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A Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine in Healthy Smokers

Sponsor
Achieve Life Sciences (Industry)
Overall Status
Terminated
CT.gov ID
NCT03303911
Collaborator
(none)
26
Enrollment
1
Location
2
Arms
12
Actual Duration (Months)
2.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objectives of this study are:

  • To evaluate the pharmacokinetic (PK) parameters during repeat dosing of 1.5 mg or 3.0 mg cytisine when administered as the commercial 25-day schedule.

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

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
26 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Repeat-Dose Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine in Healthy Smokers
Actual Study Start Date :
Oct 6, 2017
Actual Primary Completion Date :
Oct 5, 2018
Actual Study Completion Date :
Oct 5, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cytisine 1.5 mg

Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)

Drug: Cytisine
film-coated tablets; depending on arm assignment, 1 or 2 tablets to be taken with 240 mL water for each dose
Other Names:
  • Tabex

    		•
    Experimental: Cytisine 3.0 mg

    Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)

    Drug: Cytisine
    film-coated tablets; depending on arm assignment, 1 or 2 tablets to be taken with 240 mL water for each dose
    Other Names:
  • Tabex

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Maximum Observed Plasma Concentration (Cmax) [after the first dose and the last dose on Day 1; after the last dose on Days 2, 3, 12, 16, 20, 24; and after the morning dose on Day 25]

    2. Time of Occurrence of Cmax (Tmax) [after the first dose and the last dose on Day 1; after the last dose on Days 2, 3, 12, 16, 20, 24; and after the morning dose on Day 25]

    3. Minimum Observed Plasma Concentration (Cmin) [after the first dose on Days 4, 13, 17, 21 and 25]

    4. Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to the Last Sampling Time (AUC0-t) [after the administration of the final dose of cytisine on Day 25]

    5. Total AUC From Time Zero to Infinity (AUC0-∞) [after the administration of the final dose of cytisine on Day 25]

    6. Residual Area or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (%AUC) [after the administration of the final dose of cytisine on Day 25]

    7. Apparent Terminal Elimination Rate Constant (λz) [after the administration of the final dose of cytisine on Day 25]

    8. Apparent Terminal Elimination Half-Life (t1/2) [after the administration of the final dose of cytisine on Day 25]

    9. Number of Cigarettes Smoked Daily During Treatment and at Day 26 [Day 1 through Day 26]

    10. Change From Baseline in Number of Cigarettes Smoked Daily up to Day 26 [Baseline, Day 1 through Day 26]

    11. Change From Baseline in Expired Air CO up to Day 26 [Baseline, Days 4, 13, 17, 21, 26]

    12. Number of Participants Who Ceased or Continued Smoking on Day 26 [Day 26]

      A status of "ceased smoking" is defined as not having smoked any cigarettes for the past 24 hours on Day 26 and having an expired CO level <10 ppm on Day 26.

    13. Change From Baseline Over Time in Urine Cotinine [Baseline, Days 4, 13, 17, 21, 26]

    14. Change From Baseline Over Time in TCQ-SF Score: Emotionality [Baseline (Day -1), Days 4, 13, 17, 21, 26]

      The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly disagree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Emotionality scores may range from 3 to 21, with lower scores indicating weaker emotional signs of tobacco craving.

    15. Change From Baseline Over Time in TCQ-SF Score: Expectancy [Baseline (Day -1), Days 4, 13, 17, 21, 26]

      The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly disagree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Expectancy scores may range from 3 to 21, with lower scores indicating less positive expectations about smoking.

    16. Change From Baseline Over Time in TCQ-SF Score: Compulsivity [Baseline (Day -1), Days 4, 13, 17, 21, 26]

      The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly agree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Compulsivity scores may range from 3 to 21, with lower scores indicating compulsion to smoke was a lesser component of tobacco craving.

    17. Change From Baseline Over Time in TCQ-SF Score: Purposefulness [Baseline (Day -1), Days 4, 13, 17, 21, 26]

      The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly disagree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Purposefulness scores may range from 3 to 21, with lower scores indicating stronger ability to not smoke.

    18. Change From Baseline Over Time in TCQ-SF Score: Total Score [Baseline (Day -1), Days 4, 13, 17, 21, 26]

      The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly disagree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Total scores may range from 12 to 84, with lower scores indicating lower tobacco craving.

