Smoking
Conditions
Keywords
smoking, nicotine, tobacco, dependence, cessation, abstinence
Brief summary
This study provides an opportunity to combine varenicline and bupropion SR and capitalize on the potential additive benefit. The investigators hypothesize that this will further increase long-term (≥ 6 months) smoking abstinence rates.
Detailed description
Cigarette smoking is the single most important preventable cause of morbidity, mortality and excess health care costs in the United States and accounts for 30% of U.S. cancer deaths. Varenicline and bupropion SR (sustained-release) are non nicotine pharmacotherapies FDA-indicated for the treatment of tobacco dependence in cigarette smokers. Although varenicline has proven greater efficacy than bupropion SR, both medications are associated with high end-of-treatment smoking abstinence rates. However, almost two-thirds of smokers treated with varenicline report smoking at 6 months. Because varenicline and bupropion SR have different mechanisms of action and different neuropharmacologic targets, combination pharmacotherapy with these agents may increase long-term smoking abstinence rates above what is observed with single-agent therapy. In our recent pilot study of combination therapy with varenicline and bupropion SR, we observed treatment to be well-tolerated with 7-day point prevalence smoking abstinence rates of 71% (95% CI: 54-85%) at 3 months and 58% (95% CI: 41-74%) at 6 months. Determining the efficacy of combination therapy compared to single-agent therapy has immediate and important clinical implications. In this study, we will conduct a randomized, multicenter, controlled clinical trial evaluating the efficacy of combination therapy with varenicline and bupropion SR compared to varenicline and placebo in 506 cigarette smokers at the Mayo Clinic in Rochester, MN, and the University of Minnesota in Minneapolis, MN.
Interventions
DRUGVarenicline
varenicline - 1 mg bid for 12 weeks
DRUGplacebo
placebo for 12 weeks
DRUGbupropion SR
bupropion sr - 150 mg bid for 12 weeks
Sponsors
National Cancer Institute (NCI)
University of Minnesota
Mayo Clinic
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
Yes
Inclusion criteria
1. Subject is at least 18 years of age; 2. Subject has provide written informed consent; 3. Subject is smoking greater than or equal to 10 cigarettes per day for at least 6 months; 3\) Subject is able to complete all study visits 4) Subject is in good health as determined by the investigator 5) Subject has the ability to participate fully in all aspects of the study and keep scheduled appointments 6) Subject is motivated to stop smoking.
Exclusion criteria
Female and were pregnant, lactating or likely to become pregnant during the trial and not able nor willing to use contraception or had: 1. an unstable medical condition; 2. another household member participating in the study; 3. bupropion or varenicline allergy; 4. current use (previous 30 days) of a tobacco dependence treatment and unable or unwilling to discontinue use; 5. an unstable medical condition or unstable angina, myocardial infarction, or coronary angioplasty (past 3 months) or an untreated cardiac dysrhythmia; 6. a history of renal failure or were on renal dialysis; 7. a history of seizures; 8. as defined by the C-SSRS (Columbia-Suicide Severity Rating Scale), current non-specific suicidal thoughts or lifetime history of a suicidal attempt (defined as potentially self-injurious act committed with at least some wish to die, as a result of act); 9. a history of closed head trauma associated with \> 30 minutes of loss of consciousness, amnesia, skull fracture, subdural hematoma, or brain contusion; 10. a history or psychosis, bipolar disorder, bulimia or anorexia nervosa; 11. current moderate or severe depression as assessed by a score of ≥ 20 on the Beck Depression Inventory, Second Edition (BDI-II) 10; 12. active substance abuse other than nicotine; 13. current (past 14 days) use of an antipsychotic, monoamine oxidase inhibitors, or drugs known to interact with bupropion SR; 14. a recent dose change of their antidepressant (within last 3 months); 15. untreated hypertension or baseline systolic blood pressure \> 180 or diastolic \> 100; 16. current treatment with another investigational drug for tobacco dependence (previous 30 days); or 17. current use of bupropion or varenicline (previous 30 days).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prolonged Smoking Abstinence Rates at 12 Weeks in Cigarettes Smokers. | 3 months | Prolonged smoking abstinence is defined as no smoking, not even a puff, in the last 7 days, and a negative response to the question Since 2 weeks after your target quit date, have you smoked any tobacco, even a puff, for 7 consecutive days or at least once each week on 2 consecutive weeks? |
