: 
 
 
 
  TEAE 
8 (66.7) 
8 (66.7) 
16 (66.7) 
  Serious TEAE 
0 (0.0) 
0 (0.0) 
0 (0.0) 
  TEAE Leading to Withdrawal of Study Drug 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Number(%) of Subjects with TEAE by Severity: 
 
 
 
  Mild 
6 (50.0) 
3 (25.0) 
9 (37.5) 
  Moderate 
2 (16.7) 
5 (41.7) 
7 (29.2) 
  Severe 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Number(%) of Subjects with TEAE by Relationship to Cytisine: 
 
 
 
  Definite 
0 (0.0) 
0 (0.0) 
0 (0.0) 
  Probable 
0 (0.0) 
2 (16.7) 
2 (8.3) 
  Possible 
4 (33.3) 
5 (41.7) 
9 (37.5) 
  Unlikely 
2 (16.7) 
0 (0.0) 
2 (8.3) 
  Not Related 
2 (16.7) 
1 (8.3) 
3 (12.5) 
  N/A 
0 (0.0) 
0 (0.0) 
0 (0.0) 
A subject with multiple AEs was counted only once at the maximum level of severity or the highest association to cytisine. 
AE = adverse events, N/A = not applicable, TEAE = treatment emergent adverse event 
Nervous system disorders were the most commonly occurring SOC events (Table 6), with the 
most commonly occurring TEAE being headache with an overall incidence of 24 headache 
events in 10 subjects (41.7%). There was a slightly higher number of subjects reporting moderate 
headaches in the 3.0 mg vs 1.5 mg dose group (33.3% vs 16.7%) (Table 6 footnote). 
Gastrointestinal disorders were the next most commonly occurring SOC events, with an overall 
incidence of 2 nausea events in 2 subjects (8%) and 2 constipation events in 2 subjects (8%). 
 


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Table 6: 
ACH-CYT-02: Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term – 18 to 65 Years Old (Safety Set) 
 
Number of Events/Number of Subjects (%) 
SYSTEM ORGAN CLASS: 
  Preferred Term 
18-65 Years 
1.5 mg Cytisine 
(N=12) 
3.0 mg Cytisine 
(N=12) 
Overall 
(N=24) 
GASTROINTESTINAL DISORDERS: 
3 / 2 (16.7) 
5 / 3 (25.0) 
8 / 5 (20.8) 
  Constipation 
1 / 1 (8.3) 
1 / 1 (8.3) 
2 / 2 (8.3) 
  Flatulence 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
  Nausea 
0 / 0 (0.0) 
2 / 2 (16.7) 
2 / 2 (8.3) 
  Tooth loss 
2 / 1 (8.3) 
0 / 0 (0.0) 
2 / 1 (4.2) 
  Toothache 
0 / 0 (0.0) 
1 / 1 (8.3)b 
1 / 1 (4.2) 
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS: 
1 / 1 (8.3) 
2 / 2 (16.7) 
3 / 3 (12.5) 
  Chest discomfort 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
  Medical device site reaction 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Peripheral swelling 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
INFECTIONS AND INFESTATIONS: 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Rhinitis 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS: 
2 / 2 (16.7) 
0 / 0 (0.0) 
2 / 2 (8.3) 
  Muscle strain 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Procedural pain 
1 / 1 (8.3)a 
0 / 0 (0.0) 
1 / 1 (4.2) 
NERVOUS SYSTEM DISORDERS: 
9 / 4 (33.3) 
16 / 6 (50.0) 
25 /10 (41.7) 
  Headache 
9 / 4 (33.3)a  
15 / 6 (50.0)b  
24 /10 (41.7) 
  Vision blurred 
0 / 0 (0.0) 
1 / 1 (8.3)b  
1 / 1 (4.2) 
PSYCHIATRIC DISORDERS: 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
  Abnormal dreams 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS: 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Oropharyngeal pain 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Rash pruritic 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
a Moderate events of headache (16.7% of subjects) and procedural pain (8.3% of subjects). 
b Moderate events of headache (33.3% of subjects), toothache (8.3% of subjects) and blurred vision (8.3% of 
subjects). 
A subject was counted only once per system organ class and preferred term. 
Regarding preliminary pharmacodynamic results, although smokers in the study were not 
required to have a designated or predetermined quit date, subjects overall in the trial had a 
significant reduction in number of daily cigarettes smoked by the end of treatment (Figure 1). 
Mean baseline cigarette consumption in this 18 to 65 year age group was 16.25 (± 3.5) cigarettes 
per day with exhaled CO of 19.9 (± 7.3) ppm. By the end of treatment on Day 25, subjects in the 
1.5 mg cytisine treatment group were smoking only 8% of the cigarettes compared to baseline 
cigarette smoking (i.e. a 92% reduction in daily cigarette smoking). Subjects in the 3.0 mg 
cytisine treatment group were smoking only 5% of the cigarettes compared to baseline cigarette 
smoking (i.e. a 95% reduction in daily cigarette smoking).  


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Figure 1: 
ACH-CYT-02: Percent of Cigarettes Smoked Daily During Study Treatment 
Compared to Baseline Number of Cigarettes Smoked (N=24) 
 
4.2. 
Results from Study ACH-CYT-01 on the Effect of Food on Cytisine 
Bioavailability  
ACH-CYT-01 titled “A Phase 1 Open Label, Randomized, Two-Way Crossover Study in 
Healthy Volunteers to Investigate the Effect of Food on the Bioavailability of Cytisine” 
evaluated 24 healthy volunteer subjects to investigate the effect of food on the bioavailability of 
cytisine. The primary objective was to compare the bioavailability of cytisine under fed and 
fasted conditions following administration of 3 mg cytisine (2×1.5 mg cytisine tablets). 
Eligible subjects received a single-dose of 3 mg cytisine under fed and fasted conditions over 
2 treatment periods. Pharmacokinetic (PK) samples (plasma and urine) were collected predose 
and up to 24 h post-dose (Day 2) during each period (17 plasma and 6 urine samples per period) 
for the measurement of plasma and urine cytisine concentrations. 
The study enrolled 24 subjects (11 males: 13 females) with a median age of 34 years (range 
19-53 years). Two of three subjects who experienced emesis during the course of the study (both 
under fed conditions) were excluded from statistical analysis because emesis occurred at or 
before 2 times the median Tmax. 
The fasted Cmax at 29.8 ng/mL was higher than the fed Cmax at 22.3 ng/mL. The Tmax under fed 
conditions (2.75 h) was delayed when compared to the Tmax under fasted conditions (0.75 h). 
However, both AUC0-∞ and AUC0-t were comparable under fed (167.5 and 160.2 h.ng/mL) and 
fasted (172.6 and 165.9 h.ng/mL) conditions, respectively. 
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10111213141516171819202122232425
Cigarettes Smoked per day
Cytisine 1.5 mg
Cytisine 3 mg


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Table 7: 
ACH-CYT-01: Summary of Statistical Analysis of Cytisine Cmax and 
AUC 
Parameter 
Geometric LS Mean 
Geometric LSMean Ratio 
(90% CI) 
fed / fasted 
3 mg Cytisine 
fed 
(N = 22) 
3 mg Cytisine 
fasted 
(N = 22) 
Cmax  
(ng/mL)  
22.3 
29.8 
74.71 
(66.39 - 84.08) 
AUC0-∞ 
(h.ng/mL) 
167.5 
172.6 
97.04 
(94.20 - 99.98) 
AUC0-t 
(h.ng/mL)  
160.2 
165.9 
96.52 
(93.30 - 99.85) 
 
Cytisine showed rapid absorption after oral administration with over 80% of cytisine recoverable 
in urine within the 24 hours post-dosing. Since cytisine using the commercial titration schedule 
will be administered frequently (i.e. 6 times daily, approximately every 2 hours) for the first 
3 days and then administered in a decreasing frequency over the 25 day treatment course, food 
should not affect the overall treatment, primarily because the bioavailability measured as Area-
Under-the Curve (AUC0-∞ and AUC0-t) showed equivalence between fed and fasted states. In 
addition, any food restrictions for such a frequent administration would not be practical and is 
not necessary given the minor food effect on Cmax and Tmax. 
Both studies are described in more detail within the Investigator’s Brochure. 
5. 
RATIONALE FOR THE STUDY 
Previous studies dating decades ago and now more recent GCP studies have shown that cytisine 
can be effective in helping smokers to stop smoking. The recent trials have shown 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 
for millions of subjects 
who have used 
(cytisine). It is not possible to effectively determine which reported 
adverse effects associated with cytisine treatment are an effect of the drug itself, due to nicotine 
withdrawal effects, or a combination of both. However, the risk/benefit for cytisine appears very 
acceptable. Tobacco smoking contributes to some 7 million premature deaths each year 
worldwide.7 Using cytisine as a smoking cessation aid could offer far more benefit with minor 
risks of treatment-related adverse events when compared to the harms of continued smoking. 
Achieve Life Sciences and the U.S. Food and Drug Administration (FDA) have discussed 
general development plans for cytisine as a new chemical entity for aiding smoking cessation in 
the United States (US), which ultimately led to filing an IND in 2017. The titration schedule for 
the commercial product comprises a gradual reduction schedule in the number of tablets per day 
from 6 tablets to 1 tablet over a 25 day period. However, no studies are available evaluating the 
dose exposure and administration schedule. This Phase 2b trial is being conducted at sites within 
the US to evaluate cytisine dose and administration schedules within a 25-day treatment period. 
Study arms will consist of the commercial 1.5 mg dose/titration schedule that is marketed in 
European countries, a higher dose of 3.0 mg using the marketed titration schedule, 1.5 mg and 


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3.0 mg doses using a three times a day (tid) schedule and respective placebo arms. The study will 
evaluate efficacy based on the overall reduction in the number of cigarettes smoked during the 
various study treatment dosing/schedules as well as compare compliance and safety profiles 
compared to the respective placebo arms (i.e. the marketed titration schedule or a simplified tid 
schedule). 
Results from this study will also be used for defining Phase 3 sample size calculations when 
using the planned behavioral support and timing of study evaluations for the Phase 3 primary 
endpoint of abstinence from Week 5 to Week 8 post-randomization. 
6. 
STUDY OBJECTIVES 
6.1. 
Efficacy Objectives 
1. Assess whether subjects randomized to cytisine, administered using the commercial 
titration schedule, have a greater overall reduction in cigarette smoking during the study 
treatment period (Day 1- 25) as compared to subjects randomized to the same placebo 
titration schedule. 
2. Assess whether subjects randomized to cytisine, using a simplified tid schedule, have a 
greater overall reduction in cigarette smoking during the study treatment period 
(Day 1- 25) as compared to subjects randomized to the same placebo tid schedule. 
6.2. 
Other Efficacy Objectives 
Each of the following will include comparisons for 1.5 mg or 3.0 mg doses versus placebo when 
given as the commercial 25-day titration schedule and for the tid treatment schedule as well as 
comparisons between the commercial 25-day titration versus tid treatment schedules). 
1. Assess the probability of abstinence from Week 5 to Week 8 post-randomization in 
subjects randomized to cytisine as compared to subjects randomized to placebo. 
2. To compare cytisine and placebo arms on initial quit rates during study treatment, at 
Week 4 (End of Treatment) and on 7-day point prevalence abstinence at Week 5, Week 
6, Week 7, and Week 8. 
3. Among subjects abstinent at Week 4, compare time to failure to maintain abstinence 
through Week 8 between arms. 
4. To explore potential relationships between subject-reported outcomes (e.g. anxiety, 
withdrawal symptoms, depression, tobacco craving, alcohol use) with the reduction in 
cigarette smoking during the study Treatment Period, as well as smoking cessation 
outcomes at Week 4 (End of Treatment) and from Week 5 to Week 8 post-randomization. 
5. To explore a potential correlation for subject’s nicotine metabolite ratio (NMR) with the 
reduction in cigarette smoking and smoking cessation outcomes. 
6.3. 
Safety Objectives 
1. To evaluate overall safety profiles of cytisine when administered at 1.5 mg or 3.0 mg, 
using the 25-day commercial titration or simplified tid schedules, compared to placebo. 


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7. 
STUDY DESIGN OVERVIEW 
7.1. 
Study Design 
This will be a six-arm, multi-center, double-blind, randomized, placebo-controlled, Phase 2b 
study conducted in male or female adults ≥18 years of age, smoking 10+ cigarettes daily, and 
willing to set a quit date that is 5-7 days after being randomized on the study. The study will be 
double-blinded to dose but not to the administration schedule. Study treatment must start the day 
after randomization such that study treatment is initiated prior to the quit date. 
Subjects must meet all inclusion and exclusion criteria. Subjects will be stratified at 
randomization by BMI class (18.5 to <25 kg/m2; 25 to <30 kg/m2; 30 to <35 kg/m2). A total of 
approximately 250 subjects will be randomized 2:1 in a blinded manner to either Arm A or Arm 
B, vs Arm C (2:1 randomization) or Arm D or Arm E vs Arm F (2:1 randomization) as shown in 
Figure 2. 
Figure 2: 
Study Design Overview 
     
 
The study will be comprised of a pre-study screen, followed by twenty-five (25) days of study 
treatment, and post-treatment follow up visits to Week 8 post-randomization. 
Each subject will receive twenty-five (25) days treatment either using the commercial titration 
schedule (i.e. decreasing daily tablets over the 25 days) or a simplified (tid) schedule during the 
Treatment Period. Smoking assessments will occur daily during the Treatment Period via self-
reported cigarette count (number cigarettes smoked in the past 24 hours). Smoking abstinence 
 
 
 
 
R 
A 
N 
D 
O 
M 
I 
Z
E 
Arm A (N=50) 
1.5 mg cytisine dose using the commercial 25-day titration 
schedule + behavioral support 
Arm E (N=50) 
3.0 mg cytisine dose for 25 days using a simplified tid schedule 
+ behavioral support 
 
 
 
 
 
 
 
S 
C 
R 
E 
E 
N 
 
 
 
 
 
 
 
F 
 
O 
 
L 
 
L 
 
O 
   W 
 
 
 
U 
 
P 
Arm D (N=50) 
1.5 mg cytisine dose for 25 days using a simplified tid schedule 
+ behavioral support 
Arm F (N=25) 
Placebo tablets for 25 days using a simplified tid schedule 
+ behavioral support 
Arm B (N=50) 
3.0 mg cytisine dose using the commercial 25-day titration 
schedule + behavioral support 
Arm C (N=25) 
Placebo tablets using the commercial 25-day titration schedule 
+ behavioral support 


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will be further assessed during the Follow-up Period starting after the Day 27±2 (Week 4) visit 
and documented through Week 5 (±3 days), Week 6 (±3 days), Week 7 (±3 days) and Week 8 
(±3 days) post-randomization. Safety reporting will begin at randomization and continue through 
the Week 8 visit. The end of the study is defined as the last Week 8 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 Schema 
In order to blind the study treatment dose, all subjects will take 2 tablets at every scheduled 
dosing. Subjects randomly assigned to Arm A or Arm D will take one 1.5 mg cytisine tablet and 
one placebo tablet at each dosing. Arm B or Arm E subjects will take two 1.5 mg cytisine tablets 
at each dosing. Arm C and Arm F subjects will receive two placebo tablets at each daily 
scheduled dosing to correspond to cytisine dosing. Scheduled dosing and total daily cytisine 
dosing are outlined in (Table 8 and Table 9). 
Table 8: 
Scheduled Dosing and Total Daily Cytisine Dosing for Arm A and Arm B 
(Commercial Titration Schedule) 
Treatment 
Days 
Daily Scheduled 
Dosing 
Total Daily Cytisine Dose 
Approximate 
Interval 
Placebo 
1.5 mg Dose 
(Arm A) 
3.0 mg Dose 
(Arm B) 
1a -3 
6 times daily 
- 
9.0 mg 
18.0 mg 
2 hours 
4-12b 
5 times daily 
- 
7.5 mg 
15.0 mg 
2.5 hours 
13-16 
4 times daily 
- 
6.0 mg 
12.0 mg 
3 hours 
17-20 
3 times daily 
- 
4.5 mg 
9.0 mg 
4-5 hours 
21-24 
2 times daily 
- 
3.0 mg 
6.0 mg 
6 hours 
25 
1 time only 
- 
1.5 mg 
3.0 mg 
- 
aInitial treatment Day 1 for the 25-day Treatment Period must begin on the day after randomization. 
bQuit Date to be on Day 5, 6 or 7. 
 