    Secondary Outcome Measures

    1. Cytisine Amount Excreted in Urine Over Time (Ae0-24h) [Day 1 (6 times daily at 2-hour intervals); after the administration of the single dose of cytisine on Day 25]

    2. Percent of Drug Excreted in Urine (Ae%) [Day 1 (6 times daily at 2-hour intervals); after the administration of the single dose of cytisine on Day 25]

    3. Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to TEAEs [From first dose of study drug through Day 26 plus 6-8 days]

      An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) is defined as an AE that results in any of the following: results in death; is life-threatening; requires hospitalisation or prolongs existing inpatient's hospitalisation; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event which requires medical intervention to prevent any of the above outcomes.TEAEs are defined as AEs not present prior to first administration of investigational product, or AEs present before first administration of investigational product that worsen after the participant receives the first dose of investigational product.

    4. Number of Participants With Clinically Significant Values in Biochemistry, Hematology, and Urinalysis [up to Day 26]

    5. Number of Participants With Clinically Significant Values in Vital Signs and Physical Examinations [up to Day 26]

    6. Number of Participants With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Parameters [up to Day 26]

    7. Number of Participants With Holter ECG Outlier Values [on Day 1 and Day 25 at 30 and 15 minutes prior to the first dose and 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours post dose]

      Based on the mean of the triplicate recordings at each time point. Increase (↑)/decrease (↓) calculated from Baseline (BL), defined as the mean of all recordings taken prior to dosing on Day 1 (i.e. -30 minutes and -15 minutes). A participant with multiple occurrences of an event is counted only once per event.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Regular moderate cigarette smokers (minimum 10 cigarettes per day) who want to stop smoking.

    2. Urine cotinine >500 ng/mL.

    3. Expired air carbon monoxide (CO) > 11 parts per million (no cigarette 1 hour before test).

    4. Healthy males and females 18-65+ years of age.

    5. If a female subject of child bearing potential, a negative pregnancy test at screening and admission and willing to use an effective method of contraception (unless of non-childbearing potential or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from first dose until 3 months after last dose of cytisine.

    6. If a female subject of non-child bearing potential, a negative pregnancy test at screening and admission. For the purposes of this study, this is defined as the subject being amenorrheic for at least 12 consecutive months or at least 4 months post-surgical sterilisation (including bilateral fallopian tube ligation or bilateral oophorectomy with or without hysterectomy). Menopausal status will be confirmed by demonstrating at screening that levels of follicle stimulating hormone (FSH) fall within the respective pathology reference range. In the event a subject's menopause status has been clearly established (for example, the subject indicates she has been amenorrheic for 10 years), but FSH levels are not consistent with a post-menopausal condition, determination of subject eligibility will be at Investigator's discretion following consultation with the Sponsor.

    7. If a male subject, willing to use an effective method of contraception (unless anatomically sterile or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from first dose until 3 months after last dose of cytisine.

    8. Subject with no clinically significant abnormal serum biochemistry, haematology and urine examination values within 28 days before the first dose of cytisine.

    9. Subject with negative urinary drugs of abuse screen, determined within 28 days before the first dose of cytisine (a positive alcohol result may be repeated at Investigator's discretion).

    10. Subject with negative human immunodeficiency virus (HIV), hepatitis B surface antigen (Hep B) and hepatitis C virus antibody (Hep C) results.

    11. Subject with no clinically significant abnormalities in 12-lead ECG determined after minimum of 5 minutes in supine position within 28 days before the first dose of cytisine.

    12. Subject with no clinically significant abnormalities in vital signs (systolic blood pressure between 90-150 mmHg (age 18-65) and 90-160 mmHg (age >65), diastolic blood pressure (DBP) between 50 and 90 mmHg, and pulse rate (PR) between 40 110 bpm, measured on the dominant arm after minimum of 5 minutes in supine position) determined within 28 days before first dose of cytisine.

    13. Subject must be available to complete the study (including in-clinic stays and post study follow-up) and comply with study restrictions.

    14. Subject must provide written informed consent to participate in the study.

    Exclusion Criteria:

    1. Treatment with smoking cessation medications (bupropion, varenicline, any nicotine replacement therapy) within 8 weeks of first dose of cytisine.

    2. Use of other forms of nicotine (e-cigarettes, smokeless tobacco) within 8 weeks of first dose of cytisine or are planning to use these products during study.

    3. Known hypersensitivity/allergy reaction to varenicline, other cytisine-derivatives or any of the excipients in the Tabex formulation.

    4. History of severe hypersensitivity reactions to any other drugs.

    5. Current treatment with antihypertensive medicinal products, statins, tuberculostatics, cholinomimetics or anticholinesterase medicinal products.

    6. History of any medical condition (e.g. gastrointestinal, renal or hepatic) or surgical condition (e.g. cholecystectomy, gastrectomy) that may affect drug pharmacokinetics (absorption, distribution, metabolism or excretion).