| Point Prevalence Abstinence at 3 Months. | 3 months | biochemically confirmed 7-day point prevalence abstinence defined as no smoking, not even a puff, in the previous 7 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Point Prevalence Abstinence at 6 Months. | 6 months | Biochemically confirmed abstinence as no smoking, even a puff, for the prior 7 days. |
| Prolonged Smoking Abstinence Rates at 26 Weeks in Cigarettes Smokers. | 6 months | — |
| Point Prevalence Abstinence at 12 Months | 12 months | Biochemically confirmed abstinence defined as no smoking, not even a puff, in the last 7 days |
| Prolonged Abstinence at 12 Months | 12 months | — |
| Weight Gain From Baseline to 3 Months | 3 months | Weight change from baseline to three months in those who met criteria for prolonged abstinence at the 3 month visit |
Countries
United States
Participant flow
Recruitment details
Recruitment was between October 2009 and April 2012. Volunteers from local communities of Rochester, MN, Minneapolis, MN and LaCrosse, WI, were recruited using newspaper classified ads, radio, TV, internet ads, print ads in magazines, word of mouth, and volunteer wait lists.
Pre-assignment details
Study subjects who consented, were screened for entry criteria, and asked to return for a physical exam and medical history. If eligible and still interested, the volunteer was asked to return to the baseline visit at which time they would receive the study medication assignment.
Participants by arm
| Arm | Count |
|---|---|
| Varenicline and Buproprion SR Everyone randomized to this arm will receive varenicline (up to 1mg bid) and bupropion SR (150 mg bid)for 12 weeks. They will be followed up by study for an additional 9 months post end of medication - for a total of 1 year study participation. Everyone will receive behavioral counseling for the full year.
varenicline and bupropion: varenicline - 1 mg bid for 12 weeks bupropion sr - 150 mg bid for 12 weeks | 249 |
| Varenicline and Placebo Everyone randomized to this arm will receive varenicline (up to 1mg bid) and placebo (0 mg bid)for 12 weeks. They will be followed up by study for an additional 9 months post end of medication - for a total of 1 year study participation. Everyone will receive behavioral counseling for the full year.
varenicline and placebo: varenicline (1 mg bid) for 12 weeks placebo for 12 weeks | 257 |
| Total | 506 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 7 |
| Overall Study | Lost to Follow-up | 40 | 42 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 45 | 50 |
Baseline characteristics
| Characteristic | Varenicline and Placebo | Total | Varenicline and Buproprion SR |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 3 Participants | 3 Participants |
| Age, Categorical >=65 years | 4 Participants | 16 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 253 Participants | 487 Participants | 234 Participants |
| Age, Continuous | 41.9 years STANDARD_DEVIATION 12.7 | 42.1 years STANDARD_DEVIATION 12.4 | 42.2 years STANDARD_DEVIATION 12.2 |
| Race/Ethnicity, Customized other | 17 participants | 32 participants | 15 participants |
| Race/Ethnicity, Customized White, non-hispanic | 240 participants | 474 participants | 234 participants |
| Sex: Female, Male Female | 126 Participants | 239 Participants | 113 Participants |
| Sex: Female, Male Male | 131 Participants | 267 Participants | 136 Participants |
| smoking rate | 19.7 cigarettes per day STANDARD_DEVIATION 7.9 | 19.6 cigarettes per day STANDARD_DEVIATION 7.6 | 19.5 cigarettes per day STANDARD_DEVIATION 7.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 165 / 249 | 161 / 257 |
| serious Total, serious adverse events | 6 / 249 | 6 / 257 |
Outcome results
Primary
Point Prevalence Abstinence at 3 Months.
biochemically confirmed 7-day point prevalence abstinence defined as no smoking, not even a puff, in the previous 7 days.
