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Clinical Trial Results:
Repeat-Dose Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine in Healthy Smokers

Summary
EudraCT number	2017-003257-42
Trial protocol	GB
Global end of trial date	05 Oct 2018

Results information
Results version number	v2(current)
This version publication date	03 Nov 2019
First version publication date	09 Oct 2019
Other versions	v1
Version creation reason	Correction of full data set correct typo to endpoint title

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ACH-CYT-02

ISRCTN number

US NCT number

NCT03303911

WHO universal trial number (UTN)

Sponsor organisation name

Achieve Life Sciences Inc

Sponsor organisation address

520 Pike Street Suite 2250, Seattle, United States, 98101

Public contact

Daniel Cain, Vice President, Clinical Research, Achieve Life Sciences Inc, 1 425.686.1546, dcain@achievelifesciences.com

Scientific contact

Daniel Cain, Vice President, Clinical Research, Achieve Life Sciences Inc, 1 425.686.1546, dcain@achievelifesciences.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

05 Oct 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Oct 2018

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objectives of this study were: • 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.

Protection of trial subjects

The informed consent forms used for the study comply with the Declaration of Helsinki and its updates and the International Conference on Harmonization (ICH) Guidelines and have been approved by the Sponsor and the Investigator’s IRB/EC/REB. The Investigator explained the nature of the study and the treatment in such a manner that the patient was aware of his/her rights and responsibilities, as well as potential benefits and risks. Patients were 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 was recorded in the patient’s medical record or a study/clinic chart. Patients, or their legally authorized representative, gave informed consent in writing prior to the performance of any protocol-specific procedure.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Oct 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 26

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Screening assessments were carried out within 28 days before first administration of cytisine. Eligible subjects were asked to return for the treatment period.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cytisine 1.5 mg

Arm 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)

Arm type

Experimental

Investigational medicinal product name

cytisine

Investigational medicinal product code

Other name

Tabex

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1 tablet to be taken with 240 mL water for each dose

Cytisine 3.0 mg

Arm description

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)

Arm type

Experimental

Investigational medicinal product name

cytisine

Investigational medicinal product code

Other name

Tabex

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 tablets to be taken with 240 mL water for each dose

Number of subjects in period 1	Cytisine 1.5 mg	Cytisine 3.0 mg
Started	13	13
Completed	13	13

Baseline characteristics

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Reporting group title

Cytisine 1.5 mg

Reporting group description

Reporting group title

Cytisine 3.0 mg

Reporting group description

Reporting group values	Cytisine 1.5 mg	Cytisine 3.0 mg	Total
Number of subjects	13	13	26
Age categorical
Units: Subjects
Adults (18-64 years)	12	12	24
From 65-84 years	1	1	2
Age continuous
Units: years
arithmetic mean (standard deviation)	37.0 ± 12.87	40.9 ± 12.94	-
Gender categorical
Units: Subjects
Female	4	5	9
Male	9	8	17
Race
Units: Subjects
White	13	12	25
Other, not specified	0	1	1
Expired Carbon Monoxide (CO) at Screening
Units: ppm
arithmetic mean (standard deviation)	21.0 ± 8.02	20.7 ± 6.76	-
Urine Cotinine at Screening
Units: ng/mL
arithmetic mean (standard deviation)	1661.0 ± 502.57	1944.2 ± 611.16	-
Number of Cigarettes Smoked in the Past 24 hours on Day -1
Units: cigarettes
arithmetic mean (standard deviation)	16.31 ± 3.401	18.08 ± 5.171	-
Tobacco Craving Questionnaire - Short Form (TCQSF) Emotionality Score at Day -1
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.
Units: score on a scale
arithmetic mean (standard deviation)	10.9 ± 5.25	11.7 ± 5.28	-
TCQ-SF Expectancy Score at Day -1
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.
Units: score on a scale
arithmetic mean (standard deviation)	11.4 ± 5.19	14.0 ± 6.47	-
TCQ-SF Compulsivity Score at Day -1
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.
Units: score on a scale
arithmetic mean (standard deviation)	9.5 ± 4.61	9.5 ± 4.33	-
TCQ-SF Purposefulness Score at Day -1
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.
Units: score on a scale
arithmetic mean (standard deviation)	14.9 ± 3.57	15.6 ± 5.27	-
TCQ-SF Total Score at Day -1
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.
Units: score on a scale
arithmetic mean (standard deviation)	46.7 ± 12.96	50.8 ± 16.89	-
Fagerström Test for Nicotine Dependence Total Score at Day -1
The Fagerström Nicotine Dependence Questionnaire (FTND) is a measure of nicotine dependence. The FTND total score is defined as the sum of the scores from 6 questions, provided all 6 questions have been completed. The FTND responses are assigned numerical values. Total Scores may range from 0 to 10, with lower scores indicating less dependence on nicotine.
Units: score on a scale
arithmetic mean (standard deviation)	4.7 ± 1.60	5.3 ± 1.38	-