    7. Female subjects who are breast feeding.

    8. Difficulty in donating blood on either arm or known history.

    9. History of alcoholism or drug abuse within last 2 years.

    10. Use of non-prescription drugs, including vitamins, herbal and dietary supplements within 14 days (or 5 half-lives, whichever is longer) prior to the first dose of cytisine, unless in the opinion of the Principal Investigator the medication will not interfere with the study procedures or compromise subject safety.

    11. Participated in any investigational drug clinical trial within the previous 3 months or a marketed drug trial within the previous 30 days prior to randomisation on Day 1.

    12. Donation of 450 mL or more blood or had history of significant blood loss due to any reason or had plasmapheresis within 3 months before the first dose of cytisine.

    13. Inability to communicate well with Principal Investigator or designees (i.e., language problem, poor mental development or impaired cerebral function).

    14. Any other condition that the Principal Investigator considers making the subject unsuitable for this study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Simbec Research Ltd Cardiff United Kingdom CF11 9AB

    Sponsors and Collaborators

    • Achieve Life Sciences

    Investigators

    • Principal Investigator: Annelize Koch, MD, Simbec Research Ltd (Simbec)

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Achieve Life Sciences
    ClinicalTrials.gov Identifier:
    NCT03303911
    Other Study ID Numbers:
    • ACH-CYT-02
    First Posted:
    Oct 6, 2017
    Last Update Posted:
    Oct 21, 2019
    Last Verified:
    Oct 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Period Title: Overall Study
    STARTED 13 13
    COMPLETED 13 13
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg Total
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Total of all reporting groups
    Overall Participants 13 13 26
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    12
    92.3%
    12
    92.3%
    24
    92.3%
    >=65 years
    1
    7.7%
    1
    7.7%
    2
    7.7%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    37.0
    (12.87)
    40.9
    (12.94)
    39.0
    (12.80)
    Sex: Female, Male (Count of Participants)
    Female
    4
    30.8%
    5
    38.5%
    9
    34.6%
    Male
    9
    69.2%
    8
    61.5%
    17
    65.4%
    Race/Ethnicity, Customized (Count of Participants)
    White
    13
    100%
    12
    92.3%
    25
    96.2%
    Other, Not Specified
    0
    0%
    1
    7.7%
    1
    3.8%
    Expired Carbon Monoxide (CO) at Screening (ppm) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ppm]
    21.0
    (8.02)
    20.7
    (6.76)
    20.8
    (7.27)
    Urine Cotinine at Screening (ng/mL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ng/mL]
    1661.0
    (502.57)
    1944.2
    (611.61)
    1802.6
    (567.13)
    Number of Cigarettes Smoked in the Past 24 hours on Day -1 (cigarettes) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cigarettes]
    16.31
    (3.401)
    18.08
    (5.171)
    17.19
    (4.382)
    Tobacco Craving Questionnaire - Short Form (TCQ-SF) Emotionality Score at Day -1 (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    10.9
    (5.25)
    11.7
    (5.28)
    11.3
    (5.18)
    TCQ-SF Expectancy Score at Day -1 (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    11.4
    (5.19)
    14.0
    (6.47)
    12.7
    (5.90)
    TCQ-SF Compulsivity Score at Day -1 (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    9.5
    (4.61)
    9.5
    (4.33)
    9.5
    (4.38)
    TCQ-SF Purposefulness Score at Day -1 (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    14.9
    (3.57)
    15.6
    (5.27)
    15.3
    (4.42)
    TCQ-SF Total Score at Day -1 (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    46.7
    (12.96)
    50.8
    (16.89)
    48.7
    (14.90)
    Fagerström Test for Nicotine Dependence Total Score at Day -1 (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    4.7
    (1.60)
    5.3
    (1.38)
    5.0
    (1.50)

    Outcome Measures

    1. Primary Outcome
    Title Maximum Observed Plasma Concentration (Cmax)
    Description
    Time Frame after the first dose and the last dose on Day 1; after the last dose on Days 2, 3, 12, 16, 20, 24; and after the morning dose on Day 25

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) Set: All randomized participants who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria. Participants with an assessment at given timepoint.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 1, first dose
    21.1
    (24.8)
    40.0
    (26.8)
    Day 1, last dose
    33.8
    (20.0)
    81.4
    (30.1)
    Day 2, last dose
    32.9
    (22.3)
    85.1
    (20.9)
    Day 3, last dose
    35.9
    (21.7)
    88.1
    (19.3)
    Day 12, last dose
    29.9
    (24.9)
    69.9
    (31.5)
    Day 16, last dose
    23.7
    (31.4)
    50.5
    (26.5)
    Day 20, last dose
    23.0
    (22.1)
    49.7
    (30.9)
    Day 24, last dose
    16.0
    (28.3)
    42.0
    (33.6)
    Day 25
    12.6
    (19.4)
    28.1
    (27.4)
    2. Primary Outcome
    Title Time of Occurrence of Cmax (Tmax)
    Description
    Time Frame after the first dose and the last dose on Day 1; after the last dose on Days 2, 3, 12, 16, 20, 24; and after the morning dose on Day 25

