Smoking Cessation
Conditions
Brief summary
This placebo-controlled Phase 2b trial is being conducted at sites within the United States (US) to evaluate the effectiveness cytisine dosage (1.5 mg, 3.0 mg) and administration schedule (commercial titration versus simplified 3 times daily \[TID\] schedule) within a 25-day treatment period.
Interventions
DRUGCytisine
film coated tablet containing 1.5 mg cytisine in a single tablet
DRUGPlacebo Comparator
1.5 mg cellulose powder to match final weight of the cytisine tablet
BEHAVIORALBehavioral support
12 behavioral support sessions by a qualified staff member plus supportive literature and online resources
Sponsors
Achieve Life Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female subjects, age ≥ 18 years. 2. Current daily cigarette smokers (averaging ≥ 10 cigarettes per day upon completing a 7-day screening diary) and who intend to quit smoking. 3. Expired air carbon monoxide (CO) ≥ 10 parts per million (ppm). 4. Failed at least one previous attempt to stop smoking with or without therapeutic support. 5. Willing to initiate study treatment on the day after randomization and set a quit date that is 5-7 days after starting treatment. 6. Willing to actively participate in the study's smoking cessation behavioral support provided throughout the study. 7. Able to fully understand all study requirements, willing to participate, comply with dosing schedule, and sign the Informed Consent Form.
Exclusion criteria
1. Known hypersensitivity to cytisine or any of the excipients. 2. Positive urinary drugs of abuse screen, determined within 28 days before the first dose of cytisine. 3. Clinically significant abnormal serum chemistry or hematology values within 28 days of randomization (i.e. requiring treatment). 4. Clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined after minimum of 5 minutes in supine position within 28 days of randomization (i.e. requiring treatment or further assessment). 5. Body mass index (BMI) classification for being underweight (\< 18.5 kg/m\^2) or having ≥ Class 2 obesity (≥ 35 kg/m\^2). 6. Recent history (within 3 months) of acute myocardial infarction, unstable angina, stroke, cerebrovascular incident or hospitalization for congestive heart failure. 7. Current uncontrolled hypertension (blood pressure ≥ 160/100 mmHg). 8. Documented diagnosis of schizophrenia or bipolar psychiatric illness; currently psychotic; having suicidal ideation (Suicide Behaviors Questionnaire-Revised \[SBQ-R\] score ≥ 7); or current symptoms of moderate to severe depression (Hospital Anxiety and Depression Scale \[HADS\] score ≥ 11). 9. Renal impairment defined as a creatinine clearance (CrCl) \< 60 mL/min (estimated with the Cockroft-Gault equation) or hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.0 times the upper limit of normal (ULN). 10. Women who are pregnant or breast-feeding. 11. Male or Female subjects of child bearing potential who do not agree to use acceptable methods of birth control during the study treatment period. 12. Participation in a clinical study with an investigational drug within 4 weeks of randomization. 13. Treatment with other smoking cessation medications (bupropion, varenicline, nortriptyline, or any nicotine replacement therapy \[NRT\]) within 4 weeks of randomization or planned use of these other smoking cessation medications during the study. 14. Use within 2 weeks of randomization or planned use during the study of non-cigarette nicotine products (e-cigarettes, pipe tobacco, cigars, snuff, chewing tobacco, hookah) or marijuana vaping or smoking. 15. Any other reason that the investigator views the subject should not participate or would be unable to fulfill the requirements for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Efficacy Analysis of Primary Outcome Measure: Percentage of Expected Cigarettes Smoked Per Participant During Study Treatment | Day 1 through Day 25 | The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. The percentage of expected cigarettes smoked was computed as Y = (100 x N) / (T x R) where N represents total number of cigarettes smoked each day over the treatment period from Day 1 to Day 25; T represents number of post-randomization days where number of cigarettes smoked is recorded; and R represents the average number of cigarettes smoked daily over the 7-day screening period as baseline. T\*R represents the total number of cigarettes that would have been smoked without intervention over the number of recorded days. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID). |
| Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, Commercial Schedule | Day 1 through Day 25 | The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. (See Outcome Measure 1 description for details.) The sensitivity analysis of the primary outcome measure was only performed if results of Statistical Analysis 5 for Outcome Measure 1 demonstrated the placebo treatment arms (commercial and TID) were not significantly different, and so could be pooled. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID). |
| Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, TID Schedule | Day 1 through Day 25 | The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. (See Outcome Measure 1 description for details.) The sensitivity analysis of the primary outcome measure was only performed if results of Statistical Analysis 5 for Outcome Measure 1 demonstrated the placebo treatment arms (commercial and TID) were not significantly different, and so could be pooled. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1.5 mg Cytisine, Commercial Schedule 1.5 mg cytisine dose using the commercial 25-day titration schedule + behavioral support | 51 |
| 3.0 mg Cytisine, Commercial Schedule 3.0 mg cytisine dose using the commercial 25-day titration schedule + behavioral support | 50 |
| Placebo, Commercial Schedule Placebo tablets using the commercial 25-day titration schedule + behavioral support | 25 |
| 1.5 mg Cytisine, TID Schedule 1.5 mg cytisine dose for 25 days using a simplified TID schedule + behavioral support | 52 |
| 3.0 mg Cytisine, TID Schedule 3.0 mg cytisine dose for 25 days using a simplified TID schedule + behavioral support | 50 |
| Placebo, TID Schedule Placebo tablets for 25 days using a simplified TID schedule + behavioral support | 26 |
| Total | 254 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 | 2 | 1 | 1 | 0 |
| Overall Study | Other, Not Specified | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 3.0 mg Cytisine, Commercial Schedule | Placebo, Commercial Schedule | 1.5 mg Cytisine, TID Schedule | 1.5 mg Cytisine, Commercial Schedule | 3.0 mg Cytisine, TID Schedule | Placebo, TID Schedule | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 50.0 years STANDARD_DEVIATION 13.2 | 51.0 years STANDARD_DEVIATION 15.16 | 47.0 years STANDARD_DEVIATION 13.67 | 49.8 years STANDARD_DEVIATION 11.46 | 46.3 years STANDARD_DEVIATION 12.88 | 47.0 years STANDARD_DEVIATION 12.64 | 48.4 years STANDARD_DEVIATION 13.04 |
| Average Number of Cigarettes Smoked per Day Over 7 Consecutive Days | 18.0 cigarettes per day STANDARD_DEVIATION 5.51 | 16.7 cigarettes per day STANDARD_DEVIATION 4.28 | 18.0 cigarettes per day STANDARD_DEVIATION 6.69 | 17.6 cigarettes per day STANDARD_DEVIATION 5.3 | 18.0 cigarettes per day STANDARD_DEVIATION 6.12 | 18.0 cigarettes per day STANDARD_DEVIATION 5.96 | 17.8 cigarettes per day STANDARD_DEVIATION 5.75 |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 2 Participants | 6 Participants | 5 Participants | 1 Participants | 0 Participants | 15 Participants |
| Race/Ethnicity, Customized Native American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 49 Participants | 23 Participants | 46 Participants | 45 Participants | 49 Participants | 26 Participants | 238 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 3 Participants | 13 Participants | 7 Participants | 7 Participants | 7 Participants | 46 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 40 Participants | 21 Participants | 37 Participants | 43 Participants | 41 Participants | 18 Participants | 200 Participants |
| Sex: Female, Male Female | 20 Participants | 14 Participants | 29 Participants | 28 Participants | 25 Participants | 17 Participants | 133 Participants |
| Sex: Female, Male Male | 30 Participants | 11 Participants | 23 Participants | 23 Participants | 25 Participants | 9 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 50 | 0 / 25 | 0 / 52 | 0 / 50 | 0 / 26 |
| other Total, other adverse events | 16 / 51 | 16 / 50 | 5 / 25 | 15 / 52 | 14 / 50 | 8 / 26 |
| serious Total, serious adverse events | 0 / 51 | 0 / 50 | 0 / 25 | 0 / 52 | 0 / 50 | 0 / 26 |
Outcome results
Primary
Primary Efficacy Analysis of Primary Outcome Measure: Percentage of Expected Cigarettes Smoked Per Participant During Study Treatment
The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. The percentage of expected cigarettes smoked was computed as Y = (100 x N) / (T x R) where N represents total number of cigarettes smoked each day over the treatment period from Day 1 to Day 25; T represents number of post-randomization days where number of cigarettes smoked is recorded; and R represents the average number of cigarettes smoked daily over the 7-day screening period as baseline. T\*R represents the total number of cigarettes that would have been smoked without intervention over the number of recorded days. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID).
