Clinical trial NCT03848208
Conditions: Smoking Cessation
Sponsor: Achieve Life Sciences
Start date: 2019-02-28; Completion date: 2019-09-12
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are:

1. To assess the tolerability and safety of cytisine as a single oral dose.
2. To define the Cmax levels associated to the occurrence of dose-limiting adverse events.

Detailed description:

Arms: arm 1: Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 2: Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 3: Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 4: Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 5: Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 6: Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 7: Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 8: Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 9: Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 10: Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 11: Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 12: Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 13: Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 14: Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 15: Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 16: Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 17: Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. arm 18: Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours.
Interventions: intervention 1: cytisine intervention 2: placebo
Intervention descriptions: intervention 1: cytisine film-coated oral tablet intervention 2: matching placebo oral tablet

Protocol documents:
Prot_000.pdf: 
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SUMMARY OF CHANGES 
OF THIS VERSION (5.0) VERSUS PREVIOUS VERSION (4.0) 
 
 
Section 
No. 
Section title 
Nature of Change 
1.  
Study Summary  
– Study Design 
– Study Treatment 
Dosing 
Three additional dose cohorts (24 mg, 27 mg and 30 
mg) were included aiming to reach the stopping 
criteria. 
7.1 
Study Design 
1. 
Study Summary  
– Number of Subjects 
Up to twenty-four additional participants are planned to 
be enrolled in the three additional cohorts. 
7.2. 
Number of Subjects 
1.  
Study Summary  
– Duration of the Study 
The information on the duration of the study was 
updated considering up to 3 additional cohorts. 
7.4. 
Estimated Duration/ 
Completion of Study 
1.  
Study Summary  
– Study Procedures 
The sample matrix for measurement of cotinine and 3-
OH cotinine was changed from plasma to serum 
because serum is routinely collected, and sample type 
has no impact on test results.   
12.1.1. 
Screening visit (Day -28 
to Day -1) 
13.3.1. 
Routine Laboratory 
Assessments 
4.3. 
Results from Cohorts 1 
to 6 (6 mg to 21 mg) of 
Study ACH-CYT-08 
A new section has been created to include the safety 
and pharmacokinetic results of the previously 
completed 6 cohorts of the current clinical trial. 
10.8. 
Study Drug Dosing 
Schedule 
Dosing schedule was updated to include up to three 
additional cohorts. 




Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
Cytisine  
 CONFIDENTIAL 
 
4 
SYNOPSIS    . 
Protocol Number:  ACH-CYT-08 
Sponsor: Achieve Life Sciences, Inc. 
Title of Study: A Phase I, Double-blind, Randomized, Placebo-controlled, Single Dose-
escalation Study to Evaluate the Tolerability and Safety of Cytisine in Adult Smokers. 
Clinical Phase: Phase 1 
Principal Investigator:
 
Clinical Pharmacology Unit: 
 
 
 
 
 
Study Population: Male or nonpregnant female subjects ≥18 years in good general health and 
who are daily cigarette smokers. The health status will be determined by pre-study medical 
history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical 
laboratory tests. 
Rationale: (-)-Cytisine is a naturally occurring plant-based alkaloid, isolated from seeds of 
Cytisus laburnum (Golden chain), that is believed to reduce the severity of nicotine withdrawal 
symptoms while inhibiting nicotine’s effects by targeting nicotinic acetylcholine receptors 
(nAChRs) in the brain. Cytisine, as film-coated tablets of 1.5 mg cytisine, has been used as a 
smoking cessation drug since the 1960’s in Central and Eastern European countries 
 
manufactured by 
 is commercially administered using a 1.5 mg dose in a 
titration schedule over a 25-day period for a total exposure of 150 mg cytisine. Previous studies 
dating from decades ago to support use in Central and Eastern Europe, and more recent studies 
conducted to Good Clinical Practice (GCP), have shown that cytisine can be effective in 
helping smokers to stop smoking.  
This GCP conducted, Phase 1 trial is designed to assess the tolerability and safety for a single 
administered oral dose of cytisine. Since it is difficult to separate the reported adverse effects 
associated with cytisine treatment versus nicotine withdrawal effects in smokers using cytisine 
to quit smoking, this Phase 1 study will be performed in smokers who are currently smoking 
(not trying to quit), are tolerant to the effects of nicotine due to chronic smoking, and will 
receive only a single dosage of cytisine. The dosage of cytisine will be escalated in separate 
cohorts until the stopping criteria (based on the occurrence of dose-limiting adverse events) is 
reached. In addition, plasma cytisine concentrations will be evaluated in order to estimate the 
cytisine maximum observed plasma concentration (Cmax) levels associated to the occurrence of 
dose-limiting adverse events. 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
Cytisine  
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5 
Investigational Products:  
Test Product: Cytisine 1.5 mg film-coated tablets; manufactured by
, 
 
Control: Placebo film-coated tablets. 
Certificates of analysis and batch numbers will be presented in the final Clinical Study Report 
(CSR). 
Objectives:  
1. To assess the tolerability and safety of cytisine as a single oral dose. 
2. To define the Cmax levels associated to the occurrence of dose-limiting adverse events.  
Study Design:  
This is a single-center, double-blind, randomized, placebo-controlled, single dose-escalation, 
Phase 1 clinical study in adult subjects who are daily smokers, under fasting conditions. 
Cytisine or placebo will be administered to cohorts of 8 subjects per dose level. The starting 
dose was 6 mg cytisine (single oral dose) in Cohort 1. Six dose levels were studied under 
Version 4.0 of Protocol ACH-CYT-08: 6 mg, 9 mg, 12 mg, 15 mg, 18 mg and 21 mg. The 
study was escalated up to the cytisine dose of 21 mg without showing any of the predefined 
stopping criteria and remains blinded. Thus, three additional dose levels are pre-planned: 
24 mg, 27 mg and 30 mg. Within each dose level, subjects will be randomly assigned to receive 
a single oral dose of cytisine or placebo in a 3:1 ratio (6 cytisine:2 placebo). 
Upon completion of the follow-up assessment for each subject in each cohort, the data will be 
cleaned and soft-locked and then a safety review will be performed by the Principal 
Investigator (PI) and the independent Data Safety Monitors (DSMs) on unblinded data. The PI 
and DSMs will conjointly decide whether dose escalation into the next cohort will be allowed. 
Stopping criteria: The dose should not be escalated further if any of the following occurs: 
1) A serious adverse event (SAE) that is considered at least possibly related to cytisine in 1 
or more subjects;  
2) Severe non-serious adverse events that are considered at least possibly related to 
cytisine in 2 or more subjects within the same cohort;  
3) Other safety information considered to pose a risk to subjects. 
Selection Criteria: 
Inclusion Criteria 
1. Free written informed consent prior to any procedure required by the study. 
2. Male or female subjects, age ≥18 years, at the time of signing the informed consent.  
3. Current daily cigarette smokers (averaging at least 10 cigarettes per day in the past 
30 days).  
4. Expired air carbon monoxide (CO) ≥10 ppm. 
5. Able to swallow multiple tablets at one time. 
6. Able to fully understand, comply with all study requirements. 
 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
Cytisine  
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6 
 
Exclusion criteria: 
At screening 
1. Known hypersensitivity to cytisine or any of the excipients. 
2. Known severe hypersensitivity to any other drug.  
3. Positive urinary drugs of abuse screen, determined within 28 days before 
cytisine/placebo dosing. 
4. Positive ethanol breath test. 
5. Clinically significant abnormal serum chemistry, hematology, coagulation or urinalysis 
values within 28 days of randomization (i.e. requiring treatment or monitoring).  
6. Clinically significant abnormalities in 12-lead ECG determined after minimum of 
5 minutes in supine position within 28 days of randomization (i.e. requiring treatment or 
further assessment). 
7. Body Mass Index (BMI) classification for being underweight (<18.5 kg/m2) or having 
≥Class 2 obesity (≥35 kg/m2). 
8. History of acute myocardial infarction, unstable angina, stroke, cerebrovascular 
incident, cardiac arrhythmia, or hospitalization for congestive heart failure. 
9. Blood pressure ≥160/100 mmHg, measured on the dominant arm, after at least 
3 minutes in supine position. 
10. Creatinine clearance (CrCl) <80 mL/min (estimated with the Cockroft-Gault equation).  
11. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 x the upper 
limit of normal (ULN). 
12. Any inability to comply with study restrictions (See Section 9).  
13. Any inability or difficulty in fasting. 
14. Difficulty in donating blood on either arm. 
15. If woman of childbearing potential, positive result in serum beta-hCG pregnancy test. 
16. Women who are breast-feeding. 
17. Subjects who do not agree to use acceptable methods of birth control during the study 
(See Section 9.4). 
18. Participation in a clinical study with an investigational drug within the previous 
2 months. 
19. Participation in more than 2 clinical trials within the previous 12 months. 
20. Any other reason that the investigator views the subject should not participate or would 
be unable to fulfill the requirements for the study. 
At admission to each cohort 
21. Any recent disease or condition or treatment that, according to the Investigator, would 
put the subject at undue risk due to study participation. 
22. Positive urinary drugs of abuse screen. 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
Cytisine  
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7 
23. Positive ethanol breath test. 
24. If female of childbearing potential, positive result in urine beta-hCG pregnancy test. 
25. Any other reason that the investigator views the subject should not participate or would 
be unable to fulfill the requirements for the study. 
Number of Subjects: 
Eight (8) subjects per dose level will be enrolled.  
Under ACH-CYT-08 Version 4.0, 48 subjects were enrolled in the previous 6 cohorts. 
Considering the 3 additional cohorts under ACH-CYT-08 Version 5.0, a total of 72 subjects is 
estimated for completing enrollment in the study.  
Study Treatment Dosing: 
According to the randomization schema, individual subjects will receive cytisine or placebo 
tablets as follows: 
Cohort 
Number of 1.5 mg 
Cytisine Tablets 
(or placebo) 
Total Cytisine Dose 
Administered 
1 
4 
6.0 mg 
2 
6 
9.0 mg 
3 
8 
12.0 mg 
4 
10 
15.0 mg 
5 
12 
18.0 mg 
6 
14 
21.0 mg 
7 
16 
24.0 mg 
8 
18 
27.0 mg 
9 
20 
30.0 mg 
For each additional cohort, the total dose of cytisine will be increased by 3.0 mg (2 additional 
tablets at 1.5 mg each required for each successive dose level). 
Cytisine/placebo will be administered in the morning, orally, with 240 mL of water, after 
fasting overnight for at least 10 hours.  
Diet and Fluids: 
Subjects will remain fasted for at least 4 hours following investigational product administration. 
Except for water given with the investigational product, no fluids will be allowed from 1 hour 
before until 1 hour after dosing. Standardized meals and snacks identical in all cohorts will be 
provided not earlier than 4, and at 8±0.5, 12±1, 15±1 and 24±1 hours after dosing. 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
Cytisine  
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8 
Safety Assessments: 
Safety will be evaluated through the assessment of adverse events, ECG, vital signs, and 
clinical laboratory tests (see Schedule of Study Procedures). Adverse events will be monitored 
throughout the study. 
The highest dose-level that resulted in ≤1 cytisine-treated subject within a cohort presenting 
dose-limiting adverse events will be considered the maximum tolerated dose. 
Pharmacokinetic Assessments: 
Twelve (12) venous blood samples (volume of 6 mL each) will be collected for the 
determination of plasma concentrations of cytisine, at pre-dose and at predefined time points 
over 3 hours post dose. 
Cytisine plasma concentrations will be measured using a previously validated liquid 
chromatography with tandem mass spectrometry (LC-MS/MS) analytical method. 
Pharmacokinetic parameters of Cytisine will be estimated with Phoenix™ WinNonlin™ version 
8.1 or higher (Certara USA Inc, Princeton, NJ).  
The following pharmacokinetic parameters will be estimated: Cmax and time of occurrence of 
Cmax (Tmax). 
Volume of Blood Drawn: Subject’s total volume of scheduled blood drawn for the 
pharmacokinetic and clinical laboratory safety assessments will be approximately 90 mL. 
Duration of Study:  
Each cohort will require a minimum of 2 days in the clinical research facilities (subjects will be 
confined at the clinical research facilities from at least 11 hours before dosing until at least 24 
hours post-dose). Each cohort will take 7 days for completion , including a safety review and 
the final 4-5 day post study follow-up call. 
Study Procedures 
After providing signed informed consent, all subjects will be evaluated for inclusion in the 
study within a 28-day Screening Period. The Table below provides a summary of required 
procedures/evaluations during the study.  


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
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9 
Schedule of Study Procedures 
Assessments 
Screening 
Treatment Period in Each Cohort 
Follow-
up 
Admission Confinement1 Discharge2 
Days 
-28 to -1 
Day 0 
Days 1-2  
Day 2  
Day 5-63 
Written informed 
consent 
X 
 
 
 
 
Demographic 
data/height/weight 
X 
 
 
 
 
Expired CO levels 
X 
 
 
 
 
Baseline NMR10 
X 
 
 
 
 
Medical history, 
including smoking 
X 
 
 
 
 
Medical history 
update 
 
X4 
 
 
 
Physical examination 
X 
 
 
 
 
Physical examination 
update 
 
X4 
 
 
 
Vital signs (supine 
blood pressure, pulse 
rate and body 
temperature) 
X 
X 
X5 
X5 
 
Prior and concomitant 
medication 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
X6 
 
Continuous vital 
parameters 
monitoring 
 
 
X7 
 
 
Pregnancy test, if 
WOCBP 
X 
(Serum) 
X 
(Urine) 
 
X 
(Serum) 
 
Hematology 
X 
 
 
X 
 
Biochemistry 
X 
 
 
X 
 
Estimated creatinine 
clearance 
X 
 
 
 
 
Coagulation 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
Drugs-of-abuse tests 
in urine 
X 
X 
 
 
 
Ethanol breath test 
X 
X 
 
 
 
Verification of 
eligibility criteria 
X 
X 
 
 
 
Cytisine/placebo 
administration 
 
 
X8 
 
 
Blood collection for 
pharmacokinetic 
analysis 
 
 
X 
 
 
Adverse events 
monitoring 
X9 
X9 
X9 
X9 
X9 
WOCBP – Woman of childbearing potential 
1 
From at least 11 hours before dosing to at least 24 hours post dose. 
2 
At 24 hours post-dose. 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
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3 
A Post-Study Follow-up telephone call will occur 4-5 days after dosing to document any changes 
in adverse event(s) observed at discharge as well as any new adverse events and concomitant 
medications taken. 
4 
Clinically relevant changes will be reported as adverse events.  
5 
Vital signs to be recorded at pre-dose and again at approximately 2, 4 and 6 hours post-dose on 
Day 1 and at discharge on Day 2. 
6 
Repeat 12-lead ECG and assess prior to discharge. 
7 
Continuous vital parameters monitoring (lead-II ECG, heart rate, respiratory rate and pulse 
oximetry) will be performed from pre-dose up to 6 hours post-dose. 
8 
Orally, in the morning, with 240 mL of water, after an overnight fasting of at least 10 hours. 
9 
Adverse events will be monitored throughout the whole study. 
10 Serum collected for cotinine and 3-OH cotinine to determine baseline nicotine metabolite ratio 
(NMR). 
Study Diagram: 
 