    Outcome Measure Data

    Analysis Population Description
    PK Set: All randomized participants who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria. Participants with an assessment at given time point.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 1, first dose
    0.500
    0.750
    Day 1, last dose
    1.00
    1.00
    Day 2, last dose
    1.00
    1.00
    Day 3, last dose
    1.00
    1.00
    Day 12, last dose
    1.00
    1.02
    Day 16, last dose
    2.50
    2.00
    Day 20, last dose
    1.50
    1.00
    Day 24, last dose
    2.00
    1.00
    Day 25
    2.50
    2.25
    3. Primary Outcome
    Title Minimum Observed Plasma Concentration (Cmin)
    Description
    Time Frame after the first dose on Days 4, 13, 17, 21 and 25

    Outcome Measure Data

    Analysis Population Description
    PK Set: All randomized participants who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria. Participants with an assessment at given timepoint.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 4, first dose
    5.36
    (47.7)
    13.2
    (27.4)
    Day 13, first dose
    5.16
    (48.2)
    12.6
    (33.0)
    Day 17, first dose
    4.19
    (64.7)
    8.50
    (38.3)
    Day 21, first dose
    3.13
    (83.4)
    6.34
    (39.0)
    Day 25
    3.16
    (188.9)
    3.74
    (42.4)
    4. Primary Outcome
    Title Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to the Last Sampling Time (AUC0-t)
    Description
    Time Frame after the administration of the final dose of cytisine on Day 25

    Outcome Measure Data

    Analysis Population Description
    PK Set: All randomized participants who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria. Participants with an assessment.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 12 13
    Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]
    67.0
    (27.4)
    185
    (32.3)
    5. Primary Outcome
    Title Total AUC From Time Zero to Infinity (AUC0-∞)
    Description
    Time Frame after the administration of the final dose of cytisine on Day 25

    Outcome Measure Data

    Analysis Population Description
    PK Set: All randomized participants who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria. Participants with an assessment.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 12 13
    Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]
    82.6
    (30.4)
    213
    (28.0)
    6. Primary Outcome
    Title Residual Area or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (%AUC)
    Description
    Time Frame after the administration of the final dose of cytisine on Day 25

    Outcome Measure Data

    Analysis Population Description
    PK Set: All randomized participants who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria. Participants with an assessment.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 12 13
    Geometric Mean (Geometric Coefficient of Variation) [percentage of extrapolated part]
    18.0
    (28.9)
    11.7
    (40.1)
    7. Primary Outcome
    Title Apparent Terminal Elimination Rate Constant (λz)
    Description
    Time Frame after the administration of the final dose of cytisine on Day 25

    Outcome Measure Data

    Analysis Population Description
    PK Set: All randomized participants who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria. Participants with an assessment.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 12 13
    Geometric Mean (Geometric Coefficient of Variation) [1/hour]
    0.185
    (26.4)
    0.152
    (16.9)
    8. Primary Outcome
    Title Apparent Terminal Elimination Half-Life (t1/2)
    Description
    Time Frame after the administration of the final dose of cytisine on Day 25

    Outcome Measure Data

    Analysis Population Description
    PK Set: All randomized participants who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria. Participants with an assessment.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 12 13
    Mean (Standard Deviation) [hours]
    3.75
    (24.7)
    4.57
    (17.2)
    9. Primary Outcome
    Title Number of Cigarettes Smoked Daily During Treatment and at Day 26
    Description
    Time Frame Day 1 through Day 26