Time frame: Day 1 through Day 25
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Cytisine, Commercial Schedule | Primary Efficacy Analysis of Primary Outcome Measure: Percentage of Expected Cigarettes Smoked Per Participant During Study Treatment | 26.62 percentage of cigarettes smoked | Standard Error 3.085 |
| 3.0 mg Cytisine, Commercial Schedule | Primary Efficacy Analysis of Primary Outcome Measure: Percentage of Expected Cigarettes Smoked Per Participant During Study Treatment | 25.04 percentage of cigarettes smoked | Standard Error 3.123 |
| Placebo, Commercial Schedule | Primary Efficacy Analysis of Primary Outcome Measure: Percentage of Expected Cigarettes Smoked Per Participant During Study Treatment | 47.10 percentage of cigarettes smoked | Standard Error 4.417 |
| 1.5 mg Cytisine, TID Schedule | Primary Efficacy Analysis of Primary Outcome Measure: Percentage of Expected Cigarettes Smoked Per Participant During Study Treatment | 29.40 percentage of cigarettes smoked | Standard Error 3.046 |
| 3.0 mg Cytisine, TID Schedule | Primary Efficacy Analysis of Primary Outcome Measure: Percentage of Expected Cigarettes Smoked Per Participant During Study Treatment | 32.50 percentage of cigarettes smoked | Standard Error 3.105 |
| Placebo, TID Schedule | Primary Efficacy Analysis of Primary Outcome Measure: Percentage of Expected Cigarettes Smoked Per Participant During Study Treatment | 35.30 percentage of cigarettes smoked | Standard Error 4.392 |
p-value: 0.000295% CI: [-31.141, -9.821]ANOVA
p-value: <0.000195% CI: [-32.791, -11.342]ANOVA
p-value: 0.270895% CI: [-16.463, 4.66]ANOVA
p-value: 0.601895% CI: [-13.438, 7.82]ANOVA
p-value: 0.102595% CI: [-26.869, 2.535]ANOVA
Primary
Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, Commercial Schedule
The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. (See Outcome Measure 1 description for details.) The sensitivity analysis of the primary outcome measure was only performed if results of Statistical Analysis 5 for Outcome Measure 1 demonstrated the placebo treatment arms (commercial and TID) were not significantly different, and so could be pooled. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID).
Time frame: Day 1 through Day 25
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Cytisine, Commercial Schedule | Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, Commercial Schedule | 26.68 percentage of expected cigarettes smoked | Standard Error 3.065 |
| 3.0 mg Cytisine, Commercial Schedule | Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, Commercial Schedule | 25.08 percentage of expected cigarettes smoked | Standard Error 3.1 |
| Placebo, Commercial Schedule | Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, Commercial Schedule | 41.29 percentage of expected cigarettes smoked | Standard Error 3.099 |
p-value: 0.00195% CI: [-23.216, -6.009]ANOVA
p-value: 0.000395% CI: [-24.862, -7.548]ANOVA
Primary
Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, TID Schedule
The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. (See Outcome Measure 1 description for details.) The sensitivity analysis of the primary outcome measure was only performed if results of Statistical Analysis 5 for Outcome Measure 1 demonstrated the placebo treatment arms (commercial and TID) were not significantly different, and so could be pooled. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID).
Time frame: Day 1 through Day 25
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Cytisine, Commercial Schedule | Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, TID Schedule | 29.29 percentage of expected cigarettes smoked | Standard Error 3.291 |
| 3.0 mg Cytisine, Commercial Schedule | Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, TID Schedule | 32.41 percentage of expected cigarettes smoked | Standard Error 3.355 |
| Placebo, Commercial Schedule | Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, TID Schedule | 41.71 percentage of expected cigarettes smoked | Standard Error 3.358 |
p-value: 0.009195% CI: [-21.695, -3.135]ANOVA
p-value: 0.051895% CI: [-18.667, 0.075]ANOVA