Clinical trial NCT03303911
Conditions: Smoking Cessation
Sponsor: Achieve Life Sciences
Start date: 2017-10-06; Completion date: 2018-10-05
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are:

* To evaluate the pharmacokinetic (PK) parameters during repeat dosing of 1.5 mg or 3.0 mg cytisine when administered as the commercial 25-day schedule.
* To evaluate the pharmacodynamic (PD) effects (e.g., reduction in smoking) with repeat dosing of 1.5 mg or 3.0 mg cytisine when administered as the commercial 25-day schedule.

Detailed description:

Arms: arm 1: Multiple doses of 1.5 mg cytisine administered per 25-day schedule:

* 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 (Once daily) arm 2: Multiple doses of 3.0 mg cytisine administered per 25-day schedule:

* 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 (Once daily)
Interventions: intervention 1: Cytisine
Intervention descriptions: intervention 1: film-coated tablets; depending on arm assignment, 1 or 2 tablets to be taken with 240 mL water for each dose

Protocol documents:
Prot_000.pdf: 
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Protocol ACH-CYT-02, 21 September 2017, Version 2,0
C),tisine
CONF'IDENTIAI
SPONSOR SIGNATURE PAGE
PROTOCOL NUMBER
PROTOCOL TITLE
EudraCT NUMBER:
PLANNED STUDY
DOSES:
PROTOCOL VERSION
PROTOCOL DATtr
ACH-CYT.O2
Repeat-Dose Pharmacokinetic and Phzumacodynamic
Evaluation of Cytisine in Healthy Smokers
2017-003257-42
Mutiple doses of 1.5 mg cytisine and 3,0 mg cytisine
Version 2.0
2l September 2017
Approvals:
Anthony Clarke, PhD
Chief Scientific Officer
Achieve Life Sciences, Inc.
Daniel Cain
Senior Director, Clinical Itesear ch
Achieve Life Sciences, Inc.
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Date
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Date
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\
L'J r it
Regulatory Affairs Consultant
Chief Medical Officer


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0 
 
Cytisine 
 CONFIDENTIAL 
 
 
3 
SYNOPSIS  . 
NAME OF COMPANY: Achieve Life Sciences, Inc. 
NAME OF INVESTIGATIONAL MEDICINAL PRODUCT (IMP):  
Cytisine 1.5 mg film-coated tablets 
TITLE OF STUDY: Repeat-Dose Pharmacokinetic and Pharmacodynamic Evaluation of 
Cytisine in Healthy Smokers 
PRINCIPAL INVESTIGATOR: Dr An
e Koch 
STUDY CENTRE: Simbec Research Ltd (Simbec) 
     Merthyr Tydfil, CF48 4DR, UK 
CLINICAL PHASE:  1/2 
OBJECTIVES: 
Primary:  
• To evaluate the pharmacokinetic (PK) parameters during repeat dosing of 1.5 mg or 
3.0 mg cytisine when administered as the commercial 25-day schedule. 
• To evaluate the pharmacodynamic (PD) effects (e.g. reduction in smoking) with repeat 
dosing of 1.5 mg or 3.0 mg cytisine when administered as the commercial 25-day 
schedule. 
Secondary:  
• To compare the PK parameters and tolerability for repeat dosing of 1.5 and 3.0 mg 
cytisine during the 25-day schedule in healthy smokers at 18-65 and >65 (elderly) years 
of age. 
• To assess the renal elimination of cytisine via measurement of urinary concentrations of 
cytisine during treatment on Day 1 and Day 25. 
• To evaluate for effects on QT/QTc interval prolongation and cardiac safety during 
treatment on Day 1 and Day 25 in healthy smokers at 18-65 and >65 (elderly) years of 
age. 
 
METHODOLOGY:  
This is an open-label, randomised, 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 commercialised  
25-day schedule. 
NUMBER OF SUBJECTS: A total of 36 subjects, such that 24 subjects are 18-65 years and 12 
subjects are >65 years of age, will be randomised/enrolled to complete the study. An attempt will 
be made for 50% male and 50% female enrollment. 
MAIN INCLUSION CRITERIA: 
Male or female smokers (minimum 10 cigarettes per day) aged 18 – 65+ years, with no allergy or 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0 
 
Cytisine 
 CONFIDENTIAL 
 
 
4 
sensitivity to cytisine or any of its excipients, who are deemed healthy by meeting enrollment 
criteria and, unless surgically sterile, are willing to abstain from sexual intercourse or willing to 
use an effective method of contraception from the first dose and for 3 months after the last dose 
of cytisine (refered to as the IMP). 
IMP ADMINISTRATION: 
Each subject will receive the IMP (cytisine in the form of the commercial product T
®), 
(1.5 mg or 3.0 mg dose cytisine) over a 25-day period according to the current T
ex SmPC as 
follows: 
Days 
Regimen 
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 
- 
This schedule will require a total of 9 overnight stays (evenings of Day -1, Days 1, 2, 3 and Days 
12, 16, 20, 24, and Day 25). 
CRITERIA FOR EVALUATION: 
PK:  
PK Endpoints:   
Plasma:  
Estimated Cmax values will be determined as follows: 
• On Day 1, an estimate of Cmax will be made after the first daily (morning) dose from 
venous blood samples collected immediately post dose at 00:30, 00:45, 01:00, 01:15, 
01:30, and 02:00 hours. For the last evening dose on Day 1, Day 2, and Day 3, an 
estimate of Cmax will be made from venous blood samples collected immediately post 
dose at 00:30, 01:00, 01:30, 02:00, 02:30, 03:00, 03:30, 04:00, and 05:00 hours. 
• On Day 12, 16, 20, and 24, an estimate of Cmax will be made after the last daily (evening) 
dose from venous blood samples collected immediately post dose at  01:00,  01:30,  
02:00, 02:30, 03:00, 03:30 and 04:00 hours. 
Estimated Cmin values will be made from venous blood samples collected prior to the first 
morning dose on Day 4, Day 13, Day 17, Day 21 and Day 25. 
On Day 25 Cmax, Tmax, t1/2 and AUC will be determined after the administration of the final dose 
of cytisine from venous blood samples collected at the following timepoints: 00:30, 00:45, 01:00, 
01:15, 01:30, 01:45, 02:00, 02:15, 02:30, 02:45, 03:00, 03:15, 03:30, 03:45, 04:00, 05:00, 06:00, 
08:00, 10:00, 12:00 and 24:00 hours post-dose. 
Total volume of blood drawn for the pharmacokinetic and clinical laboratory safety assessments 
will be up to approximately 328 mL per subject over a 26-day period. 
Urine: Amount excreted in urine over 24 hours (Ae) and percent of drug excreted in urine (Ae%) 
over 24 hours will be calculated on Day 1 and Day 25 of treatment. 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0 
 
Cytisine 
 CONFIDENTIAL 
 
 
5 
Safety:  
Safety Endpoints: The number of subjects with adverse events, serious adverse events, and 
adverse events leading to discontinuation will be documented. Adverse events will be assessed 
by clinical observation and spontaneous reporting by subjects. In addition, number of subjects 
with clinically significant abnormalities in vital signs (supine systolic/diastolic pressure, pulse 
and oral temperature), 12 lead ECG (heart rate, PR interval, QRS width, QT interval and QT 
interval corrected using Fridericia’s (QTcF interval) formula), laboratory parameters 
(haematology, biochemistry and urinalysis) will be evaluated. 
STATISTICAL METHODS:   
All statistical analysis will be performed using SAS® version 9.3 or higher. 
Demographic and Background Data: All demographic and background data will be listed. 
Demographic data will be summarised descriptively (age, height, weight and BMI) by dose 
group, age group and overall. Subject disposition and analysis sets (safety, PK, and PD) will also 
be listed and summarised by frequency. 
PK:  Pharmacokinetic parameters of cytisine will be derived from the plasma  
concentration-time profiles, by using a non-compartmental approach with a ln-linear terminal 
phase assumption. Actual times of sampling will be used. 
The following pharmacokinetic parameters will be estimated: maximum observed plasma 
concentration (Cmax); minimum observed plasma concentration (Cmin); time of occurrence of 
Cmax (Tmax); area under the plasma concentration versus time curve (AUC) from time zero (pre-
dose) to the last sampling time with quantifiable concentrations (AUC0-t); AUC from time zero 
to infinity (AUC0-∞); residual area or percentage of extrapolated part of AUC0-∞ (%AUC); 
apparent terminal elimination rate constant (λz); and apparent elimination terminal half-life (t1/2).  
In addition, the amount of cytisine excreted in urine over time (Ae) and percent of drug excreted 
in urine (Ae%) will be derived from Day 1 and Day 25 24-hour urine collections. 
Safety: All safety data will be listed.  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 20.0. 
The incidence of treatment emergent AEs (TEAE) will be summarised by organ system, 
preferred term, severity and relationship to study drug. Abnormal laboratory safety results will 
be listed.  
QT/QTc:  Triplicate ECGs, extracted at pre-dose and 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h 
after the first dose of cytisine on Day 1 and Day 25 will be obtained from the Holter recordings 
will be listed and analysed. 
 
DURATION OF STUDY: 
Approximately 9 weeks for each individual (from screening to 
post-study follow-up). 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0 
 
Cytisine 
 CONFIDENTIAL 
 
 
6 
 
TABLE OF CONTENTS 
SYNOPSIS  . ....................................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................12 
1. 
ETHICS ......................................................................................................................14 
1.1. 
Research Ethics Committee ........................................................................................14 
1.2. 
Subject Information and Consent ...............................................................................14 
1.3. 
Indemnity Arrangements ............................................................................................15 
2. 
INTRODUCTION AND BACKGROUND ...............................................................15 
2.1. 
Smoking and Health ...................................................................................................15 
2.2. 
Cytisine .......................................................................................................................15 
2.3. 
Recent Cytisine Pharmacokinetic Studies ..................................................................16 
2.3.1. 
Study CYT-BIO-02-07 in Healthy Subjects ...............................................................16 
2.3.2. 
PK Study in Healthy Smoking Subjects published by the University of 
Auckland .....................................................................................................................18 
2.4. 
Safety Summary ..........................................................................................................20 
2.5. 
Recent Nonclinical Toxicology Studies: Estimation for Higher Human 
Equivalent Doses ........................................................................................................20 
3. 
RATIONALE FOR THE STUDY ..............................................................................22 
4. 
STUDY OBJECTIVES ..............................................................................................22 
4.1. 
Primary Objectives .....................................................................................................22 
4.2. 
Secondary Objectives .................................................................................................22 
5. 
INVESTIGATIONAL PLAN .....................................................................................22 
5.1. 
Study Design ...............................................................................................................22 
6. 
SELECTION OF STUDY POPULATION ................................................................25 
6.1. 
Inclusion Criteria ........................................................................................................25 
6.1.1. 
To be Confirmed at Screening ....................................................................................25 
6.1.2. 
To be Re-Confirmed Prior to Start of Dosing (Day -1) ..............................................27 
6.2. 
Exclusion Criteria .......................................................................................................27 
6.2.1. 
To be Confirmed at Screening ....................................................................................27 
6.2.2. 
To be Re-Confirmed Prior to Start of Dosing (Day -1): .............................................27 
6.3. 
Removal of Subjects from Therapy or Assessment ....................................................28 
7. 
RETRICTIONS PRIOR AND DURING THE STUDY ............................................28 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0 
 
Cytisine 
 CONFIDENTIAL 
 
 
7 
7.1. 
Confinement ...............................................................................................................29 
7.2. 
Smoking, Diet and Fluid Restrictions .........................................................................29 
7.2.1. 
Smoking ......................................................................................................................29 
7.2.2. 
Meal Times .................................................................................................................29 
7.2.3. 
Fluid Intake .................................................................................................................29 
7.2.4. 
Alcohol Intake ............................................................................................................29 
7.2.5. 
Caffeine .......................................................................................................................29 
7.2.6. 
Poppy and Sesame Seeds ............................................................................................29 
7.2.7. 
Grapefruit Juice and Other Restrictions .....................................................................30 
7.3. 
Other Life-Style Restrictions ......................................................................................30 
7.3.1. 
Blood Donation ...........................................................................................................30 
7.3.2. 
Contraception ..............................................................................................................30 
7.3.3. 
Sperm Donation ..........................................................................................................30 
8. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ..........................................31 
8.1. 
Cytisine 1.5 mg Film-Coated Tablets .........................................................................31 
8.2. 
Receipt and Storage ....................................................................................................31 
8.3. 
Assembly and Certification ........................................................................................32 
8.4. 
Administration ............................................................................................................32 
8.5. 
Return/Destruction ......................................................................................................32 
8.6. 
Method of Assigning Subjects to Group A or Group B .............................................32 
8.7. 
Selection of Doses in the Study ..................................................................................32 
8.8. 
Selection and Timing of Dose for Each Subject .........................................................32 
8.9. 
Dose Modifications for 3.0 mg Dose or Elderly Subjects (>65) ................................33 
8.10. 
Blinding ......................................................................................................................34 
9. 
PRIOR AND CONCOMITANT THERAPY .............................................................34 
10. 
TREATMENT COMPLIANCE .................................................................................35 
11. 
STUDY PROCEDURES ............................................................................................35 
11.1. 
Procedure Schedule ....................................................................................................36 
11.2. 
Detailed Description of Study Visits ..........................................................................38 
11.2.1. 
Screening Visit (Day -28 to Day -2) ...........................................................................38 
11.2.2. 
Day -1 .........................................................................................................................38 
11.2.3. 
Day 1 to Morning of Day 4 .........................................................................................39 
11.2.4. 
Day 4 through Day 11 .................................................................................................40 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0 
 
Cytisine 
 CONFIDENTIAL 
 
 
8 
11.2.5. 
Day 12 to Morning of Day 13 .....................................................................................41 
11.2.6. 
Day 13 through Day 15 ...............................................................................................41 
11.2.7. 
Day 16 through Morning of Day 17 ...........................................................................42 
11.2.8. 
Day 17 through Day 19 ...............................................................................................42 
11.2.9. 
Day 20 through Morning of Day 21 ...........................................................................43 
11.2.10. 
Day 21 through Day 23 ...............................................................................................43 
11.2.11. 
Day 24 through Day 26 ...............................................................................................44 
11.2.12. 
Post Study Follow-up .................................................................................................45 
12. 
DRUG CONCENTRATION MEASUREMENTS ....................................................45 
12.1. 
Pharmacokinetic Blood Sampling ..............................................................................45 
12.2. 
Pharmacokinetic Urine Collection ..............................................................................49 
12.3. 
Determination of Plasma and Urine Drug Concentrations .........................................49 
12.4. 
Incurred Samples Reanalysis ......................................................................................49 
13. 
SAFETY ASSESSMENTS ........................................................................................50 
13.1. 
Subject’s Safety ..........................................................................................................50 
13.2. 
Adverse Events ...........................................................................................................50 
13.2.1. 
Definition of Adverse Event .......................................................................................50 
13.2.2. 
Recording of Adverse Events .....................................................................................52 
13.2.3. 
Grades of Adverse Event Severity ..............................................................................52 
13.2.4. 
Assessment of Causal Relationship ............................................................................53 
13.2.5. 
Reporting of Serious Adverse Events .........................................................................53 
13.2.6. 
Monitoring of Subjects with Adverse Events .............................................................54 
13.3. 
Pregnancy ...................................................................................................................55 
13.4. 
Laboratory ...................................................................................................................55 
13.4.1. 
Routine Laboratory Assessments ...............................................................................55 
13.4.2. 
Expired Air Carbon Monoxide (CO) ..........................................................................56 
13.4.3. 
Virology ......................................................................................................................56 
13.4.4. 
Drugs of Abuse and Alcohol ......................................................................................56 
13.5. 
Vital signs ...................................................................................................................56 
13.6. 
Physical Examination .................................................................................................56 
13.7. 
ECG Measurements ....................................................................................................56 
13.8. 
12-Lead ECG Holter ...................................................................................................57 
13.9. 
Subject Diary ..............................................................................................................57 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0 
 
Cytisine 
 CONFIDENTIAL 
 
 
9 
13.10. 
Concomitant Medication ............................................................................................57 
14. 
APPROPRIATENESS OF MEASUREMENTS ........................................................57 
15. 
STATISTICAL METHODS .......................................................................................58 
15.1. 
Primary Objectives and Analysis ................................................................................58 
15.2. 
Subject Population for Analyses .................................................................................58 
15.2.1. 
Safety Analysis Set .....................................................................................................58 
15.2.2. 
PK Analysis Set ..........................................................................................................58 
15.2.3. 
Pharmacodynamic (PD) Analysis Set .........................................................................59 
15.3. 
Subjects Characteristics ..............................................................................................59 
15.4. 
Sample Size Calculation .............................................................................................59 
15.5. 
Plasma and Urine Concentrations ...............................................................................59 
15.6. 
Estimation of pharmacokinetic parameters ................................................................60 
15.7. 
Pharmacokinetic Analysis ..........................................................................................60 
15.8. 
Pharmacodynamic Data ..............................................................................................61 
15.9. 
Safety Variables and Analyses ...................................................................................61 
15.9.1. 
Holter ECGs ................................................................................................................61 
15.9.2. 
12-Lead ECGs ............................................................................................................62 
15.9.3. 
Vital Signs ..................................................................................................................62 
15.9.4. 
Adverse Events ...........................................................................................................62 
15.9.5. 
Safety Laboratory tests ...............................................................................................63 
15.10. 
Procedures for Deviations from Planned Analyses ....................................................63 
16. 
DOCUMENTATION .................................................................................................63 
16.1. 
Study File and Site Documents...................................................................................63 
16.2. 
Study Documents Supplied by the Sponsor ................................................................64 
16.3. 
Maintenance and Retention of Records ......................................................................64 
17. 
ADMINISTRATIVE PROCEDURES .......................................................................64 
17.1. 
Sponsor Responsibilities .............................................................................................64 
17.2. 
Investigator Responsibilities .......................................................................................65 
18. 
REGULATORY COMPLIANCE ..............................................................................65 
19. 
ETHICAL CONDUCT OF THE TRIAL / GOOD CLINICAL PRACTICE .............66 
20. 
PROTOCOL MODIFICATION/PREMATURE TERMINATION ...........................66 
21. 
POLICY FOR PUBLICATION AND DATA PRESENTATION .............................67 
22. 
INVESTIGATOR’S AGREEMENT ..........................................................................68 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0 
 
Cytisine 
 CONFIDENTIAL 
 
 
10 
23. 
REFERENCES ...........................................................................................................69 
APPENDIX 1. NORMAL RANGES FOR VITAL SIGNS AND ECG PARAMETERS .........70 
APPENDIX 2. FAGERSTRÖM NICOTINE DEPENDENCE QUESTIONNAIRE .................71 
APPENDIX 3. SHORT FORM OF THE TOBACCO CRAVING QUESTIONNAIRE ...........72 
 


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Protocol ACH-CYT-02, 21 September, 2017, Version 2.0  
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Cytisine  
 
 
 
12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABBREVIATION/TERM DEFINITION 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
Ae 
Amount excreted  
ANOVA 
Analysis of Variance 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC0-t 
AUC from Time Zero to Last Sampling Time with Quantifiable 
Concentrations 
AUC0-∞ 
AUC from Time Zero to Infinity 
%AUC 
Residual Area or Percentage of Extrapolated Part of AUC0-∞ 
BMI 
Body Mass Index 
Clast 
Last Quantifiable Concentration 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case Report Form 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product (for this protocol indicates 
cytisine 1.5 mg film coated tablet) 
LC-MS/MS 
Liquid Chromatography-tandem Mass Spectrometry 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Healthcare products Regulatory Agency 
NCCIH 
National Center for Complementary and Integrative Health 
(branch of US NIH) 
PD 
Pharmacodynamic  
PK 
Pharmacokinetics 
RBC 
Red Blood Cell Count 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics  
SOC 
(MedDRA) System Organ Class 
SAP 
Statistical Analysis Plan  
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment emergent Adverse Events 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0  
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Cytisine  
 
 
 
13 
ABBREVIATION/TERM DEFINITION 
Tmax 
Time to Maximum Observed Concentration 
t1/2 
Apparent Terminal Elimination Half-life 
UADR 
Unexpected Adverse Drug Reaction 
UAE 
Unexpected Adverse Event 
ULOQ 
Upper Limit of Quantification 
WBC 
White Blood Cell Count 
λz 
Apparent Terminal Elimination Rate Constant 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0  
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Cytisine  
 
 
 
14 
1. 
ETHICS 
1.1. 
Research Ethics Committee  
This study protocol will be submitted to the Research Ethics Committee (REC) for review and 
approval. The approval of the REC must be obtained before commencement of any study 
procedures. 
The favourable opinion is conditional upon the Sponsor registering the clinical trial in a publicly 
accessible database, within 6 weeks of the first participant recruited.  
All substantial protocol amendments must be approved by the REC responsible for the study. 
Non-substantial amendments will not require prior approval by the REC. 
If the study is stopped due to adverse events (AEs), it will not be recommenced without 
reference to the REC responsible for the study. 
The outcome of the study (e.g. completed) will be reported to the REC responsible for the study 
within 90 days of completion of the last subject’s final study procedures. In the event of the 
study being prematurely terminated, a summary safety report will be submitted to the REC 
responsible for the study within 15 days. 
A summary of the clinical study report will be submitted to the REC responsible for the study 
within 1 year of completion of the last subject’s final study procedures. 
The REC will be informed that S
ec is a commercial organisation and that the study is funded 
by Achieve Life Science. The subjects who take part in the clinical study will be paid for their 
inconvenience and have been informed that there may be no benefits gained by their 
participation. All potential conflicts of interest will be declared by the Principal Investigator and 
designees.  
1.2. 
Subject Information and Consent 
Potential subjects who volunteer for participation in the study will be informed of the aims, 
methods, anticipated benefits and potential hazards of the study and any possible discomfort it 
may entail. Information will be given in both oral and written form and in the manner deemed 
appropriate by the Clinical Unit standard operating procedures. Each subject will also be 
informed of his/her right to withdraw from the study at any time, for any reason. 
A written explanation (participant information sheet) and informed consent form will be 
provided and the subject will be allowed sufficient time to consider the study information. Prior 
to signing the informed consent form, the subject will be given an opportunity to discuss any 
issues concerning the study with an Principal Investigator or designee who has suitable 
knowledge of the study and will have all questions answered openly and honestly. 
If the subject is willing to participate in the study, the informed consent form will be signed and 
personally dated by the subject and the person taking consent. The subject will receive a copy of 
the informed consent form together with the participant information sheet. The original signed 
informed consent form will be retained with the study records at the Investigator site. In addition, 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0  
  CONFIDENTIAL 
 
Cytisine  
 
 
 
15 
the actions and completion of the consenting process will be recorded in the subject’s medical 
record (i.e., source document). 
1.3. 
Indemnity Arrangements 
The Sponsor and Si
c carry insurance to pay compensation for injury, accident, ill health or 
death caused by participation in this study without regard to proof of negligence in accordance 
with the insurance and compensation in the event of injury in clinical trials 2012, guidance 
issued by the ABPI, the BioIndustry Association and the Clinical Contract Research Association 
in consultation with the Department of Health and the National Research Ethics Service. 
2. 
INTRODUCTION AND BACKGROUND 
2.1. 
Smoking and Health 
Tobacco smoking contributes to some 5 million premature deaths each year worldwide.1 
Smoking is highly addictive with more than 95% of unaided attempts at cessation failing to last 6 
months.2  Every year that a smoker delays quitting beyond the mid-30s, it has been estimated that 
the person loses 3 months of life expectancy.3  The World Health Organization’s Framework 
Convention on Tobacco Control identifies evidence-based approaches to promote smoking 
cessation, which include mass-media campaigns, tax increases on tobacco, and help for smokers 
wanting to stop.4 
2.2. 
Cytisine 
(-)-Cytisine, a plant-based alkaloid isolated from seeds of Cytisus laburnum (Golden rain acacia), 
has been used as a smoking cessation drug since the 1960’s in Eastern and Central Europe, 
marketed as 
 Despite its widespread use, cytisine has not 
been clinically developed outside of S
a’s Eastern and Central European territories. 
Achieve Life Sciences has acquired the license to cytisine outside of Sop
a’s territories to 
pursue clinical development and market approvals. There is widespread support for this strategy 
from leaders in the field.7-9 
So
ma’s focus on clinical development of cytisine was in its traditional markets in Eastern 
and Central European countries where the initial clinical studies were conducted and published, 
but not in English.5 Because most of the clinical development trials leading to market approval in 
these countries occurred decades ago, the trials were not performed according to today’s standard 
Good Clinical Practice (GCP) guidelines. Cytisine has been more recently evaluated in newer 
clinical trials, including additional pharmacokinetic (PK) studies and two large randomised 
Phase 3 clinical trials that were conducted according to GCP with more than 2,000 participants. 
The overall objectives in these more recent trials were to confirm the PK, efficacy, and safety of 
cytisine according to current clinical development standards. This clinical trial is being 
conducted to assess the pharmacokinetic parameters in far greater detail than has been reported 
for the commercial dose schedule as well as assessing a higher dose, as recommended by FDA 
for a future Phase 3 trial.  
As a smoking cessation treatment using cytisine, the designated number of 1.5 mg cytisine 
tablets to achieve a particular dose or schedule are taken orally with approximately 240 mL of 


