Smoking Cessation
Conditions
Keywords
smoking reduction, smoking cessation
Brief summary
This study will determine whether varenicline is safe and helps people to quit smoking through reduction when they are not willing/able to make an abrupt quit attempt.
Interventions
Varenicline Tartrate oral tablets 2 (0.5mg) tablets twice a day for 24 weeks (first week titration)
DRUGPlacebo
Matching placebo 2 oral tablets twice a day for 24 weeks (first week titration)
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female cigarette smokers over the age of 18 years who are not willing/able to quit smoking within the next month but who are willing to attempt to reduce their smoking to work toward a quit attempt within the next 3 months. * Subjects must have smoked an average of at least 10 cigarettes per day during the past year and during the month prior to the screening visit, with no continuous period of abstinence greater than 3 months in the past year and who have an exhaled carbon monoxide (CO) \>10 ppm at screening. * Subjects with mild to moderate depression or anxiety may be included if their condition is stable.
Exclusion criteria
* Subjects with a history of a suicide attempt or any suicidal behavior in the past two years. * Subjects with severe depression or anxiety. * Subjects with psychosis, panic disorder, bipolar disorder, post traumatic stress disorder (PTSD), or schizophrenia. * Subjects with alcohol or substance abuse or dependence (except nicotine) unless in full remission for at least 12 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Carbon Monoxide (CO) Confirmed 10-Week Continuous Abstinence (CA) From Smoking | Week 15 - 24 | Percentage of participants who remained abstinent from Week 15 to Week 24, inclusive, reporting no smoking and no use of nicotine-containing products since the last study visit or contact on the Nicotine Use Inventory (NUI) and confirmed by expired CO \< 10 ppm at any time point (CO measurements conducted at the clinic visits) during Weeks 15 through 24, inclusive. Missing CO was imputed as negative (CO ≤ 10 ppm). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With CO Confirmed 4-Week CA From Smoking | Week 21 - 24 | Percentage of participants who remained abstinent from Week 21 to Week 24, inclusive, reporting no smoking and no use of nicotine-containing products since the last study visit or contact on the NUI and confirmed by expired CO \< 10 ppm at any time point (CO measurements conducted at the clinic visits) during Weeks 21 through 24, inclusive. Missing CO was imputed as negative (CO ≤ 10 ppm). |
| Percentage of Participants With CO Confirmed Long Term CA From Smoking | Weeks 21 - 52 | Percentage of participants who remained abstinent from Week 21 to Week 52, inclusive, reporting no smoking and no use of nicotine-containing products since the last study visit or contact on the NUI and confirmed by expired CO \< 10 ppm at any time point (CO measurements conducted at the clinic visits) during Weeks 21 through 52, inclusive. Missing CO was imputed as negative (CO ≤ 10 ppm). |
| Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation | Week 12, 24, and 52 | The 7-day point prevalence of abstinence was defined as being abstinent from smoking and using tobacco products during the last 7 days at Week 12, 24, and 52. The participant's smoking status and other nicotine use was evaluated based on the last 7 days questions on the NUI and confirmed by CO expiration. Responders were defined as those, who answered no to both questions (Has the subject smoked any cigarettes (even a puff) in the last 7 days?; and Has the subject used any nicotine products and/or other tobacco.... in the last 7 days?) and whose expired CO \< 10 ppm. Missing CO was imputed as negative (CO ≤ 10 ppm). |
| Percentage of Participants With 4-Week Point Prevalence of Smoking Cessation | Week 52 | The 4-week point prevalence of abstinence was defined as being abstinent from smoking and using tobacco products during the last 4 weeks of the study. The participant's smoking status and other nicotine use was evaluated based on the last 4 weeks questions on the NUI and confirmed by CO expiration. Responders were defined as those, who answered no to both questions (Has the subject smoked any cigarettes (even a puff) in the last 4 weeks?; and Has the subject used any nicotine products and/or other tobacco.... in the last 4 weeks?) and whose expired CO \< 10 ppm. Missing CO was imputed as negative (CO ≤ 10 ppm). |
Countries
Australia, Canada, Czechia, Egypt, Germany, Japan, Mexico, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
A total of 1747 participants were screened, whereof 1510 were randomized into the study, and of whom 1493 took at least 1 dose of study drug. Overall, 61 centers in 10 countries received study drug: Australia (4), Canada (6), Czech Republic (6), Germany (6), Egypt (3), United Kingdom (7), Japan (6), Mexico (4), Taiwan (7), and USA (12).