 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
Cytisine  
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Statistical Considerations:  
Analysis Sets 
Screening Analysis Set: The Screening Analysis Set is defined as all subjects who give written 
informed consent and have entered screening. Analyses will be restricted to presentation of 
baseline data and reasons for non-participation as contrasted to those enrolled and received 
study drug. 
Safety Analysis Set: The Safety Analysis Set is defined as all enrolled subjects who were 
administered the single dose of study drug. 
General Considerations 
Summaries of demographics, baseline characteristics and safety endpoints will be provided for 
the safety population, defined as all subjects who receive a single dose of cytisine or placebo. 
Unless otherwise indicated, no statistical comparisons between the cohorts are planned. 
Summaries will be provided for each cohort. Numeric variables will be summarized using the 
mean, median, standard deviation, etc. Categorical variables will be summarized with number 
and percent. 
Pharmacokinetic parameters (Cmax and Tmax) will be summarized for each cohort using the 
mean, standard deviation, median, minimum and maximum.  
Reporting: 
A CSR according to ICH E3 will be prepared on the study. The pharmacokinetic analysis will 
be integrated in the CSR. 
Ethical and Regulatory Compliance: 
The study will be conducted in accordance with the approved Protocol and in compliance with 
the Declaration of Helsinki, ICH Good Clinical Practice, and all applicable laws and 
regulations. 
 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
Cytisine  
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TABLE OF CONTENTS 
SYNOPSIS    . ..................................................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................16 
1. 
INTRODUCTION AND BACKGROUND ...............................................................18 
1.1. 
History of the Investigational Product ........................................................................18 
1.2. 
Nicotine Addiction and Impact on Health ..................................................................18 
1.3. 
Treatments for Smoking Cessation ..........................................................................18 
2. 
RECENT EVIDENCE FOR CYTISINE AS A SMOKING CESSATION 
TREATMENT ............................................................................................................20 
3. 
SAFETY OVERVIEW FOR CYTISINE ...................................................................21 
3.1. 
Non-Clinical Studies ...................................................................................................21 
3.1.1. 
Summary of 28-Day Repeat Toxicology Studies .......................................................21 
3.1.2. 
Summary of Reproductive/Developmental Studies....................................................22 
3.2. 
General Safety of Cytisine as a Marketed Product .....................................................23 
3.2.1. 
Summary of Safety Profile .........................................................................................23 
3.2.2. 
Tabulated List of Adverse Reactions ..........................................................................24 
4. 
RECENT STUDIES COMPLETED BY THE SPONSOR ........................................25 
4.1. 
Preliminary Results from Study ACH-CYT-02 on Safety and 
Pharmacodynamics of the 3.0 mg Cytisine Dose Compared to the Standard 
1.5 mg Dose ................................................................................................................25 
4.2. 
Results from Study ACH-CYT-01 on the Effect of Food on Cytisine 
Bioavailability .............................................................................................................28 
4.3. 
Results from Cohorts 1 to 6 (6 mg to 21 mg) of Study ACH-CYT-08 ......................30 
5. 
RATIONALE FOR THE STUDY ..............................................................................31 
5.1. 
Rationale .....................................................................................................................31 
5.2. 
Benefit/Risk Assessment ............................................................................................31 
6. 
STUDY OBJECTIVES ..............................................................................................32 
7. 
STUDY DESIGN OVERVIEW .................................................................................32 
7.1. 
Study Design ...............................................................................................................32 
7.2. 
Number of Subjects ....................................................................................................33 
7.3. 
Number of Clinical Sites ............................................................................................33 
7.4. 
Estimated Duration/Completion of Study ..................................................................33 
8. 
SELECTION OF STUDY POPULATION ................................................................34 
8.1. 
Inclusion Criteria ........................................................................................................34 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
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8.2. 
Exclusion Criteria .......................................................................................................34 
9. 
RESTRICTIONS PRIOR AND DURING THE STUDY ..........................................36 
9.1. 
Confinement ...............................................................................................................36 
9.2. 
Diet and Fluid Restrictions .........................................................................................36 
9.2.1. 
Meal Times .................................................................................................................36 
9.2.2. 
Fluid Intake .................................................................................................................36 
9.2.3. 
Alcohol Intake ............................................................................................................36 
9.2.4. 
Caffeine .......................................................................................................................36 
9.2.5. 
Tobacco .......................................................................................................................37 
9.2.6. 
Poppy and Sesame Seeds and Cannabinoid Smoke Exposure ...................................37 
9.2.7. 
Grapefruit Juice and Other Restrictions .....................................................................37 
9.3. 
Exercise .......................................................................................................................37 
9.4. 
Contraception Requirements ......................................................................................37 
10. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ..........................................38 
10.1. 
Cytisine 1.5 mg Film-Coated Tablets .........................................................................38 
10.2. 
Placebo Tablets ...........................................................................................................38 
10.3. 
Receipt and Storage ....................................................................................................39 
10.4. 
Administration ............................................................................................................39 
10.5. 
Return/Destruction ......................................................................................................39 
10.6. 
Method of Assigning Subjects to Cohort....................................................................39 
10.7. 
Blinding and Code Break Procedures .........................................................................39 
10.7.1. 
Emergency Code Break Procedure: ............................................................................40 
10.7.2. 
Unblinding for Safety Monitoring to Escalate into Next Cohort ...............................40 
10.8. 
Study Drug Dosing Schedule ......................................................................................40 
10.9. 
Accountability .............................................................................................................40 
11. 
PREVIOUS AND CONCOMITANT MEDICATIONS ............................................41 
12. 
STUDY PROCEDURES ............................................................................................42 
12.1. 
Detailed Description of Study Visits ..........................................................................43 
12.1.1. 
Screening Visit (Day -28 to Day -1) ...........................................................................43 
12.1.2. 
Day 0: Admission .......................................................................................................43 
12.1.3. 
Day 1: Administration of Cytisine ..............................................................................44 
12.1.4. 
Day 2: Discharge at 24 hours post-dose .....................................................................45 
12.1.5. 
Days 4-5 Post-Study Follow-up..................................................................................45 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
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12.1.6. 
Interim Safety Assessments ........................................................................................45 
12.2. 
Pharmacokinetic Blood Sampling ..............................................................................46 
13. 
SAFETY ASSESSMENTS ........................................................................................47 
13.1. 
Definitions ..................................................................................................................47 
13.2. 
Recording of Adverse Events .....................................................................................49 
13.2.1. 
Grading Adverse Event Severity ................................................................................50 
13.2.2. 
Causality Assessment .................................................................................................50 
13.2.3. 
Reporting of Serious Adverse Events .........................................................................51 
13.3. 
Laboratory ...................................................................................................................52 
13.3.1. 
Routine Laboratory Assessments ...............................................................................52 
13.4. 
Vital signs and electrocardiogram ..............................................................................53 
13.5. 
Physical Examination .................................................................................................53 
14. 
SAFETY MONITORING ..........................................................................................53 
14.1. 
Independent Data Safety Monitors .............................................................................53 
14.2. 
Stopping Criteria .........................................................................................................54 
15. 
STATISTICAL CONSIDERATIONS .......................................................................54 
15.1. 
Sample Size ................................................................................................................54 
15.2. 
Analysis Sets ...............................................................................................................54 
15.3. 
Safety Assessments .....................................................................................................54 
15.4. 
General Considerations ...............................................................................................55 
15.5. 
Pharmacokinetic Parameters .......................................................................................55 
16. 
REGULATORY AND ETHICS CONSIDERATIONS .............................................55 
16.1. 
Independent Ethics Committee ...................................................................................55 
16.2. 
Ethical Conduct of the Study ......................................................................................56 
16.3. 
Informed Consent .......................................................................................................56 
16.4. 
Review and Approval by Regulatory Authorities ......................................................56 
16.5. 
Insurance,  Indemnity and Compensation ..................................................................56 
16.6. 
Subject Confidentiality ...............................................................................................57 
17. 
DOCUMENTATION .................................................................................................57 
17.1. 
Study File and Site Documents...................................................................................57 
17.2. 
Study Documents Supplied by the Sponsor ................................................................57 
17.3. 
Maintenance and Retention of Records ......................................................................57 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................58 


Protocol ACH-CYT-08, 07 May 2019, Ver 5.0 
 
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18.1. 
Sponsor Responsibilities .............................................................................................58 
18.2. 
Investigator Responsibilities .......................................................................................58 
18.3. 
Regulatory Compliance ..............................................................................................59 
18.4. 
Protocol Modification/Premature Termination ...........................................................60 
18.5. 
Final Study Report ......................................................................................................60 
18.6. 
Policy for Publication and Data Presentation .............................................................60 
19. 
INVESTIGATOR’S AGREEMENT ..........................................................................61 
20. 
REFERENCES ...........................................................................................................62 
 
LIST OF TABLES 
Table 1: 
Calculation of Margin of Safety based on Rat and Dog Toxicology Studies .............22 
Table 2: 
Adverse Events Reported From the Recent 
 Core Data Sheet ........................24 
Table 3:  
ACH-CYT-02: Dose Timing and Total Daily Dose ...................................................25 
Table 4: 
ACH-CYT-02: Subject Demographics (Aged 18-65) ................................................26 
Table 5: 
ACH-CYT-02: Overall Summary of TEAEs by Severity and Relationship – 
18 to 65 Years Old (Safety Set) ..................................................................................27 
Table 6: 
ACH-CYT-02: Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term – 18 to 65 Years Old (Safety Set) ...............................................28 
Table 7: 
ACH-CYT-01: Summary of Statistical Analysis of Cytisine Cmax and AUC ..........29 
Table 8: 
Schedule of Study Procedures ....................................................................................42 
Table 9: 
Blood Sampling for Pharmacokinetic Assessments ...................................................46 
Table 10: Adverse Event Severity ..............................................................................................50 
Table 11: Assessment of Attribution to Study Drug ...................................................................50 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABBREVIATION/
TERM 
DEFINITION 
ACh 
Acetylcholine 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC0-∞ 
Area Under the Curve Extrapolated from Time Zero to Infinity  
AUC0-t 
Area Under the Curve from Time Zero to Last Sampling Time with 
Quantifiable Concentrations 
AUClast 
Area Under the Curve to Last Measured Concentration 
BMI 
Body Mass Index 
 
 
 
CI 
Confidence Interval 
Cmax 
Maximum Observed Plasma Concentration 
CrCl 
Creatinine Clearance  
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DLT 
Dose Limiting Toxicity 
DSM 
Data Safety Monitor 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FSH 
High Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GD 
Gestation Day 
GLP 
Good Laboratory Practice 
GI 
Gastrointestinal 
HED 
Human Equivalent Dose 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
 
 
 
IND 
Investigational New Drug 
LD 
Lactation Day 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum Tolerated Dose 
NCCIH 
US National Center for Complementary and Integrative Health 
NMR 
Nicotine Metabolite Ratio 
NOAEL 
No Observed Adverse Effect Level 
NRT 
Nicotine Replacement Therapy 
nAChRs 
Nicotinic Acetylcholine Receptors 
PK 
Pharmacokinetics 
PI 
Principal Investigator 
PSUR 
Periodic Safety Update Reports 


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ABBREVIATION/
TERM 
DEFINITION 
PT 
MedDRA Preferred Term 
RR 
Relative Risk 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SOC 
MedDRA System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Tmax 
Time to Maximum Observed Concentration 
TEAE 
Treatment-Emergent Adverse Event 
UADR 
Unexpected Adverse Drug Reaction 
UAE 
Unexpected Adverse Event 
ULN 
Upper Limit of Normal 


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1. 
INTRODUCTION AND BACKGROUND 
1.1. 
History of the Investigational Product 
(-)-Cytisine (cytisinicline) is a plant-based alkaloid isolated from seeds of Cytisus laburnum 
(Golden chain) and has been used as a smoking cessation drug since the 1960’s in Central and 
Eastern Europe, marketed as 
).1 It is estimated that over 
21 million smokers have been treated with 
. The molecular structure of cytisine has 
similarities to nicotine and acetylcholine (ACh). Nicotine addiction results, at least in part, from 
its interaction with neuronal nicotinic acetylcholine receptors (nAChRs). Both cytisine and 
nicotine compete for these receptors.2-4 Cytisine has high affinity and specificity for neuronal 
nicotinic (α4β2) receptors.  
Despite its widespread use, cytisine has not been market-approved for use outside Central and 
Eastern Europe. This may, in part, be explained by 
 focus on clinical development of 
cytisine in its traditional markets where the initial clinical studies were conducted and published, 
although not in English.1 Two more recent Phase 3 studies have been conducted and published in 
2011 and 2014 in the New England Journal of Medicine.5,6  
1.2. 
Nicotine Addiction and Impact on Health 
Nicotine is an addictive substance that is rapidly absorbed during cigarette smoking. The drug 
distributes quickly and is thought to interact with nAChRs in the central nervous system (CNS). 
Although many smokers attempt to quit smoking, few succeed without pharmacological 
supportive treatment. 
Tobacco smoking contributes to some 7 million premature deaths each year worldwide.7 It is 
highly addictive, with more than 95% of unaided attempts at cessation failing by 6 months.8 Every 
year that a smoker delays quitting beyond the mid-30s, there is an estimated 3 months reduction in 
life expectancy.9 
Although nicotine is primarily responsible for the addictive properties of cigarette smoking, 
tobacco smoke also contains several hundred gaseous substances and several thousand 
compounds. There is increasing evidence that the presence of carbon monoxide in cigarette smoke 
plays a role in cardiovascular disease and that tar is a major factor in respiratory disease and 
cancer.10 Nicotine, of which 1 to 3.0 mg is typically absorbed from each cigarette, is a peripheral 
vasoconstrictor and a sympathomimetic stimulant, which also leads to improvement in mood and 
attention. 
1.3. 
Treatments for Smoking Cessation 
The pharmacotherapies currently available in the US and Western Europe to help smokers quit 
include nicotine replacement therapy (NRT) and two non-nicotine containing medications: 
bupropion (Zyban®, Glaxo-SmithKline) and varenicline (Chantix®/Champix®, Pfizer). NRT and 
bupropion appear to have about equal efficacy.11,12 Varenicline is more effective than NRT and 
bupropion. A brief description of each pharmacotherapy is given below. 
Nicotine replacement therapy was first introduced in 1978. NRT replaces the nicotine absorbed 
from cigarettes and helps subjects stop smoking by reducing nicotine cravings, withdrawal 
symptoms, and mood changes. Available over-the-counter and prescription-only NRT products 
include: chewing gums, lozenges, transdermal patches, nasal sprays and inhalers. The purpose of 


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all NRT products is to achieve a sufficient plasma concentration of nicotine (and hence 
concentration of nicotine at central nAChRs) and so reduce craving for nicotine derived from 
cigarette smoke. However, the efficacy of NRT (expressed as a pooled Relative Risk (RR) 
compared with placebo treatment) is limited (overall RR 1.60).12 In general, the delivery of 
nicotine from NRT products is relatively slow, and the pharmacokinetic (PK) profile does not 
resemble that of cigarettes: the time to maximum observed plasma concentration (Tmax) tends to 
be longer for NRT, and the maximum observed plasma concentration (Cmax) is not characterized 
by a sharp peak, but by a lower and flatter peak. Thus, the smoker does not have the same nicotine 
experience with NRT products that they do from smoking. Although there do not appear to be 
safety concerns for NRT usage, the relatively poor response to NRT products as aids to smoking 
cessation limits their effectiveness as treatment. Side effects of NRT products include: nausea, 
dizziness, weakness, vomiting, fast or irregular heartbeat, mouth problems with the lozenge or 
gum, and redness or swelling of the skin around the patch. 
Bupropion is one of the most frequently prescribed antidepressants in the US. Zyban® is 
bupropion re-profiled as a smoking cessation medication in tablet form. Although it reduces 
nicotine withdrawal symptoms and craving and enhances tobacco cessation, the precise 
mechanism by which it aids smoking cessation is unknown. The efficacy of bupropion is similar 
to that of NRT (overall RR 1.62).11 Although the most commonly observed adverse events 
consistently associated with the use of bupropion are dry mouth and insomnia, the medication 
guide for bupropion cites other adverse events and risks related to this product, including seizures, 
high blood pressure, and allergic reactions. Because bupropion contains the same active substance 
as the antidepressant Wellbutrin®, users and potential users are urged to talk to their health care 
professional about risks of treatment with antidepressant medicines. 
Varenicline was synthetically developed as a new class of α4β2 nicotine receptor partial agonists, 
in part, using (-)-cytisine as the structural starting point.4 Varenicline is a partial agonist at 
nicotine receptors and acts as a nicotine substitute leading to a gradual decrease in the smoker's 
physical and psychological dependence on cigarettes. In a recent Cochrane analysis report 
detailing 6-month abstinence rates, varenicline was found to be more effective than placebo 
(overall RR=2.25) or bupropion (overall RR=1.39).13 The most common side effects of 
varenicline (>5% or twice the rate seen with placebo) include nausea, abnormal (vivid, unusual, or 
strange) dreams, constipation, flatulence, and vomiting. In addition, the Prescribing Information 
for varenicline cites other possible serious side effects and risks including new or worsening 
mental health problems such as changes in behavior, hostility, agitation, or depressed mood. Other 
warnings and precautions include new or worsening seizures, accidental injury (e.g., trouble 
driving or operating heavy machinery), cardiovascular events (new or worsening cardiovascular 
symptoms), allergic hypersensitivity reactions, serious skin reactions, and nausea.  
The recently published, international trial (referred as the EAGLES trial14) was a large 
randomized, double-blind, placebo-controlled and active-controlled (nicotine patch) trial 
comparing varenicline and bupropion at 140 centers in 16 countries between Nov 30, 2011, and 
Jan 13, 2015. The trial randomized, 8,144 participants. The study did not show a significant 
increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to 
nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and 
bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were 
more effective than placebo. Across cohorts, the most frequent adverse events by treatment group 
were nausea (varenicline, 25%), insomnia (bupropion, 12%), abnormal dreams (nicotine patch, 
12%), and headache (placebo, 10%). 


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In summary, new treatments are still needed that are less costly, more effective, have an 
improved safety profile, or can more successfully treat individuals who have failed to quit using 
the above treatments.  
2. 
RECENT EVIDENCE FOR CYTISINE AS A SMOKING 
CESSATION TREATMENT 
Cytisine has recently been evaluated in two large randomized Phase 3 clinical trials that were 
conducted according to Good Clinical Practice (GCP) in more than 2,000 participants. The overall 
objectives in these trials were to confirm the efficacy and safety of cytisine according to current 
clinical development standards and commercial dosing schedule. The cytisine commercial dose is 
1.5 mg and administered 6 times a day for the first 3 days, then titrated down on specific days 
within a 25-day treatment period to only one tablet on Day 25. 
The Phase 3 trial (Tabex Smoking Cessation, or TASC5 trial) was sponsored by the UK Centre for 
Tobacco Control Studies and evaluated cytisine versus placebo in 740 primarily moderate-to-
heavy smokers treated for 25 days in a single center in Warsaw, Poland. The primary outcome 
measure was sustained, biochemically-verified smoking abstinence for 12 months after the end of 
treatment. The TASC trial was conceived by Professor Robert West (Department of Epidemiology 
and Public Health, University College London) and was funded by a grant from the National 
Prevention Research Initiative, including contributions from Cancer Research UK, Medical 
Research Council, United Kingdom Department of Health, and others. The results of the TASC 
trial were published in the New England Journal of Medicine in September 2011.5 The RR for 
sustained 12-month abstinence was 3.4 for cytisine compared to placebo (8.4% cytisine arm 
compared to 2.4% placebo arm; P<0.001). The RR for sustained 6-month abstinence was 2.9 
(10.0% cytisine arm compared to 3.5% placebo arm; P<0.001). Cytisine was well tolerated with 
an increase in all-combined gastrointestinal (GI) adverse events (although there was no significant 
difference in individual GI events between the arms). The safety profile of cytisine was similar to 
that of a placebo, with no overall difference in the rate of side effects in the two arms.  
The second Phase 3 trial (Cytisine As a Smoking Cessation Aid, or CASCAID6 trial) was 
conducted by the Health Research Council of New Zealand and was an open-label trial that 
randomized 1,310 adult daily smokers. Subjects were randomized to receive either cytisine for 
25 days or NRT for 8 weeks. Both treatment groups were offered low-intensity telephone 
behavioral support during trial treatment. The primary outcome measure was continuous self-
reported abstinence from smoking one month after a quit date. The RR for continuous one-month 
abstinence was 1.3 for cytisine (40% cytisine arm compared to 31% in the NRT arm; P<0.001). A 
secondary outcome included the RR for continuous six-month abstinence which was 1.4 for 
cytisine (22% cytisine arm compared to 15% in the NRT arm; P=0.002). Cytisine was generally 
well tolerated, although self-reported adverse events were higher in the cytisine arm compared 
with the NRT arm. The most frequent adverse events were nausea and vomiting and sleep 
disorders. The results of the CASCAID trial, which were published in the New England Journal of 
Medicine in December 2014, showed that cytisine was superior to NRT for smoking cessation 
and, specifically, that cytisine was 1.43 times more likely than nicotine gums or patches to help 
participants stop smoking and remain non-smokers for six months.6 
Both studies are described in more detail within the Investigator’s Brochure15. 