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Protocol ACH-CYT-02, 21 September, 2017, Version 2.0  
  CONFIDENTIAL 
 
Cytisine  
 
 
 
17 
subjects. At 10 h after drug administration, the cytisine plasma levels exceeded LOQ in all 
subjects. Mean values and other calculated PK parameters are presented in Table 1 (extracted 
from the Study CYT-BIO-02-07 report). 
Table 1: 
Means of Pharmacokinetics Parameters for Cytisine 
 
Cmax 
ng/mL 
Clast 
ng/mL 
AUCinf 
ng.h/mL 
AUClast 
ng.h/mL 
AUCres 
ng.h/mL 
AUC % 
Ex-inf 
% 
T½ 
h 
Ka 
l/h 
λz 
1/h 
MRT 
h 
Tmax 
h 
Mean 
SD 
SEM 
Median 
15.55 
6.55 
1.09 
14.97 
2.24 
0.81 
0.13 
1.92 
73.63 
21.27 
3.55 
70.72 
59.80 
16.77 
2.79 
58.58 
13.83 
7.36 
1.23 
11.66 
18.33 
6.46 
1.08 
17.89 
4.09 
0.82 
0.14 
4.00 
2.81 
1.30 
0.38 
0.95 
0.1758 
0.0336 
0.0056 
0.1735 
6.10 
1.23 
0.21 
6.02 
0.92 
0.40 
0.07 
0.83 
Min 
Max 
5.37 
36.67 
0.88 
4.40 
38.37 
121.92 
32.49 
103.47 
4.45 
40.33 
7.20 
35.38 
2.74 
6.36 
3.01 
4.42 
0.1090 
0.2531 
4.30 
9.65 
0.33 
1.75 
CV% 
Geo Mean 
42 
14.39 
36 
2.10 
29 
70.67 
28 
57.53 
53 
12.19 
35 
15.25 
20 
4.02 
46 
2.49 
19 
0.1726 
20 
5.99 
44 
0.84 
CI 95% 
Lower 
Upper 
KS p value 
 
13.33 
17.76 
0.65 
 
1.97 
2.52 
0.22 
 
66.43 
80.83 
0.64 
 
54.13 
65.48 
0.90 
 
 
16.15 
20.52 
0.61 
 
3.81 
4.37 
0.89 
 
1.98 
3.64 
0.282 
 
0.1644 
0.1872 
0.9837 
 
5.68 
6.52 
0.55 
 
0.78 
1.06 
0.12 
Mean Cmax (maximal plasma concentration) for the 36 subjects was 15.55 ± 6.55 ng/mL with a 
mean Tmax (time to maximal plasma concentration) of 0.92 h ± 0.40, ranging from 0.33-1.75 h. 
The mean AUClast (area under the concentration-time curves over 0-t period) was 59.80 h.ng/mL 
± 16.77 and the AUCinf (area under the concentration-time curve from 0 to infinity) was 
73.63 h.ng/mL ± 21.27. The mean AUCres was less than 20% of AUCinf. The mean T½ (plasma 
elimination half-life) was 4.09 h ± 0.82 with a range from 2.74-6.36 h and MRT (mean resistance 
time) was 6.10 ± 1.23 h. 
Mean urine concentration of cytisine in urine samples are presented in Table 2 (extracted from 
the Study CYT-BIO-02-07 report). 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0  
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Cytisine  
 
 
 
18 
Table 2: 
Mean Cytisine Urine Concentrations and Pharmacokinetic Parameters.  
 
Cytisine urinary concentrations (µg) 
Aea 
% 
recovery 
0 – 3 h 
3 – 6 h 
6 – 9 h 
9 – 12 h 
12 – 24 h 
Mean 
SD 
SEM 
Median 
329.02 
102.42 
17.07 
336.98 
250.58 
98.05 
16.34 
235.98 
154.25 
73.07 
12.18 
134.31 
105.28 
43.99 
7.33 
94.76 
119.62 
56.34 
9.39 
119.93 
958.75 
238.67 
39.78 
896.22 
63.92 
15.91 
2.65 
59.75 
Min 
Max 
70.72 
519.35 
14.73 
469.20 
11.14 
357.90 
20.95 
227.97 
24.80 
250.63 
24.89 
929.79 
34.71 
100.24 
CV% 
Geo Mean 
31.13 
308.24 
39.13 
221.92 
47.37 
135.49 
41.78 
96.07 
47.10 
105.64 
24.89 
929.79 
24.89 
61.99 
CI 95% 
Lower 
Upper 
 
294.36 
363.67 
 
217.41 
283.76 
 
129.53 
178.98 
 
90.40 
120.16 
 
100.56 
138.68 
 
877.99 
1039.50 
 
58.53 
69.30 
aAe: Amount excreted 
Mean cumulated values of cytisine excreted during a 24 h period evaluated as percent of 
administered dose was 958.75 ± 238.67 μg. The results indicated that, during a 24 h period, 
around 64% of the oral dose was excreted in the urine as parent compound. 
In summary, there were marked inter-individual differences observed in plasma concentrations 
as well as in all PK parameters after cytisine administration (e.g., CV exceeding 30% was noted 
for Tmax, Cmax, and AUC). The mean half-life for cytisine was 4.09 h ± 0.82. Cumulative 
amounts of cytisine were excreted in the urine within 24 h indicating that cytisine is most likely 
readily absorbed from the gastrointestinal tract after oral administration and may not undergo 
metabolic processes, since approximately 64% of the administered dose was excreted as 
unchanged cytisine within 24 h. More details are in the Investigator’s Brochure. 
2.3.2. 
PK Study in Healthy Smoking Subjects published by the University of Auckland 
A pilot PK study was conducted at the University of Auckland in New Zealand and published by 
Soo Hee Jeong10 et al in 2014. The study developed an analytical LC-MS assay for the detection 
of cytisine in plasma and urine following a single 3 mg oral dose. The LC-MS method in this 
study complied with limits set by US FDA guidelines including accuracy, precision, specificity, 
and linearity. The PK characteristics of cytisine were evaluated in seven healthy smokers after a 
single 3 mg oral cytisine dose (i.e. double the dose used in Study CYT-BIO-02-07) over a 24 h 
period. Subjects enrolled smoked an average of 10.6 cigarettes per day and had been smoking for 
an average of 9.5 years with only two subjects having previously made an attempt to quit 
smoking. 
Ten blood samples were collected in heparinised tubes at the following times from each subject: 
0 (just before dosing), 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 h after cytisine administration. Blood 
pressure, heart rate and respiratory rate were also measured at 0 (just before dosing), 2, 4, 8, and 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0  
  CONFIDENTIAL 
 
Cytisine  
 
 
 
19 
24 h after drug administration. After providing a blood sample at 8 h, subjects went home and 
returned the next morning, 24 h post-dosing. Subjects also provided spot urine samples. Non-
linear mixed effects modelling (NONMEM) was used for modelling and estimating population 
pharmacokinetic parameters (CL, Vd). A single compartment model was fit to the data. 
After a single 3 mg oral dose, cytisine was absorbed into the bloodstream, with cytisine 
detectable in plasma as early as 15 min after dosing (Figure 2). Peak plasma concentrations were 
typically observed at 2 h after administration. In two subjects, the peak plasma concentration was 
observed at 1 h post-dose, suggesting that the peak plasma concentration may have been 
achieved between 1 and 2 h for all subjects. This is broadly consistent with the estimate of 0.92 h 
in the Study CYT-BIO-02-07. Since the blood sampling in this study had a less frequent 
sampling schedule of 0.25, 0.5, 1, and 2 h, this study was less able to accurately estimate a Tmax 
of approximately an hour. The mean Cmax was 27.76 ng/mL. Following the peak plasma 
concentration, cytisine concentrations declined in a monophasic manner and the T½ of cytisine 
was calculated to be 4.8 h.  
 
Figure 2: 
Mean plasma concentrations (ng/mL) of cytisine over 24 hours  
 
Mean plasma concentrations (ng/mL) of cytisine over 24 hours following a single 3 mg oral 
dose. Values are shown as mean ± SEM (n=7). 
The values for Vd and CL were estimated to be 115 L and 16.7 L/h, respectively with standard 
error values 0.003.  
Cytisine was still detectable in the urine collected at 24 h for all subjects (mean 24 h 
concentration was 428.15 ng/mL). Cytisine was detected in urine as unchanged cytisine and no 
metabolites were detected in plasma or in urine in any of the subjects in the study. 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0  
  CONFIDENTIAL 
 
Cytisine  
 
 
 
20 
In summary, the logarithmic plot of mean cytisine concentration versus time after Cmax showed a 
single elimination phase (i.e., no distinction was made between the distribution and elimination 
phase of the drug). This indicated that single dose PK of cytisine may be described using a 
single-compartment model. Since the apparent volume of distribution for cytisine estimated for 
the population in the study (115 L) was more than three times that of the blood compartment 
(35 L), this suggested that cytisine may distribute to other compartments very rapidly. Plasma 
cytisine concentrations declined with an average elimination half-life of 4.8 h. Thus, in this pilot 
study, the half-life for 3 mg cytisine in smokers (4.8 h) was the same for 1.5 mg cytisine in 
healthy non-smokers (4.09 h ± 0.82). This study is described in more detail in the Investigator’s 
Brochure. 
2.4. 
Safety Summary 
Given that cytisine (T
x) has been marketed in Central and Eastern Europe, including four 
Member States of the European Union (EU), for several decades, there is considerable clinical 
experience with this product. Over 20 million subjects have been treated, and over 10,000 
subjects have taken part in clinical trials, the majority of which were conducted several years 
ago. S
ma, the manufacturer of T
x, has been filing Periodic Safety Update Reports 
(PSURs) since 2005. The cumulative denominator in PSURs is now over 15 million exposures.  
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=2844) 1389 subjects 
received cytisine. The most commonly reported adverse events in the cytisine group were effects 
on the gastro-intestinal system: abdominal pain upper, 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, the statistical 
analysis did not reveal any significant difference in the nervous system adverse events between 
the cytisine and placebo groups (p=0.12). 
Please reference the cytisine Summary of Product Characteristics (SmPC) for additional human 
safety information. 
2.5. 
Recent Nonclinical Toxicology Studies: Estimation for Higher 
Human Equivalent Doses 
A number of non-clinical studies with cytisine were performed more than 25 years ago and, thus, 
pre-dated current GLP standards. The US National Center for Complementary and Integrative 
Health (NCCIH) has sponsored new non-clinical GLP studies that have included 28-day repeat 
dosing for toxicology assessments in rats and dogs to current GLP guidance.  
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 5 mg/kg/day when given orally for 28 day consecutive days in rats. This 


Protocol ACH-CYT-02, 21 September, 2017, Version 2.0  
  CONFIDENTIAL 
 
Cytisine  
 
 
 
21 
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, 1.0, 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) when cytisine is administered for 28 
consecutive days. 
Based on the findings in both the 28-day rat and 28-day dog toxicology studies, the established 
commercial dose of 1.5 mg X 6 doses/day (maximum total exposure of 9 mg/day for the first 
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 daily dose exposure of 18 mg for 
the first 3 days of treatment. This again is below the calculated HED based on all of the studies 
as shown in Table 3.  
Table 3: 
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 
commercial 
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. 
In conclusion, these margins of safety, based on HED calculations in newly conducted GLP 
toxicology studies support evaluating the pharmacokinetic parameters and pharmacodynamic 
effects of a higher 3 mg dose (maximum of 18 mg for the first 3 days) compared to the 
commercial dose of 1.5 mg (maximum of 9 mg for the first 3 days). In addition, these data are 
relevant for a future Phase 3 trial design.  


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3. 
RATIONALE FOR THE STUDY 
Although cytisine (T
x) has been marketed in Central and Eastern Europe using a standardised 
25-day treatment schedule at the manufactured 1.5 mg dose level, there have been no recent 
pharmacokinetic evaluations of repeat dosing at 1.5 mg or 3.0 mg in adult smokers, including the 
elderly (>65 years of age). Therefore, this study will evaluate the detailed pharmacokinetics of 
1.5 mg or 3.0 mg cytisine in adult smokers aged 18-65+ years as administered per the current 
T
ex labeling (25-day commercial schedule). In addition, assessment for any potential effect of 
cytisine on QT/QTc interval prolongation will be explored and analysed in relationship to the 
cytisine pharmacokinetic profile as well as general safety assessments for the 3 mg dose.  
4. 
STUDY OBJECTIVES 
4.1. 
Primary Objectives 
1. To evaluate the pharmacokinetic (PK) parameters during repeat dosing of 1.5 mg or 
3.0 mg cytisine when administered as the commercial 25-day schedule. 
2. To evaluate the pharmacodynamic (PD) effects (e.g. reduction in smoking) with repeat 
dosing of 1.5 mg or 3.0 mg cytisine when administered as the commercial 25-day 
schedule. 
4.2. 
Secondary Objectives 
1. To compare the PK parameters and tolerability for repeat dosing of 1.5 mg and 3.0 mg 
cytisine during the 25-day schedule in healthy smokers at 18-65 and >65 (elderly) years 
of age. 
2. To assess the renal elimination of cytisine via measurement of urinary concentrations of 
cytisine during treatment on Day 1 and Day 25.  
3. To evaluate for effects on QT/QTc interval prolongation and cardiac safety during 
treatment on Day 1 and Day 25 in healthy smokers at 18-65 and >65 (elderly) years of 
age. 
5. 
INVESTIGATIONAL PLAN 
5.1. 
Study Design 
This will be an open-label, randomised, multiple-dose PK and PD study conducted in adult 
smokers, 18-65+ years of age as shown in Figure 3: 


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Figure 3: 
Study Design Overview  
 
 
The study will be comprised of a pre-study screen, followed by 25 days of treatment and a post-
study follow-up.  
Screening (Day -28 to Day -1): Screening assessments will be carried out within 28 days before 
first administration of cytisine (Section 11.2.1). Eligible subjects will then be asked to return on 
the evening prior to Day 1 (i.e. Day -1) for repeat of key entry testing, baseline questionnaires 
and provide overview of the risks of smoking and quit advice according to World Health 
Organizaion (WHO) guidelines11 (Section 11.2.2). Randomisation to treatment group will occur 
on the morning of Day 1 followed by initiation of study treatment. 
Treatment Period (Day 1 to Day 25):  Eligible subjects will take cytisine as outlined in the 
 product insert (SmPC). NOTE:  Group A subjects take 1 tablet at each timepoint 
(1.5 mg), Group B subjects take 2 tablets at each timepoint (3.0 mg). 
Figure 4: 
Dose Timing and Total Daily Dose 
Days 
Regimen 
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 
- 
 
 
R 
A 
N 
D 
O 
M 
I 
S 
E 
Group B 
Multiple doses of 3.0 mg cytisine administered per 25-day 
schedule 
   12 subjects age 18-65 
   6 subjects age >65 
Group A 
Multiple doses of 1.5 mg cytisine administered per 25-day 
schedule 
   12 subjects age 18-65 
   6 subjects age >65 
 
S 
C 
R 
E 
E 
N 
 
 
F 
 
O 
 
L 
 
L 
 
O 
   W 
 
 
 
U 
 
P 


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A total of 9 overnight stays in the clinic will be required over the 26-day study period. Subject 
entry into the study may be staggered in groups in order to facilitate study management activities 
but all subjects passing screening are to provide clinic visits as follows: 
• Day -1 and Days 1-3 (4 overnight stays in clinic):  Arrive at study clinic in the 
afternoon of Day -1, repeat select screening testing and verification of 
inclusion/exclusion criteria. Provide risks of smoking and quit advice according to 
WHO guidelines that evening.11  All subjects will fast for minimum of 10 hours prior 
to first dose on Day 1. Randomisation to treatment Group assignment will occur on 
the morning of Day 1, just prior to starting treatment. On the morning of Day 1, 
obtain baseline blood and urine and CO level, initiate Holter monitoring, receive 
study drug packets, begin treatment and provide required blood and urine samples. 
Subjects may have breakfast after first dose and continue with a standard meal 
schedule. On Days 1-3, various safety assessments and blood sample collections will 
occur. On the morning of Day 4 complete vital signs, ECG, blood for haematology 
and biochemistry testing, urine for cotinine test, expired CO, completion of tobacco 
craving questionnaire, safety assessment and collection of the pre-dose PK blood 
draw. Subject will then take first Day 4 dose followed by risks of smoking and quit 
advice, review of diary requirements, reminder of next clinic visit date and will be 
discharged. 
• Day 4-11:  Subjects to maintain dosing as per schedule. 
• Day 12-13 (1 overnight stay in clinic):  Subjects return to clinic prior to last evening 
dose on Day 12 for pre-dose PK blood collection. Blood collections occur post final 
dose on Day 12 for PK. On the morning of Day 13 complete vital signs, ECG, blood 
for haematology and biochemistry testing, urine for cotinine test, expired CO, 
completion of tobacco craving questionnaire, safety assessment, and collection of the 
pre-dose PK blood draw. Subject will then take first Day 13 dose followed by risks of 
smoking and quit advice, review of diary requirements, reminder of next clinic visit 
date and will be discharged. 
•  Day 13-15:  Subjects maintain dosing as per schedule. 
• Day 16-17 (1 overnight stay in clinic):  Subjects return to clinic prior to last evening 
dose on Day 16 for pre-dose PK blood collection. Blood collections occur post final 
dose on Day 16 for PK. On the morning of Day 17 complete vital signs, ECG, blood 
for haematology and biochemistry testing, urine for cotinine test, expired CO, 
completion of tobacco craving questionnaire, safety assessment, and collection of the 
pre-dose PK blood draw. Subject will then take first Day 17 dose followed by risks of 
smoking and quit advice, review of diary requirements, reminder of next clinic visit 
date and will be discharged. 
• Day 17-19:  Subjects maintain dosing as per schedule.  
• Day 20-21 (1 overnight stay in clinic):  Subjects return to clinic prior to last evening 
dose on Day 20 for pre-dose PK blood collection. Blood collections occur post final 
dose on Day 20 for PK. On the morning of Day 21 complete vital signs, ECG, blood 
for haematology and biochemistry testing, urine for urinalysis and cotinine test, 


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expired CO, completion of tobacco craving questionnaire, safety assessment, and 
collection of the pre-dose PK blood draw. Subject will then take first Day 21 dose 
followed by risks of smoking and quit advice, review of diary requirements, reminder 
of next clinic visit date and will be discharged. 
• Day 21-23:  Subjects maintain dosing as per schedule. 
• Day 24-26 (2 overnight stays in clinic):  Subjects return to clinic prior to last evening 
dose on Day 24 for pre-dose PK blood collection. Blood collections occur post final 
dose on Day 24 for PK. All subjects will have breakfast 30 minutes prior to final dose 
on Day 25. Extensive PK blood sampling, urine collections and Holter monitoring 
occur pre and post final dose on Day 25, with final draw 24 hours post dose (Day 26). 
Final discharge from clinic on Day 26 will occur after 24 hour blood draw, vital 
signs, ECG, haematology and biochemistry testing, serum pregnancy test for female 
subjects, urine for urinalysis and cotinine test, expired CO, completion of tobacco 
craving questionnaire, safety assessment, risks of smoking and quit advice, review of 
diary requirements, and reminder of post study followup visit date. 
• Post Study: A post study follow-up visit will be conducted 6 to 8 days after last dose 
of cytisine. If any adverse events are recorded at post study follow up assessment, 
arrangements will be made with the subject, so that they are followed-up 
appropriately and the final outcome determined. Smoking history will be reviewed 
and final review of risks of smoking and quit advice provided. 
The end of study is defined as completion of safety follow-up on all subjects. The maximum 
duration of this study is estimated to be around 9 weeks (screening to last subject’s last visit).  
6. 
SELECTION OF STUDY POPULATION 
A total of 36 subjects will be required to complete the study. Of the 36 subjects, 24 are to be 
18-65 years and 12 are to be  >65 years of age. An attempt will be made for 50% male and 50% 
female enrollment. 
The study is to be conducted in adult smokers and therefore participants may receive therapeutic 
benefit from taking part. Outside of being active smokers, a healthy subject population with 
carefully considered inclusion/exclusion criteria will ensure that subjects are fit and well enough 
for participation in the study.  
The following eligibility criteria are designed to select subjects for whom protocol treatment and 
procedures are considered appropriate. All relevant medical and non-medical conditions should 
be taken into consideration when deciding whether this protocol is suitable for a particular 
subject. 
6.1. 
Inclusion Criteria 
6.1.1. 
To be Confirmed at Screening 
1. Regular moderate cigarette smokers (minimum 10 cigarettes per day) who want to stop 
smoking. 


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2. Urine cotinine >500 ng/mL. 
3. Expired air carbon monoxide (CO) > 11 parts per million (no cigarette 1 hour before 
test). 
4. Healthy males and females 18-65+ years of age. 
a. If a female subject of child bearing potential, a negative pregnancy test at screening 
and admission and willing to use an effective method of contraception (unless of non-
childbearing potential or where abstaining from sexual intercourse is in line with the 
preferred and usual lifestyle of the subject) from first dose until 3 months after last 
dose of cytisine.  
b. If a female subject of non-child bearing potential, a negative pregnancy test at 
screening and admission. For the purposes of this study, this is defined as the subject 
being amenorrheic for at least 12 consecutive months or at least 4 months post-
surgical sterilisation (including bilateral fallopian tube ligation or bilateral 
oophorectomy with or without hysterectomy). Menopausal status will be confirmed 
by demonstrating at screening that levels of follicle stimulating hormone (FSH) fall 
within the respective pathology reference range. In the event a subject's menopause 
status has been clearly established (for example, the subject indicates she has been 
amenorrheic for 10 years), but FSH levels are not consistent with a post-menopausal 
condition, determination of subject eligibility will be at Investigator's discretion 
following consultation with the Sponsor. 
c. If a male subject, willing to use an effective method of contraception (unless 
anatomically sterile or where abstaining from sexual intercourse is in line with the 
preferred and usual lifestyle of the subject) from first dose until 3 months after last 
dose of cytisine. 
5. Subject with no clinically significant abnormal serum biochemistry, haematology and 
urine examination values within 28 days before the first dose of cytisine.  
6. Subject with negative urinary drugs of abuse screen, determined within 28 days before 
the first dose of cytisine (a positive alcohol result may be repeated at Investigator's 
discretion). 
7. Subject with negative human immunodeficiency virus (HIV), hepatitis B surface antigen 
(Hep B) and hepatitis C virus antibody (Hep C) results. 
8. Subject with no clinically significant abnormalities in 12-lead ECG determined after 
minimum of 5 minutes in supine position within 28 days before the first dose of cytisine. 
9. Subject with no clinically significant abnormalities in vital signs (systolic blood pressure 
between 90-150 mmHg (age 18-65) and 90-160 mmHg (age >65), diastolic blood 
pressure (DBP) between 50 and 90 mmHg, and pulse rate (PR) between 40-110 bpm, 
measured on the dominant arm after minimum of 5 minutes in supine position) 
determined within 28 days before first dose of cytisine.  
10. Subject must be available to complete the study (including in-clinic stays and post study 
follow-up) and comply with study restrictions. 
11. Subject must provide written informed consent to participate in the study. 


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6.1.2. 
To be Re-Confirmed Prior to Start of Dosing (Day -1) 
1. Subject continues to meet all screening inclusion criteria (before the first dose only). 
2. Subject has a negative urinary drugs of abuse screen (including alcohol). 
3. Female subject has a negative pregnancy test.  
6.2. 
Exclusion Criteria 
6.2.1. 
To be Confirmed at Screening 
1. Treatment with smoking cessation medications (bupropion, varenicline, any nicotine 
replacement therapy) within 8 weeks of first dose of cytisine. 
2. Use of other forms of nicotine (e-cigarettes, smokeless tobacco) within 8 weeks of first 
dose of cytisine or are planning to use these products during study. 
3. Known hypersensitivity/allergy reaction to varenicline, other cytisine-derivatives or any 
of the excipients in the 
 formulation. 
4. History of severe hypersensitivity reactions to any other drugs. 
5. Current treatment with antihypertensive medicinal products, statins, tuberculostatics, 
cholinomimetics or anticholinesterase medicinal products. 
6. History of any medical condition (e.g. gastrointestinal, renal or hepatic) or surgical 
condition (e.g. cholecystectomy, gastrectomy) that may affect drug pharmacokinetics 
(absorption, distribution, metabolism or excretion). 
7. Female subjects who are breast feeding. 
8. Difficulty in donating blood on either arm or known history. 
9. History of alcoholism or drug abuse within last 2 years. 
10. Use of non-prescription drugs, including vitamins, herbal and dietary supplements within 
14 days (or 5 half-lives, whichever is longer) prior to the first dose of cytisine, unless in 
the opinion of the Principal Investigator the medication will not interfere with the study 
procedures or compromise subject safety. 
11. Participated in any investigational drug clinical trial within the previous 3 months or a 
marketed drug trial within the previous 30 days prior to randomisation on Day 1. 
12. Donation of 450 mL or more blood or had history of significant blood loss due to any 
reason or had plasmapheresis within 3 months before the first dose of cytisine. 
13. Inability to communicate well with Principal Investigator or designees (i.e., language 
problem, poor mental development or impaired cerebral function). 
14. Any other condition that the Principal Investigator considers making the subject 
unsuitable for this study. 
6.2.2. 
To be Re-Confirmed Prior to Start of Dosing (Day -1): 
1. Development of any exclusion criteria since screening. 