Participants by arm
| Arm | Count |
|---|---|
| Varenicline Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg BID). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID. One participant was assigned to varenicline as a male but is in fact female. Data below are presented for the treated population. | 751 |
| Placebo Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed. Data below are presented for the treated population. | 742 |
| Total | 1,493 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse event (AE) Related to Study Drug | 12 | 9 |
| Overall Study | AE Not Related to Study Drug | 1 | 4 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lack of Efficacy | 6 | 28 |
| Overall Study | Lost to Follow-up | 76 | 81 |
| Overall Study | Protocol Violation | 3 | 3 |
| Overall Study | Reason not specified | 39 | 43 |
| Overall Study | Withdrawal by Subject | 54 | 59 |
Baseline characteristics
| Characteristic | Varenicline | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 44.7 Years STANDARD_DEVIATION 11.8 | 44.4 Years STANDARD_DEVIATION 12 | 44.6 Years STANDARD_DEVIATION 11.9 |
| Sex: Female, Male Female | 330 Participants | 321 Participants | 651 Participants |
| Sex: Female, Male Male | 421 Participants | 421 Participants | 842 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 467 / 751 | 339 / 742 |
| serious Total, serious adverse events | 28 / 751 | 16 / 742 |
Outcome results
Primary
Percentage of Participants With Carbon Monoxide (CO) Confirmed 10-Week Continuous Abstinence (CA) From Smoking
Percentage of participants who remained abstinent from Week 15 to Week 24, inclusive, reporting no smoking and no use of nicotine-containing products since the last study visit or contact on the Nicotine Use Inventory (NUI) and confirmed by expired CO \< 10 ppm at any time point (CO measurements conducted at the clinic visits) during Weeks 15 through 24, inclusive. Missing CO was imputed as negative (CO ≤ 10 ppm).
Time frame: Week 15 - 24
Population: The Full Analysis Set was referred to as the Intent-to-Treat (ITT) population and was defined as all randomized participants. The ITT population was the primary analysis set for the efficacy analyses in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline | Percentage of Participants With Carbon Monoxide (CO) Confirmed 10-Week Continuous Abstinence (CA) From Smoking | 32.1 percentage of participants |
| Placebo | Percentage of Participants With Carbon Monoxide (CO) Confirmed 10-Week Continuous Abstinence (CA) From Smoking | 6.9 percentage of participants |
Comparison: Assuming true CA rate of 6.9% for placebo and 17.2% for varenicline (odds ratio ≥ 2.8), a study randomizing 1404 participants (1:1 ratio) has ≥90% power to detect a difference between the two groups. Analysis was done using a logistic regression model; treatment effect as explanatory variable and investigative center as covariate. The interaction effect was tested using an expanded logistic regression model including treatment-by-center interaction.p-value: <0.000195% CI: [6.09, 12.53]Regression, Logistic
Secondary
Percentage of Participants With 4-Week Point Prevalence of Smoking Cessation
The 4-week point prevalence of abstinence was defined as being abstinent from smoking and using tobacco products during the last 4 weeks of the study. The participant's smoking status and other nicotine use was evaluated based on the last 4 weeks questions on the NUI and confirmed by CO expiration. Responders were defined as those, who answered no to both questions (Has the subject smoked any cigarettes (even a puff) in the last 4 weeks?; and Has the subject used any nicotine products and/or other tobacco.... in the last 4 weeks?) and whose expired CO \< 10 ppm. Missing CO was imputed as negative (CO ≤ 10 ppm).
Time frame: Week 52
Population: The Full Analysis Set was referred to as the ITT population and was defined as all randomized participants. The ITT population was the primary analysis set for the efficacy analyses in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline | Percentage of Participants With 4-Week Point Prevalence of Smoking Cessation | 32.8 percentage of participants |
| Placebo | Percentage of Participants With 4-Week Point Prevalence of Smoking Cessation | 17.3 percentage of participants |
Comparison: Analysis was done using a logistic regression model including treatment effect as the explanatory variable and investigative center as covariate. In addition, the interaction effect was tested using an expanded logistic regression model including the treatment-by-center interaction. However, the inferences reported were based on the logistic regression model including only the main effects of treatment and center, regardless of the significance of the treatment by center interaction.p-value: <0.000195% CI: [2.05, 3.47]Regression, Logistic
Secondary
Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation
The 7-day point prevalence of abstinence was defined as being abstinent from smoking and using tobacco products during the last 7 days at Week 12, 24, and 52. The participant's smoking status and other nicotine use was evaluated based on the last 7 days questions on the NUI and confirmed by CO expiration. Responders were defined as those, who answered no to both questions (Has the subject smoked any cigarettes (even a puff) in the last 7 days?; and Has the subject used any nicotine products and/or other tobacco.... in the last 7 days?) and whose expired CO \< 10 ppm. Missing CO was imputed as negative (CO ≤ 10 ppm).