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamic (PD) Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation. Participants with a valid assessment at given time point.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day -1
    16.31
    (3.401)
    18.08
    (5.171)
    Day 1
    7.31
    (6.088)
    8.77
    (6.882)
    Day 2
    3.69
    (1.437)
    4.08
    (1.801)
    Day 3
    4.00
    (1.673)
    4.46
    (1.854)
    Day 4
    4.77
    (2.682)
    6.15
    (3.555)
    Day 5
    4.08
    (2.629)
    5.69
    (3.568)
    Day 6
    4.85
    (3.826)
    7.00
    (4.778)
    Day 7
    4.19
    (4.018)
    4.85
    (4.180)
    Day 8
    4.15
    (3.760)
    5.38
    (4.073)
    Day 9
    4.77
    (4.438)
    5.08
    (4.555)
    Day 10
    4.62
    (4.234)
    4.54
    (4.557)
    Day 11
    3.81
    (3.497)
    4.62
    (4.292)
    Day 12
    3.31
    (3.545)
    3.69
    (3.637)
    Day 13
    4.15
    (4.038)
    5.00
    (4.163)
    Day 14
    4.00
    (3.786)
    3.69
    (4.535)
    Day 15
    4.23
    (3.876)
    3.62
    (4.331)
    Day 16
    3.85
    (3.648)
    3.08
    (3.451)
    Day 17
    4.00
    (4.163)
    3.77
    (4.781)
    Day 18
    3.69
    (3.903)
    3.92
    (4.873)
    Day 19
    3.69
    (3.881)
    3.54
    (4.789)
    Day 20
    3.25
    (3.671)
    2.58
    (3.528)
    Day 21
    4.54
    (4.719)
    2.92
    (4.462)
    Day 22
    4.00
    (4.163)
    3.00
    (3.958)
    Day 23
    4.38
    (4.407)
    2.69
    (4.151)
    Day 24
    3.08
    (2.985)
    2.38
    (3.042)
    Day 25
    1.17
    (1.467)
    0.85
    (1.214)
    Day 26
    4.23
    (4.206)
    3.00
    (4.778)
    10. Primary Outcome
    Title Change From Baseline in Number of Cigarettes Smoked Daily up to Day 26
    Description
    Time Frame Baseline, Day 1 through Day 26

    Outcome Measure Data

    Analysis Population Description
    PD Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation. Participants with a valid assessment at given time point.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 1
    -9.00
    (5.745)
    -9.31
    (7.169)
    Day 2
    -12.62
    (3.664)
    -14.00
    (5.000)
    Day 3
    -11.91
    (3.885)
    -13.62
    (5.723)
    Day 4
    -11.54
    (4.737)
    -11.92
    (6.144)
    Day 5
    -12.23
    (4.475)
    -12.38
    (5.665)
    Day 6
    -11.46
    (4.371)
    -11.08
    (7.005)
    Day 7
    -12.12
    (4.718)
    -13.23
    (5.388)
    Day 8
    -12.15
    (4.580)
    -12.69
    (5.391)
    Day 9
    -11.54
    (5.333)
    -13.00
    (5.845)
    Day 10
    -11.69
    (4.697)
    -13.54
    (5.425)
    Day 11
    -12.50
    (4.173)
    -13.46
    (4.789)
    Day 12
    -13.00
    (4.813)
    -14.38
    (4.992)
    Day 13
    -12.15
    (4.543)
    -13.08
    (6.873)
    Day 14
    -12.31
    (4.309)
    -14.38
    (6.185)
    Day 15
    -12.08
    (4.212)
    -14.46
    (5.592)
    Day 16
    -12.46
    (3.597)
    -15.00
    (5.083)
    Day 17
    -12.31
    (4.768)
    -14.31
    (5.721)
    Day 18
    -12.62
    (4.753)
    -14.15
    (6.012)
    Day 19
    -12.62
    (4.556)
    -14.54
    (5.577)
    Day 20
    -13.17
    (3.810)
    -15.83
    (4.569)
    Day 21
    -11.77
    (5.262)
    -15.15
    (5.535)
    Day 22
    -12.31
    (4.404)
    -15.08
    (5.251)
    Day 23
    -11.92
    (4.873)
    -15.38
    (5.091)
    Day 24
    -13.23
    (4.419)
    -15.69
    (4.461)
    Day 25
    -14.83
    (3.407)
    -17.23
    (4.850)
    Day 26
    -12.08
    (4.645)
    -15.08
    (4.387)
    11. Primary Outcome
    Title Change From Baseline in Expired Air CO up to Day 26
    Description
    Time Frame Baseline, Days 4, 13, 17, 21, 26

    Outcome Measure Data

    Analysis Population Description
    PD Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation in a way that may have invalidated or biased the PD results.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 4
    -13.2
    (8.34)
    -13.8
    (7.03)
    Day 13
    -15.3
    (8.02)
    -15.9
    (6.84)
    Day 17
    -16.0
    (7.93)
    -16.2
    (5.81)
    Day 21
    -16.4
    (7.79)
    -16.5
    (6.08)
    Day 26
    -17.2
    (8.33)
    -17.9
    (6.75)
    12. Primary Outcome
    Title Number of Participants Who Ceased or Continued Smoking on Day 26
    Description A status of "ceased smoking" is defined as not having smoked any cigarettes for the past 24 hours on Day 26 and having an expired CO level <10 ppm on Day 26.
    Time Frame Day 26

    Outcome Measure Data

    Analysis Population Description
    PD Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation in a way that may have invalidated or biased the PD results.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Ceased Smoking
    5
    38.5%
    7
    53.8%
    Continued Smoking
    8
    61.5%
    6
    46.2%
    13. Primary Outcome
    Title Change From Baseline Over Time in Urine Cotinine
    Description
    Time Frame Baseline, Days 4, 13, 17, 21, 26

