Varenicline and Combined NRT for Smoking Cessation

Study Overview
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Brief Summary
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This randomized pilot phase IV trial studies the side effects and how well varenicline works compared to nicotine replacement therapy in helping patients that smoke to quit. Varenicline is a drug that acts the same way as nicotine in the brain but is not habit-forming. Nicotine replacement therapy consists of nicotine patches and lozenges. It is not yet known if varenicline is more effective than nicotine replacement therapy in helping patients quit smoking.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the main effects of varenicline 2 mg (VAR) and nicotine patch + lozenge (NPL) on smokers who remain on these medications throughout the trial. II. To estimate the probability that abstinence at twelve weeks as a function of treatment assignment at six weeks (augmentation) is moderated by initial treatment assignment (i.e. at baseline). III. To estimate the probability that abstinence at twelve weeks as a function of treatment assignment at six weeks (switching) is moderated by initial treatment assignment (i.e. at baseline). IV. To estimate the probability that treatment continuation, switching, or augmentation confers benefit conditional upon failing to quit after the initial treatment with nicotine patch + lozenge (NPL) for six weeks. V. To estimate the probability that treatment continuation, switching, or augmentation confers benefit conditional upon failing to quit after initial treatment with VAR for six weeks. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive varenicline orally (PO) once daily (QD) or twice daily (BID), placebo patches QD, and placebo lozenges PO QD beginning on day 9 and continue for 6 weeks. Patients that are abstinent at week 6 may continue treatment for an additional 6 weeks. Patients also receive behavioral smoking cessation counseling consisting of 4 in-person visits, 4 phone visits, and 4 brief supportive phone calls lasting 10-15 minutes each over the 12 weeks of treatment. GROUP II: Patients receive placebo tablets PO QD or BID, nicotine patches QD, and nicotine lozenges PO QD beginning on day 9 and continue for 6 weeks. Patients that are abstinent at week 6 may continue treatment for an additional 6 weeks. Patients also receive behavioral smoking cessation counseling consisting of 4 in-person visits, 4 phone visits, and 4 brief supportive phone calls lasting 10-15 minutes each over the 12 weeks of treatment. Patients who fail to achieve abstinence at week 6 are re-randomized to receive 6 additional weeks of therapy consisting of either a continuation of the same treatment; switching to the untried intervention (either NPL or varenicline); or receive NPL treatment with an additional patch (high-dose NPL) or high-dose varenicline. After completion of study treatment, patients are followed up at 3 and 6 months.

Official Title
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Varenicline and Combined NRT for Initial Smoking Cessation and Rescue Treatment in Smokers: A Randomized Pilot Trial

Conditions
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Cigarette Smoker, Tobacco Use Disorder

Intervention / Treatment
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* Drug: Nicotine Lozenge
* Drug: Nicotine Patch
* Other: Placebo
* Other: Tobacco Cessation Counseling
* Drug: Varenicline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Smoking 5 or more cigarettes, little cigars and/or cigarillos per day, on average, within the 2 months preceding the screening visit and expired carbon monoxide (CO) greater than or equal to 6 parts per million (ppm) (if less than or equal to 5, then positive cotinine test) Interested in treatment that might change smoking behavior Able to follow verbal and written instructions in English and complete all aspects of the study Provide informed consent and agree to all assessments and study procedures Have an address and telephone number where he/she may be reached Be the only participant in his/her household Exclusion Criteria: Within the month immediately preceding the screening visit, use of any form of tobacco products other than cigarettes, little cigars and/or cigarillos on 3 or more days within a week if the individual refuses to refrain from such tobacco use during the course of the study Current enrollment or plans to enroll in another smoking cessation program in the next 12 months Plan to use other nicotine substitutes (i.e., over-the-counter [OTC] or prescription medication for smoking cessation) or smoking cessation treatments in the next 12 months Uncontrolled hypertension (systolic blood pressure; [SBP] greater than 180 or diastolic blood pressure; [DBP] greater than 110) History of severe kidney disease (e.g. chronic or acute kidney failure) with creatinine clearance below 30 and/or severe liver disease with liver tests over 4 times the upper normal level Laboratory evaluations (kidney and liver) outside normal limits and of potential clinical significance in the opinion of the investigator Serious or unstable disease within the past 3 months History (last 3 months) of abnormal heart rhythms, cardiovascular disease (stroke, angina, heart attack) may result in ineligibility; these conditions will be evaluated on a case by case basis by the study physician Current use of certain medications: (1) smoking cessation meds (last 7 days), i.e., Wellbutrin, Bupropion, Zyban, nicotine replacement therapy (NRT), Chantix, (2) certain medications to treat depression (last 14 days), i.e. monoamine oxidase inhibitors (MAOIs) and Elavil (Amitriptyline), (3) a case by case determination will be made by study physician for medication on precautionary list, i.e. nitroglycerin, or (4) daily use of opioids for 30 days or more on phone screen or at screening is exclusionary however pro re nata (PRN) use is allowed (i.e., 3:7 days per week or less or if more frequent, use less than a month's duration) Meet criteria for the following psychiatric and/or substance use disorders as assessed by the MINI International Neuropsychiatric Interview (MINI): items C (current manic or hypomanic episode only), I (alcohol abuse - Alcohol Addendum - past 6 months only; current alcohol dependence), J (substance abuse - Substance Abuse Addendum - past 6 months only; current substance dependence), K (current/lifetime psychotic disorder or current/lifetime mood disorder with psychotic features); individuals who meet criteria for non-exclusionary psychiatric disorders that are considered clinically unstable and/or unsuitable to participate as determined by the principal investigator and/or study physician Individuals rated as moderate (9-16) to high (17 or greater) on suicidality as assessed by Module B of the MINI Psychiatric hospitalization within 1 year of screening date A positive urine pregnancy test during the screening period; women who are two years post-menopausal, or who have had a tubal ligation or a partial or full hysterectomy will not be subject to a urine pregnancy test Pregnant, breast-feeding or of childbearing potential and is not protected by a medically acceptable, effective method of birth control while enrolled in the study; medically acceptable contraceptives include: (1) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (2) barrier methods (such as a condom or diaphragm) used with a spermicide, or (3) an intrauterine device (IUD); contraceptive measures sold for emergency use after unprotected sex are not acceptable methods for routine use History of hypersensitivity or allergic reaction to varenicline, NRT, or any component of these formulations Any medical or psychiatric condition, illness, disorder, or concomitant medication that could compromise participant safety or treatment, as determined by the principal investigator and/or study physician Subject considered by the investigator as unsuitable candidate for receipt of an investigational drug, or unstable to be followed up throughout the entire duration of the study Positive toxicology screen for any of the following drugs: cocaine, opiates, methadone, benzodiazepines, barbiturates, amphetamines, methamphetamines, phencyclidine (PCP), or tetrahydrocannabinol (THC); a. participants with valid prescriptions for opiates, benzodiazepines, barbiturates, amphetamines or methadone will not be excluded; b. participants failing the toxicology screen will be allowed to re-screen once; if they test positive again, they will not be allowed to return; study physician may clear participant to continue on if there is a reasonable possibility the positive drug screen is the result of cross-reactivity with the participant's concomitant medications resulting in a false positive