Time frame: 3 months
Population: intent to treat - all subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline and Buproprion SR | Point Prevalence Abstinence at 3 Months. | 140 participants |
| Varenicline and Placebo | Point Prevalence Abstinence at 3 Months. | 125 participants |
Comparison: Logistic regression adjusted for study sitep-value: 0.0995% CI: [0.95, 1.93]Regression, Logistic
Primary
Prolonged Smoking Abstinence Rates at 12 Weeks in Cigarettes Smokers.
Prolonged smoking abstinence is defined as no smoking, not even a puff, in the last 7 days, and a negative response to the question Since 2 weeks after your target quit date, have you smoked any tobacco, even a puff, for 7 consecutive days or at least once each week on 2 consecutive weeks?
Time frame: 3 months
Population: intention-to-treat (all randomized subjects included)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline and Buproprion SR | Prolonged Smoking Abstinence Rates at 12 Weeks in Cigarettes Smokers. | 132 participants |
| Varenicline and Placebo | Prolonged Smoking Abstinence Rates at 12 Weeks in Cigarettes Smokers. | 111 participants |
Comparison: Logistic regression with covariate included for study site.p-value: 0.0395% CI: [1.05, 2.12]Regression, Logistic
Secondary
Point Prevalence Abstinence at 12 Months
Biochemically confirmed abstinence defined as no smoking, not even a puff, in the last 7 days
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline and Buproprion SR | Point Prevalence Abstinence at 12 Months | 91 participants |
| Varenicline and Placebo | Point Prevalence Abstinence at 12 Months | 75 participants |
Comparison: Logistic Regression - adjusting for sitep-value: 0.0895% CI: [0.96, 2.05]Regression, Logistic
Secondary
Point Prevalence Abstinence at 6 Months.
Biochemically confirmed abstinence as no smoking, even a puff, for the prior 7 days.
Time frame: 6 months
Population: Intention to treat - all subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline and Buproprion SR | Point Prevalence Abstinence at 6 Months. | 95 participants |
| Varenicline and Placebo | Point Prevalence Abstinence at 6 Months. | 82 participants |
Comparison: Logistic Regression adjusting for study sitep-value: 0.1495% CI: [0.91, 1.91]Regression, Logistic
Secondary
Prolonged Abstinence at 12 Months
Time frame: 12 months
Population: intention to treat - all subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline and Buproprion SR | Prolonged Abstinence at 12 Months | 77 participants |
| Varenicline and Placebo | Prolonged Abstinence at 12 Months | 63 participants |
Comparison: Logistic Regression - adjusting for study sitep-value: 0.1195% CI: [0.93, 2.07]Regression, Logistic
Secondary
Prolonged Smoking Abstinence Rates at 26 Weeks in Cigarettes Smokers.
Time frame: 6 months
Population: intention to treat - all subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline and Buproprion SR | Prolonged Smoking Abstinence Rates at 26 Weeks in Cigarettes Smokers. | 91 participants |
| Varenicline and Placebo | Prolonged Smoking Abstinence Rates at 26 Weeks in Cigarettes Smokers. | 71 participants |
Comparison: Logistic Regression - adjusting for study sitep-value: 0.0395% CI: [1.04, 2.22]Regression, Logistic
Secondary
Weight Gain From Baseline to 3 Months
Weight change from baseline to three months in those who met criteria for prolonged abstinence at the 3 month visit
Time frame: 3 months
Population: analysis was restricted to subjects who had weight measured at the 3 month visit and were classified as meeting criteria for prolonged abstinence
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Varenicline and Buproprion SR | Weight Gain From Baseline to 3 Months | 1.1 kilograms | Standard Deviation 3.4 |
| Varenicline and Placebo | Weight Gain From Baseline to 3 Months | 2.5 kilograms | Standard Deviation 2.7 |
p-value: <0.001t-test, 2 sided