End points

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Reporting group title

Cytisine 1.5 mg

Reporting group description

Reporting group title

Cytisine 3.0 mg

Reporting group description

Subject analysis set title

Pharmacokinetic Set: Cytisine 1.5 mg

Subject analysis set type

Full analysis

Subject analysis set description

All randomized subjects who completed all cytisine 1.5 mg dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria.

Subject analysis set title

Pharmacokinetic Set: Cytisine 3.0 mg

Subject analysis set type

Full analysis

Subject analysis set description

All randomized subjects who completed all cytisine 3.0 mg dosing on Days 1-3, completed >90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria.

Subject analysis set title

Pharmacodynamic Set: Cytisine 1.5 mg

Subject analysis set type

Full analysis

Subject analysis set description

All subjects in the Pharmacokinetic Set: Cytisine 1.5 mg 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.

Subject analysis set title

Pharmacodynamic Set: Cytisine 1.5 mg

Subject analysis set type

Full analysis

Subject analysis set description

All subjects in the Pharmacokinetic Set: Cytisine 3.0 mg 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.

Subject analysis set title

Safety Set: Cytisine 1.5 mg

Subject analysis set type

Safety analysis

Subject analysis set description

all randomized subjects who received at least one dose of 1.5 mg cytisine

Subject analysis set title

Safety Set: Cytisine 3.0 mg

Subject analysis set type

Safety analysis

Subject analysis set description

all randomized subjects who received at least one dose of 3.0 mg cytisine

Subject analysis set title

Electrocardiogram Set: Cytisine 1.5 mg

Subject analysis set type

Full analysis

Subject analysis set description

all subjects who received at least 1 dose of cytisine, with at least 1 available baseline electrocardiogram (ECG) and at least 1 on-treatment ECG

Subject analysis set title

Electrocardiogram Set: Cytisine 3.0 mg

Subject analysis set type

Full analysis

Subject analysis set description

all subjects who received at least 1 dose of cytisine, with at least 1 available baseline ECG and at least 1 on-treatment ECG

Primary: Maximum Observed Plasma Concentration (Cmax)

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End point title

Maximum Observed Plasma Concentration (Cmax) ^[1]

End point description

End point type

Primary

End point timeframe

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

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses (per protocol) are presented within the results data table.

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	13 ^[2]	13 ^[3]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day 1, first dose; n=13, 13	21.1 ± 24.8	40.0 ± 26.8
Day 1, last dose; n=13, 13	33.8 ± 20.0	81.4 ± 30.1
Day 2, last dose; n=13, 13	32.9 ± 22.3	85.1 ± 20.9
Day 3, last dose; n=13, 13	35.9 ± 21.7	88.1 ± 19.3
Day 12, last dose; n=13, 13	29.9 ± 24.9	69.9 ± 31.5
Day 16, last dose; n=13, 13	23.7 ± 31.4	50.5 ± 26.5
Day 20, first dose; n=12, 13	23.0 ± 22.1	49.7 ± 30.9
Day 24, first dose; n=12, 13	16.0 ± 28.3	42.0 ± 33.6
Day 25; n=12, 13	12.6 ± 19.4	28.1 ± 27.4

Notes
[2] - n=subjects with an assessment at given time point
[3] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Primary: Time of Occurrence of Cmax (Tmax)

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End point title

Time of Occurrence of Cmax (Tmax) ^[4]

End point description

End point type

Primary

End point timeframe

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

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses (per protocol) are presented within the results data table.