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (varenicline and placebo)<br>Patients receive varenicline PO QD or BID, placebo patches QD, and placebo lozenges PO QD beginning on day 9 and continue for 6 weeks. Patients that are abstinent at week 6 may continue treatment for an additional 6 weeks. Patients also receive behavioral smoking cessation counseling consisting of 4 in-person visits, 4 phone visits, and 4 brief supportive phone calls lasting 10-15 minutes each over the 12 weeks of treatment. | Other: Placebo<br>* Given PO or via patch<br>* Other names: sham therapy;Other: Tobacco Cessation Counseling<br>* Receive behavioral smoking cessation counseling<br>Drug: Varenicline<br>* Given PO<br>* Other names: CP-526555;|
| Placebo Comparator: Group II (placebo, nicotine patch and lozenge)<br>Patients receive placebo tablets PO QD or BID, nicotine patches QD, and nicotine lozenges PO QD beginning on day 9 and continue for 6 weeks. Patients that are abstinent at week 6 may continue treatment for an additional 6 weeks. Patients also receive behavioral smoking cessation counseling consisting of 4 in-person visits, 4 phone visits, and 4 brief supportive phone calls lasting 10-15 minutes each over the 12 weeks of treatment. | Drug: Nicotine Lozenge<br>* Given PO<br>* Other names: Commit;Drug: Nicotine Patch<br>* Given via patch<br>* Other names: Nicotine Transdermal Patch;Other: Placebo<br>* Given PO or via patch<br>* Other names: sham therapy;Other: Tobacco Cessation Counseling<br>* Receive behavioral smoking cessation counseling<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seven-day point prevalence and treatment or treatment strategy | Estimated rates of seven-day point prevalence for varenicline and nicotine patch + lozenge at week 6 derive from meta-analyses. | At week 6 | 
| Main effects of varenicline and nicotine patch + lozenge on smokers who remain on these medications throughout the trial as documented in questionnaires | Participants complete questionnaires about several topics including depression, mood, smoking behavior, and any effects from the study drug. | Up to 12 weeks | 
| Probability of response at week 12 conditional on response at week 6 and continuation of treatment | The probability of response at week 12 conditional on response at week 6 and continuation based on clinical consensus, taking into account the marginal rates of response at twelve weeks reported derived from meta-analysis. Monte Carlo simulations (K = 500) determined predictive power for the planned analyses. | At 12 weeks | 
| Probability of response at week 12 conditional on non-response at week 6 and continuation of treatment | The probability of response at week 12 conditional on non-response at week 6 and continuation of treatment based on clinical consensus, taking into account the marginal rates of response at twelve weeks reported derived from meta-analysis. Monte Carlo simulations (K = 500) determined predictive power for the planned analyses. | At 12 weeks | 
| Probability of response at week 12 conditional on non-response at week 6 and augmentation of treatment | The probability of response at week 12 conditional on non-response at week 6 and augmentation of treatment based on clinical consensus, taking into account the marginal rates of response at twelve weeks reported derived from meta-analysis. Monte Carlo simulations (K = 500) determined predictive power for the planned analyses. | At 12 weeks | 
| Probability of response at week 12 conditional on non-response at week 6 and treatment switching | The probability of response at week 12 conditional on non-response at week 6 and treatment switching based on clinical consensus, taking into account the marginal rates of response at twelve weeks reported derived from meta-analysis. Monte Carlo simulations (K = 500) determined predictive power for the planned analyses. | At 12 weeks | 
| Probability that treatment continuation, switching, or augmentation confers benefit conditional upon failing to quit after the initial treatment with nicotine patch + lozenge for six weeks | Monte Carlo simulations (K = 500) determined predictive power for the planned analyses. | 12 weeks | 
| Probability that treatment continuation, switching, or augmentation confers benefit conditional upon failing to quit after initial treatment with varenicline for six weeks | Monte Carlo simulations (K = 500) determined predictive power for the planned analyses. | 12 weeks |