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3. 
SAFETY OVERVIEW FOR CYTISINE 
3.1. 
Non-Clinical Studies 
The US National Center for Complementary and Integrative Health (NCCIH) designated cytisine 
as “a drug of national Public Health importance” and, in collaboration, has sponsored a series of 
more recent pharmacology and toxicology studies in support of the cytisine Investigational New 
Drug (IND) and in preparation for formal Phase 3 evaluation. In that regard, NCCIH has 
sponsored new non-clinical studies to current Good Laboratory Practice (GLP) that have included 
28-day repeat dosing for toxicology assessments in rats and dogs as well as two 
reproductive/developmental studies in rats.  
3.1.1. 
Summary of 28-Day Repeat Toxicology Studies 
Daily oral dose administration of cytisine in Sprague Dawley rats at 5 or 20 mg/kg/day for 28 
consecutive days resulted in clinical signs, such as drooling, in a dose dependent manner. Other 
clinical signs were only seen in the 20 mg/kg group including ruffled fur, hypoactivity, shoveling 
behaviors, and ataxia. Decreases in food consumption and body weight gain were observed in 
animals treated with 20 mg/kg of cytisine. No cytisine-related macroscopic and microscopic 
findings were observed. The no observed adverse effect level (NOAEL) of cytisine is considered 
to be approximately 2 mg/kg/day when given orally for 28 consecutive days in rats. This would 
calculate to an estimated Human Equivalent Dose (HED) of 0.3 mg/kg (i.e. 21 mg for a 70 kg 
human) when cytisine is administered for 28 consecutive days. 
Daily oral dose administration of cytisine via capsules in Beagle dogs at 0.5, 1, or 2 mg/kg/day for 
28 consecutive days resulted in adverse effects. The maximum tolerated dose (MTD) was 
considered to be greater than 1 mg/kg/day but less than 2 mg/kg/day. Although emesis, drooling 
and diarrhea were observed in some animals treated with 0.5 mg/kg cytisine, the severities were 
mostly slight and not dose-limiting clinically; therefore, the NOAEL was slightly less or at 
approximately 0.5 mg/kg/day following 28 days oral administration. This gives an estimated HED 
of 0.28 mg/kg (i.e. 20 mg for a 70 kg human) should cytisine be administered for 28 consecutive 
days (NOTE: cytisine is administered for 25 days using a descending dose titration regimen). 
Based on the findings in both the 28-day rat and 28-day dog toxicology studies, the established 
commercial dose of 1.5 mg × 6 doses/day (maximum total exposure of 9 mg/day for the first 
3 days of treatment) is approximately half that of the estimated HED of ~20 mg/day for humans. 
The planned higher 3 mg/dose for this study yields a maximum total exposure of 18 mg/day for 
the first 3 days of treatment. This again is below the calculated HED based on all of the studies as 
shown in Table 1.  


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Table 1: 
Calculation of Margin of Safety based on Rat and Dog Toxicology Studies 
NOAEL 
Cmax 
(ng/mL) 
AUClast 
(ng*h/mL) 
HEDa 
(mg/kg/day) 
HEDa 
(mg/day) 
Human 
Doseb 
Margin of 
Safety based 
on BSA 
7-day rat study: 
5 mg/kg 
383.5 
2926 
0.8 
56 
9 mg/day 
~6X 
7-day dog study:  
2 mg/kg 
317.5 
708.5 
1.1 
77 
9 mg/day 
~8X 
28-day rat study:  
2 mg/kg 
292.6 
1071.7 
0.3 
21 
9 mg/day 
~2X 
28-day dog study:  
0.5 mg/kg 
- 
- 
0.28 
20 
9 mg/day 
~2X 
a HED = Human Equivalent Dose 
b Human commercial dose is 9 mg/day for the first 3 days in the 25-day schedule per commercial use. 
NOTES: Cmax and AUC are determined from the NOAEL data.  
HED (mg/kg/day) = rat dose divided by 6.2 and dog dose divided by 1.8. 
HED (mg/day) = HED dose (mg/kg/day) x 70 kg. 
3.1.2. 
Summary of Reproductive/Developmental Studies 
The GLP study titled “Combined Fertility and Embryofetal Development Toxicity Study in Rats 
with Toxicokinetics” administered oral cytisine once daily to males for 10 weeks (initiating 
28 days prior to mating) and to females for 14 days prior to mating, during mating, and through 
Gestation Day (GD) 17. Reproductive assessment for 10 males/group included sperm assessments 
with sample collection for evaluation of motility and total sperm count. Females were sacrificed 
with caesarian section on GD 21 with uterine contents examined and any grossly abnormal 
cervical, thoracic and abdominal viscera noted. The placenta, amniotic sac, number of live fetuses, 
number of early or late resorptions, and number of corpora lutea and any abnormalities were also 
recorded. Fetuses were evaluated for gross, visceral, and skeletal abnormalities. This study has 
been completed and no treatment-related mortality or clinical signs of toxicity were observed. 
There was also no evidence of treatment-related effects on mating, cyclicity, impaired fertility or 
embryofetal development. 
The GLP study titled “Pre- and Postnatal Development Toxicity Study in Rats, Including Maternal 
Function” administered daily cytisine to time-mated females on Gestation Days 6 through 
Lactation Day (LD) 20. Once daily, during the dosing interval (GD 6 through LD 20), detailed 
observations were done for each maternal animal at 4 hours post-dosing. Prior to and after the 
dosing interval, detailed observations were done at the same time that body weights were taken. 
On LD 0, date of delivery, litter size, and the sex, weight, and observations of individual offspring 
were recorded. During lactation on LD 4, 7, 14, and 21 (weaning), general development was 
recorded daily for individual offspring. Maturation phase procedures on LD 22-63 were also 
evaluated and recorded for development of each offspring. This study has been completed. No 
treatment-related mortality or clinical signs of toxicity were observed, and no evidence of 
treatment-related effects on mating, cyclicity, impaired fertility or embryofetal development. A 
slight treatment-related effect on body weight/body weight gain was seen at the 10.0 mg/kg dose 
level in both males and females. Systemic exposure was generally higher in females than in males 
regardless of dose, and Cmax was slightly higher in females at the 10 mg/kg compared to males at 
the 10 mg/kg dose level.  


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An older non-GLP study titled “Embryotoxicity and Teratogenicity Study of Cytisine 
in 
Rabbits” administered cytisine in sexually mature female rabbits. After fertilization by a male, 
female rabbits were treated with cytisine daily. Fertilized animals were observed for symptoms of 
toxicity and weight gain. Female animals were sacrificed by anesthesia on day 28 of pregnancy 
and were subjected to macroscopic examination of internal organs and Caesarean section of the 
uterus. After visual examination of fetuses, placentas and fetal resorption remains, fetuses were 
weighed, examined for external anomalies as well as skeleton and brain structure development 
were evaluated. Treatment with cytisine did not cause clinical symptoms, death or negative 
influence on weight gain of pregnant rabbits. Unsuccessful pregnancies, loss of offspring or 
abortion associated with the effect of cytisine were not found. Increased pre- and post-
implantation death of the developing fetus, as well as reduced fetal weight, was not observed. No 
cases of external or visceral malformations and defects in fetal development were found. 
Malformations in the development of the skeleton and cranial bones as well as higher incidence 
rate of delayed ossification and variants in groups exposed to cytisine were also not observed. 
Refer to the Investigator’s Brochure for more detail on GLP-conducted, non-clinical studies. 
3.2. 
General Safety of Cytisine as a Marketed Product 
Cytisine has been marketed by
 in Central and Eastern Europe for over 20 years under 
the brand name
 is currently marketed in 20 countries and is estimated to have 
been administered to over 21 million subjects. 
 maintains an independently-audited pharmacovigilance system overseen by a 
pharmacovigilance Qualified Person (QPPV). Periodic Safety Update Reports (PSURs) have been 
regularly provided to the relevant European authorities since 2005 (2 years before 
 
became one of the Member States of the European Union). It is estimated that the cumulative 
number of exposures to cytisine since 2005, and forming the denominator in the cumulative 
PSURs is over 15 million cases.  
The safety information in the
 Core Data Sheet is regularly reviewed against new PSUR 
information. Sections 3.2.1 and 3.2.2 summarize the section titled “Undesirable Effects” in the 
latest
 Core Data Sheet. 
3.2.1. 
Summary of Safety Profile 
Since cytisine has a structural similarity to nicotine and is a partial agonist of nicotine 
acetylcholine receptors, the possible pharmacodynamic undesirable effects are manifested mainly 
as nicotine effects. 
In 6 placebo-controlled clinical trials (N=2,844), 1,389 subjects received cytisine. The most 
commonly reported adverse events in the cytisine group involved the gastro-intestinal system: 
upper abdominal pain, nausea, dyspepsia, dry mouth, vomiting, constipation and diarrhea. 
Nervous system and psychiatric disorders were also common, most frequently headache and 
dizziness, as well as somnolence and insomnia. However, statistical analysis did not reveal any 
significant difference in the nervous system adverse events between the cytisine and placebo 
groups (P=0.12). 


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3.2.2. 
Tabulated List of Adverse Reactions 
Adverse reactions are listed according to MedDRA system organ class (SOC) and frequency 
category. Frequency categories are defined using the following convention: very common (>1/10), 
common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very 
rare (<1/10,000), not known (cannot be estimated from the available data). 
Table 2: 
Adverse Events Reported From the Recent 
 Core Data Sheet 
System Organ 
Class 
Very 
Common 
Common 
Uncommon 
 
Rare 
 
Very 
rare 
 
Not known 
 
Cardiac disorders 
 
 
 
 
 
Tachycardia 
Palpitations 
Vascular 
disorders 
 
 
 
 
 
Slight increase in 
blood pressure 
Nervous system 
disorders 
 
Headachea 
Dizzinessa 
Insomniaa 
Drowsinessa 
 
 
Increased 
irritability 
Respiratory, 
thoracic and 
mediastinal 
disorders 
 
 
 
 
 
Dyspnea 
Gastrointestinal 
disorders 
 
Upper 
abdominal 
paina 
Nauseaa 
Dry moutha 
Dyspepsiaa 
Constipationa 
Diarrheaa 
Vomitinga 
 
 
Changes in taste 
and appetite 
Abdominal pain 
Musculoskeletal 
and connective 
tissue disorders 
 
 
 
 
 
Myalgia 
Metabolism and 
nutrition disorders 
 
 
 
 
 
Hyperhidrosis 
Weight 
decreased 
General disorders 
and 
administration 
site conditions 
 
 
 
 
 
Chest pain 
a The frequency was estimated based on data from 6 randomized clinical trials. 
Thus, from marketing safety reporting for 
 the most frequent adverse effects include: 
nausea, gastrointestinal symptoms (including abdominal pain, dyspepsia, and dry mouth), sleep 
disorder, dizziness and headache. Most reported adverse effects appear mainly at the beginning of 
therapy, are short-lived, mild-to-moderate intensity, and resolved spontaneously. It is not possible 
to dissociate these effects due to cytisine and those related to nicotine withdrawal in subjects 
attempting to quit smoking. 
Overdoses of cytisine or toxic effects have been reported as nausea, vomiting, mydriasis, 
tachycardia, and possible breathing paralysis.  


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


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


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


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Table 6: 
ACH-CYT-02: Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term – 18 to 65 Years Old (Safety Set) 
 
Number of Events/Number of Subjects (%) 
SYSTEM ORGAN CLASS: 
  Preferred Term 
18-65 Years 
1.5 mg Cytisine 
(N=12) 
3.0 mg Cytisine 
(N=12) 
Overall 
(N=24) 
GASTROINTESTINAL DISORDERS: 
3 / 2 (16.7) 
5 / 3 (25.0) 
8 / 5 (20.8) 
  Constipation 
1 / 1 (8.3) 
1 / 1 (8.3) 
2 / 2 (8.3) 
  Flatulence 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
  Nausea 
0 / 0 (0.0) 
2 / 2 (16.7) 
2 / 2 (8.3) 
  Tooth loss 
2 / 1 (8.3) 
0 / 0 (0.0) 
2 / 1 (4.2) 
  Toothache 
0 / 0 (0.0) 
1 / 1 (8.3)b 
1 / 1 (4.2) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS: 
1 / 1 (8.3) 
2 / 2 (16.7) 
3 / 3 (12.5) 
  Chest discomfort 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
  Medical device site reaction 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Peripheral swelling 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
INFECTIONS AND INFESTATIONS: 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Rhinitis 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS: 
2 / 2 (16.7) 
0 / 0 (0.0) 
2 / 2 (8.3) 
  Muscle strain 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Procedural pain 
1 / 1 (8.3)a 
0 / 0 (0.0) 
1 / 1 (4.2) 
NERVOUS SYSTEM DISORDERS: 
9 / 4 (33.3) 
16 / 6 (50.0) 
25 /10 (41.7) 
  Headache 
9 / 4 (33.3)a  
15 / 6 (50.0)b  
24 /10 (41.7) 
  Vision blurred 
0 / 0 (0.0) 
1 / 1 (8.3)b  
1 / 1 (4.2) 
PSYCHIATRIC DISORDERS: 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
  Abnormal dreams 
0 / 0 (0.0) 
1 / 1 (8.3) 
1 / 1 (4.2) 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS: 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Oropharyngeal pain 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
  Rash pruritic 
1 / 1 (8.3) 
0 / 0 (0.0) 
1 / 1 (4.2) 
a Moderate events of headache (16.7% of subjects) and procedural pain (8.3% of subjects). 
b Moderate events of headache (33.3% of subjects), toothache (8.3% of subjects) and blurred vision (8.3% of 
subjects). 
A subject was counted only once per system organ class and preferred term. 
 
4.2. 
Results from Study ACH-CYT-01 on the Effect of Food on Cytisine 
Bioavailability 
ACH-CYT-01 titled “A Phase 1 Open Label, Randomized, Two-Way Crossover Study in Healthy 
Volunteers to Investigate the Effect of Food on the Bioavailability of Cytisine” evaluated 
24 healthy volunteer subjects to investigate the effect of food on the bioavailability of cytisine. 
The primary objective was to compare the bioavailability of cytisine under fed and fasted 
conditions following administration of 3.0 mg cytisine (2×1.5 mg cytisine tablets). 
Eligible subjects received a single-dose of 3.0 mg cytisine under fed and fasted conditions over 
2 treatment periods. PK samples (plasma and urine) were collected pre-dose and up to 24 h post-
dose (Day 2) during each period (17 plasma and 6 urine samples per period) for the measurement 
of plasma and urine cytisine concentrations.  


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The study enrolled 24 subjects (11 males:  13 females) with a median age of 34 years (range 
19-53 years). Two of three subjects who experienced emesis during the course of the study (both 
under fed conditions) were excluded from statistical analysis because emesis occurred at or before 
2 times the median Tmax. 
The fasted Cmax at 29.8 ng/mL was higher than the fed Cmax at 22.3 ng/mL. The Tmax under fed 
conditions (2.75 h) was delayed when compared to the Tmax under fasted conditions (0.75 h). 
However, both AUC0-∞ and AUC0-t were comparable under fed (167.5 and 160.2 h.ng/mL) and 
fasted (172.6 and 165.9 h.ng/mL) conditions, respectively. 
Table 7: 
ACH-CYT-01: Summary of Statistical Analysis of Cytisine Cmax and 
AUC 
Parameter 
Geometric LS Mean 
Geometric LSMean Ratio 
(90% CI) 
fed / fasted 
3.0 mg Cytisine 
fed 
(N = 22) 
3.0 mg Cytisine 
fasted 
(N = 22) 
Cmax  
(ng/mL)  
22.3 
29.8 
74.71 
(66.39 - 84.08) 
AUC0-∞ 
(h.ng/mL) 
167.5 
172.6 
97.04 
(94.20 - 99.98) 
AUC0-t 
(h.ng/mL)  
160.2 
165.9 
96.52 
(93.30 - 99.85) 
 
Cytisine showed rapid absorption after oral administration with over 80% of cytisine recoverable 
in urine within the 24 hours post-dosing.  
A total of 22 TEAEs were reported by 10 (41.7%) subjects during the study; the severity was mild 
for all events, the majority of which were related to cytisine. No serious TEAEs were reported 
during the study. NOTE: that all subjects enrolled in this study were non-smoking subjects and, 
thus, were not tolerant to the effects of nicotine as a result of smoking.  
The percent of subjects with at least one TEAE was similar under fed and fasted conditions, at 
25.0% and 29.2%, respectively. The most commonly reported TEAEs were: dizziness (16.7%), 
headache (12.5%), vomiting (12.5%) and nausea (8.3%). All were expected events identified in 
the Investigator’s Brochure15 and the current Summary of Product Characteristics (SmPC)16 for 
The TEAE profile was similar under fed and fasted conditions, with a similar number of 
subjects reporting any given event. 
There were no clinically significant biochemistry, hematology, urinalysis, vital sign or safety 
12 lead electrocardiogram (ECG) values reported during the study. 
ECG data extracted from the continuous ECG Holter recordings demonstrated a moderate increase 
in heart rate but there were no clinically significant changes in QTcF during the study. There was 
no relationship between cytisine plasma concentration and QTcF. 
 
 


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4.3. 
Results from Cohorts 1 to 6 (6 mg to 21 mg) of Study ACH-CYT-08 
Under the ACH-CYT-8 Protocol Version 4.0, dated 07 Feb 2019, 6 cohorts of 8 adult smokers 
each were enrolled. In each cohort of 8 subjects, 6 subjects were randomly assigned to cytisine 
single-dose administration and 2 subjects were assigned to placebo. Cytisine doses were 6 mg 
(Cohort 1), 9 mg (Cohort 2), 12 mg (Cohort 3), 15 mg (Cohort 4), 18 mg (Cohort 5) and 21 mg 
(Cohort 6).  
Dose escalation to the next cohort was dependent upon a non-blinded interim analysis of the 
safety data of the preceding cohorts by the Data Monitoring Committee (DMC) composed by the 
Principal Investigator and two independent Data Safety Monitors (DSMs). The tolerability and 
safety results were favorable after review of each cohort, with the DMC recommending to proceed 
with the study protocol as planned. The study remains blinded to the study staff and Sponsor in 
lieu of continuing the study with additional cohorts. 
Based on the tolerability and safety results in each cohort, the study was escalated up to the 
cytisine dose of 21 mg without showing any of the predefined stopping criteria (based on the 
occurrence of dose-limiting adverse events).  
In accordance with the protocol, any occurrence of adverse events (AEs) as reported by study 
subjects were monitored throughout the study. Any clinically relevant changes in vital signs, ECG 
and clinical laboratory safety tests were also reported as AEs.  
Most TEAEs were of mild severity and resolved without requiring the use of medication. There 
were no clinically relevant abnormalities in vital signs, ECG or clinical laboratory safety tests.  
There were no severe TEAEs, Serious Adverse Events (SAEs) or any TEAEs leading to 
discontinuation. 
In conclusion, single oral doses of cytisine 6 mg to 21 mg were generally well-tolerated and safe 
in a population of adult smokers. Although data remain blinded, it appears that the incidence or 
severity of TEAEs do not yet show an apparent dose-related trend or dose-limiting toxicity and 
that further dose escalation is warranted to further explore for dose-limiting toxicity of a single 
cytisine dose. 
Preliminary blinded pharmacokinetic data are available for the six previously planned cohorts. 
Results show that median Tmax ranged from 0.84 h (6 mg) to 2.00 h (18 mg). Geometric Mean for 
Cmax ranged from 68.935 ng/mL (6 mg) to 144.693 ng/mL (21 mg). There was a less than dose-
proportional increase of Cmax (geometric mean) with increasing doses. For a cytisine dose increase 
in the ratio of 1.50:1.33:1.25:1.20:1.16, Cmax increased by 1.34:0.99:1.35:1.06:1.10. For an overall 
dose increase of 3.50, cytisine Cmax increased 2.10, corresponding to a dose-proportionality factor 
(DPF) of 0.60. 