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	13 ^[5]	13 ^[6]
Units: hours
median (full range (min-max))
Day 1, first dose; n=13, 13	0.500 (0.500 to 0.750)	0.750 (0.500 to 1.00)
Day 1, last dose; n=13, 13	1.00 (0.00 to 2.50)	1.00 (0.00 to 2.50)
Day 2, last dose; n=13, 13	1.00 (0.00 to 3.50)	1.00 (0.00 to 3.50)
Day 3, last dose; n=13, 13	1.00 (0.500 to 3.00)	1.00 (0.00 to 2.03)
Day 12, last dose; n=13, 13	1.00 (0.00 to 3.05)	1.02 (0.00 to 2.00)
Day 16, last dose; n=13, 13	2.50 (0.00 to 4.02)	2.00 (1.00 to 6.50)
Day 20, last dose; n=12, 13	1.50 (1.00 to 5.50)	1.00 (0.00 to 6.50)
Day 24, last dose; n=12, 13	2.00 (1.00 to 4.00)	1.00 (1.00 to 3.00)
Day 25; n=12, 13	2.50 (0.500 to 5.00)	2.25 (0.500 to 3.75)

Notes
[5] - n=subjects with an assessment at given time point
[6] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Primary: Minimum Observed Plasma Concentration (Cmin)

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End point title

Minimum Observed Plasma Concentration (Cmin) ^[7]

End point description

End point type

Primary

End point timeframe

after the first dose on Days 4, 13, 17, 21 and 25

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses (per protocol) are presented within the results data table.

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	13 ^[8]	13 ^[9]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day 4, first dose; n=13, 13	5.36 ± 47.7	13.2 ± 27.4
Day 13, first dose; n=13, 13	5.16 ± 48.2	12.6 ± 33.0
Day 17, first dose; n=13, 13	4.19 ± 64.7	8.50 ± 38.3
Day 21, first dose; n=13, 13	3.13 ± 83.4	6.34 ± 39.0
Day 25; n=12, 13	3.16 ± 188.9	3.74 ± 42.4

Notes
[8] - n=subjects with an assessment at given time point
[9] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Primary: Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to the Last Sampling Time (AUC0-t)

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End point title

Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to the Last Sampling Time (AUC0-t) ^[10]

End point description

End point type

Primary

End point timeframe

after the administration of the final dose of cytisine on Day 25

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses (per protocol) are presented within the results data table.

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	12 ^[11]	13
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	67.0 ± 27.4	185 ± 32.3

Notes
[11] - subjects with an assessment

No statistical analyses for this end point

Primary: Total AUC From Time Zero to Infinity (AUC0-∞)

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End point title

Total AUC From Time Zero to Infinity (AUC0-∞) ^[12]

End point description

End point type

Primary

End point timeframe

after the administration of the final dose of cytisine on Day 25

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses (per protocol) are presented within the results data table.

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	12 ^[13]	13
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	82.6 ± 30.4	213 ± 28.0

Notes
[13] - subjects with an assessment

No statistical analyses for this end point

Primary: Residual Area or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (%AUC)

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End point title

Residual Area or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (%AUC) ^[14]

End point description

End point type

Primary

End point timeframe

after the administration of the final dose of cytisine on Day 25

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses (per protocol) are presented within the results data table.

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	12 ^[15]	13
Units: percentage of extrapolated part
geometric mean (geometric coefficient of variation)	18.0 ± 28.9	11.7 ± 40.1

Notes
[15] - subjects with an assessment

No statistical analyses for this end point

Primary: Apparent Terminal Elimination Rate Constant (λz)

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End point title

Apparent Terminal Elimination Rate Constant (λz) ^[16]

End point description

End point type

Primary

End point timeframe

after the administration of the final dose of cytisine on Day 25

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses (per protocol) are presented within the results data table.

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	12 ^[17]	13
Units: 1/hour
geometric mean (geometric coefficient of variation)	0.185 ± 26.4	0.152 ± 16.9

Notes
[17] - subjects with an assessment

No statistical analyses for this end point

Primary: Apparent Terminal Elimination Half-Life (t1/2)

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End point title

Apparent Terminal Elimination Half-Life (t1/2) ^[18]

End point description

End point type

Primary

End point timeframe

after the administration of the final dose of cytisine on Day 25

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses (per protocol) are presented within the results data table.