Table 9: 
Scheduled Dosing and Total Daily Cytisine Dosing for Arm D and Arm E 
(Simplified TID Schedule) 
Treatment 
Days 
Daily Scheduled 
Dosing 
Total Daily Cytisine Dose 
Approximate 
Interval 
Placebo 
1.5 mg Dose 
(Arm D) 
3.0 mg Dose 
(Arm E) 
1a,b -20 
3 times daily 
- 
4.5 mg 
9.0 mg 
4-5 hours 
21c -24 
2 times daily 
- 
3.0 mg 
6.0 mg 
6 hours 
25 
1 time only 
- 
1.5 mg 
3.0 mg 
- 
aInitial treatment day 1 for the 25-day Treatment Period must begin on the day after randomization. 
bQuit Date to be on Day 5, 6 or 7. 
cThe reduction in the frequency of administrations starting on Day 21 is intended to match the corresponding 
reduction in the commercial titration schedule. 


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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, safety and compliance outcomes. 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. The treatment manipulations 
of interest will be study drug and the administration schedule. This Phase 2b study evaluates the 
effectiveness of the 1.5 mg and the 3.0 mg dose versus placebo using the commercial titration 
versus a simplified tid schedule. As the commercial and tid schedules will have different tablet 
administrations, a corresponding placebo layout is incorporated so that placebo-bias, compliance 
and adverse event reporting can be accurately evaluated. The use of placebo groups is therefore 
considered justified. 
7.3.2. 
Efficacy Objectives 
Cytisine was developed and is being marketed using a 25-day titration treatment schedule for 
smoking cessation using a 1.5 mg dose. The primary efficacy objective of this Phase 2b trial is to 
assess the overall reduction in daily cigarette smoking during the study treatment 
dosing/schedules compared to the respective placebo arms (i.e. the marketed titration schedule or 
a simplified tid schedule). Reduction in daily cigarette smoking was chosen as the primary 
efficacy outcome in order to better define the effects of the different dosing and schedules during 
the study treatment when such factors might have different daily effects on smoking behavior. A 
more simplified tid schedule was selected based on the pharmacokinetic profile for cytisine. In a 
recent pharmacokinetic trial (ACH-CYT-01), the geometric mean elimination half-life of 
cytisine (in the presence of food following administration of a 3 mg dose) was 4.63 h, but with a 
coefficient of variation of 24.3%. Given this variability, a tid administration schedule was chosen 
in order to ensure that subjects with a half-life at the lower end of the expected range will have 
adequate plasma concentrations of cytisine throughout the day. 
Other efficacy results from this study will be used for defining Phase 3 sample size calculations 
when using the planned behavioral support and timing of study evaluations for the Phase 3 
primary endpoint of abstinence from Week 5 to Week 8 post-randomization. 
7.3.3. 
Blinding 
Although subjects and site staff will be unblinded to the treatment schedule (commercial titration 
vs. tid) due to packaging and dose timing requirements, this remains a double-blinded study with 
regard to cytisine versus placebo dosing and the design therefore protects against subjective bias 
in reporting both efficacy and safety. Blinding will occur by coding the individual study drug 
packaging 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. 


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7.3.4. 
Unblinding  
There is no intention to unblind study treatment for individual subjects. However, during the 
study, emergency unblinding for adverse events might need to be performed. This option may be 
used only if subject well-being requires knowledge of treatment assignment. The investigator 
must first contact the Achieve Medical Monitor, or representative, who will coordinate access to 
the treatment assignment code via the independent vendor. All unblinding must be documented 
by the site and the Sponsor. 
Examples of 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. 
7.4. 
Number of Subjects 
A total of 250 subjects will be randomized, with approximately 50 subjects in each of the 
4 treatment arms and 25 subjects in each of the two placebo arms. The maximum number of 
subjects that a single site is allowed to enroll, without consent of the Sponsor, is 50 
(approximately 20% of the study total). 
7.5. 
Randomization and Stratification 
Sites will utilize an Interactive Response Technology (IRT) system for treatment arm assignment 
at randomization (Day 0). The IRT will stratify at randomization by BMI class (18.5 to 
<25 kg/m2; 25 to <30 kg/m2; 30 to <35 kg/m2). Detailed instructions are provided in the Study 
Reference Manual. 
7.6. 
 Number of Clinical Sites 
This will be a multicenter clinical trial. Approximately 7-9 clinical sites in the US will 
participate. 
7.7. 
Estimated Duration/Completion of Study 
Duration of this study is estimated to be approximately 2 months (8 weeks) for each subject 
(from randomization to the Week 8 follow-up visit). Completion of the study is estimated at 
6 months with ~1 months accrual ramp-up, an additional 3 months to complete accrual and 
2 months from the last randomized subject to complete study follow-up evaluations. 
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, and risks. Potential subjects will 


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be asked to read the consent form and to sign and date it once all of their questions have been 
answered and they voluntarily agree to participate in the study. A copy of the signed informed 
consent form will be provided to the subject. 
Upon obtaining signed informed consent, each subject will undergo the screening procedures 
outlined in Section 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. These eligibility criteria are the same criteria planned for the subsequent 
Phase 3 trials. 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 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 that 
is 5-7 days after 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, comply with 
dosing schedule, and 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. Known hypersensitivity to cytisine or any of the excipients. 
2. Positive urinary drugs of abuse screen, determined within 28 days before the first dose of 
cytisine. 
3. Clinically significant abnormal serum chemistry or hematology values within 28 days of 
randomization (i.e. requiring treatment). 
4. Clinically significant abnormalities in 12-lead ECG determined after minimum of 
5 minutes in supine position within 28 days of randomization (i.e. requiring treatment or 
further assessment). 


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5. BMI classification for being underweight (<18.5 kg/m2) or having ≥Class 2 obesity 
(≥35 kg/m2). 
6. Recent history (within 3 months) of acute myocardial infarction, unstable angina, stroke, 
cerebrovascular incident or hospitalization for congestive heart failure. 
7. Current uncontrolled hypertension (blood pressure ≥160/100 mmHg). 
8. Documented diagnosis of schizophrenia or bipolar psychiatric illness; currently 
psychotic; having suicidal ideation (SBQ-R score ≥7); or current symptoms of moderate 
to severe depression (HAD score ≥11). 
9. Renal impairment defined as a creatinine clearance (CrCl) <60 mL/min (estimated with 
the Cockroft-Gault equation) or hepatic impairment defined as alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) >2.0 x the upper limit of normal (ULN). 
10. Women who are pregnant or breast-feeding. 
11. Male or Female subjects of child bearing potential who do not agree to use acceptable 
methods of birth control during the study treatment period. 
12. Participation in a clinical study with an investigational drug within 4 weeks of 
randomization. 
13. Treatment with other smoking cessation medications (bupropion, varenicline, 
nortriptyline, or any nicotine replacement therapy [NRT]) within 4 weeks of 
randomization or planned use of these other smoking cessation medications during the 
study. 
14. Use within 2 weeks of randomization or planned use during the study of non-cigarette 
nicotine products (e-cigarettes, pipe tobacco, cigars, snuff, chewing tobacco, hookah) or 
marijuana vaping or smoking. 
15. 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. 
Discontinuation of Study Drug or Study Withdrawal Prior to Week 8 
Assessment  
8.3.1. 
Discontinuation of Study Drug 
Subjects can be discontinued from study drug for the reasons below.  However, subjects who 
discontinue study drug will continue all remaining study evaluations as outlined in the protocol 
to obtain safety and efficacy outcomes, as if they were still taking study drug. 
1. If a subject experiences a serious or intolerable adverse event that prevents them from 
continuing study drug.  
2. At the Investigator’s request (e.g. if the Investigator considers that the subject’s health 
might be compromised by continuing study drug). 
The reason for discontinuation of study drug will be recorded in the CRF. 


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8.3.2. 
Withdrawal from Study 
All subjects will be informed of their right to withdraw from the study at any time and for any 
reason. Subjects who withdraw from the study (i.e. withdraw from further study evaluations) will 
be asked to complete the Day 27/EOT assessments, if still receiving study drug, and willingness 
to attend the Week 8 assessment visit. The date and reason for study withdrawal will be recorded 
on the study completion form of the CRF. 
If a subject is discontinued and there is an 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. 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT 
(IMP)INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
9.1. 
Cytisine 1.5 mg Film-Coated Tablets 
Cytisine (cytisinicline) will be supplied by the Sponsor. The cytisine drug product is formulated 
as a compressed film-coated tablet containing 1.5 mg cytisine in a single tablet. Each tablet is 
composed of cytisine active substance (as the base) supplied by
 
 
9.2. 
Placebo Tablets 
Placebo tablets will contain the same excipients as in the cytisine tablet formulation plus an 
additional 
 to match final weight of the cytisine tablet. Placebo tablets 
will be identical in size, shape, color, and packaging to preserve the double-blind study design. 
9.3. 
Receipt and Storage  
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 folded blister packs. The folded blister 
packaging will be designed for specific days of treatment and for the two different dosing 
schedules. Thus, the commercial titration schedule will have different blister packaging 
compared to the tid schedule. At specific clinic visits, a series of blister packets will be given to 
subjects for dosing over a few days and are to be returned at subsequent clinic visits with the last 
blister packets returned upon completion of treatment. 


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Tablets should be swallowed whole with water.  
9.5. 
Return/Destruction 
All unused study drug should be destroyed by the sites unless a prearranged return to depot or 
Sponsor is necessary. 
9.6. 
Method of Assigning Subjects to Arms 
Subjects will be allocated to arms according to a predetermined randomization schedule and 
randomly assigned (2:1) to active vs. placebo once all screening procedures are completed and 
verified. Randomization will be stratified by BMI class (18.5 to <25 kg/m2; 25 to <30 kg/m2; 30 
to <35 kg/m2). 
Subjects will be assigned a unique study identification (I.D.) number upon signing the informed 
consent form, prior to conducting any protocol-specified procedures by the site. The study I.D. 
number will consist of 2 parts. The first part identifies the site (3 digits) and the second part 
identifies the subject (3 digits). Subject numbers will be assigned sequentially from 101 (i.e. 101, 
102, etc.). Study drug assignment will occur via IRT. The IRT system will identify what study 
drug packet should be used via a randomly-assigned number printed on the packet so that 
treatment assignment blind can be maintained. The site will label the assigned packet with the 
subject’s study I.D. number and include both in the applicable source documents (i.e. drug 
accountability log). 
For treatment compliance, study drug will be packaged into folded packets covering treatment 
segments that will align with clinic visits. Treatment segment packets will be distributed, 
returned and reviewed at each scheduled site visit for ongoing accountability (see Section 9.8). 
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 2 tablets for each dose. According to randomization, subjects will receive 
study drug as follows: 
 
Specified Tablets 
Arm A or 
Arm D 
(1.5 mg Dose) 
Arm B or 
Arm E 
(3.0 mg Dose) 
Arm C or 
Arm F 
(Placebo) 
Cytisine 1.5 mg tablets  
1 tablet 
2 tablets 
- 
Placebo tablets 
1 tablet 
- 
2 tablets 


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For 25-day titration schedule, study drug will be administered according to the following 
treatment day schedule: 
Treatment Day 
Daily Administration 
1a-3 
6 times daily 
4-12 
5 times daily 
13-16 
4 times daily 
17-20 
3 times daily 
21-24 
2 times daily 
25 
1 time only 
aInitial treatment day 1 for the 25-day Treatment Period must start on the day after randomization. 
 
For the tid schedule, study drug will be administered according to the following treatment 
schedule: 
Treatment Day 
Daily Administration 
1a-20 
3 times daily 
21-24 
2 times daily 
25 
1 time only 
aInitial treatment day 1 for the 25-day 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. 
To facilitate accurate compliance and accountability, study drug for each subject will be 
configured into 9 medication packs, regardless of the 25-day treatment scheduled assignment 
(commercial titration schedule or simplified tid schedule). Each of the 9 packs will contain the 
correct number of tablets for the days of treatment as follows: 
Pack Number 
Days of Treatment 
1 
1-2 
2 
3-4 
3 
5-7 
4 
8-10 
5 
11-13 
6 
14-15 
7 
16-17 
8 
18-21 
9 
22-25 
Clinic staff will distribute and collect 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 and associated blister packs. Used packs will be retained so that the Sponsor's monitoring 
staff can verify accountability records. 


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Upon completion of the study and final accountability monitoring, all the investigational 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). 
All concomitant medication(s) taken during the trial and any changes (additions, deletions, dose 
changes) must be recorded in the CRF. This must include any use of non-cigarette nicotine 
products. 
11. 
TREATMENT COMPLIANCE  
Treatment compliance will be monitored during the 25 day Treatment Period via review of 
dosing timing and drug accountability. Subjects will have a daily 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 diary, 
recording the number of tablets taken and the number of missed tablets. In addition, a 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 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, 3, 6, 12, 16, 20 (during treatment), Day 27 (End-of-Treatment [EOT] visit), and 
again at the Week 5, 6, 7 and 8 visits.  
12.1. 
Procedure Schedule 
Table 10 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. Day 1 will be defined as the first day of 
treatment. Subjects must initiate study treatment the day after randomization, such that study 
treatment is initiated prior to the quit date, which must be planned within 5-7 days after start of 
treatment. Both the planned treatment start date and the agreed-upon quit date must be 
documented at the time of randomization within the source documents and CRF.


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Table 10: 
Schedule of Study Procedures 
Study Assessment 
Screening Period 
(Day-28 to Rand) 
Randomization 
 
 
 
 
Treatment Period 
Day 1 through Day 25 
 
 
Follow-up Assessment Period1  
(± 3 Days) 
Visit 
SV
1 
SV 
22 
Day 
0 
Day  
13 
Day 
2 
Day 
3 
Day  
6 
(±1 Day) 
Day 
12 
(±1 Day) 
Day 
16 
(±1 Day) 
Day 
20 
(±1 Day) 
Day 27 
EOT  
(±2 Days)  
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Informed Consent 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Psychiatric History  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SBQ-R questionnaire 
• 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
Physical Exam 
•4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking History 
•5 
•5 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test for all 
Females6 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drugs of Abuse Screen6,7 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs including Weight  
•8 
 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Hematology and Chemistry6 
• 
 
 
 
• 
• 
• 
• 
• 
• 
• 
 
 
 
• 
12-lead ECG 
• 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
 
Concomitant Medications 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Quit Date Set and Treatment Day 1 
Scheduled 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Diary Completion 
Instructions 
•5 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Review Diary for Number of 
Cigarettes Smoked 
 
•5 
 
 
• 
• 
• 
• 
• 
• 
• 
 
 
 
 
Adverse Event Reporting 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Study Drug Distribution, 
Accountability and Collection 
 
 
• 
 
• 
• 
• 
• 
• 
• 
• 
 
 
 
 


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Study Assessment 
Screening Period 
(Day-28 to Rand) 
Randomization 
 
 
 
 
Treatment Period 
Day 1 through Day 25 
 
 
Follow-up Assessment Period1  
(± 3 Days) 
Visit 
SV
1 
SV 
22 
Day 
0 
Day  
13 
Day 
2 
Day 
3 
Day  
6 
(±1 Day) 
Day 
12 
(±1 Day) 
Day 
16 
(±1 Day) 
Day 
20 
(±1 Day) 
Day 27 
EOT  
(±2 Days)  
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Behavioral Support 
 
•9 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Fagerström Test of Nicotine 
Dependence 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Self-Efficacy Questionnaire 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Craving Questionnaire 
 
 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
HADS Questionnaire 
• 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
• 
Alcohol Use Questionnaire 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
• 
Smoking Cessation Status 
 
 
 
 
 
 
 
 
 
 
 
• 
• 
• 
• 
Expired CO 
• 
 
• 
 
 
 
 
 
 
 
• 
• 
• 
• 
• 
Plasma Cotinine6 
•10 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
1Once study drug dosing has been completed and the End-of-Treatment visit has occurred at Week 4 (Day 25-27 post-randomization), smoking cessation status will be 
performed weekly during the Follow-up Assessment Period at Week 5 through to Week 8 post-randomization. Smoking cessation status at each visit from Week 5 through 
Week 8 will be defined by self-report of no cigarette smoking and CO levels. Cigarette smoking for the past 7 days as well as from the last clinic visit will be recorded. 
2Randomization 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. 
3Clinic 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. 
4Physical exam may be conducted at either the SV1 or the SV2. 
5Number of cigarettes smoked daily will be recorded in a 7-day 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. 
6Urine pregnancy test kits supplied to site by central laboratory. All other testing performed by a central laboratory. 
7Drugs of abuse to include at a minimum amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, ecstasy, opiates, and phencyclidine. 
8To include height at screening for BMI calculations (required for stratification). 
9Setting the quit date and plan is to be considered the first behavioral support counseling session. 
10 Plasma sample will be collected at SV1 and stored on all subjects. Only samples from randomized subjects will be tested for 3-OH cotinine and cotinine levels to determine 
the nicotine metabolite ratio (NMR) at baseline. 