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2. Use of non-prescription drugs, including vitamins, herbal and dietary supplements since 
screening, unless in the opinion of the Principal Investigator or designee the medication 
will not interfere with the study procedures or compromise subject safety. 
3. Participation in a clinical study since the screening visit.  
4. Donation of 450 mL or more blood since the screening visit.  
6.3. 
Removal of Subjects from Therapy or Assessment 
Each subject will be informed of their right to withdraw from the study at any time and for any 
reason. 
The Principal Investigator will withdraw a subject from the study at any time for any of the 
following reasons: 
• If a subject experiences a serious or intolerable AE, that prevents them from 
continuing. 
• If a subject incurs a significant protocol violation which impacts on their safety or the 
scientific integrity of the study (this will be discussed on a case-by-case basis with the 
Sponsor). 
• At the request of the Sponsor. 
• If it is considered that the subject’s health is compromised by remaining in the study 
or the subject is not sufficiently cooperative. 
• If a subject is lost to follow-up. 
The reasons for any subject withdrawal will be recorded on the study completion form of the 
case report form (CRF). 
If a subject is withdrawn or chooses to withdraw from the study for any reason, every possible 
effort will be made to perform the evaluations described for the post-study follow-up. The data 
collected from withdrawn subjects will be included in the study report. 
In the event of any abnormalities considered to be clinically significant, subjects will be followed 
up with appropriate medical management until values are considered to be clinically acceptable. 
Referral or collaborative care will be organised if considered necessary. 
Since 36 subjects are required to complete the study, subjects who withdraw from the study 
before receiving any study medication will be replaced. Subjects who are withdrawn from the 
study due to significant drug-related AEs will not be replaced. Replacement of all other subjects 
withdrawn from the study after receiving study medication will be decided on a -case-by-case 
basis by the Principal Investigator (or designee) and Sponsor. 
7. 
RETRICTIONS PRIOR AND DURING THE STUDY 
To avoid possible negative effects on the measurement of plasma drug concentrations and/or on 
subject’s safety, several restrictions are to be adopted as outlined in the eligibility criteria and in 
the following sections.  


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7.1. 
Confinement 
Each subject will be required to provide a total of 9 overnight stays in the clinic over a 26-day 
period.  
7.2. 
Smoking, Diet and Fluid Restrictions 
7.2.1. 
Smoking 
There will be minimal restrictions to smoking during days of confinement, such as all smoking 
must occur within designated area(s) only and subjects cannot smoke during active PK sampling 
period (i.e. subjects must have their last cigarette a minimum of 2 hours before dosing and can 
only start smoking after final PK sample). Subjects will go for a cigarette as a group and will 
need to have their last cigarette before 23:00 while they stay in the clinic. Clinic staff will review 
these guidelines with subjects during confinement and will monitor compliance. 
7.2.2. 
Meal Times 
During days of confinement, subjects will be provided standard meals (breakfast, lunch, dinner, 
snacks) at specific times, concurrent with study treatment dosing when possible. Subjects to be 
fasting prior to the first Day 1 dose and will be fed breakfast 30 minutes prior to the last Day 25 
dose. 
7.2.3. 
Fluid Intake 
Prior to PK sampling only, no fluids (apart from water taken with dose) are allowed from 1 h 
prior to dosing until 1 h afterwards. Water is then allowed ad libitum. Decaffeinated tea and 
coffee as well as squash/cordial are allowed from 4 h post-dose. 
7.2.4. 
Alcohol Intake 
The consumption of alcohol will be limited to a maximum of 2 units (50 mL spirits, 500 mL beer 
or lager or 250 mL wine) per day from 7 days prior to the first dose of cytisine. Alcohol will be 
avoided completely for at least 2 days prior to the first dose of cytisine on Day 1 and again on 
Day 25. Alcohol will be avoided completely for 24 hours prior to each day of confinement for 
PK sampling. 
7.2.5. 
Caffeine 
Food or drink containing caffeine, including coffee, tea, cola, energy drinks or chocolates will be 
avoided completely for 24 hours prior to each day of confinement for PK sampling. 
7.2.6. 
Poppy and Sesame Seeds 
Subjects must not eat food containing poppy or sesame seeds for 3 days before drug of abuse 
testing, as consumption can lead to a positive opiate result in the drugs of abuse test. 


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7.2.7. 
Grapefruit Juice and Other Restrictions  
Food or drink containing grapefruit, cranberry, or Seville oranges (including marmalade and fruit 
juices), and/or food or drink, sweets, candies or other confectionary containing liquorice will be 
avoided completely for 24 hours prior to each day of confinement for PK sampling. 
Each subject will be questioned on the specific points at admission to the clinical unit as 
appropriate. If a subject admits a non-compliance with these restrictions, the Principal 
Investigator or designee will decide whether or not the subject will be permitted to remain in the 
study. Non-compliance with these restrictions will be noted. 
7.3. 
Other Life-Style Restrictions 
7.3.1. 
Blood Donation 
Subjects will be advised that they should not donate blood for at least 3 months after the final 
study visit. 
7.3.2. 
Contraception 
To prevent pregnancy female subjects of childbearing potential and male subjects with female 
partners of child bearing potential must take / agree to take adequate contraceptive precautions 
for the entire duration of study participation. Adequate contraceptive precautions include: 
1. Established use of oral, injected or implanted hormonal methods of contraception. 
2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).  
3. Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository.  
4. Male sterilisation (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). [For female subjects on the study, the vasectomised male partner 
should be the sole partner for that subject]. 
5. True abstinence, when this is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception]. 
The chosen contraception method(s) must be followed from the first dose until at least 3 months 
after the last dose of cytisine. 
7.3.3. 
Sperm Donation 
Subjects must not donate sperm from the first dose and for at least 3 months after the last dose of 
cytisine.  


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8. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
8.1. 
Cytisine 1.5 mg Film-Coated Tablets 
Cytisine will be supplied by the Sponsor. A cytisine tablet is formulated as a compressed film-
coated tablet containing 1.5 mg cytisine in each single tablet (See Table 4).  
Cytisine tablets are manufactured by 
 
  accordance with cGMP. 
Each tablet is composed of cytisine (as the base), with well-established tablet-forming exc
nts 
 
oxides). 
Cytisine should be administered orally according to the dose timing schedule (see Figure 4) with 
each dose to be either one (1) 1.5 mg
) 1.5 mg tablets taken with 240 m
ater 
(8 fl
es) and, when possible, with a meal or snack.  
Table 4: 
Cytisine Product Information 
Name of the Product: 
Cytisine 1.5 mg, film coated tablets (T
®) 
Strengths: 
g 
Dosage form: 
Comp
ablet 
Route/mode of administration: 
Oral 
Dosing Schedule: 
(See Figure 4) 
Dosing instructions: 
Depending of Treatment Group assignment, 
tablets to be take
ater for each dose 
Manufacturer/Marketing Authorisation Holder: 
, 
ria 
 
The documentation supplied will make it possible to retrace the composition and pharmaceutical 
quality of the product. 
8.2. 
Receipt and Storage 
Cytisine will be supplied by the Sponsor as commercial product in a format suitable for study 
specific relabeling. 
The Sponsor must notify the Principal Investigator, or the Project Manager, prior to dispatch of 
the IMP supplies, and of the anticipated date of their arrival. Cytisine should arrive at the study 
site at least 7 days before the first dosing day. The Sponsor shall address all supplies to: 


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Cytisine will be stored under quarantine in a segregated, study-specific area, at or below 25 oC in 
a secure, temperature-controlled pharmacy. Si
ec’s Qualified Person (QP) will review the 
shipping documentation. If acceptable, the supplies will subsequently be removed from 
quarantine and approved for use. 
8.3. 
Assembly and Certification 
Cytisine will be supplied to study subjects in its commercial configuration, as manufactured by 
S
ma.  
Cytisine will be labelled as specified in Annex 13 (Manufacture of IMPs) of the European 
Commission (EC) guide to Good Manufacturing Practice (GMP). 
Finished IMP will be certified by S
c’s Qualified Person according to standard operating 
procedure #BD/324/13/29. 
8.4. 
Administration 
Each subject will receive specified allocations of cytisine periodically during the treatment 
period that will allow for correct dosing as assigned at randomisation  (1.5 mg or 3.0 mg dose 
level). Cytisine allocations will be documented and actual dosing (and time of dosing) will be 
documented by each subject in their diary.  
8.5. 
Return/Destruction 
All used IMP containers and unused IMP will be held under quarantine in the Si
c Pharmacy 
pending return/destruction. Following the Sponsor’s approval, all remaining IMP will be 
destroyed or returned to the Sponsor within 8 weeks of the last dose of IMP.  
8.6. 
Method of Assigning Subjects to Group A or Group B 
Subjects will be randomised to treatment dosing (1.5 mg or 3.0 mg) according to a code 
produced by Si
c using the PROC PLAN procedure of SAS® version 9.1.3 or higher. Subjects 
will be numbered sequentially from 001 (i.e. 001, 002 etc.). Subjects will be stratified for age 
(elderly > 65 years: yes vs no) to assure that each treatment dosing has 6 elderly subjects and 12 
non-elderly subjects. Replacement subjects will be assigned the same randomisation as the 
subject they are replacing, however, 100 will be added to the number (i.e., 101 would replace 
001 etc.). 
8.7. 
Selection of Doses in the Study 
The dose selected for this study is either 1.5 mg or 3.0 mg cytisine. 
8.8. 
Selection and Timing of Dose for Each Subject 
First dose will be administered at approximately 9.00 a.m. on Day 1. Additional doses will be as 
per the Dosing Schedule (see Figure 4). A target time will be provided for each dose in the diary 
and actual time of dose will be recorded. For Days where dosing is every 2 to 3 hours, dosing 
should be ± 10 min within the targeted time. For Days where dosing is every 4-6 hours, dosing 
should be ± 30 min within the targeted time. 


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8.9. 
Dose Modifications for 3.0 mg Dose or Elderly Subjects (>65) 
Dose modifications should not be necessary, unless a severe adverse event warrants holding or 
missing a dose as outlined below during the first 1 – 16 days in the 3 mg cytisine dosage group 
or at any time in elderly subjects.  
Cytisine at higher levels in toxicology studies illicited adverse reactions primarily on the gastro-
intestinal system such as vomiting or diarrhea. Based on the HED calculations in newly 
conducted GLP toxicology studies (see Section 2.5), the safety margin supports the 3 mg dose 
(maximum of 18 mg for the first 3 days). The commercial dose of 1.5 mg (maximum of 9 mg for 
the first 3 days) has been well tolerated with no or minimal gastrointestinal symptoms. However, 
if a subject has nausea that results in vomiting or has minimal diarrhea progressing to severe 
diarrhea, the Principal Investigator/Sponsor Medical Monitor can delay, hold or skip doses. 
Dosing should resume within 48 hours when the adverse event has subsided to a moderate grade 
(see Table 8) or minimal symptoms. Dosing should then resume on the same schedule without 
modification. If the adverse event has not subsided to at least a moderate grade within 48 hours, 
the subject should be withdrawn from further study treatment. 
For all subjects randomised to the 3.0 mg dosing schedule, if a severe adverse event reoccurs 
during the Day 1-16 dosing, then dosing should be again held until the adverse event has 
subsided to a moderate grade or minimal symptoms within a 48-hour period. Dosing should then 
be reduced as specified in Table 5. If the severe adverse event reoccurs after reducing the dose, 
the subject should be withdrawn from further study treatment. If the severe adverse event does 
not reoccur, the patient can continue the study treatment with dosing at the 1.5 mg level as 
shown in Table 5. 


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Table 5: 
Dose Modification for 3.0 mg Dose Group  
Days 
Regimen 
Total Daily Dose Dose Modifications After Recurrence 
1-3 
6 times daily 
18.0 mg 
9 mg total daily dose (Reduce to one 1.5 mg 
cytisine tablet 6 times daily and follow the 
remaining schedule as for the 1.5 mg dosing 
group). 
4-12 
5 times daily 
15.0 mg 
7.5 mg total daily dose (Reduce to one 1.5 mg 
cytisine tablet 5 times daily and follow the 
remaining schedule as for the 1.5 mg dosing 
group). 
13-16 
4 times daily 
12.0 mg 
6 mg total daily dose (Reduce to one 1.5 mg 
cytisine tablet 4 times daily and follow the 
remaining schedule as for the 1.5 mg dosing 
group). 
17-20 
3 times daily 
9.0 mg 
No dose modification 
21-24 
2 times daily 
6.0 mg 
No dose modification 
25 
Once daily 
3.0 mg 
No dose modification 
For elderly subjects in the 1.5 mg dosing schedule, if a severe adverse event reoccurs at any time, 
then dosing should be held until the adverse event has subsided to a moderate grade or minimal 
symptoms within a 48-hour period. Dosing should then be reduced by one dose per day. If the 
severity of the event then reoccurs, the subject should be withdrawn from further study 
treatment. 
8.10. 
Blinding 
The study is open-label. However, as stated in the EMA guidelines on investigation of 
bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1/Corr** London, 
20 January 2010), analysis of all samples will be conducted without information on treatment. 
9. 
PRIOR AND CONCOMITANT THERAPY 
Prior Medication:  Non-prescription drugs, including vitamins, herbal and dietary supplements 
should not be taken within 14 days (or 5 half-lives, whichever is longer) prior to the first dose of 
cytisine, unless in the opinion of the Principal Investigator and Sponsor's Medical Monitor the 
medication will not interfere with the study procedures or would compromise subject safety. 
Non-prescription drugs, including vitamins, herbal and dietary supplements taken during the 
14 days before the first dose of cytisine, and the reason for taking them, will be noted in the 
subject’s CRF.  


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Inclusion of subjects who are on prescription medications or have taken prior medication will be 
reviewed on a case-by-case basis in relation to the safety aspects and objectives of this study.  
Concomitant Medication: New prescription or other non-prescription drugs, including smoking 
cessation medications, tuberculostatics, cholinomimetics or anticholinesterase medicinal 
products, statins or antihypertensive medicinal products, vitamins, herbal and dietary 
supplements should not be taken throughout the duration of the study, with the exception of 
paracetamol (which may be taken as an analgesic to a maximum of 2 g in 24 h (500 mg 4 times a 
day) and ibuprofen (which may be taken as an analgesic to a maximum of 1.2 g in 24 h (400 mg 
3 times a day).  
If intake of ANY prior or concomitant medication is necessary during the study, the daily dosage, 
duration and reasons for administration will be recorded on the subject’s CRF. 
Chewing gum will not be allowed during confinement periods. 
10. 
TREATMENT COMPLIANCE 
Each dose of cytisine taken while in the clinic will be taken under supervision and a hand and 
mouth check conducted. Subjects will be required to maintain a diary to document dosing times 
and provide medication packets for tablet accountability at each clinic visit. These will be 
reviewed by clinic staff during clinic visits. 
11. 
STUDY PROCEDURES 
All subjects will be evaluated for inclusion in the study during the Screening Period. Subjects 
who are eligible for the study will be randomised according to the randomisation schedule on 
Day 1. Subjects will receive their initial allocation of study medication on Day 1. The subjects 
will be required to make a total of 9 overnight clinic stays over a 26-day period. All subjects are 
required to complete a follow-up visit 6-8 days post last dose. 


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11.1. 
Procedure Schedule 
Table 6 provides a summary of required study evaluations. Screening evaluations are to occur within a 28-day interval from initiation 
of screening evaluations to Day -1, just prior to randomisation on Day 1. 
Table 6: 
Schedule of Study Procedures 
 
 
Screening 
Study Day 
Post-Study  
Study Day 
-28 to -2 
-11 
1-41 
4-11 
12-132 
13-15 
16-172 
17-19 
20-212 
21-23 
24-263 
6-8 days after last 
dose 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Number of cigarettes smoked in 
previous 24 hours 
X 
X 
 
 
 
 
 
 
 
 
 
 
Daily Smoking and Study 
Medication Diary4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X5 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X6 
X6 
 
X6 
 
X6 
 
X6 
 
X6 
 
Medical history 
X 
X7 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medication 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
X8 
 
X8 
 
X8 
 
X8 
 
X8 
 
Holter monitor for continuous ECG 
readings9 
 
 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy test for all females 
X 
Serum 
X 
Urine 
 
 
 
 
 
 
 
 
X 
Serum 
 
FSH (females of non-childbearing 
potential only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Haematology10 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Biochemistry10 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Virology (HIV, Hep-B, Hep-C) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
Drugs-of-abuse tests in urine 
X 
X 
 
 
 
 
 
 
 
 
 
 
Fagerström nicotine dependence 
 
X 
 
 
 
 
 
 
 
 
X 
 
Urine cotinine11 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Expired air CO11 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


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Verification of eligibility criteria  
X 
X 
X 
 
 
 
 
 
 
 
 
 
Tobacco craving questionnaire 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Risks of smoking and quit advice12 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
IMP (cytisine) administration13 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Plasma collection for PK analysis14 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine collection for PK analysis15 
 
 
X 
 
 
 
 
 
 
 
X 
 
Adverse events monitoring16 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
1 4 overnight stays in clinic, starting evening of Day -1. 
2 1 overnight say in clinic. 
3 2 overnight stays in clinic. 
4 Subject to record number of cigarettes smoked in past 24 hours on a daily basis throughout study, actual time of each medication dose and record any adverse 
events. Information to be reviewed and documented during clinic days. Subject to also maintain record of number of cigarettes smoked in each 24 hour period 
from Day 26 until final Post-Study Visit (see Section 13.9). 
5 Pre-First Dose on Day 1 
6  Vital signs (supine blood pressure, pulse rate and oral temperature) will be recorded at pre-dose and again prior to discharge from clinic. Vital signs will also be 
recorded 3 hours post last dose on Days 1, 2, 3, 12, 16, 20 and 24. 
7 Clinically relevant changes will be reported as adverse events.  
8 Obtain 12-lead ECG (triplicate) at any time if clinically indicated during clinic visits.  Repeat 12-lead ECG and assess prior to discharge. 
9  Attach ECG Holter monitor and begin recording prior to first dose on Day 1 and continue for 24 hours (discontinue just prior to first dose on Day 2.  Repeat 
again by starting Holter monitor prior to dose on Day 25 and record for 24 hours. 
10 Haematology and biochemistry testing to be completed prior to discharge on Days 4, 13, 17, 21, 26 
11 Urine cotinine and expired CO testing to be obtained at screen and prior to discharge on Days 4, 13, 17, 21, 26. 
12 Each subject given advice about the risks of smoking and quitting. This will take the form of a brief interview following WHO evidence-based 
recommendations on the treatment of tobacco dependence on Day -1 and reminders prior to discharge on Days 4, 13, 17, 21, 26 and on the final post-study visit. 
13IMP administration to follow 25-day dosing schedule (see Figure 4). 
14Plasma collection for PK anlaysis is outlined in Section 12.1. 
15 Urine to be collected for PK on Day 1 and Day 25 as follows:  pre-dose and 0-24 hours. 
16 Adverse event recording to begin upon admissions on Day -1 to post study. 


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11.2. 
Detailed Description of Study Visits 
11.2.1. 
Screening Visit (Day -28 to Day -2) 
All subjects will complete the following screening procedures within 28 days of Day 1 in order 
to verify required inclusion and exclusion criteria.  
1. Written informed consent. 
2. Document actual number of cigarettes smoked in the past 24 hours. 
3. Expired CO. 
4. Demographic data. 
5. Medical history data. 
6. Prior and concomitant medication. 
7. Physical examination, including height and weight. 
8. Vital signs (supine blood pressure, pulse rate and oral temperature). 
9. 12-lead ECGs (triplicate). 
10. Clinical laboratory safety tests (biochemistry, haematology, urinalysis, urine cotinine, 
virology, drugs of abuse, serum pregnancy for females and FSH for females of non-
childbearing potential). 
11. Verification of eligibility criteria. 
11.2.2. 
Day -1 
All subjects will check into the research facility and upon arrival to the clinic, the following 
procedures will be performed: 
1. Vital signs (supine blood pressure, pulse rate and oral temperature). 
2. Update any medical history or concomitant medications. 
3. Repeat urine testing for drugs of abuse and urine pregnancy test for female subjects. 
4. Obtain 12-lead ECG (triplicate). 
5. Verification of eligibility criteria. 
6. Record number of cigarettes smoked in past 24 hours and instruct subject how to 
document cigarette smoking and dosing times in the daily smoking/medication diary (see 
Section 13.9). 
7. Subject to complete the Fagerström nicotine dependence questionnaire (see Appendix 2). 
8. Subject to complete tobacco craving questionnaire (see Appendix 3). 
9. Each subject given advice about the risks of smoking and quitting. This will take the form 
of a brief interview following WHO evidence-based recommendations on the treatment 
of tobacco dependence. 
10. Each subject must fast for minimum of 10 hours prior to first dose on Day 1.   


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11.2.3. 
Day 1 to Morning of Day 4 
The results of screening for each subject must be reviewed by the Principal Investigator or 
designee prior to randomisation to assure eligibility criteria have been met.  
On Day 1: 
1. Vital signs (supine blood pressure, pulse rate and oral temperature). 
2. Verify and document any baseline clinically relevant adverse events. 
3. Randomise subject to treatment group. Provide IMP and instructions for administration, 
reviewing dosing schedule and documentation requirements in the study diary. 
4. Attach ECG Holter monitor, checking to ensure recording has started. Note: Holter 
monitors to remain attached to subjects approximately 24 hours, discontinued just prior to 
first dose on Day 2. 
5. Obtain pre-dose blood sample prior to first dose and PK sampling after first dose 
(Section 12.1). 
6. First dose to be taken prior to breakfast (minimum fasting of 10 hours). Breakfast and 
standard meal schedule to begin after taking first dose. 
7. Obtain urine PK samples starting prior to first dose and continuing for 24 hours (Section 
Section 12.2). 
8. Subject to take 6 doses of cytisine as outlined in Figure 4. 
9. Obtain pre-last dose PK blood sample and additional PK sampling after last dose (Section 
Section 12.1). 
10. Record vital signs (supine blood pressure, pulse rate and oral temperature) at 3 hours 
after the last dose (Note: this is the estimated highest Cmax timepoint for the daily dosing). 
11. Obtain 12-lead ECG (triplicate) at any time if clinically indicated. 
12. Record any adverse events and update concomitant medications. 
13. The number of cigarettes smoked and actual dosing times will be recorded in the CRF.  
14. All subjects will remain in the clinic overnight. 
On Day 2: 
1. Discontinue Holter monitoring approximately 24 hours after initial dose taken on Day 1 
(just prior to first dose on Day 2). 
2. Subject to take 6 doses of cytisine as outlined in Figure 4. 
3. Obtain pre-last dose PK blood sample and additional PK sampling after last dose 
(Section 12.1). 
4. Record vital signs (supine blood pressure, pulse rate and oral temperature) at 3 hours 
after the last dose (Note: this is the estimated highest Cmax timepoint for the daily dosing). 
5. Obtain 12-lead ECG (triplicate) at any time if clinically indicated. 


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6. Record any adverse events and update concomitant medications. 
7. The number of cigarettes smoked and actual dosing times will be recorded in the CRF.  
8. All subjects will remain in the clinic overnight. 
On Day 3: 
1. Subject to take 6 doses of cytisine as outlined in Figure 4. 
2. Obtain pre-last dose PK blood sample and additional PK sampling after last dose 
(Section 12.1). 
3. Record vital signs (supine blood pressure, pulse rate and oral temperature) at 3 hours 
after the last dose (Note: this is the estimated highest Cmax timepoint for the daily dosing). 
4. Obtain 12-lead ECG (triplicate) at any time if clinically indicated. 
5. Record any adverse events and update concomitant medications. 
6. The number of cigarettes smoked and actual dosing times will be recorded in the CRF.  
7. All subjects will remain in the clinic overnight. 
On Day 4: 
1. Obtain pre-dose PK blood sample prior to Day 4 dose (Section 12.1). 
2. Vital signs (supine blood pressure, pulse rate and oral temperature). 
3. Obtain 12-lead ECG (triplicate). 
4. Obtain blood for haematology and biochemistry testing. 
5. Obtain urine for cotinine test and expired air CO prior to discharge. 
6. Subject to complete tobacco craving questionnaire (see Appendix 3). 
7. Record any adverse events and update concomitant medications. 
8. Subject to take first Day 4 dose. 
9. Subject given advice about the risks of smoking and quitting.  
10. Remind subject to record number of cigarettes smoked daily and actual dosing times in 
diary, discharge subject from clinic and schedule return for Day 12. 
11.2.4. 
Day 4 through Day 11 
1. Subject to maintain dosing schedule (5 times daily). 
2. Subject to record number of cigarettes smoked and actual dosing times daily in diary (see 
Section 13.9). 
3. Subject to maintain adverse event log. 
4. Subject to bring medication packets and diary to clinic on Day 12. 