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	12 ^[19]	13
Units: hours
arithmetic mean (standard deviation)	3.75 ± 24.7	4.57 ± 17.2

Notes
[19] - subjects with an assessment

No statistical analyses for this end point

Primary: Number of Cigarettes Smoked Daily During Treatment and at Day 26

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End point title

Number of Cigarettes Smoked Daily During Treatment and at Day 26 ^[20]

End point description

End point type

Primary

End point timeframe

Day 1 through Day 26

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics are presented, per protocol.

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13 ^[21]	13 ^[22]
Units: cigarettes smoked in the past 24 hours
arithmetic mean (standard deviation)
Day -1; n=13, 13	16.31 ± 3.401	18.08 ± 5.171
Day 1; n=13, 13	7.31 ± 6.088	8.77 ± 6.882
Day 2; n=13, 13	3.69 ± 1.437	4.08 ± 1.801
Day 3; n=11, 13	4.00 ± 1.673	4.46 ± 1.854
Day 4; n=13, 13	4.77 ± 2.682	6.15 ± 3.555
Day 5; n=13, 13	4.08 ± 2.629	5.69 ± 3.568
Day 6; n=13, 13	4.85 ± 3.826	7.00 ± 4.778
Day 7; n=13, 13	4.19 ± 4.018	4.85 ± 4.180
Day 8; n=13, 13	4.15 ± 3.760	5.38 ± 4.073
Day 9; n=13, 13	4.77 ± 4.438	5.08 ± 4.555
Day 10; n=13, 13	4.62 ± 4.234	4.54 ± 4.557
Day 11; n=13, 13	3.81 ± 3.497	4.62 ± 4.292
Day 12; n=13, 13	3.31 ± 3.545	3.69 ± 3.637
Day 13; n=13, 13	4.15 ± 4.038	5.00 ± 4.163
Day 14; n=13, 13	4.00 ± 3.786	3.69 ± 4.535
Day 15; n=13, 13	4.23 ± 3.876	3.62 ± 4.331
Day 16; n=13, 13	3.85 ± 3.648	3.08 ± 3.451
Day 17; n=13, 13	4.00 ± 4.163	3.77 ± 4.781
Day 18; n=13, 13	3.69 ± 3.903	3.92 ± 4.873
Day 19; n=13, 13	3.69 ± 3.881	3.54 ± 4.789
Day 20; n=12, 13	3.25 ± 3.671	2.58 ± 3.528
Day 21; n=13, 13	4.54 ± 4.719	2.92 ± 4.462
Day 22; n=13, 13	4.00 ± 4.163	3.00 ± 3.958
Day 23; n=13, 13	4.38 ± 4.407	2.69 ± 4.151
Day 24; n=13, 13	3.08 ± 2.985	2.38 ± 3.042
Day 25; n=12, 13	1.17 ± 1.467	0.85 ± 1.214
Day 26; n=13, 13	4.23 ± 4.206	3.00 ± 4.778

Notes
[21] - n=subjects with a valid assessment at given time point
[22] - n=subjects with a valid assessment at given time point

No statistical analyses for this end point

Primary: Change From Baseline in Number of Cigarettes Smoked Daily up to Day 26

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End point title

Change From Baseline in Number of Cigarettes Smoked Daily up to Day 26 ^[23]

End point description

End point type

Primary

End point timeframe

Baseline, Day 1 through Day 26

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics are presented, per protocol.