Time frame: Week 12, 24, and 52
Population: The Full Analysis Set was referred to as the ITT population and was defined as all randomized participants. The ITT population was the primary analysis set for the efficacy analyses in this study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Varenicline | Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation | Week 12 | 31.2 percentage of participants |
| Varenicline | Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation | Week 24 | 43.2 percentage of participants |
| Varenicline | Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation | Week 52 | 34.1 percentage of participants |
| Placebo | Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation | Week 12 | 6.7 percentage of participants |
| Placebo | Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation | Week 24 | 17.5 percentage of participants |
| Placebo | Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation | Week 52 | 18.3 percentage of participants |
Comparison: Statistical analysis presented above is for Week 12. Analysis was done using logistic regression model with treatment effect as the explanatory variable and investigative center as covariate. The interaction effect was tested using an expanded logistic regression model with treatment-by-center interaction. The inferences reported were based on the logistic regression model including only the main effects of treatment and center, regardless of the significance of treatment by center interaction.p-value: <0.000195% CI: [6.03, 12.51]Regression, Logistic
Comparison: Statistical analysis presented above is for Week 24. Analysis was done using logistic regression model with treatment effect as the explanatory variable and investigative center as covariate. The interaction effect was tested using an expanded logistic regression model with treatment-by-center interaction. The inferences reported were based on the logistic regression model including only the main effects of treatment and center, regardless of the significance of treatment by center interaction.p-value: <0.000195% CI: [3.51, 5.98]Regression, Logistic
Comparison: Statistical analysis presented above is for Week 52. Analysis was done using logistic regression model with treatment effect as the explanatory variable and investigative center as covariate. The interaction effect was tested using an expanded logistic regression model with treatment-by-center interaction. The inferences reported were based on the logistic regression model including only the main effects of treatment and center, regardless of the significance of treatment by center interaction.p-value: <0.000195% CI: [2.05, 3.44]Regression, Logistic
Secondary
Percentage of Participants With CO Confirmed 4-Week CA From Smoking
Percentage of participants who remained abstinent from Week 21 to Week 24, inclusive, reporting no smoking and no use of nicotine-containing products since the last study visit or contact on the NUI and confirmed by expired CO \< 10 ppm at any time point (CO measurements conducted at the clinic visits) during Weeks 21 through 24, inclusive. Missing CO was imputed as negative (CO ≤ 10 ppm).
Time frame: Week 21 - 24
Population: The Full Analysis Set was referred to as the ITT population and was defined as all randomized participants. The ITT population was the primary analysis set for the efficacy analyses in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline | Percentage of Participants With CO Confirmed 4-Week CA From Smoking | 37.8 percentage of participants |
| Placebo | Percentage of Participants With CO Confirmed 4-Week CA From Smoking | 12.5 percentage of participants |
Comparison: Analysis was done using a logistic regression model including treatment effect as the explanatory variable and investigative center as covariate. In addition, the interaction effect was tested using an expanded logistic regression model including the treatment-by-center interaction. However, the inferences reported were based on the logistic regression model including only the main effects of treatment and center, regardless of the significance of the treatment by center interaction.p-value: <0.000195% CI: [4.21, 7.61]Regression, Logistic
Secondary
Percentage of Participants With CO Confirmed Long Term CA From Smoking
Percentage of participants who remained abstinent from Week 21 to Week 52, inclusive, reporting no smoking and no use of nicotine-containing products since the last study visit or contact on the NUI and confirmed by expired CO \< 10 ppm at any time point (CO measurements conducted at the clinic visits) during Weeks 21 through 52, inclusive. Missing CO was imputed as negative (CO ≤ 10 ppm).
Time frame: Weeks 21 - 52
Population: The Full Analysis Set was referred to as the ITT population and was defined as all randomized participants. The ITT population was the primary analysis set for the efficacy analyses in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline | Percentage of Participants With CO Confirmed Long Term CA From Smoking | 27.0 percentage of participants |
| Placebo | Percentage of Participants With CO Confirmed Long Term CA From Smoking | 9.9 percentage of participants |
Comparison: Analysis was done using a logistic regression model including treatment effect as the explanatory variable and investigative center as covariate. In addition, the interaction effect was tested using an expanded logistic regression model including the treatment-by-center interaction. However, the inferences reported were based on the logistic regression model including only the main effects of treatment and center, regardless of the significance of the treatment by center interaction.p-value: <0.000195% CI: [2.94, 5.5]Regression, Logistic