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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 will occur over a 28 day 
period prior to randomization and must include a minimum of 2 clinic visits. 
Screening (Day 28 to Randomization Day 1) 
Study procedures include: 
Screening Visit #1 
1. Written informed consent obtained. 
2. Demographic data. 
3. Medical and psychiatric history. Suicidal ideation is to be determined and documented via 
administration and assessment of the SBQ-R questionnaire (Appendix 1). Depression is to 
be assessed via administration of the HADS questionnaire (Appendix 5). 
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 average number of cigarettes smoked per day over the past 30 days. Provide 
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). 
8. Expired CO. 
9. Vital signs, including weight and height. 
10. Urine pregnancy for all female subjects. 
11. Drugs of abuse screen. 
12. Hematology and serum chemistry testing. An additional plasma sample will be stored for 
all subjects. Only samples from randomized subjects will be tested for 3-OH cotinine and 
cotinine levels to determine the nicotine metabolite ratio (NMR). 
13. 12-lead ECG. 
14. Review all inclusion and exclusion criteria and if satisfied, schedule Screening Visit #2. 
 
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. 


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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 occur 5-7 days prior to the agreed upon quit date so that the actual quit date 
falls on Treatment Day 5, 6 or 7. All other screening evaluations must be completed within 
28 days prior to the Randomization Day. Study treatment must start on the day after 
randomization. 
Study procedures include: 
1. Update concomitant medication(s). 
2. Document any existing adverse event(s). 
3. Vital signs, including weight. 
4. Expired CO. 
Upon completion of all procedures and final confirmation 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. Short Form of the Tobacco Craving questionnaire (Appendix 4).  
d. HADS questionnaire (Appendix 5). 
e. Alcohol Use questionnaire (Appendix 6). 
2. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: it should be stressed to subjects that even if they are smoking less 
during the study treatment, they must maintain their dosing schedule throughout the 
Treatment Period. 
3. Randomize according to a pre-determined, blinded, randomization schedule (see 
Section 7.5). 
4. Provide study treatment medication packs #1 and #2, which contain tablets required for 
Days 1-2 and Days 3-4. Enter actual treatment dates on the packs next to the dosing day 
designation in the space provided. Review the layout and dosing instructions printed on the 
medication packs which cover dosing requirements, timing of study drug administration 
and how to remove individual tablets from the blister pack. Instruct subject that any/all 
packs must be brought back to the clinic and should never be thrown away. 
5. Develop an appointment schedule that includes dates and times for each required clinic 
visit during the trial, providing copy to the subject. 
6. Provide diary instructions. 


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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 a diary. 
Clinic to contact subject via telephone call in afternoon or evening of Treatment Day 1 to: 
1. Verify subject is taking treatment according to their assigned dose schedule, review 
compliance requirements and answer any questions. 
2. Verify subject is recording number of cigarettes smoked in past 24 hours in the diary (to be 
recorded at the same time each day). 
3. Ask subject if any adverse events have occurred and/or any changes in concomitant 
medications. 
4. Remind subject of their appointment time for the following day and that they must bring 
with them all study medication packs. 
Treatment Day 2 
1. Subject to complete the short form of the Tobacco Craving questionnaire (Appendix 4). 
2. Review diary to verify dosing up to time of visit. Review number of cigarettes smoked in 
past 24 hours from subject’s diary (e.g. Day 1). 
3. Assess for AEs at time of visit and record. 
4. Vital signs, including weight. 
5. Review medication packs for compliance. 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: it should be stressed to subjects that even if they are smoking less, 
they must maintain their dosing schedule throughout the Treatment Period. 
7. Blood for hematology and serum chemistry testing. 
8. Remind subject of their appointment time for the following day and that they must bring 
with them all study medication packs. 
Treatment Day 3 
1. Subject to complete the short form of the Tobacco Craving questionnaire (Appendix 4). 
2. Review diary to verify dosing up to time of visit. Review number of cigarettes smoked in 
past 24 hours from subject’s diary (e.g. Day 2). 
3. Assess for AEs and any changes to concomitant medications at the clinic visit. 
4. Vital signs, including weight. 


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5. Review medication packs #1 and #2 for compliance and collect pack #1 (which should be 
empty, as it contained medication for days 1-2). Distribute pack #3 (for Days 5-7). 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: it should be stressed to subjects that even if they are smoking less 
during the study treatment, they must maintain their dosing schedule throughout the 
Treatment Period. 
7. Blood for hematology and serum chemistry testing. 
8. Remind subject of their Day 6 appointment date and time and that they must bring with 
them all study medication packs. 
Treatment Day 6 (±1 day) 
1. Reconfirm quit date on planned Treatment Day 5, 6, or 7 
2. Subject to complete the short form of the Tobacco Craving questionnaire (Appendix 4). 
3. Review diary to verify dosing up to time of visit. Review number of cigarettes smoked in 
past 24 hours from subject’s diary for each daily input (e.g. Days 3, 4 and 5). 
4. Assess for AEs and any changes to concomitant medications at the clinic visit. 
5. Vital signs, including weight. 
6. Review medication packs #2 and #3 for compliance and collect pack #2 (which should be 
empty, as it contained medication for Days 3-4). Distribute packs #4 and #5 (for Days 8-10 
and 11-13). 
7. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: it should again be stressed to subjects that even if they are smoking 
less, they must maintain their dosing schedule throughout the Treatment Period. 
8. Blood for hematology and serum chemistry testing. 
9. Remind subject of their Day 12 appointment date and time and that they must bring with 
them all study medication packs. 
Treatment Day 12 (±1 day) 
1. Subject to complete the short form of the Tobacco Craving questionnaire (Appendix 4) 
and the HADS questionnaire (Appendix 5). 
2. Review diary to verify dosing up to time of visit. Review number of cigarettes smoked in 
past 24 hours from subject’s diary for each daily input (e.g. Days 6, 7, 8, 9, 10, and 11). 
3. Assess for AEs and any changes to concomitant medications at the clinic visit. 
4. Vital signs, including weight. 
5. 12-lead ECG. 
6. Review medication packs #3, #4 and #5 for compliance and collect packs #3 and #4 
(which should be empty, as they contained medication for Days 5-7 and 8-10). Distribute 
packs #6 and #7 (for days 14-15 and 16-17). 


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7. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: it should be stressed to subjects that even if they are smoking less, 
they must maintain their dosing schedule throughout the Treatment Period. 
8. Blood for hematology and serum chemistry testing. 
9. Remind subject of their Day 16 appointment date and time and that they must bring with 
them all study medication packs. 
Treatment Day 16 (±1 day) 
1. Subject to complete the short form of the Tobacco Craving questionnaire (Appendix 4). 
2. Review diary to verify dosing up to time of visit. Review number of cigarettes smoked in 
past 24 hours from subject’s diary for each daily input (e.g. Days 12, 13, 14, and 15). 
3. Assess for AEs and any changes to concomitant medications at the clinic visit. 
4. Vital signs, including weight. 
5. Review medication packs #5, #6 and #7 for compliance and collect packs #5 and #6 
(which should be empty, as they contained medication for Days 11-13 and 14-15). 
Distribute pack #8 (for days 18-21). 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: it should be stressed to subjects that even if they are smoking less, 
they must maintain their dosing schedule throughout the Treatment Period. 
7. Blood for hematology and serum chemistry testing. 
8. Remind subject of their Day 20 appointment date and time and that they must bring with 
them all study medication packs. 
Treatment Day 20 (±1 day) 
1. Subject to complete the short form of the Tobacco Craving questionnaire (Appendix 4). 
2. Review diary to verify dosing up to time of visit. Review number of cigarettes smoked in 
past 24 hours from subject’s diary for each daily input (e.g. Days 16, 17, 18, and 19). 
3. Assess for AEs and any changes to concomitant medications at the clinic visit. 
4. Vital signs, including weight. 
5. Review medication packs #7 and #8 for compliance and collect pack #7 (which should be 
empty, as it contained medication for Days 16-17). Distribute final pack #9 (for Days 
22-25). 
6. Provide subject with behavioral support information that includes counseling 
(Appendix 7). NOTE: it should be stressed to subjects that even if they are smoking less, 
they must maintain their dosing schedule throughout the Treatment Period. 
7. Blood for hematology and serum chemistry testing. 
8. Remind subject of their End of Treatment (Day 27 ±2 days) appointment date and time 
and that they must bring with them all study medication packs. 


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Day 27 End of Treatment Visit (±2 day) 
1. Subject to complete the SBQ-R questionnaire (Appendix 1), the short form of the Tobacco 
Craving questionnaire (Appendix 4) and the HADS questionnaire (Appendix 5). 
2. Collect the completed diary from subject. Review diary to verify dosing up to time of visit. 
Review number of cigarettes smoked in past 24 hours from subject’s diary for each daily 
input (e.g. Days 20, 21, 22, 23, 24, and 25). 
3. Assess for AEs and any changes to concomitant medications at the clinic visit. 
4. Vital signs, including weight. 
5. 12-lead ECG. 
6. Review medication packs for compliance and collect packs #7, #8 and #9 (which should 
be empty, as it contained medication for Days 16-17, 18-21 and 22-25). All used packs 
must be collected and available for final accountability by the study monitor. 
7. Provide subject with behavioral support information that includes counseling 
(Appendix 7). 
8. Blood for hematology, serum chemistry and cotinine testing. 
9. Expired CO. 
10. Remind subject that although their treatment is now complete, it is critical to provide the 
required weekly visits during the follow-up assessment period (Weeks 5, 6, 7 and 8). 
Schedule date and time for their Week 5 visit. 
12.2.4. 
Follow-up Assessment Period 
All subjects are required to complete 4 clinic visits during the Follow-up Period to assess smoking 
cessation status, starting at Week 5 and continuing weekly through Week 8 (i.e. Weeks 5, 6, 7 and 
8). 
Week 5 (±3 days) 
1. Subject to complete the short form of the Tobacco Craving questionnaire (Appendix 4). 
2. Vital signs, including body weight. 
3. Record the following: 
a. Has the subject smoked any cigarettes since the last clinic (Day 27/Week 4) visit?  
b. Has the subject smoked any cigarettes over the past 7 days? 
c. If subject has smoked, subject should report the average daily number of cigarettes 
smoked. 
4. Expired CO. 
5. Record any adverse events and concomitant medication updates. 
6. Provide subject with behavioral support information and counseling (Appendix 7). 
7. Schedule Week 6 (±3 days) assessment visit. 
 
 


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Week 6 (±3 days) 
1. Subject to complete the short form of the Tobacco Craving questionnaire (Appendix 4). 
2. Vital signs, including body weight. 
3. Record the following: 
a. Has the subject smoked any cigarettes since the last clinic (Week 5) visit? 
b. Has the subject smoked any cigarettes over the past 7 days? 
c. If subject has smoked, subject should report the average daily number of cigarettes 
smoked. 
4. Expired CO. 
5. Record any adverse events and concomitant medication updates. 
6. Provide subject with behavioral support information and counseling (Appendix 7). 
7. Schedule Week 7 (±3 days) assessment visit. 
Week 7 (±3 days) 
1. Subject to complete the short form of the Tobacco Craving questionnaire (Appendix 4). 
2. Vital signs, including body weight. 
3. Record the following: 
a. Has the subject smoked any cigarettes since the last clinic (Week 6) visit? 
b. Has the subject smoked any cigarettes over the past 7 days? 
c. If subject has smoked, subject should report the average daily number of cigarettes 
smoked. 
4. Expired CO. 
5. Record any adverse events and concomitant medication updates. 
6. Provide subject with behavioral support information and counseling (Appendix 7). 
7. Schedule Week 8 (±3 days) assessment visit. 
Week 8 (±3 days) 
1. Subject to complete the following questionnaires: 
a. SBQ-R questionnaire (Appendix 1) and assessment for any changes in suicidal 
ideation. 
b. Short form of the Tobacco Craving questionnaire (Appendix 4). 
c. HADS questionnaire (Appendix 5). 
d. Alcohol Use questionnaire (Appendix 6). 
2. Vital signs, including body weight. 
3. Blood for hematology, serum chemistry and cotinine testing. 
4. Record the following: 
a. Has the subject smoked any cigarettes since the last clinic (Week 7) visit? 
b. Has the subject smoked any cigarettes over the past 7 days? 


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c. If subject has smoked, subject should report the average daily number of cigarettes 
smoked. 
5. Expired CO. 
6. Record any adverse events and concomitant medication updates. 
7. Provide subject with behavioral support information and counseling (Appendix 7). 
8. Discharge subject from study. 
12.2.5. 
Subject Diary 
A 7-day diary will be provided and 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 diary must be maintained by each subject to record daily cigarettes smoked 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 during the 25-day dosing schedule. Staff 
must review entries with the subject at each clinic visit and document on CRF. Data from the 
diary will be reviewed at all clinic visits and collected as a source document at the Day 27 End-of-
Treatment 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 (e.g. 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. 
All subjects will receive up to 12 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 Week 8 visit as outlined in (Table 10). 
Site counselor(s) are to encourage subjects to continue study drug as scheduled even if they lapse 
and have a cigarette after their quit date. It is important during this “grace” period for the subjects 
to keep trying to quit as planned. 
Each behavioral session will be subject-driven and must include direct engagement with the 
subject about their efforts to quit smoking. Each session should last up to 10 minutes (Refer to 
Appendix 7). 
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  
This Phase 2b study will evaluate the timing and daily reduction in cigarette smoking during the 
various study treatment dosing/schedules compared to the respective placebo arms (i.e. the 
commercial titration schedule or a simplified tid schedule) as the primary efficacy analyses. The 


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four primary comparisons will be based on analysis of variance with main treatment effects, BMI 
class (3 level stratification as previously specified), and with covariate of baseline cigarettes 
smoked. These analyses for reduction in cigarette smoking based on cytisine dose (1.5 mg and 
3.0 mg relative to placebo) and administration schedule (titration vs tid) for differences in timing 
or level of reduction in cigarette smoking during the treatment period. 
Secondary efficacy analyses for smoking cessation (4 weeks abstinence documented at Week 5, 6, 
7 and 8 post randomization) will also be determined and include the following standard criteria 
which are also planned for the Phase 3 studies: 
1. Self-report of smoking abstinence since the last clinic visit (continued abstinence) and over 
the prior 7 days at each clinic assessment (7-day point prevalence abstinence); 
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 8 or lost to follow up will be 
classified as failed to quit; and 
5. Continually blinded to treatment allocation during collection of follow-up data. 
14. 
SAFETY ASSESSMENTS  
All subjects will be monitored for adverse events starting at screening (pre-existing), periodically 
during the Treatment Period (1 assessment via telephone on Day 1 and clinic evaluations on Days 
2, 3, 6, 12, 16, and 20), at the End-of-Treatment (Day 27) visit and then weekly to the Week 8 
visit (see Table 10). Laboratory (hematology and chemistry) evaluations will be performed at the 
Day 2, 3, 6, 12, 16, 20, and 27 visit and again at Week 8 using a central laboratory.  
Safety will be assessed by consideration of all adverse events reported by or elicited from the 
subject, vital signs, 12-lead ECG, and abnormalities detected on hematology and serum chemistry 
tests. Worsening of other preexisting medical conditions and any changes to concomitant 
medications/treatments will also be taken into account in this evaluation. 
In addition to the planned times, any safety procedures can be performed at any time 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 8 visit will be recorded in the subject’s CRF. 


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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, i.e. the relationship cannot be ruled out and is 
judged by the investigator as at least possible (see definition below). 
An Unexpected Adverse Drug Reaction (UADR)/Unexpected Adverse Event (UAE) means an 
adverse reaction/event, the nature or severity of which is not consistent with the applicable 
product information, namely in the Investigator Brochure for an unauthorized investigational 
product or in the SmPC for an authorized product. 
The expected/unexpected status should be evaluated and assessed, by the Sponsor, based on the 
reference safety information available since expectedness in Pharmacovigilance refers strictly to 
the information listed or mentioned in the applicable reference safety information and not to 
event(s) that might be anticipated from knowledge of the pharmacological properties of a 
substance or because it was foreseeable due to the health status (e.g., age, medical history) of the 
study subjects. 
A Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) is defined as an AE that 
results in any of the following: 
• Results in death. 
• Is life-threatening. 
• Requires hospitalization or prolongs existing inpatient hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Results in a congenital abnormality or birth defect. 
• Is an important medical event that requires medical intervention to prevent any of the 
above outcomes. 
SUSARs: AEs that meet all of the following criteria will be classified as suspected unexpected 
serious adverse reactions (SUSARs): 
• Serious. 
• Unexpected (i.e., is not consistent with the applicable product information e.g. 
Investigator's brochure for an unapproved IMP or SmPC for an authorised product). 
• There is at least a reasonable possibility that there is attribution between the event and 
the medicinal product. 
Important medical events are those that may not be immediately life-threatening, but may 
jeopardize the subject and may require intervention to prevent one of the other serious outcomes 


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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 that hypothetically might 
have caused death if it were more severe. For example, drug-induced hepatitis that resolves 
without evidence of hepatic failure would not be considered life threatening even though drug-
induced hepatitis can be fatal. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital inpatient 
admission and/or prolongation of hospital stay were required for treatment of AE or occurred as a 
consequence of the event. It does not refer to pre-planned elective hospital admission for 
treatment of a pre-existing condition that has not significantly worsened, or to diagnostic 
procedures. 
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 8 visit must be followed 
until final resolution or until it is medically justifiable to stop further follow up (e.g. a chronic 
condition has been reached). Documentation of adverse events should be updated as necessary. 
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 11. Only 1 severity grade will be used for 
each AE (e.g. mild - moderate is not acceptable). 
Table 11: 
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 


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serious. For example, itching for several days may be rated as severe; however, may not be 
clinically serious. 
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 12. 
Table 12: 
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 8) must be recorded 
and reported immediately. All SAEs including those that are ongoing at the end of the Week 8 
visit will be followed until each event resolves or is assessed as chronic. 
In order to satisfy regulatory requirements, any SAE, 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 or fax. 
 