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13 ^[24]	13 ^[25]
Units: cigarettes smoked in the past 24 hours
arithmetic mean (standard deviation)
Day 1; n=13, 13	-9.00 ± 5.745	-9.31 ± 7.169
Day 2; n=13, 13	-12.62 ± 3.664	-14.00 ± 5.000
Day 3; n=11, 13	-11.91 ± 3.885	-13.62 ± 5.723
Day 4; n=13, 13	-11.54 ± 4.737	-11.92 ± 6.144
Day 5; n=13, 13	-12.23 ± 4.475	-12.38 ± 5.665
Day 6; n=13, 13	-11.46 ± 4.371	-11.08 ± 7.005
Day 7; n=13, 13	-12.12 ± 4.718	-13.23 ± 5.388
Day 8; n=13, 13	-12.15 ± 4.580	-12.69 ± 5.391
Day 9; n=13, 13	-11.54 ± 5.333	-13.00 ± 5.845
Day 10; n=13, 13	-11.69 ± 4.697	-13.54 ± 5.425
Day 11; n=13, 13	-12.50 ± 4.173	-13.46 ± 4.789
Day 12; n=13, 13	-13.00 ± 4.813	-14.38 ± 4.992
Day 13; n=13, 13	-12.15 ± 4.543	-13.08 ± 6.873
Day 14; n=13, 13	-12.31 ± 4.309	-14.38 ± 6.185
Day 15; n=13, 13	-12.08 ± 4.212	-14.46 ± 5.592
Day 16; n=13, 13	-12.46 ± 3.597	-15.00 ± 5.083
Day 17; n=13, 13	-12.31 ± 4.768	-14.31 ± 5.721
Day 18; n=13, 13	-12.62 ± 4.753	-14.15 ± 6.012
Day 19; n=13, 13	-12.62 ± 4.556	-14.54 ± 5.577
Day 20; n=12, 12	-13.17 ± 3.810	-15.83 ± 4.569
Day 21; n=13, 13	-11.77 ± 5.262	-15.15 ± 5.535
Day 22; n=13, 13	-12.31 ± 4.404	-15.08 ± 5.251
Day 23; n=13, 13	-11.92 ± 4.873	-15.38 ± 5.091
Day 24; n=13, 13	-13.23 ± 4.419	-15.69 ± 4.461
Day 25; n=12, 13	-14.83 ± 3.407	-17.23 ± 4.850
Day 26; n=13, 13	-12.08 ± 4.645	-15.08 ± 4.387

Notes
[24] - n=subjects with a valid assessment at given time point
[25] - n=subjects with a valid assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline in Expired Air CO up to Day 26

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End point title

Change From Baseline in Expired Air CO up to Day 26

End point description

End point type

Secondary

End point timeframe

Baseline, Days 4, 13, 17, 21, 26

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13 ^[26]	13 ^[27]
Units: ppm
arithmetic mean (standard deviation)
Day 4; n=13, 13	-13.2 ± 8.34	-13.8 ± 7.03
Day 13; n=13, 12	-15.3 ± 8.02	-15.9 ± 6.84
Day 17; n=13, 13	-16.0 ± 7.93	-16.2 ± 5.81
Day 21; n=13, 13	-16.4 ± 7.79	-16.5 ± 6.08
Day 26; n=13, 13	-17.2 ± 8.33	-17.9 ± 6.75

Notes
[26] - n=subjects with an assessment at given time point
[27] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Number of Subjects Who Ceased or Continued Smoking on Day 26

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End point title

Number of Subjects Who Ceased or Continued Smoking on Day 26

End point 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.

End point type

Secondary

End point timeframe

Day 26

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13	13
Units: subjects
Ceased Smoking	5	7
Continued Smoking	8	6

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in Urine Cotinine

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End point title

Change From Baseline Over Time in Urine Cotinine

End point description

End point type

Secondary

End point timeframe

Baseline, Days 4, 13, 17, 21, 26

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13	13
Units: ng/mL
arithmetic mean (standard deviation)
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

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in TCQ-SF Score: Emotionality

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End point title

Change From Baseline Over Time in TCQ-SF Score: Emotionality

End point 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.

End point type

Secondary

End point timeframe

Baseline (Day -1), Days 4, 13, 17, 21, 26

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13	13
Units: score on a scale
arithmetic mean (standard deviation)
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

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in TCQ-SF Score: Expectancy

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End point title

Change From Baseline Over Time in TCQ-SF Score: Expectancy

End point 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.

End point type

Secondary

End point timeframe

Baseline (Day -1), Days 4, 13, 17, 21, 26

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13 ^[28]	13 ^[29]
Units: score on a scale
arithmetic mean (standard deviation)
Day 4; n=13, 12	-3.8 ± 5.89	-8.0 ± 6.00
Day 13; n=13, 13	-3.5 ± 7.83	-8.4 ± 5.91
Day 17; n=13, 13	-4.7 ± 6.96	-8.8 ± 5.82
Day 21; n=13, 13	-5.2 ± 6.56	-9.2 ± 5.75
Day 26; n=13, 13	-6.2 ± 6.40	-9.8 ± 6.15

Notes
[28] - n=subjects with an assessment at given time point
[29] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in TCQ-SF Score: Compulsivity

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End point title

Change From Baseline Over Time in TCQ-SF Score: Compulsivity

End point 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.