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5. 
RATIONALE FOR THE STUDY 
5.1. 
Rationale 
Previous studies dating decades ago and now more recent GCP studies have shown that cytisine 
can be effective in helping smokers to stop smoking. Recent Phase 3 trials have shown that 
cytisine was more effective than both placebo and NRT for smoking cessation with an excellent 
safety profile that is consistent with the safety profile reported by
 for millions of 
subjects who have used 
. It is not possible to determine which reported adverse 
effects associated with cytisine treatment are an effect of the drug itself, due to nicotine 
withdrawal effects if smoking cessation occurred, or a combination of both. However, the 
risk/benefit for cytisine appears very acceptable. Since tobacco smoking contributes to some 
7 million premature deaths each year worldwide7 and remains the most important risk to 
individuals who want to stop smoking, using cytisine as a smoking cessation aid could offer far 
more benefit with minor risks of treatment when compared to that of continued smoking.  
Achieve Life Sciences and Food and Drug Administration (FDA) have discussed development 
plans for cytisine as a new chemical entity for aiding smoking cessation in the United States, 
which ultimately led to filing an IND application in 2017. This GCP conducted, Phase 1 trial is 
designed to assess the tolerability and safety for a single administered oral dose of cytisine. Since 
it is difficult to separate the reported adverse effects associated with cytisine treatment versus 
nicotine withdrawal effects in smokers using cytisine to quit smoking, this study will be 
performed in smokers who are currently smoking (not trying to quit), are tolerant to the effects of 
nicotine due to smoking, and will receive one single dose of cytisine.  
The dosage of cytisine will be escalated in separate cohorts of 8 subjects per dose level until 
stopping criteria (based on the occurrence of dose-limiting adverse events) are reached. In 
addition, plasma cytisine concentrations will be evaluated in order to estimate the cytisine Cmax 
levels associated to the occurrence of dose-limiting adverse events. 
5.2. 
Benefit/Risk Assessment 
This Phase 1 study is being conducted in healthy smokers. The treatment with cytisine for 
smoking cessation involves starting at high cytisine dosages with a reduction-titration scheme 
over a 25-day duration, believed to aid in reducing overall withdrawal symptoms and addiction to 
nicotine. In the present study, cytisine will be administered as a single dose. Therefore, there is no 
intended clinical treatment or benefit to study subjects. 
Cytisine is marketed in some countries of Central and most countries in Eastern Europe as a 
treatment for smoking cessation. However, it is not yet available for the United States of America 
(US) and Western Europe (EU) populations. Participation in this study will contribute to the 
further knowledge and understanding about the drug related to supra-therapeutic doses, thus 
allowing additional generalization for its commercialization in the US and Western EU. 
This study will investigate the tolerability and safety of supra-therapeutic doses of cytisine in 
healthy smokers. The maximum planned cytisine dose is lower than the human equivalent doses 
(HED) of the maximum tolerated doses (MTD) and of the no observed adverse effect level 
(NOAEL) doses in short duration toxicity studies in rats and dogs. Because of this, the risks of the 
planned doses in the study have been minimized based on pharmacokinetic and safety findings in 
appropriate animal toxicology studies. 


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Therefore, it is considered that the risk to the subjects will be minimal, however it is possible that 
healthy smokers on this study may experience pharmacological adverse effects. To help manage 
this risk, the study will be conducted at a dedicated Phase I unit with experience in the conduct of 
human Phase 1 studies with adequate safety monitoring capabilities. Subjects will be monitored 
during each period for a minimum of 24 hours post-dose and a follow-up assessment 4-5 days 
after dosing will occur. 
To further mitigate the potential risks, the study will follow a dose-escalation design in which 
single ascending doses of cytisine will be administered to sequential cohorts of participants. The 
progression to the next cohort will depend on a coordinated assessment of the tolerability and 
safety results of the preceding cohort by the Study Principal Investigator (PI) and two independent 
Data Safety Monitors (DSMs) prior to allowing escalation to the next dose level. Appropriate 
stopping criteria based on adverse events have been predefined and incorporated in the study 
design (Section 14.2). 
Please also refer to the Investigator’s Brochure15, including the Guidance for the Investigator, and 
the
s approved Summary of Product Characteristics16. 
6.
STUDY OBJECTIVES
1. To assess the tolerability and safety of cytisine as a single oral dose.
2. To define the Cmax levels associated to the occurrence of dose-limiting adverse events.
7.
STUDY DESIGN OVERVIEW
7.1. 
Study Design 
This will be a single-center, double-blind, randomized, placebo-controlled, single dose-escalation, 
Phase 1 clinical study 
nducted in male or female adults who are ≥18 years age, in good general 
health and who are current daily cigarette smokers, under fasting conditions.  
The study will be comprised of a pre-study screen to define eligible subjects for each cohort in the 
study. Subjects will be enrolled into dose cohorts as required (8 subjects per cohort), based on 
individual’s availability and site’s selection. Upon assignment to a dose cohort, subjects will 
arrive at the clinical research facilities on Day 0 and will undergo an overnight fast of at least 10 h 
prior to dosing on Day 1. On the morning of Day 1, subjects will receive a single dose (multiple 
1.5 mg tablets to reach the required dose level assigned). Subjects will be confined at the clinical 
research facilities from at least 11 hours before dosing until at least 24 hours post-dose for PK and 
safety assessments, being discharged in the morning of Day 2, unless an adverse event requiring 
confinement is on-going.  
Six dose levels were studied under Version 4.0 of Protocol ACH-CYT-08: 6 mg, 9 mg, 12 mg, 
15 mg, 18 mg and 21 mg. The starting dose was 6 mg cytisine (single oral dose) in Cohort 1. The 
study was escalated up to the cytisine dose of 21 mg in Cohort 6 without showing any of the 
predefined stopping criteria. Thus, three additional dose levels (Cohorts 7 to 9) are pre-planned: 
24 mg, 27 mg and 30 mg. Within each dose level, subjects will be randomly assigned to receive a 
single oral dose of cytisine or placebo in a 3:1 ratio (6 cytisine:2 placebo). Upon completion of the 
follow-up assessment for each subject in each cohort, the data will be cleaned and soft-locked and 


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a safety review will be performed by the PI and the independent DSMs on unblinded data. The PI 
and DSMs will conjointly decide whether dose escalation into the next cohort will be allowed. 
Stopping criteria: The dose should not be escalated further if any of the following occurs: 
1. A serious adverse event (SAE) that is considered at least possibly related to cytisine in 1 or 
more subjects;  
2. Severe non-serious adverse events that are considered at least possibly related to cytisine 
in 2 or more subjects within the same cohort;  
3. Other safety information considered to pose a risk to subjects. 
7.2. 
Number of Subjects 
Eight (8) subjects per dose level will be enrolled.  
Under ACH-CYT-08 Version 4.0, 48 subjects were enrolled in the previous 6 cohorts. 
Considering the 3 additional cohorts under ACH-CYT-08 Version 5.0, a total of 72 subjects is 
estimated for completing enrollment in the study. 
7.3. 
Number of Clinical Sites 
This will be a single center clinical trial. 
7.4. 
Estimated Duration/Completion of Study 
Each cohort will require a minimum of 2 nights stay in the clinical research facilities (subjects will 
be confined at the clinical research facilities from at least 11 hours before dosing until at least 
24 hours post-dose). Each cohort will take 7 days for completion, including a safety review and 
the final 4-5 day post study follow-up call. 


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8. 
SELECTION OF STUDY POPULATION 
Study subjects will be recruited from 
Phase I’s pool of healthy volunteers, according 
to the applicable standard operating procedures (SOPs). 
Each potential subject will be provided with an informed consent form that has been reviewed and 
approved by the 
 In accordance with 
the International Conference on Harmonization (ICH) guidelines on informed consent, the 
Principal Investigator (or designee) will provide potential subjects with a verbal description of the 
study including, but not limited to, study purpose, study procedures, restrictions and risks. 
Potential subjects will be asked to read the consent form and to sign and date it once all of their 
questions have been answered and they voluntarily agree to participate in the study. Subjects will 
be assured that they may abandon the study at any time without any prejudice and will receive a 
copy of the signed informed consent form. In case of amendments to the informed consent form 
during the study, a renewed written and signed consent must be obtained from each subject still 
participating in the study. 
Upon obtaining signed informed consent, each subject will undergo the screening procedures 
outlined in Section 12.1.1. A screening log will be maintained by the site and will include 
documentation for screening failures. Subjects meeting all inclusion/exclusion criteria will then be 
enrolled onto the study and begin the study procedures.  
The following eligibility criteria are designed to select subjects for whom protocol procedures are 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.  
8.1. 
Inclusion Criteria 
Subjects must meet ALL of the following criteria to be eligible for inclusion into the study: 
1. Free written informed consent prior to any procedure required by the study. 
2. Male or female subjects, age ≥18 years, at the time of signing the informed consent.  
3. Current daily cigarette smokers (averaging at least 10 cigarettes per day in the past 
30 days). 
4. Expired air carbon monoxide (CO) ≥10 ppm.  
5. Able to swallow multiple tablets at one time. 
6. Able to fully understand, comply with all study requirements. 
8.2. 
Exclusion Criteria 
Subjects meeting ANY of the following exclusion criteria will NOT be eligible for inclusion 
into the study at screening. 
1. Known hypersensitivity to cytisine or any of the excipients. 
2. Known severe hypersensitivity to any other drug. 
3. Positive urinary drugs of abuse screen, determined within 28 days before cytisine/placebo 
dosing.  
4. Positive ethanol breath test. 


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5. Clinically significant abnormal serum chemistry, hematology, coagulation or urinalysis 
values within 28 days of randomization (i.e. requiring treatment or monitoring).  
6. Clinically significant abnormalities in 12-lead ECG determined after minimum of 
5 minutes in supine position within 28 days of randomization (i.e. requiring treatment or 
further assessment). 
7. Body Mass Index (BMI) classification for being underweight (<18.5 kg/m2) or having 
≥Class 2 obesity (≥35 kg/m2). 
8. History of acute myocardial infarction, unstable angina, stroke, cerebrovascular incident, 
cardiac arrhythmia, or hospitalization for congestive heart failure. 
9. Blood pressure ≥160/100 mmHg, measured on the dominant arm, after at least 3 minutes 
in supine position. 
10. Creatinine clearance (CrCl) <80 mL/min (estimated with the Cockroft-Gault equation).  
11. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 x the upper 
limit of normal (ULN). 
12. Any inability to comply with study restrictions (See Section 9)  
13. Any inability or difficulty in fasting.  
14. Difficulty in donating blood on either arm.  
15. If woman of childbearing potential, positive result in serum beta-hCG pregnancy test.  
16. Women who are breast-feeding.  
17. Subjects who do not agree to use acceptable methods of birth control during the study (See 
Section 9.4).  
18. Participation in a clinical study with an investigational drug within the previous 2 months.  
19. Participation in more than 2 clinical trials within the previous 12 months.  
20. Any other reason that the investigator views the subject should not participate or would be 
unable to fulfill the requirements for the study.  
Subjects meeting ANY of the following exclusion criteria will NOT be eligible for inclusion 
into the study at admission to each cohort. 
21. Any recent disease or condition or treatment that, according to the Investigator, would put 
the subject at undue risk due to study participation.  
22. Positive urinary drugs of abuse screen.  
23. Positive ethanol breath test. 
24. If female of childbearing potential, positive result in urine beta-hCG pregnancy test.  
25. Any other reason that the investigator views the subject should not participate or would be 
unable to fulfill the requirements for the study.  


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9. 
RESTRICTIONS PRIOR AND DURING THE STUDY 
To standardize evaluations and avoid possible negative effects on the measurement of Cmax and/or 
on subject’s safety, several restrictions are to be adopted as outlined in the following sections.  
9.1. 
Confinement 
Each subject will be required to stay 2 nights in the clinical research facilities (arrive at the unit in 
the afternoon/evening of Day 0, at least 11 hours before dosing, and remain confined until at least 
24 hours post-dose on Day 2).  
9.2. 
Diet and Fluid Restrictions 
9.2.1. 
Meal Times 
Meals and snacks will be standardized and identical in composition in all cohorts.  
A dinner will be served on the evening of Day 0. Subjects will be fasting prior to receiving the 
single dose of cytisine until lunch. Meals will be as follows:  
• Subjects will fast overnight for at least 10 hours before dosing.  
• No breakfast on day of dosing.  
• Lunch will be served not earlier than 4 hours post-dose.  
• Snack will be served at 8±0.5 hours post-dose.  
• Dinner will be served at 12±1 hours post-dose.  
• Snack will be served at 15±1 hours post-dose. 
• Breakfast will be served at 24±1 hours post-dose.  
Subjects will be requested to fast for at least 4 hours prior to blood sampling for planned 
biochemistry tests at screening.  
Chewing gum will not be allowed during confinement.  
9.2.2. 
Fluid Intake 
No fluids (apart from water taken with dose) are allowed from 1 hour prior to dosing until 1 hour 
afterwards. Water is then allowed ad libitum.  
9.2.3. 
Alcohol Intake 
The consumption of alcohol will be limited to a maximum of 2 units per day from 7 days prior to 
the study. Alcohol will be avoided completely for at least 2 days prior to dosing and throughout 
the 24-hour study period.  
9.2.4. 
Caffeine 
Food or drink containing caffeine, including coffee, tea, cola, energy drinks or chocolates will be 
avoided completely for 2 days prior to dosing and while the subjects are confined in the clinical 
research facilities.  


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9.2.5. 
Tobacco 
Subjects should agree to abstain from smoking while confined at the clinical research facilities. 
However, subjects will be allowed to smoke outside the facilities, while accompanied by members 
of clinical research staff.  
9.2.6. 
Poppy and Sesame Seeds and Cannabinoid Smoke Exposure 
Subjects must not eat food containing poppy or sesame seeds for 3 days prior to the admission to 
study, as consumption can lead to a positive opiate result in the drugs of abuse test. In addition, 
subjects are advised to avoid indoor spaces contaminated with cannabinoid smoke as exposure 
could lead to a positive result in the drugs of abuse test.  
9.2.7. 
Grapefruit Juice and Other Restrictions 
No food or drink containing pineapple, pomelo, pomegranate, starfruit, grapefruit, cranberry, or 
Seville oranges (including marmalade and fruit juices), and/or food or drink, sweets, candies or 
other confectionary containing liquorice will be allowed 7 days prior to the study and while the 
subjects are confined in the clinical research facilities.  
9.3. 
Exercise 
Subjects will be advised to avoid performing strenuous physical exercising within 48 hours prior 
to blood collection for clinical laboratory tests, because it may affect the results.  
9.4. 
Contraception Requirements 
Only nonpregnant females can be admitted to the study and females of childbearing potential must 
not become pregnant during the study.  
A woman is not considered of childbearing potential if she:  
• Underwent a permanent sterilization method (e.g. hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy).  
• Is clinically diagnosed infertile.  
• Is in a post-menopausal state.  
NOTE: A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the post-menopausal range may 
be used to confirm a post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.  
Female participants of childbearing potential must accept to take appropriate measures to prevent 
pregnancy during the study. The acceptable contraceptive measures are the following:  
• Abstinence of heterosexual intercourse (when this is in line with preferred and usual 
lifestyle of the subject).  
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable).  


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• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal).  
• Intrauterine device.  
• Intrauterine hormone-releasing system.  
• Bilateral tubal occlusion.  
• Vasectomized partner, who has received medical assessment of the surgical success.  
The not acceptable contraceptive measures are the following:  
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.  
• Male or female condom with or without spermicide.  
• Cap, diaphragm or sponge with spermicide.  
• Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods).  
• Withdrawal (coitus interruptus).  
NOTE: Women must use a hormonal contraceptive method from at least 4 weeks prior to 
admission to study in order to prevent pregnancy, and use the hormonal contraceptive on a stable 
continuous regimen from at least 2 weeks prior to admission to study until the end of the study to 
ensure stable plasma hormonal level during the whole study duration. It is recommended that oral 
contraceptives be taken in the evening.  
A male can only be admitted to the study if he is not fertile or agrees to abstain from or to use a 
condom during sexual intercourse, and not to donate sperm, from study admission until at least 
1 month after the last administration of study drug.  
10. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
10.1. 
Cytisine 1.5 mg Film-Coated Tablets 
Cytisine will be supplied by the Sponsor. The cytisine drug product is formulated as a compressed 
film-coated tablet containing 1.5 mg cytisine in a single tablet. Each tablet is composed of cytisine 
active substance (as the base) supplied by 
 with well-established 
tablet-forming 
 
 
 
10.2. 
Placebo Tablets 
Placebo tablets will contain the same excipients as in the cytisine tablet formulation plus an 
additional 
 to match final weight of the cytisine tablet. Placebo tablets 
will be identical in size, shape, color, and packaging to preserve the double-blind study design.  