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11.2.5. 
Day 12 to Morning of Day 13 
On Day 12: 
1. Subject will check into the research facility in the afternoon, just prior to the last Day 12 
dose. 
2. Obtain pre-dose PK blood sample prior to the last Day 12 dose. Blood samples will then 
be collected and processed as outlined in (Section 12.1) after the last Day 12 dose of 
cytisine. 
3. Record vital signs (supine blood pressure, pulse rate and oral temperature) at 3 hours 
after the last dose (Note: this is the estimated highest Cmax timepoint for the daily dosing). 
4. Obtain 12-lead ECG (triplicate) if clinically indicated. 
5. Record any adverse events and update concomitant medications. 
6. Review smoking/medication diary for completeness. The number of cigarettes smoked 
and actual dosing times will be recorded in the CRF. 
7. All subjects will remain in the clinic overnight. 
On Day 13: 
1. Obtain pre-dose PK blood sample prior to initial dose (Section 12.1). 
2. Vital signs (supine blood pressure, pulse rate and oral temperature). 
3. Obtain 12-lead ECG (triplicate). 
4. Obtain blood for haematology and biochemistry testing. 
5. Obtain urine for cotinine test and expired air CO prior to discharge.  
6. Subject to complete tobacco craving questionnaire (see Appendix 3). 
7. Record any adverse events and update concomitant medications. 
8. Subject to take first Day 13 dose in clinic. 
9. Subject given advice about the risks of smoking and quitting.  
10. Remind subject to record number of cigarettes smoked and actual dosing times daily in 
diary, discharge subject from clinic and schedule return for Day 16. 
11.2.6. 
Day 13 through Day 15 
1. Subject to maintain dosing schedule (4 times daily). 
2. Subject to record number of cigarettes smoked daily and actual dosing times in diary. 
3. Subject to maintain adverse event log. 
4. Subject to bring medication packets and diary to clinic on Day 16. 


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11.2.7. 
Day 16 through Morning of Day 17 
On Day 16: 
1. Subject will check into the research facility in the afternoon, just prior to the last Day 16 
dose. 
2. Obtain pre-dose PK blood sample prior to the last Day 16 dose. Blood samples will then 
be collected and processed as outlined in (Section 12.1) after the last Day 16 dose of 
cytisine. 
3. Record vital signs (supine blood pressure, pulse rate and oral temperature) at 3 hours 
after the last dose (Note: this is the estimated highest Cmax timepoint for the daily dosing). 
4. Obtain 12-lead ECG (triplicate) if clinically indicated. 
5. Record any adverse events and update concomitant medications. 
6. Review smoking/medication diary for completeness. The number of cigarettes smoked 
and actual dosing times will be recorded in the CRF. 
7. All subjects will remain in the clinic overnight. 
On Day 17: 
1. Obtain pre-dose PK blood sample prior to initial dose (Section 12.1). 
2. Vital signs (supine blood pressure, pulse rate and oral temperature). 
3. Obtain 12-lead ECG (triplicate). 
4. Obtain blood for haematology and biochemistry testing. 
5. Obtain urine for cotinine test and expired air CO prior to discharge.  
6. Subject to complete tobacco craving questionnaire (see Appendix 3). 
7. Record any adverse events and update concomitant medications. 
8. Subject to take first Day 17 dose in clinic. 
9. Subject given advice about the risks of smoking and quitting.  
10. Remind subject to record number of cigarettes smoked daily and actual dosing times in 
diary, discharge subject from clinic and schedule return for Day 20. 
11.2.8. 
Day 17 through Day 19 
1. Subject to maintain dosing schedule (3 times daily). 
2. Subject to record number of cigarettes smoked and actual dosing times daily in diary (see 
Section 13.9). 
3. Subject to maintain adverse event log. 
4. Subject to bring medication packets to clinic on Day 20. 


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11.2.9. 
Day 20 through Morning of Day 21 
On Day 20: 
1. Subject will check into the research facility in the afternoon, just prior to the last Day 20 
dose. 
2. Obtain pre-dose PK blood sample prior to the last Day 20 dose. Blood samples will then 
be collected and processed as outlined in (Section 12.1) after the last Day 20 dose of 
cytisine. 
3. Record vital signs (supine blood pressure, pulse rate and oral temperature) at 3 hours 
after the last dose (Note: this is the estimated highest Cmax timepoint for the daily dosing). 
4. Obtain 12-lead ECG (triplicate) if clinically indicated. 
5. Record any adverse events and update concomitant medications. 
6. Review smoking/medication diary for completeness. The number of cigarettes smoked 
and actual dosing times will be recorded in the CRF. 
7. All subjects will remain in the clinic overnight. 
On Day 21: 
1. Obtain pre-dose PK blood sample prior to initial dose (Section 12.1). 
2. Vital signs (supine blood pressure, pulse rate and oral temperature). 
3. Obtain 12-lead ECG (triplicate). 
4. Obtain blood for haematology and biochemistry testing. 
5. Obtain urine for cotinine test and expired air CO prior to discharge. 
6. Subject to complete tobacco craving questionnaire (see Appendix 3). 
7. Record any adverse events and update concomitant medications. 
8. Subject to take first Day 21 dose in clinic. 
9. Subject given advice about the risks of smoking and quitting.  
10. Remind subject to record number of cigarettes smoked daily and actual dosing times in 
diary, discharge subject from clinic and schedule return for Day 24. 
11.2.10. 
Day 21 through Day 23 
1. Subject to maintain dosing schedule (2 times daily). 
2. Subject to record number of cigarettes smoked and actual dosing times daily in diary. 
3. Subject to maintain adverse event log. 
4. Subject to bring medication packets and diary to clinic on Day 24. 


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11.2.11. 
Day 24 through Day 26 
On Day 24: 
1. Subject will check into the research facility in the afternoon, just prior to the last Day 24 
dose. 
2. Obtain pre-dose PK blood sample prior to the last Day 24 dose. Blood samples will then 
be collected and processed as outlined in (Section 12.1) after the last Day 24 dose of 
cytisine. 
3. Repeat vital signs (supine blood pressure, pulse rate and oral temperature) at 3 hours after 
the last dose (Note: this is the estimated highest Cmax timepoint for the daily dosing). 
4. Obtain 12-lead ECG (triplicate) if clinically indicated. 
5. Record any adverse events and update concomitant medications. 
6. The number of cigarettes smoked and actual dosing times will be recorded in the CRF. 
7. All subjects will remain in the clinic overnight. 
On Day 25: 
1. All subjects to have breakfast 30 minutes prior to final dose. 
2. Attach ECG Holter monitor, checking to ensure recording has started. NOTE:  Holter 
monitors to remain attached to subjects approximately 24 hours, discontinued on Day 26. 
3. Record Vital signs (supine blood pressure, pulse rate and oral temperature). 
4. Obtain pre-dose PK blood sample (Section 12.1). 
5. Begin urine collection for PK as outlined in (Section 12.2). 
6. Subject to take final Day 25 dose of cytisine (documenting time of dose in diary) after 
breakfast and begin extensive PK blood and urine sampling as outlined in (Section 12.1) 
throughout day and up through 24 hours post. 
7. Obtain 12-lead ECG (triplicate) if clinically indicated. 
8. Record any adverse events and update concomitant medications. 
9. The number of cigarettes smoked will be recorded in the CRF. 
10. All subjects will remain in the clinic overnight. 
On Day 26: 
1. Complete final PK blood draw and urine collection (Section 12.1). 
2. Obtain blood and urine for haematology, biochemistry, serum pregnancy test (females 
only) and urinalysis (Section 13.4.1). 
3. Vital signs (supine blood pressure, pulse rate and oral temperature). 
4. 12-lead ECGs (triplicate). 
5. Obtain urine for cotinine test and expired air CO prior to discharge. 


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6. Subject to complete tobacco craving questionnaire (see Appendix 3). 
7. Record any adverse events and update concomitant medications. 
8. Subject given advice about the risks of smoking and quitting.  
9. Remind subject to record number of cigarettes smoked daily in diary, discharge subject 
from clinic and schedule follow up visit (within 6-8 days). 
11.2.12. 
Post Study Follow-up 
A Post-Study Follow-up visit will occur 6-8 days after last dosing to document any changes in 
concomitant medication(s) and adverse event(s) observed/documented at discharge as well as 
any new concomitant medications or adverse events. If any new adverse events are recorded at 
this follow-up visit, arrangements will be made with the subject to come into the clinic for 
assessment and then followed until outcome determined. Subject’s diary will be reviewed and 
collected (Note: diary will be used as source document for smoking history, actual dosing times 
and any self-reported adverse events). Subject given advice about the risks of smoking and 
quitting.  
12. 
DRUG CONCENTRATION MEASUREMENTS 
12.1. 
Pharmacokinetic Blood Sampling 
A total of 95 venous blood samples will be collected over a 26-day period (approximate volume 
of 3.0 mL each, total volume of approximately 285 mL) into pre-cooled lithium heparin tubes, 
according to the following schedule: 
Table 7: 
Blood Sampling for Pharmacokinetic Assessments   
Test Period 
Blood Sample 
Number 
Time from Dosing 
Day 1 (first dose) 
 
1 
Pre-Dose 
(within 60 minutes prior to dosing) 
2 
00:30 
3 
00:45 
4 
01:00 
5 
01:15 
6 
01:30 
7 
02:00 
Day 1 (last dose)  
 
 
 
8 
Pre-Last Dose 
9 
00:30 
10 
01:00 
11 
01:30 


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Test Period 
Blood Sample 
Number 
Time from Dosing 
 
 
 
 
 
 
12 
02:00 
13 
02:30 
14 
03:00 
15 
03:30 
16 
04:00 
17 
05:00 
 
Day 2 (last dose) 
18 
Pre-Last Dose 
19 
00:30 
20 
01:00 
21 
01:30 
22 
02:00 
23 
02:30 
24 
03:00 
25 
03:30 
26 
04:00 
27 
05:00 
Day 3 (last dose) 
 
28 
Pre-Last Dose 
29 
00:30 
30 
01:00 
31 
01:30 
32 
02:00 
33 
02:30 
34 
03:00 
35 
03:30  
36 
04:00 
37 
05:00 
Day 4 (prior to first dose) 
38 
Pre-Dose 
Day 12 (last dose) 
 
39 
Pre-Last Dose 
40 
01:00 
41 
01:30 
42 
02:00 


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Test Period 
Blood Sample 
Number 
Time from Dosing 
43 
02:30 
44 
03:00 
45 
03:30 
46 
04:00 
Day 13 (prior to first dose) 
47 
Pre-Dose 
 
Day 16 (last dose) 
 
48 
Pre-Last Dose 
49 
01:00 
50 
01:30 
51 
02:00 
52 
02:30 
53 
03:00 
54 
03:30 
55 
04:00 
Day 17 (prior to first dose) 
56 
Pre-Dose 
Day 20 (last dose) 
 
57 
Pre-Last Dose 
58 
01:00 
59 
01:30 
60 
02:00 
61 
02:30 
62 
03:00 
63 
03:30 
64 
04:00 
Day 21 (prior to first dose) 
65 
Pre-Dose 
Day 24 (last dose) 
 
66 
Pre-Last Dose 
67 
01:00 
68 
01:30 
69 
02:00 
70 
02:30 
71 
03:00 
72 
03:30 


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Test Period 
Blood Sample 
Number 
Time from Dosing 
73 
04:00 
Day 25 
74 
Pre-dose 
75 
00:30 
76 
00:45 
77 
01:00 
78 
01:15 
79 
01:30 
80 
01:45 
81 
02:00 
82 
02:15 
83 
02:30 
84 
02:45 
85 
03:00 
86 
03:15 
87 
03:30 
88 
03:45 
89 
04:00 
90 
05:00 
91 
06:00 
92 
08:00 
93 
10:00 
94 
12:00 
Day 26 
95 
24:00 (post Day 25 dose) 
 
The pre-dose blood samples will be collected within 60 minutes prior to dosing. The post-dose 
blood samples will be collected within +/-1 minute from the scheduled sampling time. The clock 
time will be recorded and reported for all blood draws and all subjects. A deviation greater than 
+/- 2 minutes will be reported as a protocol deviation and its cause will be recorded.  
In case blood sampling for pharmacokinetics and other procedures coincide in time, blood draws 
will have priority unless other procedures are necessary for assuring subject’s safety.  
Immediately upon sampling, the blood sample for pharmacokinetic analysis will be identified 
with a bar-coded label bearing details of study number, subject number, study phase/period, 
sampling time point, sample type and a unique 9-digit identification number. The samples will be 


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logged, immediately placed on ice and then centrifuged within 60 minutes of draw at 1500 x g, 
4°C for 10 minutes. Two equal aliquots of plasma will be transferred to polypropylene tubes 
labeled identically to the original blood sample (except sample type being plasma instead of 
whole blood) and logged when stored at approximately -20°C, pending analysis.  
12.2. 
Pharmacokinetic Urine Collection 
Two urine samples will be collected during treatment on Day 1 and on Day 25 as follows: 
• Pre-dose (pre-dose urine samples will be taken upon waking up) 
• 0-24 hour 
The urine collection containers will be identified with a bar coded label bearing details of the 
study number, subject number, study period number (Day 1 or Day 25), sampling time-point, 
sample type and a unique 9 digit identification number. 
The urine collection containers will be kept chilled (at approximately 4°C) during collections. 
After the termination of the 24 hour collection the volume excreted will be recorded and 
2 x 10 mL aliquots retained for determination of cytisine concentrations. The aliquots will be 
labelled identically to the original collection container and will be stored at -20°C pending 
analysis. 
12.3. 
Determination of Plasma and Urine Drug Concentrations 
Cytisine concentrations (ng/mL) in plasma and urine will be determined using a validated liquid 
chromatography tandem mass spectrometry method and will be conducted in accordance with 
Good Laboratory Practice regulations and guidelines.  
The sample analysis will only begin after the last sample of a study subject is collected. All 
samples from each subject will be analysed in the same analytical batch. In each run, standard 
and quality control samples will be distributed throughout the batch containing study samples. 
Samples with concentrations above the ULOQ will be diluted and re-assayed.  
Full details, including the lower (LLOQ) and upper (ULOQ) limits of quantification range, will 
be provided in a Bioanalytical Phase Plan written by 
esearch Ltd. 
Plasma and urine samples of withdrawn subjects should also be analysed for drug concentrations 
and pharmacokinetic parameters (providing withdrawal was not due to withdrawal of consent).  
Unacceptable values due to analytical reasons will be handled in accordance with the 
Bioanalytical Phase Plan.  
Details of the methodologies used and the results obtained, including details of re-measured 
samples, will be given in the Analytical Study Report. 
12.4. 
Incurred Samples Reanalysis 
In order to establish the reproducibility of the assay, 10% of the first 1000 samples and 5% of the 
number of samples exceeding 1000 samples will be reanalysed. 


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Both the original and replicate values will be presented in the Analytical Study Report with the 
percent difference between the two values. The original value will be the one used for 
pharmacokinetic analysis. 
13. 
SAFETY ASSESSMENTS 
13.1. 
Subject’s Safety 
Only current smokers who are healthy by inclusion and exclusion criteria are eligible for the 
study. Subjects’ safety will be monitored during the study. Adverse events will be monitored and 
recorded throughout the study.  
Prior to the first IMP dosing only, the Principal Investigator or designee will assess the clinical 
significance of results of ECG readings and laboratory investigations for haematology and serum 
chemistry values outside the defined normal ranges, as provided by the laboratory. All changes 
from screening during the study and meet clinically-significant definitions for laboratory adverse 
events will be recorded as an adverse event. 
In addition to the planned times, any safety procedures can be performed at any time considered 
necessary by the Principal Investigator or designee.  
On each day where subjects are in the clinic, at least one physician (Principal Investigator or 
designee) will physically remain at the clinical site, and will remain available on call at all times 
during the entire period of the study.  
In case any clinically significant abnormality is observed at pre-dose, the Principal Investigator 
or designee will decide whether the subject will proceed to investigational product administration 
or will be withdrawn from the study. 
Safety will be assessed by consideration of all adverse events reported by or elicited from the 
subject and abnormalities detected on haematology, serum chemistry tests, urinalysis, and 
12-lead ECG. Worsening of other preexisting medical conditions and any changes to 
concomitant medications/treatments will also be taken into account in this evaluation.  
All adverse events (serious and non-serious) beginning on Day 1 (prior to dosing) through post-
study follow-up visit will be recorded in the subject’s CRF.  
13.2. 
Adverse Events 
13.2.1. 
Definition of Adverse Event 
The definitions are adopted in accordance with the Directive 2001/20/EC, ICH-E2A and the 
European Commission Detailed Guidance 2011/C 172/01. 
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 a causal relationship with 
the treatment. 
An AE can therefore be any unfavorable and unintended sign (including any clinical significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 


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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 a causal relationship has at least a reasonable possibility, i.e. the relationship cannot 
be ruled out and is judged by the Principal 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 unauthorised investigational 
product or in the SmPC for an authorised 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 
events 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 hospitalisation or prolongs existing inpatient’s hospitalisation 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• Is an important medical event which requires medical intervention to prevent any of 
the above outcomes 
SUSARs: AEs which meet all of the following criteria: 
• 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 a causal relationship between the 
event and the medicinal product.  
will be classified as suspected unexpected serious adverse reactions (SUSARs). 
Important medical events are those which may not be immediately life-threatening, but may 
jeopardise the subject and may require intervention to prevent one of the other serious outcomes 
listed above. Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm, or blood dyscrasias or convulsions that do not result in 
hospitalisation. 


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The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe. For example, drug-induced hepatitis that 
resolves without evidence of hepatic failure would not be considered life threatening even 
though drug-induced hepatitis can be fatal. 
Inpatient hospitalisation or prolongation of existing hospitalisation 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. 
13.2.2. 
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 the Principal Investigator or designee in 
accordance with the definitions below. 
• Relationship to IMP to be assessed by the Principal Investigator or designee 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 should be reviewed at the end of 
each treatment period 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. 
13.2.3. 
Grades of Adverse Event Severity 
The following grades will be used by the Principal Investigator or designee to describe the 
severity of all AEs (including clinically-significant laboratory AEs) as shown in Table 8. Only 1 
severity grade will be used for each AE (e.g. mild - moderate is not acceptable). 
Table 8: 
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 or significantly interferes with daily activity and 
requires medical intervention 


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If an adverse event has multiple aspects, the aspect in the highest intensity will be graded. It is 
emphasised that the term severe is a measure of intensity; thus a severe AE is not necessarily 
serious. For example, itching for several days may be rated as severe; however, may not be 
clinically serious.  
13.2.4. 
Assessment of Causal Relationship 
The causal relationship between an adverse event and cytisine will be determined and 
documented by the Principal Investigator or designee, according to best medical judgment as 
shown in Table 9.  
Table 9: 
Assessment of Causal Relationship to Cytisine 
Catagory 
Description 
Not Related 
The event is definitely not associated with cytisine.  
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 cytisine 
Possible 
The event follows a reasonable temporal sequence from the time of cytisine 
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 cytisine 
administration, and/or follows a known response pattern to the 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 cytisine 
administration, and/or follows a known response pattern to the 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 
investigational product administration, or improves on stopping the investigational 
product. 
13.2.5. 
Reporting of Serious Adverse Events 
Any new SAE that occurs during a treatment period should be recorded and reported 
immediately. All SAEs including those that are ongoing at the end of study treatment will be 
followed until each event resolves or is assessed as chronic.  
In order to satisfy regulatory requirements, any Serious Adverse Event, whether deemed study 
drug-related or not, must be reported to the Sponsor or designee as soon as possible after the 
Principal Investigator or designee 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 to 
 


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vices Ltd will notify the Sponsor and Sponsor's Medical Monitor 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.  
The following information should be provided to accurately and completely record the event: 
• Principal Investigator name and center number 
• Subject number 
• Subject initials, if permitted 
• Subject demographics 
• Clinical event 
− description 
− date of onset 
− severity 
− treatment 
− relationship to study drug (causality) 
− 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 treatment period must be followed clinically until all 
parameters (including laboratory) have either resolved or been assessed as chronic.  
SUSARs should be reported to the REC, Healthcare products Regulatory Agency (MHRA) and 
Sponsor in accordance with applicable regulatory requirements for expedited reporting. It is 
Si
ec’s responsibility to report SUSARs to the REC and MHRA. It is the Sponsor’s 
responsibility to report any SUSAR to the FDA. 
13.2.6. 
Monitoring of Subjects with Adverse Events 
In the event of any abnormalities considered to be clinically significant by the investigating 
physician, subjects will be followed up with appropriate medical management until: 
• It has resolved/returned to normal or baseline. 
• The event has stabilised at a level acceptable to the Principal Investigator or designee 
and is not considered to be clinically significant. 


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13.3. 
Pregnancy 
Serum pregnancy test will be performed for all females regardless of post-menopausal or 
sterilised status at screening. Pregnancy tests will be performed by S
 L
 
Serum pregnancy tests will be performed using the Roche Cobas c6000 analyser series 
comprising of c501 and e601 modules.  
Pregnancies must be reported immediately and followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or new-born complications. Pregnancy 
outcomes must be collected for females who took the IMP and the female partners of any males 
who took the IMP. Consent to report information regarding these pregnancy outcomes should be 
obtained from the mother.  
13.4. 
Laboratory 
13.4.1. 
Routine Laboratory Assessments 
Routine laboratory safety samples will be analysed by 
at screening 
and prior to discharge at each clinic visit for each subject. Printed laboratory reports will include 
normal reference ranges. A decision regarding whether the result outside the reference range is 
of clinical significance or not shall be made by the Principal Investigator or designee and the 
report will be annotated accordingly. Clinically significant abnormalities at screening or 
occurring during the study will be recorded on the AE page. The reference ranges for laboratory 
parameters will also be filed in the Investigator site file. 
Haematology: Haemoglobin (HGB), haematocrit (HCT), mean cell volume (MCV), mean cell 
haemoglobin (MCH), mean cell haemoglobin concentration (MCHC), red blood cells (RBC), 
white blood cells (WBC), neutrophils (NEUT), lymphocytes (LYMP), monocytes (MONO), 
eosinophils (EOS), basophils (BASO) and platelets (PLT).  
Samples will be collected into a 2.7 mL ethylenediaminetetraacetic acid (EDTA) Sarstedt 
Monovette® collection tube (or equivalent) and analysed using the Siemens Advia 2120® or 
Siemens Advia 120®. 
Biochemistry: Total protein (TP), albumin (ALB), total bilirubin (BIL-T), alanine transaminase 
(ALT), aspartate transaminase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase 
(ALKP), glucose (GLU), sodium (NA), potassium (K), calcium (CA), bicarbonate (HCO3), 
creatinine (CREA) and urea. 
At screening, biochemistry samples will be collected into a Sarstedt Monovette 4.7 mL z-gel 
collection tube (or equivalent). This volume allows sufficient serum for virology and pregnancy 
test screening. At all other visits, biochemistry safety samples will be collected into a 4.5 mL 
plain Sarstedt Monovette collection tube (or equivalent). Biochemistry samples will be analysed 
using the Roche Cobas c6000 analyser series comprising of c501 and e601 modules. 
Urinalysis: A mid-stream urine sample will be collected into a 20 mL Sterilin tube. Urinalysis 
will be performed using the Siemens Clinitek 500 analyser or the cobas U6500. Tests included in 
the Urinalysis screen are SG, pH, leukocytes, nitrites, protein, glucose, ketones, urobilinogen, 
bilirubin, blood.  


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 In the event that the ‘dipstick’ is positive for leukocytes, nitrites, protein and blood, RBCs, 
WBCs, epithelial cells, crystals, bacteria and casts will be examined microscopically. Samples of 
menstruating females may not be send for microscopy if blood is positive. The microscopy will 
be performed at 
 using the cobas u6500 701 module or referred to a local specialist 
hospital laboratory for analysis. Other positive parameters will be managed as appropriate.  
13.4.2. 
Expired Air Carbon Monoxide (CO) 
Expired CO will be obtained using the Bedfont Micro+ Smokerlyzer®. Levels for moderate 
smokers are defined as >11 ppm, compared to 0-6 ppm for non-smokers. 
13.4.3. 
Virology 
Virology (Hep B, Hep C and HIV) will be performed at screening.  
Virology will be analysed from the Sarstedt Monovette 4.7 mL z-gel biochemistry screen by 
, S
 using the Roche Cobas c6000 analyser series comprising of c501 
and e601 modules. 
13.4.4. 
Drugs of Abuse and Alcohol 
Urine alcohol and drugs of abuse screen: Cannabinoids, amphetamines, cocaine, 
benzodiazepines, opiates and cotinine. 
A mid-stream urine sample will be collected into a 20 mL Sterilin tube. At time-points when 
both urinalysis and drugs of abuse / alcohol screening is required, all testing will be performed 
from a single 20 mL sample. 
Drug of abuse and alcohol samples will be analysed by 
, 
using the 
Roche Cobas c6000 analyser series comprising of c501 and e601 modules.Vital signs  
13.5. 
Vital signs 
Systolic/diastolic blood pressure and pulse rate and oral temperature.  
Measurements will be recorded in the supine position after 5 min supine. Blood pressure, pulse 
and temperature will be measured by the DINAMAP* Compact Vital Signs Monitor (Model TS) 
or equivalent. Normal ranges for vital signs are presented in Appendix 1. 
13.6. 
Physical Examination 
A physical examination will be performed by the Principal Investigator or designee. 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. The Principal Investigator or designee can examine other 
body systems if required, at their discretion. 
13.7. 
ECG Measurements 
ECGs will be conducted using a 12-lead ECG at Screening, Day -1 and again prior to discharge 
from the clinic on Days 4, 13, 17, 21 and 26. Heart rate, PR interval, QRS width, QT interval, 
and QT interval corrected using Fridericia’s formula (QTcF) will be documented.  