End point type

Secondary

End point timeframe

Baseline (Day -1), Days 4, 13, 17, 21, 26

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13	13
Units: score on a scale
arithmetic mean (standard deviation)
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

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in TCQ-SF Score: Purposefulness

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End point title

Change From Baseline Over Time in TCQ-SF Score: Purposefulness

End point 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.

End point type

Secondary

End point timeframe

Baseline (Day -1), Days 4, 13, 17, 21, 26

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13	13
Units: score on a scale
arithmetic mean (standard deviation)
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

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in TCQ-SF Score: Total Score

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End point title

Change From Baseline Over Time in TCQ-SF Score: Total Score

End point 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.

End point type

Secondary

End point timeframe

Baseline (Day -1), Days 4, 13, 17, 21, 26

End point values	Pharmacodynamic Set: Cytisine 1.5 mg	Pharmacodynamic Set: Cytisine 1.5 mg
Number of subjects analysed	13 ^[30]	13 ^[31]
Units: score on a scale
arithmetic mean (standard deviation)
Day 4; n=13, 12	-18.7 ± 12.88	-26.0 ± 16.06
Day 13; n=13, 13	-18.7 ± 22.11	-29.6 ± 16.58
Day 17; n=13, 13	-22.5 ± 22.17	-30.5 ± 16.51
Day 21; n=13, 13	-23.2 ± 21.79	-32.5 ± 16.62
Day 26; n=13, 13	-25.2 ± 20.55	-34.8 ± 16.85

Notes
[30] - n=subjects with an assessment at given time point
[31] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Cytisine Amount Excreted in Urine Over Time (Ae0-24h)

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End point title

Cytisine Amount Excreted in Urine Over Time (Ae0-24h)

End point description

End point type

Secondary

End point timeframe

Day 1 (6 times daily at 2-hour intervals); after the administration of the single dose of cytisine on Day 25

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	13	13
Units: mg
geometric mean (geometric coefficient of variation)
Day 1	7.95 ± 14.3	16.5 ± 12.0
Day 25	1.54 ± 17.4	3.14 ± 12.6

No statistical analyses for this end point

Secondary: Percent of Drug Excreted in Urine (Ae%)

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End point title

Percent of Drug Excreted in Urine (Ae%)

End point description

End point type

Secondary

End point timeframe

Day 1 (6 times daily at 2-hour intervals); after the administration of the single dose of cytisine on Day 25

End point values	Pharmacokinetic Set: Cytisine 1.5 mg	Pharmacokinetic Set: Cytisine 3.0 mg
Number of subjects analysed	13	13
Units: percent
geometric mean (geometric coefficient of variation)
Day 1	88.3 ± 14.3	91.6 ± 12.0
Day 25	102 ± 17.4	105 ± 12.5

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to TEAEs

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End point title

Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to TEAEs

End point 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.

End point type

Secondary

End point timeframe

From first dose of study drug through Day 26 plus 6-8 days

End point values	Safety Set: Cytisine 1.5 mg	Safety Set: Cytisine 3.0 mg
Number of subjects analysed	13	13
Units: subjects
TEAEs	9	9
Serious TEAEs	0	0
Discontinuation of Study Drug due to TEAE	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Clinically Significant Values in Biochemistry, Hematology, and Urinalysis

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End point title

Number of Subjects With Clinically Significant Values in Biochemistry, Hematology, and Urinalysis

End point description

End point type

Secondary

End point timeframe

up to Day 26

End point values	Safety Set: Cytisine 1.5 mg	Safety Set: Cytisine 3.0 mg
Number of subjects analysed	13	13
Units: subjects
Biochemistry	0	0
Hematology	0	0
Urinalysis	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Clinically Significant Values in Vital Signs and Physical Examinations

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End point title

Number of Subjects With Clinically Significant Values in Vital Signs and Physical Examinations

End point description

End point type

Secondary

End point timeframe

up to Day 26

End point values	Safety Set: Cytisine 1.5 mg	Safety Set: Cytisine 3.0 mg
Number of subjects analysed	13	13
Units: subjects
Vital Signs	0	0
Physical Examinations	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Parameters

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End point title

Number of Subjects With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Parameters

End point description

End point type

Secondary

End point timeframe

up to Day 26

End point values	Safety Set: Cytisine 1.5 mg	Safety Set: Cytisine 3.0 mg
Number of subjects analysed	13	13
Units: subjects	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Holter ECG Outlier Values

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End point title

Number of Subjects With Holter ECG Outlier Values

End point 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 subject with multiple occurrences of an event is counted only once per event.