 
A 
 Pharmacovigilance Associate will notify the Sponsor and Sponsor's Responsible 
Physician of the SAE via email within 24 h of receipt of the initial SAE report. 
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. 
 


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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 to Week 8 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. 
14.3. 
Laboratory 
14.3.1. 
Routine Laboratory Assessments 
Routine laboratory safety samples will be analysed at screening and at each clinic visit as 
identified in (Table 10) for each subject by a central laboratory. A decision regarding whether a 
result outside the reference range is of clinical significance or not shall be made by an Investigator 
and the report will be annotated accordingly. Clinically significant abnormalities occurring during 
the study will be recorded on the AE page. The reference ranges for laboratory parameters will 
also be entered in the database and filed in the Investigator site file. 


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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. 
14.3.2. 
Expired Air Carbon Monoxide (CO) and Cotinine 
Expired CO will be obtained using a calibrated instrument (e.g. the Bedfont 
Micro+Smokerlyzer®) provided and maintained by the clinical site. Each clinical site must have 
documentation of instrument used and current calibration. CO values are to be reported in parts 
per million (ppm).  Cotinine will be determined by central laboratory. 
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. 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. 
15. 
SAFETY MONITORING  
15.1. 
 Independent Data Safety Monitor 
Safety monitoring will be performed by an independent Data Safety Monitor (DSM) who will be 
appointed for this study. The DSM will be an M.D. experienced in the treatment of adult smokers. 
The primary responsibility of the DSM will be to monitor for any unexpected safety risk for 
subjects on the protocol. The DSM will: 
• Review all SUSARs and SAEs reported to the Sponsor. The Sponsor will provide the 
DSM 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 DSM with copies of all expedited SAE reports submitted to regulatory 
agencies. 
• Perform periodic reviews of specific safety data for the study (e.g. moderate and higher 
adverse events). 
The DSM 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. The Sponsor 
and sites will not be unblinded unless the DSM requests that individual or other unblinding occurs 
due to a safety concern. 


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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 (i.e., when unblinding cannot induce bias in collection 
of data and interpretation of results). 
Detailed statistical specifications are to be documented in the Statistical Analysis Plan (SAP) and 
this SAP will be developed and finalized prior to initiation of any study unblinding. 
16.1. 
Statistical Design 
This study will be analyzed without specific statistical criteria. The overall study intent is to obtain 
effect outcomes and conduct estimates to further inform the design and plans for Phase 3 studies. 
16.2. 
Efficacy Outcomes 
The primary comparisons will be: Arm A versus Arm C, Arm B versus Arm C, Arm D versus 
Arm F, and Arm E versus Arm F (comparison of active arms to the associated placebo arm). 
The primary outcome Y is the percent of expected cigarettes smoked computed for each subject as 
follows: 
Let N=total of number of cigarettes smoked each day over the treatment period from 1 to 25 days. 
Let R=representation of the average number of cigarettes smoked daily over the 7-day screening 
period as baseline. 
Let T=number of post-randomization days where number of cigarettes smoked is recorded. 
Compute Y = 
100×𝑁𝑁
𝑇𝑇×𝑅𝑅 
The denominator is the expected number of cigarettes that would have been smoked without 
intervention over the days where the number of cigarettes smoked is recorded, and the numerator 
is 100 times the actual number of cigarettes smoked (the purpose of the 100 factor is to convert to 
a percent). 
The primary analyses will include all randomized subjects by randomized arm (intent-to-treat 
analysis). The four primary comparisons will be based on analysis of variance with main effects 
arm (2 levels for the arms to be compared) and BMI class (3 level stratification as previously 
specified), and with covariate of baseline cigarettes smoked. Sensitivity analyses will include the 
assessment of the contribution of interaction terms and effect modification analyses. Analyses of 
data associated with other objectives will be specified in a statistical analysis plan (SAP). 
16.3. 
Study Size 
The trial size is based on projected realization of the effect size estimate for the primary outcome 
based on data from a Phase 1/2 study in adult smokers. The primary outcome standard deviation 
from this study was found to be approximately 17. Based on this standard deviation, the estimated 
between-arm differences in the primary comparisons can be estimated with a 95% confidence 
interval that is ±8.3. 
The trial size will not have sensitivity for a dichotomous outcome (e.g. smoking cessation as the 
secondary efficacy outcome), other than for possibly large differences. For example, if the control 


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arm outcome is 12% (3/25 defined as successes), then the experimental arm will have a two-sided 
95% confidence interval for the probability difference that excludes zero when the success 
probability is 36% (8/50) or more (computation based on exact confidence interval). 
16.4. 
Safety Objective 
Safety assessments include reported adverse events, laboratory tests results, and vital signs. 
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 adverse event data will primarily be assessed for clinical safety. Data 
will be listed and summarized for each treatment according to measurement time. 
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, 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 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 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 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 to the Sponsor 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. 
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, who must be a physician, must 
explain the nature of the study and the treatment in such a manner that the subject is aware of 
his/her rights and responsibilities, as well as potential benefits and risks. The Investigator is also 
responsible for answering any questions the subject may have throughout the study and sharing 
any new information, in a timely manner, that may be relevant to the subject’s willingness to 
continue his/her participation in the trial. 
Subjects must also be informed that participation is voluntary and that they may withdraw from 
the study at any time, without prejudice to their current or future care. Documentation of the 
discussion and the date of informed consent should be recorded in the subject’s medical record or 
a study/clinic chart. Once all of their questions have been answered and they have voluntarily 
agreed to participate in the study, subjects will be asked to sign and date the Informed Consent 
Form. 
Subjects, or their legally authorized representatives, must give informed consent in writing prior 
to the performance of any protocol-specific procedure. Subjects who cannot give informed 
consent (i.e. mentally incompetent subjects or those physically incapacitated such as comatose 
subjects) are not to be recruited into the study. Subjects who are competent but physically unable 
to sign the consent form may have the document signed by their nearest relative or legal guardian. 
A copy of the signed Informed Consent Form will be provided to the subject. 
17.4. 
Subject Confidentiality 
The Investigator must attempt to assure that the subject’s 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. 
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). 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 schedule, 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: 
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. 


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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 
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. 


Protocol ACH-CYT-09, 15 April 2019, Ver 3.0 
 
Cytisine 
 CONFIDENTIAL 
 
63 
 
 
Protocol No. ACH-CYT-09 
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 
 
Sponsor’s Representative's name 
 
 
 
Signature 
 
Signature 
 
 
 
Date (ddmmYYYY) 
 
Date (ddmmYYYY) 
 
 
 
Institution 
 


Protocol ACH-CYT-09, 15 April 2019, Ver 3.0 
 
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64 
21. 
REFERENCES  
1. 
Etter J. Cytisine for smoking cessation: A literature review and a meta-analysis. Archives 
of Internal Medicine 2006;166:1553-9. 
2. 
Papke RL, Heinemann SF. Partial agonist properties of cytisine on neuronal nicotinic 
receptors containing the beta 2 subunit. Molecular pharmacology 1994;45:142-9. 
3. 
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. 
4. 
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. 
5. 
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. 
6. 
Walker N, Howe C, Glover M, et al. Cytisine versus nicotine for smoking cessation. The 
New England journal of medicine 2014;371:2353-62. 
7. 
World Health Organization. WHO report on the global tobacoo epidemic, 2017: 
monitoring tobacco use and prevention policies. Geneva 2017. 
8. 
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. 
9. 
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. 
10. 
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. 
11. 
Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. Antidepressants for 
smoking cessation. The Cochrane database of systematic reviews 2014:Cd000031. 
12. 
Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. 
The Cochrane database of systematic reviews 2012;11:Cd000146. 
13. 
Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking 
cessation: an overview and network meta-analysis. The Cochrane database of systematic reviews 
2013:Cd009329. 
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. 
Osman A, Bagge CL, Gutierrez PM, Konick LC, Kopper BA, Barrios FX. The Suicidal 
Behaviors Questionnaire-Revised (SBQ-R): validation with clinical and nonclinical samples. 
Assessment 2001;8:443-54. 
18. 
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. 
19. 
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. 


Protocol ACH-CYT-09, 15 April 2019, Ver 3.0 
 
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65 
20. 
Heishman SJ, Singleton EG, Pickworth WB. Reliability and validity of a Short Form of 
the Tobacco Craving Questionnaire. Nicotine & tobacco research : official journal of the Society 
for Research on Nicotine and Tobacco 2008;10:643-51. 
21. 
Stern AF. The hospital anxiety and depression scale. Occupational medicine (Oxford, 
England) 2014;64:393-4. 


Protocol ACH-CYT-09, 15 April 2019, Ver 3.0 
 
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66 
APPENDIX 1. SUICIDAL BEHAVIORS QUESTIONNAIRE-REVISED 
(SBQ-R) 
The Suicidal Behaviors Questionnaire-Revised (SBQ-R)17 provides a broad range of information 
in a brief administration. Responses can be used to identify at-risk individuals and specific risk 
behaviors. This questionnaire must be completed by all potential study subjects during screening. 
A score ≥7 indicates potential for suicidal ideation and would confirm study exclusion criteria #8. 
This questionnaire must also be completed by all study subjects at the Day 27 (End of Treatment) 
and Week 8 clinic visits to monitor for any potential suicidal ideation or behaviour during the 
study as a safety parameter. An SBQ-R score ≥7 will be used to identify at-risk individuals who 
will need immediate evaluation by site personnel for any potential suicidal ideation. Any potential 
suicidal ideation or behavior will be considered an SAE. 
Copies of this questionnaire and details for interpretation and scoring will be provided in the study 
Procedure Manual and completed questionnaires must be present as source documents. Any 
subject meeting this exclusion must be followed by the clinical site according to site policies. 
 
1. Have you ever thought about or attempted to kill yourself? (check one only) 
□ 1.  Never 
□ 2.  It was just a brief passing thought 
□ 3a.  I have had a plan at least once to kill myself but did not try to do it 
□ 3b.  I have had a plan at least once to kill myself and really wanted to die 
□ 4a.  I have attempted to kill myself, but did not want to die 
□ 4b.  I have attempted to kill myself, and really hoped to die 
2. How often have you thought about killing yourself in the past year? (check one only) 
□ 1.  Never 
□ 2.  Rarely (1 time) 
□ 3.  Sometimes (2 times) 
□ 4.  Often (3-4 times) 
□ 5.  Very Often (5 or more times) 
3. Have you ever told someone that you were going to commit suicide, or that you might do 
it? (check one only) 
□ 1.  No 
□ 2a.  Yes, at one time, but did not really want to die 
□ 2b.  Yes, at one time, and really wanted to die 
□ 3a.  Yes, more than once, but did not want to do it 
□ 3b.  Yes, more than once, and really wanted to do it 
4. How likely is it that you will attempt suicide someday? (check one only) 
□ 0.  Never 
□ 1.  No chance at all 
□ 2.  Rather unlikely 
□ 3.  Unlikely 
□ 4.  Likely 
□ 5.  Rather likely 
□ 6.  Very likely 
 


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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 dependence18 and will be administered at the randomization visit only. Copies 
of this FTND will be provided in the study Procedure Manual. 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)19 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. Copies of this questionnaire will be provided in the study Procedure 
Manual. 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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APPENDIX 4. SHORT FORM OF THE TOBACCO CRAVING 
QUESTIONNAIRE 
 
The short form of the Tobacco Craving Questionnaire has been validated as a self-report 
instrument to measure tobacco craving20 and will be administered to study subjects at 
randomization and each clinic visit (Days 2, 3, 6, 12, 16, 20, 27, and Weeks 5, 6, 7, and 8). Copies 
of this questionnaire will be provided in the study Procedure Manual. Analysis of results is 
outlined in the study Statistical Analysis Plan. 
 
Question 
Response 
 
Strongly Disagree....Strongly Agree 
Factor 1 (emotionality) 
I would be less irritable now if I could smoke. 
 
 
 
 
 
 
 
If I were smoking now I could think more clearly. 
 
 
 
 
 
 
 
I could control things better right now if I could smoke. 
 
 
 
 
 
 
 
Factor 2 (expectancy) 
I would enjoy a cigarette right now. 
 
 
 
 
 
 
 
A cigarette would taste good right now. 
 
 
 
 
 
 
 
Smoking a cigarette would be pleasant. 
 
 
 
 
 
 
 
Factor 3 (compulsivity) 
If I smoked right now, I would not be able to stop. 
 
 
 
 
 
 
 
I could not stop myself from smoking if I had some 
cigarettes here. 
 
 
 
 
 
 
 
I would not be able to control how much I smoked if I 
had some cigarettes here. 
 
 
 
 
 
 
 
Factor 4 (purposefulness) 
If I had a lit cigarette in my hand, I probably would 
smoke it. 
 
 
 
 
 
 
 
It would be hard to pass up the chance to smoke. 
 
 
 
 
 
 
 
I could not easily limit how much I smoked right now. 
 
 
 
 
 
 
 


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APPENDIX 5. HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) 
The HADS questionnaire21 has been validated as a self-report instrument to measure levels of 
anxiety and depression and will be administered to study subjects at Screening Visit #1, at the Day 
12, Day 27 (End-of-Treatment visit) and again at Week 8. Copies of this questionnaire will be 
provided in the study Procedure Manual. 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 
 
 
 
 
 
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-09, 15 April 2019, Draft Ver 3.0 
 
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71 
APPENDIX 6. ALCOHOL USE QUESTIONNAIRE 
 
The following questions will be administered to study subjects at randomization and again at 
Week 8 upon completing the Follow-up Assessment Period. Copies of this questionnaire will be 
provided in the study Procedure Manual. Analysis of results is exploratory and outlined in the 
study Statistical Analysis Plan. 
 
1. Over the past 7 days, how often did you have a drink containing alcohol? Consider a 
“drink” to be a can or a bottle of beer, a glass of wine, a wine cooler, or one cocktail or a 
shot of hard liquor (like scotch, gin, or vodka). 
o Never 
o 2 to 3 times 
o 4 to 5 times 
o 6 or more times 
o Don’t know 
2. If you did drink in the past 7 days, how many drinks did you have on a typical day when 
you drank alcohol? 
o 1 to 2 drinks 
o 3 to 4 drinks 
o 5 to 6 drinks 
o 7 to 9 drinks 
o 10 or more drinks 
o Don’t know 
3. If you did drink in the past 7 days, how often did you have 6 or more drinks on one 
occasion? 
o Never 
o Daily or almost daily 
o Don’t know 
 


Protocol ACH-CYT-09, 15 April 2019, Draft Ver 3.0 
 
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 CONFIDENTIAL 
 
72 
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) a master’s level or higher degree in some sort of 
counseling profession (e.g. health educator, chemical dependence counselor) or b) completed a 
tobacco treatment training course of at least 4 hours. 
At the Screening Visit #2 visit, subjects will be provided behavioral support and assistance in 
developing a quit plan. Most importantly this ensures the subject’s quit date is chosen prior to 
randomization and that they are planning on trying to quit smoking. Site counselor(s) are to 
encourage subjects to continue study drug as scheduled even if they lapse and have a cigarette 
after their quit date. It is important during this “grace” period for the subjects to keep trying to 
quit as planned. It is also important to reiterate to each subject that the purpose of this study is to 
evaluate the potential benefits of cytisine in achieving abstinence even after a lapse or “slip” 
during study treatment because cytisine is thought to block the effects of nicotine. 
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 (e.g. 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 will receive up to 12 behavioral support sessions by a qualified staff member, starting at 
the Screening Visit #2, again at randomization and then continuing through each clinic visit up to 
the Week 8 visit. 
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 cytisine and able to clearly review and discuss these topics with the study subject. 
Subjects will be encouraged to “keep trying” if they experience set-backs or a “lapse” during 
treatment. Each session should last up to 10 minutes. 
Practical counseling (problem solving/skills training) should be given. Topics include, but are 
not limited to, the following: 
• Abstinence–Striving for total abstinence is essential. Not even a single puff after the 
quit date. 
• Past quit experience–Identify what helped and what hurt in previous quit attempts. 
Build on past success. 
• Anticipate triggers or challenges in the upcoming attempt–Discuss challenges/triggers 
and how the subject will successfully overcome them (e.g., avoid triggers, alter 
routines). 