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12-lead ECG recordings will be made using a MAC 5500 or equivalent. Each ECG trace should 
be labelled with the study number, subject number, subject initials and date of birth. An 
Investigator will provide an interpretation of each tracing. Clinically significant abnormalities 
will be recorded on the AE page. Normal ranges for 12-lead ECG parameters are presented in 
Appendix 1. 
13.8. 
12-Lead ECG Holter 
12-lead ECG Holter recording will begin on Day 1 and Day 25, prior to dosing and continue 
until approximately 24 hours post dosing. 
13.9. 
Subject Diary 
All subjects will maintain a daily smoking/medication diary, starting on Day 1 and ending at the 
Post-Study Visit (6-8 days after the last dose). This will include all time spent in the clinic. 
Subjects are to record the number of cigarettes smoked in past 24 hours (daily consumption) and 
actual time they take medication. In addition, subjects are to record any adverse events 
experienced outside of clinic. Clinic personnel are to review diary when subject is in the clinic 
and document the number of cigarettes smoked and the actual time medication was taken.  
13.10. 
Concomitant Medication 
All prior and concomitant medications taken during the study will be recorded in the subject’s 
CRF. 
14. 
APPROPRIATENESS OF MEASUREMENTS 
All measurements performed in the study are standard measurements. 
The total volume of blood to be collected from each subject during the study (approximately 
328 mL) is considered acceptable. (See Table 10).  
Table 10: 
Summary of Blood Volumes 
Procedure 
Visit 
No. Samples 
Blood 
Volume per 
Sample (mL) 
Total Blood Volume 
(mL) 
Biochemistry  Screeninga 
Day 4, 13, 
17, 21, 26 
1 
5 
4.7 
4.5 
4.7 
22.5 
Haematology  Screening 
Day 4, 13, 
17, 21, 26 
1 
5 
2.7 
2.7 
2.7 
13.5 
PK Drug 
Conc. 
Measurement 
Treatment 
Period 
95 
3.0 
285 
Total Blood Volume 
328 
a From the screening biochemistry blood samples, the serum pregnancy test and virology screen will be conducted.  


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15. 
STATISTICAL METHODS 
15.1. 
Primary Objectives and Analysis 
All data recorded during the course of the study or derived during the programming phase will be 
presented in individual data listings. 
Unless specified otherwise, continuous variables will be summarised with the following 
descriptive statistics: n (number of observations), arithmetic mean, standard deviation (SD), 
minimum value, median and maximum values. For PK summaries, the geometric mean and 
coefficient of variation (%CV) will also be used to summarise the data. Categorical data will be 
summarised with frequencies and percentages.  
Unless specified otherwise, the minimum and maximum statistics will be presented with the 
same precision as the original data. The mean, median and geometric mean will be presented to 
one more decimal place than the original data. The SD will be presented to two more decimal 
places than the original data. Unscheduled measurements will be listed in the individual data 
listings. With the exception of baseline, unscheduled measurements will be excluded from the 
descriptive statistical analysis. In case an unscheduled measurement is performed immediately 
after the scheduled measurement due to an error in the previous measurement, the unscheduled 
measurement will be included in the analysis and the original erroneous measurement will be 
excluded. 
For subject characteristics and safety analyses, missing data will not be replaced; descriptive 
statistics and statistical analysis will be performed on the basis of the available data only. 
Subjects discontinued will be included in the descriptive statistics if they have received the 
investigational product and their examinations were performed at the same scheduled time as 
other subjects. All data recorded on discontinued subjects will be listed. 
15.2. 
Subject Population for Analyses 
15.2.1. 
Safety Analysis Set 
All subjects who received at least one dose of cytisine will constitute the safety population.  
15.2.2. 
PK Analysis Set 
The PK Analysis Set will include subjects who have completed all cytisine dosing on Day 1-3, 
completed >90% cytisine dosing on Days 4-25, and comply with the following criteria: 
• Do not have an occurrence of vomiting or severe diarrhoea which renders the 
concentration profile unreliable;  
• Do not use a concomitant medication which renders the concentration profile 
unreliable;  
• Have at least one evaluable concentration that is preceded by a lower evaluable 
concentration and followed by a lower evaluable concentration for the calculation of 
Cmax; 


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• Do not violate the protocol (major protocol violation) in a way that may invalidate or 
bias the PK results. 
15.2.3. 
Pharmacodynamic (PD) Analysis Set 
The PD Analysis Set will include all subjects in the PK Analysis Set who have an available 
baseline result and at least one on-treatment result with regards to urine cotinine, expired air CO 
or daily cigarette consumption and do not incur a major protocol violation in a way that may 
invalidate or bias the PD results. 
15.3. 
Subjects Characteristics 
Separate summaries of demographics will be provided for both safety and PK analysis sets if 
applicable. 
The protocol violations will be listed per subject, describing the nature of the violation. Subjects 
failing to complete the study (as well as the date and reasons for discontinuation) will be 
displayed. Time may be added if relevant to the nature of the violation. 
Medical history will be referred in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA), version 20.0 or higher. Medications will be mentioned according to the 
Anatomical Therapeutic Chemical (ATC) classification system using WHO Drug Dictionary. 
15.4. 
Sample Size Calculation 
A total of approximately 36 subjects will be randomised to the study, with approximately 18 
subjects per treatment schedule arm (12 age 18-65 and 6 age >65).  
No previous pharmacokinetic studies with cytisine have reported the effects of repeated 
administration, so no estimates of intra-subject variability of Cmax, Cmin or AUC are available. No 
specific hypothesis testing is planned. Post-hoc analyses may be performed for PK or PD effects 
that may appear significantly different between the dosage groups or age groups. In general the 
sample size of 36 should be sufficient to meet the exploratory objectives of the study. 
Subjects who withdraw from study at any time after randomisation will not be automatically 
replaced. Replacement based on the number and reason of withdrawals will be at discretion of 
the Sponsor, following discussion with the Principal Investigator.  
15.5. 
Plasma and Urine Concentrations 
Descriptive statistics will be provided to summarise plasma and urine concentrations at each time 
point. Concentrations below the LLOQ will be replaced by zero for calculation of descriptive 
statistics.  
Individual drug plasma concentrations versus time profiles will be plotted per subject on both a 
linear and a semi-logarithmic scale. For plotting of individual data in linear scale, concentrations 
below the LLOQ will be replaced by zero. For plotting of individual data in semi-logarithmic 
scale, concentrations below the LLOQ will be set to missing. Graphical presentation of 
individual data will be based on actual blood sampling times. 
Arithmetic mean drug plasma concentration versus time profiles will be presented on both a 
linear and a semi-logarithmic scale.  


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The post-dose blood samples will be collected within ±2 minutes from the scheduled sampling 
time. A deviation greater than ±2 minutes will be reported as a protocol deviation.  
15.6. 
Estimation of pharmacokinetic parameters 
Plasma: The following pharmacokinetic parameters for cytisine will be derived by standard non-
compartmental methods from the concentration versus time profiles: 
Table 11: 
Cytisine Pharmacokinetic Parameters 
Parameter 
Description 
Cmax  
Maximum observed plasma concentration post dose, directly obtained from the observed 
concentration versus time profile. 
Tmax 
Time of occurrence of Cmax. 
Cmin  
Minimum observed plasma concentration prior to the last daily dose or prior to each 
scheduled dose change in both treatment group A and B. 
AUC0-t 
Area under the plasma concentration versus time curve (AUC) from time zero to the last 
sampling time at which concentrations were at or above the LLOQ, calculated by the 
linear-up/log-down trapezoidal rule. 
AUC0-∞ 
Total AUC from time zero to infinity, calculated as AUC0-∞ = AUC0-t + (Clast/λz), where Clast 
is the last measurable plasma concentration and λz the apparent terminal elimination rate 
constant. 
%AUC 
Residual area or percentage of extrapolated part for the calculation of AUC0-∞, calculated as 
100*[1-(AUC0-t/AUC0-∞)] 
λz 
Apparent terminal elimination rate constant. 
t1/2 
Apparent terminal elimination half-life, calculated from ln 2/λz. 
No values of λz, AUC0-∞, %AUC and t1/2 will be reported for cases where λz cannot be reliably 
determined. 
Pharmacokinetic parameters of cytisine will be derived from the plasma concentrations-time 
profiles, by using a non-compartmental approach with a ln-linear terminal phase assumption. 
Actual times of sampling will be used. 
Cmax will be calculated after the first dose and the last dose on Day 1, after the last dose on days 
2, 3, 12, 16, 20, 24 and after the morning dose on Day 25. 
Cmin will be derived from pre the first dose plasma values on days 4, 13, 17, 21 and 25.  
The t1/2 and AUC (AUC0-t and AUC0-∞) will be determined after the administration of the final 
dose of cytisine on Day 25. 
Derived plasma pharmacokinetic parameters will be listed and summarised by dose group 
(1.5 mg, 3.0 mg), and age (18-65, >65 and overall). 
Urine: The  amount excreted in urine over time (Ae) and percent of drug excreted in urine 
(Ae%) will be derived from Day 1 and Day 25 24 hour urine data for all subjects in the safety 
analysis set. Derived urine PK parameters will be listed and summarised by treatment dosing 
(1.5 mg, 3.0 mg), and age (18-65, >65 and overall).  
15.7. 
Pharmacokinetic Analysis 
Comparisons of Cmax and Cmin between schedule changes within a dose group will be performed 
using analysis of variance (ANOVA) on log-transformed data. Point estimates and 90% 


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confidence intervals (CI) will be constructed for the contrasts between schedule changes which 
will be back-transformed to give estimates of the ratios of the geometric least squares means 
(LSmean) and corresponding 90% CI. This analysis will be performed by age group (18-65, >65 
and overall) within a dose group.  
Comparisons of the Day 25 Cmax, AUC0-t and AUC0-∞ values between dose groups will be 
performed using an ANOVA on log-transformed data. Point estimates and 90% confidence 
intervals (CI) will be constructed for the contrast between the 1.5 mg and 3 mg dose groups 
which will be back-transformed to provide an estimate of the ratio of the geometric LSmean and 
corresponding 90% CI. This analysis will be performed by age group (18-65, >65 and overall). 
15.8. 
Pharmacodynamic Data 
In order to evaluate any reduction in smoking, expired air monoxide (CO), urine cotinine results 
and the number of cigarettes smoked daily will be listed and descriptive statistics of absolute and 
change from baseline results will be tabulated by dose group and age group (18-65, >65 and 
overall). The mean change from baseline values will also be presented graphically. 
15.9. 
Safety Variables and Analyses  
All safety data will be listed using the safety analysis set. Safety summaries will include the 
number of subjects with adverse events, serious adverse events, and adverse events leading to 
discontinuation. Adverse events will be assessed by clinical observation and spontaneous 
reporting by subjects. In addition, number of subjects with clinically significant abnormalities in 
laboratory values will be summarized. 
15.9.1. 
Holter ECGs 
The following ECG parameters will be extracted in triplicate from Holter recordings on Day 1 
and Day 25 at 30 and 15 minutes prior to the first dose and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h 
and 24 h post dose: 
• Heart Rate (HR) 
• PR intervals  
• QRS  
• QT  
• QTcF 
If a large change in heart rate is observed during the study, the individual QT correction method 
(QTcI) will be used as the primary QT correction method. 
The extracted ECG parameters will be listed with any out of normal range values flagged 
(“H” -high or “L” -low). The ECG results will assessed as either “normal” or “abnormal”. Any 
comments on abnormal results will also be provided. Descriptive statistics of absolute and 
change from baseline values at each time point will be tabulated by dose group and age group 
(18-65, >65 and overall).  
In addition, frequencies of QTcF data will be calculated according to the following categories: 


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For absolute values: 
• QTcF ≤ 450 mSec 
• 450 < QTcF ≤ 480 mSec 
• 480 < QTcF ≤ 500 mSec 
• QTcF > 500 mSec. 
For change from baseline: 
• QTcF increase ≤ 30 mSec  
• 30 < QTcF increase ≤ 60 mSec  
• QTcF increase > 60 mSec. 
Abnormalities in ECGs will be classified in terms of clinical significance. Clinically significant 
abnormalities will be reported as AEs. The number and percentage of subjects developing new 
ECG abnormalities will be summarised. The presence of outliers will be explored for heart rate, 
PR, QRS, QT and QTcF. Details of this analysis will be described in the Statistical Analysis Plan 
(SAP). 
In order to explore the effects of cytisine on QTc prolongation, plasma concentrations will be 
plotted against change from baseline QTcF values. 
15.9.2. 
12-Lead ECGs 
12-Lead ECG parameters will be listed with any out of normal range values flagged (“H” -high 
or “L” -low) as described in the SAP. Descriptive statistics of absolute and change from baseline 
values at each time point will be tabulated by dose group and age group (18-65, >65 and overall). 
Abnormalities in ECGs will be classified in terms of clinical significance. Clinically significant 
abnormalities will be reported as AEs. 
15.9.3. 
Vital Signs 
Vital signs parameters will be listed with any out of normal range values flagged (“H” -high or 
“L” -low). Descriptive statistics of absolute and change from baseline values at each time point 
will be tabulated by dose group and age group (18-65, >65 and overall). 
Abnormalities in vital signs will be classified in terms of clinical significance. Clinically 
significant abnormalities will be reported as AEs. 
15.9.4. 
Adverse Events 
AEs will be tabulated and summarised according to the MedDRA version 20.0 or higher, and 
classified by system organ class (SOC) and preferred term (PT). The following information 
recorded or computed is used for the description of the adverse events: reported Term; SOC and 
PT by MedDRA coding; onset date, onset time, resolution date and resolution time; seriousness; 
severity (intensity); relationship (causality); action taken; outcome. 
Treatment-emergent adverse events (TEAEs) are defined as AEs not present prior to first 
administration of investigational product, or AEs present before first administration of 


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investigational product that worsen after the subject receives the first dose of investigational 
product. TEAEs that occur after administration of investigational product in a given period are 
assigned to the treatment administered in that period. A separate listing of SAEs will be 
presented, if applicable. 
Frequencies of TEAEs will be presented by SOC and PT, severity and relationship, by dose 
group, age group and overall. 
15.9.5. 
Safety Laboratory tests 
Biochemistry, haematology and urinalysis parameters will be listed with any out of normal/alert 
range values flagged. Laboratory test results which are out of normal range will also be presented 
separately along with normal reference ranges. Descriptive statistics of absolute and change from 
baseline biochemistry and haematology values at each time point will be tabulated by dose group 
and age group (18-65, >65 and overall). 
Abnormalities in clinical laboratory tests will be classified in terms of clinical significance. 
Clinically significant abnormalities will be reported as AEs. 
15.10. 
Procedures for Deviations from Planned Analyses 
The planned statistical analyses for this study will be described in detail in a SAP. Modifications 
or additions to the analyses described above will be described in the SAP. Any decisions to 
deviate from the planned analyses described in the protocol and SAP will be documented in the 
clinical study report. The clinical study report will also provide a detailed explanation for any 
deviations from the planned analyses. 
16. 
DOCUMENTATION  
16.1. 
Study File and Site Documents 
Prior to the initiation of the study, the following items must be received by the Sponsor from the 
site: 
• Confidential Disclosure Agreement.  
• Signed protocol, and amendment(s) page(s).  
• The Principal Investigator’s curriculum vitae and where required current medical 
license. 
• Signed Clinical Study Agreement. 
• Signed Financial Disclosure Form from the relevant site personnel. 
• Signed Data Protection Form (for EU member states only). 
• Competent/Regulatory Authority written approval (if applicable). 
• EC written approval for the protocol, amendment(s), Informed Consent Form, Subject 
Information Sheet (if applicable), advertisements (if applicable). 


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• EC Membership list or an official statement from the EC/IRB stating the EC/IRB is in 
compliance with the EU Directive on Good Clinical Practice (GCP). 
• Local laboratory certification and normal ranges. 
16.2. 
Study Documents Supplied by the Sponsor 
The Sponsor will supply the Investigator with the following items: 
• Current version of the Investigator’s Brochure.  
• Current version of study protocol. 
16.3. 
Maintenance and Retention of Records 
It is the responsibility of the Investigator to maintain a comprehensive and centralised 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: 
− For a period of at least 2 years from the last marketing approval worldwide or for 
at least 15 years, whichever is the greater. 
− Or a period of at least two years after discontinuation of clinical development of 
the investigational product as confirmed by the Sponsor. 
− For a longer period if required by local regulations. 
The Investigator will be instructed to consult with the Sponsor before disposal of any study 
records and to provide written notification to the Sponsor of any change in the location, 
disposition, or custody of the study files. 
17. 
ADMINISTRATIVE PROCEDURES 
17.1. 
Sponsor Responsibilities 
The study will be monitored by representatives of the Sponsor and/or designated contract 
research organisations. Routine monitoring visits will be conducted to: 
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 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 medication. 


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5. Review the subject CRFs and source documents to ensure that reported study data are 
accurate, complete, and verifiable from source documents. 
6. Ensure that adequate records of clinical trial supplies are maintained. 
7. Verify that the Investigator and study site personnel are adequately qualified throughout 
the study. 
8. Verify that the safety information and amendments are submitted to the IRBs/ECs/REBs. 
17.2. 
Investigator Responsibilities 
All requested study data must be entered on the CRFs for the study. An explanation should be 
provided for all missing data. Correction of data on a CRF will be made with identification of the 
individual making the correction and date of the correction. Only individuals who are identified 
on the Delegation of Responsibility Form(s) may correct data on the CRF. For those subjects 
who withdraw before completion of their specified treatment regimen, all available efficacy and 
safety data must be entered in the CRF. The reason for withdrawal must be specified. Incomplete 
or inconsistent data on the CRFs will result in data queries that will be returned to the 
Investigator for resolution. 
The Investigator must maintain adequate and accurate source documents upon which CRFs for 
each subject are based. The source documents are to be separate and distinct from the CRFs, 
except for cases in which the Sponsor has predetermined that direct entry into specified pages of 
the subject’s CRF is appropriate. The documents to be maintained must include, but are not 
limited to, detailed notes on: 
1. The medical history prior to participation in the study. 
2. The basic identifying information, such as demographics, that link the subject’s source 
documents with the CRFs. 
3. The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject. 
4. The subject’s exposure to study treatment. 
5. All AEs. 
6. The subject’s exposure to any concomitant therapy, including dates of administration. 
7. All relevant observations and data on the condition of the subject throughout the study. 
8. The oral and written communication with the subject regarding the study treatment, 
including the risks and benefits of the study. The date of informed consent must be 
recorded in the source documentation. 
18. 
REGULATORY COMPLIANCE 
Quality Assurance representatives from the Sponsor or their delegate, the MHRA, and all other 
regulatory agencies 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 


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necessary to ensure that the study is conducted according to standards consistent with the ICH 
GCP Guideline. 
The Investigator agrees to discuss and correct, if necessary, any problems or deficiencies that are 
found during the course of these reviews. 
19. 
ETHICAL CONDUCT OF THE TRIAL / GOOD CLINICAL 
PRACTICE 
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, the Food and Drugs Act (Health 
Canada), and local requirements regarding IRB/EC/REB committee review, informed consent, 
and other statutes or regulations regarding the protection of the rights and welfare of human 
subjects participating in biomedical research. The Chief Investigator shall be responsible for 
ensuring that the clinical study is performed in accordance with the following: 
• Declaration of Helsinki (Brazil, 2013). 
• Association of the British Pharmaceutical Industry (ABPI) Guidelines for Phase 1 
Trials (2012). 
• International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline 
for Good Clinical Practice (GCP). 
• The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory 
Instrument 2004 No. 1031) and subsequent amendments. 
• Applicable local standard operating procedures (SOPs). 
As this clinical study will be conducted in the United Kingdom, it has been registered in the 
EudraCT database and a Clinical Trials Authorisation (CTA) will be obtained from the 
Medicines and Healthcare products Regulatory Agency (MHRA) prior to the start of the study in 
accordance with Part 3, Regulation 12 of the United Kingdom (UK) Statutory Instrument. In 
addition, this study protocol will be included in an Investigational New Drug (IND) application 
with the US FDA for cytisine development. 
20. 
PROTOCOL MODIFICATION/PREMATURE TERMINATION 
All protocol amendments must be written and approved by the Sponsor. Each IRB, EC, or REB 
will review and approve amendments prior to their implementation in the study. IRB, EC, or 
REB approval need not be obtained prior to removal of an immediate hazard to subjects. 
The Sponsor may terminate the protocol early if safety or other issues occur. 
The study may be suspended or terminated by either the Principal Investigator or the Sponsor 
after mutual consultation at any time for scientific and safety reasons. Furthermore, the study 
may also be terminated prematurely by the Sponsor for important corporate reasons, or due to 
instruction of the Regulatory Authorities due to safety reasons.  
Following a decision of temporary suspension or discontinuation, it is a responsibility of the 
Principal Investigator to inform the study subjects, Ethics Committee and Regulatory Agency, 


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stating the reasons for premature termination. Si
ec shall be responsible for expedited 
reporting and/or notification to MHRA/EMA. The Sponsor shall be responsible for expediting 
reporting and/or notification to other regulatory authorities, as applicable.  
21. 
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.  


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22. 
INVESTIGATOR’S AGREEMENT  
 
Protocol No. ACH-CYT-02 
 
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 pre-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 
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 (ddMmmYYYY) 
 
Date (ddMmmYYYY) 
 
 
 
Institution 
 


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23. 
REFERENCES 
1. 
WHO. WHO Report on the Global Tobacco Epidemic, 2008 The MPOWER package. 
Geneva2008. 
2. 
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. 
3. 
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. 
4. 
WHO. WHO Framework Convention on Tobacco Control2003. 
5. 
Etter J. Cytisine for smoking cessation: A literature review and a meta-analysis. Archives 
of Internal Medicine 2006;166:1553-9. 
6. 
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. 
7. 
Rigotti NA. Cytisine--a tobacco treatment hiding in plain sight. The New England journal 
of medicine 2014;371:2429-30. 
8. 
Aveyard P, West R. Cytisine and the failure to market and regulate for human health. 
Thorax 2013;68:989. 
9. 
Walker N, Bullen C, Barnes J, et al. Getting cytisine licensed for use world-wide: a call 
to action. 2016;111:1895-8. 
10. 
Jeong SH, Newcombe D, Sheridan J, Tingle M. Pharmacokinetics of cytisine, an alpha4 
beta2 nicotinic receptor partial agonist, in healthy smokers following a single dose. Drug testing 
and analysis 2015;7:475-82. 
11. 
Raw M, Anderson P, Batra A, et al. WHO Europe evidence based recommendations on 
the treatment of tobacco dependence. Tobacco control 2002;11:44-6. 
12. 
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. 
13. 
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. 
 
 


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APPENDIX 1. NORMAL RANGES FOR VITAL SIGNS AND ECG 
PARAMETERS 
 
 
Vital Signs: 
 
PARAMETER 
Normal Range for 
ages 18 to 65 
Normal Range for 
ages > 65 
Units 
Pulse 
40 - 110 
40 - 110 
Beats per Minute 
(BPM) 
Systolic Blood 
Pressure 
90 - 150 
90 - 160 
mmHg 
Diastolic Blood 
Pressure 
50 - 90 
50 - 90 
mmHg 
Oral Temperature 
35 - 37.5 
35 - 37.5 
Degree Celsius 
 
ECG Parameters: 
 
PARAMETER 
Normal Range for all ages  
Units 
Heart Rate 
40 - 110 
Beats per Minute (BPM) 
PR Interval 
120 - 220 
msec 
QRS width 
70 - 120 
msec 
QT 
N/A - should be corrected for heart rate 
QTcB - males 
350 - 430 
msec 
QTcB - females 
350 - 450 
msec 
QTcF - males 
350 - 430 
msec 
QTcF - females 
350 - 450 
msec 
 
 


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APPENDIX 2. FAGERSTRÖM NICOTINE DEPENDENCE 
QUESTIONNAIRE 
 
The Fagerström Nicotine Dependence Questionnaire (FTND) has been shown to be a reliable 
and valid measure of nicotine dependence12 and will be administered as outlined in this protocol. 
Analysis of results is outlined in the study Statistical Analysis Plan. 
 