End point type

Secondary

End point timeframe

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

End point values	Electrocardiogram Set: Cytisine 1.5 mg	Electrocardiogram Set: Cytisine 3.0 mg
Number of subjects analysed	13	13
Units: subjects
Day 1: Heart Rate <50 bpm & ↓ ≥ 25%	0	0
Day 1: Heart Rate >100 bpm & ↑ ≥25%	1	0
Day 1: PR Interval >200 mSec & ↑ ≥25%	0	0
Day 1: QRS Duration >100 mSec & ↑ ≥25%	0	0
Day 1: QT Interval >500 mSec & BL ≤500 mSec	0	0
Day 1: QTcF Interval >500 mSec & BL ≤500 mSec	0	0
Day 1: QTcF Interval >480 mSec & BL ≤480 mSec	0	0
Day 1: QTcF Interval >450 mSec & BL ≤450 mSec	0	1
Day 25: Heart Rate <50 bpm & ↓ ≥ 25%	0	0
Day 25: Heart Rate >100 bpm & ↑ ≥25%	1	0
Day 25: PR Interval >200 mSec & ↑ ≥25%	0	0
Day 25: QRS Duration >100 mSec & ↑ ≥25%	0	1
Day 25: QT Interval >500 mSec & BL ≤500 mSec	0	0
Day 25: QTcF Interval >500 mSec & BL ≤500 mSec	0	0
Day 25: QTcF Interval >480 mSec & BL ≤480 mSec	0	0
Day 25: QTcF Interval >450 mSec & BL ≤450 mSec	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug through Day 26 plus 6-8 days

Adverse event reporting additional 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 subject receives the first dose of investigational product.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Cytisine 1.5 mg

Reporting group description

Reporting group title

Cytisine 3.0 mg

Reporting group description

Serious adverse events	Cytisine 1.5 mg	Cytisine 3.0 mg
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 13 (0.00%)	0 / 13 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Cytisine 1.5 mg	Cytisine 3.0 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 13 (69.23%)	9 / 13 (69.23%)
Injury, poisoning and procedural complications
Muscle strain
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Procedural pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 13 (30.77%)	6 / 13 (46.15%)
occurrences all number	9	15
Vision blurred
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Medical device site reaction
subjects affected / exposed	1 / 13 (7.69%)	1 / 13 (7.69%)
occurrences all number	1	1
Peripheral swelling
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Constipation
subjects affected / exposed	1 / 13 (7.69%)	1 / 13 (7.69%)
occurrences all number	1	1
Dyspepsia
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Flatulence
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Nausea
subjects affected / exposed	0 / 13 (0.00%)	2 / 13 (15.38%)
occurrences all number	0	2
Tooth loss
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	2	0
Toothache
subjects affected / exposed	1 / 13 (7.69%)	1 / 13 (7.69%)
occurrences all number	1	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Sinonasal obstruction
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Rash pruritic
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Abnormal dreams
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Infections and infestations
Rhinitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

21 Sep 2017

The amendment was issued in line with recommendations made by the MHRA prior to authorization of the study. The recommendations included: Amendment of the inclusion criteria to remove subjects who used statins, thyroxine and antihypertensive drugs. Clarification that other medications listed in the Tabex SmPC (tuberculostatitics, cholinomimetics or anticholinesterase medicinal products, statins, or antihypertensive medicinal products) were not to be taken during the study and breast feeding was to be exclusionary. Additional vital sign assessments to be performed near expected Cmax while in the Clinical Unit and that ECGs may be performed at any time during study, if clinically indicated.