Protocol ACH-CYT-09, 15 April 2019, Draft Ver 3.0 
 
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73 
• 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 (i.e. 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 (i.e. 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? 
• How will I handle withdrawal symptoms? 
• What are my stress triggers for cravings? 
• How will I deal with these stressors instead of smoking? 
• What are my biggest concerns/fears about quitting smoking? 
• How will I remember to take my medication as directed? 
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 
V. 2.0 29-MAY-2019 
 
 
 
 
 
Page 1 of 131     
 
SPONSOR: 
Achieve Life Sciences, Inc. 
PREPARED BY: 
 
 
PROTOCOL TITLE: 
A Multicenter, Double-blind, Randomized, Placebo-controlled Phase 2b 
Trial of Cytisine in Adult Smokers 
(ACH-CYT-09) 
PROTOCOL (v.# date): 
V 2.0 26-September-2018 
SAP (v.# date): 
V 2.0 29-May-2019 
 
 
 
 
 
 
 


STA TlSTICAL ANALYSIS PLAN 
V. 2.0 29-MAY-2019
APPROVAL SIGNATURES: 
	 
By sign mg !his Ďction. t.hc individ1rnls below agree that Iď hine re, iewed !he Đcope of the 
effort described in this Smtislical Analysis Plw:i for tlie ACH-CYT-09 studđ. The signatures 
below 
 
 
 
 
 
 
 
 
 
tf
 
"uge 2 nl 131 


STATISTICAL ANALYSIS PLAN 
V. 2.0 29-MAY-2019 
 
 
 
 
 
Page 3 of 131     
 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
ADR 
Adverse Drug Reaction 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CM 
Concomitant Medication 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
FTND 
Fagerstrom Test of Nicotine Dependence 
HADS 
Hospital Anxiety and Depression Scale 
ICH 
International Conference on Harmonization 
LS Mean 
Least Squares Mean 
mg 
milligrams 
MH 
Medical History 
NMR 
Nicotine Metabolite Ratio 
RTF 
Rich Text Format 
SAP 
Statistical Analysis Plan 
SBQ-R 
Suicidal Behaviors Questionnaire-Revised 
SDTM 
Study Data Tabulation Model 
SEQ-12 
Smoking Self Efficacy Questionnaire 
SE 
Standard Error 
SI 
Système International 
SOC 
MedDRA System Organ Class 
SV1 
Screening Visit #1 
SV2 
Screening Visit #2 
TEAE 
Treatment Emergent Adverse Event 
tid 
Three Times Daily 
 
 
 


STATISTICAL ANALYSIS PLAN 
V. 2.0 29-MAY-2019 
 
 
 
 
 
Page 4 of 131     
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION ......................................................................................................12 
2. 
STUDY DESCRIPTION ............................................................................................12 
2.1. 
Study Design ...............................................................................................................12 
2.2. 
Treatment Schedules ...................................................................................................14 
2.3. 
Study Population .........................................................................................................14 
3. 
STUDY OBJECTIVES ..............................................................................................15 
3.1. 
Primary Efficacy Objectives .......................................................................................15 
3.2. 
Other Efficacy Objective(s) ........................................................................................15 
3.3. 
Safety Objective(s) .....................................................................................................15 
3.4. 
Subject Selection ........................................................................................................16 
3.5. 
Determination of Sample Size ....................................................................................16 
3.6. 
Treatment Assignment ................................................................................................16 
3.7. 
Administration of Study Medication ..........................................................................16 
4. 
EFFICACY AND SAFETY ENDPOINTS ................................................................16 
4.1. 
Efficacy Endpoints ......................................................................................................16 
4.1.1. 
Primary Efficacy Endpoint .........................................................................................17 
4.1.2. 
Other Efficacy Endpoints ...........................................................................................17 
4.2. 
Safety Endpoints .........................................................................................................19 
4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations ................................................19 
5. 
TRIAL CONDUCT CONSIDERATIONS.................................................................20 
5.1. 
Changes in Inclusion and Exclusion Criteria ..............................................................20 
5.2. 
Interim Analysis and Early Stopping ..........................................................................20 
5.3. 
Sample Size Adjustment .............................................................................................20 
6. 
DATA ANALYSIS CONSIDERATIONS .................................................................20 
6.1. 
General Considerations ...............................................................................................20 
6.2. 
Definition of Analysis Timepoints .............................................................................21 
6.3. 
Data Handling Rules ...................................................................................................22 
6.3.1. 
Missing Dates .............................................................................................................22 


STATISTICAL ANALYSIS PLAN 
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6.4. 
Analysis Sets ...............................................................................................................23 
6.5. 
Key Study Endpoints ..................................................................................................23 
6.6. 
Sensitivity Analyses ....................................................................................................24 
6.7. 
Interactions and Covariates .........................................................................................24 
7. 
SUBJECT DISPOSITION ..........................................................................................24 
7.1. 
Protocol Deviations ....................................................................................................25 
8. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....................25 
8.1. 
Demographics .............................................................................................................26 
8.2. 
Medical and Psychiatric History .................................................................................26 
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 ..................................................................28 
9.1. 
Duration of Study Drug Treatment .............................................................................28 
9.2. 
Study Drug Compliance .............................................................................................28 
9.3. 
Behavioral Support Compliance .................................................................................28 
10. 
EFFICACY ANALYSIS ............................................................................................29 
10.1. 
Analyses of Primary Efficacy Endpoint .....................................................................29 
10.1.1. 
Primary Efficacy Analysis ..........................................................................................29 
10.1.2. 
Sensitivity Analyses ....................................................................................................30 
10.1.3. 
Smoking Diary Compliance .......................................................................................31 
10.2. 
Analyses of Other Efficacy Endpoints .......................................................................31 
10.2.1. 
Abstinence from Week 5 to Week 8 ...........................................................................32 
10.2.2. 
Sensitivity Analyses for Abstinence from Week 5 to Week 8 ...................................32 
10.2.3. 
Initial Quit Rates .........................................................................................................33 
10.2.4. 
7-day Point Prevalence ...............................................................................................33 
10.2.5. 
Time to Failure to Maintain Abstinence Through Week 8 .........................................33 
10.2.6. 
Relationship Between Outcome Variables and Smoking Cessation ..........................33 


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10.2.7. 
Relationship Between Outcome Variables and Nicotine Metabolite Ratio 
(NMR) .........................................................................................................................34 
10.2.8. 
Questionnaires ............................................................................................................34 
11. 
SAFETY ANALYSIS ................................................................................................34 
11.1. 
Adverse Events ...........................................................................................................34 
11.2. 
Serious Adverse Events ..............................................................................................36 
11.3. 
Definition of Treatment Emergent Adverse Events and Serious Adverse 
Events .........................................................................................................................36 
11.4. 
Laboratory Data ..........................................................................................................37 
11.5. 
Vital Signs and Weight ...............................................................................................37 
11.6. 
12-Lead ECG Interpretation .......................................................................................38 
11.7. 
Concomitant Medications ...........................................................................................38 
12. 
PHARMACOKINETIC ANALYSES ........................................................................38 
13. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ...............................................................................................................38 
14. 
REFERENCES ...........................................................................................................39 
15. 
TABLE, LISTING AND FIGURES...........................................................................40 
Table 14.1.1 Enrollment. ....................................................................................................................41 
Table 14.1.2 Subject Disposition. ........................................................................................................42 
Table 14.1.3 Subject Disposition: Analysis Sets by Site. .......................................................................44 
Table 14.1.4 Subject Attendance by Visit. All Randomized Analysis Set. ................................................45 
Table 14.1.5 Protocol Deviations  All Randomized Analysis Set ............................................................46 
Table 14.1.6.1 Demographics and Baseline Characteristics. Screening Analysis Set...............................47 
Table 14.1.6.2 Demographics and Baseline Characteristics. All Randomized Analysis Set. .....................49 
Table 14.1.6.3 Demographics and Baseline Characteristics. Safety Analysis Set. ...................................51 
Table 14.1.7 Medical and Psychiatric History. All Randomized Analysis Set. ..........................................52 
Table 14.1.8 Prior Medications. All Randomized Analysis Set. ..............................................................53 
Table 14.1.9.1 Smoking History. All Randomized Analysis Set. .............................................................54 
Table 14.1.9.2 Baseline Smoking and Nicotine Testing. All Randomized Analysis Set. ............................56 
Table 14.1.9.3 Smoking History: Pooled Treatment Arms. All Randomized Analysis Set. .........................57 


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Table 14.1.9.4 Baseline Smoking and Nicotine Testing: Pooled Treatment Arms. All Randomized 
Analysis Set. .................................................................................................................59 
Table 14.1.10 Baseline Questionnaires. All Randomized Analysis Set. ..................................................60 
Table 14.1.11 Baseline Vital Signs. All Randomized Analysis Set. .........................................................63 
Table 14.1.12 Baseline 12-lead ECG Data. All Randomized Analysis Set. ..............................................64 
Table 14.2.1.1 Descriptive Summary of Primary Efficacy Cigarette Consumption Data. Schedule: 
Commercial. All Randomized Analysis Set. ......................................................................65 
Table 14.2.1.2 Descriptive Summary of Primary Efficacy Cigarette Consumption Data. Schedule: 
tid. All Randomized Analysis Set. ....................................................................................66 
Table 14.2.1.3 Primary Efficacy Analysis: ANOVA for Percent of Expected Cigarettes Smoked. 
Schedule: Commercial.  All Randomized Analysis Set. ......................................................67 
Table 14.2.1.4 Primary Efficacy Analysis: ANOVA for Percent of Expected Cigarettes Smoked. 
Schedule: tid.  All Randomized Analysis Set. ....................................................................68 
Table 14.2.2.1 Sensitivity Analysis for Primary Endpoint: ANOVA with Interaction Term for Percent 
of Expected Cigarettes Smoked. Schedule: Commercial.  All Randomized Analysis 
Set. ..............................................................................................................................69 
Table 14.2.2.2 Sensitivity Analysis for Primary Endpoint: ANOVA with Interaction Term for Percent 
of Expected Cigarettes. Smoked. Schedule: tid.  All Randomized Analysis Set. ...................70 
Table 14.2.2.3 Sensitivity Analysis for Primary Endpoint: ANOVA for Percent of Expected 
Cigarettes Smoked - Comparison between Placebo Arms. All Randomized Analysis 
Set. ..............................................................................................................................71 
Table 14.2.2.4 Sensitivity Analysis for Primary Endpoint: ANOVA for Percent of Expected 
Cigarettes Smoked Using Pooled Placebo Arms. Schedule: Commercial. All 
Randomized Analysis Set. ..............................................................................................72 
Table 14.2.2.5 Sensitivity Analysis for Primary Endpoint: ANOVA for Percent of Expected 
Cigarettes Smoked Using Pooled Placebo Arms. Schedule: tid. All Randomized 
Analysis Set. .................................................................................................................73 
Table 14.2.3.1 Smoking Diary Compliance. Schedule: Commercial. All Randomized Analysis Set. ...........74 
Table 14.2.3.2 Smoking Diary Compliance. Schedule: tid. All Randomized Analysis Set. .........................75 
Table 14.2.4.1 Other Efficacy Endpoint: Abstinence from Week 5 to Week 8. Schedule: 
Commercial. All Randomized Analysis Set. ......................................................................76 
Table 14.2.4.2 Other Efficacy Endpoint: Abstinence from Week 5 to Week 8. Schedule: tid. All 
Randomized Analysis Set. ..............................................................................................77 
Table 14.2.5.1 Other Efficacy Endpoint: Sensitivity Analysis for Abstinence from Week 5 to Week 
8- Comparison between Placebo Arms.  All Randomized Analysis Set. ...............................78 


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Table 14.2.5.2 Other Efficacy Endpoint: Sensitivity Analysis for Abstinence from Week 5 to Week 
8 Using Pooled Placebo Arms. Schedule: Commercial. All Randomized Analysis Set. .........79 
Table 14.2.5.3 Other Efficacy Endpoint: Sensitivity Analysis for Abstinence from Week 5 to Week 
8 Using Pooled Placebo Arms. Schedule: tid. All Randomized Analysis Set. .......................79 
Table 14.2.6.1 Other Efficacy Endpoint: Initial Quit Rate. Schedule: Commercial. All Randomized 
Analysis Set. .................................................................................................................80 
Table 14.2.6.2 Other Efficacy Endpoint: Initial Quit Rate. Schedule: tid. All Randomized Analysis 
Set. ..............................................................................................................................80 
Table 14.2.7.1 Other Efficacy Endpoint: 7-day Point Prevalence at Week 5, Week 6, Week 7 and 
Week 8. Schedule: Commercial. All Randomized Analysis Set. ..........................................81 
Table 14.2.7.2 Other Efficacy Endpoint: 7-day Point Prevalence at Week 5, Week 6, Week 7 and 
Week 8. Schedule: tid. All Randomized Analysis Set. ........................................................81 
Table 14.2.8.1 Other Efficacy Endpoint: Time to Failure to Maintain Abstinence Through Week 8 
Summary. Schedule: Commercial. All Randomized Analysis Set. .......................................82 
Table 14.2.8.2 Other Efficacy Endpoint: Time to Failure to Maintain Abstinence Through Week 8 
Summary. Schedule: tid. All Randomized Analysis Set. .....................................................82 
Table 14.2.9.1 Other Efficacy Endpoint: HADS, SBQ-R and Tobacco Craving Questionnaires 
Summary. Schedule: Commercial. All Randomized Analysis Set. .......................................83 
Table 14.2.9.2 Other Efficacy Endpoint: HADS, SBQ-R and Tobacco Craving Questionnaires 
Summary. Schedule: tid. All Randomized Analysis Set. .....................................................86 
Table 14.2.10.1 Other Efficacy Endpoint: Alcohol Use Questionnaire Summary. Schedule: 
Commercial. All Randomized Analysis Set. ......................................................................87 
Table 14.2.10.2 Other Efficacy Endpoint: Alcohol Use Questionnaire Summary. Schedule: tid. All 
Randomized Analysis Set. ..............................................................................................88 
Table 14.3.1.1.1 Study Drug Treatment Duration and Compliance. Safety Analysis Set. ..........................89 
Table 14.3.1.1.2 Behavioral Support Compliance Safety Analysis Set ....................................................91 
Table 14.3.1.2.1 Adverse Events: Overall Summary Safety Analysis Set. ...............................................92 
Table 14.3.1.2.2 Treatment-Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term. Safety Analysis Set. ...............................................................................94 
Table 14.3.1.2.3 Treatment Emergent Adverse Events by MedDRA Preferred Term. Safety 
Analysis Set. .................................................................................................................95 
Table 14.3.1.3 Treatment Emergent Adverse Events Leading to Dose Reduction or Premature 
Discontinuation of Study Drug by MedDRA Preferred Term. Safety Analysis Set. ................96 
Table 14.3.1.4.1 Related Treatment-Emergent Adverse Events by MedDRA System Organ Class 
and Preferred Term. Safety Analysis Set. .........................................................................97 


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Table 14.3.1.4.2 Related Treatment Emergent Adverse Events by MedDRA Preferred Term. 
Safety Analysis Set. .......................................................................................................98 
Table 14.3.1.5 Incidence of Treatment Emergent AEs by MedDRA Preferred Term and Severity.  
Safety Analysis Set. .......................................................................................................99 
Table 14.3.1.6 Incidence of Treatment Emergent Adverse Events by MedDRA Preferred Term and 
Relationship.  Safety Analysis Set. ................................................................................100 
Table 14.3.2.1 Serious Adverse Events by MedDRA System Organ Class and Preferred Term. 
Safety Analysis Set. .....................................................................................................101 
Table 14.3.2.2 Serious Adverse Events by MedDRA Preferred Term. Safety Analysis Set. ....................101 
Table 14.3.4.1 Clinical Laboratory Data Summary of Actual Values and Change from Baseline by 
Visit: Hematology. Safety Analysis Set. ..........................................................................102 
Table 14.3.4.2 Clinical Laboratory Data Summary of Actual Values and Change from Baseline by 
Visit: Serum Chemistry. Safety Analysis Set. ..................................................................103 
Table 14.3.4.3 Clinical Laboratory Shifts from Baseline to Post-Baseline Range by Visit: 
Hematology. Safety Analysis Set. ..................................................................................104 
Table 14.3.4.4 Clinical Laboratory Shifts from Baseline to Post-Baseline Range by Visit: Serum 
Chemistry. Safety Analysis Set. .....................................................................................105 
Table 14.3.4.5 Vital Signs: Actual Values and Change from Baseline by Visit. Safety Analysis Set. ........106 
Table 14.3.4.6 Potentially Clinically Significant Vital Signs Post-Baseline. Safety Analysis Set. ..............107 
Table 14.3.4.7 12-Lead Electrocardiogram Results by Visit. Safety Analysis Set. ..................................108 
Table 14.3.4.8 Concomitant Medications. Safety Analysis Set. ............................................................109 
Listing 16.2.1.1 Subject Disposition and Completion Status. ...............................................................110 
Listing 16.2.1.2 Subject Disposition: Subjects Who Discontinued IMP or Withdrew from Study and 
Reasons for Discontinuation/Withdrawal. .......................................................................111 
Listing 16.2.1.3 Subject Disposition: Analysis Sets.  Screening Analysis Set. ........................................112 
Listing 16.2.2.1 Subject Disposition: Protocol Deviations. ...................................................................113 
Listing 16.2.2.2 Subject Disposition: Inclusion/Exclusion Criteria. ........................................................114 
Listing 16.2.3.1 Demographics. ........................................................................................................115 
Listing 16.2.3.2 Medical and Psychiatric History. ................................................................................116 
Listing 16.2.3.3 Smoking History. ......................................................................................................117 
Listing 16.2.3.4 Baseline Cigarette Smoking and Nicotine Testing. ......................................................118 
Listing 16.2.4 Subject Diary: Cigarette Consumption from Screening to Last Treatment Day (Day 
25). .............................................................................................................................119 