    Outcome Measure Data

    Analysis Population Description
    PD Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation in a way that may have invalidated or biased the PD results.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 4
    -1040.8
    (579.78)
    -1339.2
    (550.74)
    Day 13
    -1010.0
    (797.78)
    -1309.3
    (761.77)
    Day 17
    -1012.1
    (710.39)
    -1405.2
    (814.08)
    Day 21
    -1095.1
    (679.81)
    -1446.3
    (828.68)
    Day 26
    -1362.2
    (545.84)
    -1640.2
    (688.84)
    14. Primary Outcome
    Title Change From Baseline Over Time in TCQ-SF Score: Emotionality
    Description The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly disagree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Emotionality scores may range from 3 to 21, with lower scores indicating weaker emotional signs of tobacco craving.
    Time Frame Baseline (Day -1), Days 4, 13, 17, 21, 26

    Outcome Measure Data

    Analysis Population Description
    PD Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation in a way that may have invalidated or biased the PD results.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 4
    -5.2
    (5.40)
    -6.0
    (5.03)
    Day 13
    -4.9
    (5.96)
    -7.2
    (4.88)
    Day 17
    -5.8
    (6.12)
    -7.3
    (5.06)
    Day 21
    -5.8
    (6.38)
    -7.6
    (5.09)
    Day 26
    -5.7
    (7.00)
    -8.2
    (4.98)
    15. Primary Outcome
    Title Change From Baseline Over Time in TCQ-SF Score: Expectancy
    Description The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly disagree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Expectancy scores may range from 3 to 21, with lower scores indicating less positive expectations about smoking.
    Time Frame Baseline (Day -1), Days 4, 13, 17, 21, 26

    Outcome Measure Data

    Analysis Population Description
    PD Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation in a way that may have invalidated or biased the PD results. Participants with an assessment at given time point.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 4
    -3.8
    (5.89)
    -8.0
    (6.00)
    Day 13
    -3.5
    (7.83)
    -8.4
    (5.91)
    Day 17
    -4.7
    (6.96)
    -8.8
    (5.82)
    Day 21
    -5.2
    (6.56)
    -9.2
    (5.75)
    Day 26
    -6.2
    (6.40)
    -9.8
    (6.15)
    16. Primary Outcome
    Title Change From Baseline Over Time in TCQ-SF Score: Compulsivity
    Description The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly agree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Compulsivity scores may range from 3 to 21, with lower scores indicating compulsion to smoke was a lesser component of tobacco craving.
    Time Frame Baseline (Day -1), Days 4, 13, 17, 21, 26

    Outcome Measure Data

    Analysis Population Description
    PD Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation in a way that may have invalidated or biased the PD results.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 4
    -3.2
    (3.18)
    -3.5
    (4.74)
    Day 13
    -3.7
    (6.56)
    -4.9
    (4.77)
    Day 17
    -4.4
    (6.32)
    -5.2
    (4.44)
    Day 21
    -4.4
    (5.49)
    -5.3
    (4.82)
    Day 26
    -4.3
    (5.94)
    -5.8
    (4.59)
    17. Primary Outcome
    Title Change From Baseline Over Time in TCQ-SF Score: Purposefulness
    Description The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly disagree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Purposefulness scores may range from 3 to 21, with lower scores indicating stronger ability to not smoke.
    Time Frame Baseline (Day -1), Days 4, 13, 17, 21, 26

    Outcome Measure Data

    Analysis Population Description
    PD Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation in a way that may have invalidated or biased the PD results.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 4
    -6.5
    (2.93)
    -7.5
    (4.99)
    Day 13
    -6.6
    (6.34)
    -9.1
    (5.45)
    Day 17
    -7.6
    (6.33)
    -9.2
    (6.09)
    Day 21
    -7.8
    (6.48)
    -10.3
    (5.65)
    Day 26
    -9.0
    (5.15)
    -11.1
    (5.54)
    18. Primary Outcome
    Title Change From Baseline Over Time in TCQ-SF Score: Total Score
    Description The TCQ-SF is a 12-item questionnaire that assesses 4 components of tobacco craving: emotionality (3 items), expectancy (3 items), compulsivity (3 items) and purposefulness (3 items). Responses to each item are scored from 1 (strongly disagree) through 7 (strongly disagree). Component scores are defined as the sum of the scores within each component. The total score is defined as the sum of the 4 component scores. Total scores may range from 12 to 84, with lower scores indicating lower tobacco craving.
    Time Frame Baseline (Day -1), Days 4, 13, 17, 21, 26