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10.3. 
Receipt and Storage 
The study drug shall be stored in a secure, temperature controlled location and only 
dispensed by suitably trained staff.  
10.4. 
Administration 
Study drug will be supplied as compressed tablets. Tablets should be swallowed whole with water 
on the morning of Day 1.  
10.5. 
Return/Destruction 
All unused study drug should be destroyed by the site unless a prearranged return to depot or 
Sponsor is necessary.  
10.6. 
Method of Assigning Subjects to Cohort 
Eight subjects should be ready for enrollment within each cohort at the same time. The site will 
determine what subject is enrolled into a given cohort primarily based on subject’s availability and 
ability to escalate into the next cohort.  
Using SAS® 9.4 or higher (SAS Institute Inc., Cary, NC, USA), a computer-generated block-wise 
randomization list adequate for a placebo-controlled studies will be prepared by the Data 
Management and Analysis Department of 
 Eight (8) subjects will be allocated to 
each treatment cohort. Within each treatment cohort, subjects will be randomly assigned to 
receive a single oral dose of cytisine or placebo in a 3:1 ratio (6 cytisine:2 placebo).  
Once generated, the randomization list will be final and cannot be modified.  
Upon confirmation that all entry criteria are met on Day 0 (see Section 12.1.2), subjects will be 
sequentially assigned a subject number. The subject number will be provided to the unblinded 
pharmacist on site and will define the treatment to which subjects will be allocated (test or 
placebo) per the randomization list. The clinical research staff will record study drug (tablet) 
administration and all related information on the applicable source documents, to allow 
investigational product accountability.  
10.7. 
Blinding and Code Break Procedures 
The randomization list and one set of individual sealed code break envelopes will be generated.  
The randomization list will be provided to the unblinded pharmacist for preparation of the double-
blind treatment and will indicate subject number and associated treatment. The pharmacist will be 
the only personnel to have access to the randomization list in order to prepare the drug for 
administration.  
Each code break envelope will be labeled with the subject number and the treatment (cytisine or 
placebo) will be inside of the sealed envelope. One set of the sealed code break envelopes will be 
provided to the investigational site for emergency code breaking. 
Subjects withdrawn from the study retain their subject number and associated randomization, if 
already given. New subjects must always be allotted a new subject number; once assigned, subject 
numbers are never reused within the study site.  


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10.7.1. 
Emergency Code Break Procedure: 
In case of an emergency, when knowledge of the investigational product assignment is required 
for the medical management of an individual subject, the treatment for that subject may be 
unblinded. The investigator must notify the Sponsor, DSMs and 
Drug Safety 
Manager within 24 hours after determining that it is necessary to unblind the treatment 
assignment.  
This documentation must include the name of the individual breaking the blind, the date on which 
the blind was broken, and a description of the event that led to the unblinding. The investigator 
must also indicate in source documents and in the Case Report Form (CRF) that the blind was 
broken and provide the date, time, and reason for breaking the blind. Any adverse event or serious 
adverse event associated with breaking the blind must be recorded and reported as specified in this 
protocol.  
Monitors will routinely check the integrity of the envelopes that are stored at the site. The 
envelopes will be collected from the site prior to study close-out and sent to the Sponsor to ensure 
that they were all intact.  
10.7.2. 
Unblinding for Safety Monitoring to Escalate into Next Cohort 
Upon completion of the follow-up assessment for each subject in each cohort, a safety review will 
be performed by the PI and DSMs on unblinded data. Unblinding of the subjects’ codes for the 
data review will be given by the pharmacist to the PI and DSMs.  Only the PI and DSMs will be 
unblinded for the data review. All other site personnel and subjects will remain blinded until 
completion of the study, with the above emergency exceptions. Refer to Section 14 for Safety 
Monitoring. 
10.8. 
Study Drug Dosing Schedule 
Study drug will be administered to cohorts of 8 subjects per dose level. Within each dose level, 
subjects will be randomly assigned to receive a single oral dose of cytisine or placebo in a 3:1 
ratio (6 cytisine:2 placebo).  
Six dose levels were studied under Version 4.0 of the protocol: 6 mg, 9 mg, 12 mg, 15 mg, 18 mg 
and 21 mg. The starting dose was 6 mg cytisine (single oral dose) in Cohort 1. The study was 
escalated up to the cytisine dose of 21 mg in Cohort 6 without showing any of the predefined 
stopping criteria. Thus, three additional dose levels (Cohorts 7 to 9) under Version 5.0 of the 
protocol are pre-planned: 24 mg, 27 mg and 30 mg.  
10.9. 
Accountability 
The pharmacist or pharmacist designee will maintain records of study drug receipt at the trial site, 
inventory at the site, dispensing for each subject, and any destruction of unused doses and all 
empty containers of the used doses for investigational product accountability.  


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11. 
PREVIOUS AND CONCOMITANT MEDICATIONS 
Subjects will be requested to abstain from taking any medicinal products, including vitamins, food 
supplements, herbal supplements (including St John’s Wort), within 14 days prior to admission 
until the end-of-study (refer to Section 9.2).  
At the discretion of the Investigator, the use of non-study drug medications (either prescription or 
over-the-counter) may be given if clinically-indicated during the study or if intended for 
contraception.  
If an analgesic is required, acetaminophen (paracetamol), at doses of ≤2 gram/day, is permitted 
any time during the study except during the overnight fasting prior to dosing. In case a subject is 
administered another drug its use must be reported and possible impacts on the study outcome 
must be assessed by the Investigator.  
Full details of any new medications must be recorded in the subject’s CRF.  


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12. 
STUDY PROCEDURES 
After providing signed informed consent, all subjects will be evaluated for inclusion in the study 
within a 28 day Screening Period. Table 8 provides a summary of required study evaluations.  
Table 8: 
Schedule of Study Procedures 
Assessments 
Screening 
Treatment Period in Each Cohort 
Follow-
up 
Admission 
Confinement1 
Discharge2 
Days 
-28 to -1 
Day 0 
Days 1-2 
Day 2 
Day 5-63 
Written informed 
consent 
X 
 
 
 
 
Demographic 
data/height/weight 
X 
 
 
 
 
Expired CO level  
X 
 
 
 
 
Baseline NMR10 
X 
 
 
 
 
Medical history, 
including smoking 
X 
 
 
 
 
Medical history update 
 
X4 
 
 
 
Physical examination 
X 
 
 
 
 
Physical examination 
update 
 
X4 
 
 
 
Vital signs (supine 
blood pressure, pulse 
rate and body 
temperature) 
X 
X 
X5 
X5 
 
Prior and concomitant 
medication 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
X6 
 
Continuous vital 
parameters monitoring 
 
 
X7 
 
 
Pregnancy test, if 
WOCBP 
X 
(Serum) 
X 
(Urine) 
 
X 
(Serum) 
 
Hematology 
X 
 
 
X 
 
Biochemistry 
X 
 
 
X 
 
Estimated creatinine 
clearance 
X 
 
 
 
 
Coagulation 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
Drugs-of-abuse tests in 
urine 
X 
X 
 
 
 
Ethanol breath test 
X 
X 
 
 
 
Verification of 
eligibility criteria 
X 
X 
 
 
 
Cytisine/placebo 
administration 
 
 
X8 
 
 
Blood collection for 
pharmacokinetic 
analysis 
 
 
X 
 
 
Adverse events 
monitoring 
X9 
X9 
X9 
X9 
X9 
WOCBP – Woman of childbearing potential 


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1 From at least 11 hours before dosing to at least 24 hours post dose. 
2At 24 hours post-dose. 
3A Post-Study Follow-up telephone call will occur 4-5 days after dosing to document any changes in adverse event(s) 
observed at discharge as well as any new adverse events and concomitant medications taken. 
4Clinically relevant changes will be reported as adverse events.  
5Vital signs to be recorded at pre-dose and again at approximately 2, 4 and 6 hours post-dose on Day 1 and at 
discharge on Day 2. 
6Repeat 12-lead ECG and assess prior to discharge. 
7Continuous vital parameters monitoring (lead-II ECG, heart rate, respiratory rate and pulse oximetry) will be 
performed from pre-dose up to 6 hours post-dose. 
8Orally, in the morning, with 240 mL of water, after an overnight fasting of at least 10 hours. 
9Adverse events will be monitored throughout the whole study. 
10Subjects will be tested for both cotinine and 3-OH cotinine levels for determining their baseline nicotine metabolite 
ratio (NMR). 
 
12.1. 
Detailed Description of Study Visits 
12.1.1. 
Screening Visit (Day -28 to Day -1) 
All subjects will complete the following screening procedures within 28 days of Day 0 in order to 
verify required inclusion and exclusion criteria.  
1. Written informed consent.  
2. Demographic data/height/weight.  
3. Medical history data, including smoking history.  
4. Physical examination.  
5. Vital signs (supine blood pressure, pulse rate and body temperature).  
6. 12-lead ECG.  
7. Clinical laboratory safety tests (biochemistry, hematology, coagulation, urinalysis, drugs 
of abuse and serum pregnancy test for females of child bearing potential).  
8. Estimated creatinine clearance.  
9. Expired CO. 
10. Serum for cotinine and 3-OH cotinine testing.  
11. Ethanol breath test.  
12. Prior and concomitant medication.  
13. Adverse events monitoring.  
14. Verification of eligibility criteria.  
12.1.2. 
Day 0: Admission 
The results of screening for each subject must be reviewed by the Principal Investigator prior to 
subject’s admission to assure eligibility criteria have been met.  


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On Day 0, the subject will check into the clinical research facilities and the following procedures 
are to be performed:  
1. Medical history update.  
2. Physical examination update.  
3. Vital signs (supine blood pressure, pulse rate and body temperature).  
4. Urine testing for pregnancy in females of child bearing potential.  
5. Drugs-of-abuse tests in urine.  
6. Ethanol breath test.  
7. Prior and concomitant medication.  
8. Adverse events monitoring  
9. Randomization, after verification of eligibility criteria.  
All subjects will fast for minimum of 10 hours prior to dosing on Day 1. 
All subjects will remain confined in the clinical research facilities overnight.  
12.1.3. 
Day 1: Administration of Cytisine  
The following study procedures are to be performed:  
1. Pre-dose blood draw for PK to be taken within 30 minutes prior to dosing.  
2. Vital signs (supine blood pressure, pulse rate and body temperature) will be recorded 
within 60 minutes prior to dosing.  
3. Cytisine (Per cohort dosing using 1.5 mg tablets)/placebo will be administered after the 
overnight fast of at least 10 hours and subject will continue fasting until lunch (fasting 
state). Dosing will be administered with 240 mL (8 fluid ounces) of potable water at room 
temperature. Except for fluids taken for dosing, no fluids will be allowed from 1 hour 
before dosing until 1 hour post-dosing. No food should be allowed for at least 4 hours 
post-dose until lunch is served for all subjects. Meals and snacks will then be provided as 
outlined in (Section 9.2.1). 
4. Blood will be collected and processed for Cmax assessments as outlined in Section 12.2 
after administration of cytisine/placebo (time zero).  
5. Vital signs (supine blood pressure, pulse rate and body temperature) will be recorded 
approximately 2 hours, 4 hours and 6 hours after cytisine administration. Any abnormal 
values should be followed every 2 hours until returning to baseline levels.  
6. Continuous vital parameters monitoring (lead-II ECG, heart rate, respiratory rate and pulse 
oximetry) will be performed from pre-dose up to 6 hours post-dose.  
7. Use of concomitant medications are to be documented.  
8. Adverse events monitoring.  
All subjects will remain in the clinical research facilities overnight.  


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12.1.4. 
Day 2: Discharge at 24 hours post-dose 
1. Vital signs (supine blood pressure, pulse rate and body temperature).  
2. 12-lead ECG.  
3. Clinical laboratory safety tests (hematology, biochemistry and serum pregnancy test for 
females of child bearing potential).  
4. Use of concomitant medications are to be documented.  
5. Adverse events monitoring.  
Upon final review by the study physician, the subject will be discharged from the clinical research 
facility at 24 hours post-dosing and will be scheduled for a post-study follow-up telephone call.  
12.1.5. 
Days 4-5 Post-Study Follow-up 
A Post-Study Follow-up telephone call will occur 4-5 days after dosing to document any changes 
in adverse event(s) observed at discharge as well as any new adverse events. If any new adverse 
events are recorded at this follow-up call, arrangements will be made with the subject to come into 
the clinical research facility for assessment and then followed until outcome determined. Any 
concomitant medications must also be documented.  
12.1.6. 
Interim Safety Assessments 
Upon completion of the follow-up assessment for each subject in each cohort, the data will be 
cleaned and soft-locked, and a safety review will be performed by the PI and the two independent 
DSMs on unblinded data.  
The safety review will focus on all the adverse events reported during the study and on any other 
safety-supporting data requested by the independent data safety monitors, namely safety 
laboratory, ECG, vital signs, physical examination or medical history. 
The PI and DSMs will conjointly decide whether dose escalation into the next cohort will be 
allowed, based on the cumulative results of safety and tolerability.  


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12.2. 
Pharmacokinetic Blood Sampling 
12 venous blood samples (volume of 6 mL each, total volume of approximately 72 mL) will be 
collected into pre-cooled lithium heparin tubes, according to the following schedule:  
Table 9: 
Blood Sampling for Pharmacokinetic Assessments  
Blood Sample Number 
Time from Dosing 
1 
Pre-dose (within 30 minutes prior to dosing) 
2 
00:15 
3 
00:30 
4 
00:40 
5 
00:50 
6 
01:00 
7 
01:15 
8 
01:30 
9 
01:45 
10 
02:00 
11 
02:30 
12 
03:00 
The pre-dose blood samples will be collected within 30 minutes prior to dosing. The post-dose 
blood samples will be collected within +/-2 minutes 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.  
Blood samples for pharmacokinetic analysis will be collected and processed as per the analytical 
methodology instructions provided by the Bioanalytical Laboratory.  
Samples will be labeled with self-adhesive pre-printed labels suitable to withstand freezing 
temperatures. Labels should bear the following minimum information:  
• Labels of blood sample tubes: protocol code, subject number, sample time point, 
matrix type, and the statement “for Cytisine assay” (statement can be abbreviated if 
needed).  
• Labels of plasma aliquots: protocol code, subject number, sample time point, aliquot 
series, matrix type, and the statement “for Cytisine assay” (statement can be 
abbreviated if needed).  
At agreed times, samples will be transferred to the bioanalytical laboratory, with each series of 
aliquots in separate shipments. The samples will be packed in dry ice for transport and no 
interruption of the freeze cycle is allowed. The temperature in the box during the transport will be 
monitored. Once the bioanalytical laboratory confirms receipt of the first shipment, the second 
series of aliquots will be sent, if required. For all shipments, the laboratory should acknowledge in 
writing the receipt of plasma samples in good condition.  


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13. 
SAFETY ASSESSMENTS 
Only subjects in good general health are eligible for the study. The healthy status will be 
determined by pre-study medical history, physical examination, vital signs, 12-lead ECG, 
hematology, serum chemistry, coagulation and urinalysis.  
Creatinine clearance (CrCL) will be estimated at screening by using the Cockcroft-Gault formula: 
CrCL male = [(140-age) x (weight in kg)] / [(serum Cr mg/dL) x (72)]; CrCL female = 0.85 x (CrCL 
male).  
Subjects’ safety will be monitored during the study. A summary of safety procedures is presented 
in (Table 8). AEs will be monitored throughout the study.  
The Investigator will assess the clinical significance of results of laboratory investigations outside 
the normal ranges, as defined below in Section 13.1. All changes from screening that are observed 
at any time during the study and meet the pre-defined requisites for clinical significance will be 
recorded as AEs.  
In addition to the planned times, any safety procedures can be performed at any time considered 
necessary by the Investigator.  
At least one Physician will remain at the clinical site for investigational product administration 
and until 6 hours post dose, and will remain available on call at all times during the study. The 
hospital where the clinical research facilities are located has emergency care available on a 
24-hour basis.  
13.1. 
Definitions 
The definitions adopted are 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 pharmaceutical product and which does not necessarily have to have a causal 
relationship with the treatment.  
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
laboratory value or test result), symptom, concomitant illness, accident, or the worsening of an 
existing medical condition.  
Events occurring in subjects in the course of a clinical study during treatment-free periods or on 
treatment with placebo or a comparative medicine are also to be considered AEs. The definition 
covers also medication errors and uses outside what is foreseen in the protocol, including misuses 
and abuse of the 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 investigator as at least possible (see definition below).  
An Unexpected Adverse Drug Reaction (UADR)/Unexpected Adverse Event (UAE) means an 
adverse reaction/event, the nature or severity of which is not consistent with the applicable 
product information, namely in the Investigator Brochure for an unauthorized investigational 
product or in the SmPC for an authorized product.  


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The expected/unexpected status should be evaluated and assessed, by the Sponsor, based on the 
reference safety information available since expectedness in Pharmacovigilance refers strictly to 
the information listed or mentioned in the applicable reference safety information and not to 
event(s) that might be anticipated from knowledge of the pharmacological properties of a 
substance or because it was foreseeable due to the health status (e.g., age, medical history) of the 
study subjects.  
A Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) is any untoward medical 
occurrence or effect, that, at any dose:  
• Results in death  
• Is life-threatening  
NOTE: The term “life threatening” in the scope of “serious adverse events” refers to an 
occurrence in which the subject was at immediate risk of death from the event as it 
occurred. It does not include a reaction that, if it had occurred in a more serious form, 
might have caused death. 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.  
• Requires hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability or incapacity  
• Results in a congenital abnormality or birth defect  
• Is an important medical event which requires medical intervention to prevent one of 
the above  
NOTE: Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical events 
that may not be immediately life threatening or result in death or hospitalization but 
may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above. These should also usually be considered 
serious. Examples of such medical events could include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in hospitalization, or the development of drug 
dependency or drug abuse.  
SUSARs: AEs which meet all of the following criteria will be classified as suspected unexpected 
serious adverse reactions (SUSARs):  
• Serious  
• Unexpected (i.e., is not consistent with the applicable product information e.g. 
Investigator's brochure for an unapproved IMP or SmPC for an authorised product)  
• There is at least a reasonable possibility that there is attribution between the event and 
the medicinal product.  