08 Nov 2017

This study-conduct change was issued to create adverts for use on Facebook, Google PPC and Instagram and in posters in order to aid recruitment for the study, particularly focusing on subjects aged >65. The study-conduct change was approved by the REC on 16 November 2017.

16 Jan 2018

This study-conduct change was issued to use additional Participant Identification Centers (Llandaff North Medical Centre, Llanrumney Medical Group) to aid the recruitment of subjects (aged >65) who smoked at least 10 cigarettes each day and would like to quit smoking. An application was also submitted to Research Permissions Wales for a study wide governance review. The study-conduct change was approved by REC on 16 February 2018.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Repeat-Dose Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine in Healthy Smokers

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximum Observed Plasma Concentration (Cmax)

Primary: Maximum Observed Plasma Concentration (Cmax)

Primary: Time of Occurrence of Cmax (Tmax)

Primary: Time of Occurrence of Cmax (Tmax)

Primary: Minimum Observed Plasma Concentration (Cmin)

Primary: Minimum Observed Plasma Concentration (Cmin)

Primary: Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to the Last Sampling Time (AUC0-t)

Primary: Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to the Last Sampling Time (AUC0-t)

Primary: Total AUC From Time Zero to Infinity (AUC0-∞)

Primary: Total AUC From Time Zero to Infinity (AUC0-∞)

Primary: Residual Area or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (%AUC)

Primary: Residual Area or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (%AUC)

Primary: Apparent Terminal Elimination Rate Constant (λz)

Primary: Apparent Terminal Elimination Rate Constant (λz)

Primary: Apparent Terminal Elimination Half-Life (t1/2)

Primary: Apparent Terminal Elimination Half-Life (t1/2)

Primary: Number of Cigarettes Smoked Daily During Treatment and at Day 26

Primary: Number of Cigarettes Smoked Daily During Treatment and at Day 26

Primary: Change From Baseline in Number of Cigarettes Smoked Daily up to Day 26

Primary: Change From Baseline in Number of Cigarettes Smoked Daily up to Day 26

Secondary: Change From Baseline in Expired Air CO up to Day 26

Secondary: Change From Baseline in Expired Air CO up to Day 26

Secondary: Number of Subjects Who Ceased or Continued Smoking on Day 26

Secondary: Number of Subjects Who Ceased or Continued Smoking on Day 26

Secondary: Change From Baseline Over Time in Urine Cotinine

Secondary: Change From Baseline Over Time in Urine Cotinine

Secondary: Change From Baseline Over Time in TCQ-SF Score: Emotionality

Secondary: Change From Baseline Over Time in TCQ-SF Score: Emotionality

Secondary: Change From Baseline Over Time in TCQ-SF Score: Expectancy

Secondary: Change From Baseline Over Time in TCQ-SF Score: Expectancy

Secondary: Change From Baseline Over Time in TCQ-SF Score: Compulsivity

Secondary: Change From Baseline Over Time in TCQ-SF Score: Compulsivity

Secondary: Change From Baseline Over Time in TCQ-SF Score: Purposefulness

Secondary: Change From Baseline Over Time in TCQ-SF Score: Purposefulness

Secondary: Change From Baseline Over Time in TCQ-SF Score: Total Score

Secondary: Change From Baseline Over Time in TCQ-SF Score: Total Score

Secondary: Cytisine Amount Excreted in Urine Over Time (Ae0-24h)

Secondary: Cytisine Amount Excreted in Urine Over Time (Ae0-24h)

Secondary: Percent of Drug Excreted in Urine (Ae%)

Secondary: Percent of Drug Excreted in Urine (Ae%)

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to TEAEs

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to TEAEs

Secondary: Number of Subjects With Clinically Significant Values in Biochemistry, Hematology, and Urinalysis

Secondary: Number of Subjects With Clinically Significant Values in Biochemistry, Hematology, and Urinalysis

Secondary: Number of Subjects With Clinically Significant Values in Vital Signs and Physical Examinations

Secondary: Number of Subjects With Clinically Significant Values in Vital Signs and Physical Examinations

Secondary: Number of Subjects With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Parameters

Secondary: Number of Subjects With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Parameters

Secondary: Number of Subjects With Holter ECG Outlier Values

Secondary: Number of Subjects With Holter ECG Outlier Values

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Repeat-Dose Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine in Healthy Smokers