Varenicline and Bupropion for Smoking Cessation

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.

Inclusion criteria

• Subject is at least 18 years of age;
• Subject has provide written informed consent;
• Subject is smoking greater than or equal to 10 cigarettes per day for at least 6 months;

• 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:

• an unstable medical condition;
• another household member participating in the study;
• bupropion or varenicline allergy;
• current use (previous 30 days) of a tobacco dependence treatment and unable or unwilling to discontinue use;
• an unstable medical condition or unstable angina, myocardial infarction, or coronary angioplasty (past 3 months) or an untreated cardiac dysrhythmia;
• a history of renal failure or were on renal dialysis;
• a history of seizures;
• 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");
• a history of closed head trauma associated with > 30 minutes of loss of consciousness, amnesia, skull fracture, subdural hematoma, or brain contusion;
• a history or psychosis, bipolar disorder, bulimia or anorexia nervosa;
• current moderate or severe depression as assessed by a score of ≥ 20 on the Beck Depression Inventory, Second Edition (BDI-II) 10;
• active substance abuse other than nicotine;
• current (past 14 days) use of an antipsychotic, monoamine oxidase inhibitors, or drugs known to interact with bupropion SR;
• a recent dose change of their antidepressant (within last 3 months);
• untreated hypertension or baseline systolic blood pressure > 180 or diastolic > 100;
• current treatment with another investigational drug for tobacco dependence (previous 30 days); or
• current use of bupropion or varenicline (previous 30 days).