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Listing 16.2.5 Study Drug Administration and Compliance. Safety Analysis Set. ...................................120 
Listing 16.2.6 Behavioral Support Session Attendance. Safety Analysis Set .........................................121 
Listing 16.2.7.1 Adverse Events. ......................................................................................................122 
Listing 16.2.7.2 Adverse Events Leading to Dose Reductions or Discontinuation of Study Drug. ............123 
Listing 16.2.7.3 Serious Adverse Events. ..........................................................................................124 
Listing 16.2.8.1 Clinical Laboratory Results: Hematology. ...................................................................125 
Listing 16.2.8.2 Clinical Laboratory Results: Chemistry. ......................................................................125 
Listing 16.2.9.1 Vital Signs. ..............................................................................................................126 
Listing 16.2.9.2 Vital Signs for Subjects with at Least One Potentially Clinically Significant Vital 
Sign. ...........................................................................................................................126 
Listing 16.2.10 12-Lead ECG Interpretation. ......................................................................................127 
Listing 16.2.11 Prior and Concomitant Medications. ...........................................................................127 
Figure 14.2.1.1 Side-by-Side Box Plot of Percent of Expected Cigarettes Smoked by Treatment 
Arm. Schedule: Commercial. All Randomized Analysis Set. .............................................128 
Figure 14.2.1.2 Side-by-Side Box Plot of Percent of Expected Cigarettes Smoked by Treatment 
Arm. Schedule: tid. All Randomized Analysis Set. ...........................................................128 
Figure 14.2.2.1 Side-by-Side Box Plot of Percent of Expected Cigarettes Smoked by Treatment 
Arm and BMI Class. Schedule: Commercial. All Randomized Analysis Set........................128 
Figure 14.2.2.2 Side-by-Side Box Plot of Percent of Expected Cigarettes Smoked by Treatment 
Arm and BMI Class. Schedule: tid. All Randomized Analysis Set. .....................................128 
Figure 14.2.3.1 Kaplan-Meier Plot of Time to Last Recorded Data for Abstinence Endpoints. 
Schedule: Commercial. All Randomized Analysis Set. .....................................................128 
Figure 14.2.3.2 Kaplan-Meier Plot of Time to Last Recorded Data for Abstinence Endpoints. 
Schedule: tid. All Randomized Analysis Set. ...................................................................128 
Figure 14.2.4.1 Primary Efficacy Analysis: 95% Confidence Intervals for Least Squares Means. 
Schedule: Commercial. All Randomized Analysis Set. .....................................................128 
Figure 14.2.4.2 Primary Efficacy Analysis: 95% Confidence Intervals for Least Squares Means. 
Schedule: tid. All Randomized Analysis Set. ...................................................................129 
Figure 14.2.4.3 Sensitivity Analysis for Primary Endpoint: 95% Confidence Intervals for Least 
Squares Means. Schedule: Commercial. All Randomized Analysis Set. ............................129 
Figure 14.2.4.4 Sensitivity Analysis for Primary Endpoint: 95% Confidence Intervals for Least 
Squares Means. Schedule: tid. All Randomized Analysis Set. ..........................................129 
Figure 14.2.5.1 Kaplan-Meier Plot of Time to Failure to Maintain Abstinence Through Week 8. 
Schedule: Commercial. All Randomized Analysis Set. .....................................................129 


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Figure 14.2.5.2 Kaplan-Meier Plot of Time to Failure to Maintain Abstinence Through Week 8. 
Schedule: tid. All Randomized Analysis Set. ...................................................................129 
Figure 14.2.6.1 Plot of Number of Cigarettes Smoked and Expired CO Concentration vs Study 
Day. Schedule: Commercial. All RandomizedAnalysis Set. ..............................................130 
Figure 14.2.6.2 Plot of Number of Cigarettes Smoked and Expired CO Concentration vs Study 
Day. Schedule: tid. All RandomizedAnalysis Set. ............................................................130 
Figure 14.2.7.1 Plot of Expired CO Concentration vs Study Day. Schedule: Commercial. All 
RandomizedAnalysis Set. .............................................................................................130 
Figure 14.2.7.2 Plot of Expired CO Concentration vs Study Day. Schedule: tid. All 
RandomizedAnalysis Set. .............................................................................................131 
 


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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-09: “A Multicenter, Double-blind, 
Randomized, Placebo-controlled Phase 2b Trial of Cytisine in Adult Smokers”, Version 2.0 
(26-September-2018).  
This SAP was prepared by 
 under the direction of the study sponsor, 
Achieve Life Sciences Inc. (Achieve). It includes details of data handling procedures and 
statistical methodology. The final statistical analyses will proceed in accordance with this SAP as 
approved by both Achieve and 
Any deviation from this SAP will be documented in the 
final CSR. Any deviations from methods described in the protocol are also detailed and 
explained in this SAP. 
For this study, 
is responsible for programming of datasets. 
will provide to 
Achieve the Study Data Tabulation Model (SDTM) as well as Analysis Data Model (ADaM) 
dataset specifications based on: 
• SDTM Model 1.4 and SDTM Implementation Guide (SDTM IG) version 3.2. 
• ADaM Model 2.1 and ADaM Implementation Guide (ADaM IG) version 1.1. 
In addition to the protocol, the following documents were reviewed in preparation of this SAP: 
• Electronic Case Report Form (eCRF) version 2.1, 27-Feb-2019 
• eCRF Completion Guidelines version 1.1, 28-Feb-2019 
• Data Management Plan version 1.0, 05-Sep-2018 
• Study Design Specification version 2.1, 27-Feb-2019 
2. 
STUDY DESCRIPTION 
2.1. 
Study Design 
This Phase 2b study is a six-arm, multicenter, randomized, double-blind, placebo-controlled, and 
parallel-design trial of the safety and efficacy of cytisine in adult cigarette smokers who are 
willing to set a quit date that is 5-7 days after being randomized on the study. A total of 
250 subjects are planned to be randomized at the ratio 2:1 to cytisine treatment and the respective 
placebo treatment as designated by the protocol defined schedule (i.e. the commercial titrated 
schedule vs the simplified three times daily (tid) schedule) for 25 days. Subjects will be stratified 
at randomization based on BMI class (18.5 to <25 kg/m2; 25 to <30 kg/m2; 30 to <35 kg/m2) as 
defined in the protocol. The six treatment arms will be: 


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Figure 1: 
Study Design Overview
 
The study will be comprised of a pre-study screen, followed by twenty-five (25) days of study 
treatment, an end-of-treatment visit at Week 4 (Day 27 ± 2 days), and weekly post-treatment 
follow up visits from Week 5 to Week 8 post-randomization. 
Blinding  
• The study will be double-blinded to dose (1.5 mg cytisine, 3.0 mg cytisine, placebo) 
but not to the administration schedule (commercial titration schedule, simplified tid 
schedule).  
• Sponsor and contract research personnel responsible for collecting, monitoring and 
analyzing the study data will also be blinded to dose but not to administration 
schedule. 
• In order to blind the study treatment dose, all subjects will take 2 tablets at every 
scheduled dosing. Subjects randomly assigned to Arm A or Arm D will take one 
1.5 mg cytisine tablet and one placebo tablet at each dosing. Arm B or Arm E 
subjects will take two 1.5 mg cytisine tablets at each dosing. Arm C and Arm F 
subjects will receive two placebo tablets at each daily scheduled dosing to correspond 
to cytisine dosing. 
Randomization  
• Eligible subjects will be randomized 2:1 in a blinded manner to either Arm A or 
Arm B vs Arm C (2:1 randomization) or Arm D or Arm E vs Arm F (2:1 
randomization)  


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• Subjects will be stratified at randomization by BMI class (18.5 to <25 kg/m2; 25 to 
<30 kg/m2; 30 to <35 kg/m2).  
• Unique subject number and randomization code will be assigned to each study subject  
• Parallel group design 
Multicenter Trial 
• This study will be conducted at multiple sites across the US 
Type of Comparison 
• Superiority in favor of cytisine 
2.2. 
Treatment Schedules  
For the 25-day commercial titration schedule, study drug will be administered according to the 
following schedule: 
Treatment Day 
Daily Administration 
Approximate Interval 
1-3 
6 times daily 
2 hours 
4-12 
5 times daily 
2.5 hours 
13-16 
4 times daily 
3 hours 
17-20 
3 times daily 
4-5 hours 
21-24 
2 times daily 
6 hours 
25 
1 time only 
- 
 
For the tid schedule, study drug will be administered according to the following schedule: 
Treatment Day 
Daily Administration 
Approximate Interval 
1-20 
3 times daily 
4-5 hours 
21-24 
2 times daily 
6 hours 
25 
1 time only 
- 
All subjects will receive 2 tablets for each dose according to their randomization arm.  
Subjects that work overnight will potentially be taking their daily administered dose over two 
calendar days. This is accounted for in the CRF and the date of their first dose taken will be 
recorded as the dosing start date. 
2.3. 
Study Population  
Approximately 250 subjects who are daily cigarette smokers intending to make a quit attempt 
during the study will be enrolled at multiple study sites within the US. Based on the planned 2:1 
(cytisine:placebo) randomization, it is expected that 200 subjects will be randomized to receive 


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cytisine (50 subjects at each cytisine treatment arm) and 50 subjects will be randomized to 
receive placebo (25 subjects per treatment schedule).  
3. 
STUDY OBJECTIVES 
3.1. 
Primary Efficacy Objectives 
The primary efficacy objectives of this study are: 
1. Assess whether subjects randomized to cytisine, administered using the commercial 
titration schedule, have a greater overall reduction in cigarette smoking during the study 
treatment period (Day 1 – 25) compared to subjects randomized to the same titration 
schedule of a placebo.  
2. Assess whether subjects randomized to cytisine, using a simplified tid schedule, have a 
greater overall reduction in cigarette smoking during the study treatment period 
(Day 1 - 25) compared to subjects randomized to the same tid schedule of a placebo.  
3.2. 
Other Efficacy Objective(s) 
Each of the following will include comparisons for 1.5 mg or 3.0 mg doses versus placebo when 
given as the commercial 25-day titration schedule and for the tid treatment schedule (as well as 
comparisons between the commercial 25-day titration versus tid treatment schedules). The other 
efficacy objectives are: 
1. Assess the probability of abstinence from Week 5 to Week 8 post-randomization in 
subjects randomized to cytisine as compared to subjects randomized to placebo. 
2. To compare cytisine and placebo arms on initial quit rates during study treatment, at 
Week 4 (End of Treatment) and on 7-day point prevalence abstinence at Week 5, Week 
6, Week 7, and Week 8.  
3. Among subjects abstinent at Week 4 (End of Treatment), compare time to failure to 
maintain abstinence through Week 8 between arms.  
4. To explore potential relationships between subject-reported outcomes (e.g. anxiety, 
withdrawal symptoms, depression, tobacco craving, alcohol use) with the reduction in 
cigarette smoking during the study treatment period, as well as smoking cessation 
outcomes at Week 4 (End of Treatment) and from Week 5 to Week 8 post-randomization.  
5. To explore a potential correlation for subject’s nicotine metabolite ratio (NMR) with the 
reduction in cigarette smoking and smoking cessation outcomes.  
3.3. 
Safety Objective(s) 
To evaluate overall safety profiles of cytisine when administered at 1.5 mg or 3.0 mg, using the 
commercial 25-day titration or simplified tid schedules, compared to placebo. 


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3.4. 
Subject Selection 
Only adult subjects (aged at least 18 years old) who are daily smokers (10+ cigarettes daily) with 
intention to quit smoking during the study, in addition meeting all the inclusion criteria and none 
of the exclusion criteria in the protocol will be enrolled in this study. 
3.5. 
Determination of Sample Size 
The sample size was computed based on data from a previous Phase 1/2 trial and for achieving 
narrow confidence intervals (CI) for the primary comparison estimates in this trial.  
The trial size was based on projected realization of the effect size estimate for the primary 
outcome based on data from a Phase 1/2 study in adult smokers. The primary outcome standard 
deviation from this study was found to be approximately 17. Based on this standard deviation, 
the estimated between-arm differences in the primary comparisons can be estimated with a 95% 
CI that is ±8.3. 
The trial size will not have sensitivity for a dichotomous outcome (e.g. smoking cessation as one 
of the other efficacy outcomes), other than for possibly large differences. For example, if the 
control arm outcome is 12% (3/25 defined as successes), then the experimental arm will have a 
two-sided 95% CI for the probability difference that excludes zero when the success probability 
is 36% (8/50) or more (computation based on exact CI). 
3.6. 
Treatment Assignment 
A total of approximately 250 subjects who meet the inclusion/exclusion criteria will be 
randomized at 2:1 ratio to the cytisine treatment and the respective placebo treatment as 
designated by the defined schedule, commercial titration vs simplified tid schedule. 
3.7. 
Administration of Study Medication 
All subjects will receive 2 tablets at each dosing according to the commercial titration schedule 
or to simplified tid schedule. For details, refer to the protocol.  
4. 
EFFICACY AND SAFETY ENDPOINTS 
4.1. 
Efficacy Endpoints  
Efficacy endpoints will be based on cigarette consumption data. Subjects will record their 
cigarette consumption in a daily diary for 7 consecutive days during the screening period, and 
each day during the 25-day treatment period (i.e. on Day 1 through Day 25, inclusive). After 
Day 25, subjects will attend a Day 27 End of Treatment (EOT) clinic visit and post-treatment 
follow-up visits at Week 5, Week 6, Week 7 and Week 8. At each visit clinic staff will ask 
subjects whether they have smoked since the previous clinic visit and/or over the past 7 days, 
and the number of cigarettes smoked in the past 7 days.  