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13.2. 
Recording of Adverse Events 
The period of observation for the collection of AEs extends from the time when the subject gives 
Informed Consent until the end of the study (completion of the Follow-up telephone assessment). 
For all subjects this period will be extended to follow-up on all on-going AEs after the end of the 
treatment period until final resolution or until it is medically justifiable to stop further follow-up 
(e.g. a chronic condition has been reached). Pregnancy in a woman volunteer shall be followed-up 
to determine its outcome, including spontaneous or voluntary termination, details of birth, 
presence or absence of any birth defects, congenital anomalies, or maternal and/or newborn 
complications. If the outcome of the pregnancy meets the criteria for immediate classification of a 
SAE (e.g. spontaneous or elective abortion–any congenital anomaly detected in an aborted fetus is 
to be documented, stillbirth, neonatal death, or congenital anomaly), the investigator will report 
the event by completing a SAE form.  
There is no time limit on collection of SAEs that are considered related to the investigational 
product. If the investigator detects a SAE in a study subject after the end of the period of 
observation, and considers the event possibly related to prior study treatment or procedures, he or 
she must communicate this to the Sponsor in order to mutually agree on further measures and 
appropriate reporting.  
The AEs must be documented as soon and as completely as possible on the “Adverse Events” 
pages into the electronic CRF (eCRF). Follow up information must be entered as soon as 
available.  
All of the following details will be recorded in the subject’s CRF for each AE:  
• Full description of AE.  
• Date and time of onset.  
• Date and time of resolution.  
• Severity of event, to be assessed by an Investigator, or their delegate, in accordance 
with the definitions below.  
• Relationship to study drug to be assessed by an Investigator, or their delegate, in 
accordance with the definitions below.  
• Action taken (dose not changed, not applicable, drug withdrawn).  
• Outcome and date of outcome (recovered/resolved, recovering/resolving, not 
recovered/not resolved, recovered with sequel /resolved with sequel, fatal, unknown) 
and details of any further follow-up.  
Corrections to AE details may be made, but must be dated and signed according to the ICH-GCP 
requirements. If a suspected diagnosis has been ruled out, the investigator may change the AE 
term, but should add a comment stating the original suspected diagnosis as well as reasons for 
change.  
AEs that occur during the study should be treated by established standards of care that will protect 
the life and health of the subjects. If such treatment constitutes a deviation from the protocol, the 
subjects should be withdrawn from the study and the reason must be documented into the eCRF.  
Reporting of Adverse Events 


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All AEs must be fully validated, evaluated, documented, reported (if applicable) and archived, 
whether or not they are considered to be drug-related.  
AEs defined in the protocol as critical for safety assessments and/or clinically relevant 
abnormalities (in clinical laboratory safety tests, physical examination, vital signs or ECG) should 
be reported as AEs within the time frame indicated below, in this protocol.  
All SUSARs, i.e. which are not consistent with the known safety profile of the Test product, shall 
be immediately reported.  
13.2.1. 
Grading Adverse Event Severity 
The following grades will be used by an Investigator to describe the severity of all AEs (including 
clinically-significant laboratory AEs) as shown in Table 10. Only 1 severity grade will be used for 
each AE (e.g. mild - moderate is not acceptable).  
Table 10: 
Adverse Event Severity 
Severity of AE 
Definition 
Mild 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living.  
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
Severe 
A type of AE that requires intensive therapeutic intervention. The event interrupts 
usual activities of daily living, or significantly affects clinical status. The event 
possesses a significant risk of harm to the research participant and hospitalization 
may be required. 
If an AE has multiple aspects, the aspect in the highest intensity will be graded. It is emphasized 
that the term severe is a measure of intensity; thus a severe AE is not necessarily serious. For 
example, itching for several days may be rated as severe; however, may not be clinically serious.  
13.2.2. 
Causality Assessment 
The relationship of an AE to the investigational product will be determined and documented by 
the Investigator, according to best medical judgment as shown in Table 11.  
Table 11: 
Assessment of Attribution to Study Drug  
Category 
Description 
Not Related 
The subject did not receive the investigational product or the temporal sequence of 
the AE onset relative to the administration of the investigational product is not 
reasonable or the event is clearly related to other factors such as the subject’s clinical 
state, therapeutic intervention or concomitant therapy. 
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 investigational product.  
Possible 
The event follows a reasonable temporal sequence from the time of investigational 
product 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. 


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Table 11: 
Assessment of Attribution to Study Drug  
Probable 
The event follows a reasonable temporal sequence from the time of study drug 
administration, and/or follows a known response pattern to the investigational 
product, and could not have been produced by other factors such as the subject’s 
clinical state, therapeutic intervention or concomitant therapy. 
Definite 
The event follows a reasonable temporal sequence from the time of study drug 
administration, and/or follows a known response pattern to the investigational 
product, and could not have been produced by other factors such as the subject’s 
clinical state, therapeutic intervention or concomitant therapy, and either occurs 
immediately following investigational product administration, or improves on 
stopping the investigational product. 
13.2.3. 
Reporting of Serious Adverse Events 
 Phase I will inform the 
Drug Safety Manager, DSMs and Sponsor of all 
SAEs, SARs or pregnancies occurring within 24 hours of becoming aware of the SAE/SAR or the 
pregnancy.  
Any SAE/SAR or pregnancy will be reported to the 
Drug Safety Manager, DSMs and 
Sponsor via telephone, fax, e-mail or in person. Any oral communication must be followed by 
written notes by fax or e-mail. The initial report shall be followed by a detailed written report as 
soon as possible but no later than 5 days.  
The notification should be directed to:  
 
 
 
 
 
 
 
 
 
 
 
Additional information (follow-up) about any SAE unavailable at the initial reporting should be 
forwarded by the site within 24 hours of the information becoming available.  
The following information should be provided to accurately and completely record the event:  
• Investigator name  
• Subject number  
• Subject initials  
• Subject demographics  
• Clinical event  
− description  


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− 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 AE reporting period must be followed clinically until 
all parameters (including laboratory) have either resolved or been assessed as chronic.  
All SUSARs shall be expeditiously reported to 
 and Regulatory Agency 
. 
Expeditiously means that all SUSARs will be reported within 7 days of knowledge (i.e., 7 days 
after the Sponsor was first aware of the reaction).  
The Sponsor will be responsible for expediting report of SUSARs to 
, via 
EudraVigilance, and for providing clinical site the respective copy of the Council for International 
Organizations of Medical Sciences (CIOMS) form. The Sponsor will be responsible for reporting 
SUSARs to
  
The clinical site will notify
 of all SAEs (other than SUSARs), after 
Sponsor’s review and approval.  
13.3. 
Laboratory 
13.3.1. 
Routine Laboratory Assessments 
Routine laboratory safety samples will be analysed at screening for each subject by the site 
laboratory. A decision regarding whether a result outside the reference range is of clinical 
significance or not shall be made by the site investigator and the report will be annotated 
accordingly. Clinically significant abnormalities occurring during the study will be recorded on 
the AE page. The reference ranges for the site’s laboratory parameters will also be entered in the 
database and filed in the Investigator site file.  
Hematology: Hemoglobin, red blood cells, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), coefficient variation 
of the red cell distribution width (RDW-CV), total white blood cell (WBC) count, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils and platelets.  
Chemistry: Total protein, albumin, direct bilirubin, indirect bilirubin, total bilirubin, alanine 
aminotransferase (SGPT or ALT), aspartate aminotransferase (SGOT or AST), gamma-
glutamyltransferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), glucose, 


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total cholesterol, triglycerides, sodium, potassium, calcium, creatine phosphokinase (CPK), 
creatinine, estimated creatinine clearance, uric acid and urea.  
Coagulation: prothrombin rate, prothrombin time - international normalized ratio (INR) and 
activated partial thromboplastin time (aPTT).  
Urinalysis: pH, specific gravity, protein, hemoglobin, glucose, ketones, bilirubin, nitrites, 
urobilinogen and microscopy.  
Urine test for drugs-of-abuse: cannabinoids, opiates, cocaine, amphetamines, and 
benzodiazepines.  
Expired CO will be obtained using a calibrated instrument provided and maintained by the clinical 
site. Cotinine and 3-OH cotinine will be measured in serum for determining the baseline NMR. 
Ethanol will be measured via a breath test. Pregnancy testing will be performed using both serum 
and urine beta-human chorionic gonadotropin (beta-hCG) pregnancy tests.  
13.4. 
Vital signs and electrocardiogram 
Systolic/diastolic blood pressure, pulse rate, and temperature measurements will be recorded in a 
supine position. Body weight will also be recorded. Height is to be recorded at Screening Visit for 
BMI calculation.  
12-lead ECG will be recorded in supine position.  
Post-dose vital signs and ECG recordings will be taken within ±15 minutes of scheduled time. 
When ECG or vital signs recordings coincide with a blood draw, they should preferably be 
performed before the blood collection.  
Lead-II continuous (real time) ECG monitoring will be performed from pre-dose to at least 
6 hours post-dose.  
13.5. 
Physical Examination 
A physical examination will be performed by an Investigator. The examination will include 
general appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory 
system, gastrointestinal system, central nervous system, lymph nodes and musculoskeletal. An 
Investigator can examine other body systems if required, at their discretion.  
14. 
SAFETY MONITORING  
14.1. 
 Independent Data Safety Monitors 
Safety monitoring will be performed by two independent DSMs who will be appointed for this 
study. The DSMs will be M.D.s experienced in the treatment of adult smokers. The primary 
responsibility of the DSMs will be to monitor for any unexpected safety risk for subjects on the 
protocol. The DSMs will:  
• Review all SUSARs and SAEs. The 
l Drug Safety Manager will provide 
each DSM with a copy of any unexpected study drug-related SAE Report Form within 
7 business days of receipt. The 
 Drug Safety Manager (or designee) will 


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also provide the DSMs with copies of all expedited SAE reports submitted to 
regulatory agencies.  
• Review overall safety for the study (e.g. severe adverse events and other possible dose-
limiting adverse events) with the Principal Investigator prior to doses being escalated 
into the next cohort. The DSMs have the authority to suspend dosing in any cohort at 
any time.  
• The DSMs must review and approve any replacement of a subject within a cohort to 
assure that the reason for the subject withdrawal did not involve a potential safety issue 
or hidden dose-limiting adverse event. A subject who enrolled but then withdrew prior 
to receiving any study treatment may be replaced without DSMs approval.  
14.2. 
Stopping Criteria 
Upon completion of the follow-up assessment for each subject in each cohort, the data will be 
cleaned and soft-locked and a safety review will be performed by the PI and the DSMs on 
unblinded data. Dose escalation to the next level will be conjointly decided by the PI and the 
DSMs. 
The dose should not be escalated further if any of the following occurs: 
1. A serious adverse event (SAE) that is considered at least possibly related to cytisine in 1 or 
more subjects;  
2. Severe non-serious adverse events that are considered at least possibly related to cytisine 
in 2 or more subjects within the same cohort;  
3. Other safety information considered to pose a risk to subjects. 
The maximum tolerated dose (MTD) will be defined as one dose-level below which stopping 
criteria has been observed.  
15. 
STATISTICAL CONSIDERATIONS   
15.1. 
Sample Size 
The sample size of eight subjects per cohort is based on what is reasonable and feasible for a 
Phase 1 dose-escalation study.  
15.2. 
Analysis Sets 
Screening Analysis Set: The Screening Analysis Set is defined as all subjects who give written 
informed consent and have entered screening. Analyses will be restricted to presentation of 
baseline data and reasons for non-participation as contrasted to those enrolled and received study 
drug.  
Safety Analysis Set: The Safety Analysis Set is defined as all enrolled subjects who were 
administered the single dose of study drug.  
15.3. 
Safety Assessments 
Clinically significant abnormalities will be reported as AEs.  


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Adverse events will be coded using the MedDRA dictionary version 21.0 or higher. Coding 
includes SOC and preferred term (PT). The following information recorded or computed is used 
for the description of the AEs: reported Term; SOC and PT by MedDRA coding; onset date, onset 
time, offset date and offset time; seriousness; severity (intensity); relationship (causality); action 
taken; outcome.  
The profiles of adverse events for the arms with regard to incidences of TEAEs will be 
assessed. TEAEs are defined as AEs not present prior to administration of investigational product, 
or AEs present before administration of investigational product that worsen after the subject 
receives the dose of investigational product. A separate listing of SAEs will be presented, if 
applicable. Frequencies of TEAEs will be presented by SOC and PT, by Test product and placebo 
and overall.  
Dose-limiting adverse event determinations are described in Section 14.2 and safety summaries 
are described in the Statistical Analysis Plan (SAP).  
15.4. 
General Considerations 
Summaries of demographics, baseline characteristics and safety endpoints will be provided for the 
safety population, defined as all subjects who receive a single dose of cytisine or placebo.  
Unless otherwise indicated, no statistical comparisons between the cohorts are planned. 
Summaries will be provided for each cohort. Numeric variables will be summarized using the 
mean, median, standard deviation, etc. Categorical variables will be summarized with number and 
percent.  
Assessments for trends in dose-limiting adverse events or Cmax levels in relationship to BMI 
categories/levels and baseline NMR may be explored.  
Unless otherwise indicated, safety summaries will be produced using SAS® software, version 9.4 
or higher.  
15.5. 
Pharmacokinetic Parameters 
Pharmacokinetic parameters (Cmax and Tmax) will be summarized for each cohort using the mean, 
standard deviation, median, minimum and maximum.  
Cmax will be calculated as the maximum observed plasma concentration (ng/mL) and summarized 
by mean (90% CI).  
Tmax will be the time to occurrence of maximum plasma concentration (h) and summarized using 
the median with minimum and maximum.  
16. 
REGULATORY AND ETHICS CONSIDERATIONS 
16.1. 
Independent Ethics Committee  
This protocol, informed consent form, details of subject compensations and any subject recruiting 
materials will be submitted to 
 
) for evaluation and approval, prior to the start of the study.  


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The study will not start until the 
has approved the documents. The letter of the 
 
approval will be appended to the final CSR.  
All amendments or revisions to the protocol must undergo review by 
.  
A copy of the 
approval letter must be forwarded to the Sponsor or Sponsor’s representative 
before the study is implemented. The approval letter must clearly state the protocol title and 
version that was reviewed, as well as any associated documents. The Investigator also must 
forward copies of subsequent amendment approval letters to the Sponsor upon receipt.  
16.2. 
Ethical Conduct of the Study 
This trial will be conducted in accordance with the current version of the Declaration of Helsinki, 
as well as the ICH Guidelines on GCP, and applicable laws and regulations.  
16.3. 
Informed Consent 
The informed consent forms used for the study must comply with the Declaration of Helsinki and 
its updates and the ICH GCP and must have been approved by the Sponsor or Sponsor’s 
representatives. The Investigator or an authorized associate, who must be a physician, must 
explain the nature of the study and the treatment in such a manner that the subject is aware of 
his/her rights and responsibilities, as well as potential benefits and risks. The Investigator is also 
responsible for answering any questions the subject may have throughout the study and sharing 
any new information, in a timely manner, that may be relevant to the subject’s willingness to 
continue his/her participation in the trial.  
Subjects must also be informed that participation is voluntary and that they may withdraw from 
the study at any time, without prejudice to their current or future care. Documentation of the 
discussion and the date of informed consent should be recorded in the subject’s medical record or 
a study/clinic chart. Once all of their questions have been answered and they have voluntarily 
agreed to participate in the study, subjects will be asked to sign and date the Informed Consent 
Form.  
Subjects must give informed consent in writing prior to the performance of any protocol-specific 
procedure. A copy of the signed Informed Consent Form will be provided to the subject.  
In case of amendments to the Informed Consent Form during the study, a renewed written and 
signed consent must be obtained from each subject still participating in the study.  
16.4. 
Review and Approval by Regulatory Authorities 
The study will be submitted to the review and approval of 
 
 according to rules in force. The letter of the 
 approval will be 
appended to the final report.  
16.5. 
Insurance,  Indemnity and Compensation 
It is the Sponsor’s responsibility to guarantee sufficient insurance coverage for this study should 
any serious events or deaths result directly from the execution of the present protocol.  


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The present article is not to be interpreted as engaging the Sponsor’s responsibility in the event of 
fault or negligence of the subjects, investigators, or any persons or employees under the control of 
  
16.6. 
Subject Confidentiality 
The Investigator must attempt to assure that the subjects’ confidentiality will be maintained within 
the limit of the law. Subjects will be identified by subject screening and/or randomization number 
on all documents submitted to the Sponsor. Subjects will not be identified by name.  
All records will be kept in a secure place in the clinical research site. Computer data entry and 
data review programs will be done using subject screening and/or randomization numbers only. 
Clinical information will not be released without written permission of the subject, as outlined in 
the subject consent form.  
The Investigator must maintain a log of subject names and identification codes.  
17. 
DOCUMENTATION 
17.1. 
Study File and Site Documents 
Prior to the activation of the study, at a minimum, the following items must be received by the 
Sponsor from the site:  
1. Confidential Disclosure Agreement  
2. Signed protocol, and amendment(s) page(s)  
3. The Principal Investigator’s curriculum vitae and current medical license.  
4. Signed Clinical Study Agreement  
5. Signed Financial Disclosure Form from the relevant site personnel  
6. 
 written approval for the protocol, amendment(s), Informed 
Consent Form  
7. FDA Form 1572  
17.2. 
Study Documents Supplied by the Sponsor 
The Sponsor will supply the investigator with the following items:  
1. Current version of the Investigator’s Brochure  
2. Current version of study protocol  
3. Master CRF  
4. Informed Consent Form template  
17.3. 
Maintenance and Retention of Records 
It is the responsibility of the investigator to maintain a comprehensive and centralized filing 
system of all relevant documentation.  