Question 
Response 
Points* 
How soon after you wake up do you smoke your 
first cigarette? 
Within 5 minutes 
 
3 
6-30 minutes 
 
2 
31-60 minutes 
 
1 
After 60 minutes 
 
0 
 
 
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 
 
1 
No 
 
0 
 
 
Which cigarette would you hate most to give up? 
The first one in the 
morning 
 
1 
All others 
 
0 
 
 
How many cigarettes/day do you smoke? 
10 or less 
 
0 
11-20 
 
1 
21-30 
 
2 
31 or more 
 
3 
 
 
Do you smoke more frequently during the first 
hours after waking than during the rest of the day? 
Yes 
 
1 
No 
 
0 
 
 
Do you smoke if you are so ill that you are in bed 
most of the day? 
Yes 
 
1 
No 
 
0 
 
 
*Note: The actual questionnaire will not contain the points column, which is provided here to 
show how responses will be scored for analysis. 
 


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APPENDIX 3. SHORT FORM OF THE TOBACCO CRAVING 
QUESTIONNAIRE 
 
The template below has been validated as a self-report instrument to measure tobacco craving13 
and will be administered to study subjects as outlined in this protocol. 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. 
 
 
 
 
 
 
 
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. 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Achieve Life Sciences, Inc.: ACH-CYT-02 
Statistical Analysis Plan
 
 
 
 
Version date: 23 Apr 2018 
 
 
 
 
 
 
 
Page 1 of 141 
 
 
 
 
Statistical Analysis Plan 
 
Sponsor Protocol Number: ACH-CYT-02 
 
Repeat-Dose Pharmacokinetic and Pharmacodynamic Evaluation of 
Cytisine in Healthy Smokers 
 
 
 
Prepared for: 
Achieve Life Sciences, Inc. 
 
Prepared by: 
 
  
 
 
 
 
CONFIDENTIAL 
 
Version  
Author 
Final 1.0 
 
 
 


Achieve Life Sciences, Inc.: ACH-CYT-02 
Statistical Analysis Plan 
Statistical Analysis Plan 
Sponsor Protocol Number: ACH-CYT -02 
Repeat-Dose Pharmacokinetic and Pharmacodynamic Evaluation of 
Cytisine in Healthy Smokers 
Author. 
Version: 
Simbec Protocol ID: RD 735/33716 
Kerry Williams 
Final 1.0 
The undersigned have reviewed and revised this SAP and find it to be consistent with the study 
requirements: 
---------------·----·· ·--------·--·-···-·------
• 
1:,11 
-


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TABLE OF CONTENTS 
1 
INTRODUCTION ................................................................................................................................. 7 
1.1 
GENERAL ...............................................................................................................................................7 
1.2 
CHANGES FROM PROTOCOL .......................................................................................................7 
1.3 
CHANGES FROM PREVIOUS VERSIONS OF THE SAP ...........................................................7 
2 
STUDY OBJECTIVES ............................................................................................................................ 7 
3 
STUDY DESIGN ................................................................................................................................... 8 
3.1 
OVERVIEW ............................................................................................................................................8 
3.2 
INCLUSION AND EXCLUSION CRITERIA .................................................................................9 
3.3 
STUDY TREATMENT ..........................................................................................................................9 
3.4 
SCHEDULE OF STUDY PROCEDURES ...................................................................................... 10 
3.5 
SAMPLE SIZE CONSIDERATIONS ............................................................................................... 12 
3.6 
RANDOMISATION .......................................................................................................................... 12 
4 
STUDY VARIABLES AND COVARIATES .............................................................................................. 12 
4.1 
PRIMARY VARIABLES ...................................................................................................................... 12 
4.2 
SECONDARY VARIABLES .............................................................................................................. 13 
5 
DEFINITIONS AND DERIVED VARIABLES .......................................................................................... 13 
6 
ANALYSIS SETS ................................................................................................................................. 14 
6.1 
SAFETY SET......................................................................................................................................... 14 
6.2 
PK SET .................................................................................................................................................. 14 
6.3 
PD SET .................................................................................................................................................. 15 
6.4 
ECG SET ............................................................................................................................................... 15 
6.5 
ECG-PK SET ........................................................................................................................................ 15 
7 
SAFETY MONITORING ..................................................................................................................... 15 
8 
INTERIM ANALYSES ......................................................................................................................... 15 
9 
DATA ................................................................................................................................................ 15 
9.1 
CRF DATA .......................................................................................................................................... 15 
9.1.1 
Laboratory Data ................................................................................................................................. 15 
9.1.2 
Pharmacokinetic Data ....................................................................................................................... 16 
9.1.3 
ECG Holter Monitoring Data ......................................................................................................... 16 
9.2 
RANDOMISATION LIST ................................................................................................................. 16 
9.3 
PROGRAMMING AND DATA REVIEW .................................................................................... 16 
10 STATISTICAL METHODS ................................................................................................................... 17 
10.1 
GENERAL PRINCIPLES .................................................................................................................... 17 
10.2 
STRATIFICATION AND COVARIATE ADJUSTMENT .......................................................... 18 


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10.3 
MISSING DATA ................................................................................................................................. 18 
10.4 
POOLING OF SITES ......................................................................................................................... 18 
10.5 
MULTIPLE COMPARISONS ........................................................................................................... 18 
10.6 
SUBGROUP ANALYSES .................................................................................................................. 19 
10.7 
STATISTICAL ISSUES ....................................................................................................................... 19 
11 STATISTICAL OUTPUT ...................................................................................................................... 19 
11.1 
SUBJECT DISPOSITION .................................................................................................................. 19 
11.2 
SUBJECT CHARACTERISTICS AT BASELINE ........................................................................... 19 
11.2.1 Demographic and Baseline Characteristics ................................................................................. 19 
11.3 
EFFICACY ANALYSES...................................................................................................................... 20 
11.4 
PK ANALYSES .................................................................................................................................... 20 
11.4.1 Plasma Concentration Data ............................................................................................................ 20 
11.4.2 Urine Concentration Data .............................................................................................................. 20 
11.4.3 Derived PK Parameters ................................................................................................................... 21 
11.5 
PD ANALYSES .................................................................................................................................... 22 
11.6 
SAFETY ANALYSES .......................................................................................................................... 24 
11.6.1 Adverse Events ................................................................................................................................... 24 
11.6.2 Laboratory Data ................................................................................................................................. 25 
11.6.3 Vital Signs ............................................................................................................................................. 25 
11.6.4 Electrocardiogram ............................................................................................................................. 26 
11.7 
PK/PD .................................................................................................................................................... 28 
11.8 
OTHER ................................................................................................................................................. 28 
11.8.1 Prior and Concomitant Medications ............................................................................................. 28 
11.8.2 Extent of Exposure ............................................................................................................................ 28 
11.8.3 All Other Data ................................................................................................................................... 28 
12 VALIDATION .................................................................................................................................... 29 
13 LITERATURE CITATIONS/REFERENCES ............................................................................................. 29 
14 LIST OF TABLES, FIGURES AND LISTINGS ......................................................................................... 30 
15 SHELLS FOR TABLES, FIGURES AND LISTINGS .................................................................................. 36 
16 APPENDICES .................................................................................................................................. 141 
16.1 
NORMAL RANGES ......................................................................................................................... 141 
 
 
 
 


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GLOSSARY OF ABBREVIATIONS 
 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
Ae 
Amount Excreted 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Plasma Concentration Curve 
AUC0-∞ 
Area Under the Plasma Concentration-time Curve calculated from the time 
of dosing to infinity 
AUC0-t 
Area Under the Plasma Concentration-time Curve calculated from the time 
of dosing to the last measurable concentration 
BLQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
CI 
Confidence Interval 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration 
CO 
Carbon Monoxide 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
DBL 
Database Lock 
DMP 
Data Management Plan 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
FTND 
Fagerström Test for Nicotine Dependence 
GM 
Geometric Mean 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
LLOQ 
Lower Limit of Quantification 
LSMean 
Least Squares Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 


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mg 
Milligram 
 
mL 
Millilitre 
NCS 
Not Clinically Significant 
PD 
Pharmacodynamic 
PK 
Pharmacokinetics 
PT 
Preferred Term 
QC 
Quality Control 
RBC 
Red Blood Cell  
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
TCQ-SF 
Tobacco Craving Questionnaire – Short Form 
TEAE 
Treatment Emergent Adverse Event 
TFL 
Table/Figure/Listing 
Tmax 
Time from dosing to the maximum observed plasma concentration 
WBC 
White Blood Cell  
 
  
 
 


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1
INTRODUCTION 
1.1
GENERAL  
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analysis of data collected under the ACH-CYT-02 protocol dated 21st September 2017 and should be 
read in conjunction with the study protocol and case report form (CRF).   
 
This version of the plan has been developed using the protocol version 2.0 dated 21st September 2017 
and the annotated CRF dated 4th October 2017.  Any further changes to the protocol or CRF will be 
reviewed for potential impact on the SAP, which will be amended if it is deemed necessary. 
 
Draft versions of the SAP will undergo review by the statistical reviewer, Project Manager, PK Analyst, 
Medical Writer and the Sponsor/Sponsor representative. The analysis plan will be finalised and approved 
by the Sponsor prior to Database Lock (DBL). 
 
 
1.2
CHANGES FROM PROTOCOL 
x
Change from baseline Tobacco Craving Questionnaire – Short Form scores will be included as 
a pharmacodynamic endpoint.  
x
The protocol identified reduction in smoking as a pharmacodynamic endpoint but did not refer 
to smoking cessation as an endpoint. Smoking cessation has been included in this SAP as a 
pharmacodynamic endpoint. 
x
Summaries of smoking cessation will be presented. 
x
Individual QT corrections (QTcI) will not be performed because it was not feasible for this study 
as a substantial amount of pre-treatment data across a large range of heart rates was required. 
x
Inclusion of an ECG analysis set and ECG-PK analysis set. 
x
The summary of Holter ECG QTcF categories will not include the categories QTcF ≤ 450 mSec 
and QTcF increase ≤ 30 mSec.  
x
Summaries of prior and concomitant medications will be included. 
x
Smoking history at baseline will be summarised. 
 
 
1.3
CHANGES FROM PREVIOUS VERSIONS OF THE SAP 
Not applicable. 
 
2
STUDY OBJECTIVES 
Primary Objectives: 
The primary objectives of this study are: 
x
to evaluate the pharmacokinetic (PK) parameters during repeat dosing of 1.5 mg or 3.0 mg 
cytisine when administered as the commercial 25-day schedule; 
x
to evaluate the pharmacodynamic (PD) effects (e.g. reduction in smoking) with repeat dosing 
of 1.5 mg or 3.0 mg cytisine when administered as the commercial 25-day schedule. 


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Secondary Objectives: 
The secondary objectives of this study are: 
x
to compare the PK parameters and tolerability for repeat dosing of 1.5 mg and 3.0 mg cytisine 
during the 25-day schedule in healthy smokers at 18-65 and >65 (elderly) years of age; 
x
to assess the renal elimination of cytisine via measurement of urinary concentrations of cytisine 
during treatment on Day 1 and Day 25; 
x
to evaluate for effects on QT/QTc interval prolongation and cardiac safety during treatment on 
Day 1 and Day 25 in healthy smokers at 18-65 and >65 (elderly) years of age. 
 
3
STUDY DESIGN 
3.1
OVERVIEW 
This is an open-label, randomised, multiple-dose PK and PD 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 commercialised 25-day 
schedule. A total of 36 healthy adult smokers, such that 24 subjects are 18-65 years of age and 12 
subjects are >65 years of age will be randomised to complete the study, as shown in Figure 1. An attempt 
will be made for 50% male and 50% female enrolment.  
 
Figure 1: Study Design Overview 
 
 
 
The study is comprised of a pre-study screen, followed by 25 days of treatment and a post-study follow-
up. Screening assessments will be carried out within 28 days prior to first administration of cytisine. 
Eligible subjects will be asked to return on the evening prior to Day 1 (i.e. Day -1) for repeat of key 
entry testing, baseline questionnaires and an overview of the risks of smoking and quit advice according 
to the World Health Organisation (WHO) guidelines.  Randomisation to dose groups will occur on the 
morning of Day 1 followed by initiation of study treatment. Eligible subjects will take cytisine (in the form 
of the commercial product 
 as outlined in Table 1. Group A subjects will take 1 tablet at each 
time point (1.5 mg) and Group B subjects will take 2 tablets at each time point (3.0 mg). A post-study 
follow-up visit will be conducted 6 to 8 days after the last dose of cytisine. The maximum duration of 
this study is estimated to be around 9 weeks (screening to last subject’s last visit). 
 
 


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Table 1: Dose Timing and Total Daily Dose 
 
Days 
Regimen 
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 
- 
 
3.2
INCLUSION AND EXCLUSION CRITERIA 
To be eligible for inclusion into this study, each subject must fulfil all inclusion criteria and not violate 
any exclusion criteria (for the protocol under which they are entered) during screening prior to 
randomisation. Details of the inclusion and exclusion criteria are presented within the protocol (sections 
6.1, 6.2). 
 
3.3
STUDY TREATMENT 
Each subject will receive one of the following treatments in accordance with the randomisation schedule: 
 
x
Group A: 1.5 mg cytisine (1 x 1.5 mg tablet) administered per commercialised 25-day schedule; 
 
x
Group B: 3.0 mg cytisine (2 x 1.5 mg tablets) administered per commercialised 25-day schedule. 
 
Cytisine should be administered orally according to the dose timing schedule (see Table 1) with each 
dose to be either one 
 and, when possible, 
with a meal or a snack. 
 
 


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3.4
 SCHEDULE OF STUDY PROCEDURES 
 
 
Screening 
Study Day 
Post-Study  
Study Day 
-28 to -2 
-11
1-41 
4-11 
12-132 
13-15 
16-172 
17-19 
20-212 
21-23 
24-263 
6-8 days after 
last dose 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Number of cigarettes smoked in previous 24 hours 
X 
X 
 
 
 
 
 
 
 
 
 
 
Daily Smoking and Study Medication Diary4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X5 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X6 
X6 
 
X6 
 
X6 
 
X6 
 
X6 
 
Medical history 
X 
X7 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medication 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
X8 
 
X8 
 
X8 
 
X8 
 
X8 
 
Holter monitor for continuous ECG readings9 
 
 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy test for all females 
X 
Serum 
X 
Urine 
 
 
 
 
 
 
 
 
X 
Serum 
 
FSH (females of non-childbearing potential only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Haematology10 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Biochemistry10 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Virology (HIV, Hep-B, Hep-C) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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1 4 overnight stays in clinic, starting evening of Day -1. 
2 1 overnight stay in clinic. 
3 2 overnight stays in clinic. 
4 Subject to record number of cigarettes smoked in past 24 hours on a daily basis throughout study, actual time of each medication dose and record any adverse events. Information to be reviewed and 
documented during clinic days. Subject to also maintain record of number of cigarettes smoked in each 24 hour period from Day 26 until final Post-Study Visit (see protocol Section 13.9). 
5 Pre-First Dose on Day 1 
6  Vital signs (supine blood pressure, pulse rate and oral temperature) will be recorded at pre-dose and again prior to discharge from clinic. Vital Signs will also be recorded 3 hours post-last dose on Days 1, 2, 
3, 12, 16, 20 and 24. 
7 Clinically relevant changes will be reported as adverse events.  
8 Obtain 12-lead ECG (triplicate) at any time if clinically indicated during clinic visits. Repeat 12-lead ECG and assess prior to discharge. 
9  Attach ECG Holter monitor and begin recording prior to first dose on Day 1 and continue for 24 hours (discontinue just prior to first dose on Day 2.  Repeat again by starting Holter monitor prior to dose 
on Day 25 and record for 24 hours. 
10 Haematology and biochemistry testing to be completed prior to discharge on Days 4, 13, 17, 21, 26 
11 Urine cotinine and expired CO testing to be obtained at screen and prior to discharge on Days 4, 13, 17, 21, 26. 
12 Each subject given advice about the risks of smoking and quitting. This will take the form of a brief interview following WHO evidence-based recommendations on the treatment of tobacco dependence on 
Day -1 and reminders prior to discharge on Days 4, 13, 17, 21, 26 and on the final post-study visit. 
13IMP administration to follow 25-day dosing schedule (see Table 1). 
14Plasma collection for PK analysis is outlined in protocol Section 12.1. 
15 Urine to be collected for PK on Day 1 and Day 25 as follows:  pre-dose and 0-24 hours. 
16 Adverse event recording to begin upon admissions on Day -1 to post-study.
 
Screening 
Study Day 
Post-Study  
Study Day 
-28 to -2 
-11 
1-41 
4-11 
12-132 
13-15 
16-172 
17-19 
20-212 
21-23 
24-263 
6-8 days after 
last dose 
Drugs-of-abuse tests in urine 
X 
X 
 
 
 
 
 
 
 
 
 
 
Fagerström test for nicotine dependence 
 
X 
 
 
 
 
 
 
 
 
X 
 
Urine cotinine11 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Expired air CO11 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Verification of eligibility criteria  
X 
X 
X 
 
 
 
 
 
 
 
 
 
Tobacco craving questionnaire (short form) 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Risks of smoking and quit advice12 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
IMP (cytisine) administration13 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Plasma collection for PK analysis14 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine collection for PK analysis15 
 
 
X 
 
 
 
 
 
 
 
X 
 
Adverse events monitoring16 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 


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3.5
SAMPLE SIZE CONSIDERATIONS 
A total of approximately 36 subjects will be randomised to the study, with approximately 18 subjects 
per treatment arm (12 aged 18-65 and 6 aged >65).  
 
No previous pharmacokinetic studies with cytisine have reported the effects of repeated administration, 
so no estimates of intra-subject variability of Cmax, Cmin or AUC are available. No specific hypothesis 
testing is planned. Post-hoc analyses may be performed for PK or PD effects that may appear significantly 
different between the dosage groups or age groups. In general, the sample size of 36 should be sufficient 
to meet the exploratory objectives of the study. 
 
Subjects who withdraw from study at any time after randomisation will not be automatically replaced. 
Replacement based on the number and reason of withdrawals will be at discretion of the Sponsor, 
following discussion with the Principal Investigator. 
 
3.6
RANDOMISATION  
Subjects will be allocated to Group A (1.5 mg) or Group B (3.0 mg) in accordance with a randomisation 
code produced by 
 using the PROC PLAN procedure of SAS® version 9.3. Subjects will be 
numbered sequentially from 001 (i.e. 001, 002 etc.). Any replacement subjects will be assigned the same 
randomisation as the subjects they are replacing with 100 added to the subject number (i.e. 101 would 
replace 001 etc.). Subjects will be stratified for age (elderly > 65 years: yes vs no) to ensure that each 
dose group has 6 elderly subjects and 12 non-elderly subjects.  
4
STUDY VARIABLES AND COVARIATES 
4.1
PRIMARY VARIABLES 
The plasma cytisine pharmacokinetic endpoints for this study are as follows: 
x
Cmax 
Maximum observed plasma concentration post dose, directly obtained 
from the observed concentration versus time profile.  
x
Tmax 
Time of occurrence of Cmax.  
x
Cmin 
Minimum observed plasma concentration prior to the last daily dose or 
prior to each scheduled dose change.  
x
AUC0-t 
Area under the plasma concentration versus time curve (AUC) from time 
zero to the last sampling time at which concentrations were at or above 
the lower limit of quantification (LLOQ), calculated by the linear-up/log-
down trapezoidal rule. 
x
AUC0-inf 
Total AUC from zero to infinity, calculated as AUC0-inf = AUC0-t + 
(Clast/λz), where Clast is the last measurable plasma concentration and λz 
the apparent terminal elimination rate constant. 
x
%AUC 
Residual area or percentage of extrapolated part for the calculation of 
AUC0-∞, calculated as 100*[1-(AUC0-t/ AUC0-∞)].  
x
λz 
Apparent terminal elimination rate constant.  
x
t1/2 
Apparent terminal elimination half-life, calculated from ln 2/λz. 


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The pharmacodynamic endpoints for this study are as follows: 
x
Number of cigarettes smoked daily during treatment and at Day 26 
x
Reduction in number of cigarettes smoked from baseline, daily during study treatment and at 
      Day 26 
x
Reduction in expired air carbon monoxide (CO) from baseline, during study treatment and at 
      Day 26; 
x
Number of subjects at Day 26 that did not smoke any cigarettes for the past 24 hrs and had 
      biochemical confirmation of a CO level less than 10ppm on Day 26 (smoking cessation)  
x
Change from baseline urine cotinine results; 
x
Change from baseline Tobacco Craving Questionnaire – Short Form (TCQ-SF) scores: total  
      score and component scores for emotionality, expectancy, compulsivity, purposefulness.  
 
4.2
SECONDARY VARIABLES 
The urine cytisine pharmacokinetic endpoints for this study are as follows: 
x
Ae 
Amount excreted in urine over time.  
x
Ae% 
Percentage of drug excreted in urine.  
 
The safety endpoints for this study are as follows: 
x
Adverse events (AEs). 
x
Laboratory safety data (biochemistry, haematology, urinalysis and microscopy). 
x
Vital signs (supine systolic/diastolic blood pressure, pulse rate and oral temperature). 
x
12-lead ECG (heart rate, PR interval, QRS duration, QT interval and QT interval corrected using 
 
Fridericia’s formula (QTcF interval). 
x
ECG Holter Monitoring (heart rate, PR interval, QRS duration, QT interval and QTcF interval). 
 
 
5
DEFINITIONS AND DERIVED VARIABLES 
Study drug/IMP: 1.5 mg or 3.0 mg cytisine. 
Treatment/dose: 1.5 mg or 3.0 mg cytisine as per commercialised 25-day dosing schedule. 
Dose group: 1.5 mg Cytisine, 3.0 mg Cytisine. 
Age group: 18-65 yrs, >65 yrs, all ages. 
Baseline: In general, baseline is defined by subject and by variable as the last non-missing value (including 
repeats) before the first dose of study drug. This is normally the pre-dose assessment on Day 1 but if 
this assessment is missing (or not planned) then the assessment at the Screening/Day -1 visit will be used 
instead, if available. 


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For Holter ECG endpoints, a baseline value will be derived for each subject and ECG parameter (heart 
rate, PR interval, QRS duration, QT interval and QTcF interval) by calculating the mean of all individual 
results recorded prior to the administration of study drug on Day 1 (i.e., at the -30 minute and -15 
minute time points). 
Study Day: Study day is the number of days since start of treatment where the date of first dose is 
counted as Day 1. 
Bleed Time Deviation: Actual time of blood sample – theoretical time of blood sample. 
Protocol Deviation: a deviation related to study inclusion or exclusion criteria, conduct of the trial, 
subject management or subject assessment. This refers to any change, divergence, or departure from 
the study design or procedures defined in the protocol. Deviations recorded by the Project Manager or 
detected by Data Management or by statistical programming checks will be identified and discussed at 
the Data Review Meeting (DRM) before Database Lock (DBL). All protocol deviations within the study 
database will be classified as either ‘Major’ or ‘Minor’ prior to DBL, details of which will be included 
within the Protocol Deviations listing. 
Duration of Exposure: (Date of last dose of cytisine – date of first dose of cytisine) + 1. 
6
ANALYSIS SETS 
Membership of the analysis sets will be reviewed and agreed prior to DBL. These will be reviewed by 
the Sponsor, Study Statistician, PK analyst and Project Manager and signed off. If PK data is not available 
at the time of DBL, then subjects will be assumed to be included in the analysis set unless the PK data 
provide reason to exclude a subject, in which case this will be discussed with the Sponsor and 
documented within the Analysis Sets listing (Listing 16.2.3.1). 
 
6.1
SAFETY SET 
All randomised subjects who receive at least one dose of cytisine will constitute the Safety Set. 
This analysis set will be used for baseline and safety summaries as well as for all study listings. 
 
6.2
PK SET 
The PK Set will include all subjects who have completed all cytisine dosing on Days 1-3, completed >90% 
cytisine dosing on Days 4-25 and comply with the following criteria: 
x
Do not have an occurrence of vomiting or severe diarrhoea which renders the concentration 
profile unreliable (i.e. vomiting occurring at or before 2 times median Tmax);  
x
Do not use a concomitant medication which renders the concentration profile unreliable;  
x
Have at least one evaluable concentration that is preceded by a lower evaluable concentration 
and followed by a lower evaluable concentration for the calculation of Cmax, Tmax and AUCs (i.e. 
at least 3 evaluable concentrations in total); 
x
Do not violate the protocol (major protocol deviation) in a way that may invalidate or bias the 
PK results. 
 


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6.3
PD SET 
The PD Set will include all subjects in the PK Set who have an available baseline result and at least one 
on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and 
do not incur a major protocol deviation in a way that may invalidate or bias the PD results. 
 
6.4
ECG SET 
The ECG Set will include all subjects who receive at least one dose of cytisine, with at least one available 
baseline ECG and at least one on-treatment ECG.  
 