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4.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be based on the daily cigarette consumption data recorded in 
the subject diary. The primary efficacy endpoint is defined as the percent of expected cigarettes 
smoked computed for each subject, at end of treatment. This percent is designated by Y, Y is 
calculated as below:  
             Y = 
𝟏𝟏𝟏𝟏𝟏𝟏×𝑵𝑵
𝑻𝑻×𝑹𝑹 
where N represents total number of cigarettes smoked each day over the treatment period from 
Day 1 to Day 25; T represents number of post-randomization days where number of cigarettes 
smoked is recorded; and R represents the average number of cigarettes smoked daily over the 
7-day screening period as baseline. T*R represents the total number of cigarettes that would have 
been smoked without intervention over the number of recorded days. 
If a subject has no cigarette-count data collected post-randomization, then the primary endpoint 
will be imputed to a value of 100 (i.e., no change from baseline cigarette consumption). This is 
equivalent to imputing the total number of post-randomization days with data recorded (T) is 25 
and the total number of cigarettes smoked over the treatment period (N) is the average number 
smoked daily at baseline (R) times 25.  
The primary comparisons for this endpoint will be comparisons of active arms to the associated 
placebo arm, refer to Figure 1:  
Arm A (1.5 mg cytisine commercial schedule) versus Arm C (placebo commercial schedule),  
Arm B (3.0 mg cytisine commercial schedule) versus Arm C (placebo commercial schedule),  
Arm D (1.5 mg cytisine tid schedule) versus Arm F (placebo tid schedule), and  
Arm E (3.0 mg cytisine tid schedule) versus Arm F (placebo tid schedule). 
4.1.2. 
Other Efficacy Endpoints 
The endpoints associated with the other efficacy objectives are: 
Abstinence from Week 5 to Week 8 is a binary endpoint (success, failure). Success is defined 
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 Week 5 to Week 8 with biochemical 
verification at each assessment. Biochemical verification will be defined by a CO concentration 
in exhaled breath of less than 10 ppm. Subjects will be allowed only 1 missed visit (smoking 
status and/or biochemical verification status unknown) between Week 5 and Week 8 (i.e. one of 
Week 6 or Week 7 visits only) for analysis of the abstinence from Week 5 to Week 8 endpoint.  
Any outcome other than success will be regarded as a failure. There are therefore two types of 
failure for subjects: (1) subjects with adequate data that they were smoking at any time from 
Week 5 to Week 8 (either by the subject’s self-report of smoking or CO ≥10 ppm) and (2) 
subjects having insufficient data to be determined as a success for abstinence from Week 5 to 


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Week 8 endpoint (e.g., subjects lost to follow-up, missing the Week 5 and/or Week 8 clinic visit, 
or missing both the Week 6 and Week 7 visits). 
All subjects will have a realization of this endpoint, thereby enabling analyses that follow the 
intent-to-treat (ITT) principle without imputation. 
Initial quit rate is a binary endpoint (success, failure) at Week 4 (Day 27 EOT). Success is 
defined for a subject as having reported smoking zero cigarettes in the subject diary at Day 25, 
with biochemical verification by an expired-air CO reading <10 ppm at the Day 27 EOT clinic 
visit. Any other outcome will be regarded as a failure. This endpoint is defined at the End of 
Treatment visit so that subjects have approximately a 2½-week grace period after the Day 5-7 
quit date. All subjects will have a realization for this endpoint, thereby enabling analyses that 
follow the ITT principle without imputation.  
7-day point prevalence is a binary endpoint (success, failure) at each of the following visits: 
Week 5, Week 6, Week 7 and Week 8. At each visit, success is defined for a subject as having 
reported not smoking any cigarettes over the past 7 days with biochemical verification by an 
expired-air CO reading <10 ppm. 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. 
Time to failure to maintain abstinence through Week 8 will be evaluated for the subgroup of 
subjects who were classified as a success for the initial quit rate endpoint (see previous 
definition). 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 4 (Day 27 EOT) visit. The end date of abstinence will be defined as the earliest 
date that the subject was known to have resumed smoking. Specifically:  
• At a visit, if a subject reported not smoking in the past 7 days but has smoked since 
the last visit (either by the subject’s self-report or CO ≥10 ppm), the end date of 
abstinence will be the date of that last visit. 
• At a visit, if a subject reported not smoking since the last visit but has smoked in the 
past 7 days (either by the subject’s self-report or CO ≥10 ppm), the end date of 
abstinence will be defined as the date of the visit minus 7 days. 
• Subjects who have not resumed smoking at the final (Week 8) visit will have end date 
of abstinence censored at the date of the Week 8 visit. 
Relationship between Outcome Variables and Smoking Reduction and Cessation 
Endpoints: The relationships between subject-reported outcomes (e.g. anxiety, depression, 
withdrawal symptoms, tobacco craving, alcohol use) and the following smoking efficacy 
endpoints will be evaluated:  
• The primary efficacy endpoint, which measures reduction in smoking during the 
study treatment period. 
• Initial quit rate, which evaluates smoking cessation at Week 4 (Day 27/EOT). 


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• Abstinence from Week 5 to Week 8. 
It is expected that the relationship between each of these efficacy variables and the following 
subject-reported outcome variables will be evaluated for this objective: 
• Change during the treatment period, in self-reported number of cigarettes smoked 
over the previous 24 hours.  
• Total scores and change from baseline for the following questionnaires: HADS-
Anxiety, HADS- Depression, Tobacco Craving (TC). 
• TC subscores for Emotionality, Expectancy, Compulsivity, and Purposefulness.  
• Responses on the Alcohol Use questionnaire. 
• Adverse event outcomes such as whether the subject experienced any adverse events, 
any serious adverse events. 
• Compliance outcomes such as percent of study drug taken, number of behavioral 
support sessions attended.  
The potential correlation for subjects’ nicotine metabolite ratio (NMR) with both reduction 
in cigarette use and smoking cessation will be explored during the study treatment period and at 
Week 8.  
4.2. 
Safety Endpoints 
The safety endpoints are: 
• Adverse events. 
• Laboratory assessment 
− Hematology 
− Chemistry 
• Vital signs 
• ECG results 
• Concomitant medications 
4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations 
None planned. 


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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. 
General Considerations 
The overall goal of the study is to obtain estimates of effect size for efficacy and safety endpoints 
that will be used to inform the design of future studies. As stated in the protocol, this study will 
be analyzed without specific statistical criteria. That is, no formal statistical hypothesis testing 
will be conducted and consequently a level of significance (α level) is not specified in this 
Statistical Analysis Plan. There will be statistical testing with P values and confidence intervals 
computed. The P values will be interpreted as an assessment of consistency with the play of 
chance (small P values indicating a small likelihood the observed effect is due to chance) and 
will be used qualitatively in decisions concerning next steps. 
Statistical analyses will be performed at the conclusion of the study once all data have been 
collected, cleaned, and the 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 21.0.  
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHODRUG) Version Sep-2017 B2. 
All statistical programming will be done using SAS® version 9.4 (SAS® Institute, Cary, North 
Carolina). All tables, figures and listings will be produced in landscape format.  
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. The 6 treatment arms are: 1.5 mg Cytisine – Commercial Schedule, 3.0 mg 
Cytisine – Commercial Schedule, Placebo – Commercial Schedule and 1.5 mg Cytisine – tid 
Schedule, 3.0 mg Cytisine – tid Schedule, Placebo – tid Schedule.  


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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, mean, standard deviation, 
minimum, median and maximum. In case of n<2, where n indicates the number of evaluable 
subjects 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. 
6.2. 
Definition of Analysis Timepoints 
• Baseline: The last non-missing observation prior to the first dose of study drug 
(cytisine and/or placebo), unless otherwise specified. If both a planned assessment 
and repeat assessment (e.g., retest) meet the above criteria and were collected on the 
same date and time, the repeat assessment will be used as baseline. 
• Change from Baseline: The change from baseline values will be derived for each 
subject as the post-baseline value minus the baseline value. 
• Pre-treatment Period: Prior to first dose of study drug on Day 1.  
• Study Treatment Period: Starts on the date of the first dose of study drug (Day 1), 
continues through the last dose of study drug (Day 25) and ends on the date of the 
Week 4 (Day 27 EOT) visit. 
• Smoking Cessation Period: Includes the weekly visits at Week 5, Week 6, Week 7, 
and Week 8. 
• Follow-up Period: Includes the weekly visits at Week 5, Week 6, Week 7, and 
Week 8. 


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• Study Day: Study day will be calculated for safety endpoints relative to the first dose 
of study drug (cytisine and/or placebo). The first dose of study treatment 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). 
6.3. 
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. 
6.3.1. 
Missing Dates 
Partial or missing dates will be imputed only if a date is required to derive a study endpoint 
(e.g. time to failure, duration of AE). Otherwise no date imputation will be done. Date 
imputation will follow the rules below. 
Efficacy Related Dates  
Partial or missing dates required to computing efficacy endpoints will be imputed as follows: 
• 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. 
• 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. 
• Missing month, day, and year: Missing dates will be imputed as the date of first dose. 
• In situations where the above rules result in an illogical time (e.g., 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. 
Safety Related Dates 
For safety data 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.  


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• 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 
(i.e., 01-Jan-2019). 
• 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 
(i.e., 01-Jan-2019). 
• Missing month, day, and year: Missing start dates will be imputed as the date of first 
dose. 
6.4. 
Analysis Sets  
Three analysis sets will be used.  
Screening Analysis Set: all subjects who give written informed consent and have entered 
screening. The Screening Analysis Set consists of two mutually exclusive subgroups:  
• subjects who were not randomized at completion of screening, generally due to 
failure of one or more of the study entry criteria (i.e., the inclusion/exclusion criteria) 
and  
• subjects who were randomized at completion of screening  
Safety Analysis 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 Analysis Set will be the primary set for safety summaries. Safety 
summaries may also be provided based on the treatment actually received. 
All Randomized Analysis Set: all randomized subjects. Subjects will be evaluated by their 
randomized treatment arm (‘intent-to-treat’ analysis) unless otherwise specified. The All 
Randomized Analysis Set will be the primary set for efficacy analyses.  
Achieve will approve the list of subjects to be excluded from the Safety and All Randomized 
analysis sets after database lock. Achieve must approve this list before any analysis to be 
performed. 
6.5. 
Key Study Endpoints 
Achieve has identified the following endpoints as key study endpoints: 
• Percent of expected cigarettes smoked (primary efficacy endpoint, see Section 4.1.1) 
• Abstinence from Week 5 to Week 8 (other efficacy endpoint, see Section 4.1.2 ) 
• Adverse events (serious adverse events, adverse events that resulted in dose reduction or 
discontinuation of study drug, all adverse events) 


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• Exposure to study drug, including study drug compliance 
6.6. 
Sensitivity Analyses 
Sensitivity analyses will include the assessment of the contribution of interaction terms and effect 
modification analyses.  
Unless otherwise indicated, the sensitivity and effect modifier analyes will be conducted by an 
independent statistician (
) who will document the 
results of those analyses in a statistical report that will be included as an appendix to the clinical 
study report.  
The sensitivity analyses outlined in this Statistical Analysis Plan will be performed for both the 
primary efficacy endpoint (see Section 10.1.2) and the abstinence from Week 5 to Week 8 
endpoint (see Section 10.2.2). 
 
6.7. 
Interactions and Covariates 
Interactions: Assessment of the effect of interaction between treatment (1.5 mg cytisine, 3.0 mg 
cytisine, placebo) and the BMI stratification factor (18.5 to <25 kg/m2; 25 to <30 kg/m2; 30 to 
<35 kg/m2) will be included in the sensitivity analyses.  
Covariates: Baseline cigarettes smoked, defined as the average number of cigarettes smoked 
daily over the 7-day screening period. 
7. 
SUBJECT DISPOSITION  
The number of subjects who were screened, failed screening, randomized and treated will be 
summarized overall.  The reason for failing screening will also be summarized. 
The number of subjects screened, randomized, treated, discontinuing and completing study drug, 
completing and withdrawing from the 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 screened, 
randomized and treated will be summarized by investigational site for each treatment arm.  
For subjects who discontinued study drug, the reasons for discontinuation (e.g. 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 (e.g. adverse event, 
withdrawal by subject, physician decision) 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. 
Reasons will also be reported for why subjects were excluded from each analysis set. The list of 
subjects who are excluded from the Safety Analysis Set (subjects randomized but who never 


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took any study drug before discontinuing from the study) will be reported only if those subjects 
had safety information collected.  
Attendance at each study visit will be reported with the number and percentage of subjects who 
attended each visit (i.e. Screening #1, Screening #2, Randomization, Treatment Day 1, etc.). 
Similarly, the last study visit attended will be reported with the number and percentage of 
subjects having their last study visit at Week 8, Week 7, etc.  
The number and percentage of subjects who completed the Treatment Period (i.e., attended the 
Day 27 EOT) and Follow-up Assessment Period (i.e., attended the Week 8 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 (i.e., time from date of randomization to date of last smoking cessation 
data recorded at or prior to the Week 8 visit). Smoking cessation data includes the self-reports of 
cigarette smoking [number of cigarettes smoked in previous 24 hours, whether any cigarettes 
were smoked 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-09 Monitoring Plan and 
documented in the CRF. Each deviation will be classified as either “major” or “minor”. Major 
deviations were defined in the monitoring plan as those requiring direct/immediate escalation to 
the Sponsor/Medical Monitor in order to determine if the subject can continue with his/her study 
participation. These included deviations in the following categories:  
• Inadequate informed consent procedures, 
• Violations of inclusion/exclusion criteria, 
• Errors in randomization/stratification, 
• 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 (e.g., informed consent, 
inclusion/exclusion criteria, etc.) will be summarized by treatment arm.  
8. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and other baseline characteristics will be listed and summarized.  


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8.1. 
Demographics  
Demographic data (gender, age, race, ethnicity, body weight, height, and BMI) will be 
summarized for each of the subgroups in the Screening Set, and overall.  
Demographic data will also be summarized by treatment arm and overall for both the All 
Randomized Analysis Set and the Safety Analysis Set.  
8.2. 
Medical and Psychiatric History 
A medical and psychiatric history summary will be provided for the All Randomized Analysis 
Set. The number and percentage of subjects with events will be summarized for each treatment 
arm by MedDRA SOC and preferred term. Multiple occurrences of the same event within a 
subject will be counted only once.  
8.3. 
Prior Medications 
Per protocol, concomitant medications will be recorded beginning at the Screening #1 (SV1) 
visit. Prior medications are defined as medications with a stop date prior to the first dose of study 
drug. Prior medications will be summarized for the All Randomized Analysis 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. 
8.4. 
Smoking History 
At SV1 the following subject-reported smoking history variables will be summarized by 
treatment arm.  
• Duration of smoking (years) 
• Average number of cigarettes the subject reported smoking per day over the past 
30 days 
• Number (%) of subjects who attempted to quit in the past 
• Number of previous quit attempts 
• Time from last quit attempt to date of SV1 visit 
In addition, the number (%) of subjects reporting past use of various smoking cessation 
treatments will be summarized for both 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: 


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• Average number of cigarettes smoked per day over 7 consecutive days, as reported in the 
subject diary  
• Expired CO (ppm) at SV1 
• Expired CO (ppm) at Day 0 
• Nicotine metabolism ratio (NMR) at SV1. NMR will be derived as the ratio of the results 
for 3-hydroxycotinine (3-OH cotinine) and cotinine (i.e., 3-OH cotinine / cotinine).  
8.6. 
Baseline Questionnaires 
Subjects will complete the Suicidal Behaviors Questionnaire – Revised (SBQ-R) and Hospital 
Anxiety and Depression (HADS) questionnaires at SV1 and the Fagerstrom Test of Nicotine 
Dependence (FTND), Self-efficacy Questionnaire (SEQ-12), Tobacco Craving Questionnaire 
(TCQ) and Alcohol Use Questionnaire at Day 0, prior to randomization. The following scores 
will be derived and summarized at baseline by treatment arm: 
• SBQ-R: total score 
• HADS: scores for depression and anxiety (see Appendix 5, study protocol) 
• FTND: total score 
• SEQ-12: internal stimuli score (items 1-6), external stimuli score (items 7-12) and total 
score (items 1-12) 
• TCQ: scores for emotionality, expectancy, compulsivity and purposefulness (see 
Appendix 4, study protocol), as well as a total score. 
In addition, the number and percentage of subjects with each item response on the baseline 
Alcohol Use Questionnaire will be summarized by treatment arm.  
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.  
Serum chemistry and hematology testing will be performed at SV1. Baseline laboratory test 
results will be summarized by treatment arm. 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 (ALT), alanine aminotransferase (AST), alkaline 
phosphatase, glucose, sodium, potassium, calcium, creatinine and urea) and creatinine-clearance.  
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. 


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9. 
EXPOSURE TO STUDY TREATMENT 
Study treatment consisted of administration of study drug in combination with behavioral 
support. 
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 Analysis 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 Analysis Set. The number (%) of subjects who had duration of 
25 days will be summarized by treatment arm.  
9.2. 
Study Drug Compliance 
A dose of study drug consisted of 2 tablets. Subjects assigned to the 25-day commercial schedule 
will be prescribed a total of 100 doses of study drug. Subjects assigned to the tid schedule will be 
prescribed a total of 69 doses.  
Each dose of study drug taken by the subject will be recorded in a subject diary. For each dosing 
day (Day 1 to Day 25), the dosing date will be recorded as well as each of the dosing times and, 
for each dosing time, whether the dose was taken by the subject or missed. The total dose of 
study drug taken over the 25-day treatment period will be derived for each subject.  
The following variables will be summarized by treatment arm for the Safety Analysis Set:  
• total dose of study drug, 
• total number of missed doses,  
• percentage of doses missed: (# missed doses/ # doses prescribed) * 100 
• study drug compliance: [(# doses prescribed - # missed doses) / # doses prescribed] * 
100.  
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 administration and compliance will be listed. The listing will include the total 
number of doses taken by the subject, total number of doses missed, percentage of doses missed, 
and percentage of doses taken (i.e. compliance with study drug) in addition to the details of each 
dose (date of administration, time of administration and whether dose was taken or missed). 
9.3. 
Behavioral Support Compliance 
Per protocol, subjects will receive a total of 13 behavioral support sessions at visits: SV2, Day 0, 
Day 2, Day 3, Day 6, Day 12, Day 16, Day 20, Day 27 EOT, Week 5, Week 6, Week 7 and 
Week 8.  