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Investigators will be instructed to retain all study records required by the Sponsor and regulatory 
authorities in a secure and safe facility with limited access for one of the following time periods 
based on notification from the Sponsor:  
1. For a period of 25 years after completion or discontinuation of the trial, or  
2. For a period of at least 2 years from the last marketing approval worldwide,  
3. Or a period of at least 2 years after discontinuation of clinical development of the 
investigational product as confirmed by the Sponsor.  
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.  
18. 
ADMINISTRATIVE PROCEDURES  
18.1. 
Sponsor Responsibilities 
The study will be monitored by representatives of the Sponsor and/or designated contract research 
organizations (CROs). Routine monitoring visits will be conducted to (at a minimum):  
1. Assure compliance with the study protocol.  
2. Verify that the research facilities, including laboratories and equipment, are adequate to 
safely and properly conduct the study.  
3. Verify that the investigational product is stored properly and under the proper conditions, 
is in sufficient supply, and that receipt, use, and destruction or return of investigational 
product at the study sites are controlled and documented adequately.  
4. Verify that written informed consent was obtained before any protocol-specific screening 
procedures are performed solely for the purpose of determining eligibility for the clinical 
study and/or prior to the provision of study drug.  
5. Review the subject CRFs and source documents to ensure that reported study data are 
accurate, complete, and verifiable from source documents.  
6. Verify that the Investigator and study site personnel are adequately qualified throughout 
the study.  
7. Verify that the safety information and amendments are submitted to 
 
.  
18.2. 
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 


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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.  
18.3. 
Regulatory Compliance 
The study will be conducted and submitted to quality control to assure data integrity, in 
accordance with applicable
 SOPs. These SOPs require quality control on the 
following processes: medical writing, source documents and eCRF data entry completion and 
accuracy, data management and study reporting.  
The monitoring will be done at the trial site by an independent study monitor. The study monitor 
will be allowed to check all study documents. It will be his/her responsibility to verify the 
adherence to the protocol and the completeness, consistency and accuracy of the clinical data.  
Quality Assurance representatives from the Sponsor or their delegate, as required will be allowed 
to periodically visit the Investigators to discuss the conduct of the trial and, upon request, to 
inspect the records of the trial. These reviews are necessary to ensure that the study is conducted 
according to standards consistent with the ICH GCP Guidelines.  
The Principal Investigator will allow the verification of records (source data) during audits by 
Sponsor or inspections by national or foreign regulatory bodies, in case such authorities require a 
regulatory inspection.  
The Investigator agrees to discuss and correct, if necessary, any problems or deficiencies that are 
found during the course of these reviews.  


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18.4. 
Protocol Modification/Premature Termination 
All protocol amendments must be written and approved by the Sponsor. 
 
will review and approve amendments prior to their implementation in the study. 
and 
approval need not be obtained prior to removal of an immediate hazard to subjects.  
Deviations from the pre-specified dose escalation and decision-making criteria will be submitted 
to Ethics Committee 
 and Competent Authority 
as substantial 
amendment(s) for its approval, prior to implementation. 
The Sponsor may suspend or terminate the protocol early if safety or other issues occur. 
Furthermore, the study may also be terminated prematurely by the Sponsor for important 
corporate reasons, or due to instruction of the Regulatory Authorities due to safety reasons.  
The Principal Investigator may terminate participation at his/her site at any time but must provide 
all study data for subjects randomized.  
Following a decision of temporary suspension or discontinuation, it is a responsibility of the 
Principal Investigator to inform the study subjects and 
 stating the reasons 
for premature termination. The Sponsor shall be responsible for expedited reporting and/or 
notification to the FDA, as applicable.  
18.5. 
Final Study Report 
At the end of the study, an integrated CSR will be prepared following the European electronic 
Common Technical Document (e-CTD) format specifications and in accordance with the 
applicable SOPs. The pharmacokinetic analysis will be included in the integrated CSR.  
18.6. 
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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Protocol No. ACH-CYT-08, Version 5.0 
19. 
INVESTIGATOR’S AGREEMENT 
I have carefully read the foregoing protocol including all appendices and agree that it contains all 
the necessary information for conducting the study safely.  
I will conduct this study in strict accordance with this protocol and according to the current GCP 
guidelines and will attempt to complete the study within the time designated.  
I will provide copies of the protocol and all other information submitted by the Sponsor relating to 
non-clinical and prior clinical experience to all personnel for whom I am responsible that 
participate in the study. I will discuss this information with them to assure that they are adequately 
informed regarding the drug and conduct of the study.  
I agree to keep records on all subject information (case report forms, shipment and drug 
return/destruction forms and all other information collected during the study) in accordance with 
the current GCP and local regulations.  
 
 
 
 
Site Principal Investigator’s name 
 
Sponsor’s Representative's name 
 
 
 
 
Signature 
 
Signature 
 
 
 
Date (ddMMMyyyy) 
 
Date (ddMMMyyyy) 
 
 
 
 
 
 
 
 
 


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20. 
REFERENCES  
1. Etter J. Cytisine for smoking cessation: A literature review and a meta-analysis. Archives of 
Internal Medicine 2006;166:1553-9. 
2. Papke RL, Heinemann SF. Partial agonist properties of cytisine on neuronal nicotinic receptors 
containing the beta 2 subunit. Molecular pharmacology 1994;45:142-9. 
3. Parker MJ, Beck A, Luetje CW. Neuronal nicotinic receptor beta2 and beta4 subunits confer 
large differences in agonist binding affinity. Molecular pharmacology 1998;54:1132-9. 
4. Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic receptor partial 
agonist for smoking cessation. Journal of medicinal chemistry 2005;48:3474-7. 
5. West  R, Zatonski  W, Cedzynska  M, et al. Placebo-Controlled Trial of Cytisine for Smoking 
Cessation. New England Journal of Medicine 2011;365:1193-200. 
6. Walker N, Howe C, Glover M, et al. Cytisine versus nicotine for smoking cessation. The New 
England journal of medicine 2014;371:2353-62. 
7. World Health Organization. WHO report on the global tobacoo epidemic, 2017: monitoring 
tobacco use and prevention policies. Geneva 2017. 
8. Hughes JR, Keely J, Naud S. Shape of the relapse curve and long-term abstinence among 
untreated smokers. Addiction (Abingdon, England) 2004;99:29-38. 
9. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years' 
observations on male British doctors. BMJ (Clinical research ed) 2004;328:1519. 
10. Foulds J, Burke M, Steinberg M, Williams JM, Ziedonis DM. Advances in pharmacotherapy 
for tobacco dependence. Expert opinion on emerging drugs 2004;9:39-53. 
11. Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. Antidepressants for smoking 
cessation. The Cochrane database of systematic reviews 2014:Cd000031. 
12. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. The 
Cochrane database of systematic reviews 2012;11:Cd000146. 
13. Cahill K, Lindson-Hawley N, Thomas KH, Fanshawe TR, Lancaster T. Nicotine receptor 
partial agonists for smoking cessation. The Cochrane database of systematic reviews 
2016:Cd006103. 
14. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of 
varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders 
(EAGLES): a double-blind, randomised, placebo-controlled clinical trial. The Lancet 
2016;387:2507-20. 
15. Cytisine 1.5 mg Film-coated Tablets Investigator’s Brochure, Version 6.0, 15FEB2019 
16. 
 dated January 2018.  

SAP_001.pdf: 
ACH-CYT-08 Clinical Study Report, 01 July 2020 
Cytisine 
Confidential 
16. Appendices
16.1. Study Information
16.1.9. Documentation of Statistical Methods
Statistical Analysis Plan, version 2.0, 09 October 2019
16.1.9 - page 1


Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
Page 1 of 95 
STATISTICAL ANALYSIS PLAN
STUDY TITLE: 
A Phase I, Double-blind, Randomized, Placebo-controlled, Single Dose-escalation 
Study to Evaluate the Tolerability and Safety of Cytisine in Adult Smokers 
Protocol Code: ACH-CYT-08 
Type: Interventional, Phase I 
EudraCT No.: 2018-003344-22 
SAP Version: 2.0 
Date: 09OCT2019 
Supersedes version: 
Date: 20MAY2019 
Protocol Version 5.0 
Sponsor: Achieve Life Sciences, Inc. 
520 Pike Street, Suite 2250 
Seattle, Washington, USA 98101 
Phone: 604 736 3678   
Fax: 604 736 3687 
Clinical Pharmacology Unit: 
 
  
 
 
  
CONFIDENTIALITY DISCLAIMER 
This document is confidential and is available for review to investigators, 
regulatory bodies and study audit personnel. No part of this document may be 
used, published, copied or otherwise disclosed without prior written authorization 
from 
 Achieve Life Sciences, Inc. 
 
 
16.1.9 - page 2


Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
 
 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
l. 
SIGNATURE PAGES 
1.1. 
Clinical Pharmacology Unit's Representatives 
 
 
 
 
 
 
 
...
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
16.1.9 - page 3


Protocol: ACH-CYT-08 
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Date: 09OCT2019 
1.2. 
Sponsor's Representatives 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
Date 
l..4?.~9.~~}- Zbl 9 
Date 
Date 
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Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
 
Cyllslne (Fasting) 
EudraCT No: 2018-003344-22 
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Sponsor's Representatives 
Date 
 
.. l.'1.M~~11 
Date 
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1.1. 
CLINICAL PHARMACOLOGY UNIT’S REPRESENTATIVES .......................................................................... 2
1.2. 
SPONSOR’S REPRESENTATIVES ................................................................................................................... 3
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2.1. 
TABLE OF CONTENTS .................................................................................................................................... 4
2.2. 
LIST OF ABBREVIATIONS .............................................................................................................................. 6
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3.1. 
SUMMARY OF CHANGES FROM PROTOCOL OR ITS AMENDMENTS......................................................... 8
3.2. 
REPORTING AND DELIVERABLES ................................................................................................................ 8
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4.1. 
PRIMARY ......................................................................................................................................................... 8
4.2. 
SECONDARY .................................................................................................................................................... 8
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5.1. 
STUDY DESIGN ............................................................................................................................................... 9
5.2. 
NUMBER OF SUBJECTS .................................................................................................................................. 9
5.3. 
NUMBER OF CLINICAL SITES ..................................................................................................................... 10
5.4. 
METHOD OF ASSIGNING SUBJECTS TO TREATMENTS ........................................................................... 10
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6.1. 
SAFETY VARIABLES ..................................................................................................................................... 10
6.2. 
PHARMACODYNAMIC VARIABLES ............................................................................................................. 12
6.3. 
PHARMACOKINETIC VARIABLES ............................................................................................................... 12
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7.1. 
DATA MANAGEMENT ................................................................................................................................. 12
7.2. 
ACCEPTANCE OF DATA .............................................................................................................................. 12
7.3. 
DATA TRANSFORMATION (CDISC) ........................................................................................................ 13
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8.1. 
ANALYSIS SETS ............................................................................................................................................ 14
 
Screening Analysis Set ..................................................................................................... 14
 
Safety Analysis Set ............................................................................................................. 14
 
Pharmacokinetic Analysis Set ...................................................................................... 14
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8.2. 
SUBJECT DISPOSITION ................................................................................................................................ 14
8.3. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................................................. 14
8.4. 
MEDICAL AND SMOKING HISTORY ........................................................................................................... 14
8.5. 
DOSING ......................................................................................................................................................... 15
8.6. 
PROTOCOL DEVIATIONS ............................................................................................................................ 15
8.7. 
SAFETY ASSESSMENTS ............................................................................................................................... 15
Adverse Events....................................................................................................................15
 
Laboratory Data ................................................................................................................ 16
 
Vital Signs ............................................................................................................................. 16
 
Electrocardiograms .......................................................................................................... 16
 
Physical Examinations .................................................................................................... 17
 
Previous and Concomitant Medications ................................................................... 17
8.8. 
PLASMA CONCENTRATIONS ...................................................................................................................... 17
8.9. 
PHARMACOKINETIC PARAMETERS ........................................................................................................... 17
8.10. 
DOSE-PROPORTIONALITY .......................................................................................................................... 18
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9.1.
STATISTICAL OUTPUT SPECIFICATION .................................................................................................... 18
 
In-text Tables and Figures ............................................................................................. 18
 
List of Subject Data Listings (Section 16.2 of CSR)............................................... 22
 
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Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 6 of 95 
 
 
2.2. 
List of Abbreviations 
 
ADAE 
Analysis Data Adverse Events 
ADaM 
Analysis Data Model 
ADEG 
Analysis Data Electrocardiogram 
ADaMIG 
Analysis Data Model Implementation Guide 
ADLB 
Analysis Data Laboratory 
ADPC 
Analysis Data Pharmacokinetic Concentrations 
ADPP 
Analysis Data Pharmacokinetic Parameters 
ADSL 
Analysis Dataset, Subject-Level 
ADVS 
Analysis Data Vital Signs 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
Amean 
Arithmetic mean 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Class 
BLQ 
Below the Limit of Quantification  
BMI 
Body Mass Index 
Cmax 
Maximum Observed Plasma Concentration 
CO 
Carbon Monoxide 
CPK 
Creatine Phosphokinase 
CR 
Clinically Relevant 
CrCL 
Creatinine Clearance 
CSR 
Clinical Study Report 
CV% 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DSM 
Data Safety Monitor 
ECG 
Electrocardiogram  
GGT 
Gamma-Glutamyltransferase 
GLP 
Good Laboratory Practice 
Gmean 
Geometric mean 
hCG 
Human Chorionic Gonadotropin 
HIV 
Human Immunodeficiency Virus 
INR 
International Normalized Ratio 
LC-MS/MS  
Liquid Chromatography with Tandem Mass Spectrometry 
LDH 
Lactate Dehydrogenase 
LLOQ 
Lower Limit of Quantification 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCR 
Not Clinically Relevant 
NMR 
Nicotine Metabolite Ratio 
PI  
Principal Investigator 
PT  
MedDRA Preferred Term 
RBC 
Red Blood Cell 
 
 
16.1.9 - page 8


 
Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 7 of 95 
 
 
RDW-CV 
Coefficient Variation of the Red Cell Distribution Width 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
MedDRA System Organ Class 
TEAE 
Treatment-Emergent Adverse Events 
TFLs 
Tables, figures and listings 
Tmax 
Time of Occurrence of Maximum Observed Plasma Concentration  
ULOQ 
Upper Limit of Quantification 
WBC 
White Blood Cell 
 
 
 
 
 
16.1.9 - page 9


 
Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 8 of 95 
 
 
3. 
INTRODUCTION 
 
This Statistical Analysis Plan (SAP) presents the details of the analysis and presentation 
of the safety and pharmacokinetic (PK) results for Clinical Study ACH-CYT-08. 
 
The analyses described are based on the Clinical Study Protocol (CSP) version 5.0, 
dated 07MAY2019 [1].  
 
This SAP will be finalized and approved by the Achieve Life Sciences (Achieve) and 
s representatives prior to the planned database lock and unblinding of 
study treatment assignment code. Any deviations from this SAP will be described in 
detail and justified in the Clinical Study Report (CSR). If additional analyses are 
required to complement the analyses planned in the SAP, they may be performed and 
will be identified in the Clinical Study Report (CSR). 
 
3.1. 
Summary of Changes from Protocol or Its Amendments 
 
There are no changes from the protocol or its amendments. 
 
3.2. 
Reporting and Deliverables 
 
The CSR will be written using the Achieve’s template. Tables, Figures and Listings 
(TFLs) will be prepared as described in the TFL shells within this SAP. In-text Tables 
and Figures will be included in the main body of the CSR. After review by the Sponsor, 
the TFLs will be finalized. 
 
Before performing the analysis, all data collected will be integrated into a common 
repository, using SAS 9.4 (SAS Institute Inc, Cary, NC, USA). Derived analysis 
datasets will be generated in accordance to CDISC. ADaM compliant datasets will be 
delivered to the Sponsor. 
 
 
4. 
STUDY OBJECTIVES 
 
4.1. 
Primary 
 
To assess the tolerability and safety of cytisine as a single oral dose. 
 
4.2. 
Secondary  
 
To define the Cmax levels associated to the occurrence of dose-limiting adverse events. 
 
 
 
 
 
 
16.1.9 - page 10


 
Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 9 of 95 
 
 
5. 
STUDY DESIGN OVERVIEW 
 
5.1. 
Study Design  
 
This was a single-center, double-blind, randomized, placebo-controlled, single dose-
escalation, Phase 1 clinical study conducted in male or female adults who were in good 
general health and were current daily cigarette smokers, under fasting conditions. 
 
Nine dose levels were pre-planned under version 5.0 of Protocol ACH-CYT-08: 6 mg, 
9 mg, 12 mg, 15 mg, 18 mg, 21 mg, 24 mg, 27 mg and 30 mg. The starting dose was 
6 mg cytisine (single oral dose) in Cohort 1. The study was escalated up to the cytisine 
dose of 30 mg in Cohort 9 without showing any of the predefined stopping criteria. 
Within each dose level, subjects were randomly assigned to receive a single oral dose of 
cytisine or placebo in a 3:1 ratio (6 cytisine:2 placebo).  
 
Upon completion of a cohort, a safety review was performed by the Principal 
Investigator (PI) and two independent Data Safety Monitors (DSMs) on unblinded data. 
The PI and DSMs conjointly decided whether dose escalation into the next cohort was 
to be allowed. 
 
Table 1 presents an overview of study design. 
 
Figure 1. Study Diagram: 
 
 
5.2. 
Number of Subjects 
 
The study protocol defined a sample size of 8 subjects per cohort, which is consistent 
with standard practice in early-phase clinical trials with similar study objectives.  
 
Considering that 9 cohorts were pre-planned, a total of 72 subjects was estimated for 
enrollment. 
 
Screening 
D-28to D-1 
Eligibility 
Evaluation 
 
 
Treatment Period in Each Cohort 
Admission 
Confinement 
D O 
D I 
D2 
I l l 
Eligibility Check 
Single-dose 
Discharge 
Administrntion 
Randomization 
6 cytisine : 2 placebo 
Adverse Events Monitoring 
I 
Follow-up 
D 5/ D6 
Escalation to 
Next Cohort 
Decision 
Safety Review 
16.1.9 - page 11


 
Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 10 of 95 
 
 
5.3. 
Number of Clinical Sites 
 
This was a single center clinical trial. 
 
5.4. 
Method of Assigning Subjects to Treatments 
 
Using SAS® 9.4, a computer-generated block-wise randomization list adequate for 
placebo-controlled studies was prepared by the Programming & Biostatistics 
Department of 
. At each cohort, 6 subjects were randomly assigned to 
receive cytisine and 2 subjects randomized to receive placebo. 
 
Upon confirmation that all eligibility criteria are met on Day 0, subjects were 
sequentially assigned a randomization number. The randomization number was 
provided to the unblinded Pharmacist on site and defined the treatment to which 
subjects were allocated (test or placebo) per the randomization list. 
 