    Outcome Measure Data

    Analysis Population Description
    PD Set: All participants in the PK set who had an available baseline result and at least 1 on-treatment result with regards to urine cotinine, expired air CO or daily cigarette consumption and did not incur a major protocol deviation in a way that may have invalidated or biased the PD results. Participants with an assessment at given time point.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 4
    -18.7
    (12.88)
    -26.0
    (16.06)
    Day 13
    -18.7
    (22.11)
    -29.6
    (16.58)
    Day 17
    -22.5
    (22.17)
    -30.5
    (16.51)
    Day 21
    -23.2
    (21.79)
    -32.5
    (16.62)
    Day 26
    -25.2
    (20.55)
    -34.8
    (16.85)
    19. Secondary Outcome
    Title Cytisine Amount Excreted in Urine Over Time (Ae0-24h)
    Description
    Time Frame Day 1 (6 times daily at 2-hour intervals); after the administration of the single dose of cytisine on Day 25

    Outcome Measure Data

    Analysis Population Description
    PK Set: All randomized subjects who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 1
    7.95
    (14.3)
    16.5
    (12.0)
    Day 25
    1.54
    (17.4)
    3.14
    (12.6)
    20. Secondary Outcome
    Title Percent of Drug Excreted in Urine (Ae%)
    Description
    Time Frame Day 1 (6 times daily at 2-hour intervals); after the administration of the single dose of cytisine on Day 25

    Outcome Measure Data

    Analysis Population Description
    PK Set: All randomized subjects who completed all cytisine dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 1
    88.3
    (14.3)
    91.6
    (12.0)
    Day 25
    102
    (17.4)
    105
    (12.5)
    21. Secondary Outcome
    Title Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to TEAEs
    Description An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) is defined as an AE that results in any of the following: results in death; is life-threatening; requires hospitalisation or prolongs existing inpatient's hospitalisation; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event which requires medical intervention to prevent any of the above outcomes.TEAEs are defined as AEs not present prior to first administration of investigational product, or AEs present before first administration of investigational product that worsen after the participant receives the first dose of investigational product.
    Time Frame From first dose of study drug through Day 26 plus 6-8 days

    Outcome Measure Data

    Analysis Population Description
    Safety Set: all randomized participants who received at least one dose of cytisine.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    TEAEs
    9
    69.2%
    9
    69.2%
    Serious TEAEs
    0
    0%
    0
    0%
    Discontinuation of Study Drug due to TEAE
    0
    0%
    0
    0%
    22. Secondary Outcome
    Title Number of Participants With Clinically Significant Values in Biochemistry, Hematology, and Urinalysis
    Description
    Time Frame up to Day 26

    Outcome Measure Data

    Analysis Population Description
    Safety Set: all randomized participants who received at least one dose of cytisine.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Biochemistry
    0
    0%
    0
    0%
    Hematology
    0
    0%
    0
    0%
    Urinalysis
    0
    0%
    0
    0%
    23. Secondary Outcome
    Title Number of Participants With Clinically Significant Values in Vital Signs and Physical Examinations
    Description
    Time Frame up to Day 26

    Outcome Measure Data

    Analysis Population Description
    Safety Set: all randomized participants who received at least one dose of cytisine.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Vital Signs
    0
    0%
    0
    0%
    Physical Examinations
    0
    0%
    0
    0%
    24. Secondary Outcome
    Title Number of Participants With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Parameters
    Description
    Time Frame up to Day 26

    Outcome Measure Data

    Analysis Population Description
    ECG Set: all participants who received at least 1 dose of cytisine, with at least 1 available baseline ECG and at least 1 on-treatment ECG.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Count of Participants [Participants]
    0
    0%
    0
    0%
    25. Secondary Outcome
    Title Number of Participants With Holter ECG Outlier Values
    Description Based on the mean of the triplicate recordings at each time point. Increase (↑)/decrease (↓) calculated from Baseline (BL), defined as the mean of all recordings taken prior to dosing on Day 1 (i.e. -30 minutes and -15 minutes). A participant with multiple occurrences of an event is counted only once per event.
    Time Frame on Day 1 and Day 25 at 30 and 15 minutes prior to the first dose and 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours post dose