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The total number of behavioural support sessions received will be calculated for each subject and 
summarized by treatment arm for the Safety Analysis Set. Summaries will also be provided for 
compliance with behavioral support [ (# behavioral support sessions received) / (# behavioral 
support sessions planned ] * 100.  
10. 
EFFICACY ANALYSIS
The efficacy analyses will be conducted using subjects in the All Randomized Analysis Set, as 
defined in Section 6.4. 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.  
The planned figures for efficacy endpoints are displayed in Section 15. 
10.1. 
Analyses of Primary Efficacy Endpoint 
10.1.1. 
Primary Efficacy Analysis 
The two primary objectives, one for each administration schedule (commercial, tid), are stated in 
Section 3.1. The primary efficacy endpoint, percent of expected cigarettes smoked computed for 
each subject at end of treatment, is defined in Section 4.1.1.  
The distribution of the primary efficacy endpoint for each treatment arm will be displayed by 
treatment arm using side-by-side box plots. There will be one plot for each administration 
schedule. Side-by-side box plots will also be provided by treatment arm and BMI class (3 level 
stratification).  
The primary comparisons will compare active arms to the associated placebo arm as follows: 
1. 1.5 mg Cytisine – Commercial Schedule vs Placebo – Commercial Schedule
2. 3.0 mg Cytisine – Commercial Schedule vs Placebo – Commercial Schedule
3. 1.5 mg Cytisine – tid Schedule vs Placebo – tid Schedule
4. 3.0 mg Cytisine – tid Schedule vs Placebo – tid Schedule
The primary comparisons will be conducted using an analysis of variance model with fixed 
effect terms for treatment arm (3 level categorical variable: placebo, 1.5 mg, and 3.0 mg) and 
BMI class (3 level stratification), and a covariate of baseline cigarettes. There will be one 
analysis for each administration schedule. The least squares means (LS Means), differences of 
the LS Means, and their respective 95% CIs will be reported. Forest plots will be used to display 
95% CIs for the differences of the LS Means.  


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10.1.2. 
Sensitivity Analyses 
Sensitivity analyses will include the assessment of the contribution of interaction terms and 
effect modification analyses. 
The following sensitivity analyses will be performed by 
 
• For each of the primary comparisons, an analysis of variance model will be fit that adds 
an arm-by-BMI interaction term to the model. That is, the sensitivity model will include 
treatment arm, BMI class, arm-by-BMI-class interaction, and a covariate of baseline 
cigarettes. If there is evidence of an interaction then each of the primary comparisons will 
be repeated within each level of the BMI class variable. 
• The placebo treatment arms (Placebo – Commercial Schedule, Placebo – tid Schedule) 
will be compared using an analysis of variance model with fixed effects for treatment arm 
(2 levels) and BMI class (3 levels) and a covariate of baseline cigarettes. The Least 
Square (LS) Means, LS Means Differences, and their respective 95% CIs will be 
reported.  
• If the placebo treatment arms are similar then the primary efficacy analysis will be 
repeated using the pooled placebo arms. The sensitivity analysis described in the previous 
paragraph will also be repeated. 
Additional sensitivity analyses for the primary comparisons will be conducted by an independent 
statistician (
). These include a sensitivity analysis 
that computes the standard error (SE) for each subject of the cigarette-count data collected 
post-randomization and uses 1/(SE2) as a weight.  
Exploratory analyses will also be conducted by 
 as described below in order to 
identify effect modifiers. The objective of these analyses is to assess the homogeneity of 
treatment effect within strata (subgroups) defined by each potential effect-modifying variable. 
Strata for continuous effect modifiers will be defined by either logical considerations (e.g., age 
>65 years) or statistical criteria (e.g., quantile (median, tertile) split). The variables (factors) that 
will be evaluated as effect modifiers include, but are not limited to:  
• demographic charateristics (e.g., sex, age, race, BMI),  
• smoking history variables (e.g., duration of smoking, average number of cigarettes the 
subject reported smoking per day over the past 30 days, number of previous quit 
attempts),  
• baseline smoking variables (e.g. average number of cigarettes smoked per day over 7 
consecutive days as reported in the subject diary, baseline CO (ppm)),  
• baseline questionnaire scores (see Section 8.6), 
• clinical site.  


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Each factor will be evaluated in a two-arm analysis of variance model with fixed effect terms for 
treatment arm (experimental arm, control arm), the factor, and arm-by-factor interaction, and the 
covariate of baseline cigarettes. The following summary statistics will be reported for each level 
of a factor: the number of subjects overall and within each treatment arm, the mean difference 
between treatment arms in the primary endpoint (percent of expected cigarettes smoked), and the 
95% CI for the difference. Forest plots will be used to display the 95% Cis for all factors. 
The sensitivity analyses described above will be repeated using an analysis of variance model 
that does not include the covariate of baseline cigarettes, and for models with BMI class as a 
stratifier and without BMI as a stratifier. 
10.1.3. 
Smoking Diary Compliance 
Subjects will record their cigarette consumption in a daily diary for 7 consecutive days during 
the screening period, and each day during the 25-day treatment period (i.e. on Day 1 through 
Day 25, inclusive). For each period (screening, treatment), compliance with diary reporting 
requirements will be derived as: 
          [ (# diary days entered by subject) / (# diary days expected for subject ] * 100. 
The number of diary days expected is 7 days for the screening period and 25 days for the 
treatment period. The number of diary days and compliance will be summarized for each period 
by treatment arm. Compliance will be summarized both as a continuous variable and as a 
categorical variable (<80%, 80-<90%, 90-<100%, 100%).  
Other elements of protocol-compliance are described in Section 9.2 (study drug compliance) and 
Section 9.3 (behavioral support compliance).  
10.2. 
Analyses of Other Efficacy Endpoints 
The other efficacy objectives are stated in Section 3.2. The other efficacy endpoints are defined 
in Section 4.1.2. The results for each endpoint will be displayed graphically by treatment arm. 
Side-by-side bar charts will be used to display categorical endpoints, Kaplan-Meier figures will 
be used for time-to-event endpoints. For binary endpoints, forest plots will be used to display 
95% CIs for the odds ratio.  
The other efficacy analyses will be conducted using subjects in the All Randomized Analysis Set 
described in Section 6.4.  
For each of the other efficacy endpoints identified below, 4 within-schedule comparisons of 
cytisine vs placebo will be performed:  
1. 1.5 mg Cytisine – Commercial Schedule vs Placebo – Commercial Schedule
2. 3.0 mg Cytisine – Commercial Schedule vs Placebo – Commercial Schedule
3. 1.5 mg Cytisine – tid Schedule vs Placebo – tid Schedule


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4. 3.0 mg Cytisine – tid Schedule vs Placebo – tid Schedule 
The statistical analyses that will be performed for the other efficacy endpoints are described 
below.  
10.2.1. 
Abstinence from Week 5 to Week 8 
Abstinence from Week 5 to Week 8 is a binary (success, failure) endpoint. 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. Following is template SAS code for doing each of the statistical 
comparisons where s is the stratification factor (BMI, 3 levels), x is the treatment arm (2 levels, 
each comparison), and y is the efficacy endpoint (success vs failure).  
proc freq data=data; 
  exact fisher or comor eqor; 
  table s*x*y / nopercent nocol; 
run; 
The effect size estimate of each comparison will be based on the common odds ratio estimate 
using exact computations for stratified 2x2 frequency tables.  
Homogeneity of odds ratios will be assessed using Zelen’s Exact Test. If there is evidence of odds 
ratio heterogeneity across the strata (p-value ≤ 0.10) then the analysis will be performed separately 
for each level of the stratification factor and stratum-specific estimates of the odds ratios and CIs for 
those odds ratios will be reported.  
10.2.2. 
Sensitivity Analyses for Abstinence from Week 5 to Week 8 
The following sensitivity analyses will be performed for the Abstinence from Week 5 to Week 8 
endpoint by 
 
• The placebo treatment arms (Placebo – Commercial Schedule, Placebo – tid Schedule) 
will be compared. If the proportion of subjects classified as a success is similar for the 
two placebo arms then each of the cytisine treatment arms will be compared to the pooled 
placebo arms.  
All other sensitivity analyses for the Abstinence from Week 5 to Week 8 endpoint will be 
conducted by an independent statistician (
). These 
analyses will include exploratory analyses to identify effect modifiers. The variables that will be 
evaluated as effect modifiers are identified Section 10.1.2. The relationship between treatment 
arm and the proportion of subjects with abstinence will be evaluated within stratum defined by 
the effect modifier. For each stratum, the number (%) of subjects within each stratum with 
abstinence will be reported for each treatment arm. Odds ratios (1.5 mg cytisine vs. placebo, 3.0 
mg cytisine vs. placebo) and their 95% CIs will also be reported. Forest plots will be used to 
display the stratum-specific 95% CIs.  


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A tipping point analysis will be performed.1 
10.2.3. 
Initial Quit Rates 
The initial quit rate endpoint is binary (success, failure) defined at Week 4 (Day 27 EOT). For 
each comparison (see Section 10.2), the treatment arms will be compared in terms of the 
proportion of subjects classified as a success (Section 4.1.2). The effect size estimate of each 
comparison will be based on the common odds ratio estimate using exact computations for 
stratified 2x2 frequency tables. 
If there is evidence of odds ratio heterogeneity across the strata (p-value for Zelen’s Exact Test 
≤ 0.10) then the analysis will be performed separately for each level of the stratification factor and 
stratum-specific estimates of the odds ratios and their 95% CIs will be reported.  
10.2.4. 
7-day Point Prevalence 
The 7-day point prevalence endpoints are binary (success, failure) endpoints defined at each of 
the following visits: Week 5, Week 6, Week 7 and Week 8.  
For each comparison (see Section 10.2), the treatment arms will be compared in terms of the 
proportion of subjects classified as a success (Section 4.1.2 ). The effect size estimate of each 
comparison will be based on the common odds ratio estimate using exact computations for 
stratified 2x2 frequency tables.  
If there is evidence of odds ratio heterogeneity across the strata (p-value for Zelen’s Exact Test 
≤ 0.10) then the analysis will be performed separately for each level of the stratification factor and 
stratum-specific estimates of the odds ratios and their CIs will be reported.  
10.2.5. 
Time to Failure to Maintain Abstinence Through Week 8  
Time to failure to maintain abstinence through Week 8 (Section 4.1.2) will be evaluated for the 
subgroup of subjects who were classified as a success on the initial quit rate endpoint. Time to 
failure (days) will be calculated for individual subjects as described in Section 4.1.2. Subjects 
who are still abstinent at Week 8 will have time to failure censored at the date of the Week 8 
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. Two Kaplan-Meier figures of treatment arm by time to failure will be produced, one 
figure for each schedule (commercial, tid). 
10.2.6. 
Relationship Between Outcome Variables and Smoking Cessation 
This objective will explore relationships between subject-reported outcomes and smoking 
cessation outcomes during the study treatment period (primary efficacy endpoint), as well as 
smoking cessation endpoints at Week 4 (initial quit rate endpoint) and from Week 5 to Week 8 
(abstinence from Week 5 to Week 8 endpoint). It is expected that the relationship between each 


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of these endpoints and each of the following subject-reported outcome variables will be 
evaluated for this objective: 
• Change during the treatment period, in self-reported number of cigarettes smoked 
over the previous 24 hours.  
• Total scores, and change from baseline scores, for the following questionnaires: 
HADS, SBQ-R, Tobacco Craving, and Alcohol Use. 
• Adverse event outcomes such as whether the subject experienced any adverse events, 
any serious adverse events. 
• Compliance outcomes such as percent of study drug taken, number of behavioral 
support sessions attended.  
10.2.7. 
Relationship Between Outcome Variables and Nicotine Metabolite Ratio (NMR)  
The correlation of NMR with reduction in cigarette use (primary efficacy endpoint), initial quite 
rate and abstinence from Week 5 to Week 8 will be explored. Descriptive statistics for NMR, 
reduction in cigarette use and the cessation endpoints will be produced. 
10.2.8. 
Questionnaires 
The HADS, SBQ-R, Tobacco Craving and Alcohol Use questionnaires will be administered at 
Section 8.6.  
The HADS, SBQ-R and Tobacco Craving questionnaires will be summarized using descriptive 
statistics. For each questionnaire 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 baseline and the post-baseline visit will be summarized at each time point.  
The individual items on the Alcohol Use questionnaire will be summarized categorically by 
treatment arm and visit.  
11. 
SAFETY ANALYSIS  
All safety analyses described below will be presented for each treatment arm using the Safety 
Analysis Set defined in Section 6.4. 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. Adverse 
event reporting will start at the date of informed consent and continue through the end of study 
(Week 8 visit).  


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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 by treatment arm.  
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. Events meeting the following specific criteria will be 
presented in this table:  
• Any reported adverse event (i.e., both pre-existing and treatment-emergent events) 
• For treatment-emergent AEs: 
− Any TEAE 
− Any 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 (recovered no sequelae, recovered with sequelae, ongoing, 
death)  
In addition to the overall summary, the following summaries of the number (%) of subjects with 
at least one TEAE will be produced: 
• Incidence by SOC and PT, in alphabetical order of SOC and PT, for both all TEAE 
and related TEAE 
• Incidence by PT, in decreasing frequency of PT, for both all TEAE and related TEAE 
• Incidence of TEAEs that resulted in dose reduction or discontinuation of study drug 
(i.e., action taken with study drug reported as dose reduced, dose interrupted, or drug 
withdrawn), in decreasing frequency of PT 
• Incidence of TEAE by PT and severity (mild, moderate, severe), in alphabetical order 
of SOC and PT 
• Incidence of TEAE by PT and relationship (yes, no), in alphabetical order of SOC 
and PT 
• Kaplan-Meier figure of time to first treatment-emergent adverse event (i.e., time from 
date of randomization to earliest TEAE start date) by treatment arm.  


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In these summaries, 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. 
In addition to summary tables, the following listings will be produced. 
• All AEs 
• AEs which resulted in dose reduction or discontinuation of study drug (i.e., action 
taken with study drug reported as dose reduced, dose interrupted, or drug withdrawn) 
Pre-existing AEs will be flagged in the listing of all AEs. 
11.2. 
Serious Adverse Events  
Serious adverse events (SAEs) will be summarized by preferred term and SOC for each 
treatment arm using counts and percentages. The followings summaries of SAEs will be 
produced. 
• Incidence by SOC and PT, in alphabetical order of SOC and PT 
• Incidence by PT, in decreasing frequency of PT 
In addition to summary tables, a listing of SAEs will be produced. 
11.3. 
Definition of Treatment Emergent Adverse Events and Serious 
Adverse Events 
A treatment-emergent AE (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?”  
A Serious Adverse Event (SAE) is defined as an AE that:  
• Results in death.  
• Is life-threatening.  
• Requires hospitalization or prolongs existing inpatient hospitalization.  
• Results in persistent or significant disability or incapacity.  
• Results in a congenital abnormality or birth defect.  


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• Is an important medical event that requires medical intervention to prevent any of the 
above outcomes.  
11.4. 
Laboratory Data 
Routine laboratory safety samples will be collected at SV1, each clinic visit during the Treatment 
Period, and Week 8. 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). 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. Samples will be 
analyzed by a central laboratory. If the central laboratory does not provide results in Système 
International (SI) units then 
 will convert all laboratory results to SI units prior to 
analysis.  
The following laboratory summaries will be provided for the protocol-specified tests by 
treatment arm: 
• Actual value and change from baseline will be summarized using descriptive 
statistics, by laboratory test and visit. 
• 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. 
11.5. 
Vital Signs and Weight 
Vital signs, including weight, will be assessed at SV1, Randomization, each clinic visit during 
the Treatment Period and each clinic visit during the Follow-Up 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 (baseline, 
Day 2 through Day 27 EOT, Week 5 through Week 8) using descriptive statistics. For change 
from baseline, only subjects with non-missing results at both baseline and the 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 are defined as 
follows: 


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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 
 
≥20 mmHg 
>160 mmHg 
 
≥20 mmHg 
Diastolic Blood Pressure 
<40 mmHg 
 
≥10 mmHg 
>90 mmHg 
 
≥10 mmHg 
Heart Rate 
<35 bpm 
 
≥15 bpm 
>100 bpm 
 
≥15 bpm 
11.6. 
12-Lead ECG Interpretation 
A 12-lead ECG was done at SV1, Day 12 and Day 27 EOT. An overall interpretation (normal, 
abnormal – not clinically significant, abnormal – clinically significant) was recorded in the CRF.  
The number and percentage of subjects with at least one shift from normal at baseline to 
abnormal – clinically significant at any time post-baseline will be summarized by treatment arm.  
In addition, an ECG listing will be provided.  
11.7. 
Concomitant Medications 
Concomitant medications will be defined as any medication (other than study drug) taken during 
the course of treatment, i.e. 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 
during the screening period and the stop date of the medication is either missing (not available) 
or reported as ongoing. 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. 
12. 
PHARMACOKINETIC ANALYSES 
None planned. 
13. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES  
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. 
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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15. 
TABLE, LISTING AND FIGURES 
 
 
 
 
 
 
 
 
  
 


 
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