6.5
ECG-PK SET 
The ECG-PK Set will include all subjects who receive at least one dose of cytisine, with a time-matched 
ECG-PK pair at baseline and at least one time-matched pair on-treatment.  
 
7
SAFETY MONITORING 
Not applicable. 
8
INTERIM ANALYSES 
Not applicable. 
9
DATA 
9.1
CRF DATA 
 
CRF data will be provided by 
Data Management to the Statistics department as SAS datasets in 
standard format. SDTM datasets will be derived from the raw database and ADaM from SDTM.  
Both SDTM and ADaM domains will be used for programming the outputs to be included in the Clinical 
Study Report (CSR). SDTM/ADaM programming will begin when populated 
 standard SAS 
datasets are available.  
9.1.1
Laboratory Data 
Transfers of safety laboratory data will be available from the Pathology laboratory and delivered to Data 
Management via electronic transfer and stored within the study database. Details of laboratory data are 
documented in the Data Management Plan (DMP). Populated test transfers will be received before 
programming can start. The following results will be included: 
x
Haematology: Haemoglobin, haematocrit, mean cell volume, mean cell haemoglobin, mean cell 
haemoglobin concentration, red blood cells, white blood cells, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils and platelets.


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x
Biochemistry: Total protein, albumin, total bilirubin, alanine transaminase, aspartate 
transaminase, gamma glutamyl transferase, alkaline phosphatase, glucose, sodium, potassium, 
calcium, bicarbonate, creatinine and urea.
x
Urinalysis: Glucose, specific gravity, protein, leukocytes, ketones, urobilinogen, bilirubin, 
nitrites, pH and blood. 
x
Microscopy: In the event that the ‘dipstick’ is positive for leukocytes, nitrites, protein and 
blood, the parameters red blood cells, white blood cells, epithelial cells, crystals, bacteria and 
casts will be examined microscopically. 
x
Virology: Hep B, Hep C and HIV. 
x
Drugs of Abuse and Alcohol: Urine alcohol and drugs of abuse screen: cannabinoids, 
amphetamines, cocaine, benzodiazepines, opiates and cotinine. 
x
Urine cotinine: Urine cotinine will be collected throughout the study as a PD parameter. 
x
Pregnancy/post-menopausal assessment: serum/urine pregnancy test and follicle 
stimulating hormone.  
x
Other parameters: Any further parameters that are taken that are not included as part of the 
above categories will be included in an ‘Other Laboratory Data’ listing. 
 
 
9.1.2 Pharmacokinetic Data 
Plasma and urine concentration data will be received as an Excel file from the Bioanalytical department 
via an electronic transfer and stored as a SAS dataset. This data will then be stored in the appropriate 
SDTM domain and subsequent ADaM domain which will be used to produce the file provided to the 
pharmacokinetic team in order to derive the PK parameters using Phoenix WinNonlin 6.4.  Derived PK 
parameters will be received by the Statistics department from the Project Manager/PK analyst in a 
SAS.xpt file in an agreed format and then stored as a SAS dataset and subsequently within SDTM/ADaM 
domains. 
 
9.1.3 ECG Holter Monitoring Data 
ECG Holter data will be received as an Excel file from CardioAnalytics (3rd party cardiac monitoring 
service managed by 
 via an electronic transfer and stored as a SAS dataset. This data will then 
be stored in the appropriate SDTM domain and subsequent ADaM domain. 
 
 
9.2
RANDOMISATION LIST 
 
The randomisation list will be uploaded to a SAS dataset and incorporated into the relevant 
SDTM/ADaM domains. 
 
 
9.3
PROGRAMMING AND DATA REVIEW 
 
Programming of datasets, tables, figures and listings may be ongoing while study data management 
activities are in progress.  


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Prior to DBL, a review of the clinical database (i.e. CRF data, laboratory data) in the form of Excel data 
listings will be conducted.  A Data Review Meeting (DRM) will be held to discuss the outcome of this 
review, any potential impact on the analyses, analysis sets and protocol deviations.  Once all data issues 
have been resolved and the analysis sets approved, the database will be locked.  The SDTM/ADaM 
datasets will be finalised and the final run of outputs and quality control (QC) will take place. 
Due to issues with the recruitment of the elderly cohort, two database locks are required. The database 
for non-elderly subjects (<=65 yrs) will be locked while recruitment for the elderly cohort (>65 yrs) is 
ongoing. The database for the elderly subjects will be locked at a later date. Therefore, two sets of TFLs 
will be produced – an ‘interim’ set presenting data for the non-elderly subjects only followed by a second 
set which will include data from both the non-elderly and elderly cohorts. The second set consisting of 
data from all subjects will be included in the clinical study report (CSR). 
10 STATISTICAL METHODS 
10.1 GENERAL PRINCIPLES 
x
All statistical methods will be based on the International Conference on Harmonisation (ICH) 
E9 document “Statistical Principles for Clinical Trials”. 
x
All data collected will be presented within data listings and any unscheduled visits will be listed.  
x
Data will be summarised by dose group (1.5 mg Cytisine, 3.0 mg Cytisine), age group (18-65 yrs, 
>65 yrs, all ages) and overall (both dose groups pooled) where appropriate. The format of the 
summaries is defined in the shells at the end of this document. 
x
In summary and analysis tables of continuous variables, standard descriptive statistics (N 
[number within analysis set, or cohort, or subgroup], n [number of observations included in 
analysis], mean, standard deviation [SD], median, minimum and maximum) will be presented. 
Least squares mean (LS mean) and 90/95% confidence interval (CI) will be presented in the 
statistical analysis outputs as appropriate. For PK summaries, geometric mean, and coefficient of 
variation (%CV) will also be used to summarise the data.  
x
Unless otherwise specified, the minimum and maximum statistics will be presented in summary 
tables to the same number of decimal places as the original data.  The mean, median, LS mean, 
geometric mean and CI will be presented to one more decimal place than the original data. SD 
will be presented to two more decimal places than the original data. %CV will be presented to 
one decimal place. 
x
In summary tables of categorical variables, the number of non-missing observations by category 
will be presented along with percentages. Unless otherwise specified, the denominator for each 
percentage will be the number of non-missing observations. All percentages will be presented 
to one decimal place. 
x
All plots will use a linear time scale for the nominal times of the visits and will be labelled by 
time point. 
x
Original values will be used in summary tables, unscheduled measurements will be listed only.  
However, where repeats of baseline values occur, unless specified otherwise (i.e. 12-lead ECG), 
the last assessment will be used within any summary tables and used to calculate change from 
baseline. In case an unscheduled measurement is performed immediately after the scheduled 


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measurement due to an error in the original measurement, unless specified otherwise (i.e. 12-
lead ECG) the unscheduled measurement will be included in the analysis and the original 
erroneous measurement will be excluded. 
x
The date format for all output presentations will be as captured in the database. 
x
All statistical analysis will be performed using SAS 9.3 or higher. 
x
All hypothesis testing will be carried out at the 5% (2-sided) significance level unless stated 
otherwise.  
x
P-values will be rounded to four decimal places.  P-values less than 0.0001 will be reported as 
<0.0001 in tables.   
x
Generally, character values will be left aligned and numeric values will be decimally aligned. 
x
If any of the assumptions underlying the formal statistical methods proposed are violated during 
the analysis of the final data, alternative statistical methods will be used and any changes 
documented in the statistical methods section of the clinical study report (CSR), including the 
rationale for use. 
x
For numeric data which includes non-numeric values (e.g. PK data reported as BLQ or 
laboratory results reported as < 10 or >100) the following principles will be applied when 
summarising the data: 
¾
BLQ will be replaced with a zero. 
¾
Results reported as <x or >x will be treated as x. 
 
10.2 STRATIFICATION AND COVARIATE ADJUSTMENT 
In order to investigate any possible effects of age, analyses will be presented by non-elderly subjects (18-
65 years) and elderly subjects (>65 years). 
 
10.3 MISSING DATA 
Generally, no methods to impute missing data will be used.  However, for the purpose of calculating 
change from baseline, in the instance of a missing baseline result (generally the assessment at Day 1, Pre-
Dose) the results obtained at the Screening/Day -1 visit will be used instead, if available.  
 
In the instance of missing pharmacokinetic blood samples, the linear-up/log-down trapezoidal rule will 
be employed between the samples immediately before and after the missing sample for the AUC 
calculations. 
 
10.4 POOLING OF SITES 
Not applicable. 
 
10.5 MULTIPLE COMPARISONS 
Not applicable. 
 


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10.6 SUBGROUP ANALYSES 
Analyses will be performed by age group (18-35 yrs, >65 yrs, all ages). Due to the small sample sizes, 
noteably for subjects > 65 years, these analyses are exploratory in nature. The primary comparison of 
interest is between dose groups. 
 
10.7 STATISTICAL ISSUES 
None. 
11 STATISTICAL OUTPUT 
General principles for layout of the statistical output are described in Section 10.1.  Layout and 
specifications are illustrated for each unique table and listing within the shells presented in Section 14.  
 
11.1 SUBJECT DISPOSITION 
The subject disposition table will summarise the following data for all randomised subjects: 
x
The number (%) of subjects within each analysis set; 
x
The number (%) of subjects dosed; 
x
The number (%) of subjects who completed the study/withdrew from the study and the 
associated reasons for early study termination.  
The disposition summary will be presented by dose group and overall. 
Screening and study completion/termination data will also be listed.  A listing of all subjects with protocol 
deviations will be presented including major/minor classification. A data listing presenting subject 
eligibility for each analysis set and the reason for exclusion from an analysis set will also be presented.  
 
11.2 SUBJECT CHARACTERISTICS AT BASELINE 
11.2.1 Demographic and Baseline Characteristics 
Demographic data will be listed (including informed consent information) and descriptive statistics for 
the continuous variables age, height, weight and BMI and frequencies for the categorical variables race 
and gender will be tabulated. These descriptive statistics will be presented by dose group, age group and 
overall. 
Alcohol and cotinine results collected at Screening and Day -1 will be listed and summarised using 
frequencies (n, %). 
Demographic and baseline data will be listed and summarised using the Safety Set. Demographic data 
may also be summarised using the PK Set, if appropriate. 
Smoking history variables reported at baseline will be listed and summarized by dose group, age group 
and overall. The total number of cigarettes smoked in the past 24h will be summarized as a continuous 


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variable, and also using frequencies (n, %). Descriptive statistics will be reported for baseline expired 
CO (ppm), urine cotinine, FTND total score, and TCQ-SF total score.  Baseline is defined as results 
obtained at Screening for expired CO and urine cotinine and as Day -1 for the daily cigarette 
consumption, FTND and TCQ-SF. 
 
11.3 EFFICACY ANALYSES 
Not applicable. 
 
11.4 PK ANALYSES 
The primary analysis set for summaries of PK data will be the PK Set. If the PK Set and the Safety Set 
are not equivalent, then all PK summaries described below will also be produced for the Safety Set.  
11.4.1 Plasma Concentration Data 
Plasma PK samples will be collected for measurement of cytisine at the following time points:  
x
Day 1, first dose: Pre-first dose, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h; 
x
Day 1, last dose: Pre-last dose, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h; 
x
Days 2 and 3: Pre-last dose, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h; 
x
Days 4, 13, 17, 21: Pre-first dose; 
x
Days 12, 16, 20, 24: Pre-last dose, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h; 
x
Day 25: Pre-dose, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 1.75h, 2h, 2.25h, 2.5h, 2.75h, 3h, 3.25h, 3.5h, 
3.75h, 4h, 5h, 6h, 8h, 10h, 12h, 24h. 
 
Cytisine concentrations in plasma will be listed and summarised by dose group and age group using the 
descriptive statistics N, n, arithmetic mean, arithmetic standard deviation (SD), coefficient of variation 
(CV%), minimum, median and maximum.  
 
The individual subject plasma cytisine concentration profiles over time will be presented graphically using 
actual blood sampling times on a linear and semi-logarithmic scale. Arithmetic mean plasma cytisine 
concentration profiles over time will be presented on linear and semi-logarithmic scales with profiles 
presented for each study day as appropriate and a separate plot for each dose group and age group.  
 
For inclusion within the summary tables and linear scale plots, concentrations below the limit of 
quantification (BLQ) will be assigned a value of zero. For inclusion within the semi-logarithmic scale plots, 
concentrations below the limit of quantification (BLQ) will be set to missing. Concentrations above the 
upper limit of quantification (ULOQ) will be obtained via dilution into the calibration range and are valid 
results.  
 
Plasma concentration data listings and individual plots will be presented using the Safety Set. Plasma 
concentration data summaries and mean plots will be presented using the PK Set and the Safety Set. All 
plasma concentration data included in listings and summaries will be presented to three significant figures. 
 
11.4.2 Urine Concentration Data 
Urine PK samples will be collected for measurement of cytisine on Day 1 and Day 25 at the following 
time intervals: Pre-dose (taken upon waking), 0-24h post-dose. 
 


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Cytisine concentrations in urine will be listed and summarised for each dose group and age group using 
the descriptive statistics N, n, arithmetic mean, arithmetic standard deviation (SD), coefficient of 
variation (CV%), minimum, median and maximum.  
 
Urine concentration data listings will be presented using the Safety Set. Urine concentration data 
summaries will be presented using the PK Set and the Safety Set. 
 
11.4.3 Derived PK Parameters 
The derived pharmacokinetic parameters of cytisine in plasma (listed in section 4) will be determined 
using WinNonlin Phoenix 6.4 from the individual concentration versus time data using standard non-
compartmental methods. The derived urine pharmacokinetic parameters, Ae and Ae% (individual and 
cumulative), will be determined from the individual concentration versus time data using SAS version 
9.3. 
 
For the calculation of derived pharmacokinetic parameters, concentrations below the limit of 
quantification (BLQ) will be assigned a value of zero. In case of a deviation from the theoretical time, the 
actual time of blood sample will be used in the calculation of the derived pharmacokinetic parameters.  
 
The terminal elimination rate constant (λz) will be determined by plotting the concentration data versus 
time on a semi-logarithmic scale.  The parameter will be estimated by linear least square regression 
analysis, using the last three (or more) non-zero concentrations.  The upper and the lower time points, 
as well as the number of time points, used for λz estimation will be reported.  
 
AUC0-t will be calculated using the linear-up/log-down trapezoidal method. 
 
The derived urine PK parameter Ae will be calculated from as: urine volume * urine cytisine 
concentration. Ae% will be derived as: 100*Ae/Dose.  
 
Values of λz, AUC0-∞, %AUC and t½ will not be reported for cases where λz cannot be reliably 
determined. 
 
Cmax (and Tmax) will be calculated after the first dose and the last dose on Day 1, after the last dose on 
days 2, 3, 12, 16, 20, 24 and after the morning dose on Day 25. Cmax and Tmax values will be calculated 
as follows: 
x
On Day 1, Cmax after the first daily dose will be estimated from venous blood samples 
collected 0.5h, 0.75h, 1h, 1.25h, 1.5h, and 2h after the first dose.  
x
On Day 1, Day 2, and Day 3 estimates of Cmax after the last daily dose will be made from 
venous blood samples collected 0.5 h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, and 5h following the last 
dose.  
x
On Day 12, 16, 20, and 24, Cmax estimates will be made from venous blood samples collected 
1h, 1.5h, 2h, 2.5h, 3h, 3.5h, and 4h after the last daily dose.  
x
On Day 25 Cmax will be estimated from venous blood samples collected 0.5h, 0.75h, 1h, 1.25h, 
1.5h, 1.75h, 2h, 2.25h, 2.5h, 2.75h, 3h, 3.25h, 3.5h, 3.75h, 4h, 5h, 6h, 8h, 10h, 12h, and 24h 
post-dose.  
 
Cmin will be derived from the pre-first dose plasma values on days 4, 13, 17, 21 and 25. 
 
The t½, λz, AUC0-t, AUC0-inf and %AUCextrap values will be determined after the administration of the 
final dose of cytisine on Day 25. On Day 25 t1/2 and AUC will be determined after the administration 


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of the final dose of cytisine from venous blood samples collected 0.5h, 0.75h, 1h, 1.25h, 1.5h, 1.75h, 2h, 
2.25h, 2.5h, 2.75h, 3h, 3.25h, 3.5h, 3.75h, 4h, 5h, 6h. 8h, 10h, 12h, and 24h post-dose. 
  
The derived urine parameters Ae and Ae% will be calculated from 0-24h on Day 1 and Day 25. 
 
Derived pharmacokinetic parameters will be listed and summarised for each dose group and age group. 
The descriptive statistics presented will be N, n, arithmetic mean, arithmetic standard deviation (SD), 
coefficient of variation (CV%), minimum, median, maximum and geometric mean (with the exception of 
Tmax). 
 
PK parameter data listings will be presented using the Safety Set. PK data summaries will be presented 
using the PK Set and the Safety Set. All PK parameter data included in listings and summaries will be 
presented to three significant figures with the exception of the CV% which will be presented to one 
decimal place. 
 
11.4.3.1 Statistical Analysis of PK Parameters 
 
Dosing Schedule Comparison 
The dosing schedule comparison analysis will be performed separately within each of the dose groups.  
 
In order to perform comparisons between schedule changes within each dose group, following 
logarithmic transformation, Cmax values (post-last dose on days 3, 12, 16, 20, 24 and 25), and Cmin values 
(pre-first dose on days 4, 13, 17, 21 and 25) will be subjected to an analysis of variance (ANOVA) 
including a fixed effect for study day and a random effect of subject. Point estimates and 90% confidence 
intervals (CI) will be constructed for the contrasts between consecutive study days using the residual 
mean square error obtained from the ANOVA.  The point and interval estimates will be back-
transformed to give estimates of the ratios of the geometric least squares means (LSmean) and 
corresponding 90% CI.  In addition, estimated geometric means will be presented. The analysis will be 
performed by age group (18-65 yrs, >65 yrs, all ages). 
 
Dose Group Comparison 
The dose group comparison will be a between-group analysis. 
Following logarithmic transformation, Cmax, AUC0-t and AUC0-inf values on Day 25 will be subjected to 
an analysis of variance (ANOVA) including a fixed effect for dose group. Point estimates and 90% 
confidence intervals (CI) will be constructed for the contrast between the 1.5 mg and 3.0 mg dose 
groups using the residual mean square error obtained from the ANOVA.  The point and interval 
estimates will be back-transformed to give estimates of the ratios of the geometric least squares means 
(LSmean) and corresponding 90% CI.  In addition, estimated geometric means will be presented. The 
analysis will be peformed by age group (18-65 yrs, >65 yrs, all ages). 
 
11.5 PD ANALYSES 
 
11.5.1 Number of Cigarettes Smoked and Expired CO 
The number of cigarettes smoked in the past 24 hours will be recorded at Screening and daily from 
Day -1 to Post-Study. Expired air carbon monoxide (CO) data will be obtained at Screening and prior 
to discharge on days 4, 13, 17, 21 and 26.  


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The number of cigarettes smoked during the past 24 hours will be taken from the values recorded in 
the CRF (at CPU) for Screening and Day -1 to Day 3 and from the subject diaries thereafter. In order 
to evaluate any reduction in smoking, the number of cigarettes smoked daily will be assessed as well as 
smoking cessation status at Day 26. For each individual subject a smoking cessation status of ‘Ceased 
smoking’ will be defined as not having smoked any cigarettes for the past 24 hours on Day 26 and 
confirmed by an expired CO level <10ppm on Day 26. If these criteria are not satisfied, a smoking 
cessation status of ‘Continued smoking’ will be assigned to a subject, including subjects who have 
missing data at Day 26 for either the number of cigarettes smoked or expired CO level, or both.  
  
The number of cigarettes smoked daily and smoking cessation status will be listed. Frequencies (n, %) of 
smoking cessation status at Day 26 will be calculated by dose group and age group. For those subjects 
who had ceased smoking by Day 26, frequencies of the day of first smoking cessation (defined as smoking 
0 cigarettes and where cessation is sustained without relapse) will be presented by dose group and age 
group. Descriptive statistics (N, n, mean, SD, minimum, median and maximum) of absolute and change 
from baseline (Day -1) number of cigarettes smoked will be tabulated by dose group and age group. The 
mean absolute values and mean change from baseline will also be presented graphically. Individual subject 
plots of the number of cigarettes smoked daily will also be produced.  
 
Expired CO levels will be included in the listing that presents the smoking cessation status data.  
Descriptive statistics (N, n, mean, SD, minimum, median and maximum) of absolute and change from 
baseline (Screening) expired CO results will be tabulated by dose group and age group. The mean 
absolute values and mean change from baseline values will also be presented graphically. Individual subject 
plots of expired CO levels will also be produced. 
 
The summary tables described above for number of cigarettes smoked daily and expired CO levels will 
also be produced for two subgroups of subjects, defined by smoking cessation status (‘Ceased smoking’, 
‘Continued smoking’). The graphs described above of mean absolute values and mean change from 
baseline will also be presented by smoking cessation subgroup.  
 
 
11.5.2  Urine Cotinine 
Urine cotinine data will be obtained at Screening and prior to discharge on days 4, 13, 17, 21 and 26.  
 
Urine cotinine levels will be included in the listing that presents the smoking cessation status data.  
Descriptive statistics (N, n, mean, SD, minimum, median and maximum) of absolute and change from 
baseline (Screening) urine cotinine levels will be tabulated by dose group and age group. The mean 
absolute values and mean change from baseline values will also be presented graphically. Individual subject 
plots of urine cotinine levels will also be produced. 
 
 
11.5.3 Tobacco Craving Questionnaire 
 
The Tobacco Craving Questionnaire – Short Form (TCQ-SF) will be completed on days -1, 4, 13, 17, 
21 and 26. 
 
The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 
items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each 
item are scored from 1 (strongly disagree) through 7 (strongly disagree).  Component scores are defined 


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as the sum of the scores within each component. The total score is defined as the sum of the 4 
component scores. If any item responses are missing then the relevant component score(s), as well as 
the total score, will not be calculated.  
 
The TCQ-SF total score and component scores for emotionality, expectancy, compulsivity and 
purposefulness will be listed and descriptive statistics (N, n, mean, SD, minimum, median and maximum) 
of absolute and change from baseline (Day -1) results will be tabulated by dose group and age group. For 
the total score, the mean absolute values and mean change from baseline values will also be presented 
graphically.  
 
11.6 SAFETY ANALYSES 
11.6.1 Adverse Events 
All AEs will be coded using the MedDRA dictionary using the version specified in the Data Management 
Plan (DMP).  
All AEs, including those which occurred prior to the first dose of study drug, will be listed.  Only 
treatment emergent adverse events (TEAEs), i.e., existing conditions that worsen or events that occur 
during the course of the study after administration of IMP, will be included within the summary tables. 
TEAEs will be summarised by dose group, age group and overall. 
An overall summary of AEs will be produced including the number of TEAEs; the number and % of 
subjects reporting at least 1 TEAE, serious TEAE (where SAE is reported as ‘Yes’), TEAE leading to 
withdrawal from study drug (Action recorded as ‘Study Drug Discontinued’); the number and % of 
subjects reporting TEAEs by severity and relationship to study drug.  A subject with multiple occurrences 
of any AE is counted only once at the maximum level of severity or the highest association to study drug. 
The number of TEAEs and the number and % of subjects reporting at least one TEAE will be tabulated 
by system organ class (SOC) and preferred term (PT).  A subject reporting multiple episodes of a 
particular AE will only contribute one count towards the corresponding SOC and preferred term. The 
number of TEAEs and the number and % of subjects reporting at least one TEAE will also be tabulated 
by preferred term (PT), with the PTs sorted in descending order of frequency.  A subject reporting 
multiple episodes of a particular AE will only contribute one count towards the corresponding PT. 
In addition, the number and % of subjects reporting TEAEs will be tabulated by maximum severity and 
strongest relationship to study drug.  For the summary of TEAEs by severity, if a subject has multiple 
events occurring within the same SOC or preferred term the event with the highest severity will be 
counted.  Similarly, for TEAEs by relationship to study drug, if a subject has multiple events occurring 
within the same SOC or PT, the event with the highest association to study drug will be counted. 
Data will be listed by dose group and age group.  For any adverse event taken prior to first administration 
of study drug, treatment will be described as ‘Prior to Dosing’.  
Where there are only partial dates/times recorded for adverse events, adverse events will be assigned 
to treatment unless it can be ruled out based on the partial information.  
The derived variables, ‘Time from Dose’ and ‘Duration’ will be presented where full date and time are 
present. If partial dates are present for any parameter required in the calculation, then the variable will 
not be populated. The following will be used to calculate the variables: 


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Duration (dd:hh:mm): (Date/Time of Resolution-Date/Time of Onset) + 1 minute; 
 
Time from Dose (dd:hh:mm): (Date/Time of Onset-Date/Time of Start of Dose). 
 
The following will be presented in listing format within the data summaries: 
 
Serious Adverse Events – If there are none present, the listing will be produced stating: ‘No subjects 
experienced any serious adverse events’. 
 
Adverse Events which Led to Withdrawal of Study Drug – If there are none present, the listing will be 
produced stating: ‘No subjects experienced any adverse events that led to withdrawal of study drug’. 
 