    Outcome Measure Data

    Analysis Population Description
    ECG Set: all participants who received at least 1 dose of cytisine, with at least 1 available baseline ECG and at least 1 on-treatment ECG.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    Measure Participants 13 13
    Day 1: Heart Rate <50 bpm & ↓ ≥ 25%
    0
    0%
    0
    0%
    Day 1: Heart Rate >100 bpm & ↑ ≥25%
    1
    7.7%
    0
    0%
    Day 1: PR Interval >200 mSec & ↑ ≥25%
    0
    0%
    0
    0%
    Day 1: QRS Duration >100 mSec & ↑ ≥25%
    0
    0%
    0
    0%
    Day 1: QT Interval >500 mSec & BL ≤500 mSec
    0
    0%
    0
    0%
    Day 1: QTcF Interval >500 mSec & BL ≤500 mSec
    0
    0%
    0
    0%
    Day 1: QTcF Interval >480 mSec & BL ≤480 mSec
    0
    0%
    0
    0%
    Day 1: QTcF Interval >450 mSec & BL ≤450 mSec
    0
    0%
    1
    7.7%
    Day 25: Heart Rate <50 bpm & ↓ ≥ 25%
    0
    0%
    0
    0%
    Day 25: Heart Rate >100 bpm & ↑ ≥25%
    1
    7.7%
    0
    0%
    Day 25: PR Interval >200 mSec & ↑ ≥25%
    0
    0%
    0
    0%
    Day 25: QRS Duration >100 mSec & ↑ ≥25%
    0
    0%
    1
    7.7%
    Day 25: QT Interval >500 mSec & BL ≤500 mSec
    0
    0%
    0
    0%
    Day 25: QTcF Interval >500 mSec & BL ≤500 mSec
    0
    0%
    0
    0%
    Day 25: QTcF Interval >480 mSec & BL ≤480 mSec
    0
    0%
    0
    0%
    Day 25: QTcF Interval >450 mSec & BL ≤450 mSec
    0
    0%
    0
    0%

    Adverse Events

    Time Frame From first dose of study drug through Day 26 plus 6-8 days
    Adverse Event Reporting Description TEAEs are presented. TEAEs are defined as AEs not present prior to first administration of investigational product, or AEs present before first administration of investigational product that worsen after the participant receives the first dose of investigational product.
    Arm/Group Title Cytisine 1.5 mg Cytisine 3.0 mg
    Arm/Group Description Multiple doses of 1.5 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily) Multiple doses of 3.0 mg cytisine administered per 25-day schedule: Days 1-3 (6 times daily) Days 4-12 (5 times daily) Days 13-16 (4 times daily) Days 17-20 (3 times daily) Days 21-24 (2 times daily) Day 25 (Once daily)
    All Cause Mortality
    Cytisine 1.5 mg Cytisine 3.0 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/13 (0%) 0/13 (0%)
    Serious Adverse Events
    Cytisine 1.5 mg Cytisine 3.0 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/13 (0%) 0/13 (0%)
    Other (Not Including Serious) Adverse Events
    Cytisine 1.5 mg Cytisine 3.0 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/13 (69.2%) 9/13 (69.2%)
    Gastrointestinal disorders
    Abdominal pain upper 0/13 (0%) 1/13 (7.7%)
    Constipation 1/13 (7.7%) 1/13 (7.7%)
    Dyspepsia 0/13 (0%) 1/13 (7.7%)
    Flatulence 0/13 (0%) 1/13 (7.7%)
    Nausea 0/13 (0%) 2/13 (15.4%)
    Tooth loss 1/13 (7.7%) 0/13 (0%)
    Toothache 1/13 (7.7%) 1/13 (7.7%)
    General disorders
    Chest discomfort 0/13 (0%) 1/13 (7.7%)
    Medical device site reaction 1/13 (7.7%) 1/13 (7.7%)
    Peripheral swelling 0/13 (0%) 1/13 (7.7%)
    Infections and infestations
    Rhinitis 1/13 (7.7%) 0/13 (0%)
    Injury, poisoning and procedural complications
    Muscle strain 1/13 (7.7%) 0/13 (0%)
    Procedural pain 1/13 (7.7%) 0/13 (0%)
    Nervous system disorders
    Headache 4/13 (30.8%) 6/13 (46.2%)
    Vision blurred 0/13 (0%) 1/13 (7.7%)
    Psychiatric disorders
    Abnormal dreams 0/13 (0%) 1/13 (7.7%)
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain 1/13 (7.7%) 0/13 (0%)
    Sinonasal obstruction 1/13 (7.7%) 0/13 (0%)
    Skin and subcutaneous tissue disorders
    Rash pruritic 1/13 (7.7%) 0/13 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Principal Investigators are bound by requirements outlined in their individual clinical trial agreements with regard to publication of trial results.

    Results Point of Contact

    Name/Title Daniel Cain, Vice President, Clinical Research
    Organization Achieve Life Sciences
    Phone 425.686.1546
    Email dcain@achievelifesciences.com
    Responsible Party:
    Achieve Life Sciences
    ClinicalTrials.gov Identifier:
    NCT03303911
    Other Study ID Numbers:
    • ACH-CYT-02
    First Posted:
    Oct 6, 2017
    Last Update Posted:
    Oct 21, 2019
    Last Verified:
    Oct 1, 2019