Varenicline and Bupropion for Smoking Cessation

Study Overview
=================
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.

Official Title
-----------------
Combination Therapy With Varenicline and Bupropion for Smoking Cessation

Conditions
-----------------
Smoking

Intervention / Treatment
-----------------
* Drug: Varenicline
* Drug: placebo
* Drug: bupropion SR


Participation Criteria
=================
Eligibility Criteria
-----------------
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; 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: 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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: varenicline and buproprion SR<br>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. | Drug: Varenicline<br>* varenicline - 1 mg bid for 12 weeks<br>* Other names: chantix;Drug: bupropion SR<br>* bupropion sr - 150 mg bid for 12 weeks<br>* Other names: zyban;|
| Placebo Comparator: varenicline and placebo<br>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. | Drug: Varenicline<br>* varenicline - 1 mg bid for 12 weeks<br>* Other names: chantix;Drug: placebo<br>* placebo for 12 weeks<br>* Other names: sugar pill;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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? | 3 months | 
| 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. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prolonged Smoking Abstinence Rates at 26 Weeks in Cigarettes Smokers. |  | 6 months | 
| 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 | 3 months | 
| Point Prevalence Abstinence at 6 Months. | Biochemically confirmed abstinence as no smoking, even a puff, for the prior 7 days. | 6 months | 
| Prolonged Abstinence at 12 Months |  | 12 months | 
| Point Prevalence Abstinence at 12 Months | Biochemically confirmed abstinence defined as no smoking, not even a puff, in the last 7 days | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
smoking, nicotine, tobacco, dependence, cessation, abstinence