Adverse event data will be summarised and listed using the Safety Set. 
11.6.2 Laboratory Data 
Routine biochemistry and haematology tests will be carried out at Screening and prior to discharge on 
days 4, 13, 17, 21 and 26. Urinalysis will be performed at Screening and Day 26. 
 
The laboratory parameters required for this study are listed in section 9.2.1. 
 
Laboratory data listings will be presented in two ways: 
x
Out of range values -  any values that fall outside of the normal/alert ranges (presented in listing 
format within the data summaries) 
x
All laboratory data (including physician’s review (Normal, Abnormal-NCS, Abnormal-CS)) with 
any out of range values flagged (presented within the data listings).  
 
Descriptive statistics (N, n, mean, SD, minimum, median and maximum) of absolute and change from 
baseline (Screening) biochemistry and haematology parameters at each time point up to and including 
Day 26 will be tabulated by dose group and age group. 
 
Laboratory data will be listed and summarised using the Safety Set. 
 
11.6.3 Vital Signs 
Supine blood pressure, pulse rate and oral temperature will be taken as follows: Screening; Day -1; Days 
1, 2 and 3 pre-first dose and 3h post-last dose; Days 4, 13, 17, 21, 25 pre-first dose; Day 12, 16, 20 and 
24 3h post-last dose; Day 25 24h. 
 
Vital signs parameters (supine systolic and diastolic blood pressure and pulse rate and oral temperature) 
will be listed with any out of normal range values (see Appendix 1) flagged (flag ‘H’ or ‘L’ appended to 
relevant result). Descriptive statistics (N, n, mean, SD, minimum, median and maximum) of absolute and 
change from baseline (Day 1, pre-first dose) at each time point up to and including Day 25, 24h will be 
tabulated by dose group and age group. 
 
Vital signs data will be summarised and listed using the Safety Set. 
 


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11.6.4 Electrocardiogram 
11.6.4.1 12-Lead ECG 
12-lead ECGs will be performed in triplicate as follows: Screening; Day -1; Days 4, 13, 17 and 21 pre-
first dose; Day 26. 
12-lead ECG parameters (heart rate, PR interval, QRS duration, QT interval and QTcF interval) will be 
listed with any out of normal range values (see Appendix 16.1) flagged (flag ‘H’ or ‘L’ appended to relevant 
result). The ECG findings (i.e. parameter values as well as morphologic findings (rhythm, conduction, 
evidence of MI, ST segments, T waves etc.)) will also be assessed by a physician as either ‘normal’ or 
abnormal’ with comments on abnormal results also presented.  
Descriptive statistics (N, n, mean, SD, minimum, median and maximum) of absolute and change from 
baseline (Day -1) values at each time point up to and including Day 26, will be tabulated by dose group. 
The mean of the triplicate recordings at each time point will be calculated for use in the summary tables. 
Any ECG traces that are determined to contain a technical error/interference will not be included in 
the calculation of mean values. If an ECG recording is repeated, all 3 of the original triplicate recordings 
(or whatever number of ECGs are free of technical errors) and the repeat recording(s) will be included 
in the calculation of the mean, provided that the original and repeat recordings are within 5 minutes of 
each other.  Otherwise, the mean will be derived separately for the original and repeat recordings and 
the last mean value prior to dosing will be used for the summary tables. 
 
12-lead ECG data will be listed and summarised using the Safety Set. 
 
11.6.4.2 Holter Monitoring 
The ECG extraction time points will be from extraction windows which precede the PK blood draws. 
ECG parameters (heart rate, PR interval, QRS duration, QT interval and QTcF interval) will be extracted 
in triplicate from Holter recordings on Day 1 and Day 25 at 30 and 15 minutes prior to the first dose 
and at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h post dose. 
The extracted ECG parameters will be listed with any out of normal range values (see Appendix 1) 
flagged (flag ‘H’ or ‘L’ appended to relevant result). The ECG results will also be assessed as either 
‘normal’ or abnormal’ with comments on abnormal results also presented.   
The mean of the triplicate recordings at each time point will be calculated for use in the summary tables 
and plots. Any ECG traces that are determined to contain a technical error will not be included in the 
calculation of the mean values. At each time point, the mean value will be derived from all ECGs 
(generally three) that are free of technical errors. Descriptive statistics (N, n, mean, SD, minimum, 
median and maximum) of absolute and change from baseline (see definition, Section 5) values on Day 1 
and Day 25 at each time point up to 24h, will be tabulated for each dose group and age group. The 
change from baseline ECG results will also be plotted over time by dose group and age group. 
In addition, frequencies of QTcF data will be calculated according to the following categories: 
For absolute values: 
x
QTcF > 450 mSec  
x
QTcF > 480 mSec 
x
QTcF > 500 mSec 


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For change from baseline: 
x
QTcF increase > 30 mSec  
x
QTcF increase > 60 mSec. 
The presence of outliers will be explored for heart rate, PR interval, QRS duration, QT interval and 
QTcF interval). The outlier analysis will use the time-averaged baseline (see definition, Section 5) and 
compare that baseline value to each of the individual on-treatment ECG time point values. Outliers are 
defined as follows for this analysis: 
x
Heart rate:  A value for a subject will be considered to be an outlier at a pre-defined post dose time 
point if the heart rate measurement at that time point is <50 bpm and the measure is at least a 25% 
decrease from the subject’s baseline mean heart rate (i.e., a bradycardic event) or if the heart rate 
measurement at the pre-defined post dose time point is >100 bpm and the measure is at least a 25% 
increase from the baseline mean heart rate (i.e., a tachycardic event). 
x
PR interval:  A value for a subject will be considered to be an outlier at a pre-defined post dose time 
point if the PR interval at that pre-defined post dose time point is >200 mSec and it is at least a 25% 
increase from the subject’s baseline mean PR interval. 
x
QRS duration:  A value for a subject will be considered to be an outlier at a pre-defined post dose 
time point if the QRS duration at that pre-defined post dose time point is >100 mSec and it is at 
least a 25% increase from the subject’s baseline mean QRS duration. 
x
QT interval:  A value for a subject will be considered to be an outlier at a pre-defined post dose 
time point if the QT interval at that pre-defined post dose time point is >500 mSec and the subject’s 
baseline mean QT interval is d500 mSec. 
x
QTcF interval:  A value for a subject will be considered to be an outlier at a pre-defined post dose 
time point if the QTcF interval at that pre-defined post dose time point is >500 mSec and the 
subject’s baseline mean QTcF interval is d500 mSec. Outlier values will also be presented if the 
QTcF interval at a pre-defined post dose time point is >480 mSec when the subject’s baseline mean 
QTcF interval is d480 mSec and when a pre-defined post dose time point is >450 mSec when the 
subject’s baseline mean QTcF interval is d450 mSec. Subjects will be included on a ‘worst case’ basis, 
i.e. if a subject has a baseline d450 mSec and has a post dose value of >500 mSec, the subject will be 
counted in the >500 mSec category only. 
 
The number of events and number (%) of subjects with at least one outlier will be summarized on Day 
1 and Day 25 by dose group and age group for each ECG parameter. For heart rate, separate summaries 
will be provided for bradycardic events (i.e., decreases) and tachycardic events (i.e. increases).  
 
Holter ECG data will be listed for the Safety Set and summarised using the ECG Set. 
 
 


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11.7 PK/PD 
In order to explore the effects of cytisine on QTc prolongation, individual cytisine concentrations in 
plasma and individual (mean of triplicate recordings) absolute and change from baseline Holter QTcF 
values will be presented together in a listing. A scatter plot will be produced with the individual change 
from baseline Holter QTcF values at the extraction time points 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h 
plotted against the corresponding cytisine concentrations. Both dose groups will be presented on the 
same plot along with their correlation coefficients with plots for each age group (18-65, >65, all ages) 
presented separately.   
 
Holter ECG versus plasma concentration data will be listed for the Safety Set and plotted for subjects 
in the ECG-PK Set.  
 
 
11.8 OTHER 
11.8.1 Prior and Concomitant Medications 
All medications will be coded using the WHO Drug Dictionary (version as specified in the DMP) and 
listed using the ATC Level 4 class, Preferred Term and verbatim text. A medication will be regarded as 
‘prior’ if it stops prior to dosing, ‘prior and ongoing’ if it starts prior to dosing and continues after dosing 
and ‘concomitant’ if it starts after dosing. Frequencies of prior medications and concomitant medications 
within an ATC Level 4 class and Preferred Term will be presented by dose group, age group and overall. 
Medications regarded as ‘prior and ongoing’ will be assigned to treatment and included within the summary 
of concomitant medications.  
 
11.8.2 Extent of Exposure 
Exposure will be summarized by dose group and age group using counts and percentages for categorical 
variables and descriptive statistics (N, n, mean, SD, minimum, median and maximum) for continuous 
variables. The following will be calculated for each subject and summarized by dose group, age group 
and overall: duration of exposure to cytisine (days), number of cytisine doses administered, total dose 
of cytisine (mg) administered, percentage of planned dose of cytisine administered. One-hundred (100) 
doses of cytisine are to be administered over 25 days. The total planned dose of cytisine is 100 x 1.5 mg 
in the 1.5 mg dose group and 100 x 3.0 mg in the 3.0 mg dose group. Duration of exposure to cytisine 
will be summarized both as a categorical variable and as a continuous variable. 
 
11.8.3 All Other Data 
All data will be listed, including the following: Tobacco and Alcohol Use, Visit Dates, Medical History 
and Concurrent Conditions, Menstrual and Obstetric History, Pregnancy Test Results, Eligibility Check, 
Physical Examination, Inclusion/Exclusion Criteria Failures, Virology Results, Alcohol and Drugs of Abuse 
Results, Dose Administration, Urine Volumes, Additional Notes, Holter Monitoring Information and 
Daily Smoking and Study Medication Diary, Drug Accountability, Fagerström Test for Nicotine 
Dependence Questionnaire. 
 
 


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Derivations within listings: 
PK Blood Sampling Time Deviations: Calculate sample time deviation as: actual time – theoretical time, 
display in minutes. 
Analysis Sets: Detail whether subject should be included in each of the analysis sets along with 
corresponding comments if not included. 
Inclusion/Exclusion Criteria: Only failures to be recorded.  If no failures display ‘All subjects passed 
inclusion/exclusion criteria’. 
Protocol Deviations: Major/minor classification to be assigned and confirmed by Sponsor. 
Fagerström Test for Nicotine Dependence Questionnaire: The FTND responses will be assigned 
numerical values as follows: 
x
A question with a yes/no response: ‘No’ = 0; ‘Yes’ = 1. 
x
How soon after you wake up do you smoke your first cigarette: ‘After 60 minutes’ = 0; ’31 – 60 
minutes’ = 1; ‘6 – 30 minutes’ = 2; ‘Within 5 minutes’ = 3. 
x
Which cigarette would you hate most to give up: ‘All others’ = 0; ‘The first one in the morning’ = 
1. 
x
How many cigarettes in a day do you smoke: ’10 or less’ = 0; ‘11 – 20’ = 1; ‘21 – 30 ‘= 2; ’31 or 
more’ = 3.  
The FTND total score is defined as the sum of the scores from all 6 questions, provided all 6 questions 
have been completed. If any of the questions have a missing response, the total score will not be 
calculated. 
 
12 VALIDATION 
All tables, figures and listings will be subject to independent quality control and visual review. Unique 
tables will be independently programmed. Findings will be documented in an Output Summary file quality 
control form and actions taken will also be documented.  
The study summary sheet of the Output Summary file will be completed and signed by all persons who 
performed QC. The final version of the Output Summary, including the signed summary sheet, will be 
printed and stored in the Data Management File. The study summary sheet of the Output Summary file 
will be completed and signed by all persons who performed QC. The final version of the Output 
Summary, including the signed summary sheet, will be printed and stored in the Data Management File 
(DMF). 
13 LITERATURE CITATIONS/REFERENCES 
None. 
 


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14 LIST OF TABLES, FIGURES AND LISTINGS 
List of Tables and Figures Contained in Report Section 14 
 
 
14.1 
Disposition and Demographic Data 
14.1.1 Disposition Data 
Table 14.1.1.1 
Summary of Study Disposition 
Safety Set 
 
14.1.2 Demographic Data 
Table 14.1.2.1 
Summary of Demographic Data 
Safety Set 
Table 14.1.2.2 
Summary of Demographic Data - (if applicable) 
PK Set 
 
14.1.3 Smoking History 
Table 14.1.3.1 
Summary of Smoking History at Baseline 
Safety Set 
Table 14.1.3.2 
Summary of Number of Cigarettes Smoked at Baseline 
Safety Set 
 
14.2 
Efficacy Data 
Not Applicable. 
 
14.3 
Safety Data 
14.3.1 Adverse Events 
Table 14.3.1.1 
Summary of Treatment Emergent Adverse Events 
Safety Set 
Table 14.3.1.2 
Summary of Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
Safety Set 
Table 14.3.1.3 
Summary of Treatment Emergent Adverse Events by 
Preferred Term  
Safety Set 
Table 14.3.1.4 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term and Severity 
Safety Set 
Table 14.3.1.5 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term and Relationship 
Safety Set 
Table 14.3.1.6 
Serious Adverse Events 
Safety Set 
Table 14.3.1.7 
Adverse Events Leading to Withdrawal of Study Drug 
Safety Set 
 
 
 
 


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14.3.2 Laboratory Safety  
Table 14.3.2.1 
Biochemistry Out of Range Data 
Safety Set 
Table 14.3.2.2 
Haematology Out of Range Data 
Safety Set 
Table 14.3.2.3 
Urinalysis Out of Range Data 
Safety Set 
Table 14.3.2.4 
Summary of Absolute and Change from Baseline 
Biochemistry Data 
Safety Set 
Table 14.3.2.5 
Summary of Absolute and Change from Baseline 
Haematology Data 
Safety Set 
 
 14.3.3 Vital Signs  
Table 14.3.3.1  
Summary of Absolute and Change from Baseline Vital Signs 
Data 
Safety Set 
 
14.3.4 ECG 
Table 14.3.4.1 
Summary of Absolute and Change from Baseline 12-lead 
ECG Data 
Safety Set 
Table 14.3.4.2  
Summary of Absolute and Change from Baseline Holter 
ECG Data 
ECG Set 
Table 14.3.4.3 
Summary of Holter ECG QTcF Categories 
ECG Set 
Table 14.3.4.4 
Summary of Holter ECG Outliers 
ECG Set 
Figure 14.3.4.1 
Mean Change from Baseline Holter ECG Data 
ECG Set 
Figure 14.3.4.2 
Individual Change from Baseline Holter ECG QTcF versus 
Plasma Cytisine Concentration Data 
ECG-PK Set 
 
14.4 
Pharmacokinetics 
14.4.1 Concentration-Time Data   
Table 14.4.1.1 
Summary of Plasma Cytisine Concentration Data 
PK Set 
Table 14.4.1.2 
Summary of Plasma Cytisine Concentration Data 
Safety Set 
Table 14.4.1.3 
Summary of Urine Cytisine Concentration Data 
PK Set 
Table 14.4.1.4 
Summary of Urine Cytisine Concentration Data 
Safety Set 
Figure 14.4.1.1 
Mean Plasma Cytisine Concentration-Time Curves - Linear 
Scale 
PK Set 
Figure 14.4.1.2 
Mean Plasma Cytisine Concentration-Time Curves - Linear 
Scale 
Safety Set 
Figure 14.4.1.3  
Mean Plasma Cytisine Concentration-Time Curves - Semi-
Logarithmic Scale 
PK Set 


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14.5 
Pharmacodynamics 
 
 
Figure 14.4.1.4 
Mean Plasma Cytisine Concentration-Time Curves - Semi-
Logarithmic Scale– Non-Elderly Subjects 
Safety Set 
14.4.2 Derived Pharmacokinetic Data 
Table 14.4.2.1 
Summary of Derived Cytisine Pharmacokinetic Parameters 
PK Set 
Table 14.4.2.2 
Summary of Derived Cytisine Pharmacokinetic Parameters 
Safety Set 
Table 14.4.2.3 
Summary of Statistical Analysis of Cytisine Cmax and Cmin – 
Dose Schedule Comparison 
PK Set 
Table 14.4.2.4 
Summary of Statistical Analysis of Cytisine Cmax and Cmin – 
Dose Schedule Comparison 
Safety Set 
Table 14.4.2.5 
Summary of Statistical Analysis of Day 25 Cytisine Cmax and 
AUC – Dose Group Comparison 
PK Set 
Table 14.4.2.6 
Summary of Statistical Analysis of Day 25 Cytisine Cmax and 
AUC – Dose Group Comparison 
Safety Set 
14.5.1 Pharmacodynamic Data   
Table 14.5.1.1 
Summary of Absolute and Change from Baseline Daily Cigarette 
Consumption 
PD Set 
Table 14.5.1.2 
Summary of Smoking Cessation Status 
PD Set 
Table 14.5.1.3 
Summary of Absolute and Change from Baseline Daily Cigarette 
Consumption by Smoking Cessation Status 
PD Set 
Table 14.5.1.4 
Summary of First Day of Smoking Cessation for Subjects Who 
Ceased Smoking by Day 26 
PD Set 
Table 14.5.1.5 
Summary of Absolute and Change from Baseline Expired Air 
Carbon Monoxide (CO) Data 
PD Set 
Table 14.5.1.6 
Summary of Absolute and Change from Baseline Expired Air 
Carbon Monoxide (CO) by Smoking Cessation Status 
PD Set 
Table 14.5.1.7 
Summary of Absolute and Change from Baseline Urine Cotinine 
Data 
PD Set 
Table 14.5.1.8 
Summary of Absolute and Change from Baseline Tobacco 
Craving Questionnaire – Short Form Scores 
PD Set 
Figure 14.5.1.1 
Mean Daily Cigarette Consumption 
PD Set 
Figure 14.5.1.2 
Mean Change from Baseline Daily Cigarette Consumption 
PD Set 
Figure 14.5.1.3 
Mean Daily Cigarette Consumption by Smoking Cessation 
Status 
PD Set 


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14.6 
Other 
 
 
Subject Data: Listings Contained in Report Appendix 16.2 
 
  
Figure 14.5.1.4 
Mean Change from Baseline Daily Cigarette Consumption by 
Smoking Cessation Status 
PD Set 
Figure 14.5.1.5 
Mean Expired Air Carbon Monoxide (CO) Data 
PD Set 
Figure 14.5.1.6 
Mean Change from Baseline Expired Air Carbon Monoxide 
(CO) Data 
PD Set 
Figure 14.5.1.7 
Mean Expired Air Carbon Monoxide (CO) by Smoking 
Cessation Status 
PD Set 
Figure 14.5.1.8 
Mean Change from Baseline Expired Air Carbon Monoxide 
(CO) by Smoking Cessation Status 
PD Set 
Figure 14.5.1.9 
Mean Urine Cotinine Data 
PD Set 
Figure 14.5.1.10 
Mean Change from Baseline Urine Cotinine Data 
PD Set 
Figure 14.5.1.11 
Mean Tobacco Craving Questionnaire – Short Form Total 
Score 
PD Set 
Figure 14.5.1.12 
Mean Change from Baseline Tobacco Craving Questionnaire – 
Short Form Total Score 
PD Set 
14.6.1      Alcohol and Cotinine Results 
Table 14.6.1.1 
Summary of Baseline Urine Alcohol and Cotinine Results 
Safety Set 
Table 14.6.1.2 
Summary of Prior Medications 
Safety Set 
Table 14.6.1.3 
Summary of Concomitant Medications 
Safety Set 
Table 14.6.1.4 
Summary of Extent of Exposure 
Safety Set 
Table 14.6.1.5 
Summary of Duration of Exposure to Cytisine 
Safety Set 
16.2.1 
Visit Dates, Dosing Information and Disposition 
Listing 16.2.1.1 
Visit Dates 
Safety Set 
Listing 16.2.1.2 
Dose Administration 
Safety Set 
Listing 16.2.1.3 
Drug Accountability  
Safety Set 
Listing 16.2.1.4 
Subject Disposition 
Safety Set 
Listing 16.2.1.5 
Additional Notes  
Safety Set 
16.2.2 
Protocol Deviations  
Listing 16.2.2.1 
Protocol Deviations 
Safety Set 


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Not applicable. 
 
 
 
16.2.3 
Analysis Sets 
Listing 16.2.3.1 
Analysis Sets  
Safety Set 
16.2.4 
Demographic Data and Other Baseline Characteristics  
Listing 16.2.4.1 
Demographic Data  
Safety Set 
Listing 16.2.4.2 
Medical History and Concurrent Conditions  
Safety Set 
Listing 16.2.4.3 
Virology Result 
Safety Set 
Listing 16.2.4.4 
Tobacco and Alcohol Use 
Safety Set 
Listing 16.2.4.5 
Drugs of Abuse Results  
Safety Set 
Listing 16.2.4.6 
Menstrual and Obstetric History  
Safety Set 
Listing 16.2.4.7 
Pregnancy Test Results 
Safety Set 
Listing 16.2.4.8 
Inclusion/Exclusion Criteria Failures  
Safety Set 
Listing 16.2.4.9 
Eligibility Check 
Safety Set 
16.2.5 
Drug Concentration Data and Pharmacokinetics 
Listing 16.2.5.1 
Plasma Cytisine Concentration Data 
Safety Set 
Listing 16.2.5.2 
Urine Cytisine Concentration Data  
Safety Set 
Listing 16.2.5.3 
Individual Derived Cytisine Pharmacokinetic Parameters  
Safety Set 
Figure 16.2.5.1 
Individual Plasma Cytisine Concentration-Time Curves 
on a Linear Scale 
Safety Set 
Figure 16.2.5.2 
Individual Plasma Cytisine Concentration-Time Curves 
on a Semi-Logarithmic Scale  
Safety Set 
16.2.6 
Efficacy  
16.2.7 
Adverse Events  
Listing 16.2.7.1 
Adverse Events 
Safety Set 
16.2.8 
Individual Laboratory Safety Measurements  
Listing 16.2.8.1 
Biochemistry Data 
Safety Set 
Listing 16.2.8.2 
Haematology Data 
Safety Set 


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Listing 16.2.8.3 
Urinalysis Data  
Safety Set 
Listing 16.2.8.4 
Microscopy Data 
Safety Set 
16.2.9 
Vital Signs 
Listing 16.2.9.1 
Vital Signs Data 
Safety Set 
16.2.10 
Physical Examination 
Listing 16.2.10.1 
Physical Examination Data  
Safety Set 
16.2.11 
ECG 
Listing 16.2.11.1 
12-Lead ECG Data  
Safety Set 
Listing 16.2.11.2 
Holter Monitoring ECG Data 
Safety Set 
Listing 16.2.11.3 
Change and Percentage Change from Baseline Holter ECG 
Data 
Safety Set 
Listing 16.2.11.4 
Holter ECG QTcF and Plasma Cytisine Concentration 
Data 
Safety Set 
Listing 16.2.11.5 
Holter Monitoring Information  
Safety Set 
16.2.12 
Prior and Concomitant Medication 
Listing 16.2.12.1 
Prior and Concomitant Medication Use 
Safety Set 
16.2.13 
Pharmacodynamics  
Listing 16.2.13.1 
Daily Cigarette Consumption and Expired Air Carbon 
Monoxide (CO) Data 
Safety Set 
Listing 16.2.13.2 
Urine Cotinine Data  
Safety Set 
Listing 16.2.13.3 
Fagerström Test for Nicotine Dependence Questionnaire Safety Set 
Listing 16.2.13.4 
Tobacco Craving Questionnaire – Short Form 
Safety Set 
Figure 16.2.13.1 
Individual Daily Cigarette Consumption 
Safety Set 
Figure 16.2.13.2 
Individual Expired Air Carbon Monoxide (CO) Data 
Safety Set 
Figure 16.2.13.3 
Individual Urine Cotinine Data 
Safety Set 


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15 SHELLS FOR TABLES, FIGURES AND LISTINGS 
 
  
 
  
 
 
 
 
                                                         
  
                                                    
 
                                                       
 
                                                     
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 


 
 
 
     
 
 
 
 
 
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16 APPENDICES 
16.1 NORMAL RANGES 
 
Vital Signs Normal Ranges: 
 
Parameter 
Normal Range 
Units 
Pulse Rate 
40-110 
Beats per minute (bpm) 
Systolic Blood Pressure 
90-150 
mmHg 
Diastolic Blood Pressure 
50-90 
mmHg 
Respiratory Rate 
12-18 
Breaths per minute 
Oral Temperature 
35.0-37.5 
Degrees Celsius (°C) 
Pulse Oximetry 
94-100 
% 
 
12-Lead ECG Normal Ranges: 
 
Parameter 
Normal Range 
Units 
Heart Rate 
40-110 
Beats per minute (bpm) 
PR Interval 
120-220 
mSec 
QRS Duration 
70-120 
mSec 
QT Interval 
N/a 
N/a 
QTc Interval (=QTcF) (Fridericia’s) 
350-430 (males) 
mSec 
350-450 (females) 
mSec