 
6. 
STUDY VARIABLES 
 
6.1. 
Safety variables 
 
− 
Drug exposure 
− 
Adverse events:  
- 
Reported Term 
- 
MedDRA SOC coding 
- 
MedDRA PT coding 
- 
Start date 
- 
Start time 
- 
End date 
- 
End time 
- 
Seriousness 
- 
Severity:  
- 
Mild 
- 
Moderate  
- 
Severe 
- 
Relationship (causality):  
- 
not related 
- 
unlikely 
- 
possible 
- 
probable 
- 
definite 
- 
Action taken 
- 
Outcome 
− 
Clinical laboratory evaluations: 
- 
Biochemistry:  
- 
aspartate aminotransferase (AST) 
- 
alanine aminotransferase (ALT) 
 
 
16.1.9 - page 12


 
Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 11 of 95 
 
 
- 
gamma-glutamyltransferase (GGT)  
- 
lactate dehydrogenase (LDH) 
- 
alkaline phosphatase (ALP) 
- 
creatine phosphokinase (CPK) 
- 
creatinine 
- 
estimated creatinine clearance (CRCL) 
- 
urea 
- 
sodium 
- 
potassium 
- 
calcium 
- 
glucose 
- 
total cholesterol 
- 
triglycerides 
- 
albumin 
- 
total protein 
- 
uric acid 
- 
direct bilirubin 
- 
indirect bilirubin 
- 
total bilirubin 
- 
Hematology:  
- 
hemoglobin 
- 
hematocrit 
- 
hypochromic red blood cell 
- 
red blood cell (RBC) count 
- 
mean corpuscular volume (MCV) 
- 
mean corpuscular hemoglobin (MCH) 
- 
mean corpuscular hemoglobin concentration (MCHC) 
- 
coefficient variation of the red cell distribution width (RDW-CV) 
- 
total white blood cell (WBC) count 
- 
neutrophils 
- 
eosinophils 
- 
lymphocytes 
- 
monocytes 
- 
basophils 
- 
platelet count 
- 
Coagulation:  
- 
prothrombin rate 
- 
prothrombin time - international normalized ratio (INR) 
- 
activated partial thromboplastin time (aPTT) 
- 
Urinalysis:  
- 
pH 
- 
specific gravity 
- 
protein 
- 
hemoglobin 
- 
glucose 
- 
ketones 
- 
bilirubin 
- 
nitrites 
I 
 
16.1.9 - page 13


 
Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 12 of 95 
 
 
- 
urobilinogen 
- 
microscopy 
- 
Drugs of abuse test:  
- 
cannabinoids 
- 
opiates 
- 
cocaine 
- 
amphetamines 
- 
benzodiazepines 
- 
Serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test 
- 
Urine beta-hCG pregnancy test 
- 
Ethanol breath test 
− 
Vital signs: 
- 
Systolic blood pressure (SBP) 
- 
Diastolic blood pressure (DBP) 
- 
Pulse rate 
- 
Body temperature 
− 
Physical examination 
− 
12-lead Electrocardiogram (ECG) 
− 
CO 
 
6.2. 
Pharmacodynamic variables 
 
None. 
 
6.3. 
Pharmacokinetic Variables 
 
- 
Plasma concentrations of cytisine 
- 
Maximum observed plasma concentration post dose, directly obtained from 
the observed cytisine concentration versus time profile (Cmax) 
- 
Time of occurrence of Cmax (Tmax) 
 
 
7. 
DATA REVIEW / TRANSFORMATION 
 
7.1. 
Data Management 
 
Data handling will be conducted in accordance with the Clinical Data Management 
section of the CSP and the Data Management Plan developed by 
l for this 
study. 
 
7.2. 
Acceptance of Data 
 
TFLs may start being programmed prior to, or during, the course of the trial. However, 
the programming of analysis datasets (ADS) and TFLs will only be finished and 
quality-controlled after database soft lock and unblinding of the data. Only audited 
cytisine plasma concentration data released by the Bioanalytical Laboratory will be used 
 
 
16.1.9 - page 14


 
Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 13 of 95 
 
 
for programming the final pharmacokinetic ADS and TFLs.    
 
7.3. 
Data Transformation (CDISC) 
 
Before performing the statistical analysis, all data collected (multiple sources) will be 
integrated into a common repository, using SAS® 9.4.  
 
For standardization and regulatory submission purposes, all data will be transformed 
according to Clinical Data Interchange Standards Consortium (CDISC):  
− Study Data Tabulation Model (SDTM) version 1.4 or later; 
− Study Data Tabulation Model Implementation Guide (SDTMIG) version 3.2 or later; 
− The following analysis datasets will be generated (Analysis Data Model [ADaM] 
version 2.1; Analysis Data Model Implementation Guide [ADaMIG], version 1.1) to 
support the results and ease the programming activities during the statistical 
analysis:  
 
Subject-Level Analysis Dataset (ADSL) 
 
Analysis Data Adverse Events (ADAE) 
 
Analysis Data Electrocardiogram (ADEG) 
 
Analysis Data Vital Signs (ADVS) 
 
Analysis Data Laboratory (ADLB) 
 
Analysis Data Pharmacokinetic Concentrations (ADPC)  
 
Analysis Data Pharmacokinetic Parameters (ADPP)  
 
 
8. 
STATISTICAL METHODS 
 
The statistical analysis and TFLs will be done using SAS® for version 9.4. 
 
PK parameters for cytisine (Cmax and Tmax) will be estimated using non-compartmental 
analysis (NCA) in Phoenix® WinNonlin® version 8.1 (Pharsight Corp., Mountain View, 
CA). 
 
Summaries of demographics, baseline characteristics and safety endpoints will be 
provided for the Safety Analysis Set, defined as all subjects who received a single dose 
of cytisine or placebo.  
 
Unless otherwise indicated, numerical variables will be summarized using: number of 
observations (n), arithmetic mean, standard deviation, coefficient of variation (CV%), 
median and range (minimum and maximum). Categorical variables will be summarized 
with number of subjects and percentage within a treatment (dose level). Descriptive 
statistics will be presented with the same precision as the original data, i.e, the same 
number of decimals or significant digits. Tmax is stated with the same number of 
significant digits as the actual sampling time. Baseline for post-dose assessments is 
defined as the last observation recorded before dose. Summaries will be provided for 
each dose level/treatment (Placebo; 6.0 mg cytisine; 9.0 mg cytisine, etc.). Unless 
otherwise indicated, no statistical comparisons between the cohorts are planned.  
 
Unscheduled measurements will be listed in the individual data listings. With the 
 
 
16.1.9 - page 15


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Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 19 of 95 
 
 
 
In-text Tables 
Title 
Table A 
Study Flow-Chart (to be captured from the CSP) 
Table B 
Identity of Investigational Products 
Table C 
Treatment Assignment 
Table D 
Subjects Disposition 
Table E 
Major Protocol Deviations  
Table F.1 
Demographic Data – Safety Analysis Set 
Table F.2 
Smoking History – Safety Analysis Set  
Table F.3 
Baseline CO – Safety Analysis Set 
Table G.1 
Treatment Emergent Adverse Events – All Causalities 
Table G.2 
Treatment Emergent Adverse Events – Related 
Table H 
Cytisine: Cmax and Tmax Following Administration of Cytisine (6 
mg, 9 mg, 12 mg, 15 mg, 18 mg, 21 mg, 24 mg, 27 mg and 30 
mg) 
Table I 
Cytisine: Dose Proportionality of Cmax 
 
In-text Figures 
Legend 
Figure A 
Cytisine: Arithmetic Mean Plasma Concentration Versus Time 
Profile Following Administration of Cytisine (6 mg, 9 mg, 12 
mg, 15 mg, 18 mg, 21 mg, 24 mg, 27 mg and 30 mg) – Linear 
Scale. 
Figure B 
Cytisine: Arithmetic Mean Plasma Concentration Versus Time 
Profile Following Administration of Cytisine (6 mg, 9 mg, 12 
mg, 15 mg, 18 mg, 21 mg, 24 mg, 27 mg and 30 mg) – Semi-
Logarithmic Scale 
Figure C 
Cytisine: Dose Proportionality of Cmax 
Figure D 
Cytisine: Boxplots of Cmax as a Function of Dose 
 
 
End-of-Text 
Tables 
Title 
14.1 DEMOGRAPHIC DATA 
14.1.1 
Demographic Data – Safety Analysis Set 
14.1.2 
Smoking History – Safety Analysis Set (Part I) 
14.1.3 
Smoking History – Safety Analysis Set (Part II) 
14.1.4 
Smoking History – Expired CO at Screening 
14.1.5 
Medical History – Safety Analysis Set 
 
 
14.2 SAFETY DATA 
14.2.1 
Treatment Emergent Adverse Events  
14.2.1.1 
Adverse Events Leading to Discontinuation or Withdrawal 
14.2.1.2 
Listings of Serious Adverse Events 
14.2.1.3 
Summary of Treatment Emergent Adverse Events – All 
Causalities 
14.2.1.4 
Summary of Treatment Emergent Adverse Events - Related 
14.2.1.5 
Summary of Treatment Emergent Adverse Events by Severity – 
 
 
16.1.9 - page 21


 
Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 20 of 95 
 
 
All Causalities 
14.2.1.6 
Summary of Treatment Emergent Adverse Events by Severity – 
Related 
 
 
14.3 PHARMACOKINETIC DATA 
14.3.1 
Deviations from Blood Sampling Schedule 
14.3.1.1 
Deviations from Blood Sampling Schedule 
14.3.1.2 
Missing Blood Samples 
14.3.2 
Plasma Concentrations 
14.3.2.1 
Cytisine 6 mg: Individual Data and Descriptive Statistics of 
Plasma Concentrations 
14.3.2.2 
Cytisine 9 mg: Individual Data and Descriptive Statistics of 
Plasma Concentrations 
14.3.2.3 
Cytisine 12 mg: Individual Data and Descriptive Statistics of 
Plasma Concentrations 
14.3.2.4 
Cytisine 15 mg: Individual Data and Descriptive Statistics of 
Plasma Concentrations 
14.3.2.5 
Cytisine 18 mg: Individual Data and Descriptive Statistics of 
Plasma Concentrations 
14.3.2.6 
Cytisine 21 mg: Individual Data and Descriptive Statistics of 
Plasma Concentrations 
14.3.2.7 
Cytisine 24 mg: Individual Data and Descriptive Statistics of 
Plasma Concentrations 
14.3.2.8 
Cytisine 27 mg: Individual Data and Descriptive Statistics of 
Plasma Concentrations 
14.3.2.9 
Cytisine 30 mg: Individual Data and Descriptive Statistics of 
Plasma Concentrations 
14.3.3 
Pharmacokinetic Parameters  
14.3.3.1 
Cytisine 6 mg: Individual Data and Descriptive Statistics of 
Pharmacokinetic Parameters 
14.3.3.2 
Cytisine 9 mg: Individual Data and Descriptive Statistics of 
Pharmacokinetic Parameters 
14.3.3.3 
Cytisine 12 mg: Individual Data and Descriptive Statistics of 
Pharmacokinetic Parameters 
14.3.3.4 
Cytisine 15 mg: Individual Data and Descriptive Statistics of 
Pharmacokinetic Parameters 
14.3.3.5 
Cytisine 18 mg: Individual Data and Descriptive Statistics of 
Pharmacokinetic Parameters 
14.3.3.6 
Cytisine 21 mg: Individual Data and Descriptive Statistics of 
Pharmacokinetic Parameters 
14.3.3.7 
Cytisine 24 mg: Individual Data and Descriptive Statistics of 
Pharmacokinetic Parameters 
14.3.3.8 
Cytisine 27 mg: Individual Data and Descriptive Statistics of 
Pharmacokinetic Parameters 
14.3.3.9 
Cytisine 30 mg: Individual Data and Descriptive Statistics of 
Pharmacokinetic Parameters 
 
 
 
 
16.1.9 - page 22


 
Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
 
Page 21 of 95 
 
 
 
End-of-Text 
Figures 
Title 
14.3 PHARMACOKINETIC DATA 
14.3.4 
Cytisine Plasma Concentration-Time Profiles of All Subjects 
14.3.4.1 
Cytisine 6 mg: Plasma Concentration-Time Profiles of All 
Subjects 
14.3.4.2 
Cytisine 9 mg: Plasma Concentration-Time Profiles of All 
Subjects 
14.3.4.3 
Cytisine 12 mg: Plasma Concentration-Time Profiles of All 
Subjects 
14.3.4.4 
Cytisine 15 mg: Plasma Concentration-Time Profiles of All 
Subjects 
14.3.4.5 
Cytisine 18 mg: Plasma Concentration-Time Profiles of All 
Subjects 
14.3.4.6 
Cytisine 21 mg: Plasma Concentration-Time Profiles of All 
Subjects 
14.3.4.7 
Cytisine 24 mg: Plasma Concentration-Time Profiles of All 
Subjects 
14.3.4.8 
Cytisine 27 mg: Plasma Concentration-Time Profiles of All 
Subjects 
14.3.4.9 
Cytisine 30 mg: Plasma Concentration-Time Profiles of All 
Subjects 
 
 
14.3.5 
Cytisine Arithmetic Mean Plasma Concentration-Time 
Profiles 
14.3.5.1 
Cytisine 6 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Linear Scale 
14.3.5.2 
Cytisine 6 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Semi-Logarithmic Scale 
14.3.5.3 
Cytisine 9 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Linear Scale 
14.3.5.4 
Cytisine 9 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Semi-Logarithmic Scale 
14.3.5.5 
Cytisine 12 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Linear Scale 
14.3.5.6 
Cytisine 12 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Semi-Logarithmic Scale 
14.3.5.7 
Cytisine 15 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Linear Scale 
14.3.5.8 
Cytisine 15 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Semi-Logarithmic Scale 
14.3.5.9 
Cytisine 18 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Linear Scale 
14.3.5.10 
Cytisine 18 mg: Arithmetic Mean Plasma Concentration Versus 
Time Profile – Semi-Logarithmic Scale 
14.3.5.11 
Cytisine 21 mg: Arithmetic Mean Plasma Concentration Versus 
 
 
16.1.9 - page 23


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Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
Page 23 of 95 
16.2.5.7 
Non-Treatment-Emergent Adverse Events 
16.2.6 
Listing Laboratory Measurements by Subject 
16.2.6.1 
Normal Range of Laboratory Values 
16.2.6.2 
Hematology (Part I) 
16.2.6.3 
Hematology (Part II) 
16.2.6.4 
Biochemistry (Part I) 
16.2.6.5 
Biochemistry (Part II) 
16.2.6.6 
Biochemistry (Part III) 
16.2.6.7 
Coagulation 
16.2.6.8 
Urinalysis 
16.2.6.9 
Urine Microscopy 
16.2.6.10 
Pregnancy Test 
16.2.6.11 
Additional (Not Planned) Laboratory Safety Tests 
16.2.7 
Vital Signs 
16.2.7.1 
Vital Signs 
16.2.8 
12-Lead ECG 
16.2.8.1 
12-Lead ECG 
16.2.9 
Individual Pharmacokinetic Data 
16.2.9.1 
Individual Pharmacokinetic Data 
16.2.9.1.1 
Cytisine: Individual Drug Concentration Data 
16.2.9.1.2 
Cytisine: Individual Pharmacokinetic Parameters 
16.2.9.2 
Documentation of Non-Compartmental Analysis (NCA) 
16.2.9.3 
Cytisine: ACH-CYT-08 Phoenix NCA Output 
16.2.10 
Concomitant Medication 
16.2.10.1 
Concomitant Medication 
16.4 INDIVIDUAL SUBJECT DATA LISTINGS (US Archival Listings) 
10.
REFERENCES
[1] ACH-CYT-08 Clinical Study Protocol, Version 5.0, 07MAY2019. 
 
 
16.1.9 - page 25


Protocol: ACH-CYT-08 
Version: 2.0 
Date: 09OCT2019 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
Page 24 of 95 
11.
APPENDICES
 
 
16.1.9 - page 26


ACH-CYT-08 
TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
Page 25 of 95 
Table A. Study flow-chart 
Note: To be captured from the Clinical Study Protocol and Amendments. 
Table B. Identity of Investigational Products 
Note: To be generated by the MW. 
 
 
16.1.9 - page 27


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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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TFL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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TFL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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TFL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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TFL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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TFL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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TFL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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ACH-CYT-08 
TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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TFL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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I 
 
16.1.9 - page 37


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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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EudraCT No: 2018-003344-22 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
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EudraCT No: 2018-003344-22 
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EudraCT No: 2018-003344-22 
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EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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16.1.9 - page 54


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EudraCT No: 2018-003344-22 
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EudraCT No: 2018-003344-22 
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 2 
 
 
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EudraCT No: 2018-003344-22 
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EudraCT No: 2018-003344-22 
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EudraCT No: 2018-003344-22 
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EudraCT No: 2018-003344-22 
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EudraCT No: 2018-003344-22 
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EudraCT No: 2018-003344-22 
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ACH-CYT-08 
TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
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Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
 
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TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
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ACH-CYT-08 
TFL 
Date: ddMMMyyyy 
Cytisine (Fasting) 
EudraCT No: 2018-003344-22 
CONFIDENTIAL 
Page 95 of 95 
12.
ANNEXES
[1] Data Blind Review Process Minutes – 10OCT2019.
[2] List of Dosed Subjects.
 
 
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ACH-CYT-08 
Annex 2 
Annex 2: Data Blind Review Process Minute 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 1 of3 
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CONFIDENTIAL 
ACH-CYT-08 
Annex 2 
Page 2 of 3 
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ACH-CYT-08 
Annex 2 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 3 of 3 
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Subtitle: Deviations Log 
Study code: 
Last update: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pagelof14 
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Page3of14 
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0MS-PHl-011-001 
VersJon: 1.0 
Effective Date: 06APR2018 
Page4of14 
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0MS-PHl-011-001 
VersJon: 1.0 
Effective Date: 06APR2018 
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0MS-PHl-011-001 
VersJon: 1.0 
Effective Date: 06APR2018 
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0MS-PHl-011-001 
VersJon: 1.0 
Effective Date: 06APR2018 
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0MS-PHl-011-001 
VersJon:1.0 
Effective Date: 06APR2018 
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0MS-PHl-011-001 
VersJon:1.0 
Effective Date: 06APR2018 
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0MS-PHl-011-001 
VersJon:1.0 
Effective Date: 06APR2018 
PagelO of 14 
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0MS-PHl-011-001 
VersJon: 1.0 
Effective Date: 06APR2018 
Pagell of 14 
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l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0MS-PHl-011-001 
VersJon: 1.0 
Effective Date: 06APR2018 
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0MS-PHl-011-001 
VersJon: 1.0 
Effective Date: 06APR2018 
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Subtitle: Concomitant Medication 
Study code: 
Last update: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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